Effects on Tree Swallows Exposed to Dioxin-like Compounds Associated With: the Tittabawassee River and Floodplain near

Abstract-Concentrations of dioxin-like compounds, primarily polychlorinated dibenzofurans (PCDFs) and polychlorinated dibenzo-pdioxins (PCDDs), in soils and sediments downstream of Midland, Michigan (USA) were greater than upstream sites and prompted a sitespecific hazard assessment of tree swallows breeding in the associated floodplains. Potential for adverse population-level effects from site-specific contaminant exposures were evaluated at study areas (SAs) along the Tittabawassee and Saginaw rivers downstream of Midland. The site-specific multiple lines of evidence approach to hazard assessment included endpoints for dietary-and tissue-based exposures, and population productivity measurements for tree swallows ([TS]; Tachycineta bicolor) measured during the 2005, 2006, and 2007 breeding seasons. Exposure to dioxin-like compounds in TS eggs were some of the greatest recorded and were similar among all upstream and downstream study sites. Conversely, concentrations in nestlings from SAs were significantly greater compared to reference areas (RAs). The pattern of relative concentrations of PCDD/DFs in eggs and nestlings at RAs was dominated by dioxin congeners, whereas at SAs it was dominated by furan congeners. No statistically significant differences were noted in exposure to PCDD/DFs or in population-level responses when compared among locations, and total clutch failures were rare. Hatching success and fledging success were weakly negatively correlated with concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TEQs) in individual eggs and nestlings, respectively. On-site concentrations of TEQs in floodplain soils were some of the greatest ever reported in the environment, and several lines of evidence indicate potential population-level effects on TS overall reproductive productivity

Effects on Tree Swallows Exposed to Dioxin-like Compounds Associated With: the Tittabawassee River and Floodplain near

Abstract-Concentrations of dioxin-like compounds, primarily polychlorinated dibenzofurans (PCDFs) and polychlorinated dibenzo-pdioxins (PCDDs), in soils and sediments downstream of Midland, Michigan (USA) were greater than upstream sites and prompted a sitespecific hazard assessment of tree swallows breeding in the associated floodplains. Potential for adverse population-level effects from site-specific contaminant exposures were evaluated at study areas (SAs) along the Tittabawassee and Saginaw rivers downstream of Midland. The site-specific multiple lines of evidence approach to hazard assessment included endpoints for dietary-and tissue-based exposures, and population productivity measurements for tree swallows ([TS]; Tachycineta bicolor) measured during the 2005, 2006, and 2007 breeding seasons. Exposure to dioxin-like compounds in TS eggs were some of the greatest recorded and were similar among all upstream and downstream study sites. Conversely, concentrations in nestlings from SAs were significantly greater compared to reference areas (RAs). The pattern of relative concentrations of PCDD/DFs in eggs and nestlings at RAs was dominated by dioxin congeners, whereas at SAs it was dominated by furan congeners. No statistically significant differences were noted in exposure to PCDD/DFs or in population-level responses when compared among locations, and total clutch failures were rare. Hatching success and fledging success were weakly negatively correlated with concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TEQs) in individual eggs and nestlings, respectively. On-site concentrations of TEQs in floodplain soils were some of the greatest ever reported in the environment, and several lines of evidence indicate potential population-level effects on TS overall reproductive productivity

Environmental Toxicology RISK ASSESSMENT OF GREAT HORNED OWLS (BUBO VIRGINIANUS) EXPOSED TO POLYCHLORINATED BIPHENYLS AND DDT ALONG THE KALAMAZOO RIVER, MICHIGAN, USA

Abstract-The great horned owl (GHO; Bubo virginianus) was used in a multiple lines of evidence study of polychlorinated biphenyls (PCBs) and p,pЈ-dichlorodiphenyltrichloroethane (DDT) exposures at the Kalamazoo River Superfund Site (KRSS), Kalamazoo, Michigan, USA. The study examined risks from total PCBs, including 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TEQ World Health Organization [WHO]-Avian Toxicity Equivalency Factor [TEF] ), and total DDTs (sum of DDT, dichlorodiphenyldichloroethylene [DDE], and dichlorodiphenyldichloroethane [DDD]; ⌺DDT) by measuring concentrations in eggs and nestling blood plasma in two regions of the KRSS (upper, lower) and an upstream reference area (RA). An ecological risk assessment compared concentrations of the contaminants of concern (COCs) in eggs or plasma to toxicity reference values. Productivity and relative abundance measures for KRSS GHOs were compared with other GHO populations. Egg shell thickness was measured to assess effects of p,pЈ-DDE. The concentrations of PCBs in eggs were as great as 4.7 ϫ 10 2 and 4.0 ϫ 10 4 ng PCB/g, wet weight at the RA and combined KRSS sites, respectively. Egg TEQ WHO-Avian calculated from aryl hydrocarbon receptor-active PCB congeners and WHO TEFs ranged to 8.0 and 1.9 ϫ 10 2 pg TEQ WHO-Avian /g, (wet wt) at the RA and combined KRSS, respectively. Egg ⌺DDT concentrations were as great as 4.2 ϫ 10 2 and 5.0 ϫ 10 3 ng ⌺DDT/g (wet wt) at the RA and combined KRSS, respectively. Hazard quotients (HQs) for the upper 95% confidence interval (UCI) (geometric mean) and least observable adverse effect concentration (LOAEC) for COCs in eggs were Յ1.0 for all sites. Hazard quotient values based on the no observable adverse effect concentration (NOAEC) 95% UCI in eggs were Յ1.0, except at the LKRSS (PCB HQ ϭ 3.1; TEQ WHO-Avian HQ ϭ 1.3). Productivity and relative abundance measures indicated no population level effects in the UKRSS

Environmental Toxicology RISK ASSESSMENT OF GREAT HORNED OWLS (BUBO VIRGINIANUS) EXPOSED TO POLYCHLORINATED BIPHENYLS AND DDT ALONG THE KALAMAZOO RIVER, MICHIGAN, USA

Abstract-The great horned owl (GHO; Bubo virginianus) was used in a multiple lines of evidence study of polychlorinated biphenyls (PCBs) and p,pЈ-dichlorodiphenyltrichloroethane (DDT) exposures at the Kalamazoo River Superfund Site (KRSS), Kalamazoo, Michigan, USA. The study examined risks from total PCBs, including 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TEQ World Health Organization [WHO]-Avian Toxicity Equivalency Factor [TEF] ), and total DDTs (sum of DDT, dichlorodiphenyldichloroethylene [DDE], and dichlorodiphenyldichloroethane [DDD]; ⌺DDT) by measuring concentrations in eggs and nestling blood plasma in two regions of the KRSS (upper, lower) and an upstream reference area (RA). An ecological risk assessment compared concentrations of the contaminants of concern (COCs) in eggs or plasma to toxicity reference values. Productivity and relative abundance measures for KRSS GHOs were compared with other GHO populations. Egg shell thickness was measured to assess effects of p,pЈ-DDE. The concentrations of PCBs in eggs were as great as 4.7 ϫ 10 2 and 4.0 ϫ 10 4 ng PCB/g, wet weight at the RA and combined KRSS sites, respectively. Egg TEQ WHO-Avian calculated from aryl hydrocarbon receptor-active PCB congeners and WHO TEFs ranged to 8.0 and 1.9 ϫ 10 2 pg TEQ WHO-Avian /g, (wet wt) at the RA and combined KRSS, respectively. Egg ⌺DDT concentrations were as great as 4.2 ϫ 10 2 and 5.0 ϫ 10 3 ng ⌺DDT/g (wet wt) at the RA and combined KRSS, respectively. Hazard quotients (HQs) for the upper 95% confidence interval (UCI) (geometric mean) and least observable adverse effect concentration (LOAEC) for COCs in eggs were Յ1.0 for all sites. Hazard quotient values based on the no observable adverse effect concentration (NOAEC) 95% UCI in eggs were Յ1.0, except at the LKRSS (PCB HQ ϭ 3.1; TEQ WHO-Avian HQ ϭ 1.3). Productivity and relative abundance measures indicated no population level effects in the UKRSS

Multiple Lines of Evidence Risk Assessment of Terrestrial Passerines Exposed to PCDFs and PCDDs in the Tittabawassee River Floodplain, Midland, Michigan, USA

A site-specific multiple lines of evidence risk assessment was conducted for house wrens (Troglodytes aedon) and eastern bluebirds (Sialia sialis) along the Tittabawassee River downstream of Midland, Michigan, where concentrations of polychlorinated dibenzofurans (PCDFs) and polychlorinated dibenzo-p-dioxins (PCDDs) in flood-plain soils and sediments are greater compared to upstream areas and some of the greatest anywhere in the world. Lines of evidence supporting the population-level assessment endpoints included site-specific dietary- and tissue-based exposure assessments and population productivity measurements during breeding seasons 2005–2007. While a hazard assessment based on site-specific diets suggested that populations residing in the downstream floodplain had the potential to be affected, concentrations in eggs compared to appropriate toxicity reference values (TRVs) did not predict a potential for population-level effects. There were no significant effects on reproductive success of either species. The most probable cause of the apparent difference between the dietary- and tissue-based exposure assessments was that the dietary-based TRVs were overly conservative based on intraperitoneal injections in the ring-necked pheasant. Agreement between the risk assessment based on concentrations of PCDFs and PCDDs in eggs and reproductive performance in both species supports the conclusion of a small potential for population-level effects at this site

Can oral corticosteroids reduce the severity or duration of an acute cough, and the associated National Health Service and societal costs, in adults presenting to primary care?: study protocol for a randomised controlled trial

Background: Acute lower respiratory tract infection (LRTI) is one of the most common conditions managed internationally and is costly to health services and patients. Despite good evidence that antibiotics are not effective for improving the symptoms of uncomplicated LRTI, they are widely prescribed, contributing to antimicrobial resistance. Many of the symptoms observed in LRTI are mediated by inflammatory processes also observed in exacerbations of asthma, for which there is strong evidence of corticosteroid effectiveness. The primary aim of the OSAC (Oral Steroids for Acute Cough) Trial is to determine whether oral prednisolone (40 mg daily for 5 days) can reduce the duration of moderately bad (or worse) cough and the severity of all its associated symptoms on days 2 to 4 post-randomisation (day 1 is trial entry) by at least 20% in adults ≥18 years with acute LRTI presenting to primary care. Methods/design: OSAC is a two-arm, multi-centre, placebo-controlled, randomised superiority trial. The target sample size is 436 patients, which allows for a 20% dropout rate. Patients will be recruited from primary care sites (General Practitioner surgeries) across England and followed up until symptom resolution. The two primary clinical outcomes are the duration of moderately bad (or worse) cough, and the severity of all its associated symptoms on days 2 to 4 post-randomisation. Secondary outcomes include: antibiotic consumption; symptom burden; adverse events; participant satisfaction with treatment and intention to consult for future similar illnesses. A parallel economic evaluation will investigate the cost-effectiveness of the intervention. Discussion: Results from the OSAC trial will increase knowledge regarding the clinical and cost-effectiveness of corticosteroids for LRTI, and will establish the potential of a new treatment option that could substantially improve patient health. We have chosen a relatively high ‘efficacy dose’ as this will enable us to decide on the potential for further research into lower dose oral and/or inhaled corticosteroids. This trial will also contribute to a growing body of research investigating the natural course of this very common illness, as well as the effects of steroids on the undesirable inflammatory symptoms associated with infection. Trial registration: Current Controlled Trials ISRCTN57309858 (31 January 2013)

Hepatic P450 Enzyme Activity, Tissue Morphology and Histology of Mink (Mustela vison) Exposed to Polychlorinated Dibenzofurans

Dose- and time-dependent effects of environmentally relevant concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TEQ) of 2,3,7,8-tetrachlorodibenzofuran (TCDF), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), or a mixture of these two congeners on hepatic P450 enzyme activity and tissue morphology, including jaw histology, of adult ranch mink were determined under controlled conditions. Adult female ranch mink were fed either TCDF (0.98, 3.8, or 20 ng TEQTCDF/kg bw/day) or PeCDF (0.62, 2.2, or 9.5 ng TEQPeCDF/kg bw/day), or a mixture of TCDF and PeCDF (4.1 ng TEQTCDF/kg bw/day and 2.8 ng TEQPeCDF/kg bw/day, respectively) for 180 days. Doses used in this study were approximately eight times greater than those reported in a parallel field study. Activities of the cytochrome P450 1A enzymes, ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-deethylase (MROD) were significantly greater in livers of mink exposed to TCDF, PeCDF, and a mixture of the two congeners; however, there were no significant histological or morphological effects observed. It was determined that EROD and MROD activity can be used as sensitive biomarkers of exposure to PeCDF and TCDF in adult female mink; however, under the conditions of this study, the response of EROD/MROD induction occurred at doses that were less than those required to cause histological or morphological changes

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Structural and functional annotation of the porcine immunome

Background: The domestic pig is known as an excellent model for human immunology and the two species share many pathogens. Susceptibility to infectious disease is one of the major constraints on swine performance, yet the structure and function of genes comprising the pig immunome are not well-characterized. The completion of the pig genome provides the opportunity to annotate the pig immunome, and compare and contrast pig and human immune systems.[br/] Results: The Immune Response Annotation Group (IRAG) used computational curation and manual annotation of the swine genome assembly 10.2 (Sscrofa10.2) to refine the currently available automated annotation of 1,369 immunity-related genes through sequence-based comparison to genes in other species. Within these genes, we annotated 3,472 transcripts. Annotation provided evidence for gene expansions in several immune response families, and identified artiodactyl-specific expansions in the cathelicidin and type 1 Interferon families. We found gene duplications for 18 genes, including 13 immune response genes and five non-immune response genes discovered in the annotation process. Manual annotation provided evidence for many new alternative splice variants and 8 gene duplications. Over 1,100 transcripts without porcine sequence evidence were detected using cross-species annotation. We used a functional approach to discover and accurately annotate porcine immune response genes. A co-expression clustering analysis of transcriptomic data from selected experimental infections or immune stimulations of blood, macrophages or lymph nodes identified a large cluster of genes that exhibited a correlated positive response upon infection across multiple pathogens or immune stimuli. Interestingly, this gene cluster (cluster 4) is enriched for known general human immune response genes, yet contains many un-annotated porcine genes. A phylogenetic analysis of the encoded proteins of cluster 4 genes showed that 15% exhibited an accelerated evolution as compared to 4.1% across the entire genome.[br/] Conclusions: This extensive annotation dramatically extends the genome-based knowledge of the molecular genetics and structure of a major portion of the porcine immunome. Our complementary functional approach using co-expression during immune response has provided new putative immune response annotation for over 500 porcine genes. Our phylogenetic analysis of this core immunome cluster confirms rapid evolutionary change in this set of genes, and that, as in other species, such genes are important components of the pig’s adaptation to pathogen challenge over evolutionary time. These comprehensive and integrated analyses increase the value of the porcine genome sequence and provide important tools for global analyses and data-mining of the porcine immune response