Inhalation characteristics of asthma patients, COPD patients and healthy volunteers with the Spiromax® and Turbuhaler® devices: a randomised, cross-over study.

BACKGROUND: Spiromax® is a novel dry-powder inhaler containing formulations of budesonide plus formoterol (BF). The device is intended to provide dose equivalence with enhanced user-friendliness compared to BF Turbuhaler® in asthma and chronic obstructive pulmonary disease (COPD). The present study was performed to compare inhalation parameters with empty versions of the two devices, and to investigate the effects of enhanced training designed to encourage faster inhalation. METHODS: This randomised, open-label, cross-over study included children with asthma (n = 23), adolescents with asthma (n = 27), adults with asthma (n = 50), adults with COPD (n = 50) and healthy adult volunteers (n = 50). Inhalation manoeuvres were recorded with each device after training with the patient information leaflet (PIL) and after enhanced training using an In-Check Dial device. RESULTS: After PIL training, peak inspiratory flow (PIF), maximum change in pressure (∆P) and the inhalation volume (IV) were significantly higher with Spiromax than with the Turbuhaler device (p values were at least <0.05 in all patient groups). After enhanced training, numerically or significantly higher values for PIF, ∆P, IV and acceleration remained with Spiromax versus Turbuhaler, except for ∆P in COPD patients. After PIL training, one adult asthma patient and one COPD patient inhaled <30 L/min through the Spiromax compared to one adult asthma patient and five COPD patients with the Turbuhaler. All patients achieved PIF values of at least 30 L/min after enhanced training. CONCLUSIONS: The two inhalers have similar resistance so inhalation flows and pressure changes would be expected to be similar. The higher flow-related values noted for Spiromax versus Turbuhaler after PIL training suggest that Spiromax might have human factor advantages in real-world use. After enhanced training, the flow-related differences between devices persisted; increased flow rates were achieved with both devices, and all patients achieved the minimal flow required for adequate drug delivery. Enhanced training could be useful, especially in COPD patients

Human papillomavirus 16 is an aetiological factor of scrotal cancer

Background: Squamous cell scrotal carcinoma (SCSC) is an infrequent skin cancer associated historically with occupational carcinogens. Human papillomavirus (HPV) DNA has been associated with SCSC but there is no definitive proof of its oncogenic role. Methods: Human papillomavirus-DNA and -E6*I mRNA were analysed in six invasive histologically typed SCSC. LCM-PCR was used to localise HPV DNA to tumour cells. P16(INK4a)and p53 expression were studied by immunohistochemistry. Results: In three warty or basaloid SCSC HPV16-DNA and E6*I-mRNA were detected. LCM-PCR confirmed HPV16 was in p16(INK4a)-positive malignant cells. However, of three usual-type SCSC, all were HPV-negative and two expressed p53 protein but not p16(INK4a). Conclusions: Human papillomavirus 16 was present in tumour cells and oncogenically active in basaloid and warty SCSC, whereas usual SCSC was HPV-negative and showed immunostaining, suggesting p53 mutation. The dual pathways of oncogenesis and relation between histological type of SCSC and HPV are similar to that in penile cancers

Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis

African trypanosomiasis is a deadly neglected disease caused by the extracellular parasite Trypanosoma brucei. Current therapies are characterized by high drug toxicity and increasing drug resistance mainly associated with loss-of-function mutations in the transporters involved in drug import. The introduction of new antiparasitic drugs into therapeutic use is a slow and expensive process. In contrast, specific targeting of existing drugs could represent a more rapid and cost-effective approach for neglected disease treatment, impacting through reduced systemic toxicity and circumventing resistance acquired through impaired compound uptake. We have generated nanoparticles of chitosan loaded with the trypanocidal drug pentamidine and coated by a single domain nanobody that specifically targets the surface of African trypanosomes. Once loaded into this nanocarrier, pentamidine enters trypanosomes through endocytosis instead of via classical cell surface transporters. The curative dose of pentamidine-loaded nanobody-chitosan nanoparticles was 100-fold lower than pentamidine alone in a murine model of acute African trypanosomiasis. Crucially, this new formulation displayed undiminished in vitro and in vivo activity against a trypanosome cell line resistant to pentamidine as a result of mutations in the surface transporter aquaglyceroporin 2. We conclude that this new drug delivery system increases drug efficacy and has the ability to overcome resistance to some anti-protozoal drugs.JAGS was funded by the European Union, grant FP7-HEALTH-2007-B-2.3.4-1.223048, NANOTRYP and Ministerio de Economía y Competitividad, Spain Plan Nacional de Investigación grant SAF2011- 30528. JLA was funded by Instituto de Salud Carlos III, Spain, grant FIS. 11/02571. HPdK was supported by a grant from the Medical Research Council (84733)

Symmetrical Corticobasal Syndrome Caused by a Novel c.314dup Progranulin Mutation

Corticobasal syndrome (CBS) is characterised by asymmetrical parkinsonism and cognitive impairment. The underlying pathology varies between corticobasal degeneration, progressive supranuclear palsy, Alzheimer’s disease, Creutzfeldt–Jakob disease and frontotemporal lobar degeneration sometimes in association with GRN mutations. A 61-year-old male underwent neurological examination, neuropsychological assessment, MRI, and HMPAO-SPECT at our medical centre. After his death at the age of 63, brain autopsy, genetic screening and mRNA expression analysis were performed. The patient presented with slow progressive walking disabilities, non-fluent language problems, behavioural changes and forgetfulness. His family history was negative. He had primitive reflexes, rigidity of his arms and postural instability. Later in the disease course he developed dystonia of his left leg, pathological crying, mutism and dysphagia. Neuropsychological assessment revealed prominent ideomotor and ideational apraxia, executive dysfunction, non-fluent aphasia and memory deficits. Neuroimaging showed symmetrical predominant frontoparietal atrophy and hypoperfusion. Frontotemporal lobar degeneration (FTLD)-TDP type 3 pathology was found at autopsy. GRN sequencing revealed a novel frameshift mutation c.314dup, p.Cys105fs and GRN mRNA levels showed a 50% decrease. We found a novel GRN mutation in a patient with an atypical (CBS) presentation with symmetric neuroimaging findings. GRN mutations are an important cause of CBS associated with FTLD-TDP type 3 pathology, sometimes in sporadic cases. Screening for GRN mutations should also be considered in CBS patients without a positive family history

Intracellular Serine Protease Inhibitor SERPINB4 Inhibits Granzyme M-Induced Cell Death

Granzyme-mediated cell death is the major pathway for cytotoxic lymphocytes to kill virus-infected and tumor cells. In humans, five different granzymes (i.e. GrA, GrB, GrH, GrK, and GrM) are known that all induce cell death. Expression of intracellular serine protease inhibitors (serpins) is one of the mechanisms by which tumor cells evade cytotoxic lymphocyte-mediated killing. Intracellular expression of SERPINB9 by tumor cells renders them resistant to GrB-induced apoptosis. In contrast to GrB, however, no physiological intracellular inhibitors are known for the other four human granzymes. In the present study, we show that SERPINB4 formed a typical serpin-protease SDS-stable complex with both recombinant and native human GrM. Mutation of the P2-P1-P1′ triplet in the SERPINB4 reactive center loop completely abolished complex formation with GrM and N-terminal sequencing revealed that GrM cleaves SERPINB4 after P1-Leu. SERPINB4 inhibited GrM activity with a stoichiometry of inhibition of 1.6 and an apparent second order rate constant of 1.3×104 M−1s−1. SERPINB4 abolished cleavage of the macromolecular GrM substrates α-tubulin and nucleophosmin. Overexpression of SERPINB4 in tumor cells inhibited recombinant GrM-induced as well as NK cell-mediated cell death and this inhibition depended on the reactive center loop of the serpin. As SERPINB4 is highly expressed by squamous cell carcinomas, our results may represent a novel mechanism by which these tumor cells evade cytotoxic lymphocyte-induced GrM-mediated cell death

The tribulations of trials: Lessons learnt recruiting 777 older adults into REtirement in ACTion (REACT), a trial of a community, group-based active ageing intervention targeting mobility disability

This is the author accepted manuscriptBackground: Challenges of recruitment to randomised controlled trials (RCTs) and successful strategies to overcome them should be clearly reported to improve recruitment into future trials. REtirement in ACTion (REACT) is a UK-based multi-centre RCT recruiting older adults at high risk of mobility disability to a 12-month group-based exercise and behaviour maintenance programme or to a minimal Healthy Ageing control intervention. Methods:The recruitment target was 768 adults, aged 65 years and older scoring 4 to 9 on the Short Physical Performance Battery (SPPB). Recruitment methods included: a) invitations mailed by General Practitioners (GPs); b) invitations distributed via third sector organisations; c) public relations (PR) campaign. Yields, efficiency and costs were calculated. Results: The study recruited 777 (33.9% men) community-dwelling, older adults (mean age 77.55 years (SD 6.79), mean SPPB score 7.37 (SD 1.56)), 95.11% white (n=739) and broadly representative of UK quintiles of deprivation. Over a 20-month recruitment period, 25,559 invitations were issued. Eighty-eight percent of participants were recruited via GP invitations, 5.4% via the PR campaign, 3% via word-of-mouth and 2.5% via third sector organisations. Mean recruitment cost per participant was £78.47, with an extra £26.54 per recruit paid to GPs to cover research costs. Conclusions: REACT successfully recruited to target. Response rates were lower than initially predicted and recruitment timescales required adjustment. Written invitations from General Practitioners were the most efficient method for recruiting older adults at risk of mobility disability. Targeted efforts could achieve more ethnically diverse cohorts. All trials should be required to provide recruitment data to enable evidence-based planning of future trials.National Institute for Health Research, Public Health Research Programm

Combining transcriptional profiling and genetic linkage analysis to uncover gene networks operating in hematopoietic stem cells and their progeny

Stem cells are unique in that they possess both the capacity to self-renew and thereby maintain their original pool as well as the capacity to differentiate into mature cells. In the past number of years, transcriptional profiling of enriched stem cell populations has been extensively performed in an attempt to identify a universal stem cell gene expression signature. While stem-cell-specific transcripts were identified in each case, this approach has thus far been insufficient to identify a universal group of core “stemness” genes ultimately responsible for self-renewal and multipotency. Similarly, in the hematopoietic system, comparisons of transcriptional profiles between different hematopoietic cell stages have had limited success in revealing core genes ultimately responsible for the initiation of differentiation and lineage specification. Here, we propose that the combined use of transcriptional profiling and genetic linkage analysis, an approach called “genetical genomics”, can be a valuable tool to assist in the identification of genes and gene networks that specify “stemness” and cell fate decisions. We review past studies of hematopoietic cells that utilized transcriptional profiling and/or genetic linkage analysis, and discuss several potential future applications of genetical genomics

Delinquent Behavior of Dutch Rural Adolescents

This article compares Dutch rural and non-rural adolescents’ delinquent behavior and examines two social correlates of rural delinquency: communal social control and traditional rural culture. The analyses are based on cross-sectional data, containing 3,797 participants aged 13–18 (48.7% females). The analyses show that rural adolescents are only slightly less likely to engage in delinquent behavior. Furthermore, while rural adolescents are exposed more often to communal social control, this does not substantially reduce the likelihood that they engage in delinquent behavior. Concerning rural culture, marked differences appeared between rural and non-rural adolescents. First, alcohol use and the frequency of visiting pubs were more related to rural adolescents’ engagement in delinquent behavior. Second, the gender gap in delinquency is larger among rural adolescents: whereas rural boys did not differ significantly from non-rural boys, rural girls were significantly less likely to engage in delinquent behavior than non-rural girls. However, the magnitude of the effects of most indicators was rather low. To better account for the variety of rural spaces and cultures, it is recommended that future research into antisocial and criminal behavior of rural adolescents should adopt alternative measurements of rurality, instead of using an indicator of population density only

Cost-effectiveness of early detection of breast cancer in Catalonia (Spain)

<p>Abstract</p> <p>Background</p> <p>Breast cancer (BC) causes more deaths than any other cancer among women in Catalonia. Early detection has contributed to the observed decline in BC mortality. However, there is debate on the optimal screening strategy. We performed an economic evaluation of 20 screening strategies taking into account the cost over time of screening and subsequent medical costs, including diagnostic confirmation, initial treatment, follow-up and advanced care.</p> <p>Methods</p> <p>We used a probabilistic model to estimate the effect and costs over time of each scenario. The effect was measured as years of life (YL), quality-adjusted life years (QALY), and lives extended (LE). Costs of screening and treatment were obtained from the Early Detection Program and hospital databases of the IMAS-Hospital del Mar in Barcelona. The incremental cost-effectiveness ratio (ICER) was used to compare the relative costs and outcomes of different scenarios.</p> <p>Results</p> <p>Strategies that start at ages 40 or 45 and end at 69 predominate when the effect is measured as YL or QALYs. Biennial strategies 50-69, 45-69 or annual 45-69, 40-69 and 40-74 were selected as cost-effective for both effect measures (YL or QALYs). The ICER increases considerably when moving from biennial to annual scenarios. Moving from no screening to biennial 50-69 years represented an ICER of 4,469€ per QALY.</p> <p>Conclusions</p> <p>A reduced number of screening strategies have been selected for consideration by researchers, decision makers and policy planners. Mathematical models are useful to assess the impact and costs of BC screening in a specific geographical area.</p