Photocatalytic oxidation of soot by P25TiO(2) films

The photomineralisation of soot by P25 titania films is studied using FT-IR and the process shown to involve the oxidation of carbon to CO2 exclusively. The efficiency of this process is low, however, with a formal quantum efficiency of 1.1 X 10(-4) molecules of carbon oxidized per incident photon of UVA light. The cause of this low efficiency is attributed largely to the less than intimate contact between the fibrous soot layer and the surface of the photocatalyst. (c) 2006 Elsevier Ltd. All rights reserved.

RESIDUES OF THE BETA-AGONIST CLENBUTEROL IN TISSUES OF MEDICATED FARM-ANIMALS

Reports of the illegal use of clenbuterol as a growth promotant prompted the development of a competitive enzyme immunoassay for this drug. This procedure was utilized to study the elimination of clenbuterol from tissues in sheep medicated with both therapeutic and growth-promoting doses of the drug. The results indicated that prior to removal of medication clenbuterol was widely distributed throughout the animal tissues. However as the withdrawal periods increased fluid targets such as urine and bile became less effective at detecting clenbuterol usage. At both therapeutic and growth-enhancing concentrations of clenbuterol liver samples remained positive up to the maximum withdrawal time given in this experiment (15 days). Concentrations of clenbuterol likely to cause food poisoning (> 100 ng/g) were only detected in liver samples taken prior to the removal of medication. The highest recorded concentration of clenbuterol in muscle was 22.5 ng/g.

Effect of glucose on endothelin-1-induced calcium transients in cultured bovine retinal pericytes

Published work has shown that endothelin-l-induced contractility of bovine retinal pericytes is reduced after culture in high concentrations of glucose. The purpose of the present study was to establish the profile of endothelin-l-induced calcium transients in pericytes and to identify changes occurring after culture in high concentrations of glucose. Glucose had no effect on basal levels of cytosolic calcium or on endothelin-l-induced calcium release from intracellular stores. However, influx of calcium from the extracellular medium after endothelin-l stimulation was reduced in pericytes that had been cultured in 25 mM D-glucose. L-type Ca2+ currents were identified by patch clamping. The L-type Ca2+ channel agonist, (-)-Bay K8644, caused less influx of calcium from the extracellular medium in pericytes that had been cultured in 25 mM D-glucose than in those cultured with 5 mM D-glucose. However, 3-O-methylglucose, a nonmetabolizable analogue of glucose which can cause glycation, had similar effects to those of high concentrations of glucose. The results suggest that reduced function of the L-type Ca2+ channel that occurs in bovine retinal pericytes after culture in high concentrations of D-glucose is probably due to glycation of a channel protein.

Early pain experience, child and family factors, as precursors of somatization:a prospective study of extremely premature and fullterm children

In a prospective study of 36 children who were extremely low birthweight (ELBW: <1000 g) preterm infants and 36 matched full-term controls, differences were found in somatization at age 4 1/2 years. Only children who had been extremely premature, and thereby experienced prolonged hospitalization and repeated medical intervention in infancy, had clinically high somatization scores on the Personality Inventory for Children. The combination of family relations at age 4 1/2 years, neonatal intensive care experience, poor maternal sensitivity to child cues in mother-child interaction observed at age 3 years, and child avoidance of touch or holding at age 3, predicted somatization scores, prior to school entry. Due to the known higher incidence of actual medical problems among children with a history of extreme prematurity, the high somatization ELBW children were compared with the normal somatization ELBW children. There were no differences in prevalence of actual medical problems between the 2 ELBW groups, and the importance of maternal factors in relation to somatization was confirmed. Child temperament at age 3, but not personality at 4 1/2, was related to somatization. The etiology of recurrent physical complaints of no known medical cause appears to be a multi-dimensional problem. Non-optimal parenting may contribute to the development of inappropriate strategies for coping with common pains of childhood, or of chronic pain patterns, in some children who have experienced prolonged or repeated pain as neonates.

Sexual offences against children: An exploration of attrition in the Northern Ireland criminal justice system

Objective: This paper uses data provided by the Police Service for Northern Ireland (PSNI) to compare the characteristics and outcomes of reported sexual offences involving child and adult victims and explore the factors associated with case outcomes.
Method: PSNI provided data on 8,789 sexual offences recorded between April 2001 and March 2006. Case outcomes were based on whether a case was recorded by police as having sufficient evidence to summons, charge, or caution an offender (detected). Where an offender was summonsed, charged, or cautioned, this is classified as detection with a formal sanction. A case can also be classified as "detected" without a formal sanction. The analysis focused on two key categories of detection without formal sanction: cases in which the police deem there to be sufficient evidence to charge an offender but took no further action because the victim did not wish to prosecute, or because the police or the Public Prosecution Service (PPS) decided that no useful purpose would be served by proceeding.
Results: The analysis confirmed that the characteristics of recorded sexual offences involving adult and child victims vary significantly according to gender, offence type, the timing of report and victim-offender relationship. Almost half of child sex abuse cases are not detected by police and a quarter do not proceed through the criminal justice system because either the victim declines to prosecute or the Police/PPS decide not to proceed. Only one in five child cases involved detection with a formal sanction. Child groups with lower detection with formal sanction rates included children under 5, teenagers, those who do not report when the abuse occurs but disclose at a later date; and those who experience abuse at the hands of peers and adults known to them but not related. The analysis also highlighted variation in formal sanction rates depending on where the offence was reported.
Conclusions: Consideration needs to be given to improving the criminal justice response to specific child groups as well as monitoring detection rates in different police areas in order to address potential practice variation.
Practice implications: Consideration needs to be given to improving the professional response in relation to with particularly lower detection with formal sanction rates. There is also a need to monitor case outcomes to ensure that child victims in different areas receive a similar service.

Glycation, glycoxidation, and cross-linking of collagen by glucose. Kinetics, mechanisms, and inhibition of late stages of the Maillard reaction

The Maillard or browning reaction between sugar and protein contributes to the increased chemical modification and cross-linking of long-lived tissue proteins in diabetes. To evaluate the role of glycation and oxidation in these reactions, we have studied the effects of oxidative and antioxidative conditions and various types of inhibitors on the reaction of glucose with rat tail tendon collagen in phosphate buffer at physiological pH and temperature. The chemical modifications of collagen that were measured included fructoselysine, the glycoxidation products N epsilon-(carboxymethyl)lysine and pentosidine and fluorescence. Collagen cross-linking was evaluated by analysis of cyanogen bromide peptides using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and by changes in collagen solubilization on treatment with pepsin or sodium dodecylsulfate. Although glycation was unaffected, formation of glycoxidation products and cross-linking of collagen were inhibited by antioxidative conditions. The kinetics of formation of glycoxidation products proceeded with a short lag phase and were independent of the amount of Amadori adduct on the protein, suggesting that autoxidative degradation of glucose was a major contributor to glycoxidation and cross-linking reactions. Chelators, sulfhydryl compounds, antioxidants, and aminoguanidine also inhibited formation of glycoxidation products, generation of fluorescence, and cross-linking of collagen without significant effect on the extent of glycation of the protein. We conclude that autoxidation of glucose or Amadori compounds on protein plays a major role in the formation of glycoxidation products and cross-liking of collagen by glucose in vitro and that chelators, sulfhydryl compounds, antioxidants, and aminoguanidine act as uncouplers of glycation from subsequent glycoxidation and cross-linking reactions.

Intermittent chemotherapy plus either intermittent or continuous cetuximab for first-line treatment of patients with KRAS wild-type advanced colorectal cancer (COIN-B): a randomised phase 2 trial

Background: Advanced colorectal cancer is treated with a combination of cytotoxic drugs and targeted treatments. However, how best to minimise the time spent taking cytotoxic drugs and whether molecular selection can refine this further is unknown. The primary aim of this study was to establish how cetuximab might be safely and effectively added to intermittent chemotherapy.

Methods: COIN-B was an open-label, multicentre, randomised, exploratory phase 2 trial done at 30 hospitals in the UK and one in Cyprus. We enrolled patients with advanced colorectal cancer who had received no previous chemotherapy for metastases. Randomisation was done centrally (by telephone) by the Medical Research Council Clinical Trials Unit using minimisation with a random element. Treatment allocation was not masked. Patients were assigned (1:1) to intermittent chemotherapy plus intermittent cetuximab or to intermittent chemotherapy plus continuous cetuximab. Chemotherapy was FOLFOX (folinic acid and oxaliplatin followed by bolus and infused fluorouracil). Patients in both groups received FOLFOX and weekly cetuximab for 12 weeks, then either had a planned interruption (those taking intermittent cetuximab) or planned maintenance by continuing on weekly cetuximab (continuous cetuximab). On RECIST progression, FOLFOX plus cetuximab or FOLFOX was recommenced for 12 weeks followed by further interruption or maintenance cetuximab, respectively. The primary outcome was failure-free survival at 10 months. The primary analysis population consisted of patients who completed 12 weeks of treatment without progression, death, or leaving the trial. We tested BRAF and NRAS status retrospectively. The trial was registered, ISRCTN38375681.

Findings: We registered 401 patients, 226 of whom were enrolled. Results for 169 with KRAS wild-type are reported here, 78 (46%) assigned to intermittent cetuximab and 91 (54%) to continuous cetuximab. 64 patients assigned to intermittent cetuximab and 66 of those assigned to continuous cetuximab were included in the primary analysis. 10-month failure-free survival was 50% (lower bound of 95% CI 39) in the intermittent group versus 52% (lower bound of 95% CI 41) in the continuous group; median failure-free survival was 12·2 months (95% CI 8·8–15·6) and 14·3 months (10·7–20·4), respectively. The most common grade 3–4 adverse events were skin rash (21 [27%] of 77 patients vs 20 [22%] of 92 patients), neutropenia (22 [29%] vs 30 [33%]), diarrhoea (14 [18%] vs 23 [25%]), and lethargy (20 [26%] vs 19 [21%]).

Interpretation: Cetuximab was safely incorporated in two first-line intermittent chemotherapy strategies. Maintenance of biological monotherapy, with less cytotoxic chemotherapy within the first 6 months, in molecularly selected patients is promising and should be validated in phase 3 trials.

Intravitreal Injection of Normal Saline Induces Retinal Degeneration in the C57BL/6J Mouse

Purpose: To investigate the adverse effect of intravitreal injection of normal saline (NS) and phosphate buffered saline (PBS) in mouse eyes.

Methods: NS or PBS was injected intravitreally into C57BL/6J mouse eyes. Retinal lesions were monitored by fundus imaging, spectral-domain optical coherence tomography (SD-OCT), and histological investigations. Retinal immune gene expression was determined by real-time polymerase chain reaction (PCR). The toxic effect of NS and PBS or retinal protein from NS- or PBS-injected eyes on retinal pigment epithelium (RPE) was tested in B6-RPE-07 mouse RPE cell cultures.

Results: Intravitreal injection of NS dose-dependently induced localized retinal lesion in mice. Histological investigations revealed multiple vacuoles in photoreceptor outer segments and RPE cells. The lesions recovered over time and by 3 weeks post injection the majority of lesions vanished in eyes receiving 1 μl NS. Inflammatory genes, including TNF-α, IL-1β, IL-6, iNOS, and VEGF were upregulated in NS injected eyes. Intravitreal injection of PBS did not cause any pathology. The treatment of B6-RPE07 cells with 30% PBS or 30% NS did not affect RPE viability. However, incubation of 1-μg/ml retinal protein from NS-injected eyes, but not PBS-injected eyes induced RPE cell death.

Conclusion: NS is toxic to the C57BL/6J mouse retina and should not be used as a vehicle for intraocular injection. PBS is not toxic to the retina and is a preferred vehicle.

Translational Relevance: NS is not a physiological solution for intraocular injection in the C57BL/6J mice and questions its suitability for intraocular injection in other species, including human.

Epigenome-Wide Association Study for Parkinson's Disease

A methylation-based EWAS on carefully phenotyped individuals with Parkinson’s disease (PD) was conducted to reveal prioritised genes and pathways with statistically significant and sizable changes in PD and in the anxiety that often accompanies it. This was followed by subsequent replication of top-ranked CpG sites. Using the Infinium® HumanMethylation 450K beadchip (Illumina Inc., USA), twenty unique genes with a sizable difference in methylation (P adjusted < 0.05, Δβ ≥ 0.2), after correction for multiple testing, were identified between PD and controls, while seventeen were identified between PD with anxiety and PD without anxiety. Twelve top ranked, significantly associated loci in PD were evaluated in an independent replicate population using Sequenom EpiTYPER for 219 individuals with similar phenotypes to the cross-sectional case–control discovery design. FANCC cg14115740 and TNKS2 cg11963436 show significant differential methylation between PD cases and controls using both techniques and their Δβ values, which have the same direction of effect, are reasonable to warrant further investigation

The statistical significance of randomized controlled trial results is frequently fragile: A case for a Fragility Index

Objectives

A P-value <0.05 is one metric used to evaluate the results of a randomized controlled trial (RCT). We wondered how often statistically significant results in RCTs may be lost with small changes in the numbers of outcomes.

Study Design and Setting

A review of RCTs in high-impact medical journals that reported a statistically significant result for at least one dichotomous or time-to-event outcome in the abstract. In the group with the smallest number of events, we changed the status of patients without an event to an event until the P-value exceeded 0.05. We labeled this number the Fragility Index; smaller numbers indicated a more fragile result.

Results

The 399 eligible trials had a median sample size of 682 patients (range: 15-112,604) and a median of 112 events (range: 8-5,142); 53% reported a P-value <0.01. The median Fragility Index was 8 (range: 0-109); 25% had a Fragility Index of 3 or less. In 53% of trials, the Fragility Index was less than the number of patients lost to follow-up.

Conclusion

The statistically significant results of many RCTs hinge on small numbers of events. The Fragility Index complements the P-value and helps identify less robust results. 

Mechanistic studies of the photocatalytic oxidation of microcystin-LR: An investigation of byproducts of the decomposition process

Microcystins (cyclic heptapeptides) are produced by a number of freshwater cyanobacteria and cause concern in potable water supplies due to their acute and chronic toxicity. The present study reports the structural characterization of the degradation products of the photocatalytic oxidation of microcystin-LR, so aiding the mechanistic understanding of this process. TiO₂ photocatalysis is a promising technology for removal of these toxins from drinking water. However, before it can be adopted in any practical application it is necessary to have a sufficient knowledge of degradation byproducts and their potential toxicity. Liquid chromatography-mass spectrometry analysis demonstrated that the major destruction pathway of microcystin appears to be initiated via three mechanisms: UV irradiation, hydroxyl radical attack, and oxidation. UV irradiation caused geometrical isomerization of microcystin converting the (4E), (6E) of the Adda configuration to (4E), 6(Z) or 4(Z), 6(E). Hydroxyl radical attack on the conjugated diene structure of Adda moiety produced dihyroxylated products. Further oxidation cleaved the hydroxylated 4-5 and/or 6-7 bond of Adda to form aldehyde or ketone peptide residues, which then were oxidized into the corresponding carboxylic acids. Photocatalysis also hydrolyzed the peptide bond on the ring structure of microcystin to form linear structures although this appeared to be a minor pathway.

The application of metabolomic biomarker screening tools for improved Bovine Respiratory Disease diagnosis and management

Bovine Respiratory Disease (BRD) is considered to be one of the most significant causes of economic loss in cattle worldwide. The disease has multifactorial aetiology, where viral induced respiratory damage can predispose animals to developing secondary bacterial infections. Accurate identification of viral infected animals prior to the onset of bacterial infection is necessary to reduce the overuse of antimicrobial treatments and minimize further economic losses from reduced production capacity and death. This research focuses on Bovine Parainfluenza Virus Type 3 (BPIV-3), one of the viruses involved in generating BRD. Vaccination measures for BPIV-3 can induce a level of immunity preventing disease progression, however, not all animals respond equally and immunization can complicate disease diagnosis. Alternative diagnostic approaches are required to identify animals which fail to respond to vaccination during infection outbreaks and are therefore likely to be more susceptible to secondary bacterial infections. Mass spectrometry based metabolomics was employed to identify plasma markers capable of differentiating between vaccinated and non-vaccinated calves after challenge with BPIV-3. Differentiation of vaccinated and non-vaccinated study groups (n=6) was possible as early as day 2 post-BPIV-3 challenge up until day 20 using a panel of potential metabolite markers. This study illustrates the potential for metabolomics to provide more detailed information on animal vaccination status that could be used to develop tools for improved herd health management, reduce economic loss through rapid identification and isolation of animals without immune protection (improving herd level immunity) and help reduce the usage of antimicrobial therapeutic treatments in animals.

Learning Bayesian Networks with Thousands of Variables

We present a method for learning Bayesian networks from data sets containing thousands of variables without the need for structure constraints. Our approach is made of two parts. The first is a novel algorithm that effectively explores the space of possible parent sets of a node. It guides the exploration towards the most promising parent sets on the basis of an approximated score function that is computed in constant time. The second part is an improvement of an existing ordering-based algorithm for structure optimization. The new algorithm provably achieves a higher score compared to its original formulation. Our novel approach consistently outperforms the state of the art on very large data sets.

Step by step: reconstruction of terrestrial animal movement paths by dead-reckoning

BACKGROUND: Research on wild animal ecology is increasingly employing GPS telemetry in order to determine animal movement. However, GPS systems record position intermittently, providing no information on latent position or track tortuosity. High frequency GPS have high power requirements, which necessitates large batteries (often effectively precluding their use on small animals) or reduced deployment duration. Dead-reckoning is an alternative approach which has the potential to 'fill in the gaps' between less resolute forms of telemetry without incurring the power costs. However, although this method has been used in aquatic environments, no explicit demonstration of terrestrial dead-reckoning has been presented.

RESULTS: We perform a simple validation experiment to assess the rate of error accumulation in terrestrial dead-reckoning. In addition, examples of successful implementation of dead-reckoning are given using data from the domestic dog Canus lupus, horse Equus ferus, cow Bos taurus and wild badger Meles meles.

CONCLUSIONS: This study documents how terrestrial dead-reckoning can be undertaken, describing derivation of heading from tri-axial accelerometer and tri-axial magnetometer data, correction for hard and soft iron distortions on the magnetometer output, and presenting a novel correction procedure to marry dead-reckoned paths to ground-truthed positions. This study is the first explicit demonstration of terrestrial dead-reckoning, which provides a workable method of deriving the paths of animals on a step-by-step scale. The wider implications of this method for the understanding of animal movement ecology are discussed.

Antifungal Activity of LL-37 and Truncated Mimetics

Background: Candida albicans is a commensal organism and a constituent of the normal oral flora. Cell concentrations of 1x102 cells/ml and below are indicative of commensal colonisation in the oral cavity, above this level C. albicans can become an opportunistic pathogen; it is the most prevalent human fungal pathogen and a causal agent of the oral infection, candidiasis. The capacity of C. albicans to cause infection arises from its ability to exist in a biofilm ecosystem. Mature C. albicans biofilms display a high level of resistance to antifungals and the need for other therapeutic options has become paramount. Objectives: The objectives of the current study were to determine the antifungal activity of LL-37 (a member of the human cathelicidin family) and two truncated peptide mimetics against C. albicans in both planktonic and biofilm form. Methods: Radial diffusion assays were used to obtain the minimum inhibitory concentration (MIC) of LL-37 and the truncated mimetics KE-18 and KR-12 against planktonic C. albicans. A 96 well microtitre plate assay was employed to study the effects of the peptides on early candida biofilm formation (up to 24 hours) compared with the antifungal drug fluconazole. Biofilm quantification was achieved using the crystal violet assay. Results: MIC values obtained: LL-37 >250µg/ml; KE-18 51µg/ml; and KR-12 11µg/ml. LL-37 significantly reduced the quantity of biofilm formed by C.albicans at both the 4 h and 24 h timepoints (p <0.0001). KE-18 showed significant biofilm reduction over 4 h and 24 h (p=0.0002, p=0.013 respectively), KR-12 showed significant reduction at the 24 h time point only (p=0.0256). Conclusions: Results suggest that LL-37 has the ability to disrupt early biofilm formation of C. albicans with its potency of action similar with that of fluconazole.