Bacterial causes of empyema in children, Australia, 2007-2009

An increase in the incidence of empyema worldwide could be related to invasive pneumococcal disease caused by emergent nonvaccine replacement serotypes. To determine bacterial pathogens and pneumococcal serotypes that cause empyema in children in Australia, we conducted a 2-year study of 174 children with empyema. Blood and pleural fluid samples were cultured, and pleural fluid was tested by PCR. Thirty-two (21.0%) of 152 blood and 53 (33.1%) of 160 pleural fluid cultures were positive for bacteria; Streptococcus pneumoniae was the most common organism identified. PCR identified S. pneumoniae in 74 (51.7%) and other bacteria in 19 (13.1%) of 145 pleural fluid specimens. Of 53 samples in which S. pneumoniae serotypes were identified, 2 (3.8%) had vaccine-related and 51 (96.2%) had nonvaccine serotypes; 19A (n = 20; 36.4%), 3 (n = 18; 32.7%), and 1 (n = 8; 14.5%) were the most common. High proportions of nonvaccine serotypes suggest the need to broaden vaccine coverage.     

Mechanism Underlying the Effects of Estrogen Deficiency on Otoconia

Otoconia-related vertigo and balance deficits, particularly benign paroxysmal positional vertigo (BPPV), are common. Our recent studies in humans show that, while BPPV prevalence greatly increases with age in both genders, peri-menopausal women are especially susceptible. In the present study, we show that bilateral ovariectomized (OVX) mice have significant balance behavioral deficits, and that estrogen deficiency compromises otoconia maintenance and anchoring by reducing the expression of otoconial component and anchoring proteins. There is ectopic debris formation in the ampulla under estrogen deficiency due to aberrant matrix protein expression. Furthermore, phytoestrogen is effective in rescuing the otoconia abnormalities. By comparing the expression levels of known estrogen receptor (Esr) subtypes, and by examining the otoconia phenotypes of null mice for selected receptors, we postulate that Esr2 may be critical in mediating the effects of estrogen in otoconia maintenance.     

The AREST CF experience in biobanking — More than just tissues,tubes and time

Research to further improve outcomes for people with CF is dependent upon well characterised, archived and accessible clinical specimens. The recent article by Beekman et al. published in Journal of Cystic Fibrosis summarised a scientific meeting at the 13th ECFS Basic Science Conference. This meeting discussed how well-annotated, clinical biobanks for CF could be established in Europe to meet the needs of therapeutic development. The Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) has conducted biobanking of CF research and clinical specimens since the late 1990s and is custodian of the most comprehensive paediatric CF biobank in the world that focuses on the first years of life. This short communication will describe the approach undertaken by AREST CF in establishing a clinical specimen biobank.     

Human ketosteroid receptors interact with hazardous phthalate plasticizers and their metabolites: an in silico study

Phthalic acid esters or phthalates are ubiquitous environmental pollutants known for their adverse health effects in test animals and, of late, in humans. Thus, in this molecular docking study – using Glide (Schrödinger) – the molecular interactions of 31 ligands, including 12 diphthalates, their monophthalates and phthalic acid with selected human ketosteroid receptors, i.e., androgen (hAR), progesterone (hPR) and glucocorticoid (hGR) receptors were explored and their binding affinities were compared with that of corresponding natural steroids and a known endocrine disrupting xenobiotic, bisphenol A (BPA). Mostly, diphthalates and monophthalates showed the potential for antisteroidal activity by interacting with hAR, hPR and hGR. Of them, diphenyl phthalate showed the highest G score (–7.70 kcal mol^–1) with hAR, and the crucial amino acid (aa) residues in the ligand binding domain (LBD) of this receptor involved in the molecular interactions were Phe 764, Leu 704, Asn 705 and Thr 877. The mono‐iso‐decyl phthalate showed the highest G score (–8.36) with the hPR, and the crucial aa residues in the LBD interactions were Arg 766 Gln 725 and Phe 778. The mono‐iso‐decyl phthalate also showed more affinity (–8.44) towards hGR than the natural ligand, and the aa residues in the LBD interactions were Gln 570 and Met 604. In addition to these, some other phthalates established comparable interactions with certain aa residues located in the LBD of these receptors, which resulted in higher G scores. Contrastingly, BPA and some natural ligands tested in this study showed lower G scores with these receptors than certain phthalates reported herein, i.e., certain phthalates are more toxic than the proven toxic BPA. Copyright © 2015 John Wiley & Sons, Ltd.     

The flavoprotein FOXRED2 reductively activates nitro-chloromethylbenzindolines and other hypoxia-targeting prodrugs

The nitro-chloromethylbenzindoline prodrug SN29428 has been rationally designed to target tumour hypoxia. SN29428 is metabolised to a DNA minor groove alkylator via oxygen-sensitive reductive activation initiated by unknown one-electron reductases. The present study sought to identify reductases capable of activating SN29428 in tumours. Expression of candidate reductases in cell lines was modulated using forced expression and, for P450 (cytochrome) oxidoreductase (POR), by zinc finger nuclease-mediated gene knockout. Affymetrix microarray mRNA expression of flavoreductases was correlated with SN29428 activation in a panel of 23 cancer cell lines. Reductive activation and cytotoxicity of prodrugs were measured using mass spectrometry and antiproliferative assays, respectively. SN29428 activation under hypoxia was strongly attenuated by the pan-flavoprotein inhibitor diphenyliodonium, but less so by knockout of POR suggesting other flavoreductases contribute. Forced expression of 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), as well as POR, increased activation of SN29428 in hypoxic HCT 116 cells. SN29428 activation strongly correlated with expression of POR and also FAD-dependent oxidoreductase domain containing 2 (FOXRED2), in cancer cell lines. This association persisted after removing the effect of POR enzyme activity using first-order partial correlation. Forced expression of FOXRED2 increased SN29428 activation and cytotoxicity in hypoxic HEK293 cells and also increased activation of hypoxia-targeted prodrugs PR-104A, tirapazamine and SN30000, and increased cytotoxicity of the clinical-stage prodrug TH-302. Thus this study has identified three flavoreductases capable of enzymatically activating SN29428, one of which (FOXRED2) has not previously been implicated in xenobiotic metabolism. These results will inform future development of biomarkers predictive of SN29428 sensitivity.     

Health benefits of adapting cleaner brick manufacturing technologies in Dhaka,Bangladesh

A total of 1,000 kilns producing 3.5 billion bricks and consuming 0.85 million tons of coal per year resulted in an estimated 2,200 to 4,000 premature deaths and 0.2 to 0.5 million asthma attacks per year in the Greater Dhaka region. In this paper, the emission reductions and health cost savings are presented for moving to cleaner brick manufacturing technologies for the districts of Gazipur, Savar, Dhamrai, Rupganj, Manikganj, Kaliganj, and Narayanganj. A summary of various technologies and feasibility of these technologies based on lessons learnt from the pilots is discussed. We explored three “what-if” scenarios through 2020 for better energy efficiency, lower coal consumption, and lower emission rates, under which the total health cost savings are estimated to range between USD12 million annually for short-term implementation and up to 55 million annually for long-term implementation. Between 2015 and 2020, the cumulative health cost savings could range between USD126 and 234 million, which clearly outweigh any cost of capital investment necessary for the technology change. An improvement in energy efficiency will result in USD1.8 to 3.0 million per year in coal savings, which will accrue to the kiln owners collectively, and these savings will pay back the capital investment within 3–4 years, in addition to the health cost savings for the city inhabitants. Hence, the entrepreneurs have all the social, environmental, and economic incentives to adopt cleaner technologies. A major gap at the regulatory level is in building awareness for the entrepreneurs and setting up an incentive structure to implement this transition, which is being addressed by an advisory committee by the Government of Bangladesh responsible for the revision of the Brick Burning Act of 1989 and related legislations.     

A novel activity from an old compound: Manzamine A reduces the metastatic potential of AsPC-1 pancreatic cancer cells and sensitizes them to TRAIL-induced apoptosis

Purpose: Pancreatic cancer is the fourth leading cause of cancer death in the United States, and new drugs to treat the disease are needed. Pancreatic cancer cells are highly metastatic and exhibit resistance to apoptosis. Small molecules that can restore sensitivity to apoptosis or reduce metastasis would have therapeutic potential against this disease. Manzamine A is an alkaloid isolated from marine sponges that was suspected to have inhibitory activity against the mitogen activated kinase kinase (MEK). Because of this, the effects of Manzamine A were studied in pancreatic cancer cells. Methods: AsPC-1 cells were treated for 48 h in the presence of various concentrations of Manzamine A and their phenotype, cytotoxicity, cell invasion and susceptibility to apoptosis were observed. Results: Manzamine A decreased single cell formation, abrogated cell migration and restored the susceptibility of the cells to TRAIL-induced apoptosis in AsPC-1 cells. Its mechanism of action remains unknown, as manzamine A does not inhibit MEK. Conclusions: Manzamine A appears to have a formerly unrecognized activity in blocking tumor cell invasion as well as in restoring cancer cell susceptibility to apoptosis in vitro and therefore has the potential to be used as an adjuvant to existing cancer therapies.