A decision support tool for health service re-design

Many of the outpatient services are currently only available in hospitals, however there are plans to provide some of these services alongside with General Practitioners. Consequently, General Practitioners could soon be based at polyclinics. These changes have caused a number of concerns to Hounslow Primary Care Trust (PCT). For example, which of the outpatient services are to be shifted from the hospital to the polyclinic? What are the current and expected future demands for these services? To tackle some of these concerns, the first phase of this project explores the set of specialties that are frequently visited in a sequence (using sequential association rules). The second phase develops an Excel based spreadsheet tool to compute the current and expected future demands for the selected specialties. From the sequential association rule algorithm, endocrinology and ophthalmology were found to be highly associated (i.e. frequently visited in a sequence), which means that these two specialties could easily be shifted from the hospital environment to the polyclinic. We illustrated the Excel based spreadsheet tool for endocrinology and ophthalmology, however, the model is generic enough to cope with other specialties, provided that the data are available

The Interplay Between GUT and Flavour Symmetries in a Pati-Salam x S4 Model

Both Grand Unified symmetries and discrete flavour symmetries are appealing ways to describe apparent structures in the gauge and flavour sectors of the Standard Model. Both symmetries put constraints on the high energy behaviour of the theory. This can give rise to unexpected interplay when building models that possess both symmetries. We investigate on the possibility to combine a Pati-Salam model with the discrete flavour symmetry $S_4$ that gives rise to quark-lepton complementarity. Under appropriate assumptions at the GUT scale, the model reproduces fermion masses and mixings both in the quark and in the lepton sectors. We show that in particular the Higgs sector and the running Yukawa couplings are strongly affected by the combined constraints of the Grand Unified and family symmetries. This in turn reduces the phenomenologically viable parameter space, with high energy mass scales confined to a small region and some parameters in the neutrino sector slightly unnatural. In the allowed regions, we can reproduce the quark masses and the CKM matrix. In the lepton sector, we reproduce the charged lepton masses, including bottom-tau unification and the Georgi-Jarlskog relation as well as the two known angles of the PMNS matrix. The neutrino mass spectrum can present a normal or an inverse hierarchy, and only allowing the neutrino parameters to spread into a range of values between $\lambda^{-2}$ and $\lambda^2$, with $\lambda\simeq0.2$. Finally, our model suggests that the reactor mixing angle is close to its current experimental bound.Comment: 62 pages, 4 figures; references added, version accepted for publication in JHE

Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial–mesenchymal transition in ovarian carcinomas

Epidermal growth factor receptor (EGFR) is overexpressed in ovarian carcinomas, with direct or indirect activation of EGFR able to trigger tumour growth. We demonstrate significant activation of both signal transducer and activator of transcription (STAT)3 and its upstream activator Janus kinase (JAK)2, in high-grade ovarian carcinomas compared with normal ovaries and benign tumours. The association between STAT3 activation and migratory phenotype of ovarian cancer cells was investigated by EGF-induced epithelial–mesenchymal transition (EMT) in OVCA 433 and SKOV3 ovarian cancer cell lines. Ligand activation of EGFR induced a fibroblast-like morphology and migratory phenotype, consistent with the upregulation of mesenchyme-associated N-cadherin, vimentin and nuclear translocation of β-catenin. This occurred concomitantly with activation of the downstream JAK2/STAT3 pathway. Both cell lines expressed interleukin-6 receptor (IL-6R), and treatment with EGF within 1 h resulted in a several-fold enhancement of mRNA expression of IL-6. Consistent with that, EGF treatment of both OVCA 433 and SKOV3 cell lines resulted in enhanced IL-6 production in the serum-free medium. Exogenous addition of IL-6 to OVCA 433 cells stimulated STAT3 activation and enhanced migration. Blocking antibodies against IL-6R inhibited IL-6 production and EGF- and IL-6-induced migration. Specific inhibition of STAT3 activation by JAK2-specific inhibitor AG490 blocked STAT3 phosphorylation, cell motility, induction of N-cadherin and vimentin expression and IL6 production. These data suggest that the activated status of STAT3 in high-grade ovarian carcinomas may occur directly through activation of EGFR or IL-6R or indirectly through induction of IL-6R signalling. Such activation of STAT3 suggests a rationale for a combination of anti-STAT3 and EGFR/IL-6R therapy to suppress the peritoneal spread of ovarian cancer

Mating alters gene expression patterns in Drosophila melanogaster male heads

<p>Abstract</p> <p>Background</p> <p>Behavior is a complex process resulting from the integration of genetic and environmental information. <it>Drosophila melanogaster </it>rely on multiple sensory modalities for reproductive success, and mating causes physiological changes in both sexes that affect reproductive output or behavior. Some of these effects are likely mediated by changes in gene expression. Courtship and mating alter female transcript profiles, but it is not known how mating affects male gene expression.</p> <p>Results</p> <p>We used <it>Drosophila </it>genome arrays to identify changes in gene expression profiles that occur in mated male heads. Forty-seven genes differed between mated and control heads 2 hrs post mating. Many mating-responsive genes are highly expressed in non-neural head tissues, including an adipose tissue called the fat body. One fat body-enriched gene, <it>female-specific independent of transformer </it>(<it>fit</it>), is a downstream target of the somatic sex-determination hierarchy, a genetic pathway that regulates <it>Drosophila</it> reproductive behaviors as well as expression of some fat-expressed genes; three other mating-responsive loci are also downstream components of this pathway. Another mating-responsive gene expressed in fat, <it>Juvenile hormone esterase </it>(<it>Jhe</it>), is necessary for robust male courtship behavior and mating success.</p> <p>Conclusions</p> <p>Our study demonstrates that mating causes changes in male head gene expression profiles and supports an increasing body of work implicating adipose signaling in behavior modulation. Since several mating-induced genes are sex-determination hierarchy target genes, additional mating-responsive loci may be downstream components of this pathway as well.</p

Enhancement strategies for transdermal drug delivery systems: current trends and applications

Transdermal drug delivery systems have become an intriguing research topic in pharmaceutical technology area and one of the most frequently developed pharmaceutical products in global market. The use of these systems can overcome associated drawbacks of other delivery routes, such as oral and parenteral. The authors will review current trends, and future applications of transdermal technologies, with specific focus on providing a comprehensive understanding of transdermal drug delivery systems and enhancement strategies. This article will initially discuss each transdermal enhancement method used in the development of first-generation transdermal products. These methods include drug/vehicle interactions, vesicles and particles, stratum corneum modification, energy-driven methods and stratum corneum bypassing techniques. Through suitable design and implementation of active stratum corneum bypassing methods, notably microneedle technology, transdermal delivery systems have been shown to deliver both low and high molecular weight drugs. Microneedle technology platforms have proven themselves to be more versatile than other transdermal systems with opportunities for intradermal delivery of drugs/biotherapeutics and therapeutic drug monitoring. These have shown that microneedles have been a prospective strategy for improving transdermal delivery systems. Graphical abstract: [Figure not available: see fulltext.]</p

Calnexin co-expression and the use of weaker promoters increase the expression of correctly assembled Shaker potassium channel in insect cells.

Voltage-gated potassium channels control the membrane potential of excitable cells. To understand their function, knowledge of their structure is essential. However, these channels are scarce in natural sources, and overexpression is necessary to generate material for structural studies. We have compared functional expression of the Drosophila Shaker H4 potassium channel in stable insect cell lines and in baculovirus-infected insect cells, using three different baculovirus promoters. Stable insect cell lines expressed correctly assembled channel, which was glycosylated and found predominantly at, or close to, the cell surface. In comparison, the majority of baculovirus-overexpressed Shaker was intracellular and incorrectly assembled. The proportion of functional Shaker increased, however, if the weaker basic protein promoter was used rather than the stronger p10 or polyhedrin promoters. In addition, co-expression of the molecular chaperone, calnexin, increased the quantity of correctly assembled channel protein, suggesting that calnexin can be used to increase the efficiency of channel expression in insect cells