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1.  The Canadian systemic sclerosis oral health study: orofacial manifestations and oral health-related quality of life in systemic sclerosis compared with the general population 
Rheumatology (Oxford, England)  2014;53(8):1386-1394.
Objective. The aim of this study was to compare oral abnormalities and oral health-related quality of life (HRQoL) of patients with SSc with the general population.
Methods. SSc patients and healthy controls were enrolled in a multisite cross-sectional study. A standardized oral examination was performed. Oral HRQoL was measured with the Oral Health Impact Profile (OHIP). Multivariate regression analyses were performed to identify associations between SSc, oral abnormalities and oral HRQoL.
Results. We assessed 163 SSc patients and 231 controls. SSc patients had more decayed teeth (SSc 0.88, controls 0.59, P = 0.0465) and periodontal disease [number of teeth with pocket depth (PD) >3 mm or clinical attachment level (CAL) ≥5.5 mm; SSc 5.23, controls 2.94, P < 0.0001]. SSc patients produced less saliva (SSc 147.52 mg/min, controls 163.19 mg/min, P = 0.0259) and their interincisal distance was smaller (SSc 37.68 mm, controls 44.30 mm, P < 0.0001). SSc patients had significantly reduced oral HRQoL compared with controls (mean OHIP score: SSc 41.58, controls 26.67, P < 0.0001). Multivariate regression analyses confirmed that SSc was a significant independent predictor of missing teeth, periodontal disease, interincisal distance, saliva production and OHIP scores.
Conclusion. Subjects with SSc have impaired oral health and oral HRQoL compared with the general population. These data can be used to develop targeted interventions to improve oral health and HRQoL in SSc.
PMCID: PMC4103515  PMID: 24464709
systemic sclerosis; quality of life; oral health; dental caries; periodontal disease; Sjögren’s syndrome; tooth loss
2.  Relationship Between Disease Characteristics and Orofacial Manifestations in Systemic Sclerosis: Canadian Systemic Sclerosis Oral Health Study III 
Arthritis care & research  2015;67(5):681-690.
Systemic sclerosis (SSc; scleroderma) is associated with decreased saliva production and interincisal distance, more missing teeth, and periodontal disease. We undertook this study to determine the clinical correlates of SSc with these oral abnormalities.
Subjects were recruited from the Canadian Scleroderma Research Group cohort. Detailed dental and clinical examinations were performed according to standardized protocols. Associations between dental abnormalities and selected clinical and serologic manifestations of SSc were examined.
One hundred sixty-three SSc subjects were included: 90% women, mean ± SD age 56 ± 11 years, mean ± SD disease duration 14 ± 8 years, 72% with limited cutaneous disease, and 28% with diffuse cutaneous disease. Decreased saliva production was associated with Sjögren’s syndrome–related autoantibodies (β = −43.32; 95% confidence interval [95% CI] −80.89, −5.75), but not with disease severity (β = −2.51; 95% CI −8.75, 3.73). Decreased interincisal distance was related to disease severity (β = −1.02; 95% CI −1.63, −0.42) and the modified Rodnan skin thickness score (β = −0.38; 95% CI −0.53, −0.23). The number of missing teeth was associated with decreased saliva production (relative risk [RR] 0.97; 95% CI 0.94, 0.99), worse hand function (RR 1.52; 95% CI 1.13, 2.02), and the presence of gastroesophageal reflux disease (GERD; RR 1.68 [95% CI 1.14, 2.46]). No clinical or serologic variables were correlated with periodontal disease.
In SSc, diminished interincisal distance is related to overall disease severity. Decreased saliva production is related to concomitant Sjögren’s syndrome antibodies. Tooth loss is associated with poor upper extremity function, GERD, and decreased saliva. The etiology of excess periodontal disease is likely multifactorial and remains unclear.
PMCID: PMC4464822  PMID: 25303223 CAMSID: cams4711
3.  N-Myristoyltransferase Is a Cell Wall Target in Aspergillus fumigatus 
ACS Chemical Biology  2015;10(6):1425-1434.
Treatment of filamentous fungal infections relies on a limited repertoire of antifungal agents. Compounds possessing novel modes of action are urgently required. N-myristoylation is a ubiquitous modification of eukaryotic proteins. The enzyme N-myristoyltransferase (NMT) has been considered a potential therapeutic target in protozoa and yeasts. Here, we show that the filamentous fungal pathogen Aspergillus fumigatus possesses an active NMT enzyme that is essential for survival. Surprisingly, partial repression of the gene revealed downstream effects of N-myristoylation on cell wall morphology. Screening a library of inhibitors led to the discovery of a pyrazole sulphonamide compound that inhibits the enzyme and is fungicidal under partially repressive nmt conditions. Together with a crystallographic complex showing the inhibitor binding in the peptide substrate pocket, we provide evidence of NMT being a potential drug target in A. fumigatus.
PMCID: PMC4477619  PMID: 25706802
4.  The invasive land planarian Platydemus manokwari (Platyhelminthes, Geoplanidae): records from six new localities, including the first in the USA 
PeerJ  2015;3:e1037.
The land planarian Platydemus manokwari de Beauchamp, 1963 or “New Guinea flatworm” is a highly invasive species, mainly in the Pacific area, and recently in Europe (France). We report specimens from six additional countries and territories: New Caledonia (including mainland and two of the Loyalty Islands, Lifou and Maré), Wallis and Futuna Islands, Singapore, Solomon Islands, Puerto Rico, and Florida, USA. We analysed the COI gene (barcoding) in these specimens with two sets of primers and obtained 909 bp long sequences. In addition, specimens collected in Townsville (Australia) were also sequenced. Two haplotypes of the COI sequence, differing by 3.7%, were detected: the “World haplotype” found in France, New Caledonia, French Polynesia, Singapore, Florida and Puerto Rico; and the “Australian haplotype” found in Australia. The only locality with both haplotypes was in the Solomon Islands. The country of origin of Platydemus manokwari is New Guinea, and Australia and the Solomon Islands are the countries closest to New Guinea from which we had specimens. These results suggest that two haplotypes exist in the area of origin of the species, but that only one of the two haplotypes (the “World haplotype”) has, through human agency, been widely dispersed. However, since P. manokwari is now recorded from 22 countries in the world and we have genetic information from only 8 of these, with none from New Guinea, this analysis provides only partial knowledge of the genetic structure of the invasive species. Morphological analysis of specimens from both haplotypes has shown some differences in ratio of the genital structures but did not allow us to interpret the haplotypes as different species. The new reports from Florida and Puerto Rico are firsts for the USA, for the American continent, and the Caribbean. P. manokwari is a known threat for endemic terrestrial molluscs and its presence is a matter of concern. While most of the infected territories reported until now were islands, the newly reported presence of the species in mainland US in Florida should be considered a potential major threat to the whole US and even the Americas.
PMCID: PMC4485254  PMID: 26131377
Invasive species; Alien species; Land planarian; USA; New Caledonia; Solomon Island; Singapore; French Polynesia; Flatworm; Puerto Rico
5.  Are interventions to promote healthy eating equally effective for all? Systematic review of socioeconomic inequalities in impact 
BMC Public Health  2015;15:457.
Interventions to promote healthy eating make a potentially powerful contribution to the primary prevention of non communicable diseases. It is not known whether healthy eating interventions are equally effective among all sections of the population, nor whether they narrow or widen the health gap between rich and poor.
We undertook a systematic review of interventions to promote healthy eating to identify whether impacts differ by socioeconomic position (SEP).
We searched five bibliographic databases using a pre-piloted search strategy. Retrieved articles were screened independently by two reviewers. Healthier diets were defined as the reduced intake of salt, sugar, trans-fats, saturated fat, total fat, or total calories, or increased consumption of fruit, vegetables and wholegrain. Studies were only included if quantitative results were presented by a measure of SEP.
Extracted data were categorised with a modified version of the “4Ps” marketing mix, expanded to 6 “Ps”: “Price, Place, Product, Prescriptive, Promotion, and Person”.
Our search identified 31,887 articles. Following screening, 36 studies were included: 18 “Price” interventions, 6 “Place” interventions, 1 “Product” intervention, zero “Prescriptive” interventions, 4 “Promotion” interventions, and 18 “Person” interventions.
“Price” interventions were most effective in groups with lower SEP, and may therefore appear likely to reduce inequalities. All interventions that combined taxes and subsidies consistently decreased inequalities. Conversely, interventions categorised as “Person” had a greater impact with increasing SEP, and may therefore appear likely to reduce inequalities. All four dietary counselling interventions appear likely to widen inequalities.
We did not find any “Prescriptive” interventions and only one “Product” intervention that presented differential results and had no impact by SEP. More “Place” interventions were identified and none of these interventions were judged as likely to widen inequalities.
Interventions categorised by a “6 Ps” framework show differential effects on healthy eating outcomes by SEP. “Upstream” interventions categorised as “Price” appeared to decrease inequalities, and “downstream” “Person” interventions, especially dietary counselling seemed to increase inequalities.
However the vast majority of studies identified did not explore differential effects by SEP. Interventions aimed at improving population health should be routinely evaluated for differential socioeconomic impact.
Electronic supplementary material
The online version of this article (doi:10.1186/s12889-015-1781-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4423493  PMID: 25934496
Noncommunicable diseases; Socioeconomic inequalities; Healthy eating; Intervention
6.  Identification and structure solution of fragment hits against kinetoplastid N-myristoyltransferase 
N-Myristoyltransferase (NMT) has been shown to be an attractive target for the development of novel therapeutic agents for the treatment of human African trypanosomiasis. A fragment library has been screened using NMR spectroscopy and the binding mode of the hits was confirmed by X-ray crystallography using L. major NMT as a structural surrogate.
Trypanosoma brucei N-myristoyltransferase (TbNMT) is an attractive therapeutic target for the treatment of human African trypanosomiasis. Pyrazole sulfonamide (DDD85646), a potent inhibitor of TbNMT, has been identified in previous studies; however, poor central nervous system exposure restricts its use to the haemolymphatic form (stage 1) of the disease. In order to identify new chemical matter, a fragment screen was carried out by ligand-observed NMR spectroscopy, identifying hits that occupy the DDD85646 binding site. Crystal structures of hits from this assay have been obtained in complex with the closely related NMT from Leishmania major, providing a structural starting point for the evolution of novel chemical matter.
PMCID: PMC4427169  PMID: 25945713
N-myristoyltransferase; Trypanosoma brucei; African trypanosomiasis
7.  Joint modelling of repeated measurements and time-to-event outcomes: flexible model specification and exact likelihood inference 
Random effects or shared parameter models are commonly advocated for the analysis of combined repeated measurement and event history data, including dropout from longitudinal trials. Their use in practical applications has generally been limited by computational cost and complexity, meaning that only simple special cases can be fitted by using readily available software. We propose a new approach that exploits recent distributional results for the extended skew normal family to allow exact likelihood inference for a flexible class of random-effects models. The method uses a discretization of the timescale for the time-to-event outcome, which is often unavoidable in any case when events correspond to dropout. We place no restriction on the times at which repeated measurements are made. An analysis of repeated lung function measurements in a cystic fibrosis cohort is used to illustrate the method.
PMCID: PMC4384944  PMID: 25866468
Cystic fibrosis; Dropout; Joint modelling; Repeated measurements; Skew normal distribution; Survival analysis
8.  Comparing cystic fibrosis outcomes across the pond 
Thorax  2014;70(3):203-204.
PMCID: PMC4345901  PMID: 25538210
Cystic Fibrosis; Paediatric Lung Disaese; Clinical Epidemiology
9.  Specific immunotherapy modifies allergen-specific CD4+ T cell responses in an epitope-dependent manner 
Understanding the mechanisms by which the immune system induces and controls allergic inflammation at the T cell epitope level is critical for the design of new allergy vaccine strategies.
To characterize allergen-specific T cell responses linked with allergy or peripheral tolerance and to determine how CD4+ T cell responses to individual allergen-derived epitopes change over allergen-specific immunotherapy (ASIT).
Timothy grass pollen (TGP) allergy was used as a model for studying grass pollen allergies. The breadth, magnitude, epitope hierarchy and phenotype of the DR04:01-restricted TGP-specific T cell responses in ten grass pollen allergic, five non-atopic and six allergy vaccine-treated individuals was determined using an ex vivo pMHCII-tetramer approach.
CD4+ T cells in allergic individuals are directed to a broad range of TGP epitopes characterized by defined immunodominance hierarchy patterns and with distinct functional profiles that depend on the epitope recognized. Epitopes that are restricted specifically to either TH2 or TH1/TR1 responses were identified. ASIT was associated with preferential deletion of allergen-specific TH2 cells and without significant change in frequency of TH1/TR1 cells.
Preferential allergen-specific TH2-cells deletion after repeated high doses antigen stimulation can be another independent mechanism to restore tolerance to allergen during immunotherapy.
PMCID: PMC3961577  PMID: 24373351
Immunotherapy; allergy; epitope; pollen; T cells; CD4; peptide-MHC class II tetramer; peripheral tolerance; ex vivo
10.  Characterization of saltern based Streptomyces sp. and statistical media optimization for its improved antibacterial activity 
A moderately halotolerant Streptomyces strain, designated JAJ13 was characterized and a culture medium was statistically optimized to improve its antibacterial activity. Based on the phenotypic and molecular characteristics, strain JAJ13 was identified as a moderately halotolerant Streptomyces sp. JAJ13. Novelty of the strain JAJ13 in production of antibacterial compound was assessed by sequence analysis of KSα gene and LC-MS analysis of the active compound. Optimization of the culture medium for antibacterial compound production by the strain JAJ13 was performed with statistical methodology based on experimental designs. Initially, a starch based basal production medium was selected out of eight different production media screened for antibacterial compound production by Streptomyces sp. JAJ13. Plackett-Burman design was employed to screen the influential media components affecting the antibacterial compound production. Subsequently, statistical optimization of selected medium components was performed by employing the response surface methodology (RSM) with Box-Behnken design. The optimum initial level of CuSO4.5H2O, (NH4)2SO4 and K2HPO4 for the highest antibacterial activity was determined to be at 4.45 mg, 1.96 g, and 1.15 g in 1 L of distilled H2O, respectively. PBD and RSM guided design of experiments resulted in a maximum antibacterial activity of 23.37 ± 2.08 mm, which is a 78.8% increase in comparison with that obtained in the unoptimized medium. This study points the success of statistical model in developing an optimized production media for enhanced antibacterial compound production by Streptomyces sp. JAJ13.
PMCID: PMC4301002  PMID: 25653640
Plackett-Burman design; response surface methodology; Box-Behnken design; solar saltern; Streptomyces; antibiotics
11.  Epidemiology of nontuberculous mycobacteria among patients with cystic fibrosis in Scandinavia 
Journal of Cystic Fibrosis  2015;14(1):46-52.
Nontuberculous mycobacteria (NTM) are an emerging threat to cystic fibrosis (CF) patients but their epidemiology is not well described.
In this retrospective observational study we identified all Scandinavian CF patients with a positive NTM culture from airway secretions from 2000 to the end of 2012 and used national CF databases to describe microbiological and clinical characteristics.
During the 13-year period 157 (11%) CF patients were culture positive for NTM at least once. Mycobacterium abscessus complex (MABSC) (45%) and Mycobacterium avium complex (MAC) (32%) were the predominant species with geographical differences in distribution. Younger patients were more prone to MABSC (p < 0.01). Despite treatment, less than one-third of MABSC patients with repeated positive cultures cleared their infection and a quarter had a lung transplant or died.
NTM are significant CF pathogens and are becoming more prevalent in Scandinavia. MABSC and MAC appear to target distinct patient groups. Having multiple positive cultures despite treatment conveys a poor outcome.
PMCID: PMC4298356  PMID: 25178871
Mycobacterium abscessus; Mycobacterium avium; Prevalence; Susceptibility
12.  Characterization of Antibiotic Producing Rare Actinomycete Nonomuraea sp. JAJ18 Derived from an Indian Coastal Solar Saltern 
The Scientific World Journal  2014;2014:456070.
Rare actinomycete genera are accepted as a promising source of novel metabolites having pharmaceutical importance. One such genus of rare actinomycete is Nonomuraea. The present study was aimed at characterizing the antibiotic producing Nonomuraea strain JAJ18 which was previously isolated from coastal solar saltern. Strain JAJ18 was recognized as a member of genus Nonomuraea based on its almost complete 16S rRNA gene sequence and phenotypic characteristics. The strain JAJ18 was found to be closely related to Nonomuraea maheshkhaliensis 16-5-14T (98.90%), Nonomuraea candida HMC10T (98.58%), and Nonomuraea jabiensis A4036T (98.43%). From cell-free culture broth of strain JAJ18, an antibiotic was extracted and purified by silica column chromatography. The obtained antibiotic was found to be active against a range of Gram-positive and Gram-negative bacteria including drug-resistant Staphylococcus, with minimal inhibitory concentration (MIC) ranging from 0.5 to 16.0 µg mL−1. The structural characteristics of antibiotic were determined by FTIR and NMR spectroscopy. The antibiotic was identified to be an aliphatic rich compound with significant dissimilarity to known antibiotics reported from members of the genus, Nonomuraea. As the trends to discover novel metabolites from Nonomuraea are vibrant, further studies are needed to understand the structural and biotechnological significance of antibiotic compound produced by Nonomuraea sp. JAJ18.
PMCID: PMC4281464  PMID: 25587565
13.  Smorgasbord or symphony? Assessing public health nutrition policies across 30 European countries using a novel framework 
BMC Public Health  2014;14:1195.
Countries across Europe have introduced a wide variety of policies to improve nutrition. However, the sheer diversity of interventions represents a potentially bewildering smorgasbord.
We aimed to map existing public health nutrition policies, and examine their perceived effectiveness, in order to inform future evidence-based diet strategies.
We created a public health nutrition policy database for 30 European countries . National nutrition policies were classified and assigned using the marketing "4Ps" approach Product (reformulation, elimination, new healthier products); Price (taxes, subsidies); Promotion (advertising, food labelling, health education) and Place (schools, workplaces, etc.).
We interviewed 71 senior policy-makers, public health nutrition policy experts and academics from 14 of the 30 countries, eliciting their views on diverse current and possible nutrition strategies.
Product Voluntary reformulation of foods is widespread but has variable and often modest impact. Twelve countries regulate maximum salt content in specific foods.
Denmark, Austria, Iceland and Switzerland have effective trans fats bans.
Price EU School Fruit Scheme subsidies are almost universal, but with variable implementation.
Taxes are uncommon. However, Finland, France, Hungary and Latvia have implemented ‘sugar taxes’ on sugary foods and sugar-sweetened beverages. Finland, Hungary and Portugal also tax salty products.
Promotion Dialogue, recommendations, nutrition guidelines, labelling, information and education campaigns are widespread. Restrictions on marketing to children are widespread but mostly voluntary.
Place Interventions reducing the availability of unhealthy foods were most commonly found in schools and workplace canteens.
Interviewees generally considered mandatory reformulation more effective than voluntary, and regulation and fiscal interventions much more effective than information strategies, but also politically more challenging.
Public health nutrition policies in Europe appear diverse, dynamic, complex and bewildering. The "4Ps" framework potentially offers a structured and comprehensive categorisation.
Encouragingly, the majority of European countries are engaged in activities intended to increase consumption of healthy food and decrease the intake of "junk" food and sugary drinks. Leading countries include Finland, Norway, Iceland, Denmark, Hungary, Portugal and perhaps the UK. However, all countries fall short of optimal activities. More needs to be done across Europe to implement the most potentially powerful fiscal and regulatory nutrition policies.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2458-14-1195) contains supplementary material, which is available to authorized users.
PMCID: PMC4251675  PMID: 25413832
Public health nutrition; Public health policy; Europe; Food policy mapping; Qualitative
14.  Fathering of Dizygotic Twins and Risk of Prostate Cancer: Nationwide, Population-Based Case-Control Study 
PLoS ONE  2014;9(10):e110506.
An association between male fertility and risk of prostate cancer has been suggested, possibly through lower androgen levels in subfertile men. We evaluated male fertility in relation to risk of prostate cancer by assessing the frequency of fathering of dizygotic twins, a marker of high fertility, among cases of prostate cancer and controls.
We performed a case-control study in Prostate Cancer data Base Sweden (PCBaSe), a nationwide, population-based cohort. PCBaSe was linked to the Swedish twin register for information on zygosity for same-sex twins and to other nationwide health care registers and demographic databases for information on socioeconomic factors, comorbidity, and tumor characteristics for 96 301 prostate cancer cases and 378 583 matched controls. To account for the influence of in vitro fertilization on dizygotic twinning, analyses were restricted to men who had fathered children before 1991, when in vitro fertilization was still uncommon in Sweden.
1 112 cases and 4 538 controls had fathered dizygotic twins. Men with dizygotic twins had no increased risk of prostate cancer compared to fathers of singletons; neither for total prostate cancer odds ratio (OR) 0.95(95% CI 0.89–1.02), nor for any risk category, OR 0.97 (95% CI 0.84–1.12) for low-risk disease, and OR 1.04 (95% CI 0.90–1.22) for metastatic disease.
The lack of association between fathering of dizygotic twins and prostate cancer risk give no support for an association between male fertility and prostate cancer risk.
PMCID: PMC4206421  PMID: 25337702
15.  Comprehensive geriatric assessment for older adults admitted to hospital 
Comprehensive geriatric assessment (CGA) is a multidimensional, interdisciplinary diagnostic process to determine the medical, psychological and functional capabilities of a frail elderly person in order to develop a co-ordinated and integrated plan for treatment and long-term follow up.
We sought to evaluate the effectiveness of CGA in hospital for older adults admitted as an emergency.
Search methods
We searched the Cochrane Effective Practice and Organisation of Care (EPOC) Group Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), the Database of Abstracts of Reviews of Effects (DARE), MEDLINE, EMBASE, CINAHL and AARP Ageline, and handsearched high-yield journals.
Selection criteria
We searched for randomised controlled trials comparing CGA (whether by mobile teams or in designated wards) to usual care.
Data collection and analysis
Two review authors initially assessed eligibility and trial quality and extracted published data.
Main results
Twenty-two trials evaluating 10,315 participants in six countries were identified. Patients in receipt of CGA were more likely to be alive and in their own homes at up to six months (OR 1.25, 95% CI 1.11 to 1.42, P = 0.0002) and at the end of scheduled follow up (median 12 months) (OR 1.16, 95% CI 1.05 to 1.28, P = 0.003) when compared to general medical care. In addition, patients were less likely to be institutionalised (OR 0.79, 95% CI 0.69 to 0.88, P < 0.0001). They were less likely to suffer death or deterioration (OR 0.76, 95% CI 0.64 to 0.90, P = 0.001), and were more likely to experience improved cognition in the CGA group (OR 1.11, 95% CI 0.20 to 2.01, P = 0.02). Subgroup interaction in the primary outcomes suggests that the effects of CGA are primarily the result of CGA wards.
Authors’ conclusions
Comprehensive geriatric assessment increases a patient’s likelihood of being alive and in their own home at up to 12 months.
PMCID: PMC4164377  PMID: 21735403
*Frail Elderly; *Hospitalization; *Outcome and Process Assessment (Health Care); Comprehensive Health Care [*methods]; Emergencies; Geriatric Assessment [*methods]; Independent Living; Mortality; Aged; Humans
16.  Successive Nonstatistical and Statistical Approaches for the Improved Antibiotic Activity of Rare Actinomycete Nonomuraea sp. JAJ18 
BioMed Research International  2014;2014:906097.
The selection and optimization of nutritional constituents as well as their levels for the improved production of antibiotic by Nonomuraea sp. JAJ18 were carried out using combination of both nonstatistical one-factor-at-a-time (OFAT) method and statistical response surface methodology (RSM). Using OFAT method, starch and (NH4)2SO4 were identified as suitable carbon and nitrogen sources, respectively. Subsequently, starch, NaCl, and MgSO4·7H2O were recognized as the most significant media components with confidence level of above 95% using the Plackett-Burman design. The levels of the three media components were further optimized using RSM employed with Box-Behnken design. Accordingly, a second-order polynomial regression model was fitted into the experimental data. By analyzing the response surface plots as well as using numerical optimization method, the optimal levels for starch, NaCl, and MgSO4·7H2O were determined as 15.6 g/L, 0.8 g/L, and 1.98 g/L, respectively. With the optimized medium, 15.5% increase was observed in antibiotic activity of JAJ18. Results further support the use of RSM for media optimization. To the best of our knowledge, this is the first report of statistical media optimization for antibiotic production in rare actinomycete Nonomuraea species, which will be useful for the development of Nonomuraea cultivation process for efficient antibiotic production on a large scale.
PMCID: PMC4168032  PMID: 25276828
17.  Prevalence of Anti-Peptidylarginine Deiminase Type 4 Antibodies in Rheumatoid Arthritis and Unaffected First-Degree Relatives in Indigenous North American Populations 
The Journal of rheumatology  2013;40(9):1523-1528.
The objective of this study was to determine whether anti-peptidylarginine deiminase type 4 (PAD4) antibodies were present in first-degree relatives of rheumatoid arthritis (RA) patients in two indigenous North American populations with high prevalence of RA.
Participants were recruited from two indigenous populations in Canada and the United States, including RA patients (probands), their unaffected first-degree relatives, and healthy unrelated controls. Sera were tested for the presence of anti-PAD4 antibodies, anti-cyclic citrullinated peptide (CCP) antibodies, and rheumatoid factor (RF). HLA-DRB1 subtyping was performed and participants were classified according to number of shared epitope alleles present.
Antibodies to PAD4 were detected in 24 of 82 (29.3%) probands; 2 of 147 (1.4%) relatives; and no controls (p <0.0001). Anti-CCP was present in 39/144 (27.1%) of the relatives, and there was no overlap between positivity for anti-CCP and PAD4 in the relatives. In RA patients, anti-PAD4 antibodies were associated with disease duration (p=0.0082) and anti-CCP antibodies (p=0.008), but not smoking or shared epitope alleles.
Despite a significant prevalence of anti-CCP in first-degree relatives, anti-PAD4 antibodies were almost exclusively found in established RA. The prevalence of anti-PAD4 antibodies in RA is similar to the prevalence described in other populations and these autoantibodies are associated with disease duration and anti-CCP in RA.
PMCID: PMC3969032  PMID: 23908443
Arthritis; Rheumatoid; Autoantibodies; peptidylarginine deiminase
18.  Impact of the 2008 Economic and Financial Crisis on Child Health: A Systematic Review 
The aim of this study was to provide an overview of studies in which the impact of the 2008 economic crisis on child health was reported. Structured searches of PubMed, and ISI Web of Knowledge, were conducted. Quantitative and qualitative studies reporting health outcomes on children, published since 2007 and related to the 2008 economic crisis were included. Two reviewers independently assessed studies for inclusion. Data were synthesised as a narrative review. Five hundred and six titles and abstracts were reviewed, from which 22 studies were included. The risk of bias for quantitative studies was mixed while qualitative studies showed low risk of bias. An excess of 28,000–50,000 infant deaths in 2009 was estimated in sub-Saharan African countries, and increased infant mortality in Greece was reported. Increased price of foods was related to worsening nutrition habits in disadvantaged families worldwide. An increase in violence against children was reported in the U.S., and inequalities in health-related quality of life appeared in some countries. Most studies suggest that the economic crisis has harmed children’s health, and disproportionately affected the most vulnerable groups. There is an urgent need for further studies to monitor the child health effects of the global recession and to inform appropriate public policy responses.
PMCID: PMC4078594  PMID: 25019121
adolescent; child health; economic and financial crisis; inequalities
19.  Implementation of Ultrasonic Sensing for High Resolution Measurement of Binary Gas Mixture Fractions 
Sensors (Basel, Switzerland)  2014;14(6):11260-11276.
We describe an ultrasonic instrument for continuous real-time analysis of the fractional mixture of a binary gas system. The instrument is particularly well suited to measurement of leaks of a high molecular weight gas into a system that is nominally composed of a single gas. Sensitivity < 5 × 10−5 is demonstrated to leaks of octaflouropropane (C3F8) coolant into nitrogen during a long duration (18 month) continuous study. The sensitivity of the described measurement system is shown to depend on the difference in molecular masses of the two gases in the mixture. The impact of temperature and pressure variances on the accuracy of the measurement is analysed. Practical considerations for the implementation and deployment of long term, in situ ultrasonic leak detection systems are also described. Although development of the described systems was motivated by the requirements of an evaporative fluorocarbon cooling system, the instrument is applicable to the detection of leaks of many other gases and to processes requiring continuous knowledge of particular binary gas mixture fractions.
PMCID: PMC4118389  PMID: 24961217
ultrasonic; binary gas analysis; leak detection
20.  Unexplored hypersaline habitats are sources of novel actinomycetes 
PMCID: PMC4034035  PMID: 24904555
actinomycetes; hypersaline environments; antibiotic; Streptomyces; drug discovery
21.  Predicting outcomes after blunt chest wall trauma: development and external validation of a new prognostic model 
Critical Care  2014;18(3):R98.
Blunt chest wall trauma accounts for over 15% of all trauma admissions to Emergency Departments worldwide. Reported mortality rates vary between 4 and 60%. Management of this patient group is challenging as a result of the delayed on-set of complications. The aim of this study was to develop and validate a prognostic model that can be used to assist in the management of blunt chest wall trauma.
There were two distinct phases to the overall study; the development and the validation phases. In the first study phase, the prognostic model was developed through the retrospective analysis of all blunt chest wall trauma patients (n = 274) presenting to the Emergency Department of a regional trauma centre in Wales (2009 to 2011). Multivariable logistic regression was used to develop the model and identify the significant predictors for the development of complications. The model’s accuracy and predictive capabilities were assessed. In the second study phase, external validation of the model was completed in a multi-centre prospective study (n = 237) in 2012. The model’s accuracy and predictive capabilities were re-assessed for the validation sample. A risk score was developed for use in the clinical setting.
Significant predictors of the development of complications were age, number of rib fractures, chronic lung disease, use of pre-injury anticoagulants and oxygen saturation levels. The final model demonstrated an excellent c-index of 0.96 (95% confidence intervals: 0.93 to 0.98).
In our two phase study, we have developed and validated a prognostic model that can be used to assist in the management of blunt chest wall trauma patients. The final risk score provides the clinician with the probability of the development of complications for each individual patient.
PMCID: PMC4095687  PMID: 24887537
22.  Exo70E2 is essential for exocyst subunit recruitment and EXPO formation in both plants and animals 
Molecular Biology of the Cell  2014;25(3):412-426.
Exocyst-positive organelle (EXPO) is a double-membrane organelle mediating unconventional protein secretion in plants. The Arabidopsis exocyst subunit AtExo70E2 is essential for the recruitment of other exocyst subunits to EXPO and plays a key role in EXPO formation in both plant and animal cells.
In contrast to a single copy of Exo70 in yeast and mammals, the Arabidopsis genome contains 23 paralogues of Exo70 (AtExo70). Using AtExo70E2 and its GFP fusion as probes, we recently identified a novel double-membrane organelle termed exocyst-positive organelle (EXPO) that mediates an unconventional protein secretion in plant cells. Here we further demonstrate that AtExo70E2 is essential for exocyst subunit recruitment and for EXPO formation in both plants and animals. By performing transient expression in Arabidopsis protoplasts, we established that a number of exocyst subunits (especially the members of the Sec family) are unable to be recruited to EXPO in the absence of AtExo70E2. The paralogue AtExo70A1 is unable to substitute for AtExo70E2 in this regard. Fluorescence resonance energy transfer assay and bimolecular fluorescence complementation analyses confirm the interaction between AtExo70E2 and Sec6 and Sec10. AtExo70E2, but not its yeast counterpart, is also capable of inducing EXPO formation in an animal cell line (HEK293A cells). Electron microscopy confirms the presence of double-membraned, EXPO-like structures in HEK293A cells expressing AtExo70E2. Inversely, neither human nor yeast Exo70 homologues cause the formation of EXPO in Arabidopsis protoplasts. These results point to a specific and crucial role for AtExo70E2 in EXPO formation.
PMCID: PMC3907280  PMID: 24307681
23.  The histone chaperones Vps75 and Nap1 form ring-like, tetrameric structures in solution 
Nucleic Acids Research  2014;42(9):6038-6051.
NAP-1 fold histone chaperones play an important role in escorting histones to and from sites of nucleosome assembly and disassembly. The two NAP-1 fold histone chaperones in budding yeast, Vps75 and Nap1, have previously been crystalized in a characteristic homodimeric conformation. In this study, a combination of small angle X-ray scattering, multi angle light scattering and pulsed electron–electron double resonance approaches were used to show that both Vps75 and Nap1 adopt ring-shaped tetrameric conformations in solution. This suggests that the formation of homotetramers is a common feature of NAP-1 fold histone chaperones. The tetramerisation of NAP-1 fold histone chaperones may act to shield acidic surfaces in the absence of histone cargo thus providing a ‘self-chaperoning’ type mechanism.
PMCID: PMC4027167  PMID: 24688059
24.  AZD3514: a small molecule that modulates androgen receptor signaling and function in vitro and in vivo 
Molecular cancer therapeutics  2013;12(9):1715-1727.
Continued androgen receptor (AR) expression and signaling is a key driver in castration resistant prostate cancer (CRPC) after classical androgen ablation therapies have failed, and therefore remains a target for the treatment of progressive disease. Here we describe the biological characterization of AZD3514, an orally bioavailable drug that inhibits androgen-dependent and–independent AR signaling. AZD3514 modulates AR signaling through two distinct mechanisms, an inhibition of ligand driven nuclear translocation of AR and a down-regulation of receptor levels, both of which were observed in vitro and in vivo. AZD3514 inhibited testosterone-driven seminal vesicle development in juvenile male rats and the growth of androgen-dependent Dunning R3327H prostate tumors in adult rats. Furthermore, this class of compound demonstrated anti-tumor activity in the HID28 mouse model of CRPC in vivo. AZD3514 is currently in Phase I clinical evaluation.
PMCID: PMC3769207  PMID: 23861347
25.  Phosphorylation of Sli15 by Ipl1 Is Important for Proper CPC Localization and Chromosome Stability in Saccharomyces cerevisiae 
PLoS ONE  2014;9(2):e89399.
The chromosomal passenger complex (CPC) is a key regulator of eukaryotic cell division, consisting of the protein kinase Aurora B/Ipl1 in association with its activator (INCENP/Sli15) and two additional proteins (Survivin/Bir1 and Borealin/Nbl1). Here we have identified multiple sites of CPC autophosphorylation on yeast Sli15 that are located within its central microtubule-binding domain and examined the functional significance of their phosphorylation by Ipl1 through mutation of these sites, either to non-phosphorylatable alanine (sli15-20A) or to acidic residues to mimic constitutive phosphorylation (sli15-20D). Both mutant sli15 alleles confer chromosome instability, but this is mediated neither by changes in the capacity of Sli15 to activate Ipl1 kinase nor by decreased efficiency of chromosome biorientation, a key process in cell division that requires CPC function. Instead, we find that mimicking constitutive phosphorylation of Sli15 on the Ipl1 phosphorylation sites causes delocalization of the CPC in metaphase, whereas blocking phosphorylation of Sli15 on the Ipl1 sites drives excessive localization of Sli15 to the mitotic spindle in pre-anaphase cells. Consistent with these results, direct interaction of Sli15 with microtubules in vitro is greatly reduced either following phosphorylation by Ipl1 or when constitutive phosphorylation at the Ipl1-dependent phosphorylation sites is mimicked by aspartate or glutamate substitutions. Furthermore, we find that mimicking Ipl1 phosphorylation of Sli15 interferes with the ‘tension checkpoint’ – the CPC-dependent mechanism through which cells activate the spindle assembly checkpoint to delay anaphase in the absence of tension on kinetochore-microtubule attachments. Ipl1-dependent phosphorylation of Sli15 therefore inhibits its association with microtubules both in vivo and in vitro and may negatively regulate the tension checkpoint mechanism.
PMCID: PMC3928436  PMID: 24558497

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