Propofol and children--what we know and what we do not know.

The pharmacokinetics of propofol are relatively well described in the pediatric population. Recent work has confirmed the validity of allometric scaling for predicting propofol disposition across different species and for describing pediatric ontogenesis. In the first year of life, allometric models require adjustment to reflect ontogeny of maturation. Pharmacodynamic data for propofol in children are scarcer, because of practical difficulties in data collection and the limitations of currently available depth of anesthesia monitors for pediatric use. Hence, questions relating to the comparative sensitivity of children to propofol, and differences in time to peak effect relative to adults, remain unanswered. K(eo) half-lives have been determined for pediatric kinetic models using time to peak effect techniques but are not currently incorporated into commercially available target-controlled infusion pumps

Migrant workers in the East Midlands labour market 2007

This report provides a profile of international migrants in the East Midlands and their role in the regional labour marke

The MRC trial of assessment and management of older people in the community: objectives, design and interventions [ISRCTN23494848].

BACKGROUND: The benefit of regular multidimensional assessment of older people remains controversial. The majority of trials have been too small to produce adequate evidence to inform policy. Despite the lack of a firm evidence base, UK primary care practitioners (general practitioners) are required to offer an annual health check to patients aged 75 years and over. DESIGN: Cluster-randomised factorial trial in primary care comparing a package of assessments (i) universal versus targeted assessment and (ii) management by the primary care team (PC) or a multidisciplinary geriatric assessment team (GM). The unit of randomization is the general practice. METHODS: Older people aged 75 and over eligible for the over 75s health check and excluding those in nursing homes or terminally ill were invited to participate. All participants receive a brief assessment covering all areas of the over 75s check. In the universal arm all participants also receive a detailed health and social assessment by a study nurse while in the targeted arm only participants with a pre-determined number and range of problems at the brief assessment go on to have the detailed assessment. The study nurse follows a standard protocol based on results and responses in the detailed assessment to make referrals to (i) the randomised management team (PC or GM) (ii) other medical services, health care workers or agencies (iii) emergency referrals to the GP. The main outcomes are mortality, hospital and institutional admissions and quality of life. 106 practices and 33,000 older people have been recruited to the trial

Migrant workers in the East Midlands labour market 2010

This report is an update of previous intelligence (Migrant Workers in the East Midlands Labour Market 2007) on the profile and economic impact of migrant labour in the East Midlands economy

Stochastic epigenetic outliers can define field defects in cancer

BACKGROUND: There is growing evidence that DNA methylation alterations may contribute to carcinogenesis. Recent data also suggest that DNA methylation field defects in normal pre-neoplastic tissue represent infrequent stochastic “outlier” events. This presents a statistical challenge for standard feature selection algorithms, which assume frequent alterations in a disease phenotype. Although differential variability has emerged as a novel feature selection paradigm for the discovery of outliers, a growing concern is that these could result from technical confounders, in principle thus favouring algorithms which are robust to outliers. RESULTS: Here we evaluate five differential variability algorithms in over 700 DNA methylomes, including two of the largest cohorts profiling precursor cancer lesions, and demonstrate that most of the novel proposed algorithms lack the sensitivity to detect epigenetic field defects at genome-wide significance. In contrast, algorithms which recognise heterogeneous outlier DNA methylation patterns are able to identify many sites in pre-neoplastic lesions, which display progression in invasive cancer. Thus, we show that many DNA methylation outliers are not technical artefacts, but define epigenetic field defects which are selected for during cancer progression. CONCLUSIONS: Given that cancer studies aiming to find epigenetic field defects are likely to be limited by sample size, adopting the novel feature selection paradigm advocated here will be critical to increase assay sensitivity

Caspase 8 activation independent of Fas (CD95/APO-1) signaling may mediate killing of B-chronic lymphocytic leukemia cells by cytotoxic drugs or gamma radiation.

Ligation of the cell-surface Fas molecule by its ligand (Fas-L) or agonistic anti-Fas monoclonal antibodies results in the cleavage and activation of the cysteine protease procaspase 8 followed by the activation of procaspase 3 and by apoptosis. In some leukemia cell lines, cytotoxic drugs induce expression of Fas-L, which may contribute to cell killing through the ligation of Fas. The involvement of Fas, Fas-L, and caspase 8 was studied in the killing of B-cell chronic lymphocytic leukemia (B-CLL) cells by chlorambucil, fludarabine, or gamma radiation. Spontaneous apoptosis was observed at 24-hour incubation, with additional apoptosis induced by each of the cytotoxic treatments. Although Fas mRNA expression was elevated after exposure to chlorambucil, fludarabine, or gamma radiation, Fas protein levels only increased after irradiation. Therefore, Fas expression may be regulated by multiple mechanisms that allow the translation of Fas mRNA only in response to restricted cytotoxic stimuli. None of the cytotoxic stimuli studied here induced Fas-L expression. An agonistic anti-Fas monoclonal antibody (CH-11) did not significantly augment apoptosis induction by any of the death stimuli. A Fas-blocking antibody (ZB4) did not inhibit spontaneous, chlorambucil-, fludarabine-, or radiation-induced apoptosis. However, procaspase 8 processing was induced by all cytotoxic stimuli. These data suggest that the Fas/Fas-L signaling system does not play a major role in the induction of apoptosis in B-CLL cells treated with cytotoxic drugs or radiation. However, Fas-independent activation of caspase 8 may play a crucial role in the regulation of apoptosis in these cells

HO<inf>2</inf>NO<inf>2</inf> and HNO<inf>3</inf> in the coastal Antarctic winter night: A lab-in-the-field experiment

Abstract. Observations of peroxynitric acid (HO2NO2) and nitric acid (HNO3) were made during a 4 month period of Antarctic winter darkness at the coastal Antarctic research station, Halley. Mixing ratios of HNO3 ranged from instrumental detection limits to ~8 parts per trillion by volume (pptv), and of HO2NO2 from detection limits to ~5 pptv; the average ratio of HNO3 : HO2NO2 was 2.0(± 0.6) : 1, with HNO3 always present at greater mixing ratios than HO2NO2 during the winter darkness. An extremely strong association existed for the entire measurement period between mixing ratios of the respective trace gases and temperature: for HO2NO2, R2 = 0.72, and for HNO3, R2 = 0.70. We focus on three cases with considerable variation in temperature, where wind speeds were low and constant, such that, with the lack of photochemistry, changes in mixing ratio were likely to be driven by physical mechanisms alone. We derived enthalpies of adsorption (ΔHads) for these three cases. The average ΔHads for HNO3 was −42 ± 2 kJ mol−1 and for HO2NO2 was −56 ± 1 kJ mol−1; these values are extremely close to those derived in laboratory studies. This exercise demonstrates (i) that adsorption to/desorption from the snow pack should be taken into account when addressing budgets of boundary layer HO2NO2 and HNO3 at any snow-covered site, and (ii) that Antarctic winter can be used as a natural "laboratory in the field" for testing data on physical exchange mechanisms. This study is part of the British Antarctic Survey Polar Science for Planet Earth Programme. It was funded by The Natural Environment Research Council (NERC).This is the final published version. It first appeared at http://www.atmos-chem-phys.net/14/11843/2014/acp-14-11843-2014.html