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1.  Chemical structure determines target organ carcinogenesis in rats 
SAR models were developed for 12 rat tumour sites using data derived from the Carcinogenic Potency Database. Essentially, the models fall into two categories: Target Site Carcinogen – Non-Carcinogen (TSC-NC) and Target Site Carcinogen – Non-Target Site Carcinogen (TSC-NTSC). The TSC-NC models were composed of active chemicals that were carcinogenic to a specific target site and inactive ones that were whole animal non-carcinogens. On the other hand, the TSC-NTSC models used an inactive category also composed of carcinogens but to any/all other sites but the target site. Leave one out validations produced an overall average concordance value for all 12 models of 0.77 for the TSC-NC models and 0.73 for the TSC-NTSC models.
Overall, these findings suggest that while the TSC-NC models are able to distinguish between carcinogens and non-carcinogens, the TSC-NTSC models are identifying structural attributes that associate carcinogens to specific tumour sites. Since the TSC-NTSC models are composed of active and inactive compounds that are genotoxic and non-genotoxic carcinogens, the TSC-NTSC models may be capable of deciphering non-genotoxic mechanisms of carcinogenesis. Together, models of this type may also prove useful in anticancer drug development since they essentially contain chemicals moieties that target specific tumour site.
doi:10.1080/1062936X.2012.728996
PMCID: PMC3547634  PMID: 23066888
structure-activity relationship; cancer; organ-specific carcinogens; genotoxic carcinogens; non-genotoxic carcinogens
2.  Global structure–activity relationship model for nonmutagenic carcinogens using virtual ligand-protein interactions as model descriptors 
Carcinogenesis  2012;33(10):1940-1945.
Structure–activity relationship (SAR) models are powerful tools to investigate the mechanisms of action of chemical carcinogens and to predict the potential carcinogenicity of untested compounds. We describe the use of a traditional fragment-based SAR approach along with a new virtual ligand-protein interaction-based approach for modeling of nonmutagenic carcinogens. The ligand-based SAR models used descriptors derived from computationally calculated ligand-binding affinities for learning set agents to 5495 proteins. Two learning sets were developed. One set was from the Carcinogenic Potency Database, where chemicals tested for rat carcinogenesis along with Salmonella mutagenicity data were provided. The second was from Malacarne et al. who developed a learning set of nonalerting compounds based on rodent cancer bioassay data and Ashby’s structural alerts. When the rat cancer models were categorized based on mutagenicity, the traditional fragment model outperformed the ligand-based model. However, when the learning sets were composed solely of nonmutagenic or nonalerting carcinogens and noncarcinogens, the fragment model demonstrated a concordance of near 50%, whereas the ligand-based models demonstrated a concordance of 71% for nonmutagenic carcinogens and 74% for nonalerting carcinogens. Overall, these findings suggest that expert system analysis of virtual chemical protein interactions may be useful for developing predictive SAR models for nonmutagenic carcinogens. Moreover, a more practical approach for developing SAR models for carcinogenesis may include fragment-based models for chemicals testing positive for mutagenicity and ligand-based models for chemicals devoid of DNA reactivity.
doi:10.1093/carcin/bgs197
PMCID: PMC3463155  PMID: 22678118
3.  Mammary Carcinogen-Protein Binding Potentials: Novel and Biologically Relevant Structure-Activity Relationship Model Descriptors 
Previously, SAR models for carcinogenesis used descriptors that are essentially chemical descriptors. Herein we report the development of models with the cat-SAR expert system using biological descriptors (i.e., ligand-receptor interactions) rat mammary carcinogens. These new descriptors are derived from the virtual screening for ligand-receptor interactions of carcinogens, non-carcinogens, and mammary carcinogens to a set of 5494 target proteins. Leave-one-out validations of the ligand mammary carcinogen non-carcinogen model had a concordance between experimental and predicted results of 71% and the mammary carcinogen non-mammary carcinogen model was 72% concordant. The development of a hybrid fragment-ligand model improved the concordances to 85 and 83%, respectively. In a separate external validation exercise, hybrid fragment-ligand models had concordances of 81 and 76%. Analyses of example rat mammary carcinogens including the food mutagen and estrogenic compound PhIP, the herbicide atrazine, and the drug indomethacin, the ligand model identified a number of proteins associated with each compound that had previously been referenced in Medline in conjunction with the test chemical and separately with association to breast cancer. This new modelling approach can enhance model predictivity and help bridge the gap between chemical structure and carcinogenic activity by descriptors that are related to biological targets.
doi:10.1080/1062936X.2010.501818
PMCID: PMC3383027  PMID: 20818582
4.  Circumcision and risk of sexually transmissible infections in a community-based cohort of HIV-negative homosexual men in Sydney, Australia 
The Journal of infectious diseases  2009;200(12):1813-1819.
Background
Circumcision status was examined as an independent risk factor for STIs in the HIM cohort of homosexual men in Sydney.
Methods
From 2001–2004, 1,427 initially HIV-negative men were enrolled and followed to mid-2007. All participants were offered annual STI testing. Past history of STIs was collected at baseline and information on sexual risk behaviors, every 6 months. At annual face-to-face visits, participants reported STI diagnoses made in the previous year.
Results
Circumcision was not associated with prevalent or incident HSV-1, HSV-2, or self-reported genital warts. There was also no independent association of circumcision with incident urethral gonorrhea or chlamydia. Being circumcised was associated with a significantly reduced risk of incident (HR 0.35, 95% CI 0.15–0.84), but not prevalent (OR 0.71, 95% CI 0.35–1.44) syphilis. The association was somewhat stronger among men who reported predominantly insertive unprotected anal intercourse (HR 0.10, 95% CI 0.01–0.82).
Conclusions
These are the first prospective data in homosexual men to assess circumcision status as a risk factor for STIs. Circumcised men were at reduced risk of incident syphilis but no other prevalent or incident STIs. Circumcision is unlikely to have a substantial public health impact in reducing acquisition of most STIs in homosexual men.
doi:10.1086/648376
PMCID: PMC2784211  PMID: 19911990
circumcision; sexually transmitted diseases; homosexuality, male; prospective studies
5.  A methodology to establish a database to study gene environment interactions for childhood asthma 
Background
Gene-environment interactions are likely to explain some of the heterogeneity in childhood asthma. Here, we describe the methodology and experiences in establishing a database for childhood asthma designed to study gene-environment interactions (PAGES - Paediatric Asthma Gene Environment Study).
Methods
Children with asthma and under the care of a respiratory paediatrician are being recruited from 15 hospitals between 2008 and 2011. An asthma questionnaire is completed and returned by post. At a routine clinic visit saliva is collected for DNA extraction. Detailed phenotyping in a proportion of children includes spirometry, bronchodilator response (BDR), skin prick reactivity, exhaled nitric oxide and salivary cotinine. Dietary and quality of life questionnaires are completed. Data are entered onto a purpose-built database.
Results
To date 1045 children have been invited to participate and data collected in 501 (48%). The mean age (SD) of participants is 8.6 (3.9) years, 57% male. DNA has been collected in 436 children. Spirometry has been obtained in 172 children, mean % predicted (SD) FEV1 97% (15) and median (IQR) BDR is 5% (2, 9). There were differences in age, socioeconomic status, severity and %FEV1 between the different centres (p≤0.024). Reasons for non-participation included parents not having time to take part, children not attending clinics and, in a small proportion, refusal to take part.
Conclusions
It is feasible to establish a national database to study gene-environment interactions within an asthmatic paediatric population; there are barriers to participation and some different characteristics in individuals recruited from different centres. Recruitment to our study continues and is anticipated to extend current understanding of asthma heterogeneity.
doi:10.1186/1471-2288-10-107
PMCID: PMC3019209  PMID: 21134251
6.  Microglia and the urokinase plasminogen activator receptor/uPA system in innate brain inflammation 
Glia  2009;57(16):1802-1814.
The urokinase plasminogen activator (uPA) receptor (uPAR) is a GPI-linked cell surface protein that facilitates focused plasmin proteolytic activity at the cell surface. uPAR has been detected in macrophages infiltrating the central nervous system (CNS) and soluble uPAR has been detected in the cerebrospinal fluid during a number of CNS pathologies. However, its expression by resident microglial cells in vivo remains uncertain. In this work, we aimed to elucidate the murine CNS expression of uPAR and uPA as well as that of tissue plasminogen activator and plasminogen activator inhibitor 1 (PAI-1) during insults generating distinct and well-characterized inflammatory responses; acute intracerebral lipopolysaccharide (LPS), acute kainate-induced neurodegeneration, and chronic neurodegeneration induced by prion disease inoculation. All three insults induced marked expression of uPAR at both mRNA and protein level compared to controls (naïve, saline, or control inoculum-injected). uPAR expression was microglial in all cases. Conversely, uPA transcription and activity was only markedly increased during chronic neurodegeneration. Dissociation of uPA and uPAR levels in acute challenges is suggestive of additional proteolysis-independent roles for uPAR. PAI-1 was most highly expressed upon LPS challenge, whereas tissue plasminogen activator mRNA was constitutively present and less responsive to all insults studied. These data are novel and suggest much wider involvement of the uPAR/uPA system in CNS function and pathology than previously supposed. © 2009 Wiley-Liss, Inc.
doi:10.1002/glia.20892
PMCID: PMC2816357  PMID: 19459212
chronic neurodegeneration; neuroinflammation; plasminogen; proteolysis; activation
7.  The implantable cardioverter-defibrillator: postcode prescribing in the UK 1998–2002 
Heart  2005;91(10):1280-1283.
Objective: To determine the rate of implantable cardioverter-defibrillator (ICD) implantation across the UK during the period 1998 to 2002.
Design: Observational self reporting with cross checking.
Setting: All ICD implanting centres coordinated by the National Pacemaker and ICD Database.
Patients: Every patient receiving an ICD in the UK from 1998 to 2002.
Main outcome measures: Date of implantation and postcode of each ICD recipient during the study period.
Results: ICD implantation increased in the UK in the five year period studied but fell far short of the European average and national targets. Implantation rates varied greatly by region.
Conclusions: The low rate of ICD implantation in the UK and the disparity between regions require further study to determine the barriers to this evidence based treatment.
doi:10.1136/hrt.2004.048512
PMCID: PMC1769132  PMID: 15797937
ICD; implantable cardioverter-defibrillator
8.  Effects of improved home heating on asthma in community dwelling children: randomised controlled trial 
Objective To assess whether non-polluting, more effective home heating (heat pump, wood pellet burner, flued gas) has a positive effect on the health of children with asthma.
Design Randomised controlled trial.
Setting Households in five communities in New Zealand.
Participants 409 children aged 6-12 years with doctor diagnosed asthma.
Interventions Installation of a non-polluting, more effective home heater before winter. The control group received a replacement heater at the end of the trial.
Main outcome measures The primary outcome was change in lung function (peak expiratory flow rate and forced expiratory volume in one second, FEV1). Secondary outcomes were child reported respiratory tract symptoms and daily use of preventer and reliever drugs. At the end of winter 2005 (baseline) and winter 2006 (follow-up) parents reported their child’s general health, use of health services, overall respiratory health, and housing conditions. Nitrogen dioxide levels were measured monthly for four months and temperatures in the living room and child’s bedroom were recorded hourly.
Results Improvements in lung function were not significant (difference in mean FEV1 130.7 ml, 95% confidence interval −20.3 to 281.7). Compared with children in the control group, however, children in the intervention group had 1.80 fewer days off school (95% confidence interval 0.11 to 3.13), 0.40 fewer visits to a doctor for asthma (0.11 to 0.62), and 0.25 fewer visits to a pharmacist for asthma (0.09 to 0.32). Children in the intervention group also had fewer reports of poor health (adjusted odds ratio 0.48, 95% confidence interval 0.31 to 0.74), less sleep disturbed by wheezing (0.55, 0.35 to 0.85), less dry cough at night (0.52, 0.32 to 0.83), and reduced scores for lower respiratory tract symptoms (0.77, 0.73 to 0.81) than children in the control group. The intervention was associated with a mean temperature rise in the living room of 1.10°C (95% confidence interval 0.54°C to 1.64°C) and in the child’s bedroom of 0.57°C (0.05°C to 1.08°C). Lower levels of nitrogen dioxide were measured in the living rooms of the intervention households than in those of the control households (geometric mean 8.5 μg/m3 v 15.7 μg/m3, P<0.001). A similar effect was found in the children’s bedrooms (7.3 μg/m3 v 10.9 μg/m3, P<0.001).
Conclusion Installing non-polluting, more effective heating in the homes of children with asthma did not significantly improve lung function but did significantly reduce symptoms of asthma, days off school, healthcare utilisation, and visits to a pharmacist.
Trial registration Clinical Trials NCT00489762.
doi:10.1136/bmj.a1411
PMCID: PMC2658826  PMID: 18812366
9.  Effect of insulating existing houses on health inequality: cluster randomised study in the community 
BMJ : British Medical Journal  2007;334(7591):460.
Objective To determine whether insulating existing houses increases indoor temperatures and improves occupants' health and wellbeing.
Design Community based, cluster, single blinded randomised study.
Setting Seven low income communities in New Zealand.
Participants 1350 households containing 4407 participants.
Intervention Installation of a standard retrofit insulation package.
Main outcome measures Indoor temperature and relative humidity, energy consumption, self reported health, wheezing, days off school and work, visits to general practitioners, and admissions to hospital.
Results Insulation was associated with a small increase in bedroom temperatures during the winter (0.5°C) and decreased relative humidity (−2.3%), despite energy consumption in insulated houses being 81% of that in uninsulated houses. Bedroom temperatures were below 10°C for 1.7 fewer hours each day in insulated homes than in uninsulated ones. These changes were associated with reduced odds in the insulated homes of fair or poor self rated health (adjusted odds ratio 0.50, 95% confidence interval 0.38 to 0.68), self reports of wheezing in the past three months (0.57, 0.47 to 0.70), self reports of children taking a day off school (0.49, 0.31 to 0.80), and self reports of adults taking a day off work (0.62, 0.46 to 0.83). Visits to general practitioners were less often reported by occupants of insulated homes (0.73, 0.62 to 0.87). Hospital admissions for respiratory conditions were also reduced (0.53, 0.22 to 1.29), but this reduction was not statistically significant (P=0.16).
Conclusion Insulating existing houses led to a significantly warmer, drier indoor environment and resulted in improved self rated health, self reported wheezing, days off school and work, and visits to general practitioners as well as a trend for fewer hospital admissions for respiratory conditions.
doi:10.1136/bmj.39070.573032.80
PMCID: PMC1808149  PMID: 17324975
10.  Seroprevalence of hepatitis B and C in a Merseyside hospital for the mentally handicapped. 
Epidemiology and Infection  1994;112(1):195-200.
This study reports the prevalence of antibodies to hepatitis B virus (HBV) and C virus (HCV), and the frequency of potential exposure to these viruses among patients and staff in six long-stay wards of a hospital caring for mentally handicapped adults from the Mersey region. A retrospective survey of risk behaviour among 134 patients and questionnaire survey of 75 nursing staff was performed. Serum samples from both groups were tested for HBV markers and patient sera for antibodies to HCV by enzyme-linked immunosorbent assay (ELISA). None of the 102 patients tested had antibodies against HCV, although 17 had detectable antibody to HBV core (anti-HBc). Seven out of the 17 were positive for HBV surface antigen. None was positive for IgM antibody to HBV core. Only 1 out of 61 staff had anti-HBc and none was positive for surface antigen. Twenty-nine of 75 (39%) staff reported bites sufficient to break the skin and 52 (69%) significant other injuries from patients; 25 (31%) of staff had not received HBV vaccination. None of the patients had received HBV vaccine. We conclude that HCV does not appear to be a major hazard in this closed community but the prevalence of HBV markers indicating past exposure among patients is high, vaccine uptake is incomplete and incidents which may allow viral transmission are frequent.
PMCID: PMC2271497  PMID: 7509754
11.  Relationships Between Perceived STD-Related Stigma, STD-Related Shame and STD Screening Among a Household Sample of Adolescents 
Context
Important barriers to STD testing for an individual may include STD-related stigma, defined as personal fears about negative societal attitudes toward STD infection, and STD-related shame, defined as anticipated negative personal feelings resulting from a positive STD test. Obtaining a clear understanding of the relationship between STD-related stigma, STD-related shame, and STD testing may help inform programs and policies to reduce STD transmission.
Methods
Measures derived from previously published scales were used to assess an urban, household sample of 594 15–24 year olds’ perceptions of STD-related stigma (Cronbach’s alpha 0.92), STD-related shame (Crobach’s alpha = 0.89), and receipt of an STD test in the past year. Logistic regression was used to examine the associations between STD testing and perceptions of stigma, shame, and other participant characteristics.
Results
Thirty-seven percent of males and 70% of females reporting receiving an STD test in the past year, the majority of which occurred in the context of a routine health care visit. For both males and females, perceiving higher levels of STD-related stigma was independently associated with decreased odds of having been STD tested (OR = 0.54 and 0.48, respectively). STD-related shame was not related to STD testing.
Conclusions
STD-related stigma may be an important barrier to STD screening for adolescents and young adults. Given the fact that most participants reported receiving an STD test during a routine health visit, it is unclear whether STD-related stigma may be associated with care seeking versus acceptance of STD screening at a routine health visit.
doi:10.1363/4122509
PMCID: PMC4334654  PMID: 20444177
12.  Locomotor Activity Predicts Acquisition of Self-Administration Behavior but Not Cocaine Intake 
Behavioral neuroscience  2005;119(2):464-472.
The current study investigates locomotor activity in a novel environment and correlates these activity levels with cocaine self-administration in rats that were either trained or untrained on a lever-pressing task prior to cocaine self-administration. The authors report that it is the rate of learning the lever-pressing task, not cocaine self-administration, that correlates with locomotor activity. The results suggest that a correlation between locomotor activity and cocaine self-administration is secondary to a link between locomotor activity and rate of learning to lever press for a reward. The authors conclude that locomotor activity is not necessarily an indicator of propensity to self-administer cocaine and demonstrate that environmental novelty and rate of learning an operant task are important considerations when designing experiments on drug-seeking behaviors.
doi:10.1037/0735-7044.119.2.464
PMCID: PMC4327862  PMID: 15839792
addiction; learning; self-administration; cocaine; locomotion
14.  Down-regulation of vinculin upon MK886-induced apoptosis in LN18 glioblastoma cells 
Neoplasma  2007;54(6):517-526.
Glioblastomas are a type of malignant brain tumor and are among the most difficult cancers to treat. One strategy to treat aggressive cancers is the use of drugs that target multiple signaling pathways. MK886 is a drug known to inhibit both 5-lipoxygenase-activating-protein (FLAP) and peroxisome proliferator activated receptor-α (PPAR-α). The objectives of this study were to investigate the ability of MK886 to induce apoptotic cell death in LN18 glioblastoma cells and to characterize the cell death mechanisms. MK886 induced massive apoptotic LN18 cell death that was manifested by the release of nucleosomes, annexinV binding to phosphatidylserine in the absence of nuclear staining, and changes in the fluorescent intensity of Mito Tracker Deep Red 633 indicating changes in mitochondrial oxidative function and mass. The alteration of the mitochondrial function implied that MK886 induced apoptosis in LN18 cells via a mitochondrial pathway. The broad caspases inhibitor ZVAD-FMK inhibited MK886-induced nucleosome release, but not annexinV binding or MK886-altered mitochondrial function. Real time RT-PCR demonstrated that LN18 cells expressed significant levels of FLAP and PPAR-α mRNAs. A low level of arachidonate 5-lipoxygenase (ALOX-5) mRNA was detected, but little, if any, arachidonate 12-lipoxygenase (ALOX-12) mRNA was present. In addition, MK886-induced apoptosis in LN18 cells was accompanied by a decrease in the protein and mRNA levels of vinculin, but not other focal adhesion proteins. In summary, the data presented here indicate that disruption of the actin-vinculin-cell-cytoskeleton matrix of the LN18 glioblastoma is a component of the MK886 induced apoptosis. In addition, MK886 treated LN18 cells could provide one model in which to investigate drugs that target lipoxygenase and PPAR-α pathways in the chemotherapeutic treatment of glioblastomas.
PMCID: PMC4320946  PMID: 17949236
Glioblastoma; Apoptosis; PPAR-α; FLAP; 5-Lipoxygenase; MK886
15.  Discrimination between adenocarcinoma and normal pancreatic ductal fluid by proteomic and glycomic analysis 
Journal of proteome research  2013;13(2):395-407.
Sensitive and specific biomarkers for pancreatic cancer are currently unavailable. The high mortality associated with adenocarcinoma of the pancreatic epithelium justifies the broadest possible search for new biomarkers that can facilitate early detection or monitor treatment efficacy. Protein glycosylation is altered in many cancers, leading many to propose that glycoproteomic changes may provide suitable biomarkers. In order to assess this possibility for pancreatic cancer, we have performed an in-depth LC-MS/MS analysis of the proteome and MSn-based characterization of the N-linked glycome of a small set of pancreatic ductal fluid obtained from normal, pancreatitis, intraductal papillary mucinous neoplasm (IPMN), and pancreatic adenocarcinoma patients. Our results identify a set of seven proteins that were consistently increased in cancer ductal fluid compared to normal (AMYP, PRSS1, GP2-1, CCDC132, REG1A, REG1B, and REG3A) and one protein that was consistently decreased (LIPR2). These proteins are all directly or indirectly associated with the secretory pathway in normal pancreatic cells. Validation of these changes in abundance by Western blotting revealed increased REG protein glycoform diversity in cancer. Characterization of the total N-linked glycome of normal, IPMN, and adenocarcinoma ductal fluid clustered samples into three discrete groups based on the prevalence of 6 dominant glycans. Within each group, the profiles of less prevalent glycans were able to distinguish normal from cancer on this small set of samples. Our results emphasize that individual variation in protein glycosylation must be considered when assessing the value of a glycoproteomic marker, but also indicate that glycosylation diversity across human subjects can be reduced to simpler clusters of individuals whose N-linked glycans share structural features.
doi:10.1021/pr400422g
PMCID: PMC3946306  PMID: 24328148
Pancreatic cancer; Proteomics; Biomarker; N-linked glycan; Glycomics
16.  Mortality associated with avian reovirus infection in a free-living magpie (Pica pica) in Great Britain 
Background
Avian reoviruses (ARVs) cause a range of disease presentations in domestic, captive and free-living bird species. ARVs have been reported as a cause of significant disease and mortality in free-living corvid species in North America and continental Europe. Until this report, there have been no confirmed cases of ARV-associated disease in British wild birds.
Case presentation
Sporadic individual magpie (Pica pica) mortality was detected at a single site in Buckinghamshire, England, April-September 2013. An adult female magpie was found moribund and subsequently died. Post-mortem examination identified hepatomegaly and splenomegaly as the most severe macroscopic abnormalities. Histopathological examination revealed extensive hepatic and splenic necrosis. Transmission electron microscopy (TEM) identified virions of a size (circa 78 nm diameter) and morphology consistent with ARV in both the liver and the small intestinal (SI) contents. Nucleic acid extracted from pooled liver and spleen was positive on both a pan-reovirus nested PCR targeting the RNA-dependent RNA polymerase gene and a PCR using primers specific to the ARV sigma C protein gene. Virus isolated from the liver and the SI contents was characterised by a syncytial-type cytopathic effect, a reovirus-like appearance on TEM and sequence identical to that from PCR of tissues. In situ hybridisation confirmed co-localisation of ARV with lesions in the liver and spleen, implicating ARV as the causative agent. Splenic lymphoid atrophy and necrotic stomatitis associated with Aspergillus fumigatus infection were consistent with generalised immunosuppression and resultant opportunistic infection.
Conclusions
The pathology and comprehensive virus investigations in this case indicate ARV as the primary pathogen in this magpie, with concurrent secondary infection subsequent to immunosuppression, as has been observed with reoviral infections in other bird species. ARV should be considered as a differential diagnosis for magpie, and potentially other corvid, disease and mortality incidents. This is the first demonstration of ARV-associated mortality in a wild bird in Britain. The prevalence and significance of ARV infection in British wild birds, and its implications for poultry and captive bird health, are currently unknown.
doi:10.1186/s12917-015-0329-5
PMCID: PMC4336486
Avian reovirus; Magpie; Pica pica; Hepatic necrosis; Splenic necrosis
17.  High prevalence of Trichinella pseudospiralis in Florida panthers (Puma concolor coryi) 
Parasites & Vectors  2015;8:67.
Background
Parasites of the genus Trichinella are zoonotic nematodes common in carnivores throughout the world. We determined the prevalence and species of Trichinella infections in Florida panthers (Puma concolor coryi).
Methods
Tongues from Florida panthers were collected at necropsy and examined by pepsin-HCl artificial digestion for infection with Trichinella spp. DNA was extracted from larvae and multiplex PCR using Trichinella species-specific primers was used to genotype the worms.
Results
Trichinella spp. larvae were detected in 24 of 112 (21.4%; 14.6%–30.3%) panthers. Sixteen of the panthers (14.3%) were infected with T. pseudospiralis, 1 (0.9%) was infected with T. spiralis, and 2 (1.8%) had mixed infections of T. pseudospiralis and T. spiralis. Trichinella spp. larvae from 5 panthers were not identified at the species level due to degraded DNA.
Conclusions
This is the highest prevalence of T. pseudospiralis detected in North America up to now and suggests the Florida panther is a key mammalian reservoir of this parasite in southern Florida. Trichinella pseudospiralis can infect both mammals and birds indicating the source of infection for Florida panthers could be broader than believed; however, birds represent a small percentage (0.01%) of the cat’s diet. Since wild pigs (Sus scrofa) can be parasitized by both T. pseudospiralis and T. spiralis and these swine can comprise a large portion (~40%) of a panther’s diet in Florida, we believe that Florida panthers acquired these zoonotic parasites from feeding on wild pigs.
doi:10.1186/s13071-015-0674-z
PMCID: PMC4324651  PMID: 25649739
Florida panther; Puma concolor coryi; Trichinella spiralis; Trichinella pseudospiralis; Zoonotic
18.  Desulfovibrio legallii Prosthetic Shoulder Joint Infection and Review of Antimicrobial Susceptibility and Clinical Characteristics of Desulfovibrio Infections 
Journal of Clinical Microbiology  2014;52(8):3105-3110.
We describe a case of shoulder hemiarthroplasty infection with Desulfovibrio legallii. Antimicrobial susceptibilities of 36 Desulfovibrio isolates are presented. Metronidazole and carbapenems exhibited reliable activity, although piperacillin-tazobactam did not. Eleven previous cases of Desulfovibrio infection are reviewed; most arose from a gastrointestinal tract-related source.
doi:10.1128/JCM.00083-14
PMCID: PMC4136176  PMID: 24850351
19.  Anthracimycin Activity Against Contemporary Methicillin-Resistant Staphylococcus aureus 
The Journal of antibiotics  2014;67(8):549-553.
Anthracimycin is a recently discovered novel marine-derived compound with activity against Bacillus anthracis. We tested anthracimycin against an expanded panel of Staphylococcus aureus strains in vitro and in vivo. All strains of S. aureus tested, including methicillin-sensitive (MSSA), methicillin-resistant (MRSA), and vancomycin-resistant strains of S. aureus were sensitive to anthracimycin at minimum inhibitory concentrations (MIC) of < 0.25 mg/L. Although its post-antibiotic effects were minimal, anthracimycin exhibited potent and rapid bactericidal activity, with a > 4-log kill of USA300 MRSA within 3 hours at 5 times its MIC. At concentrations significantly below the MIC, anthracimycin slowed MRSA growth and potentiated the bactericidal activity of the human cathelicidin, LL-37. The bactericidal activity of anthracimycin was somewhat mitigated in the presence of 20% human serum, and the compound was minimally toxic to human cells, with an IC50 = 70 mg/L against human carcinoma cells. At concentrations near the MIC anthracimycin inhibited S. aureus nucleic acid synthesis as determined by optimized macromolecular synthesis methodology, with inhibition of DNA and RNA synthesis occurring in the absence of DNA intercalation. Anthracimycin at a single dose of 1 or 10 mg/kg was able to protect mice from MRSA-induced mortality in a murine peritonitis model of infection. Anthracimycin provides an interesting new scaffold for future development of a novel MRSA antibiotic.
doi:10.1038/ja.2014.36
PMCID: PMC4146678  PMID: 24736856
Anthracimycin; Methicillin-resistant Staphylococcus aureus; novel antibiotic
20.  Nonvisual Cues for Aligning to Cross Streets 
Accurately aligning to the crosswalk is an important component of safe street crossing for pedestrians who are blind. Six alignment cues were evaluated in a simulated crosswalk environment in which crosswalk angle was not always in line with ramp slope. The effectiveness of each cue is reported and implications are discussed.
PMCID: PMC4311395
21.  Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses 
Journal of psychosomatic research  2008;65(3):229-238.
Delirium is a common and serious acute neuropsychiatric syndrome with core features of inattention and cognitive impairment, and associated features including changes in arousal, altered sleep-wake cycle, and other changes in mental status. The main risk factors are old age, cognitive impairment, and other comorbidities. Though delirium has consistent core clinical features, it has a very wide range of precipitating factors, including acute illness, surgery, trauma, and drugs. The molecular mechanisms by which these precipitating factors lead to delirium are largely obscure. In this article we attempt to narrow down some specific causal pathways. We propose a basic classification for the aetiological factors: (a) direct brain insults, and (b) aberrant stress responses. Direct brain insults are largely indiscriminate and include general and regional energy deprivation (eg. hypoxia, hypoglycaemia, stroke), metabolic abnormalities (eg. hyponatraemia, hypercalcaemia), and the effects of drugs. Aberrant stress responses are conceptually and mechanistically distinct in that they constitute adverse effects of stress-response pathways which, in health, are adaptive. Ageing and central nervous system disease, two major predisposing factors for delirium, are associated with alterations in the magnitude or duration of stress and sickness behaviour responses, and increased vulnerability to the effects of these responses. We discuss in detail two stress response systems that are likely to be involved in the pathophysiology of delirium: inflammation and the sickness behaviour response, and activity of the limbic-hypothalamic-pituitary-adrenal axis. We conclude by discussing the implications for future research and the development of new therapies for delirium.
doi:10.1016/j.jpsychores.2008.05.019
PMCID: PMC4311661  PMID: 18707945
23.  Changes in waist circumference and body mass index in the US CARDIA cohort: Fixed-effect associations with self-reported experiences of racial/ethnic discrimination 
Journal of biosocial science  2012;45(2):267-278.
Prior studies examining the association between self-reported experiences of racial/ethnic discrimination and obesity have had mixed results and primarily been cross-sectional. This study tests the hypothesis that an increase in self-reported experiences of racial/ethnic discrimination predicts gains in waist circumference and body mass index in Black and White women and men over eight years. In race/ethnicity- and gender-stratified models, this study examined whether change in self-reported experiences of racial/ethnic discrimination predicts changes in waist circumference and body mass index over time using a fixed-effect regression approach in SAS statistical software, providing control for both measured and unmeasured time-invariant covariates. Between 1992–93 and 2000–01, self-reported experiences of racial/ethnic discrimination decreased among 843 Black women (75% to 73%), 601 Black men (80% to 77%), 893 White women (30% to 23%), and 856 White men (28% to 23%). In fixed-effect regression models, controlling for all time-invariant covariates, social desirability bias, and changes in education and parity (women only) over time, an increase in self-reported experiences of racial/ethnic discrimination over time was significantly associated with an increase in waist circumference (b=1.09, 95% CI: 0.00–2.19, p=0.05) and an increase in body mass index (b=0.67, 95% CI: 0.19–1.16, p=0.007) among Black women. No associations were observed among Black men and White women and men. These findings suggest that an increase in self-reported experiences of racial/ethnic discrimination may be associated with increases in waist circumference and body mass index among Black women over time.
doi:10.1017/S0021932012000429
PMCID: PMC4310212  PMID: 22856616
24.  The M3 Muscarinic Receptor Is Required for Optimal Adaptive Immunity to Helminth and Bacterial Infection 
PLoS Pathogens  2015;11(1):e1004636.
Innate immunity is regulated by cholinergic signalling through nicotinic acetylcholine receptors. We show here that signalling through the M3 muscarinic acetylcholine receptor (M3R) plays an important role in adaptive immunity to both Nippostrongylus brasiliensis and Salmonella enterica serovar Typhimurium, as M3R-/- mice were impaired in their ability to resolve infection with either pathogen. CD4 T cell activation and cytokine production were reduced in M3R-/- mice. Immunity to secondary infection with N. brasiliensis was severely impaired, with reduced cytokine responses in M3R-/- mice accompanied by lower numbers of mucus-producing goblet cells and alternatively activated macrophages in the lungs. Ex vivo lymphocyte stimulation of cells from intact BALB/c mice infected with N. brasiliensis and S. typhimurium with muscarinic agonists resulted in enhanced production of IL-13 and IFN-γ respectively, which was blocked by an M3R-selective antagonist. Our data therefore indicate that cholinergic signalling via the M3R is essential for optimal Th1 and Th2 adaptive immunity to infection.
Author Summary
Recent data indicate that acetylcholine (ACh), a neurotransmitter which regulates a variety of physiological functions, also influences the immune system, and that lymphocytes have the capacity to synthesise and release ACh, controlling local innate immune responses and suppressing inflammation. Thus far however there has been little evidence to suggest that ACh influences adaptive immunity, characterised by activation and effector functions of lymphocytes. We show here that during the immune response to two different pathogens, ACh signals through muscarinic receptors, and the M3 receptor subtype specifically, resulting in enhanced activation and cytokine production by ‘helper’ T lymphocytes which protect the host against infection.
doi:10.1371/journal.ppat.1004636
PMCID: PMC4309615  PMID: 25629518
25.  BOADICEA breast cancer risk prediction model: updates to cancer incidences, tumour pathology and web interface 
British Journal of Cancer  2013;110(2):535-545.
Background:
The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is a risk prediction model that is used to compute probabilities of carrying mutations in the high-risk breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, and to estimate the future risks of developing breast or ovarian cancer. In this paper, we describe updates to the BOADICEA model that extend its capabilities, make it easier to use in a clinical setting and yield more accurate predictions.
Methods:
We describe: (1) updates to the statistical model to include cancer incidences from multiple populations; (2) updates to the distributions of tumour pathology characteristics using new data on BRCA1 and BRCA2 mutation carriers and women with breast cancer from the general population; (3) improvements to the computational efficiency of the algorithm so that risk calculations now run substantially faster; and (4) updates to the model's web interface to accommodate these new features and to make it easier to use in a clinical setting.
Results:
We present results derived using the updated model, and demonstrate that the changes have a significant impact on risk predictions.
Conclusion:
All updates have been implemented in a new version of the BOADICEA web interface that is now available for general use: http://ccge.medschl.cam.ac.uk/boadicea/.
doi:10.1038/bjc.2013.730
PMCID: PMC3899766  PMID: 24346285
breast cancer; risk prediction; BOADICEA; BRCA1; BRCA2; incidence; update; tumour; user interface; CIMBA; BCAC

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