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1.  Use of multiple markers demonstrates a cryptic western refugium and postglacial colonisation routes of Atlantic salmon (Salmo salar L.) in northwest Europe 
Heredity  2013;111(1):34-43.
Glacial and postglacial processes are known to be important determinants of contemporary population structuring for many species. In Europe, refugia in the Italian, Balkan and Iberian peninsulas are believed to be the main sources of species colonising northern Europe after the glacial retreat; however, there is increasing evidence of small, cryptic refugia existing north of these for many cold-tolerant species. This study examined the glacial history of Atlantic salmon in western Europe using two independent classes of molecular markers, microsatellites (nuclear) and mitochondrial DNA variation. Alongside the well-documented refuge in the Iberian Peninsula, evidence for a cryptic refuge in northwest France is also presented. Critically, methods utilised to estimate divergence times between the refugia indicated that salmon in these two regions had diverged a long time before the last glacial maximum; coalescence analysis (as implemented in the program IMa2) estimated divergence times at around 60 000 years before present. Through the examination of haplotype frequencies, previously glaciated areas of northwest Europe, that is, Britain and Ireland, appear to have been colonised from salmon expanding out of both refugia, with the southwest of England being the primary contact zone and exhibiting the highest genetic diversity.
PMCID: PMC3692316  PMID: 23512011
phylogeography; refugia; microsatellite; haplotype; ND1 gene
2.  Safety of the Surrogate Microorganism Enterococcus faecium NRRL B-2354 for Use in Thermal Process Validation 
Enterococcus faecium NRRL B-2354 is a surrogate microorganism used in place of pathogens for validation of thermal processing technologies and systems. We evaluated the safety of strain NRRL B-2354 based on its genomic and functional characteristics. The genome of E. faecium NRRL B-2354 was sequenced and found to comprise a 2,635,572-bp chromosome and a 214,319-bp megaplasmid. A total of 2,639 coding sequences were identified, including 45 genes unique to this strain. Hierarchical clustering of the NRRL B-2354 genome with 126 other E. faecium genomes as well as pbp5 locus comparisons and multilocus sequence typing (MLST) showed that the genotype of this strain is most similar to commensal, or community-associated, strains of this species. E. faecium NRRL B-2354 lacks antibiotic resistance genes, and both NRRL B-2354 and its clonal relative ATCC 8459 are sensitive to clinically relevant antibiotics. This organism also lacks, or contains nonfunctional copies of, enterococcal virulence genes including acm, cyl, the ebp operon, esp, gelE, hyl, IS16, and associated phenotypes. It does contain scm, sagA, efaA, and pilA, although either these genes were not expressed or their roles in enterococcal virulence are not well understood. Compared with the clinical strains TX0082 and 1,231,502, E. faecium NRRL B-2354 was more resistant to acidic conditions (pH 2.4) and high temperatures (60°C) and was able to grow in 8% ethanol. These findings support the continued use of E. faecium NRRL B-2354 in thermal process validation of food products.
PMCID: PMC3957640  PMID: 24413604
3.  Snailtrack corneal changes following subconjunctival injection of 5-fluorouracil 
Eye  2012;26(11):1495-1496.
PMCID: PMC3496093  PMID: 22878445
4.  Lactobacillus helveticus: the proteolytic system 
Lactobacillus helveticus is one of the species of lactic acid bacteria (LAB) most commonly used in the production of fermented milk beverages and some types of hard cheese. The versatile nature of this bacterium is based on its highly efficient proteolytic system consisting of cell-envelope proteinases (CEPs), transport system and intracellular peptidases. Besides use of L. helveticus in cheese processing, the production of fermented milk preparations with health promoting properties has become an important industrial application. Studies have shown that fermented dairy products are able to decrease blood pressure, stimulate the immune system, promote calcium absorption, and exert an anti-virulent effect against pathogens. These beneficial effects are produced by a variety of peptides released during the hydrolysis of milk proteins by the proteolytic system of L. helveticus, which provides the bacterium with its nutritional requirements for growth. In recent years, studies have focused on understanding the factors that affect the kinetics of milk protein hydrolysis by specific strains and have concentrated on the effect of pH, temperature, growth phase, and matrix composition on the bacterial enzymatic system. This review focuses on the role of the proteolytic system of L. helveticus in the production of bioactive compounds formed during fermentation of dairy products. Taking advantage of the powerful proteolytic system of this bacterium opens up future opportunities to search for novel food-derived compounds with potential health promoting properties.
PMCID: PMC3587842  PMID: 23467265
proteolytic; Lactobacillus; helveticus; milk; proteins
5.  Encephalitis caused by flaviviruses 
The genus Flavivirus, family Flaviviridae, contains some of the most important arboviral pathogens of man. The genus includes several aetiological agents of encephalitis, the most significant being Japanese encephalitis virus, West Nile virus and tick-borne encephalitis virus. In each case, the majority of exposed individuals will not develop disease, but a minority will develop a severe illness with a significant chance of permanent neurological damage or death. The factors that determine this are numerous, involving complex interactions between virus and host and are still being actively uncovered. In many cases it appears that the immune response, while crucial to containing the virus and limiting spread to the brain, is also responsible for causing neurological damage. Innate responses can limit viral replication but may also be responsible for generating pathological levels of inflammation. Neutralizing antibody responses are protective but take time to develop. The role of T cells is less clear, and may be either protective or pathogenic. This review summarizes recent developments in the understanding of the pathogenesis of encephalitis caused by flaviviruses.
PMCID: PMC3285924  PMID: 22367423
6.  Response to Melo and Spaeth 
Eye  2011;26(1):174.
PMCID: PMC3259599
7.  Risk-based classification of leukemia by cytogenetic and multiplex molecular methods: results from a multicenter validation study 
Blood Cancer Journal  2012;2(7):e78-.
Modern management of leukemia and selection of optimal treatment approaches entails the analysis of multiple recurrent cytogenetic abnormalities with independent diagnostic or prognostic value. We report the first multicenter validation of a multiplex molecular assay for 12 relevant fusion transcripts relative to cytogenetic methods. Performance was evaluated using a set of 280 adult and pediatric acute or chronic leukemias representative of the variety of presentations and pre-analytical parameters encountered in the clinical setting. The positive, negative and overall agreements were >98.5% with high concordance at each of the four sites. Positive detection of cases with low blast count or at relapse was consistent with a method sensitivity of 1%. There was 98.7% qualitative agreement with independent reference molecular tests. Apparent false negatives corresponded to rare alternative splicing isoforms not included in the panel. We further demonstrate that clinical sensitivity can be increased by adding those rare variants and other relevant transcripts or submicroscopic abnormalities. We conclude that multiplex RT-PCR followed by liquid bead array detection is a rapid and flexible method attuned to the clinical laboratory workflow, complementing standard cytogenetic methods and generating additional information valuable for the accurate diagnosis, prognosis and subsequent molecular monitoring of leukemia.
PMCID: PMC3408638  PMID: 22852047
leukemia; diagnosis; prognosis; molecular classification; RT-PCR; multiplex
8.  Biocontrol of Listeria monocytogenes and Escherichia coli O157:H7 in Meat by Using Phages Immobilized on Modified Cellulose Membranes ▿  
Applied and Environmental Microbiology  2011;77(18):6379-6387.
The ability of phages to specifically interact with and lyse their host bacteria makes them ideal antibacterial agents. The range of applications of bacteriophage can be extended by their immobilization on inert surfaces. A novel method for the oriented immobilization of bacteriophage has been developed. The method was based on charge differences between the bacteriophage head, which exhibits an overall net negative charge, and the tail fibers, which possess an overall net positive charge. Hence, the head would be more likely to attach to positively charged surfaces, leaving the tails free to capture and lyse bacteria. Cellulose membranes modified so that they had a positive surface charge were used as the support for phage immobilization. It was established that the number of infective phages immobilized on the positively charged cellulose membranes was significantly higher than that on unmodified membranes. Cocktails of phages active against Listeria or Escherichia coli immobilized on these membranes were shown to effectively control the growth of L. monocytogenes and E. coli O157:H7 in ready-to-eat and raw meat, respectively, under different storage temperatures and packaging conditions. The phage storage stability was investigated to further extend their industrial applications. It was shown that lyophilization can be used as a phage-drying method to maintain their infectivity on the newly developed bioactive materials. In conclusion, utilizing the charge difference between phage heads and tails provided a simple technique for oriented immobilization applicable to a wide range of phages and allowed the retention of infectivity.
PMCID: PMC3187159  PMID: 21803890
9.  Demonstrating Intertumoural Differences in Vascular-Metabolic Phenotype with Dynamic Contrast-Enhanced CT-PET 
Purpose. To assess whether the differences in vascular-metabolic relationships between lymphoma masses and colorectal liver metastases predicted from previous histopathological studies can be demonstrated by dynamic contrast-enhanced CT (DCE-CT) combined with fluorodeoxyglucose positron emission tomography (FDG-PET). Methods. DCE-CT and FDG-PET studies were drawn from an imaging archive for patients with either lymphoma masses (n = 11) or hepatic metastases from colorectal cancer (CRM: n = 12). Tumour vascularity was assessed using DCE-CT measurements of perfusion. Tumour glucose metabolism was expressed as the mean FDG Standardised Uptake Value (SUVFDG). The relationship between metabolism and vascularity in each group was assessed from SUVFDG /perfusion ratios and Pearson correlation coefficients. Results. An SUVFDG threshold of 3.0 was used to designate lymphoma masses as active (AL, n = 6) or inactive lymphoma (IL, n = 5). Tumour perfusion was significantly higher in AL (0.65 mL/min/mL) than CRM (0.37 mL/min/mL: P = .031) despite similar SUVFDG (5.05 and 5.33, resp.). AL demonstrated higher perfusion values than IL (0.24 mL/min/mL: P = .006). SUVFDG/perfusion was significantly higher in CRM (15.3 min) than IL (4.2 min, P < .01). There was no correlation between SUVFDG and perfusion for any patient group.
PMCID: PMC3094879  PMID: 21629862
10.  Microsatellite standardization and evaluation of genotyping error in a large multi-partner research programme for conservation of Atlantic salmon (Salmo salar L.) 
Genetica  2011;139(3):353-367.
Microsatellite genotyping is a common DNA characterization technique in population, ecological and evolutionary genetics research. Since different alleles are sized relative to internal size-standards, different laboratories must calibrate and standardize allelic designations when exchanging data. This interchange of microsatellite data can often prove problematic. Here, 16 microsatellite loci were calibrated and standardized for the Atlantic salmon, Salmo salar, across 12 laboratories. Although inconsistencies were observed, particularly due to differences between migration of DNA fragments and actual allelic size (‘size shifts’), inter-laboratory calibration was successful. Standardization also allowed an assessment of the degree and partitioning of genotyping error. Notably, the global allelic error rate was reduced from 0.05 ± 0.01 prior to calibration to 0.01 ± 0.002 post-calibration. Most errors were found to occur during analysis (i.e. when size-calling alleles; the mean proportion of all errors that were analytical errors across loci was 0.58 after calibration). No evidence was found of an association between the degree of error and allelic size range of a locus, number of alleles, nor repeat type, nor was there evidence that genotyping errors were more prevalent when a laboratory analyzed samples outside of the usual geographic area they encounter. The microsatellite calibration between laboratories presented here will be especially important for genetic assignment of marine-caught Atlantic salmon, enabling analysis of marine mortality, a major factor in the observed declines of this highly valued species.
Electronic supplementary material
The online version of this article (doi:10.1007/s10709-011-9554-4) contains supplementary material, which is available to authorized users.
PMCID: PMC3059809  PMID: 21279823
Atlantic salmon; Microsatellite; Calibration; Standardization; Genotyping error; Conservation
11.  The Regulation of the CNS Innate Immune Response Is Vital for the Restoration of Tissue Homeostasis (Repair) after Acute Brain Injury: A Brief Review 
Neurons and glia respond to acute injury by participating in the CNS innate immune response. This involves the recognition and clearance of “not self ” pathogens and “altered self ” apoptotic cells. Phagocytic receptors (CD14, CD36, TLR–4) clear “not self” pathogens; neurons and glia express “death signals” to initiate apoptosis in T cells.The complement opsonins C1q, C3, and iC3b facilitate the clearance of apoptotic cells by interacting with CR3 and CR4 receptors. Apoptotic cells are also cleared by the scavenger receptors CD14, Prs-R, TREM expressed by glia. Serpins also expressed by glia counter the neurotoxic effects of thrombin and other systemic proteins that gain entry to the CNS following injury. Complement pathway and T cell activation are both regulated by complement regulatory proteins expressed by glia and neurons. CD200 and CD47 are NIRegs expressed by neurons as “don't eat me” signals and they inhibit microglial activity preventing host cell attack. Neural stem cells regulate T cell activation, increase the Treg population, and suppress proinflammatory cytokine expression. Stem cells also interact with the chemoattractants C3a, C5a, SDF-1, and thrombin to promote stem cell migration into damaged tissue to support tissue homeostasis.
PMCID: PMC2989866  PMID: 21152121
12.  Oriented Immobilization of Bacteriophages for Biosensor Applications▿  
A method was developed for oriented immobilization of bacteriophage T4 through introduction of specific binding ligands into the phage head using a phage display technique. Fusion of the biotin carboxyl carrier protein gene (bccp) or the cellulose binding module gene (cbm) with the small outer capsid protein gene (soc) of T4 resulted in expression of the respective ligand on the phage head. Recombinant bacteriophages were characterized in terms of infectivity. It was shown that both recombinant phages retain their lytic activity and host range. However, phage head modification resulted in a decreased burst size and an increased latent period. The efficiency of bacteriophage immobilization with streptavidin-coated magnetic beads and cellulose-based materials was investigated. It was shown that recombinant bacteriophages form specific and strong bonds with their respective solid support and are able to specifically capture and infect the host bacterium. Thus, the use of immobilized BCCP-T4 bacteriophage for an Escherichia coli B assay using a phage multiplication approach and real-time PCR allowed detection of as few as 800 cells within 2 h.
PMCID: PMC2805203  PMID: 19948867
13.  B‐type natriuretic peptide in reversible myocardial ischaemia 
Journal of Clinical Pathology  2006;59(11):1216-1217.
Coronary heart disease is associated with increased B‐type natriuretic peptides (BNPs), and, although controversial, may cause exaggerated exercise‐induced BNP secretion. We investigated BNP in relation to reversible myocardial ischaemia.
Materials and methods
Serum N‐terminal proBNP (NT‐proBNP) was measured before and after an exercise electrocardiogram test (ETT) in 14 patients with and 45 patients without exercise‐induced myocardial ischaemia. Statistical analysis was carried out on logarithmically transformed data. Results, however, are pre‐transformed data.
NT‐proBNP increased with exercise both in ETT‐positive patients (mean (SD) 71.4 (41.2) v 76.8 (44.0) ng/l; p<0.001) and ETT‐negative patients (54.0 (61.2) v 60.1 (69.0) ng/l; p<0.001). Pre‐exercise and post‐exercise NT‐proBNP were higher (p<0.05) in ETT‐positive than in ETT‐negative patients. Incremental NT‐proBNP was similar in ETT‐positive (4.7 (4.2) ng/l) and ETT‐negative (6.2 (8.6) ng/l) patients.
Serum NT‐proBNP concentrations are higher in patients with exercise‐induced myocardial ischaemia than in those without. Exercise‐induced electrocardiographic myocardial ischaemia, however, is not associated with exaggerated BNP secretion.
PMCID: PMC1860506  PMID: 17071810
14.  Tongue ties and breast feeding 
PMCID: PMC2082757
tongue tie; breast feeding
15.  PMX464, a thiol-reactive quinol and putative thioredoxin inhibitor, inhibits NF-κB-dependent proinflammatory activation of alveolar epithelial cells 
British Journal of Pharmacology  2008;155(5):661-672.
Background and purpose:
Subtle changes in the intracellular reduction–oxidation (redox) state can modulate nuclear factor-κB (NF-κB) activity. Thioredoxin-1 (Trx) is a small, ubiquitous, redox-active thiol (-SH) protein that, with thioredoxin reductase-1 (TrxR), modifies the redox status of NF-κB pathway components. PMX464 is a novel thiol-reactive quinol thought to inhibit the Trx/TrxR system. The aim of this work was to investigate whether PMX464 inhibited NF-κB-mediated proinflammatory activation of human type II alveolar epithelial cells (A549).
Experimental approach:
Intercellular adhesion molecule-1 (ICAM-1), granulocyte-macrophage colony-stimulating factor (GM-CSF) and CXCL8, NF-κB DNA binding, nuclear translocation of NF-κB p65 subunit, IκBα degradation, IκB phosphorylation and IκB kinase (IKK) activity were assessed in A549 cells stimulated with IL-1β with or without PMX464 pretreatment. Effects of PMX464 on ICAM-1 expression in human lung microvascular endothelial cells (HLMVEC) were also investigated. For comparison, selected measurements (ICAM-1 and IκB-α phospho-IκB-α) were made on A549 cells after RNA interference-mediated silencing (siRNA) of Trx.
Key results:
PMX464 reduced ICAM-1, GM-CSF and CXCL8 expression in IL-1β-stimulated A549 cells and ICAM-1 in HLMVEC. PMX464 inhibited IL-1β-induced NF-κB DNA binding, nuclear translocation of NF-κB p65 subunit and factors involved in NF-κB activation; specifically, IκBα degradation, IκB phosphorylation and IκB kinase (IKK) activity in A549. By contrast, Trx siRNA did not alter ICAM-1 expression or IκBα degradation/phosphorylation in IL-1β-stimulated A549 cells.
Conclusion and implications:
PMX464 inhibits a proinflammatory response in A549 cells targeting the NFκB pathway above IKK. The lack of effect with Trx siRNA suggests that PMX464 acts on thiol proteins, in addition to Trx, to elicit anti-inflammatory responses in lung epithelial cells.
PMCID: PMC2442904  PMID: 18587424
PMX464; quinol; A549 epithelial cells; ICAM-1; CXCL8; GM-CSF; thioredoxin; thioredoxin reductase; NF-κB pathway; Trx siRNA
16.  The exercise addiction inventory: a quick and easy screening tool for health practitioners 
Objectives: To test further the EAI's psychometric properties and show that it would be quick and simple to administer by general practitioners.
Methods: A sample of 200 habitual exercisers were given the EAI and two existing exercise addiction scales (obligatory exercise questionnaire; exercise dependence scale). Two weeks later, another sample of 79 exercisers were administered the EAI to determine the test-retest reliability of the questionnaire.
Results: The original data from the preliminary report were reanalysed to determine the split half correlation of the EAI. This was found to be 0.84 (Guttman split-half coefficient). A correlation between weekly frequency of exercising and EAI scores was also determined, and it was found that the two variables shared 29% of the variance (r2 = 0.29). The test-retest reliability of the scale was found to be very good (0.85).
Conclusions: The EAI is a valid and reliable tool which would be capable of helping general practitioners to quickly and easily identify people affected by, or at risk of, exercise addiction.
PMCID: PMC1725234  PMID: 15911594
17.  E-mentoring: Does it have a place in medicine? 
Postgraduate Medical Journal  2005;81(956):389-390.
PMCID: PMC1743283  PMID: 15937205
18.  A fatal case of disseminated aspergillosis caused by a non-sporulating strain of Aspergillus fumigatus 
Journal of Clinical Pathology  2004;57(9):991-992.
This report describes the case of a 38 year old pregnant woman with fatal disseminated aspergillosis and multiorgan failure, which was preceded by a long history of allergic bronchopulmonary aspergillosis. Postmortem revealed massive infarction and abscess formation in both lungs. Histology revealed a focal granulomatous response. Fungal infiltration with areas of necrosis were also seen in the liver, spleen, and paratracheal, mediastinal, para-aortic, and hilar lymph nodes. Culture of tissue samples produced a non-sporulating, beige coloured fungus that developed green pigmentation only after three weeks of incubation. Nucleotide sequencing of the D1–D2 region of the large ribosomal subunit revealed 100% homology with Aspergillus fumigatus. Minimum inhibitory concentrations for amphotericin B and itraconazole were both 0.25 mg/litre (susceptible). Further work is urgently required to determine the prevalence of such non-sporulating strains and their relevance to clinical infection.
PMCID: PMC1770428  PMID: 15333665
Aspergillus fumigatus; aspergillosis; non-sporulating; non-sporing
19.  Efficacy and Pharmacokinetics of Bacteriophage Therapy in Treatment of Subclinical Staphylococcus aureus Mastitis in Lactating Dairy Cattle†  
Bovine mastitis is an inflammation of the udder caused by microbial infection. Mastitis caused by Staphylococcus aureus is a major concern to the dairy industry due to its resistance to antibiotic treatment and its propensity to recur chronically. Growing concerns surrounding antibiotic resistance have spurred research into alternative treatment methods. The ability of lytic S. aureus bacteriophage K to eliminate bovine S. aureus intramammary infection during lactation was evaluated in a placebo-controlled, multisite trial. Twenty-four lactating Holstein cows with preexisting subclinical S. aureus mastitis were treated. Treatment consisted of 10-ml intramammary infusions of either 1.25 × 1011 PFU of phage K or saline, administered once per day for 5 days. The cure rate was established by the assessment of four serial samples collected following treatment. The cure rate was 3 of 18 quarters (16.7%) in the phage-treated group, while none of the 20 saline-treated quarters were cured. This difference was not statistically significant. The effects of phage intramammary infusion on the bovine mammary gland were also studied. In healthy lactating cows, a single infusion of either filter-sterilized broth lysate or a CsCl gradient-purified phage preparation elicited a large increase in the milk somatic cell count. This response was not observed when phage was infused into quarters which were already infected with S. aureus. Phage-infused healthy quarters continued to shed viable bacteriophage into the milk for up to 36 h postinfusion. The phage concentration in the milk suggested that there was significant degradation or inactivation of the infused phage within the gland.
PMCID: PMC1563511  PMID: 16940081
20.  Child and adolescent psychiatry, 4th edition 
PMCID: PMC1719414
21.  Role of Efflux Pumps in Adaptation and Resistance of Listeria monocytogenes to Benzalkonium Chloride 
In this study, potential mechanisms underlying resistance and adaptation to benzalkonium chloride (BC) in Listeria monocytogenes were investigated. Two groups of strains were studied. The first group consisted of strains naturally sensitive to BC which could be adapted to BC. The second group consisted of naturally resistant strains. For all adapted isolates, there was a correlation between the resistance to BC and ethidium bromide, but this was not the case for the naturally resistant isolates. To investigate the role of efflux pumps in adaptation or resistance, reserpine, an efflux pump inhibitor, was added to the strains. Addition of reserpine to the sensitive and adapted strains resulted in a decrease in the MIC for BC, whereas no such decrease was observed for the resistant strains, indicating that efflux pumps played no role in the innate resistance of certain strains of L. monocytogenes to this compound. Two efflux pumps (MdrL and Lde) have been described in L. monocytogenes. Studies showed low and intermediate levels of expression of the genes encoding the efflux pumps for two selected resistant strains, H7764 and H7962, respectively. Adaptation to BC of sensitive isolates of L. monocytogenes resulted in significant increases in expression of mdrl (P < 0.05), but no such increase was observed for lde for two adapted strains of L. monocytogenes, LJH 381 (P = 0.91) and C719 (P = 0.11). This indicates that the efflux pump Mdrl is at least partly responsible for the adaptation to BC.
PMCID: PMC1472371  PMID: 16672496
22.  Rapid and Quantitative Detection of Hepatitis A Virus from Green Onion and Strawberry Rinses by Use of Real-Time Reverse Transcription-PCR 
In this study, an immunomagnetic capture method and a real-time reverse transcription-PCR assay were used to quantify hepatitis A virus (HAV) in green onion and strawberry rinses. This combined protocol detected as low as 0.5 PFU HAV in produce rinses and concentrated HAV levels up to 20-fold.
PMCID: PMC1214659  PMID: 16151164
23.  The pulmonary physician in critical care c 9: Non-ventilatory strategies in ARDS 
Thorax  2002;57(9):823-829.
PMCID: PMC1746421  PMID: 12200529
24.  The pulmonary physician in critical care: towards comprehensive critical care? 
Thorax  2002;57(1):77-78.
PMCID: PMC1746189  PMID: 11809995
25.  The pulmonary physician in critical care • 1: Pulmonary investigations for acute respiratory failure 
Thorax  2002;57(1):79-85.
PMCID: PMC1746170  PMID: 11809996

Results 1-25 (100)