Understanding the mental health needs of secondary school children in Manchester

Background In a time of limited resources and the need for cohesive services, understanding levels of need and prevalence is key. Manchester has a diverse range of cultures and socio-economic groups; national data is valuable but not always representative of local need.Aim To assess the prevalence of mental health needs in secondary school pupils in Manchester.Method Parents and teachers in three secondary schools were invited to complete the Strengths and Difficulties Questionnaire (SDQ) and a tool examining unmet needs.Results Initially, 560 pupils were chosen. Having excluded families that opted out, 503 questionnaires were distributed. Teachers returned 200 questionnaires and parents returned 127. Higher than average levels of need were identified with teachers reporting that 18% of pupils scored abnormally on the SDQ. Parent rates were also higher than the national average at 13.4%.Discussion Parents and teachers wanted children to be seen at home and at school, the need for consultation and outreach from mental health into schools is emphasised.     

Opposing roles for membrane bound and soluble Fas ligand in glaucoma-associated retinal ganglion cell death

Glaucoma, the most frequent optic neuropathy, is a leading cause of blindness worldwide. Death of retinal ganglion cells (RGCs) occurs in all forms of glaucoma and accounts for the loss of vision, however the molecular mechanisms that cause RGC loss remain unclear. The pro-apoptotic molecule, Fas ligand, is a transmembrane protein that can be cleaved from the cell surface by metalloproteinases to release a soluble protein with antagonistic activity. Previous studies documented that constitutive ocular expression of FasL maintained immune privilege and prevented neoangeogenesis. We now show that FasL also plays a major role in retinal neurotoxicity. Importantly, in both TNFα triggered RGC death and a spontaneous model of glaucoma, gene-targeted mice that express only full-length FasL exhibit accelerated RGC death. By contrast, FasL-deficiency, or administration of soluble FasL, protected RGCs from cell death. These data identify membrane-bound FasL as a critical effector molecule and potential therapeutic target in glaucoma.     

Complex evolutionary history of a Neotropical lowland forest bird (Lepidothrix coronata) and its implications for historical hypotheses of the origin of Neotropical avian diversity

Here we apply a combination of phylogeographic and historical demographic analyses to the study of mtDNA sequence variation within the Blue-crowned Manakin (Lepidothrix coronata), a widespread Neotropical bird. A high degree of phylogeographic structure allowed us to demonstrate that several vicariant events, including Andean uplift, the formation of riverine barriers, and climatically induced vegetational shifts, as well as a non-vicariant process, range expansion, have all acted, at varying spatial and temporal scales, to influence genetic structure within L. coronata, suggesting that current historical hypotheses of the origin of Neotropical avian diversity that focus on single vicariant mechanisms may be overly simplistic. Our data also support an origin (>2 mybp) that is substantially older than the late Pleistocene for the genetic structure within this species and indicate that phylogeographic patterns within the species are not concordant with plumage-based subspecific taxonomy. These data add to a growing body of evidence suggesting that the origin of several Neotropical avian species may have occurred in the mid-Pliocene, thus, geological arguments surrounding putative Pleistocene vicariant events, while interesting in their own right, may have little relevance to Neotropical avian diversification at the species level.     

Lead optimization of 7-benzyloxy 2-(4'-pyridylmethyl)thio isoflavone aromatase inhibitors

Aromatase, the enzyme responsible for estrogen biosynthesis, is a particularly attractive target in the treatment of hormone-dependent breast cancer. The synthesis and biological evaluation of a series of 2-(4'-pyridylmethyl)thio, 7-alkyl- or aryl-substituted isoflavones as potential aromatase inhibitors are described. The isoflavone derivatives demonstrate IC(50) values from 79 to 553 nM and compete with the endogenous substrate, androstenedione. Data supporting the ability of these analogs to suppress aromatase enzyme activity in the SK-BR-3 breast cancer cell line are also presented.     

Fishing for Answers with Transposons

Transposons are one means that nature has used to introduce new genetic material into chromosomes of organisms from every kingdom. They have been extensively used in prokaryotic and lower eukaryotic systems, but until recently there was no transposon that had significant activity in vertebrates. The Sleeping Beauty (SB) transposon system was developed to direct the integration of precise DNA sequences into chromosomes. The SB system was derived from salmonid sequences that had been inactive for more than 10 million years. SB transposons have been used for two principle uses – as a vector for transgenesis and as a method for introducing various trap vectors into (gene-trap) or in the neighborhood of (enhancer-trap) genes to identify their functions. Results of these studies show that SB-mediated transgenesis is more efficient than that by injection of simple plasmids and that expression of transgenesis is stable and reliable following passage through the germline.     

Airway cellularity, lipid laden macrophages and microbiology of gastric juice and airways in children with reflux oesophagitis

Background and methods

Human metapneumovirus (hMPV) is a recently discovered respiratory virus associated with bronchiolitis, pneumonia, croup and exacerbations of asthma. Since respiratory viruses are frequently detected in patients with acute exacerbations of COPD (AE-COPD) it was our aim to investigate the frequency of hMPV detection in a prospective cohort of hospitalized patients with AE-COPD compared to patients with stable COPD and to smokers without by means of quantitative real-time RT-PCR.

Results

We analysed nasal lavage and induced sputum of 130 patients with AE-COPD, 65 patients with stable COPD and 34 smokers without COPD. HMPV was detected in 3/130 (2.3%) AE-COPD patients with a mean of 6.5 × 10⁵ viral copies/ml in nasal lavage and 1.88 × 10⁵ viral copies/ml in induced sputum. It was not found in patients with stable COPD or smokers without COPD.

Conclusion

HMPV is only found in a very small number of patients with AE-COPD. However it should be considered as a further possible viral trigger of AE-COPD because asymptomatic carriage is unlikely.     

Reliability of computerized image analysis for the evaluation of serial synovial biopsies in randomized controlled trials in rheumatoid arthritis

Analysis of biomarkers in synovial tissue is increasingly used in the evaluation of new targeted therapies for patients with rheumatoid arthritis (RA). This study determined the intrarater and inter-rater reliability of digital image analysis (DIA) of synovial biopsies from RA patients participating in clinical trials. Arthroscopic synovial biopsies were obtained before and after treatment from 19 RA patients participating in a randomized controlled trial with prednisolone. Immunohistochemistry was used to detect CD3⁺ T cells, CD38⁺ plasma cells and CD68⁺ macrophages. The mean change in positive cells per square millimetre for each marker was determined by different operators and at different times using DIA. Nonparametric tests were used to determine differences between observers and assessments, and to determine changes after treatment. The intraclass correlations (ICCs) were calculated to determine the intrarater and inter-rater reliability. Intrarater ICCs showed good reliability for measuring changes in T lymphocytes (R = 0.87), plasma cells (R = 0.62) and macrophages (R = 0.73). Analysis by Bland–Altman plots showed no systemic differences between measurements. The smallest detectable changes were calculated and their discriminatory power revealed good response in the prednisolone group compared with the placebo group. Similarly, inter-rater ICCs also revealed good reliability for measuring T lymphocytes (R = 0.68), plasma cells (R = 0.69) and macrophages (R = 0.72). All measurements identified the same cell types as changing significantly in the treated patients compared with the placebo group. The measurement of change in total positive cell numbers in synovial tissue can be determined reproducibly for various cell types by DIA in RA clinical trials.     

Molecular identification of a malaria merozoite surface sheddase

Proteolytic shedding of surface proteins during invasion by apicomplexan parasites is a widespread phenomenon, thought to represent a mechanism by which the parasites disengage adhesin-receptor complexes in order to gain entry into their host cell. Erythrocyte invasion by merozoites of the malaria parasite Plasmodium falciparum requires the shedding of ectodomain components of two essential surface proteins, called MSP1 and AMA1. Both are released by the same merozoite surface "sheddase," but the molecular identity and mode of action of this protease is unknown. Here we identify it as PfSUB2, an integral membrane subtilisin-like protease (subtilase). We show that PfSUB2 is stored in apical secretory organelles called micronemes. Upon merozoite release it is secreted onto the parasite surface and translocates to its posterior pole in an actin-dependent manner, a trafficking pattern predicted of the sheddase. Subtilase propeptides are usually selective inhibitors of their cognate protease, and the PfSUB2 propeptide is no exception; we show that recombinant PfSUB2 propeptide binds specifically to mature parasite-derived PfSUB2 and is a potent, selective inhibitor of MSP1 and AMA1 shedding, directly establishing PfSUB2 as the sheddase. PfSUB2 is a new potential target for drugs designed to prevent erythrocyte invasion by the malaria parasite.