The effect of cigarette smoke exposure on the development of inflammation in lungs, gut and joints of TNFΔARE mice

The inflammatory cytokine TNF-alpha is a central mediator in many immune-mediated diseases, such as Crohn's disease (CD), spondyloarthritis (SpA) and chronic obstructive pulmonary disease (COPD). Epidemiologic studies have shown that cigarette smoking (CS) is a prominent common risk factor in these TNF-dependent diseases. We exposed TNF Delta ARE mice; in which a systemic TNF-alpha overexpression leads to the development of inflammation; to 2 or 4 weeks of air or CS. We investigated the effect of deregulated TNF expression on CS-induced pulmonary inflammation and the effect of CS exposure on the initiation and progression of gut and joint inflammation. Upon 2 weeks of CS exposure, inflammation in lungs of TNF Delta ARE mice was significantly aggravated. However, upon 4 weeks of CS-exposure, this aggravation was no longer observed. TNF Delta ARE mice have no increases in CD4+ and CD8+ T cells and a diminished neutrophil response in the lungs after 4 weeks of CS exposure. In the gut and joints of TNF Delta ARE mice, 2 or 4 weeks of CS exposure did not modulate the development of inflammation. In conclusion, CS exposure does not modulate gut and joint inflammation in TNF Delta ARE mice. The lung responses towards CS in TNF Delta ARE mice however depend on the duration of CS exposure

From DNA sequence to application: possibilities and complications

The development of sophisticated genetic tools during the past 15 years have facilitated a tremendous increase of fundamental and application-oriented knowledge of lactic acid bacteria (LAB) and their bacteriophages. This knowledge relates both to the assignments of open reading frames (ORF’s) and the function of non-coding DNA sequences. Comparison of the complete nucleotide sequences of several LAB bacteriophages has revealed that their chromosomes have a fixed, modular structure, each module having a set of genes involved in a specific phase of the bacteriophage life cycle. LAB bacteriophage genes and DNA sequences have been used for the construction of temperature-inducible gene expression systems, gene-integration systems, and bacteriophage defence systems. The function of several LAB open reading frames and transcriptional units have been identified and characterized in detail. Many of these could find practical applications, such as induced lysis of LAB to enhance cheese ripening and re-routing of carbon fluxes for the production of a specific amino acid enantiomer. More knowledge has also become available concerning the function and structure of non-coding DNA positioned at or in the vicinity of promoters. In several cases the mRNA produced from this DNA contains a transcriptional terminator-antiterminator pair, in which the antiterminator can be stabilized either by uncharged tRNA or by interaction with a regulatory protein, thus preventing formation of the terminator so that mRNA elongation can proceed. Evidence has accumulated showing that also in LAB carbon catabolite repression in LAB is mediated by specific DNA elements in the vicinity of promoters governing the transcription of catabolic operons. Although some biological barriers have yet to be solved, the vast body of scientific information presently available allows the construction of tailor-made genetically modified LAB. Today, it appears that societal constraints rather than biological hurdles impede the use of genetically modified LAB.

Diclofenac Prolongs Repolarization in Ventricular Muscle with Impaired Repolarization Reserve

Background: The aim of the present work was to characterize the electrophysiological effects of the non-steroidal anti- inflammatory drug diclofenac and to study the possible proarrhythmic potency of the drug in ventricular muscle. Methods: Ion currents were recorded using voltage clamp technique in canine single ventricular cells and action potentials were obtained from canine ventricular preparations using microelectrodes. The proarrhythmic potency of the drug was investigated in an anaesthetized rabbit proarrhythmia model. Results: Action potentials were slightly lengthened in ventricular muscle but were shortened in Purkinje fibers by diclofenac (20 mM). The maximum upstroke velocity was decreased in both preparations. Larger repolarization prolongation was observed when repolarization reserve was impaired by previous BaCl 2 application. Diclofenac (3 mg/kg) did not prolong while dofetilide (25 mg/kg) significantly lengthened the QT c interval in anaesthetized rabbits. The addition of diclofenac following reduction of repolarization reserve by dofetilide further prolonged QT c . Diclofenac alone did not induce Torsades de Pointes ventricular tachycardia (TdP) while TdP incidence following dofetilide was 20%. However, the combination of diclofenac and dofetilide significantly increased TdP incidence (62%). In single ventricular cells diclofenac (30 mM) decreased the amplitude of rapid (I Kr ) and slow (I Ks ) delayed rectifier currents thereby attenuating repolarization reserve. L-type calcium current (I Ca ) was slightly diminished, but the transient outward (I to ) and inward rectifier (I K1 ) potassium currents were not influenced. Conclusions: Diclofenac at therapeutic concentrations and even at high dose does not prolong repolarization markedly and does not increase the risk of arrhythmia in normal heart. However, high dose diclofenac treatment may lengthen repolarization and enhance proarrhythmic risk in hearts with reduced repolarization reserve

Social entrepreneurs in challenging places: A Delphi study of experiences and perspectives

Social Enterprises have grown in number and scope in response to reductions in state-provided welfare and increasing ambition to improve social conditions. While a range of issues have been identified in the literature as affecting the ability of Social Enterprises to successfully conduct their activities, there is currently a dearth of research into the relative influence of these factors. This study explores and ranks the challenges faced by social entrepreneurs in South Wales. Based on a Delphi study with 21 social entrepreneurs, government policy-developers and scholars, it presents a hierarchy of 14 factors, useful instruments for informing social entrepreneurs and policy-makers about the way social enterprises are managed, and how national and local policy should be developed. As part of this, the study also identifies four novel factors that affect the sustainability of social enterprises: ‘Professionalisation of Marketing’, ‘Perception of Validity’, ‘Leadership’ and ‘Situatedness’

Incidence and duration of total occlusion of the radial artery in newborn infants after catheter removal

The incidence and duration of total occlusion of the radial artery after catheter removal was determined using repeated Doppler flow measurements. Thirty-two newborn infants with birthweights ranging from 945 g to 3890 g (median 1935 g) and gestational age ranging from 26 to 40 weeks (median 32 weeks) were studied. In 20 out of 32 infants (63%), complete occlusion of the radial artery occurred. The number of occlusions were not related to birthweight, gestational age or duration of cannulation. In all infants, blood flow in the radial artery resumed within 1-29 days after catheter removal. The duration of occlusion was directly related to the duration of cannulation and inversely related to birthweight. This study demonstrates a high frequency of total occlusion of the radial artery in newborn infants after percutaneous radial artery cannulation. In the majority of infants with a radial artert catheter, blood flow to the tissue distal to the cannulation site is dependent solely on the existence of an adequate arterial palmar collateral circulation

A cluster of Candida krusei infections in a haematological unit

<p>Abstract</p> <p>Background</p> <p><it>Candida krusei </it>infections are associated with high mortality. In order to explore ways to prevent these infections, we investigated potential routes for nosocomial spread and possible clonality of <it>C. krusei </it>in a haematological unit which had experienced an unusually high incidence of cases.</p> <p>Methods</p> <p>We searched for <it>C. krusei </it>contamination of the hospital environment and determined the level of colonization in patients and health care workers. We also analyzed the possible association between exposure to prophylactic antifungals or chemotherapeutic agents and occurrence of <it>C. krusei</it>. The <it>C. krusei </it>isolates found were genotyped by pulsed-field electrophoresis method in order to determine possible relatedness of the cases.</p> <p>Results</p> <p>Twelve patients with invasive <it>C. krusei </it>infection and ten patients with potentially significant infection or mucosal colonization were documented within nine months. We were unable to identify any exogenic source of infection or colonization. Genetic analysis of the isolates showed little evidence of clonal transmission of <it>C. krusei </it>strains between the patients. Instead, each patient was colonized or infected by several different closely related genotypes. No association between medications and occurrence of <it>C. krusei </it>was found.</p> <p>Conclusion</p> <p>Little evidence of nosocomial spread of a single <it>C. krusei </it>clone was found. The outbreak may have been controlled by cessation of prophylactic antifungals and by intensifying infection control measures, e.g. hand hygiene and cohorting of the patients, although no clear association with these factors was demonstrated.</p

Coronary MR angiography at 3T: fat suppression versus water-fat separation

Objectives: To compare Dixon water-fat suppression with spectral pre-saturation with inversion recovery (SPIR) at 3T for coronary magnetic resonance angiography (MRA) and to demonstrate the feasibility of fat suppressed coronary MRA at 3T without administration of a contrast agent. Materials and methods: Coronary MRA with Dixon water-fat separation or with SPIR fat suppression was compared on a 3T scanner equipped with a 32-channel cardiac receiver coil. Eight healthy volunteers were examined. Contrast-to-noise ratio (CNR), signal-to-noise ratio (SNR), right coronary artery (RCA), and left anterior descending (LAD) coronary artery sharpness and length were measured and statistically compared. Two experienced cardiologists graded the visual image quality of reformatted Dixon and SPIR images (1: poor quality to 5: excellent quality). Results: Coronary MRA images in healthy volunteers showed improved contrast with the Dixon technique compared to SPIR (CNR blood-fat: Dixon = 14.9 ± 2.9 and SPIR = 13.9 ± 2.1; p = 0.08, CNR blood-myocardium: Dixon = 10.2 ± 2.7 and SPIR = 9.11 ± 2.6; p = 0.1). The Dixon method led to similar fat suppression (fat SNR with Dixon: 2.1 ± 0.5 vs. SPIR: 2.4 ± 1.2, p = 0.3), but resulted in significantly increased SNR of blood (blood SNR with Dixon: 19.9 ± 4.5 vs. SPIR: 15.5 ± 3.1, p < 0.05). This means the residual fat signal is slightly lower with the Dixon compared to the SIPR technique (although not significant), while the SNR of blood is significantly higher with the Dixon technique. Vessel sharpness of the RCA was similar for Dixon and SPIR (57 ± 7 % vs. 56 ± 9 %, p = 0.2), while the RCA visualized vessel length was increased compared to SPIR fat suppression (107 ± 21 vs. 101 ± 21 mm, p < 0.001). For the LAD, vessel sharpness (50 ± 13 % vs. 50 ± 7 %, p = 0.4) and vessel length (92 ± 46 vs. 90 ± 47 mm, p = 0.4) were similar with both techniques. Consequently, the Dixon technique resulted in an improved visual score of the coronary arteries in the water fat separated images of healthy subjects (RCA: 4.6 ± 0.5 vs. 4.1 ± 0.7, p = 0.01, LAD: 4.1 ± 0.7 vs. 3.5 ± 0.8, p = 0.007). Conclusions: Dixon water-fat separation can significantly improve coronary artery image quality without the use of a contrast agent at 3T

Design of the New Life(style) study: a randomised controlled trial to optimise maternal weight development during pregnancy. [ISRCTN85313483]

BACKGROUND: Preventing excessive weight gain during pregnancy is potentially important in the prevention of overweight and obesity among women of childbearing age. However, few intervention studies aiming at weight management during pregnancy have been performed and most of these interventions were not as successful as expected. In this paper the design of the New Life(style) study is described as well as the content of the individually tailored intervention program, which focuses on controlling weight development during pregnancy. METHODS: The effectiveness of the New Life(style) intervention program versus usual care by midwives is evaluated in a randomised controlled trial. Women who expect their first child and visit one of the participating midwifery practices are included. The intervention is standardised in a protocol and executed by trained counsellors with the women who are randomised in the intervention group. During 5 sessions – at 18, 22, 30 and 36 weeks of pregnancy and at 8 weeks postpartum – individual weight gain is discussed in relation to weight gain guidelines for pregnant women of the American Institute of Medicine. Counsellors coach the women to maintain or optimise a healthy lifestyle, in a period of drastic physical and mental changes. Data is collected at 15, 25, 35 weeks of pregnancy and at 6, 26, and 52 weeks after delivery. Primary outcome measures are body weight, BMI, and skinfold thickness. Secondary outcome measures include physical activity, nutrition and blood levels of factors that are associated with energy homeostasis. DISCUSSION: Results of the current RCT will improve the knowledge of determinants of weight gain during pregnancy, weight retention after childbirth and of the effectiveness of the intervention program that is described. Caregivers and researchers in the field of health promotion are offered more insight in specific elements of the New Life(style) intervention program

A phase II randomized trial comparing radiotherapy with concurrent weekly cisplatin or weekly paclitaxel in patients with advanced cervical cancer

<p>Abstract</p> <p>Purpose/Objective</p> <p>This is a prospective comparison of weekly cisplatin to weekly paclitaxel as concurrent chemotherapy with standard radiotherapy for locally advanced cervical carcinoma.</p> <p>Materials/Methods</p> <p>Between May 2000 and May 2004, 31 women with FIGO stage IB2-IVA cervical cancer or with postsurgical pelvic recurrence were enrolled into this phase II study and randomized to receive on a weekly basis either 40 mg/m²Cisplatin (group I; 16 patients) or 50 mg/m²paclitaxel (group II; 15 patients) concurrently with radiotherapy. Median total dose to point A was 74 Gy (range: 66-92 Gy) for group I and 66 Gy (range: 40-98 Gy) for group II. Median follow-up time was 46 months.</p> <p>Results</p> <p>Patient and tumor characteristics were similar in both groups. The mean number of chemotherapy cycles was also comparable with 87% and 80% of patients receiving at least 4 doses in groups I and II, respectively. Seven patients (44%) of group I and 8 patients (53%) of group II developed tumor recurrence. The Median Survival time was not reached for Group I and 53 months for group II. The proportion of patients surviving at 2 and 5 years was 78% and 54% for group I and 73% and 43% for group II respectively.</p> <p>Conclusions</p> <p>This small prospective study shows that weekly paclitaxel does not provide any clinical advantage over weekly cisplatin for concurrent chemoradiation for advanced carcinoma of the cervix.</p

Fluctuation-Driven Flocking Movement in Three Dimensions and Scale-Free Correlation

Recent advances in the study of flocking behavior have permitted more sophisticated analyses than previously possible. The concepts of “topological distances” and “scale-free correlations” are important developments that have contributed to this improvement. These concepts require us to reconsider the notion of a neighborhood when applied to theoretical models. Previous work has assumed that individuals interact with neighbors within a certain radius (called the “metric distance”). However, other work has shown that, assuming topological interactions, starlings interact on average with the six or seven nearest neighbors within a flock. Accounting for this observation, we previously proposed a metric-topological interaction model in two dimensions. The goal of our model was to unite these two interaction components, the metric distance and the topological distance, into one rule. In our previous study, we demonstrated that the metric-topological interaction model could explain a real bird flocking phenomenon called scale-free correlation, which was first reported by Cavagna et al. In this study, we extended our model to three dimensions while also accounting for variations in speed. This three-dimensional metric-topological interaction model displayed scale-free correlation for velocity and orientation. Finally, we introduced an additional new feature of the model, namely, that a flock can store and release its fluctuations