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2.
Gait Posture ; 107: 28-34, 2024 01.
Article in English | MEDLINE | ID: mdl-37729768

ABSTRACT

BACKGROUND: The influence of load carriage in operational police officers is not well understood despite a relatively high injury rate. Assessing load related changes in head and torso coordination may provide valuable insight into plausible injury mechanisms. RESEARCH QUESTION: Do typical police tactical vest loads alter head and torso coordination during running? METHODS: Thirty-eight UK police officers ran at a self-selected pace (>2 ms-1) on a non-motorised treadmill in four vest load conditions (unloaded, and low, high and evenly distributed loads). Peak head and torso tilt, and peak vest displacement were compared between all four conditions. Timings between vest and torso change of direction were compared between the three loaded conditions. The coupling angle between the head and torso calculated using modified vector coding were compared between unloaded and each loaded conditions using Statistical Parametric Mapping. RESULTS: No significant differences were found between conditions for peak head or torso tilt alone (p > 0.05). Loading equipment low on the vest led to significantly greater mediolateral vest displacements (38 mm) away from the torso than a high (34 mm) or evenly distributed (30 mm) conditions. The vest was found to change direction vertically before the torso in the anterior-posterior direction, and then influence torso motion. The loaded conditions changed the head-torso coupling from in-phase (with head-dominancy) to anti-phase (with torso dominancy) between 55% and 77% stance. Anti-phase with a relatively stationary head and the torso rotating forward likely places a greater concentric demand on the posterior neck muscles relative to unloaded running. SIGNIFICANCE: Current tactical vest designs allow significant extra displacement of load away from the body during running, altering coordination at the head and torso.


Subject(s)
Police , Running , Humans , Torso/physiology , Exercise Test , Running/physiology , Motion
3.
Transl Psychiatry ; 7(9): e1240, 2017 09 26.
Article in English | MEDLINE | ID: mdl-28949339

ABSTRACT

The identification of an early biomarker of psychotic disorder is important as early treatment is associated with improved patient outcome. Metabolomic and lipidomic approaches in combination with multivariate statistical analysis were applied to identify plasma alterations in children (age 11) (38 cases vs 67 controls) and adolescents (age 18) (36 cases vs 117 controls) preceeding or coincident with the development of psychotic disorder (PD) at age 18 in the Avon Longitudinal Study of Parents and Children (ALSPAC). Overall, 179 lipids were identified at age 11, with 32 found to be significantly altered between the control and PD groups. Following correction for multiple comparisons, 8 of these lipids remained significant (lysophosphatidlycholines (LPCs) LPC(18:1), LPC(18:2), LPC(20:3); phosphatidlycholines (PCs) PC(32:2; PC(34:2), PC(36:4), PC(0-34-3) and sphingomyelin (SM) SM(d18:1/24:0)), all of which were elevated in the PD group. At age 18, 23 lipids were significantly different between the control and PD groups, although none remained significant following correction for multiple comparisons. In conclusion, the findings indicate that the lipidome is altered in the blood during childhood, long before the development of psychotic disorder. LPCs in particular are elevated in those who develop PD, indicating inflammatory abnormalities and altered phospholipid metabolism. These findings were not found at age 18, suggesting there may be ongoing alterations in the pathophysiological processes from prodrome to onset of PD.


Subject(s)
Psychotic Disorders/blood , Psychotic Disorders/diagnosis , Adolescent , Biomarkers/blood , Child , Humans , Lipids/blood , Longitudinal Studies , Metabolomics , Multivariate Analysis , Psychotic Disorders/metabolism
4.
Anal Chim Acta ; 964: 45-54, 2017 Apr 29.
Article in English | MEDLINE | ID: mdl-28351638

ABSTRACT

The aim of this study was to investigate the potential of the recently developed ensemble Monte Carlo Variable Selection (EMCVS) method to identify the relevant portions of high resolution 1H NMR spectra as a metabolite fingerprinting tool and compare to a widely used method (Variable importance on projection (VIP)) and recently proposed variable selected methods i.e. selectivity ratio (SR) and significance multivariate correlation (sMC). As case studies two quantitative publicly available datasets: wine samples, urine samples of rats, and an experiment on mushroom (Agaricus bisporus) were examined. EMCVS outperformed the three other variable selection methods in most cases, selecting fewer chemical shifts and leading to improved classification of mushrooms and prediction of onion by-products intake and wine components. These fewer chemical shift regions facilitate the interpretation of the NMR spectra, fingerprinting and identification of metabolite markers.


Subject(s)
Agaricus/chemistry , Biomarkers/metabolism , Magnetic Resonance Imaging , Urine/chemistry , Wine/analysis , Animals , Monte Carlo Method , Proton Magnetic Resonance Spectroscopy , Rats
5.
Foot Ankle Surg ; 23(1): 40-43, 2017 Mar.
Article in English | MEDLINE | ID: mdl-28159041

ABSTRACT

BACKGROUND: The Akin osteotomy is commonly performed as an adjunct to osteotomies of the first metatarsal for the correction of hallux valgus such as the scarf or chevron osteotomies. The Akin osteotomy is indicated for the correction of a hallux valgus interphalangeus and can be used supplementary in any first metatarsal osteotomy for a hallux valgus. Various techniques have been described for fixation of the osteotomy. Most commonly the osteotomy is held and fixed with metalwork consisting of either a staple [2,3], a screw [4,5] or wiring [6,7]. While these techniques have been shown to be effective they are not without complications. They may require the use of additional instrumentation and in particular there is a described incidence of subsequent implant removal due to irritation of surrounding tissues and migration of the implanted metalwork [8-12]. Suture fixation of osteotomies in the foot has previously been described [14,15]. This offers a cost effective method with reliable results without the risk of implant complication. METHOD: In this study we report the outcomes of a large series performed by a single surgeon and compare them to a similar series of Akin osteotomies performed by a different surgeon at the same institute using the staple technique. RESULTS: The results demonstrate no significant difference in outcome between the two series and a significant cost saving with the use of the suture fixation. CONCLUSIONS: As a result of the study, we advocate the use of suture fixation of Akin osteotomy as a cost effective and reliable alternative to other forms of fixation.


Subject(s)
Hallux Valgus/surgery , Metatarsal Bones/surgery , Osteotomy , Suture Techniques , Adolescent , Adult , Aged , Aged, 80 and over , Cost-Benefit Analysis , Female , Humans , Male , Middle Aged , Reproducibility of Results , Retrospective Studies , Treatment Outcome , Young Adult
6.
Proc Nutr Soc ; 76(3): 295-302, 2017 08.
Article in English | MEDLINE | ID: mdl-28091346

ABSTRACT

Traditional methods for the assessment of dietary intake are prone to error; in order to improve and enhance these methods increasing interest in the identification of dietary biomarkers has materialised. Metabolomics has emerged as a key tool in the area of dietary biomarker discovery and to date the use of metabolomics has identified a number of putative biomarkers. Applications to identify novel biomarkers of intake have in general taken three approaches: (1) specific acute intervention studies to identify specific biomarkers of intake; (2) searching for biomarkers in cohort studies by correlating to self-reported intake of a specific food/food group(s); (3) analysing dietary patterns in conjunction with metabolomic profiles to identify biomarkers and nutritypes. A number of analytical technologies are employed in metabolomics as currently there is no single technique capable of measuring the entire metabolome. These approaches each have their own advantages and disadvantages. The present review will provide an overview of current technologies and applications of metabolomics in the determination of new dietary biomarkers. In addition, it will address some of the current challenges in the field and future outlooks.


Subject(s)
Diet/adverse effects , Metabolomics/methods , Biomarkers/metabolism , Biomedical Research/methods , Biomedical Research/trends , Congresses as Topic , Dietetics/methods , Dietetics/trends , Humans , Metabolomics/trends , Nutritional Sciences/methods , Nutritional Sciences/trends , Reproducibility of Results , Self Report , Societies, Scientific
7.
Reprod Fertil Dev ; 29(4): 658-669, 2017 Apr.
Article in English | MEDLINE | ID: mdl-26511586

ABSTRACT

The aims of the present study were to: (1) characterise the metabolome of follicular fluid and serum in dairy cows with similar genetic merit for milk production but with extremes of good (Fert+) or poor (Fert-) genetic merit for fertility; and (2) identify potential biomarkers of dairy cow fertility. Follicular fluid from the first wave dominant follicle and serum were collected on Day 7 of the oestrous cycle. The most pronounced effect of genotype was noted in the serum, where the abundance of total polyunsaturated fatty acids and n-6 polyunsaturated fatty acids was greater in Fert+ cows, and the abundance of total saturated fatty acids was greater in Fert- cows. The abundance of nine fatty acids (arachidic acid, heneicosanoic acid, myristic acid, behenic acid, myristoleic acid, heptadecenoic acid, cis-11-eicosanoic acid, nervonic acid and γ-linolenic acid) in follicular fluid was affected by genotype. Concentrations of cysteine, leucine, ornithine, proline and tyrosine in follicular fluid, and asparagine, creatinine, cysteine, methionine, proline and valine in serum, were also affected by genotype. Receiver operating characteristic curve analysis indicated that the follicular fluid and serum fatty acids and follicular fluid amino acids that were significantly affected by genotype were highly predictive of fertility genotype.


Subject(s)
Fatty Acids/metabolism , Fertility/genetics , Follicular Fluid/metabolism , Animals , Cattle , Estrous Cycle/metabolism , Female , Genotype , Lactation/metabolism , Metabolome , Milk , Ovarian Follicle/metabolism
8.
Theriogenology ; 87: 221-228, 2017 Jan 01.
Article in English | MEDLINE | ID: mdl-27678515

ABSTRACT

The hypothesis of this study was that different in vitro parameters are required to predict the in vivo fertility of non-sorted (NS) and sex-sorted (SS) semen. Thus, the aim was to correlate in vitro bull sperm functional parameters (experiment 1) and seminal plasma composition (experiment 2) with pregnancy rates using 2 cohorts of bulls (NS and SS). Experiment 1: ejaculates from each bull (n = 3 ejaculates per bull; n = 6 bulls for both NS and SS) were assessed for motility, thermal stress tolerance and morphology using microscopy, and viability, osmotic resistance, mitochondrial membrane potential, and acrosome integrity using flow cytometry. Fertilizing ability was assessed using IVF. Experiment 2: ejaculates (n = 3 per bull; n = 8 and 6 bulls for NS and SS, respectively) were collected, seminal plasma harvested and frozen and later analyzed for amino acid and fatty acid composition using gas chromatography mass spectrometry. In the NS cohort of bulls, there was no correlation between pregnancy rate and any of the sperm functional parameters assessed. However, within the SS cohort, motility and viability were correlated with pregnancy rate (r = 0.84 and 0.80, respectively; P < 0.05). There was no correlation between IVF outcome and pregnancy rate in either the SS or NS cohort of bulls. In the NS cohort of bulls, concentrations of the amino acid isoleucine and the fatty acid tricosylic acid (C23:0) were correlated with pregnancy rate (r = 0.80 and 0.74, respectively; P < 0.05). Within the SS cohort of bulls, the amino acid glutamic acid and the fatty acid arachidic acid (C20:0) were correlated with pregnancy rate (r = 0.84 and 0.82, respectively; P < 0.05). In conclusion, this study suggests that different in vitro markers of fertility are required to predict the fertility of NS and SS sperm.


Subject(s)
Cattle/physiology , Insemination, Artificial/veterinary , Semen/chemistry , Sex Preselection/veterinary , Acrosome , Animals , Cell Survival , DNA Fragmentation , Female , Male , Membrane Potential, Mitochondrial/physiology , Pregnancy , Spermatozoa/physiology
9.
J Hosp Infect ; 94(4): 351-357, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27624807

ABSTRACT

BACKGROUND: Carbapenemase-producing Enterobacteriaceae (CPE) may cause healthcare-associated infections with high mortality rates. New Delhi metallo-ß-lactamase-1 (NDM-1) is among the most recently discovered carbapenemases. AIM: To report the first outbreak of NDM-1 CPE in Ireland, including microbiological and epidemiological characteristics, and assessing the impact of infection prevention and control measures. METHODS: This was a retrospective microbiological and epidemiological review. Cases were defined as patients with a CPE-positive culture. Contacts were designated as roommates or ward mates. FINDINGS: This outbreak involved 10 patients with a median age of 71 years (range: 45-90), located in three separate but affiliated healthcare facilities. One patient was infected (the index case); the nine others were colonized. Nine NDM-1-producing Klebsiella pneumoniae, an NDM-1-producing Escherichia coli and a K. pneumoniae carbapenemase (KPC)-producing Enterobacter cloacae were detected between week 24, 2014 and week 37, 2014. Pulsed-field gel electrophoresis demonstrated similarity. NDM-1-positive isolates were meropenem resistant with minimum inhibitory concentrations (MICs) ranging from 12 to 32 µg/mL. All were tigecycline susceptible (MICs ≤1 µg/mL). One isolate was colistin resistant (MIC 4.0 µg/mL; mcr-1 gene not detected). In 2015, four further NDM-1 isolates were detected. CONCLUSION: The successful management of this outbreak was achieved via the prompt implementation of enhanced infection prevention and control practices to prevent transmission. These patients did not have a history of travel outside of Ireland, but several had frequent hospitalizations in Ireland, raising concerns regarding the possibility of increasing but unrecognized prevalence of NDM-1 and potential decline in value of travel history as a marker of colonization risk.


Subject(s)
Carrier State/epidemiology , Disease Outbreaks , Enterobacteriaceae Infections/epidemiology , Enterobacteriaceae/enzymology , beta-Lactamases/metabolism , Adult , Aged , Aged, 80 and over , Carrier State/microbiology , Disease Transmission, Infectious/prevention & control , Electrophoresis, Gel, Pulsed-Field , Enterobacteriaceae/classification , Enterobacteriaceae/genetics , Enterobacteriaceae/isolation & purification , Enterobacteriaceae Infections/microbiology , Female , Humans , Infection Control/methods , Ireland/epidemiology , Male , Microbial Sensitivity Tests , Middle Aged , Molecular Typing , Prevalence , Retrospective Studies
10.
MedEdPORTAL ; 12: 10426, 2016 Jul 21.
Article in English | MEDLINE | ID: mdl-31008206

ABSTRACT

INTRODUCTION: Innovative and effective curricula for medical students and physicians are needed to increase knowledge and confidence for instructing patients on lifestyle management of diseases. We developed an active collaborative session that integrates evidence-based medicine (EBM), clinical decision-making, nutrition, exercise, and personalized patient care for the instruction of lifestyle management of obesity in the preclinical medical curriculum. METHODS: Before the session, learners critically appraised an EBM article (meta-analysis of commercial weight-loss programs' efficacy). In class, there was an EBM discussion assessed and facilitated by multiple-choice questions, followed by a collaborative activity where learners solved a clinical scenario of a patient who wants to use a commercial weight-loss program. Each small group was assigned to a different program but given the same clinical scenario. The objectives of the session were to identify and interpret EBM/non-EBM resources in order to describe the components, advantages, and disadvantages of the weight-loss programs, make a personalized clinical recommendation, and present it to the class. RESULTS: Generating debate and fostering engagement, the session was perceived as a positive learning experience by the learners. By accomplishing the learning objectives, the participants became well versed in various weight-loss programs. DISCUSSION: Our results suggest that learners developed interpretation and knowledge integration skills, which may increase their comfort in discussing the lifestyle management of obesity and other diseases. This activity is designed to be implemented at other institutions seeking to integrate active collaborative learning of nutrition, exercise, and clinical decision-making during preclinical and clinical medical education and clinical practice.

11.
J Hosp Infect ; 90(4): 316-21, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25648941

ABSTRACT

AIM: To report the first Irish outbreak of cfr-mediated linezolid-resistant Staphylococcus epidermidis. METHODS: Linezolid-resistant S. epidermidis isolated at University Hospital Limerick from four blood cultures, one wound and four screening swabs (from nine patients) between April and June 2013 were characterized by pulsed-field gel electrophoresis (PFGE), multi-locus sequence typing (MLST) and staphylococcal cassette chromosome (SCCmec) typing. Antibiotic susceptibilities were determined according to the guidelines of the British Society for Antimicrobial Chemotherapy. The outbreak was controlled through prohibiting prescription and use of linezolid, adherence to infection prevention and control practices, enhanced environmental cleaning, isolation of affected patients, and hospital-wide education programmes. FINDINGS: PFGE showed that all nine isolates represented a single clonal strain. MLST showed that they belonged to ST2, and SCCmec typing showed that they encoded a variant of SCCmecIII. All nine isolates were cfr positive, and eight isolates were positive for the G2576T 23S rRNA mutation commonly associated with linezolid resistance. Isolates exhibited multiple antibiotic resistances (i.e. linezolid, gentamicin, methicillin, clindamycin, ciprofloxacin, fusidic acid and rifampicin). The adopted infection prevention intervention was effective, and the outbreak was limited to the affected intensive care unit. CONCLUSIONS: This is the first documented outbreak of cfr-mediated linezolid-resistant S. epidermidis in the Republic of Ireland. Despite this, and due to existing outbreak management protocols, the responsible micro-organism and source were identified efficiently. However, it became apparent that staff knowledge of antimicrobial susceptibilities and appropriate hygiene practices were suboptimal at the time of the outbreak, and that educational interventions (and re-inforcement) are necessary to avoid occurrence of antimicrobial resistance and outbreaks such as reported here.


Subject(s)
Cross Infection , Infection Control/methods , Staphylococcal Infections/epidemiology , Staphylococcal Infections/prevention & control , Staphylococcus epidermidis/drug effects , Staphylococcus epidermidis/isolation & purification , Adult , Aged , Aged, 80 and over , Anti-Bacterial Agents/pharmacology , Cross Infection/epidemiology , Cross Infection/microbiology , Cross Infection/prevention & control , Disease Outbreaks/prevention & control , Drug Resistance, Multiple, Bacterial/drug effects , Drug Resistance, Multiple, Bacterial/genetics , Electrophoresis, Gel, Pulsed-Field , Female , Hospitals, Teaching , Humans , Incidence , Ireland/epidemiology , Linezolid/pharmacology , Male , Middle Aged , Mutation , RNA, Ribosomal, 23S , Staphylococcal Infections/drug therapy , Staphylococcus epidermidis/genetics , Treatment Outcome
12.
Oncogene ; 34(12): 1563-74, 2015 Mar 19.
Article in English | MEDLINE | ID: mdl-24704833

ABSTRACT

In a model of peritoneal metastasis in immune-competent mice, we show that nuclear factor (NF)-κB inhibition in CT26 colon cancer cells prevents metastasis. NF-κB inhibition, by stable overexpression of IκB-α super-repressor, induced differential polarization of co-cultured macrophages to an M1-like anti-tumour phenotype in vitro. NF-κB-deficient cancer cell-conditioned media (CT26/IκB-α SR) induced interleukin (IL)-12 and nitric oxide (NO) synthase (inducible NO synthase (iNOS)) expression in macrophages. Control cell (CT26/EV) conditioned media induced high levels of IL-10 and arginase in macrophages. In vivo, this effect translated to reduction in metastasis in mice injected with CT26/ IκB-α SR cells and was positively associated with increased CD8(+)CD44(+)CD62L(-) and CD4(+)CD44(+)CD62L(-) effector T cells. Furthermore, inhibition of NF-κB activity induced high levels of NO in infiltrating immune cells and decreases in matrix metalloproteinase-9 expression, simultaneous with increases in tissue inhibitor of metalloproteinases 1 and 2 within tumours. CT26/IκB-α SR tumours displayed increased pro-inflammatory gene expression, low levels of angiogenesis and extensive intratumoral apoptosis, consistent with the presence of an anti-tumour macrophage phenotype. Macrophage depletion reduced tumour size in CT26/EV-injected animals and increased tumour size in CT26/IκB-α SR cells compared with untreated tumours. Our data demonstrate, for the first time, that an important implication of targeting tumour cell NF-κB is skewing of macrophage polarization to an anti-tumour phenotype. This knowledge offers novel therapeutic opportunities for anticancer treatment.


Subject(s)
I-kappa B Proteins/metabolism , Macrophages/metabolism , NF-kappa B/metabolism , Peritoneal Neoplasms/metabolism , Peritoneal Neoplasms/secondary , Animals , Cell Line, Tumor , Colonic Neoplasms/pathology , Culture Media, Conditioned , Female , Humans , Mice , Mice, Inbred BALB C , NF-KappaB Inhibitor alpha , Neoplasm Transplantation , Nitric Oxide/metabolism , Signal Transduction
13.
Eye (Lond) ; 28(10): 1190-200, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25060843

ABSTRACT

PURPOSE: To determine whether there are differences in retinal vascular oxygen saturation measurements, estimated using a hyperspectral fundus camera, between normal eyes and treated eyes of subjects with asymmetrical primary open-angle glaucoma (POAG). METHODS: A noninvasive hyperspectral fundus camera was used to acquire spectral images of the retina at wavelengths between 556 and 650 nm in 2-nm increments. In total, 14 normal eyes and both eyes of 11 treated POAG subjects were imaged and analyzed using algorithms that use the spectral variation of the optical densities of blood vessels to estimate the oxygen saturation of blood within the retinal vasculature. In the treated POAG group, each of the eyes were categorized, based on the mean deviation of the Humphrey visual-field analyzer result, as either more-advanced or less-advanced, glaucomatous eyes. Unpaired t-tests (two-tailed) with Welch's correction were used to compare the mean oxygen saturation between the normal subjects and the treated POAG subgroups. RESULTS: In less-advanced and more-advanced-treated POAG eyes, mean retinal venular oxygen saturations (48.2±21.6% and 42.6±18.8%, respectively) were significantly higher than in normal eyes (27.9±9.9%; P=0.03 and 0.01, respectively). Arteriolar oxygen saturation was not significantly different between normal eyes and treated POAG eyes. CONCLUSIONS: The increased oxygen saturation of the retinal venules in advanced-treated POAG eyes may indicate reduced metabolic consumption of oxygen in the inner retinal tissues.


Subject(s)
Glaucoma, Open-Angle/blood , Oximetry/instrumentation , Oxygen/blood , Retinal Artery/metabolism , Retinal Vein/metabolism , Adult , Aged , Antihypertensive Agents/therapeutic use , Blood Pressure/physiology , Diagnostic Techniques, Ophthalmological/instrumentation , Female , Glaucoma, Open-Angle/drug therapy , Humans , Intraocular Pressure/physiology , Male , Middle Aged , Prospective Studies , Visual Acuity/physiology , Visual Fields/physiology
15.
J. physiol. biochem ; 70(2): 593-602, jun. 2014.
Article in English | IBECS | ID: ibc-122978

ABSTRACT

The application of metabolomics in nutritional research may be a useful tool to analyse and predict the response to a dietary intervention. The aim of this study was to examine metabolic changes in serum samples following exposure to an energy-restricted diet (-15 % of daily energy requirements) over a period of 8 weeks in overweight and obese older adults (n = 22) using a gas chromatography/mass spectrometry (GC/MS) metabolomic approach. After 8 weeks, there were significant reductions in weight (7 %) and metabolic improvement (glucose and lipid profiles). Metabolomic analysis found that total saturated fatty acids (SFAs), including palmitic acid (C16:0) and stearic acid (C18:0) and monounsaturated fatty acids (MUFAs), were significantly decreased after the 8-week intervention. Furthermore, palmitoleic acid (C16:1) was found to be a negative predictor of change in body fat loss. Both the total ω-6 and ω-3 polyunsaturated fatty acids (PUFAs) significantly decreased, although the overall total amounts of PUFAs did not. The branched chain amino acid (BCAA) isoleucine significantly decreased in the serum samples after the intervention. In conclusion, this study demonstrated that the weight loss intervention based on a hypocaloric diet identified changes in the metabolic profiles of serum in overweight and obese older adults, with a reduction in anthropometric and biochemical parameters also found


Subject(s)
Humans , Metabolomics/methods , Amino Acids/metabolism , Fatty Acids/metabolism , Overweight/metabolism , Obesity/metabolism , Diet, Reducing , Weight Loss/physiology
16.
Cell Death Dis ; 5: e1202, 2014 May 01.
Article in English | MEDLINE | ID: mdl-24787014

ABSTRACT

Nerve growth factor (NGF) is well characterised as an important pro-survival factor in neuronal cells that can inhibit apoptotic cell death upstream of mitochondrial outer membrane permeabilisation. Here we addressed the question of whether NGF can also protect against apoptosis downstream of caspase activation. NGF treatment promoted a rapid reduction in the level of the p17 subunit of active caspase-3 in PC12 cells that had been induced to undergo apoptosis by various cytotoxins. The mechanism involved TrkA-dependent activation of extracellular signal-regulated kinase (ERK1/2) but not phosphatidylinositol 3-kinase (PI3K)/Akt, and de novo protein synthesis. Involvement of inhibitor of apoptosis proteins (IAPs) and proteasomal degradation were ruled out. In contrast, inhibition of lysosome function using chloroquine and concanamycin A reversed NGF-induced removal of p17. Moreover, in NGF-treated cells, active caspases were found to be localised to lysosomes. The involvement of macroautophagy and chaperone-mediated autophagy were ruled out. Taken together, these findings suggest an anti-apoptotic mechanism by which NGF induces removal of active caspase-3 in a lysosome-dependent manner.


Subject(s)
Apoptosis/drug effects , Caspase 3/metabolism , Lysosomes/metabolism , Nerve Growth Factor/pharmacology , Animals , Autophagy/drug effects , Biocatalysis/drug effects , Cell Survival/drug effects , Enzyme Activation/drug effects , Extracellular Signal-Regulated MAP Kinases/metabolism , Kinetics , Lysosomes/drug effects , Mice , Molecular Chaperones/metabolism , Neurogranin/metabolism , PC12 Cells , Proteasome Endopeptidase Complex/metabolism , Proteolysis/drug effects , Rats , Receptor, trkA/metabolism , Signal Transduction/drug effects , Thapsigargin/pharmacology
17.
Article in English | MEDLINE | ID: mdl-24565891

ABSTRACT

Reliable dietary assessments are essential when attempting to understand the complex links between diet and health. Traditional methods for collecting dietary exposure can be unreliable, therefore there is an increasing interest in identifying biomarkers to provide a more accurate measurement. Metabolomics is a technology that offers great promise in this area. The aim of this study was to use a multivariate statistical strategy to link lipidomic patterns with dietary data in an attempt to identify dietary biomarkers. We assessed the relationship between lipidomic profiles and dietary data in volunteers (n=34) from the Metabolic Challenge Study (MECHE). Principal component analysis (PCA), linear regression and receiver operating characteristic (ROC) analysis were used to (1) reduce the lipidomic data into lipid patterns (LPs), (2) investigate relationships between these patterns and dietary data and (3) identify biomarkers of dietary intake. Our study identified a total of 6 novel LPs. LP1 was highly predictive of dietary fat intake (area under the curve AUC=0.82). A random forest (RF) classification model used to discriminate between low and high consumers resulted with an error rate of >10%, with a panel of six metabolites identified as the most predictive. LP4 was highly predictive of alcohol intake (AUC=0.81) with lysophosphatidylcholine alkyl C18:0 (LPCeC18:0) identified as a potential biomarker of alcohol consumption. LP6 had a reasonably good ability to predict dietary fish intake (AUC=0.76), with lysophosphatidylethanolamine acyl C18:2 (LPEaC18:2) phoshatidylethanolamine diaclyl C38:4 (PEaaC38:4) identified as potential biomarkers. The identification of these LPs and specific biomarkers will help in better classifying a persons dietary intake and in turn will improve the assessment of the relationship between diet and disease. Linking these LPs and specific biomarkers with health parameters will be an important future step.


Subject(s)
Diet , Dietary Fats/administration & dosage , Lipids/blood , Metabolomics/methods , Adult , Area Under Curve , Biomarkers/blood , Biomarkers/chemistry , Dietary Fats/blood , Female , Humans , Lipids/chemistry , Male , Middle Aged , Models, Statistical , ROC Curve , Young Adult
18.
J Physiol Biochem ; 70(2): 593-602, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24402878

ABSTRACT

The application of metabolomics in nutritional research may be a useful tool to analyse and predict the response to a dietary intervention. The aim of this study was to examine metabolic changes in serum samples following exposure to an energy-restricted diet (-15% of daily energy requirements) over a period of 8 weeks in overweight and obese older adults (n = 22) using a gas chromatography/mass spectrometry (GC/MS) metabolomic approach. After 8 weeks, there were significant reductions in weight (7%) and metabolic improvement (glucose and lipid profiles). Metabolomic analysis found that total saturated fatty acids (SFAs), including palmitic acid (C16:0) and stearic acid (C18:0) and monounsaturated fatty acids (MUFAs), were significantly decreased after the 8-week intervention. Furthermore, palmitoleic acid (C16:1) was found to be a negative predictor of change in body fat loss. Both the total ω-6 and ω-3 polyunsaturated fatty acids (PUFAs) significantly decreased, although the overall total amounts of PUFAs did not. The branched chain amino acid (BCAA) isoleucine significantly decreased in the serum samples after the intervention. In conclusion, this study demonstrated that the weight loss intervention based on a hypocaloric diet identified changes in the metabolic profiles of serum in overweight and obese older adults, with a reduction in anthropometric and biochemical parameters also found.


Subject(s)
Amino Acids/blood , Fatty Acids/blood , Metabolomics , Overweight/blood , Weight Loss , Adult , Energy Intake , Female , Gas Chromatography-Mass Spectrometry , Humans , Male
19.
Br J Cancer ; 109(8): 2131-41, 2013 Oct 15.
Article in English | MEDLINE | ID: mdl-24052043

ABSTRACT

BACKGROUND: Taxanes are routinely used for the treatment of prostate cancer, however the majority of patients eventually develop resistance. We investigated the potential efficacy of EL102, a novel toluidine sulphonamide, in pre-clinical models of prostate cancer. METHODS: The effect of EL102 and/or docetaxel on PC-3, DU145, 22Rv1 and CWR22 prostate cancer cells was assessed using cell viability, cell cycle analysis and PARP cleavage assays. Tubulin polymerisation and immunofluorescence assays were used to assess tubulin dynamics. CWR22 xenograft murine model was used to assess effects on tumour proliferation. Multidrug-resistant lung cancer DLKPA was used to assess EL102 in a MDR1-mediated drug resistance background. RESULTS: EL102 has in vitro activity against prostate cancer, characterised by accumulation in G2/M, induction of apoptosis, inhibition of Hif1α, and inhibition of tubulin polymerisation and decreased microtubule stability. In vivo, a combination of EL102 and docetaxel exhibits superior tumour inhibition. The DLKP cell line and multidrug-resistant DLKPA variant (which exhibits 205 to 691-fold greater resistance to docetaxel, paclitaxel, vincristine and doxorubicin) are equally sensitive to EL102. CONCLUSION: EL102 shows potential as both a single agent and within combination regimens for the treatment of prostate cancer, particularly in the chemoresistance setting.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Prostatic Neoplasms/drug therapy , Sulfonamides/pharmacology , Toluidines/pharmacology , ATP Binding Cassette Transporter, Subfamily B , Animals , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Docetaxel , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Drug Synergism , Humans , Male , Mice , Microtubules/drug effects , Microtubules/metabolism , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Random Allocation , Sulfonamides/administration & dosage , Taxoids/administration & dosage , Toluidines/administration & dosage , Tubulin/metabolism , Xenograft Model Antitumor Assays
20.
Reproduction ; 146(4): 389-95, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23886995

ABSTRACT

The use of metabolomic based techniques to aid oocyte and embryo selection has gained attention in recent years. Previous work from our laboratory has demonstrated that the (1)H NMR-based metabolic profile of follicular fluid correlates with oocyte developmental potential. Patients undergoing IVF at the Merrion Fertility Clinic had follicular fluid collected at the time of oocyte retrieval. The fatty acid composition of follicular fluid from follicles where oocytes fertilised and developed into multi-cell embryos (n=15) and from oocytes that fertilised normally but failed to cleave (n=9) (cleaved vs non-cleaved) was compared. Statistical analysis was performed on the data using univariate and multivariate techniques. Analysis of the fatty acid composition revealed that there were nine fatty acids significantly different between follicular fluid from the cleaved and the non-cleaved sample groups. Of particular interest were the higher concentration of total saturated (P=0.03) and the lower concentration of total polyunsaturated fatty acids in the non-cleaved sample group (P=0.001). Random forest classification models were used to predict successful cleavage in follicular fluid samples producing models with errors rates of <10%. Receiver operating characteristic analysis demonstrated that the model had good predictability with an area under the curve of 0.96. The panel of fatty acid biomarkers identified in this study indicates that the fatty acid composition of follicular fluid may be more predictive in comparison to other previously identified biomarkers. Following validation in a larger cohort, these biomarkers may have the potential to be used in fertility clinics to aid the selection of oocytes in the future.


Subject(s)
Biomarkers/metabolism , Fatty Acids/metabolism , Follicular Fluid/metabolism , Metabolomics , Oocytes/cytology , Oocytes/metabolism , Adult , Area Under Curve , Female , Gas Chromatography-Mass Spectrometry , Humans , Magnetic Resonance Spectroscopy , ROC Curve
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