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Systematic assessment in an animal model of the angiogenic potential of different human cell sources for therapeutic revascularization
G Robin Barclay, Olga Tura, Kay Samuel, Patrick WF Hadoke, Nicholas L Mills, David E Newby, Marc L Turner
Stem Cell Research & Therapy , 2012, DOI: 10.1186/scrt114

Abstract: Human cells employed were mononuclear cells from normal peripheral blood and HPC-rich cell sources (umbilical cord blood, mobilized peripheral blood, bone marrow), CD34+ enriched or depleted subsets of these, and outgrowth cell populations from these. An established sponge implant angiogenesis model was adapted to determine the effects of different human cells on vascularization of implants in immunodeficient mice. Angiogenesis was quantified by vessel density and species of origin by immunohistochemistry.CD34+ cells from mobilized peripheral blood or umbilical cord blood HPC were the only cells to promote new vessel growth, but did not incorporate into vessels. Only endothelial outgrowth cells (EOC) incorporated into vessels, but these did not promote vessel growth.These studies indicate that, since EPC are very rare, any benefit seen in clinical trials of HPC in therapeutic vascular regeneration is predominantly mediated by indirect proangiogenic effects rather than through direct incorporation of any rare EPC contained within these sources. It should be possible to produce autologous EOC for therapeutic use, and evaluate the effect of EPC distinct from, or in synergy with, the proangiogenic effects of HPC therapies.Circulating endothelial progenitor cells (EPC) were first recognized in 1997 [1,2], introducing the concept that circulating EPC might supplement local angiogenesis which had heretofore been viewed as arising solely by outgrowth from pre-existing vasculature. Thus EPC had potential for development of cell-based therapeutic angiogenesis. EPC in adults were proposed to share a common stem cell with hematopoietic progenitor cells (HPC)[3], and like HPC express CD34 and mobilize from bone marrow [1,2]. It was proposed that, in the absence of a precise phenotype definition, EPC would coincide with HPC. Consequently, development of therapy progressed rapidly through preclinical studies to early clinical studies by employing HPC sources as therapeutic cells o

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Routine Habitat Change: A Source of Unrecognized Transient Alteration of Intestinal Microbiota in Laboratory Mice
Betty W. Ma, Nicholas A. Bokulich, Patricia A. Castillo, Anchasa Kananurak, Mark A. Underwood, David A. Mills, Charles L. Bevins
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0047416

Abstract: The mammalian intestine harbors a vast, complex and dynamic microbial population, which has profound effects on host nutrition, intestinal function and immune response, as well as influence on physiology outside of the alimentary tract. Imbalance in the composition of the dense colonizing bacterial population can increase susceptibility to various acute and chronic diseases. Valuable insights on the association of the microbiota with disease critically depend on investigation of mouse models. Like in humans, the microbial community in the mouse intestine is relatively stable and resilient, yet can be influenced by environmental factors. An often-overlooked variable in research is basic animal husbandry, which can potentially alter mouse physiology and experimental outcomes. This study examined the effects of common husbandry practices, including food and bedding alterations, as well as facility and cage changes, on the gut microbiota over a short time course of five days using three culture-independent techniques, quantitative PCR, terminal restriction fragment length polymorphism (TRFLP) and next generation sequencing (NGS). This study detected a substantial transient alteration in microbiota after the common practice of a short cross-campus facility transfer, but found no comparable alterations in microbiota within 5 days of switches in common laboratory food or bedding, or following an isolated cage change in mice acclimated to their housing facility. Our results highlight the importance of an acclimation period following even simple transfer of mice between campus facilities, and highlights that occult changes in microbiota should be considered when imposing husbandry variables on laboratory animals.

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Experimental exposure to diesel exhaust increases arterial stiffness in man
Magnus Lundb？ck, Nicholas L Mills, Andrew Lucking, Stefan Barath, Ken Donaldson, David E Newby, Thomas Sandstr？m, Anders Blomberg
Particle and Fibre Toxicology , 2009, DOI: 10.1186/1743-8977-6-7

Abstract: In a double-blind randomized fashion, 12 healthy volunteers were exposed to diesel exhaust (approximately 350 μg/m3) or filtered air for one hour during moderate exercise. Arterial stiffness was measured using applanation tonometry at the radial artery for pulse wave analysis (PWA), as well as at the femoral and carotid arteries for pulse wave velocity (PWV). PWA was performed 10, 20 and 30 min, and carotid-femoral PWV 40 min, post-exposure. Augmentation pressure (AP), augmentation index (AIx) and time to wave reflection (Tr) were calculated.Blood pressure, AP and AIx were generally low reflecting compliant arteries. In comparison to filtered air, diesel exhaust exposure induced an increase in AP of 2.5 mmHg (p = 0.02) and in AIx of 7.8% (p = 0.01), along with a 16 ms reduction in Tr (p = 0.03), 10 minutes post-exposure.Acute exposure to diesel exhaust is associated with an immediate and transient increase in arterial stiffness. This may, in part, explain the increased risk for cardiovascular disease associated with air pollution exposure. If our findings are confirmed in larger cohorts of susceptible populations, this simple non-invasive method of assessing arterial stiffness may become a useful technique in measuring the impact of real world exposures to combustion derived-air pollution.The adverse health effects of air pollution have been studied intensely over the last 50 years. Epidemiological studies have identified a strong association between air pollution and increased cardiovascular and respiratory morbidity and mortality [1]. Airborne particles with a diameter of less than 2.5 μm (PM2.5) are considered the main cause of these adverse health effects [2]. In most countries, diesel exhaust (DE) is a major contributor to combustion-derived PM in urban areas [3], exposure to which appears to be an important trigger for acute myocardial infarction [4].In recent years, there has been considerable interest and scientific research into the mechanisms that underpin

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Stress Hyperglycaemia in Hospitalised Patients and Their 3-Year Risk of Diabetes: A Scottish Retrospective Cohort Study
David A. McAllister ,Katherine A. Hughes,Nazir Lone,Nicholas L. Mills,Naveed Sattar,John McKnight,Sarah H. Wild
PLOS Medicine , 2014, DOI: 10.1371/journal.pmed.1001708

Abstract: Background Hyperglycaemia during hospital admission is common in patients who are not known to have diabetes and is associated with adverse outcomes. The risk of subsequently developing type 2 diabetes, however, is not known. We linked a national database of hospital admissions with a national register of diabetes to describe the association between admission glucose and the risk of subsequently developing type 2 diabetes. Methods and Findings In a retrospective cohort study, patients aged 30 years or older with an emergency admission to hospital between 2004 and 2008 were included. Prevalent and incident diabetes were identified through the Scottish Care Information (SCI)-Diabetes Collaboration national registry. Patients diagnosed prior to or up to 30 days after hospitalisation were defined as prevalent diabetes and were excluded. The predicted risk of developing incident type 2 diabetes during the 3 years following hospital discharge by admission glucose, age, and sex was obtained from logistic regression models. We performed separate analyses for patients aged 40 and older, and patients aged 30 to 39 years. Glucose was measured in 86,634 (71.0%) patients aged 40 and older on admission to hospital. The 3-year risk of developing type 2 diabetes was 2.3% (1,952/86,512) overall, was <1% for a glucose ≤5 mmol/l, and increased to approximately 15% at 15 mmol/l. The risks at 7 mmol/l and 11.1 mmol/l were 2.6% (95% CI 2.5–2.7) and 9.9% (95% CI 9.2–10.6), respectively, with one in four (21,828/86,512) and one in 40 (1,798/86,512) patients having glucose levels above each of these cut-points. For patients aged 30–39, the risks at 7 mmol/l and 11.1 mmol/l were 1.0% (95% CI 0.8–1.3) and 7.8% (95% CI 5.7–10.7), respectively, with one in eight (1,588/11,875) and one in 100 (120/11,875) having glucose levels above each of these cut-points. The risk of diabetes was also associated with age, sex, and socio-economic deprivation, but not with specialty (medical versus surgical), raised white cell count, or co-morbidity. Similar results were obtained for pre-specified sub-groups admitted with myocardial infarction, chronic obstructive pulmonary disease, and stroke. There were 25,193 deaths (85.8 per 1,000 person-years) over 297,122 person-years, of which 2,406 (8.1 per 1,000 person-years) were attributed to vascular disease. Patients with glucose levels of 11.1 to 15 mmol/l and >15 mmol/l had higher mortality than patients with a glucose of <6.1 mmol/l (hazard ratio 1.54; 95% CI 1.42–1.68 and 2.50; 95% CI 2.14–2.95, respectively) in models adjusting for age and sex.

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Stop the press: why censorship has made headline news (again)
L Mills
Potchefstroom Electronic Law Journal/Potchefstroomse Elektroniese Regsblad , 2007,

Abstract: The recent publication of proposed amendments to the Films and Publications Act 65 of 1996 drew some sharp criticism from the media. Some organisations described these amendments as, inter alia, unconstitutional, outrageous and as part of the erosion of freedom of speech, while the Department of Home Affairs defended the amendments as an attempt to protect children from potentially harmful and age-inappropriate material. This discussion briefly examines the historical development of censorship as well as the current classification process in South Africa, followed by a discussion of the proposed amendments as well as the reaction thereto. The conclusion is that the media maybe has overreacted with regard to some of the amendments and may not understand the effect of the current classification process, while some of their concerns with regard to some of the other amendments may be justified. The true challenge will be that all stakeholders have an honest discussion with each other and would have to try and strike a balance between the important right of the child to dignity as well as his right to not be exploited, and that of the freedom of speech. The printed media also will have to realise that it is the duty of all members of society to protect the rights of the child and there can be no reason as to why newspapers may be excluded from this duty.

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Stop the Press: Why Censorship Has Made Headline News (AGAIN)
L Mills
Potchefstroom Electronic Law Journal/Potchefstroomse Elektroniese Regsblad , 2007,

Abstract: The recent publication of proposed amendments to the Films and Publications Act 65 of 1996 drew some sharp criticism from the media. Some organizations described these amendments as, inter alia, unconstitutional, outrageous and as part of the erosion of freedom of speech, while the Department of Home Affairs defended the amendments as an attempt to protect children from potentially harmful and age-inappropriate material. This discussion briefly examines the historical development of censorship as well as the current classification process in South Africa, followed by a discussion of the proposed amendments as well as the reaction thereto. The conclusion is that the media maybe has overreacted with regard to some of the amendments and may not understand the effect of the current classification process, while some of their concerns with regard to some of the other amendments may be justified. The true challenge will be that all stakeholders have an honest discussion with each other and would have to try and strike a balance between the important right of the child to dignity as well as his right to not be exploited, and that of the freedom of speech. The printed media also will have to realise that it is the duty of all members of society to protect the rights of the child and there can be no reason as to why newspapers may be excluded from this duty.

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Exposure to diesel exhaust induces changes in EEG in human volunteers
Bj？rn Crüts, Ludo van Etten, H？kan T？rnqvist, Anders Blomberg, Thomas Sandstr？m, Nicholas L Mills, Paul JA Borm
Particle and Fibre Toxicology , 2008, DOI: 10.1186/1743-8977-5-4

Abstract: We exposed 10 human volunteers to dilute diesel exhaust (DE, 300 μg/m3) as a model for ambient PM exposure and filtered air for one hour using a double blind randomized crossover design. Brain activity was monitored during and for one hour following each exposure using quantitative electroencephalography (QEEG) at 8 different sites on the scalp. The frequency spectrum of the EEG signals was used to calculate the median power frequency (MPF) and specific frequency bands of the QEEG.Our data demonstrate a significant increase in MPF in response to DE in the frontal cortex within 30 min into exposure. The increase in MPF is primarily caused by an increase in fast wave activity (β2) and continues to rise during the 1 hour post-exposure interval.This study is the first to show a functional effect of DE exposure in the human brain, indicating a general cortical stress response. Further studies are required to determine whether this effect is mediated by the nanoparticles in DE and to define the precise pathways involved.Several epidemiological studies have identified diesel exhaust as an important component in determining the adverse health effects of particulate matter (PM) air pollution [1,2]. The molecular toxicity of diesel exhaust [3], is suggested to include oxidative stress-mediated inflammation, through particle surface, polycyclic aromatic hydrocarbons and redox active metals. Inflammation is considered to be central to both the pulmonary and systemic adverse health effects of diesel through environmental PM exposure [4]. Over the past decades several, several studies have suggested that inhaled nanoparticles are able to translocate to the brain via the olfactory nerves [5,6], where they have been associated with inflammatory changes at sites of deposition [7,8]. Passage to the brain is of particular concern since nanoparticles are potent inducers of oxidative stress [4,9] and the brain is very sensitive to damage caused by oxidative stress [10]. Oxidative stress

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A single-particle characterization of a mobile Versatile Aerosol Concentration Enrichment System for exposure studies
Evelyn J Freney, Mathew R Heal, Robert J Donovan, Nicholas L Mills, Kenneth Donaldson, David E Newby, Paul HB Fokkens, Flemming R Cassee
Particle and Fibre Toxicology , 2006, DOI: 10.1186/1743-8977-3-8

Abstract: The particle size distribution was unaltered by the concentrator over the size range 0.2–2.6 μm, with an average enrichment factor during this study of ~5 (after dilution of the final air stream). The mass spectra from single particles were objectively grouped into 20 clusters using the multivariate K-means algorithm and then further grouped manually, according to similarity in composition and time sequence, into 8 main clusters. The particle ensemble was dominated by pure and reacted sea salt and other coarse inorganic dusts (as a consequence of the prevailing maritime-source climatology during the study), with relatively minor contributions from carbonaceous and secondary material. Very minor variations in particle composition were noted pre- and post-particle concentration, but overall there was no evidence of any significant change in particle composition.These results confirm, via single particle analysis, the preservation of the size distribution and chemical composition of fine ambient PM in the size range 0.2–2.6 μm after passage through the VACES concentration instrumentation.Epidemiological studies have consistently shown that elevated levels of particulate matter (PM) air pollution are associated with increases in asthma severity and worsening of respiratory ill-health, as well as increased mortality not only from respiratory causes but also from cardiovascular disease [1,2]. The associations are often strongest for the fine (PM2.5) fraction [3] which penetrates to the alveoli of the respiratory system [4].Two of the most important challenges for researchers in this field are to establish (i) the physicochemical properties of the inhaled particles responsible for observed ill-health associations, and (ii) the consequent biological mechanisms of causation. Progress on the former requires enhanced size and chemical characterisation of the ambient particles to which populations or panel members are exposed, whilst progress on the latter requires experiments

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