MyMedR

Displaying all 7 publications

Abstract:

Sort:

Childhood pneumonia: a neglected, climate-sensitive disease?

Paynter S, Ware RS, Weinstein P, Williams G, Sly PD

Lancet, 2010 Nov 27;376(9755):1804-5.
PMID: 21111894 DOI: 10.1016/S0140-6736(10)62141-1
When water is thicker than blood: recognising a systemic cause of haemoptysis

Wedge E, Abrahamson E, Tudor-Williams G, Nadel S, Deal J

Arch Dis Child Educ Pract Ed, 2017 Aug;102(4):210-219.
PMID: 27780827 DOI: 10.1136/archdischild-2015-308957

The case of an 11-year-old child presenting with acute haemoptysis and breathlessness is described. The girl was Malaysian and had recently arrived in the UK. She subsequently deteriorated, developing respiratory failure. The course of the illness is described, with reference to the diagnostic process at each stage. The case demonstrates the importance of having a broad investigatory approach in acute haemoptysis.
Protection of hydroquinone-induced apoptosis by downregulation of Fau is mediated by NQO1

Siew EL, Chan KM, Williams GT, Ross D, Inayat-Hussain SH

Free Radic. Biol. Med., 2012 Oct 15;53(8):1616-24.
PMID: 22687461 DOI: 10.1016/j.freeradbiomed.2012.05.046

The Fau gene (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV)-associated ubiquitously expressed gene) was identified as a potential tumor suppressor gene using a forward genetics approach. Downregulation of Fau by overexpression of its reverse sequence has been shown to inhibit apoptosis induced by DNA-damaging agents. To address a potential role of Fau in benzene toxicity, we investigated the apoptotic effects of hydroquinone (HQ), a major benzene metabolite, in W7.2 mouse thymoma cells transfected with either a plasmid construct expressing the antisense sequence of Fau (rfau) or the empty vector (pcDNA3.1) as a control. HQ induced apoptosis via increased production of reactive oxygen species and DNA damage, measured using dihydroethidine (HE) staining and alkaline Comet assay, respectively, in W7.2 pcDNA3.1 cells. In contrast, when Fau was downregulated by the antisense sequence in W7.2 rfau cells, HQ treatment did not cause DNA damage and oxidative stress and these cells were markedly more resistant to HQ-induced apoptosis. Further investigation revealed that there was an upregulation of NAD(P)H: quinone oxidoreductase 1 (NQO1), a detoxification enzyme for benzene-derived quinones, in W7.2 rfau cells. Compromising cellular NQO1 by use of a specific mechanism-based inhibitor (MAC 220) and NQO1 siRNA resensitized W7.2 rfau cells to HQ-induced apoptosis. Silencing of Fau in W7.2 wild-type cells resulted in increased levels of NQO1, confirming that downregulation of Fau results in NQO1 upregulation which protects against HQ-induced apoptosis.
Fulltext Goniothalamin-induced oxidative stress, DNA damage and apoptosis via caspase-2 independent and Bcl-2 independent pathways in Jurkat T-cells

Inayat-Hussain SH, Chan KM, Rajab NF, Din LB, Chow SC, Kizilors A, et al.

Toxicol Lett, 2010 Mar 1;193(1):108-14.
PMID: 20026395 DOI: 10.1016/j.toxlet.2009.12.010

Goniothalamin (GTN) isolated from Goniothalamus sp. has been demonstrated to induce apoptosis in a variety of cancer cell lines including Jurkat T leukemia cells. However, the mechanism of GTN-induced apoptosis upstream of mitochondria is still poorly defined. In this study, GTN caused a decrease in GSH with an elevation of reactive oxygen species as early as 30 min and DNA damage as assessed by Comet assay. Analysis using topoisomerase II processing of supercoiled pBR 322 DNA showed that GTN caused DNA damage via a topoisomerase II-independent pathway suggesting that cellular oxidative stress may contribute to genotoxicity. A 12-fold increase of caspase-2 activity was observed in GTN-treated Jurkat cells after 4h treatment and this was confirmed using Western blotting. Although the caspase-2 inhibitor Z-VDVAD-FMK inhibited the proteolytic activity of caspase-2, apoptosis ensued confirming that caspase-2 activity was not crucial for GTN-induced apoptosis. However, GTN-induced apoptosis was completely abrogated by N-acetylcysteine further confirming the role of oxidative stress. Since cytochrome c release was observed as early as 1h without any appreciable change in Bcl-2 protein expression, we further investigated whether overexpression of Bcl-2 confers resistance in GTN-induced cytotoxicity. Using a panel of Jurkat Bcl-2 transfectants, GTN cytotoxicity was not abrogated in these cells. In conclusion, GTN induces DNA damage and oxidative stress resulting in apoptosis which is independent of both caspase-2 and Bcl-2.
Fulltext RACK-1 overexpression protects against goniothalamin-induced cell death

Inayat-Hussain SH, Wong LT, Chan KM, Rajab NF, Din LB, Harun R, et al.

Toxicol Lett, 2009 Dec 15;191(2-3):118-22.
PMID: 19698770 DOI: 10.1016/j.toxlet.2009.08.012

Goniothalamin, a styryllactone, has been shown to induce cytotoxicity via apoptosis in several tumor cell lines. In this study, we have examined the potential role of several genes, which were stably transfected into T-cell lines and which regulate apoptosis in different ways, on goniothalamin-induced cell death. Overexpression of full-length receptor for activated protein C-kinase 1 (RACK-1) and pc3n3, which up-regulates endogenous RACK-1, in both Jurkat and W7.2 T cells resulted in inhibition of goniothalamin-induced cell death as assessed by MTT and clonogenic assays. However, overexpression of rFau (antisense sequence to Finkel-Biskis-Reilly murine sarcoma virus-associated ubiquitously expressed gene) in W7.2 cells did not confer resistance to goniothalamin-induced cell death. Etoposide, a clinically used cytotoxic agent, was equipotent in causing cytotoxicity in all the stable transfectants. Assessment of DNA damage by Comet assay revealed goniothalamin-induced DNA strand breaks as early as 1 h in vector control but this effect was inhibited in RACK-1 and pc3n3 stably transfected W7.2 cells. This data demonstrate that RACK-1 plays a crucial role in regulating cell death signalling pathways induced by goniothalamin.
Fulltext Comparison of Pediatric Severe Sepsis Managed in U.S. and European ICUs

Giuliano JS, Markovitz BP, Brierley J, Levin R, Williams G, Lum LC, et al.

Pediatr Crit Care Med, 2016 06;17(6):522-30.
PMID: 27124566 DOI: 10.1097/PCC.0000000000000760

OBJECTIVES: Pediatric severe sepsis remains a significant global health problem without new therapies despite many multicenter clinical trials. We compared children managed with severe sepsis in European and U.S. PICUs to identify geographic variation, which may improve the design of future international studies.
DESIGN: We conducted a secondary analysis of the Sepsis PRevalence, OUtcomes, and Therapies study. Data about PICU characteristics, patient demographics, therapies, and outcomes were compared. Multivariable regression models were used to determine adjusted differences in morbidity and mortality.
SETTING: European and U.S. PICUs.
PATIENTS: Children with severe sepsis managed in European and U.S. PICUs enrolled in the Sepsis PRevalence, OUtcomes, and Therapies study.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: European PICUs had fewer beds (median, 11 vs 24; p < 0.001). European patients were younger (median, 1 vs 6 yr; p < 0.001), had higher severity of illness (median Pediatric Index of Mortality-3, 5.0 vs 3.8; p = 0.02), and were more often admitted from the ward (37% vs 24%). Invasive mechanical ventilation, central venous access, and vasoactive infusions were used more frequently in European patients (85% vs 68%, p = 0.002; 91% vs 82%, p = 0.05; and 71% vs 50%; p < 0.001, respectively). Raw morbidity and mortality outcomes were worse for European compared with U.S. patients, but after adjusting for patient characteristics, there were no significant differences in mortality, multiple organ dysfunction, disability at discharge, length of stay, or ventilator/vasoactive-free days.
CONCLUSIONS: Children with severe sepsis admitted to European PICUs have higher severity of illness, are more likely to be admitted from hospital wards, and receive more intensive care therapies than in the United States. The lack of significant differences in morbidity and mortality after adjusting for patient characteristics suggests that the approach to care between regions, perhaps related to PICU bed availability, needs to be considered in the design of future international clinical trials in pediatric severe sepsis.
Fulltext Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

Goodson WH, Lowe L, Carpenter DO, Gilbertson M, Manaf Ali A, Lopez de Cerain Salsamendi A, et al.

Carcinogenesis, 2015 Jun;36 Suppl 1:S254-96.
PMID: 26106142 DOI: 10.1093/carcin/bgv039

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.