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1.  Photosensitizing Agents and the Risk of Non-Melanoma Skin Cancer: A Population-Based Case-Control Study 
It is well-known that ultraviolet (UV) light exposure and a sun sensitive phenotype are risk factors for the development of non-melanoma skin cancer (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). In this New Hampshire population-based case-control study, we collected data from 5,072 individuals, including histologically-confirmed cases of BCC and SCC, and controls via a personal interview to investigate possible associations between photosensitizing medication use and NMSC. After adjustment for potentially confounding factors (e.g. lifetime number of painful sunburns), we found a modest increase in risk of SCC (OR = 1.2, 95% CI = 1.0–1.4) and BCC (OR = 1.2, 95% CI = 0.9–1.5), in particular early-onset BCC, (≤ 50 years of age) (OR = 1.5, 95% CI = 1.1–2.1) associated with photosensitizing medication use. For SCC the association was strongest amongst those with tendency to sunburn rather than tan. We also specifically found associations with BCC, and especially early-onset BCC, and photosensitizing antimicrobials. In conclusion, certain commonly prescribed photosensitizing medications may enhance the risk of developing SCC, especially in individuals with a sun sensitive phenotype, and may increase the risk of developing BCC and incidence of BCC at a younger age.
doi:10.1038/jid.2013.33
PMCID: PMC3655101  PMID: 23344461
2.  A Proteomic Survey of Nonribosomal Peptide and Polyketide Biosynthesis in Actinobacteria 
Journal of Proteome Research  2011;11(1):85-94.
Actinobacteria such as streptomycetes are renowned for their ability to produce bioactive natural products including nonribosomal peptides (NRPs) and polyketides (PKs). The advent of genome sequencing has revealed an even larger genetic repertoire for secondary metabolism with most of the small molecule products of these gene clusters still unknown. Here, we employed a “protein-first” method called PrISM (Proteomic Investigation of Secondary Metabolism) to screen 26 unsequenced actinomycetes using mass spectrometry-based proteomics for the targeted detection of expressed nonribosomal peptide synthetases or polyketide synthases. Improvements to the original PrISM screening approach (Nature Biotechnology, 2009, 27, 951 – 956), e.g. improved de novo peptide sequencing, have enabled the discovery of ten NRPS/PKS gene clusters from six strains. Taking advantage of the concurrence of biosynthetic enzymes and the secondary metabolites they generate, two natural products were associated with their previously ‘orphan’ gene clusters. This work has demonstrated the feasibility of a proteomics-based strategy for use in screening for NRP/PK production in actinomycetes (often >8 Mbp, high GC genomes) versus the bacilli (2–4 Mbp genomes) used previously.
doi:10.1021/pr2009115
PMCID: PMC3253196  PMID: 21978092
Nonribosomal peptide; polyketide; natural product biosynthesis; Actinobacteria; de novo sequencing; Fourier-Transform Mass Spectrometry
3.  Early Fluid Resuscitation Reduces Morbidity Among Patients with Acute Pancreatitis 
Background & Aims
Early fluid resuscitation is recommended to reduce morbidity and mortality among patients with acute pancreatitis (AP), although the impact of this intervention has not been quantified. We investigated the association between early fluid resuscitation and outcome of patients admitted to the hospital with AP.
Methods
Non-transfer patients admitted to our center with AP, from 1985 to 2009, were identified retrospectively. Patients were stratified into groups based on early (n=340) or late resuscitation (n=94). Early resuscitation was defined as receiving ≥ 1/3 of the total 72 h fluid volume within 24 hours of presentation, whereas late resuscitation was defined as receiving ≤ 1/3 of the total 72 h fluid volume within 24 hours of presentation. The primary outcomes were frequency of the systemic inflammatory response syndrome (SIRS), organ failure, and death.
Results
Early resuscitation was associated with decreased SIRS, compared with late resuscitation, at 24 h (15% vs. 32% P=0.001), 48 h (14% vs. 33%, P =0.001), and 72 h (10% vs. 23%, P =0.01), as well as reduced organ failure at 72 h (5% vs. 10%, P <0.05), a lower rate of admission to the intensive-care unit (6% vs. 17%, P< 0.001), and a reduced length of hospital stay (8 vs. 11 days, P=0.01). Subgroup analysis demonstrated that these benefits were more pronounced in patients with interstitial, rather than severe, pancreatitis at admission.
Conclusions
In patients with AP, early fluid resuscitation was associated with reduced incidence of SIRS and organ failure at 72 hours. These effects were most pronounced in patients admitted with interstitial, rather than severe, disease.
doi:10.1016/j.cgh.2011.03.032
PMCID: PMC3143229  PMID: 21554987
pancreas; inflammation; treatment; efficacy
4.  Generation of Spatial Patterns through Cell Polarity Switching 
Science (New York, N.y.)  2011;333(6048):1436-1440.
The mechanisms that generate dynamic spatial patterns within proliferating tissues are poorly understood, largely because of difficulties in unravelling interactions between cell specification, polarity, asymmetric division, rearrangements and growth. Here we address this problem for stomatal spacing in plants, which offer the simplifying advantage that cells do not rearrange. By tracking lineages and gene activities over extended periods, we show that limited stem cell behavior of stomatal precursors depends on maintenance of the SPEECHLESS (SPCH) transcription factor in single daughter cells. Modelling shows how this property can lead to observed stereotypical stomata lineages through a post-mitotic polarity switching mechanism. The model predicts the location of a polarity determinant BASL over multiple divisions, which we validate experimentally. Our results highlight the dynamic two-way interactions between stem cells and their neighborhood during developmental patterning.
doi:10.1126/science.1202185
PMCID: PMC3383840  PMID: 21903812
5.  Proteomics-Based Discovery of Koranimine, a Cyclic-Imine Natural Product 
Nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) are large enzymes responsible for the biosynthesis of medically and ecologically important secondary metabolites. In a previous report we described a proteomics approach to screen for expressed NRPSs or PKSs from bacteria with or without sequenced genomes. Here we use this proteome mining approach to discover a novel natural product arising from rare adenylation (A) and reductase (Red) domains in its biosynthetic machinery. We also clone the entire gene cluster and elucidate the biosynthesis of the new compound produced by an unsequenced Bacillus sp. isolated from soil collected in Koran, Louisiana.
doi:10.1021/ja2015795
PMCID: PMC3103991  PMID: 21520944
Nonribosomal peptide synthetase; natural products; proteomics; Fourier-transform mass spectrometry
6.  The Biostructural Features of Additional Jasplakinolide (Jaspamide) Analogues† 
Journal of natural products  2011;74(3):341-351.
The cyclodepsipeptide jasplakinolide (1) (a.k.a. jaspamide), isolated previously from the marine sponge Jaspis splendens, is a unique cytotoxin and molecular probe that operates through stabilization of filamentous actin (F-actin). We have recently disclosed that two analogues of 1, jasplakinolides B (3) and E, were referred to the National Cancer Institute's (NCI) Biological Evaluation Committee and the objective of this study was to re-investigate a Fijian collection of J. splendens in an effort to find jasplakinolide congeners with similar biological properties. The current efforts have afforded six known jasplakinolide analogues (4 - 7, 9 - 10), two structures requiring revision (8 and 14) and four new congeners of 1 (11 - 13, 15) including open chain derivatives and structures with modified β-tyrosine residues. Compounds were evaluated for biological activity in the NCI's 60 cell line screen and in a microfilament disruption assay in both HCT-116 and HeLa cells. These two phenotypic screens provide evidence that each cytotoxic analogue, including jasplakinolide B (3), operates by modification of microfilaments. The new structure jasplakinolide V (13) has also been selected for study by the NCI's Biological Evaluation Committee. In addition, the results of a clonogenic dose response study on jasplakinolide are presented.
doi:10.1021/np100721g
PMCID: PMC3070360  PMID: 21241058
7.  Surveys of Non-Ribosomal Peptide and Polyketide Assembly Lines in Fungi and Prospects for Their Analysis in vitro and in vivo 
With many bioactive non-ribosomal peptides and polyketides produced in fungi, studies of their biosyntheses are an active area of research. Practical limitations of working with mega-dalton synthetases including cell lysis and protein extraction to recombinant gene and pathway expression has slowed understanding of many secondary metabolic processes relative to bacterial counterparts. Recent advances in accessing fungal biosynthetic machinery are beginning to change this. Here we describe the successes of some studies of thiotemplate biosynthesis in fungal systems, along with very recent advances in chemical tagging and mass spectrometric strategies to selectively study biosynthetic conveyer belts in isolation, and within a few years, in endogenous fungal proteomes.
doi:10.1016/j.fgb.2010.06.012
PMCID: PMC2965788  PMID: 20601041
fungal metabolism; nonribosomal peptide synthetases; polyketide synthases; thiotemplate biosynthesis; secondary metabolism; proteomics; mass spectrometry; Fourier-Transform mass spectrometry
8.  New Structures and Bioactivity Properties of Jasplakinolide (Jaspamide) Analogues from Marine Sponges 
Journal of medicinal chemistry  2010;53(4):1651-1661.
The goal of this study was to isolate and study additional jasplakinolide analogues from two taxonomically distinct marine sponges including two Auletta spp. and one Jaspis splendens. This led to the isolation of jasplakinolide (1) and eleven jasplakinolide analogues (3 – 13) including seven new analogues (6 – 10, 12, and 13). Structure elucidation of the new compounds was based on a combination of 1D and 2D NMR analysis, optical rotation, circular dichroism, and preparation of Mosher’s esters. Five of the new compounds are oxidized tryptophan derivatives of 1, including a unique quinazoline derivative (9). Compounds 1, 3, 5 – 8, and 11 were evaluated in the NCI 60 cell line screen and all compounds were tested in a microfilament disruption assay. Jasplakinolide B (11) exhibited potent cytotoxicity (GI50 < 1 nM vs. human colorectal adenocarcinoma (HCT-116) cells) but did not exhibit microfilament-disrupting activity at 80 nM.
doi:10.1021/jm9013554
PMCID: PMC2848536  PMID: 20121114
9.  Using Enzyme Assays to Evaluate the Structure and Bioactivity of Sponge-Derived Meroterpenes 
Journal of natural products  2009;72(10):1857-1863.
Enzyme screening of crude sponge extracts prioritized a 2005 Papua New Guinea collection of Hyrtios sp. for further study. The MeOH extract contained puupehenone and four puupehenone analogs (1, 2, 3, 5, and 7) along with a new diastereomer, 20-epi-hydroxyhaterumadienone (4) and a new analog 15-oxo-puupehenoic acid (6). The drimane terpene core of 4 and 6 was rapidly dereplicated, and modified Mosher’s method identified 4 while 1D and 2D NMR techniques were used to solve 6. These compounds plus noteworthy repository natural products and standards were tested against three lipoxygenase isozymes, human 5-, 12- and 15-lipoxygenases. Significant potency and selectivity profiles were exhibited in the human 5-lipoxygenase assay by puupehenone (1) and jaspaquinol (9) and structural factors responsible for activity identified.
doi:10.1021/np900465e
PMCID: PMC2996101  PMID: 19848434
10.  The Proteomes of Human Parotid and Submandibular/Sublingual Gland Salivas Collected as the Ductal Secretions 
Journal of proteome research  2008;7(5):1994-2006.
Saliva is a body fluid with important functions in oral and general health. A consortium of three research groups catalogued the proteins in human saliva collected as the ductal secretions: 1166 identifications—914 in parotid and 917 in submandibular/sublingual saliva—were made. The results showed that a high proportion of proteins that are found in plasma and/or tears are also present in saliva along with unique components. The proteins identified are involved in numerous molecular processes ranging from structural functions to enzymatic/catalytic activities. As expected, the majority mapped to the extracellular and secretory compartments. An immunoblot approach was used to validate the presence in saliva of a subset of the proteins identified by mass spectrometric approaches. These experiments focused on novel constituents and proteins for which the peptide evidence was relatively weak. Ultimately, information derived from the work reported here and related published studies can be used to translate blood-based clinical laboratory tests into a format that utilizes saliva. Additionally, a catalogue of the salivary proteome of healthy individuals allows future analyses of salivary samples from individuals with oral and systemic diseases, with the goal of identifying biomarkers with diagnostic and/or prognostic value for these conditions; another possibility is the discovery of therapeutic targets.
doi:10.1021/pr700764j
PMCID: PMC2839126  PMID: 18361515
Human saliva; parotid; submandibular; sublingual; ductal secretion; proteomics; mass spectrometry
11.  The College of Emergency Medicine curriculum: is the specialty‐specific knowledge section fit for purpose? 
Emergency Medicine Journal : EMJ  2007;24(3):194-197.
Objective
To determine whether the knowledge specified in the specialty‐specific section of the College of Emergency Medicine curriculum covered the diagnoses presenting to a UK teaching hospital emergency department.
Method
An audit of 1000 sets of notes was undertaken, the diagnosis abstracted and mapped to the curriculum.
Results
1076 diagnoses were derived and all were covered by the curriculum. The three most common diagnostic categories were musculoskeletal, wound management and cardiology.
Conclusion
The curriculum covered all the diagnoses in this sample. Knowing the frequency of a diagnosis could be used to inform training and assessment.
doi:10.1136/emj.2006.040410
PMCID: PMC2660027  PMID: 17351225
12.  Revisiting the Sponge Sources, Stereostructure, and Biological Activity of Cyclocinamide A 
Journal of natural products  2008;71(8):1475-1478.
The dramatic biogeographical variations in the secondary metabolites from Psammocinia aff. bulbosa have complicated our efforts to re-isolate the two most cytotoxic of its metabolites, (+)-psymberin and (+)-cyclocinamide A. Reported now are the results of a new study that demonstrates our ability to repeatedly isolate these two compounds through targeted collection efforts. Additional study of the new sample of (+)-cyclocinamide A has enabled finalizing its biological activity and absolute stereochemistry as 4S, 7S, 11S, 14S.
doi:10.1021/np800230d
PMCID: PMC2772108  PMID: 18590311
13.  Building research capacity for evidence-informed tobacco control in Canada: a case description 
Tobacco Induced Diseases  2009;5(1):12.
Tobacco use remains the leading cause of death and disability in Canada. Insufficient research capacity can inhibit evidence-informed decision making for tobacco control. This paper outlines a Canadian project to build research capacity, defined as a community's ability to produce research that adequately informs practice, policy, and future research in a timely, practical manner. A key component is that individuals and teams within the community must mutually engage around common, collectively negotiated goals to address specific practices, policies or programs of research. An organizing framework, a set of activities to build strategic recruitment, productivity tools, and procedures for enhancing social capital are described. Actions are intended to facilitate better alignment between research and the priorities of policy developers and service providers, enhance the external validity of the work performed, and reduce the time required to inform policy and practice.
doi:10.1186/1617-9625-5-12
PMCID: PMC2746799  PMID: 19664224
14.  Low grade inflammation, as evidenced by basal high sensitivity CRP, is not correlated to outcome measures in IVF 
Purpose
To assess the relationship between low-grade inflammation, measured as basal high sensitivity (hs)-CRP, and IVF outcome.
Methods
We recruited a total of 220 women undergoing infertility work up prior to IVF. Patients were selected for a BMI < 30 kg/m2 with an upper age limit of 40 years. Serum hs-CRP levels were measured on day 3 of a spontaneous menstrual cycle preceding ovarian stimulation. A sensitive two-site ELISA was used for analysis. Dose of gonadotrophins required, follicles days 8 and 10, number of oocytes collected, number of oocytes fertilised and pregnancy outcome were recorded.
Results
Median hs-CRP was 1.08 mg/L (0.43–3.00 mg/L). The hs-CRP was significantly related to BMI (r = 0.386, P < .001) but not to age and smoking habit. There were no significant relationships between basal hs-CRP and any of the measured IVF outcomes.
Conclusions
These findings demonstrate that serum hs-CRP concentration is not a predictive marker of cycle or pregnancy outcome in women undergoing IVF treatment.
doi:10.1007/s10815-008-9253-y
PMCID: PMC2582128  PMID: 18810632
Controlled ovarian hyperstimulation; hs-CRP; Inflammation; IVF; Pregnancy rate
15.  Is satisfaction a direct predictor of nursing turnover? Modelling the relationship between satisfaction, expressed intention and behaviour in a longitudinal cohort study 
Background
The theory of planned behaviour states that attitudinal variables (e.g. job satisfaction) only have an indirect effect on retention whereas intentions have a direct effect. This study uses secondary data from a longitudinal cohort of newly qualified nurses to test for the direct and indirect effects of job satisfaction (client care, staffing, development, relationships, education, work-life interface, resources, pay) and intentions to nurse on working as a nurse during the 3 years after qualification.
Methods
A national sample (England) of newly qualified (1997/98) nurses (n = 3669) were surveyed at 6 months, 18 months and 3 years. ANOVA and MANOVA were used for comparison of mean job satisfaction scores between groups; intentions to nurse (very likely, likely vs. unlikely, very unlikely and unable to say at this stage); working (or not working as a nurse) at each time-point. Indirect and direct effects were tested using structural equation and logistic regression models.
Results
Intentions expressed at 6 months to nurse at 18 months were associated with higher scores on pay and relationships, and intentions at 3 years were associated with higher scores on care, development, relationships, work-life interface, resources, pay respectively. Intentions expressed at 18 months to nurse at 3 years were associated with higher scores on development, relationships, education and work-life interface. Associations with actual nursing were fewer. Those working as a nurse had higher satisfaction scores for development (18 months) and relationships (3 years). Regression models found significant associations between the pay and staffing factors and intentions expressed at 6 months to nurse at 18 months, and between pay and intentions to nurse at 3 years. Many of the associations between intentions and working as a nurse were significant. Development was the only job satisfaction factor significantly associated with working as a nurse and just at 18 months.
Conclusion
Results partially support the theory of planned behaviour. Intentions expressed by nurses are stronger predictors of working as a nurse than job satisfaction. Retention strategies should focus on identifying nurses showing early signs of departure with emphasis on developmental aspects, mentoring and support.
doi:10.1186/1478-4491-6-22
PMCID: PMC2600630  PMID: 18976478
16.  Job satisfaction trends during nurses' early career 
BMC Nursing  2008;7:7.
Background
Job satisfaction is an important component of nurses' lives that can impact on patient safety, productivity and performance, quality of care, retention and turnover, commitment to the organisation and the profession. Little is known about job satisfaction in early career and how it varies for different groups of nurses. This paper investigates how the components of job satisfaction vary during early career in newly qualified UK nurses.
Methods
Nurses were sampled using a combined census and multi-stage approach (n = 3962). Data were collected by questionnaire at 6 months, 18 months and 3 years after qualification between 1998 and 2001. Scores were calculated for seven job satisfaction components and a single item that measured satisfaction with pay. Scores were compared longitudinally and between nursing speciality (general, children's, mental health) using a mixed model approach.
Results
No single pattern across time emerged. Trends varied by branch and job satisfaction component. Rank order of job satisfaction components, from high to low scores, was very similar for adult and child branch nurses and different for mental health. Nurses were least satisfied with pay and most satisfied with relationships at 6 and 18 months and with resources (adult and child) and relationships (mental health) at 3 years. Trends were typically upwards for adult branch nurses, varied for children's nurses and downwards for mental health nurses.
Conclusion
The impact of time on job satisfaction in early career is highly dependent on specialism. Different contexts, settings and organisational settings lead to varying experiences. Future research should focus on understanding the relationships between job characteristics and the components of job satisfaction rather than job satisfaction as a unitary construct. Research that further investigates the benefits of a formal one year preceptorship or probationary period is needed.
doi:10.1186/1472-6955-7-7
PMCID: PMC2435528  PMID: 18534023
17.  Studying Seabird Diet through Genetic Analysis of Faeces: A Case Study on Macaroni Penguins (Eudyptes chrysolophus) 
PLoS ONE  2007;2(9):e831.
Background
Determination of seabird diet usually relies on the analysis of stomach-content remains obtained through stomach flushing; this technique is both invasive and logistically difficult. We evaluate the usefulness of DNA-based faecal analysis in a dietary study on chick-rearing macaroni penguins (Eudyptes chrysolophus) at Heard Island. Conventional stomach-content data was also collected, allowing comparison of the approaches.
Methodology/Principal Findings
Prey-specific PCR tests were used to detect dietary DNA in faecal samples and amplified prey DNA was cloned and sequenced. Of the 88 faecal samples collected, 39 contained detectable DNA from one or more of the prey groups targeted with PCR tests. Euphausiid DNA was most commonly detected in the early (guard) stage of chick-rearing, and detection of DNA from the myctophid fish Krefftichthys anderssoni and amphipods became more common in samples collected in the later (crèche) stage. These trends followed those observed in the penguins' stomach contents. In euphausiid-specific clone libraries the proportion of sequences from the two dominant euphausiid prey species (Euphausia vallentini and Thysanoessa macrura) changed over the sampling period; again, this reflected the trend in the stomach content data. Analysis of prey sequences in universal clone libraries revealed a higher diversity of fish prey than identified in the stomachs, but non-fish prey were not well represented.
Conclusions/Significance
The present study is one of the first to examine the full breadth of a predator's diet using DNA-based faecal analysis. We discuss methodological difficulties encountered and suggest possible refinements. Overall, the ability of the DNA-based approach to detect temporal variation in the diet of macaroni penguins indicates this non-invasive method will be generally useful for monitoring population-level dietary trends in seabirds.
doi:10.1371/journal.pone.0000831
PMCID: PMC1959119  PMID: 17786203

Results 1-18 (18)