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2.
Br J Dermatol ; 182(1): 97-103, 2020 01.
Article in English | MEDLINE | ID: mdl-31218665

ABSTRACT

BACKGROUND: Several preclinical studies have identified the antiproliferative effects of 25-hydroxyvitamin D [25(OH)D; vitamin D]. Ultraviolet radiation (UVR) is essential for vitamin D synthesis yet increases the risk of melanoma. Observational studies on the association of vitamin D levels with melanoma risk have reported inconclusive results, and are difficult to interpret owing to the potential confounding from the dual role of UVR. OBJECTIVES: To determine whether there is a causal association between genetically predicted 25(OH)D concentrations and melanoma using a Mendelian randomization (MR) approach. METHODS: We performed MR using summary data from a large genome-wide association study (GWAS) meta-analysis of melanoma risk, consisting of 12 874 cases and 23 203 controls. Five single nucleotide polymorphisms associated with 25(OH)D concentration - rs12785878, rs10741657, rs2282679, rs6013897 and rs116970203 - were selected as instrumental variables. An inverse variance weighted method was used to access the evidence for causality. MR results from the melanoma meta-analysis were combined with results from an MR study based on a melanoma risk GWAS using UK Biobank data. RESULTS: A 20 nmol L-1 decrease in 25(OH)D was not associated with melanoma risk [odds ratio (OR) 1·06, 95% confidence interval (CI) 0·95-1·19]. Results from the UK Biobank were concordant with this, with meta-analysis of our and UK Biobank-derived MR causal estimates showing no association (OR 1·02, 95% CI 0·92-1·13 for a 20 nmol L-1 decrease). CONCLUSIONS: The results suggest that vitamin D levels may not be causally associated with the risk of melanoma. What's already known about this topic? Antitumour activity of vitamin D has been identified in preclinical studies. Observational studies link vitamin D deficiency with an increased risk of a range of cancers. There is a growing public interest for vitamin D supplementation. Observational studies of melanoma are fraught with difficulties because while higher ultraviolet radiation levels increase vitamin D levels, such exposure is also associated with increased melanoma risk. Results from observational studies are inconclusive regarding the effect of vitamin D on melanoma risk. What does this study add? Using Mendelian randomization, an approach to causal inference, which is analogous to a natural randomized controlled trial, we found no causal association between vitamin D levels and melanoma.


Subject(s)
Melanoma , Mendelian Randomization Analysis , Genome-Wide Association Study , Humans , Melanoma/genetics , Polymorphism, Single Nucleotide/genetics , Ultraviolet Rays/adverse effects , Vitamin D
3.
Br J Dermatol ; 183(2): 303-310, 2020 08.
Article in English | MEDLINE | ID: mdl-31747047

ABSTRACT

BACKGROUND: Melanoma develops as the result of complex interactions between sun exposure and genetic factors. However, data on these interactions from prospective studies are scant. OBJECTIVES: To quantify the association between ambient and personal ultraviolet exposure and incident melanoma in a large population-based prospective study of men and women residing in a setting of high ambient ultraviolet radiation, and to examine potential gene-environment interactions. METHODS: Data were obtained from the QSkin Sun and Health Study, a prospective cohort study of men and women aged 40-69 years, randomly sampled from the Queensland population in 2011. Participants were genotyped and assessed for ultraviolet exposure. RESULTS: Among participants with genetic data (n = 15 373), 420 (2·7%) developed cutaneous melanoma (173 invasive, 247 in situ) during a median follow-up time of 4·4 years. Country of birth, age at migration, having > 50 sunburns in childhood or adolescence, and a history of keratinocyte cancer or actinic lesions were significantly associated with melanoma risk. CONCLUSIONS: An interaction with polygenic risk was suggested: among people at low polygenic risk, markers of cumulative sun exposure (as measured by actinic damage) were associated with melanoma. In contrast, among people at high polygenic risk, markers of high-level early-life ambient exposure (as measured by place of birth) were associated with melanoma (hazard ratio for born in Australia vs. overseas 3·16, 95% confidence interval 1·39-7·22). These findings suggest interactions between genotype and environment that are consistent with divergent pathways for melanoma development. What's already known about this topic? The relationship between sun exposure and melanoma is complex, and exposure effects are highly modified by host factors and behaviours. The role of genotype on the relationship between ultraviolet radiation exposure and melanoma risk is poorly understood. What does this study add? We found that country of birth, age at migration, sunburns in childhood or adolescence, and history of keratinocyte cancer or actinic lesions were significantly associated with melanoma risk, while other measures of continuous or more intermittent patterns of sun exposure were not. We found evidence for gene-environment interactions that are consistent with divergent pathways for melanoma development. Linked Comment: Cust. Br J Dermatol 2020; 183:205-206. Plain language summary available online.


Subject(s)
Melanoma , Skin Neoplasms , Adult , Aged , Australia/epidemiology , Female , Humans , Male , Melanoma/etiology , Melanoma/genetics , Middle Aged , Prospective Studies , Queensland/epidemiology , Risk Factors , Skin Neoplasms/etiology , Skin Neoplasms/genetics , Sunlight/adverse effects , Ultraviolet Rays/adverse effects
5.
J Hosp Infect ; 103(2): 185-192, 2019 Oct.
Article in English | MEDLINE | ID: mdl-31145931

ABSTRACT

BACKGROUND: The spread of pathogens via the airborne route is often underestimated, and little is known about the extent to which airborne microbial contamination levels vary throughout the day and night in hospital facilities. AIMS: To evaluate airborne contamination levels within intensive care unit (ICU) isolation rooms over 10-24-h periods in order to improve understanding of the variability of environmental aerial bioburden, and the extent to which ward activities may contribute. METHODS: Environmental air monitoring was conducted within occupied and vacant inpatient isolation rooms. A sieve impactor sampler was used to collect 500-L air samples every 15 min over 10-h (08:00-18:00 h) and 24-h (08:00-08:00 h) periods. Samples were collected, room activity was logged, and bacterial contamination levels were recorded as colony-forming units (cfu)/m3 air. FINDINGS: A high degree of variability in levels of airborne contamination was observed across all scenarios in the studied isolation rooms. Air bioburden increased as room occupancy increased, with air contamination levels highest in rooms occupied for the longest time during the study (10 days) (mean 104.4 cfu/m3, range 12-510 cfu/m3). Counts were lowest in unoccupied rooms (mean 20 cfu/m3) and during the night. CONCLUSION: Peaks in airborne contamination were directly associated with an increase in activity levels. This study provides the first clear evidence of the extent of variability in microbial airborne levels over 24-h periods in ICU isolation rooms, and found direct correlation between microbial load and ward activity.


Subject(s)
Air Microbiology , Bacteria/isolation & purification , Bacterial Load , Intensive Care Units , Patient Isolation , Adult , Aged , Colony Count, Microbial , Female , Humans , Male , Middle Aged
6.
Thromb Res ; 178: 132-138, 2019 Jun.
Article in English | MEDLINE | ID: mdl-31030032

ABSTRACT

BACKGROUND: Symptomatic venous thromboembolism (VTE) is an unpredictable and life-threatening toxicity, which occurs early in childhood acute lymphoblastic leukemia (ALL) therapy. Approximately 5% of children will experience VTE which is treated with anticoagulation. Asparaginase and corticosteroids are etiologic factors for VTE, however other clinical factors may modify this risk. PROCEDURE: We sought to i) assess published pre-treatment VTE risk factors ii) identify early clinical factors that were associated with VTE and iii) determine whether single nucleotide polymorphisms (SNPs) associated with VTE in non-cancer patients contributed to VTE in children with ALL. We performed a detailed, retrospective analysis of 1021 ALL patients treated between 1998 and 2013. Individual patient records were reviewed to ascertain VTE incidence and document treatment-related clinical variables. RESULTS: The incidence of VTE was 5.1%. Extremes of weight at diagnosis (<5th or >95th centile) was an independent risk factor in multivariable analysis, when added to published risk factors of age ≥10 years and mediastinal mass. When factors during induction/consolidation were considered separately: bacteremia, elevated serum gamma-glutamyl transferase and bilirubin were associated with VTE occurrence. None of the SNPs associated with VTE in non-cancer populations were significantly associated with VTE in our cohort. CONCLUSION: We found two known risk factors (age ≥ 10 years and mediastinal mass) in a large cohort of children treated for ALL and identified other factors associated with VTE such as weight extremes at diagnosis, bacteremia, and abnormal liver function which warrant further study. These VTE risk factors may form the basis of future thromboprophylaxis trials.


Subject(s)
Polymorphism, Single Nucleotide/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Venous Thromboembolism/etiology , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Risk Factors
7.
J Hosp Infect ; 98(1): 67-73, 2018 Jan.
Article in English | MEDLINE | ID: mdl-28716671

ABSTRACT

BACKGROUND: Previous work has shown that a ceiling-mounted, 405 nm high-intensity narrow-spectrum light environmental decontamination system (HINS-light EDS) reduces bacterial contamination of environmental surfaces in a burns unit by between 27% and 75%. Examination of the efficacy of the light over extended exposure times and its probable mode of action was performed. AIM: To ascertain the correlation between bacterial kill achieved on sampled surface sites around the burns unit and both irradiance levels of the 405 nm light, and exposure time. METHODS: Seventy samples were taken using contact agar plates from surfaces within an occupied side-room in the burns unit before, during, and after a seven-day use of the HINS-light EDS. This was repeated in three separate studies. Statistical analysis determined whether there was significant decrease in environmental contamination during prolonged periods of HINS-light treatment, and whether there was an association between irradiance and bacterial kill. FINDINGS: A decrease of between 22% and 86% in the mean number of surface bacteria was shown during the use of the HINS-light EDS. When the light ceased to be used, increases of between 78% and 309% occurred. There was no correlation between bacterial kill and irradiance levels at each sampling site but strong correlation between bacterial kill and exposure time. CONCLUSION: Prolonged exposure to the HINS-light EDS causes a cumulative decontamination of the surfaces within a burns unit. The importance of exposure time and possible airborne effect over irradiance levels is emphasized.


Subject(s)
Bacteria/radiation effects , Decontamination/methods , Environmental Microbiology , Light , Microbial Viability/radiation effects , Patients' Rooms , Adult , Aged , Bacteria/isolation & purification , Colony Count, Microbial , Hospitals , Humans , Male , Middle Aged , Time Factors
8.
J Fish Dis ; 40(4): 557-570, 2017 Apr.
Article in English | MEDLINE | ID: mdl-27453998

ABSTRACT

Disease due to non-tuberculous mycobacteria (NTM) is common in fish. Current recommendations focus on outbreak management by depopulating entire fish stocks and disinfecting tanks. Treatment is not advocated. Treatment may be appropriate, however, where individual, valuable fish are concerned. ZSL London Zoo managed an outbreak of mycobacteriosis in a valuable group of imported F1 captive-bred Australian lungfish (Neoceratodus fosteri) by depopulation, isolation, extensive testing and daily oral antibiotic treatment. Four species of Mycobacterium (M. marinum, M. fortuitum, M. chelonae and M. peregrinum) were involved in this outbreak, each with unique antibiotic sensitivities. Triple therapy with rifampicin, doxycycline and enrofloxacin for 8 months was the most effective antibiotic combination, resulting in full disease resolution. No side effects were noted and, more than 18 months post-treatment, no recurrence had occurred. This is the first report of mycobacterial disease in lungfish and the first report of a polymycobacterial outbreak in fish involving these four species of Mycobacterium. This report demonstrates the value of extensive isolation and identification. Also, as therapies currently advised in standard texts did not reflect the antibiotic sensitivity of the NTM found in the fish reported here, we recommend that antibiotic treatment should always be based on sensitivity testing.


Subject(s)
Animals, Zoo , Anti-Bacterial Agents/pharmacology , Fish Diseases/epidemiology , Fish Diseases/prevention & control , Fishes , Mycobacterium Infections/veterinary , Mycobacterium/physiology , Administration, Oral , Animals , Australia , Disease Outbreaks/veterinary , Fish Diseases/microbiology , Mycobacterium/classification , Mycobacterium Infections/epidemiology , Mycobacterium Infections/microbiology , Mycobacterium Infections/prevention & control
9.
Sarcoma ; 2015: 826124, 2015.
Article in English | MEDLINE | ID: mdl-26696773

ABSTRACT

Embryonal rhabdomyosarcoma (eRMS) is one of the most common soft tissue sarcomas in children and adolescents. Parameningeal eRMS is a variant that is often more difficult to treat than eRMS occurring at other sites. A 14-year-old female with persistent headaches and rapid weight loss was diagnosed with parameningeal eRMS. She progressed and died despite chemotherapy with vincristine, actinomycin-D, and cyclophosphamide plus 50.4 Gy radiation therapy to the primary tumor site. Tumor specimens were acquired by rapid autopsy and tumor tissue was transplanted into immunodeficient mice to create a patient-derived xenograft (PDX) animal model. As autopsy specimens had an ALK R1181C mutation, PDX tumor bearing animals were treated with the pan-kinase inhibitor lestaurtinib but demonstrated no decrease in tumor growth, suggesting that single agent kinase inhibitor therapy may be insufficient in similar cases. This unique parameningeal eRMS PDX model is publicly available for preclinical study.

10.
J Eur Acad Dermatol Venereol ; 29(11): 2120-7, 2015 Nov.
Article in English | MEDLINE | ID: mdl-25864459

ABSTRACT

BACKGROUND: A substantial number of melanoma patients will develop multiple primary melanomas (MPM). Currently, little is known about the impact of MPM on survival. OBJECTIVE: We aimed to determine whether melanoma survival is worse for patients with MPM compared to those with a single invasive primary melanoma (SPM). MATERIALS AND METHODS: A cohort study was conducted. Patients were sourced from an Australian population, with follow-up information collected retrospectively from registry data. Melanoma-specific survival analysis was performed to find associated variables after adjustment for known prognostic factors, using four different models, each selecting a different index melanoma lesion. RESULTS: 1068 stage I and II melanoma patients were followed up for a median of 24.4 years. MPM was found in 17.8% of the cohort (190 patients), more likely among males and older age groups. Other clinicopathological parameters were similar between the MPM and SPM (878 patients) cohorts. After adjustment for age, sex and Breslow thickness, MPM was a hazard for death from melanoma, across all models, reaching significance when considering the last invasive lesion as the index melanoma (HR = 2.76, P = 0.017). CONCLUSION: Patients with multiple invasive lesions seem more at risk of death from melanoma, independent of known prognostic factors.


Subject(s)
Melanoma/mortality , Melanoma/pathology , Neoplasms, Second Primary/mortality , Neoplasms, Second Primary/pathology , Skin Neoplasms/mortality , Skin Neoplasms/pathology , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Infant , Infant, Newborn , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Staging , Proportional Hazards Models , Queensland/epidemiology , Retrospective Studies , Sex Factors , Survival Rate , Young Adult
11.
Bone Joint J ; 97-B(2): 283-8, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25628296

ABSTRACT

High-intensity narrow-spectrum (HINS) light is a novel violet-blue light inactivation technology which kills bacteria through a photodynamic process, and has been shown to have bactericidal activity against a wide range of species. Specimens from patients with infected hip and knee arthroplasties were collected over a one-year period (1 May 2009 to 30 April 2010). A range of these microbial isolates were tested for sensitivity to HINS-light. During testing, suspensions of the pathogens were exposed to increasing doses of HINS-light (of 123mW/cm(2) irradiance). Non-light exposed control samples were also used. The samples were then plated onto agar plates and incubated at 37°C for 24 hours before enumeration. Complete inactivation (greater than 4-log10 reduction) was achieved for all of the isolates. The typical inactivation curve showed a slow initial reaction followed by a rapid period of inactivation. The doses of HINS-light required ranged between 118 and 2214 J/cm(2). Gram-positive bacteria were generally found to be more susceptible than Gram-negative. As HINS-light uses visible wavelengths, it can be safely used in the presence of patients and staff. This unique feature could lead to its possible use in the prevention of infection during surgery and post-operative dressing changes. Cite this article: Bone Joint J 2015;97-B:283-8.


Subject(s)
Arthroplasty, Replacement, Hip/adverse effects , Arthroplasty, Replacement, Knee/adverse effects , Microbial Viability/radiation effects , Phototherapy/methods , Prosthesis-Related Infections/microbiology , Prosthesis-Related Infections/therapy , Aged , Aged, 80 and over , Bacterial Infections/microbiology , Bacterial Infections/therapy , Candidiasis, Invasive/microbiology , Candidiasis, Invasive/therapy , Female , Humans , Male , Middle Aged
12.
J Hosp Infect ; 88(1): 1-11, 2014 Sep.
Article in English | MEDLINE | ID: mdl-25066049

ABSTRACT

BACKGROUND: Although the germicidal properties of ultraviolet (UV) light have long been known, it is only comparatively recently that the antimicrobial properties of visible violet-blue 405 nm light have been discovered and used for environmental disinfection and infection control applications. AIM: To review the antimicrobial properties of 405 nm light and to describe its application as an environmental decontamination technology with particular reference to disinfection of the hospital environment. METHODS: Extensive literature searches for relevant scientific papers and reports. FINDINGS: A large body of scientific evidence is now available that provides underpinning knowledge of the 405 nm light-induced photodynamic inactivation process involved in the destruction of a wide range of prokaryotic and eukaryotic microbial species, including resistant forms such as bacterial and fungal spores. For practical application, a high-intensity narrow-spectrum light environmental disinfection system (HINS-light EDS) has been developed and tested in hospital isolation rooms. The trial results have demonstrated that this 405 nm light system can provide continuous disinfection of air and exposed surfaces in occupied areas of the hospital, thereby substantially enhancing standard cleaning and infection control procedures. CONCLUSION: Violet-blue light, particularly 405 nm light, has significant antimicrobial properties against a wide range of bacterial and fungal pathogens and, although germicidal efficacy is lower than UV light, this limitation is offset by its facility for safe, continuous use in occupied environments. Promising results on disinfection efficacy have been obtained in hospital trials but the full impact of this technology on reduction of healthcare-associated infection has yet to be determined.


Subject(s)
Bacteria/radiation effects , Disinfection/methods , Environmental Microbiology , Fungi/radiation effects , Light , Humans
13.
Fungal Biol ; 117(7-8): 519-27, 2013.
Article in English | MEDLINE | ID: mdl-23931117

ABSTRACT

This study assessed the effects of high-intensity violet light on selected yeast and mould fungi. Cell suspensions of Saccharomyces cerevisiae, Candida albicans, and dormant and germinating spores (conidia) of the mould Aspergillus niger were exposed to high-intensity narrow band violet light with peak output at 405 nm generated from a light-emitting diode (LED) array. All three fungal species were inactivated by the 405-nm light without a requirement for addition of exogenous photosensitiser chemicals. Of the fungal species tested, S. cerevisiae was most sensitive and dormant conidia of A. niger were most resistant to 405-nm light exposure. Five-log10 colony forming units per millilitre (CFU ml(-1)) reductions of the tested species required exposure doses of 288 J cm(-2) for S. cerevisiae, 576 J cm(-2) for C. albicans, and a much higher value of 2.3 kJ cm(-2) for dormant conidia of A. niger. During germination, A. niger conidia became more sensitive to 405-nm light exposure and sensitivity increased as germination progressed over an 8 h test period. Light exposure under aerobic and anaerobic conditions, together with results obtained using ascorbic acid as a scavenger of reactive oxygen species, revealed that 405-nm light inactivation in fungi involved an oxygen-dependent mechanism, as previously described in bacteria. The inactivation results achieved with yeast cells and fungal spores together with operational advantages associated with the use of a visible (nonultraviolet (UV)) light source highlight the potential of 405-nm light for fungal decontamination applications.


Subject(s)
Aspergillus niger/radiation effects , Candida albicans/radiation effects , Saccharomyces cerevisiae/radiation effects , Spores, Fungal/growth & development , Aspergillus niger/growth & development , Candida albicans/growth & development , Microbial Viability/radiation effects , Saccharomyces cerevisiae/growth & development , Spores, Fungal/radiation effects , Ultraviolet Rays
14.
Eur Cell Mater ; 25: 204-14, 2013 Mar 07.
Article in English | MEDLINE | ID: mdl-23471732

ABSTRACT

Infection rates after arthroplasty surgery are between 1-4 %, rising significantly after revision procedures. To reduce the associated costs of treating these infections, and the patients' post-operative discomfort and trauma, a new preventative method is required. High intensity narrow spectrum (HINS) 405 nm light has bactericidal effects on a wide range of medically important bacteria, and it reduced bacterial bioburden when used as an environmental disinfection method in a Medical Burns Unit. To prove its safety for use for environmental disinfection in orthopaedic theatres during surgery, cultured osteoblasts were exposed to HINS-light of intensities up to 15 mW/cm2 for 1 h (54 J/cm2). Intensities of up to 5 mW/cm2 for 1 h had no effect on cell morphology, activity of alkaline phosphatase, synthesis of collagen or osteocalcin expression, demonstrating that under these conditions this dose is the maximum safe exposure for osteoblasts; after exposure to 15 mW/cm2 all parameters of osteoblast function were significantly decreased. Viability (measured by protein content and Crystal Violet staining) of the osteoblasts was not influenced by exposure to 5 mW/cm2 for at least 2 h. At 5 mW/cm2 HINS-light is an effective bactericide. It killed 98.1 % of Staphylococcus aureus and 83.2 % Staphylococcus epidermis populations seeded on agar surfaces, and is active against both laboratory strains and clinical isolates from infected hip and knee arthroplasties. HINS-light could have potential for development as a method of disinfection to reduce transmission of bacteria during arthroplasty, with wider applications in diverse surgical procedures involving implantation of a medical device.


Subject(s)
Arthroplasty , Disinfection/methods , Light , Osteoblasts/radiation effects , Staphylococcus aureus/radiation effects , Staphylococcus epidermidis/radiation effects , Alkaline Phosphatase/metabolism , Animals , Cell Shape/radiation effects , Cell Survival/radiation effects , Cells, Cultured , Collagen/metabolism , Microbial Viability/radiation effects , Osteoblasts/enzymology , Osteoblasts/physiology , Osteocalcin/metabolism , Rats , Staphylococcal Infections/microbiology , Staphylococcal Infections/prevention & control , Staphylococcus aureus/isolation & purification , Staphylococcus epidermidis/isolation & purification , Surgical Wound Infection/microbiology , Surgical Wound Infection/prevention & control
15.
Mol Psychiatry ; 17(1): 36-48, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21042317

ABSTRACT

Major depressive disorder (MDD) is a common complex disorder with a partly genetic etiology. We conducted a genome-wide association study of the MDD2000+ sample (2431 cases, 3673 screened controls and >1 M imputed single-nucleotide polymorphisms (SNPs)). No SNPs achieved genome-wide significance either in the MDD2000+ study, or in meta-analysis with two other studies totaling 5763 cases and 6901 controls. These results imply that common variants of intermediate or large effect do not have main effects in the genetic architecture of MDD. Suggestive but notable results were (a) gene-based tests suggesting roles for adenylate cyclase 3 (ADCY3, 2p23.3) and galanin (GAL, 11q13.3); published functional evidence relates both of these to MDD and serotonergic signaling; (b) support for the bipolar disorder risk variant SNP rs1006737 in CACNA1C (P=0.020, odds ratio=1.10); and (c) lack of support for rs2251219, a SNP identified in a meta-analysis of affective disorder studies (P=0.51). We estimate that sample sizes 1.8- to 2.4-fold greater are needed for association studies of MDD compared with those for schizophrenia to detect variants that explain the same proportion of total variance in liability. Larger study cohorts characterized for genetic and environmental risk factors accumulated prospectively are likely to be needed to dissect more fully the etiology of MDD.


Subject(s)
Adenylyl Cyclases/genetics , Calcium Channels, L-Type/genetics , Depressive Disorder, Major/genetics , Galanin/genetics , Genetic Predisposition to Disease/genetics , Polymorphism, Single Nucleotide/genetics , Adolescent , Adult , Female , Genome-Wide Association Study , Genotype , Humans , Male , Middle Aged , Odds Ratio , Principal Component Analysis , Sex Factors , Young Adult
16.
Mol Psychiatry ; 17(12): 1328-39, 2012 Dec.
Article in English | MEDLINE | ID: mdl-21968932

ABSTRACT

In a previous study, we detected a 6p25-p24 region linked to schizophrenia in families with high composite cognitive deficit (CD) scores, a quantitative trait integrating multiple cognitive measures. Association mapping of a 10 Mb interval identified a 260 kb region with a cluster of single-nucleotide polymorphisms (SNPs) significantly associated with CD scores and memory performance. The region contains two colocalising genes, LYRM4 and FARS2, both encoding mitochondrial proteins. The two tagging SNPs with strongest evidence of association were located around the overlapping putative promoters, with rs2224391 predicted to alter a transcription factor binding site (TFBS). Sequencing the promoter region identified 22 SNPs, many predicted to affect TFBSs, in a tight linkage disequilibrium block. Luciferase reporter assays confirmed promoter activity in the predicted promoter region, and demonstrated marked downregulation of expression in the LYRM4 direction under the haplotype comprising the minor alleles of promoter SNPs, which however is not driven by rs2224391. Experimental evidence from LYRM4 expression in lymphoblasts, gel-shift assays and modelling of DNA breathing dynamics pointed to two adjacent promoter SNPs, rs7752203-rs4141761, as the functional variants affecting expression. Their C-G alleles were associated with higher transcriptional activity and preferential binding of nuclear proteins, whereas the G-A combination had opposite effects and was associated with poor memory and high CD scores. LYRM4 is a eukaryote-specific component of the mitochondrial biogenesis of Fe-S clusters, essential cofactors in multiple processes, including oxidative phosphorylation. LYRM4 downregulation may be one of the mechanisms involved in inefficient oxidative phosphorylation and oxidative stress, increasingly recognised as contributors to schizophrenia pathogenesis.


Subject(s)
Cognition Disorders/genetics , Genes, Overlapping/genetics , Iron-Regulatory Proteins/genetics , Mitochondrial Proteins/genetics , Promoter Regions, Genetic/genetics , Schizophrenia/genetics , Schizophrenic Psychology , Adolescent , Adult , Aged , Aged, 80 and over , Alleles , Case-Control Studies , Cell Line , Cognition Disorders/complications , Female , Gene Expression/genetics , Genetic Association Studies/statistics & numerical data , Humans , Iron-Regulatory Proteins/metabolism , Male , Middle Aged , Mitochondrial Proteins/metabolism , Phenylalanine-tRNA Ligase/genetics , Polymorphism, Single Nucleotide/genetics , Schizophrenia/complications
17.
Dalton Trans ; 40(27): 7181-92, 2011 Jul 21.
Article in English | MEDLINE | ID: mdl-21666895

ABSTRACT

The molecular structures of 1,2-closo-P(2)B(10)H(10) (1) and 1,2-closo-As(2)B(10)H(10) (2) have been determined by gas electron diffraction and the results obtained compared with those from computation at the MP2/6-31G** level of theory. The level of agreement is good for 2 (root-mean-square [rms] misfit for As and B atoms 0.0297 Å) and very good for 1 (rms misfit for P and B atoms 0.0082 Å). In comparing the structures of 1 and 2 with that of 1,2-closo-C(2)B(10)H(12) (I) it is evident that expansion of the polyhedron from I to 1 to 2 is restricted only to the heteroatom vertices and the B(6) face to which these are bound. Following deboronation (at B3) and subsequent metallation, compounds 1 and 2 have been converted into the new metalladiheteroboranes 3-(η-C(9)H(7))-3,1,2-closo-CoAs(2)B(9)H(9) (4), 3-(η-C(10)H(14))-3,1,2-closo-RuAs(2)B(9)H(9) (5), 3-(η-C(5)H(5))-3,1,2-closo-CoP(2)B(9)H(9) (6), 3-(η-C(9)H(7))-3,1,2-closo-CoP(2)B(9)H(9) (7) and 3-(η-C(10)H(14))-3,1,2-closo-RuP(2)B(9)H(9) (8), the last three constituting the first examples of metalladiphosphaboranes. Together with the known compound 3-(η-C(5)H(5))-3,1,2-closo-CoAs(2)B(9)H(9) (3), compounds 4-8 have been analysed by NMR spectroscopy and (except for 8) single-crystal X-ray diffraction. The (11)B NMR spectra of analogous pairs of metalladiphosphaborane and metalladiarsaborane (6 and 3, 7 and 4, 8 and 5) reveal a consistently narrower (9-10 ppm) chemical shift range for the metalladiarsaboranes, the combined result of a deshielding of the lowest frequency resonance (B6) and an increased shielding of the highest frequency resonance (B8) via an antipodal effect. In crystallographic studies, compounds 3 and 5B (one of two crystallographically-independent molecules) suffer As/B disorder, but in both cases it was possible to refine distinct, ordered, components of the disorder, the first time this has been reported for metalladiarsaboranes. Moreover, whilst the Cp compounds 6 and 3 are disordered, their indenyl analogues 7 and 4 are either ordered or significantly less disordered, a consequence of both the reduced symmetry of an indenyl ligand compared to a Cp ligand and the preference of the former for a distinct conformation relative to the cage heteroatoms. Unexpectedly, whilst this conformation in the cobaltadiphosphaborane 7 is cis-staggered (similar to that previously established for the analogous cobaltadicarborane), in the cobaltadiarsaborane 4 the conformation is close to cis-eclipsed.

18.
Ecohealth ; 7(3): 294-306, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20945078

ABSTRACT

Salmonellosis has been reported as an important cause of mortality of garden birds in several countries, including Norway and Scotland. We investigated the frequency of the disease in garden birds submitted for postmortem examination by members of the public in England and Wales between 1993 and 2003, inclusive. We found salmonellosis to be the most frequent cause of death due to infectious disease in the garden birds submitted. This disease was confirmed in 7 of the 45 bird species that were examined postmortem, with the greenfinch (Carduelis chloris) and the house sparrow (Passer domesticus) most frequently affected. Salmonella Typhimurium definitive phage type (DT) 40, DT56 variant(v), and DT160 accounted for the majority of isolates. Salmonellosis incidents chiefly occurred in the English Midlands, the English/Welsh border region, and southern England. Variation in the temporal and spatial distribution of the phage types occurred over the study period. While birds were examined throughout the year, there was a marked winter seasonality in salmonellosis. A significant sex bias was observed in affected greenfinches, with males more frequently diagnosed with salmonellosis than females. No sex bias was observed for other affected species. Further research is required to determine if salmonellosis is an important constraint to the populations of affected species and if disease outbreaks are driven by human factors, such as provisioning.


Subject(s)
Passeriformes/microbiology , Salmonella Infections, Animal/epidemiology , Salmonella Infections, Animal/microbiology , Salmonella Phages/isolation & purification , Salmonella typhimurium/isolation & purification , Animals , Autopsy , Birds , Disease Outbreaks , England/epidemiology , Female , Geography , Male , Risk Factors , Salmonella Infections, Animal/mortality , Seasons , Wales/epidemiology
19.
J Hosp Infect ; 76(3): 247-51, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20864210

ABSTRACT

The performance of a new decontamination technology, referred to as 'high-intensity narrow-spectrum light environmental decontamination system' (HINS-light EDS) was evaluated by a series of three studies carried out in a hospital isolation room used to treat burns patients. The ceiling-mounted HINS-light EDS emits high-intensity 405nm light which, although bactericidal, is harmless to patients and staff thereby permitting continuous environmental disinfection throughout the day. Performance efficacy was assessed by contact agar plate sampling and enumeration of staphylococcal bacteria on environmental surfaces within the room before, during and after HINS-light EDS treatment. When the room was unoccupied, use of HINS-light EDS resulted in ∼90% reduction of surface bacterial levels and when the room was occupied by an MRSA-infected burns patient, reductions between 56% and 86% were achieved, with the highest reduction (86%) measured following an extended period of HINS-light EDS operation. In an on/off intervention study, surface bacterial levels were reduced by 62% by HINS-light EDS treatment and returned to normal contamination levels two days after the system was switched off. These reductions of staphylococci, including Staphylococcus aureus and meticillin-resistant S. aureus, by HINS-light EDS treatment were greater than the reductions achieved by normal infection control and cleaning activities alone. The findings provide strong evidence that HINS-light EDS, used as a supplementary procedure, can make a significant contribution to bacterial decontamination in clinical environments.


Subject(s)
Decontamination/methods , Hospital Units , Infection Control/methods , Light , Patient Isolation , Colony Count, Microbial , Environment , Humans , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Methicillin-Resistant Staphylococcus aureus/radiation effects , Staphylococcal Infections/prevention & control , Staphylococcus aureus/isolation & purification , Staphylococcus aureus/radiation effects
20.
Heredity (Edinb) ; 105(2): 229-34, 2010 Aug.
Article in English | MEDLINE | ID: mdl-19997123

ABSTRACT

The Norfolk Island population in the South Pacific is primarily the product of recent admixture between a small number of British male and Polynesian female founders. We identified and genotyped 128 Ancestry Informative Markers (AIMs) spread across the autosomes, X/Y chromosomes and mitochondrial DNA genome, to explore and quantify the current levels of genetic admixture in the Norfolk Islanders. On the basis of autosomal AIMs, the population shows mean European and Polynesian ancestry proportions of 88 and 12%, respectively. However, there is a substantial variation between individuals ranging from total European ancestry to near total Polynesian origin. There is a strong correlation between individual genetic estimates of Polynesian ancestry and those derived from the extensive pedigree and genealogical records of Islanders. Also in line with historical accounts, there is a substantial asymmetry in the maternal and paternal origins of the Islanders with almost all Y-chromosomes of European origin whereas at least 25% of mtDNAs appear to have a Polynesian origin. Accurate knowledge of ancestry will be important in future attempts to use the Island population in admixture mapping approaches to find the genes that underlie differences in the risk to some diseases between Europeans and Polynesians.


Subject(s)
Native Hawaiian or Other Pacific Islander/genetics , White People/genetics , DNA, Mitochondrial/genetics , Female , Humans , Male , Melanesia , Sex Chromosomes/genetics
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