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2.
Am J Hosp Palliat Care ; 40(1): 67-73, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36270635

ABSTRACT

Background: Death can be difficult to address personally, to discuss and to plan for. Since 2016 The Omega Course (Omega) has educated local people in Kenilworth, UK, about death and dying; broaching these issues and teaching communication skills whilst enabling social interaction. It aspires to produce practical outcomes with positive implications for end of life (EoL) planning and future neighbourhood care within the town. Aim: To investigate the impact of Omega on the attitudes and actions of participants. Method: Anonymous questionnaires, distributed by Qualtrics, or by post if preferred, were sent to 62 participants of Omega aged 22-94 two and a half years post course institution. Thematic analysis and inferential statistics were used. Results: 23 replies (37%) scored changes across 4 areas; barriers to discussion, ease discussing death, fears about death and future planning capability. All showed a significant beneficial change using a Paired Sample t-test (P< .01). Respondents noted common fears of death and dying, barriers to discussing the topic and planning for it. The course helped to allay fear, enabled discussion and encouraged planning for death and EoL. Respondents rated the course as 9.1/10 for achieving its aims. They appreciated discussing death and dying in a supportive environment and found the approach effective in developing their skills and changing attitudes. Conclusion: Omega has the potential to change attitudes towards death; promoting discussion, planning, and tackling misconceptions.


Subject(s)
Advance Care Planning , Terminal Care , Humans , Surveys and Questionnaires , Communication , Educational Status
3.
FEMS Microbiol Lett ; 367(10)2020 05 01.
Article in English | MEDLINE | ID: mdl-32407499

ABSTRACT

Bile salts, including sodium deoxycholate (DOC), are secreted into the intestine to aid fat digestion and contribute to antimicrobial protection. Gram-negative pathogens such as Escherichia coli, however, are highly resistant to DOC, using multiple mechanisms of which the multidrug efflux pump AcrAB-TolC is the dominant one. Given that TolC-mediated efflux masks the interaction of DOC with potential targets, we sought to identify those targets by identifying genes whose mutations cause an increase in the MIC to DOC relative to the ∆tolC parental strain, that lacks TolC-associated functional efflux pumps. Using a mutant screen, we isolated twenty independent spontaneous mutants that had a higher MICDOC than the E. coli parental ∆tolC strain. Whole genome sequencing of these mutants mapped most mutations to the ptsI or cyaA gene. Analysis of knock-out mutants and complementation showed that elimination of PtsI, a component of the carbohydrate phosphotransferase system, or one of the two key proteins involved in cAMP synthesis and signaling, adenylate cyclase (CyaA) or cAMP receptor protein (Crp) causes low-level increased resistance of a ∆tolC E. coli strain to DOC.


Subject(s)
Bile Acids and Salts/pharmacology , Drug Resistance, Bacterial/genetics , Escherichia coli/drug effects , Escherichia coli/genetics , Gene Knockout Techniques , Microbial Sensitivity Tests , Mutation , Whole Genome Sequencing
4.
BMJ ; 368: m1272, 2020 03 31.
Article in English | MEDLINE | ID: mdl-32234753
5.
BMC Microbiol ; 20(1): 5, 2020 01 06.
Article in English | MEDLINE | ID: mdl-31906851

ABSTRACT

BACKGROUND: Antimicrobial combinations have been proven as a promising approach in the confrontation with multi-drug resistant bacterial pathogens. In the present study, we identify and characterize a synergistic interaction of broad-spectrum nitroreductase-activated prodrugs 5-nitrofurans, with a secondary bile salt, Sodium Deoxycholate (DOC) in growth inhibition and killing of enterobacteria. RESULTS: Using checkerboard assay, we show that combination of nitrofuran furazolidone (FZ) and DOC generates a profound synergistic effect on growth inhibition in several enterobacterial species including Escherichia coli, Salmonella enterica, Citrobacter gillenii and Klebsiella pneumoniae. The Fractional Inhibitory Concentration Index (FICI) for DOC-FZ synergy ranges from 0.125 to 0.35 that remains unchanged in an ampicillin-resistant E. coli strain containing a ß-lactamase-producing plasmid. Findings from the time-kill assay further highlight the synergy with respect to bacterial killing in E. coli and Salmonella. We further characterize the mechanism of synergy in E. coli K12, showing that disruption of the tolC or acrA genes that encode components of multidrug efflux pumps causes, respectively, a complete or partial loss, of the DOC-FZ synergy. This finding indicates the key role of TolC-associated efflux pumps in the DOC-FZ synergy. Overexpression of Nitric Oxide-detoxifying enzyme Hmp results in a three-fold increase in FICI for DOC-FZ interaction, suggesting a role of nitric oxide in the synergy. We further demonstrate that DOC-FZ synergy is largely independent of NfsA and NfsB, the two major activation enzymes of the nitrofuran prodrugs. CONCLUSIONS: This study is to our knowledge the first report of nitrofuran-deoxycholate synergy against Gram-negative bacteria, offering potential applications in antimicrobial therapeutics. The mechanism of DOC-FZ synergy involves FZ-mediated inhibition of TolC-associated efflux pumps that normally remove DOC from bacterial cells. One possible route contributing to that effect is via FZ-mediated nitric oxide production.


Subject(s)
Deoxycholic Acid/pharmacology , Drug Resistance, Bacterial/drug effects , Enterobacteriaceae/growth & development , Furazolidone/pharmacology , Bacterial Outer Membrane Proteins/genetics , Citrobacter/drug effects , Citrobacter/growth & development , Drug Synergism , Enterobacteriaceae/drug effects , Escherichia coli/drug effects , Escherichia coli/growth & development , Escherichia coli Proteins/genetics , Gene Expression Regulation, Bacterial/drug effects , Klebsiella pneumoniae/drug effects , Klebsiella pneumoniae/growth & development , Lipoproteins/genetics , Membrane Transport Proteins/genetics , Microbial Viability/drug effects , Prodrugs/pharmacology , Salmonella enterica/drug effects , Salmonella enterica/growth & development
6.
Article in English | MEDLINE | ID: mdl-31481448

ABSTRACT

The global spread of multidrug-resistant enterobacteria warrants new strategies to combat these pathogens. One possible approach is the reconsideration of "old" antimicrobials, which remain effective after decades of use. Synthetic 5-nitrofurans such as furazolidone, nitrofurantoin, and nitrofurazone are such a class of antimicrobial drugs. Recent epidemiological data showed a very low prevalence of resistance to this antimicrobial class among clinical Escherichia coli isolates in various parts of the world, forecasting the increasing importance of its uses to battle antibiotic-resistant enterobacteria. However, although they have had a long history of clinical use, a detailed understanding of the 5-nitrofurans' mechanisms of action remains limited. Nitrofurans are known as prodrugs that are activated in E. coli by reduction catalyzed by two redundant nitroreductases, NfsA and NfsB. Furazolidone, nevertheless, retains relatively significant antibacterial activity in the nitroreductase-deficient ΔnfsA ΔnfsBE. coli strain, indicating the presence of additional activating enzymes and/or antibacterial activity of the unreduced form. Using genome sequencing, genetic, biochemical, and bioinformatic approaches, we discovered a novel 5-nitrofuran-activating enzyme, AhpF, in E. coli The discovery of a new nitrofuran-reducing enzyme opens new avenues for overcoming 5-nitrofuran resistance, such as designing nitrofuran analogues with higher affinity for AhpF or screening for adjuvants that enhance AhpF expression.


Subject(s)
Escherichia coli/enzymology , Nitroreductases/metabolism , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Drug Resistance, Bacterial/genetics , Escherichia coli/drug effects , Escherichia coli/genetics , Escherichia coli Proteins/genetics , Escherichia coli Proteins/metabolism , Furazolidone/chemistry , Furazolidone/pharmacology , Microbial Sensitivity Tests , Molecular Docking Simulation , Nitrofurans/metabolism , Nitrofurans/pharmacology , Nitrofurantoin/chemistry , Nitrofurantoin/pharmacology , Nitrofurazone/chemistry , Nitrofurazone/pharmacology , Nitroreductases/genetics , Peroxiredoxins/genetics , Peroxiredoxins/metabolism
7.
Arch Dis Child ; 102(5): 475-476, 2017 May.
Article in English | MEDLINE | ID: mdl-27836825

ABSTRACT

Gastrointestinal dysmotility is common in children and young people with neurodisabling conditions. In this article we seek to highlight the increasing difficulties faced by paediatricians in managing intestinal failure in this patient group. It is becoming clear that, as the median age for survival increases, intestinal failure is a significant problem, and can in some cases become life-limiting. The ethical issues around starting children with life-limiting conditions on parenteral nutrition (PN) are extremely complicated, not least because we are ignorant of the mechanism of intestinal failure in these children, and indeed, which of these children might be able to return to enteral feeding after a period of PN. Our article highlights these issues, drawing on our experience of a particularly difficult case, which we hope will stimulate further discussion among paediatricians providing care for children with neurodisabling conditions.


Subject(s)
Malabsorption Syndromes/etiology , Neurodevelopmental Disorders/complications , Adolescent , Colonic Diseases/etiology , Colonic Diseases/surgery , Enteral Nutrition , Gastrointestinal Motility , Humans , Intestinal Obstruction/etiology , Intestinal Obstruction/surgery , Malabsorption Syndromes/therapy , Male , Parenteral Nutrition
9.
Inflamm Bowel Dis ; 20(2): 291-300, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24374875

ABSTRACT

BACKGROUND: The combination of the severity of pediatric-onset inflammatory bowel disease (IBD) phenotypes and the need for intense medical treatment may increase the risk of malignancy and mortality, but evidence regarding the extent of the problem is scarce. Therefore, the Porto Pediatric IBD working group of ESPGHAN conducted a multinational-based survey of cancer and mortality in pediatric IBD. METHODS: A survey among pediatric gastroenterologists of 20 European countries and Israel on cancer and/or mortality in the pediatric patient population with IBD was undertaken. One representative from each country repeatedly contacted all pediatric gastroenterologists from each country for reporting retrospectively cancer and/or mortality of pediatric patients with IBD after IBD onset, during 2006-2011. RESULTS: We identified 18 cases of cancers and/or 31 deaths in 44 children (26 males) who were diagnosed with IBD (ulcerative colitis, n = 21) at a median age of 10.0 years (inter quartile range, 3.0-14.0). Causes of mortality were infectious (n = 14), cancer (n = 5), uncontrolled disease activity of IBD (n = 4), procedure-related (n = 3), other non-IBD related diseases (n = 3), and unknown (n = 2). The most common malignancies were hematopoietic tumors (n = 11), of which 3 were hepatosplenic T-cell lymphoma and 3 Ebstein-Barr virus-associated lymphomas. CONCLUSIONS: Cancer and mortality in pediatric IBD are rare, but cumulative rates are not insignificant. Mortality is primarily related to infections, particularly in patients with 2 or more immunosuppressive agents, followed by cancer and uncontrolled disease. At least 6 lymphomas were likely treatment-associated by virtue of their phenotype.


Subject(s)
Inflammatory Bowel Diseases/complications , Neoplasms/etiology , Neoplasms/mortality , Adolescent , Child , Child, Preschool , Europe/epidemiology , Female , Follow-Up Studies , Humans , Incidence , Inflammatory Bowel Diseases/epidemiology , Male , Retrospective Studies , Risk Factors , Survival Rate/trends
10.
J Pediatr Gastroenterol Nutr ; 48(1): 48-54, 2009 Jan.
Article in English | MEDLINE | ID: mdl-19172123

ABSTRACT

OBJECTIVE: To evaluate whether fecal calprotectin (FC) and fecal lactoferrin (FL) can be used as noninvasive markers in children and young people (4-17 years) with active inflammatory bowel disease (IBD). PATIENTS AND METHODS: Stool samples were collected from 3 groups of children: those with active IBD, control individuals with other gastrointestinal (GI) diseases (GI control) and control individuals with no GI disease (non-GI control). The number of patients for the FC assay was as follows: IBD = 26, GI control = 30, non-GI control = 25. The number of patients for the FL assay was as follows: IBD = 24, GI control = 26, non-GI = 24. FC and FL were measured by use of enzyme-linked immunoassays. RESULTS: The median concentrations of FC and FL in isolation, and their interaction, were significantly higher in the IBD group than in the GI and non-GI control groups (P < 0.001). Although the area under the curve, sensitivity, and specificity for FC, FL, and FC x FL interaction were significantly better than chance, FL consistently had the lowest area under the curve, and FC x FL consistently had the highest area under the curve. CONCLUSIONS: FC and FL are both significantly elevated in children with IBD, and the interaction of these 2 biomarkers may produce a better initial diagnostic test compared with their use in isolation.


Subject(s)
Biomarkers/analysis , Feces/chemistry , Inflammatory Bowel Diseases/diagnosis , Lactoferrin/analysis , Leukocyte L1 Antigen Complex/analysis , Adolescent , Child , Child, Preschool , Gastrointestinal Diseases/metabolism , Humans , Inflammatory Bowel Diseases/metabolism , Logistic Models , Reference Values
11.
Ultrason Sonochem ; 13(2): 126-32, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16293520

ABSTRACT

The electro- and sonoelectro-chemical oxidation of anthracene in acetonitrile has been explored at room and low temperature (-40 degrees C) at a platinum micro- and macro-electrode, respectively. From both methodologies, the effective number of electrons, n(eff), in the oxidation process is evaluated at both room temperature and at the limit of the solvent-electrolyte freezing point. It is observed that n(eff) is close to 1 at low temperature while at room temperature it is higher, indicating sluggish follow up kinetics at lower temperature. The oxidative electrolysis of anthracene within an undivided cell, under various conditions is investigated with the product(s) obtained analysed and quantified by (1)H NMR. At room temperature under both 'silent' and 'sono' conditions the electrochemical oxidation produces 9,10-anthraquinone and bianthrone while at low temperature with acoustic streaming, anthracene-9,10-diol is additionally produced. Electrolyses with intentionally added water and also with oxygen saturation is investigated and its influence on the reaction pathway reported. In particular, the addition of water (1.4M) favours the formation of anthraquinone in a 3:1 ratio with bianthrone. Overall, the effect of lower temperature is to favour the formation of anthraquinone or its reduced form whilst the addition of insonation at low temperature is to substantially enhance the product yield per Coulomb of charge injected.

13.
J Am Chem Soc ; 127(2): 506-7, 2005 Jan 19.
Article in English | MEDLINE | ID: mdl-15643858

ABSTRACT

Chlorination-elimination chemistry coupled with three-component Joullié-Ugi reaction and facile deprotection allowed efficient access to an array of polyhydroxylated pyrrolidines through parallel synthesis that may be considered to be a library of imino (aza) sugars (glycomimetics) and/or dihydroxyprolyl peptides (peptidomimetics). The utility of generating such a library was illustrated by screening against 15 different targets that revealed potent and selective inhibition of the Gaucher's disease glycosyltransferase enzyme glucosylceramide synthase and of primary pathogen model for human hepatitis C virus (HCV) and bovine diarrhoeal virus (BVDV). An observed selectivity for this HCV model over hepatitis B virus and remarkably low toxicity suggest a novel mode of action.


Subject(s)
Antiviral Agents/chemistry , Biomimetic Materials/chemistry , Glycopeptides/chemistry , Pyrrolidines/chemistry , Antiviral Agents/pharmacology , Aza Compounds/chemistry , Aza Compounds/pharmacology , Biomimetic Materials/pharmacology , Carbohydrates/chemistry , Carbohydrates/pharmacology , Diarrhea Viruses, Bovine Viral/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Erythritol/chemistry , Erythritol/pharmacology , Glycopeptides/pharmacology , Glycoside Hydrolases/antagonists & inhibitors , Hepatitis B virus/drug effects , Hydroxyproline/analogs & derivatives , Hydroxyproline/pharmacology , Pyrrolidines/pharmacology , Sugar Alcohols/chemistry , Sugar Alcohols/pharmacology
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