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1.  Cervical Dystonia: A Disorder of the Midbrain Network for Covert Attentional Orienting 
While the pathogenesis of cervical dystonia remains unknown, recent animal and clinical experimental studies have indicated its probable mechanisms. Abnormal temporal discrimination is a mediational endophenotype of cervical dystonia and informs new concepts of disease pathogenesis. Our hypothesis is that both abnormal temporal discrimination and cervical dystonia are due to a disorder of the midbrain network for covert attentional orienting caused by reduced gamma-aminobutyric acid (GABA) inhibition, resulting, in turn, from as yet undetermined, genetic mutations. Such disinhibition is (a) subclinically manifested by abnormal temporal discrimination due to prolonged duration firing of the visual sensory neurons in the superficial laminae of the superior colliculus and (b) clinically manifested by cervical dystonia due to disinhibited burst activity of the cephalomotor neurons of the intermediate and deep laminae of the superior colliculus. Abnormal temporal discrimination in unaffected first-degree relatives of patients with cervical dystonia represents a subclinical manifestation of defective GABA activity both within the superior colliculus and from the substantia nigra pars reticulata. A number of experiments are required to prove or disprove this hypothesis.
PMCID: PMC4009446  PMID: 24803911
cervical dystonia; temporal discrimination; covert attention; GABA; superior colliculus
2.  Revision Arthroplasty in the Haemophiliac Patient 
Case Reports in Orthopedics  2013;2013:348080.
Arthroplasty in the haemophiliac patient is associated with higher rates of infection and is traditionally performed in a younger age group. Despite this there is little evidence in the literature regarding revision arthroplasty in this cohort of patients. We describe the case of a periprosthetic fracture in a haemophiliac patient requiring revision arthroplasty, who did not consent to receiving blood products due to religious beliefs, with a successful outcome.
PMCID: PMC3659652  PMID: 23738171
3.  Attitudes of undergraduate health science students towards patients with intellectual disability, substance abuse, and acute mental illness: a cross-sectional study 
BMC Medical Education  2010;10:71.
There is a long history of certain medical conditions being associated with stigma, stereotypes, and negative attitudes. Research has shown that such attitudes can have a detrimental effect on patients presenting with stigmatised medical conditions and can even flow on to impact their family. The objective of this study was to measure the attitudes of undergraduate students enrolled in six different health-related courses at Monash University toward patients with intellectual disability, substance abuse, and acute mental illness.
A convenience sample of undergraduate students enrolled in six health-related courses in first, second and third years at Monash University were surveyed. The Medical Condition Regard Scale - a valid and reliable, self-report measure of attitudes - was administered to students along with a brief demographic form. Mean scores, t-tests, and ANOVA were used to analyse student attitudes. Ethics approval was granted.
548 students participated. Statistically significant differences were found between the courses (p = 0.05), year of the course (p = 0.09), and gender (p = 0.04) for the medical condition of intellectual disability. There was no statistically significant difference between the courses, year of the course, gender, and age group for substance abuse or acute mental illness conditions.
The findings suggest that students in undergraduate health-related courses, as a group, have a strong regard for patients with intellectual disability and some regard for patients with acute mental illness, but not for patients presenting with substance abuse problems.
PMCID: PMC2972293  PMID: 20964840
4.  Myocarditis as a prognostic indicator in systemic lupus erythematosus 
Postgraduate Medical Journal  2004;80(944):366-367.
Lupus myocarditis is a life threatening complication of systemic lupus erythematosus (SLE). A case of left ventricular failure secondary to myocarditis occurring in a patient with SLE is reported. Despite resolution of the cardiac failure with pulsed cyclophosphamide and steroids, she eventually died of non-cardiac complications 18 months later. The literature is also reviewed.
PMCID: PMC1743021  PMID: 15192176
Folic acid supplements can protect against neural tube defects (NTDs). Low folate and low vitamin B12 status may be maternal risk factors for having an NTD affected pregnancy. However, not all NTDs are preventable by having an adequate folate/ B12 status and other potentially modifiable factors may be involved. Folate and vitamin B12 status have important links to iron metabolism. Animal studies support an association between poor iron status and NTDs but human data are scarce. We examined the relevance of low iron status in a nested NTD case-control study of women within a pregnant population-based cohort.
Pregnant women were recruited between 1986 and 1990, when vitamin or iron supplementation in early pregnancy was rare. Blood samples, taken at an average of 14 weeks gestation, were used to measure ferritin and hemoglobin in 64 women during an NTD affected pregnancy and 207 women with unaffected pregnancies.
No significant differences in maternal ferritin or hemoglobin concentrations were observed between NTD affected and non-affected pregnancies (case median ferritin 16.8μg/L and hemoglobin 12.4g/dL versus 15.4μg/L and 12.3g/dL in controls). As reported previously, red cell folate and vitamin B12 concentrations were significantly lower in cases. Furthermore, there was no significant association of iron status with type of NTD lesion (anencephaly or spina bifida)
We conclude that low maternal iron status during early pregnancy is not an independent risk factor for NTDs. Adding iron to folic acid for periconceptional use may improve iron status but is not likely to prevent NTDs.
PMCID: PMC4018583  PMID: 24535840
ferritin; iron; hemoglobin; neural tube defects
6.  Emergence of Mixed-Sex Friendship Groups during Adolescence: Developmental Associations with Substance Use & Delinquency 
Developmental psychology  2014;50(11):2449-2461.
Prospective longitudinal data from over 14,000 youth residing in 28 communities in the rural U.S. were analyzed to examine the emergence of mixed-sex friendship groups in early adolescence. Youth were surveyed on five occasions between fall of 6th grade and spring of 9th grade. At each assessment, youth reported the names of up to seven same-grade friends and described patterns of alcohol use, cigarette use and delinquency. Approximately 800 – 900 friendship groups (Mean = 10.5 members) were identified at each assessment and categorized in terms of gender composition (all-girl, mostly-girl, mixed-sex, mostly-boy, all-boy). The proportion of groups categorized as mixed-sex increased with grade level (10% in 6th grade, 22% in 9th grade), but gender-homogenous groups predominated at all grade levels (76% in 6th grade, 51% in 9th grade). Mixed-sex groups were slightly larger than all-girl groups but the same size as all-boy groups. All-girl groups had the highest levels of tightknittedness (i.e., density, reciprocity and transitivity), with mixed-sex groups having the lowest levels and all-boy groups having intermediate levels. After controlling for demographic factors, future mixed-sex group membership was predicted by lower popularity, higher levels of delinquency and lower levels of alcohol use; and mixed-sex friendship group membership was associated with increased likelihood of cigarette use. Results are partially consistent with Dunphy’s classic account of the emergence of mixed-sex groups in adolescence, but suggest that in early adolescence, mixed-sex group affiliation is significantly associated with deviant behavior and peripheral social status, not with popularity.
PMCID: PMC4315307  PMID: 25221839
Friendship; peer groups; gender; adolescence; substance use; delinquency
7.  Trisomy 8 Acute Myeloid Leukemia Analysis Reveals New Insights of DNA Methylome with Identification of HHEX as Potential Diagnostic Marker 
Biomarkers in Cancer  2015;7:1-6.
Trisomy 8 acute myeloid leukemia (AML) is the commonest numerical aberration in AML. Here we present a global analysis of trisomy 8 AML using methylated DNA immunoprecipitation-sequencing (MeDIP-seq). The study is based on three diagnostic trisomy 8 AML and their parallel relapse status in addition to nine non-trisomic AML and four normal bone marrows (NBMs). In contrast to non-trisomic DNA samples, trisomy 8 AML showed a characteristic DNA methylation distribution pattern because an increase in the frequency of the hypermethylation signals in chromosome 8 was associated with an increase in the hypomethylation signals in the rest of the chromosomes. Chromosome 8 hypermethylation signals were found mainly in the CpG island (CGI) shores and interspersed repeats. Validating the most significant differentially methylated CGI (P = 7.88 × 10−11) identified in trisomy 8 AML demonstrated a specific core region within the gene body of HHEX, which was significantly correlated with HHEX expression in both diagnostic and relapse trisomy 8 AMLs. Overall, the existence of extra chromosome 8 was associated with a global impact on the DNA methylation distribution with identification of HHEX gene methylation as a potential diagnostic marker for trisomy 8 AML.
PMCID: PMC4315123
trisomy 8; MeDIP-seq; CGI shores; HHEX
8.  An Open Science Peer Review Oath 
F1000Research  2015;3:271.
One of the foundations of the scientific method is to be able to reproduce experiments and corroborate the results of research that has been done before. However, with the increasing complexities of new technologies and techniques, coupled with the specialisation of experiments, reproducing research findings has become a growing challenge. Clearly, scientific methods must be conveyed succinctly, and with clarity and rigour, in order for research to be reproducible. Here, we propose steps to help increase the transparency of the scientific method and the reproducibility of research results: specifically, we introduce a peer-review oath and accompanying manifesto. These have been designed to offer guidelines to enable reviewers (with the minimum friction or bias) to follow and apply open science principles, and support the ideas of transparency, reproducibility and ultimately greater societal impact. Introducing the oath and manifesto at the stage of peer review will help to check that the research being published includes everything that other researchers would need to successfully repeat the work. Peer review is the lynchpin of the publishing system: encouraging the community to consciously (and conscientiously) uphold these principles should help to improve published papers, increase confidence in the reproducibility of the work and, ultimately, provide strategic benefits to authors and their institutions.
PMCID: PMC4304228  PMID: 25653839
10.  Out & Online; effectiveness of a tailored online multi-symptom mental health and wellbeing program for same-sex attracted young adults: study protocol for a randomised controlled trial 
Trials  2014;15(1):504.
Same-sex attracted young adults have been found to experience higher rates of mental health problems and greater difficulties in accessing specialist mental health care services compared to their heterosexual peers. Internet-based mental health interventions have the potential to be more engaging and accessible to young adults compared to those delivered face-to-face. However, they are rarely inclusive of lesbian women and gay men. Thus, the current study aims to evaluate the effectiveness of an online mental health and wellbeing program, Out & Online (, in comparison to a wait-list control group, for reducing anxiety and depressive symptoms in same-sex attracted young adults aged between 18 and 25 years.
We are recruiting, through media and community organisations, 200 same-sex attracted young adults with anxiety and/or depressive symptoms and mild to moderate psychological distress (Kessler-10 score between 16 to 21). Participants will be randomly allocated to the intervention (the online program) or the wait-list control group based on a permuted blocked randomisation method to allow for stratification by gender. Participants in the intervention group will receive a tailored program for up to three types of mental health difficulties simultaneously. The primary outcome of anxiety and/or depressive symptoms, and secondary outcomes related to psychological distress, wellbeing and health behaviour will be measured at pre-intervention (0 week), post-intervention (8 weeks) and at a 3-month follow-up (20 weeks).
This online mental health and wellbeing program will be one of the first online interventions to be designed specifically to be relevant for same-sex attracted individuals. If the program is found to be effective it will improve access to specialist same-sex attracted-relevant mental health services for young adults and will facilitate wellbeing outcomes for these individuals. This program will also be a significant development in the delivery of tailored interventions that target multiple types of mental health conditions simultaneously.
Trial registration
Australian New Zealand Clinical Trials Registry: ACTRN12611000700932. Date registered: 7 July 2011.
PMCID: PMC4308019  PMID: 25534310
eHealth; eMental health; Same-sex attraction; Young adults; Sexual orientation; Wellbeing; Mental health; Randomised controlled trial; Intervention; Cognitive behaviour therapy
11.  An association between the PTGS2 rs5275 polymorphism and colorectal cancer risk in families with inherited non-syndromic predisposition 
European Journal of Human Genetics  2013;21(12):1389-1395.
Recently our group completed a genome-wide linkage study investigating Australian and Spanish families with inherited risk of colorectal cancer (CRC). A minor linkage peak from that study located on chromosome 1 correlates with the location of a known CRC risk-modifying gene, prostaglandin synthase (PTGS2). PTGS2 encodes the inducible prostaglandin synthase enzyme cyclooxygenase-2 (COX-2). Prostaglandins are implicated in the initiation of carcinogenesis and progression of tumours. Sequencing of PTGS2 in a small subset of affected individuals identified a high frequency of the minor C allele of single nucleotide polymorphism rs5275. We then genotyped the rs5275 polymorphism in 183 affected and 223 unaffected individuals from our CRC predisposed families. Tests for association in the presence of linkage were made using family-based association tests. The C allele was found to be significantly associated (P<0.01) with diagnosis of hereditary non-syndromic CRC (P=0.0094, dominant model) and an earlier age of diagnosis (P=0.0089, heterozygous-advantage model). Interestingly, by stratifying the age of diagnosis data, we observed a speculative gender-discordant effect. Relative to other groups, female CC carriers were diagnosed less when young, but by 60 years of age were the most at risk group. Conversely, CT carriers of both genders showed a consistently earlier diagnosis relative to TT carriers. Our results suggest potential differential age-and gender-dependent efficacies of chemopreventative COX-2 inhibitors in the context of non-syndromic colorectal cancer.
PMCID: PMC3831072  PMID: 23531863
PTGS2; COX-2; rs5275; colorectal; cancer; hereditary
12.  Identification and characterisation of eight novel SERPINA1 Null mutations 
Alpha-1 antitrypsin (AAT) is the most abundant circulating antiprotease and is a member of the serine protease inhibitor (SERPIN) superfamily. The gene encoding AAT is the highly polymorphic SERPINA1 gene, found at 14q32.1. Mutations in the SERPINA1 gene can lead to AAT deficiency (AATD) which is associated with a substantially increased risk of lung and liver disease. The most common pathogenic AAT variant is Z (Glu342Lys) which causes AAT to misfold and polymerise within hepatocytes and other AAT-producing cells. A group of rare mutations causing AATD, termed Null or Q0, are characterised by a complete absence of AAT in the plasma. While ultra rare, these mutations confer a particularly high risk of emphysema.
We performed the determination of AAT serum levels by a rate immune nephelometric method or by immune turbidimetry. The phenotype was determined by isoelectric focusing analysis on agarose gel with specific immunological detection. DNA was isolated from whole peripheral blood or dried blood spot (DBS) samples using a commercial extraction kit. The new mutations were identified by sequencing all coding exons (II-V) of the SERPINA1 gene.
We have found eight previously unidentified SERPINA1 Null mutations, named: Q0cork, Q0perugia, Q0brescia, Q0torino, Q0cosenza, Q0pordenone, Q0lampedusa, and Q0dublin . Analysis of clinical characteristics revealed evidence of the recurrence of lung symptoms (dyspnoea, cough) and lung diseases (emphysema, asthma, chronic bronchitis) in M/Null subjects, over 45 years-old, irrespective of smoking.
We have added eight more mutations to the list of SERPINA1 Null alleles. This study underlines that the laboratory diagnosis of AATD is not just a matter of degree, because the precise determination of the deficiency and Null alleles carried by an AATD individual may help to evaluate the risk for the lung disease.
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-014-0172-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4255440  PMID: 25425243
Alpha-1 antitrypsin deficiency; Q0 mutation; Lung diseases; Serpins
13.  Affinity proteomics reveals human host factors implicated in discrete stages of LINE-1 retrotransposition 
Cell  2013;155(5):1034-1048.
LINE-1s are active human DNA parasites that are agents of genome dynamics in evolution and disease. These streamlined elements require host factors to complete their lifecycles, whereas hosts have developed mechanisms to combat retrotransposition’s mutagenic effects. As such, endogenous L1 expression levels are extremely low, creating a roadblock for detailed interactomic analyses. Here we describe a system to express and purify highly active L1 RNP complexes from human suspension cell culture and characterize the co-purified proteome, identifying 37 high-confidence candidate interactors. These datasets include known interactors PABPC1 and MOV10 and, with in-cell imaging studies, suggest existence of at least three types of compositionally and functionally distinct L1 RNPs. Among the novel findings, UPF1, a key nonsense-mediated decay factor, and PCNA, the polymerase-delta-associated sliding DNA clamp, were identified and validated. PCNA interacts with ORF2p via a PIP box motif; mechanistic studies suggest this occurs during or immediately after target-primed reverse transcription.
PMCID: PMC3904357  PMID: 24267889
14.  The Open Science Peer Review Oath 
F1000Research  2014;3:271.
One of the foundations of the scientific method is to be able to reproduce experiments and corroborate the results of research that has been done before. However, with the increasing complexities of new technologies and techniques, coupled with the specialisation of experiments, reproducing research findings has become a growing challenge. Clearly, scientific methods must be conveyed succinctly, and with clarity and rigour, in order for research to be reproducible. Here, we propose steps to help increase the transparency of the scientific method and the reproducibility of research results: specifically, we introduce a peer-review oath and accompanying manifesto. These have been designed to offer guidelines to enable reviewers (with the minimum friction or bias) to follow and apply open science principles, and support the ideas of transparency, reproducibility and ultimately greater societal impact. Introducing the oath and manifesto at the stage of peer review will help to check that the research being published includes everything that other researchers would need to successfully repeat the work. Peer review is the lynchpin of the publishing system: encouraging the community to consciously (and conscientiously) uphold these principles should help to improve published papers, increase confidence in the reproducibility of the work and, ultimately, provide strategic benefits to authors and their institutions. Future incarnations of the various national Research Excellence Frameworks (REFs) will evolve away from simple citations towards measurable societal value and impact. The proposed manifesto aspires to facilitate this goal by making transparency, reproducibility and citizen-scientist engagement (with the knowledge-creation and dissemination processes) the default parameters for performing sound research.
PMCID: PMC4304228  PMID: 25653839
15.  Large Retrospective Evaluation of the Effectiveness and Safety of Ceftaroline Fosamil Therapy 
Ceftaroline has been approved for acute bacterial skin infections and community-acquired bacterial pneumonia. Limited clinical experience exists for use outside these indications. The objective of this study was to describe the outcomes of patients treated with ceftaroline for various infections. Retrospective analyses of patients receiving ceftaroline ≥72 h from 2011 to 2013 were included. Clinical and microbiological outcomes were analyzed. Clinical success was defined as resolution of all signs and symptoms of infection with no further need for escalation while on ceftaroline treatment during hospitalization. A total of 527 patients received ceftaroline, and 67% were treated for off-label indications. Twenty-eight percent (148/527) of patients had bacteremia. Most patients (80%) were initiated on ceftaroline after receipt of another antimicrobial, with 48% citing disease progression as a reason for switching. The median duration of ceftaroline treatment was 6 days, with an interquartile range of 4 to 9 days. A total of 327 (62%) patients were culture positive, and the most prevalent pathogen was Staphylococcus aureus, with a frequency of 83% (271/327). Of these patients, 88.9% (241/271) were infected with methicillin-resistant S. aureus (MRSA). Clinically, 88% (426/484) achieved clinical success and hospital mortality was seen in 8% (40/527). While on ceftaroline, adverse events were experienced in 8% (41/527) of the patients and 9% (28/307) were readmitted within 30 days after discharge for the same infection. Patients treated with ceftaroline for both FDA-approved and off-label infections had favorable outcomes. Further research is necessary to further describe the role of ceftaroline in a variety of infections and its impact on patient outcomes.
PMCID: PMC3993242  PMID: 24550331
16.  Riboflavin status modifies the effects of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms on homocysteine 
Genes & Nutrition  2014;9(6):435.
Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR), riboflavin-dependent enzymes, participate in homocysteine metabolism. Reported effects of riboflavin status on the association between the MTHFR 677C>T polymorphism and homocysteine vary, and the effects of the MTRR 66A>G or MTRR 524C>T polymorphisms on homocysteine are unclear. We tested the hypothesis that the effects of the MTHFR 677C>T, MTRR 66A>G and MTRR 524C>T polymorphisms on fasting plasma total homocysteine (tHcy) depend on riboflavin status (erythrocyte glutathionine reductase activation coefficient, optimum: <1.2; marginally deficient: 1.2–1.4; deficient: ≥1.4) in 771 adults aged 18–75 years. MTHFR 677T allele carriers with middle or low tertile plasma folate (<14.7 nmol/L) had 8.2 % higher tHcy compared to the 677CC genotype (p < 0.01). This effect was eliminated when riboflavin status was optimal (p for interaction: 0.048). In the lowest cobalamin quartile (≤273 pmol/L), riboflavin status modifies the relationship between the MTRR 66 A>G polymorphism and tHcy (p for interaction: 0.034). tHcy was 6.6 % higher in MTRR 66G allele carriers compared to the 66AA genotype with marginally deficient or optimal riboflavin status, but there was no difference when riboflavin status was deficient (p for interaction: 0.059). tHcy was 13.7 % higher in MTRR 524T allele carriers compared to the 524CC genotype when cobalamin status was low (p < 0.01), but no difference was observed when we stratified by riboflavin status. The effect of the MTHFR 677C>T polymorphism on tHcy depends on riboflavin status, that of the MTRR 66A>G polymorphism on cobalamin and riboflavin status and that of the MTRR 524C>T polymorphism on cobalamin status.
PMCID: PMC4235830  PMID: 25322900
Homocysteine; MTHFR; MTRR; Riboflavin; EGRAC; Vitamin B6; EASTAC
17.  NILVAD protocol: a European multicentre double-blind placebo-controlled trial of nilvadipine in mild-to-moderate Alzheimer's disease 
BMJ Open  2014;4(10):e006364.
This study is a European multicentre, randomised, double-blind, placebo-controlled trial investigating the efficacy and safety of nilvadipine as a disease course modifying treatment for mild-to-moderate Alzheimer's disease (AD) in a phase III study that will run for a period of 82 weeks with a treatment period of 78 weeks.
Methods and analysis
Adult patients, males and females over 50 years with mild-to-moderate AD as defined by the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease and Related Disorders Association (NINCDS-ADRDA) criteria, will be included in the study. It aims to recruit a total of 500 patients with AD; 250 in the nilvadipine group and 250 in the placebo group. Participants will be randomised to receive nilvadipine, an 8 mg overencapsulated, sustained release capsule, or a matching overencapsulated placebo (sugar pill) for a period of 78 weeks of treatment. The primary efficacy outcome measure in this study is the change in cognitive function as assessed by the Alzheimer's disease Assessment Scale (ADAS-Cog 12) from baseline to the end of treatment duration (78 weeks). There are two key secondary outcome measures, the Clinical Dementia Rating Scale Sum of Boxes (CDR-sb) and the Disability Assessment for Dementia (DAD). If a statistically significant effect is seen in the primary outcome, CDR-sb will be considered to be a coprimary end point and only the DAD will contribute to the secondary outcome analysis.
Ethics and dissemination
The study and all subsequent amendments have received ethical approval within each participating country according to national regulations. Each participant will provide written consent to participate in the study. All participants will remain anonymised throughout and the results of the study will be published in an international peer-reviewed journal.
Trial registration number
EUDRACT Reference Number: 2012-002764-27.
PMCID: PMC4194801  PMID: 25300460
18.  Semi-Automated Volumetric Quantification of Tumor Necrosis in Soft Tissue Sarcoma Using Contrast Enhanced MRI 
Anticancer research  2012;32(11):4951-4961.
Response Evaluation Criteria in Solid Tumors (RECIST) defined measurements are limited when evaluating soft tissue sarcoma (STS) response to therapy. Histopathologic assessment of STS response requires a determination of necrosis following resection. A novel semiautomated technique for volumetric measurement of tumor necrosis, using enhanced magnetic resonance imaging (CE-MRI), is described.
Patients and Methods
Eighteen patients with STS were treated with neoadjuvant therapy and then resected. CE-MRI, obtained prior to resection, were evaluated by two observers using semi-automated segmentation. Tumor volume and percent necrosis was compared with histology and RECIST measurements.
The median percent necrosis, determined histologically and from CE-MRI, was 71.9% and 67.8%, respectively. Accuracy of these semiautomated measurements was confirmed, being statistically similar to those obtained at histopathologic assessment of the resected tumor. High Intra-class correlation coefficients suggest good inter-observer reproducibility. Tumor necrosis did not correlate with RECIST measurements.
Semi-automated determination of tumor volume and necrosis, using CE-MRI, is suggested to be accurate and reproducible.
PMCID: PMC4180491  PMID: 23155265
Sarcoma; necrosis; magnetic resonance imaging; segmentation
19.  Cryptosporidium and Giardia in Surface Water: A Case Study from Michigan, USA to Inform Management of Rural Water Systems 
Cryptosporidium and Giardia pose a threat to human health in rural environments where water supplies are commonly untreated and susceptible to contamination from agricultural animal waste/manure, animal wastewater, septic tank effluents and septage. Our goals for this paper are to: (1) explore the prevalence of these protozoan parasites, where they are found, in what quantities, and which genotypes are present; (2) examine relationships between disease and land use comparing human health risks between rural and urban environments; and (3) synthesize available information to gain a better understanding of risk and risk management for rural water supplies. Our results indicate that Cryptosporidium and Giardia were more prevalent in rural versus urban environments based on the number of positive samples. Genotyping showed that both the human and animal types of the parasites are found in rural and urban environments. Rural areas had a higher incidence of disease compared to urban areas based on the total number of disease cases. Cryptosporidiosis and giardiasis were both positively correlated (p < 0.001) with urban area, population size, and population density. Finally, a comprehensive strategy that creates knowledge pathways for data sharing among multiple levels of management may improve decision-making for protecting rural water supplies.
PMCID: PMC4210991  PMID: 25317981
Cryptosporidium; Giardia; genotyping; land use; rural water supply; water management
20.  Screening for markers of frailty and perceived risk of adverse outcomes using the Risk Instrument for Screening in the Community (RISC) 
BMC Geriatrics  2014;14(1):104.
Functional decline and frailty are common in community dwelling older adults, increasing the risk of adverse outcomes. Given this, we investigated the prevalence of frailty-associated risk factors and their distribution according to the severity of perceived risk in a cohort of community dwelling older adults, using the Risk Instrument for Screening in the Community (RISC).
A cohort of 803 community dwelling older adults were scored for frailty by their public health nurse (PHN) using the Clinical Frailty Scale (CFS) and for risk of three adverse outcomes: i) institutionalisation, ii) hospitalisation and iii) death, within the next year, from one (lowest) to five (highest) using the RISC. Prior to scoring, PHNs stated whether they regarded patients as frail.
The median age of patients was 80 years (interquartile range 10), of whom 64% were female and 47.4% were living alone. The median Abbreviated Mental Test Score (AMTS) was 10 (0) and Barthel Index was 18/20 (6). PHNs regarded 42% of patients as frail, while the CFS categorized 54% (scoring ≥5) as frail. Dividing patients into low-risk (score one or two), medium-risk (score three) and high-risk (score four or five) using the RISC showed that 4.3% were considered high risk of institutionalization, 14.5% for hospitalization, and 2.7% for death, within one year of the assessment. There were significant differences in median CFS (4/9 versus 6/9 versus 6/9, p < 0.001), Barthel Index (18/20 versus 11/20 versus 14/20, p < 0.001) and mean AMTS scores (9.51 versus 7.57 versus 7.00, p < 0.001) between those considered low, medium and high risk of institutionalisation respectively. Differences were also statistically significant for hospitalisation and death. Age, gender and living alone were inconsistently associated with perceived risk. Frailty most closely correlated with functional impairment, r = −0.80, p < 0.001.
The majority of patients in this community sample were perceived to be low risk for adverse outcomes. Frailty, cognitive impairment and functional status were markers of perceived risk. Age, gender and social isolation were not and may not be useful indicators when triaging community dwellers. The RISC now requires validation against adverse outcomes.
PMCID: PMC4177708  PMID: 25238874
Screening; Frailty; Risk; Adverse outcomes; Clinical frailty scale (CFS); Risk instrument for screening in the community (RISC); Public health nurses (PHNs); Comorbidities; Cognitive impairment; Barthel index (BI); Abbreviated mental test score (AMTS)
21.  Maternal Vitamin B12 Status and Risk of Neural Tube Defects in a Population With High Neural Tube Defect Prevalence and No Folic Acid Fortification 
Pediatrics  2009;123(3):917-923.
Folic acid fortification has reduced neural tube defect prevalence by 50% to 70%. It is unlikely that fortification levels will be increased to reduce neural tube defect prevalence further. Therefore, it is important to identify other modifiable risk factors. Vitamin B12 is metabolically related to folate; moreover, previous studies have found low B12 status in mothers of children affected by neural tube defect. Our objective was to quantify the effect of low B12 status on neural tube defect risk in a high-prevalence, unfortified population.
We assessed pregnancy vitamin B12 status concentrations in blood samples taken at an average of 15 weeks’ gestation from 3 independent nested case-control groups of Irish women within population-based cohorts, at a time when vitamin supplementation or food fortification was rare. Group 1 blood samples were from 95 women during a neural tube defect–affected pregnancy and 265 control subjects. Group 2 included blood samples from 107 women who had a previous neural tube defect birth but whose current pregnancy was not affected and 414 control subjects. Group 3 samples were from 76 women during an affected pregnancy and 222 control subjects.
Mothers of children affected by neural tube defect had significantly lower B12 status. In all 3 groups those in the lowest B12 quartiles, compared with the highest, had between two and threefold higher adjusted odds ratios for being the mother of a child affected by neural tube defect. Pregnancy blood B12 concentrations of <250 ng/L were associated with the highest risks.
Deficient or inadequate maternal vitamin B12 status is associated with a significantly increased risk for neural tube defects. We suggest that women have vitamin B12 levels of >300 ng/L (221 pmol/L) before becoming pregnant. Improving B12 status beyond this level may afford a further reduction in risk, but this is uncertain.
PMCID: PMC4161975  PMID: 19255021
vitamin B12; cobalamin; neural tube defects; folic acid fortification; folate
22.  The effect of resting condition on resting-state fMRI reliability and consistency: A comparison between resting with eyes open, closed, and fixated 
NeuroImage  2013;78:463-473.
Resting-state fMRI (rs-fMRI) has been demonstrated to have moderate to high reliability and produces consistent patterns of connectivity across a wide variety of subjects, sites, and scanners. However, there is no one agreed upon method to acquire rs-fMRI data. Some sites instruct their subjects, or patients, to lie still with their eyes closed, while other sites instruct their subjects to keep their eyes open or even fixating on a cross during scanning. Several studies have compared those three resting conditions based on connectivity strength. In our study, we assess differences in metrics of test–retest reliability (using an intraclass correlation coefficient), and consistency of the rank-order of connections within a subject and the ranks of subjects for a particular connection from one session to another (using Kendall's W tests). Twenty-five healthy subjects were scanned at three different time points for each resting condition, twice the same day and another time two to three months later. Resting-state functional connectivity measures were evaluated in motor, visual, auditory, attention, and default-mode networks, and compared between the different resting conditions. Of the networks examined, only the auditory network resulted in significantly higher connectivity in the eyes closed condition compared to the other two conditions. No significant between-condition differences in connectivity strength were found in default mode, attention, visual, and motor networks. Overall, the differences in reliability and consistency between different resting conditions were relatively small in effect size but results were found to be significant. Across all within-network connections, and within default-mode, attention, and auditory networks statistically significant greater reliability was found when the subjects were lying with their eyes fixated on a cross. In contrast, primary visual network connectivity was most reliable when subjects had their eyes open (and not fixating on a cross).
PMCID: PMC4003890  PMID: 23597935
Resting-state; fMRI; Functional connectivity; Reliability; Eyes open; Eyes closed; Eyes fixate
23.  Lack of Association between Folate-Receptor Autoantibodies and Neural-Tube Defects 
The New England journal of medicine  2009;361(2):152-160.
A previous report described the presence of autoantibodies against folate receptors in 75% of serum samples from women with a history of pregnancy complicated by a neural-tube defect, as compared with 10% of controls. We sought to confirm this finding in an Irish population, which traditionally has had a high prevalence of neuraltube defects.
We performed two studies. Study 1 consisted of analysis of stored frozen blood samples collected from 1993 through 1994 from 103 mothers with a history of pregnancy complicated by a neural-tube defect (case mothers), 103 mothers with a history of pregnancy but no complication by a neural-tube defect (matched with regard to number of pregnancies and sampling dates), 58 women who had never been pregnant, and 36 men. Study 2, conducted to confirm that the storage of samples did not influence the folate-receptor autoantibodies, included fresh samples from 37 case mothers, 22 control mothers, 10 women who had never been pregnant, and 9 men. All samples were assayed for blocking and binding autoantibodies against folate receptors.
In Study 1, blocking autoantibodies were found in 17% of case mothers, as compared with 13% of control mothers (odds ratio, 1.54; 95% confidence interval [CI], 0.70 to 3.39), and binding autoantibodies in 29%, as compared with 32%, respectively (odds ratio, 0.82; 95% CI, 0.44 to 1.50). Study 2 showed similar results, indicating that sample degradation was unlikely.
The presence and titer of maternal folate-receptor autoantibodies were not significantly associated with a neural-tube defect–affected pregnancy in this Irish population.
PMCID: PMC4149290  PMID: 19587340
24.  Macrophage migration inhibitory factor engages PI3K/Akt signalling and is a prognostic factor in metastatic melanoma 
BMC Cancer  2014;14(1):630.
Macrophage migration inhibitory factor (MIF) is a widely expressed cytokine involved in a variety of cellular processes including cell cycle regulation and the control of proliferation. Overexpression of MIF has been reported in a number of cancer types and it has previously been shown that MIF is upregulated in melanocytic tumours with the highest expression levels occurring in malignant melanoma. However, the clinical significance of high MIF expression in melanoma has not been reported.
MIF expression was depleted in human melanoma cell lines using siRNA-mediated gene knockdown and effects monitored using in vitro assays of proliferation, cell cycle, apoptosis, clonogenicity and Akt signalling. In silico analyses of expression microarray data were used to correlate MIF expression levels in melanoma tumours with overall patient survival using a univariate Cox regression model.
Knockdown of MIF significantly decreased proliferation, increased apoptosis and decreased anchorage-independent growth. Effects were associated with reduced numbers of cells entering S phase concomitant with decreased cyclin D1 and CDK4 expression, increased p27 expression and decreased Akt phosphorylation. Analysis of clinical outcome data showed that MIF expression levels in primary melanoma were not associated with outcome (HR = 1.091, p = 0.892) whereas higher levels of MIF in metastatic lesions were significantly associated with faster disease progression (HR = 2.946, p = 0.003 and HR = 4.600, p = 0.004, respectively in two independent studies).
Our in vitro analyses show that MIF functions upstream of the PI3K/Akt pathway in human melanoma cell lines. Moreover, depletion of MIF inhibited melanoma proliferation, viability and clonogenic capacity. Clinically, high MIF levels in metastatic melanoma were found to be associated with faster disease recurrence. These findings support the clinical significance of MIF signalling in melanoma and provide a strong rationale for both targeting and monitoring MIF expression in clinical melanoma.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-630) contains supplementary material, which is available to authorized users.
PMCID: PMC4155090  PMID: 25168062
Akt signalling; BRAF; Cell cycle; MIF; Melanoma; Metastasis; Prognostic factor; Proliferation
25.  The necrotrophic effector protein SnTox3 re-programs metabolism and elicits a strong defence response in susceptible wheat leaves 
BMC Plant Biology  2014;14(1):215.
The fungus Stagonospora nodorum is a necrotrophic pathogen of wheat. It causes disease by secreting proteinaceous effectors which interact with proteins encoded by dominant susceptibility genes in the host. The outcome of these interactions results in necrosis, allowing the fungus to thrive on dead plant material. The mechanisms of these effectors though are poorly understood. In this study, we undertake a comprehensive transcriptomics, proteomic and metabolomic approach to understand how a susceptible wheat cultivar responds to exposure to the Stagonospora nodorum effector protein SnTox3.
Microarray and proteomic studies revealed that SnTox3 strongly induced responses consistent with those previously associated with classical host defence pathways including the expression of pathogenicity-related proteins and the induction of cell death. Collapse of the photosynthetic machinery was also apparent at the transcriptional and translational level. SnTox3-infiltrated wheat leaves also showed a strong induction of enzymes involved in primary metabolism consistent with increases in hexoses, amino acids and organic acids as determined by primary metabolite profiling. Methionine and homocysteine metabolism was strongly induced upon exposure to SnTox3. Pathogenicity in the presence of homocysteine was inhibited confirming that the compound has a role in plant defence. Consistent with the strong defence responses observed, secondary metabolite profiling revealed the induction of several compounds associated with plant defence, including the phenylpropanoids chlorogenic acid and feruloylquinic acid, and the cyanogenic glucoside dhurrin. Serotonin did not accumulate subsequent to SnTox3 infiltration.
These data support the theory that the SnTox3 effector protein elicits a host cell death response to facilitate the pathogen’s necrotrophic infection cycle. Our data also demonstrate that the mechanism of SnTox3 appears distinct from the previously characterised Stagonospora nodorum effector SnToxA. Collectively, this comprehensive analysis has advanced our understanding of necrotrophic effector biology and highlighted the complexity of effector-triggered susceptibility.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-014-0215-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4243954  PMID: 25123935
Effector triggered susceptibility; Stagonospora nodorum; Necrotrophic fungal pathogen; Wheat; Necrotrophic effectors

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