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Chintapalli V.R.,University of Glasgow | Terhzaz S.,University of Glasgow | Wang J.,University of Glasgow | Al Bratty M.,Strathclyde Institute for Pharmacy and Biomedical science | And 4 more authors.
PLoS ONE | Year: 2012

Background: In humans and other animals, the internal organs are positioned asymmetrically in the body cavity, and disruption of this body plan can be fatal in humans. The mechanisms by which internal asymmetry are established are presently the subject of intense study; however, the functional significance of internal asymmetry (outside the brain) is largely unexplored. Is internal asymmetry functionally significant, or merely an expedient way of packing organs into a cavity? Methodology/Principal Findings: Like humans, Drosophila shows internal asymmetry, with the gut thrown into stereotyped folds. There is also renal asymmetry, with the rightmost pair of renal (Malpighian) tubules always ramifying anteriorly, and the leftmost pair always sitting posteriorly in the body cavity. Accordingly, transcriptomes of anterior-directed (right-side) and posterior-directed (left-side) Malpighian (renal) tubules were compared in both adult male and female Drosophila. Although genes encoding the basic functions of the tubules (transport, signalling) were uniformly expressed, some functions (like innate immunity) showed positional or gender differences in emphasis; others, like calcium handling or the generation of potentially toxic ammonia, were reserved for just the right-side or left-side tubules, respectively. These findings correlated with the distinct locations of each tubule pair within the body cavity. Well known developmental genes (like dorsocross, dachshund and doublesex) showed continuing, patterned expression in adult tubules, implying that somatic tissues maintain both left-right and gender identities throughout life. Gender asymmetry was also noted, both in defence and in male-specific expression of receptors for neuropeptide F and sex-peptide: NPF elevated calcium only in male tubules. Conclusions/Significance: Accordingly, the physical asymmetry of the tubules in the body cavity is directly adaptive. Now that the detailed machinery underlying internal asymmetry is starting to be delineated, our work invites the investigation, not just of tissues in isolation, but in the context of their unique physical locations and milieux. © 2012 Chintapalli et al.


Bennie M.,Strathclyde Institute for Pharmacy and Biomedical science | Bishop L.,Head and Senior Researcher | Godman B.,Karolinska Institutet | Campbell S.,University of Manchester | And 3 more authors.
Quality in Primary Care | Year: 2013

Background There are on-going initiatives in Scotland to improve the quality and efficiency of prescribing in primary care. Activities to enhance prescribing of angiotensin-converting enzyme inhibitors (ACEIs) versus angiotensin receptor blockers (ARBs) include prescribing guidance, guidelines, benchmarking, prescribing targets and financial incentives. These measures stabilised reimbursed expenditure for renin-angiotensin inhibitor drugs between 2001 and 2007 despite a 159% increase in volumes. Generic losartan was included in the Drug Tariff from July 2010. As there is no appreciable difference between ARBs, and the prices of generic losartan are falling, health boards should be actively encouraging its prescribing. Aim To primarily assess changes in utilisation patterns of losartan versus other ARBs after July 2010. Second, to assess the utilisation of generic versus originator losartan. Method We used an interrupted time series analysis of ARB utilisation, measured in defined daily doses (DDDs) before and after July 2010. Utilisation data were obtained from the NHS National Services Scotland Corporate Warehouse. Results There was no significant change in the utilisation pattern of losartan or other ARBs combined before or after the introduction of generic losartn. Losartan accounted for 32% of total ARBs 12 months after listing. Between 98 and 99% of losartan was prescribed generically. In March 2012, the price of losartan was 88% below prepatent prices with potential savings of £8m per year. Conclusion Specific measures are needed to change prescribing habils especially wilh complex messages. The cost of deriving savings must be weighed against other quality initiatives and other ARBs losing or shortly losing their patents. © 2013 Radcliffe Publishing.


Shweash M.,Strathclyde Institute for Pharmacy and Biomedical science | Adrienne McGachy H.,Strathclyde Institute for Pharmacy and Biomedical science | Schroeder J.,Strathclyde Institute for Pharmacy and Biomedical science | Neamatallah T.,Strathclyde Institute for Pharmacy and Biomedical science | And 5 more authors.
Molecular Immunology | Year: 2011

The effects of Leishmania mexicana metacyclic promastigotes upon MAP kinase signalling in mouse bone marrow macrophages and subsequent expression of the disease regulatory proteins iNOS and COX-2 were studied. At a ratio of 5:1, promastigotes caused a marked increase in phosphorylation of the three major MAP kinases, ERK, p38 and JNK. MAP kinase signalling was substantially reduced in TLR-4-/- but not TLR-2-/- deficient macrophages and completely abolished in double TLR-2/4-/- macrophages. A similar outcome was observed using cysteine peptidase B deficient amastigotes. Furthermore, whilst promastigotes had no independent effect on iNOS or COX-2 expression, they prolonged the induction of these proteins stimulated by LPS and enhanced PGE2 and NO production. Induction of COX-2 and iNOS was also TLR-4 dependent. Blockade of either PGE2 or NO production with indomethacin or l-NAME reversed promastigote inhibition of LPS induced IL-12 production. Promastigotes also increased macrophage arginase-1 expression and enhanced arginase activity, both of which were substantially reduced in TLR-4 but not TLR-2 deficient macrophages. Surprisingly, arginase inhibition by Nor-NOHA also caused a reversal of promastigote mediated inhibition of macrophage IL-12 production. These data demonstrate for the first time the role of TLR-4 in mediating the effects of L. mexicana promastigotes on MAP kinase activation, up-regulation of COX-2, iNOS as well as arginase-1 expression in macrophages and further shows that PGE2, NO and arginase activity all contribute substantially to the inhibition of host cell IL-12 production. © 2011 Elsevier Ltd.


Bratty M.A.,Strathclyde Institute for Pharmacy and Biomedical science | Hobani Y.,University of Glasgow | Dow J.A.T.,University of Glasgow | Dow J.A.T.,King Saud University | Watson D.G.,Strathclyde Institute for Pharmacy and Biomedical science
Metabolomics | Year: 2011

Metabolomic profiling using hydrophilic interaction chromatography in combination with Fourier transform mass spectrometry was used to study the effects of the xanthine oxidase inhibitor allopurinol on wild type Drosophila melanogaster. Allopurinol treatment phenocopied the rosy mutation causing an elevation in the levels of xanthine and hypoxanthine and a fall in the levels of uric acid and allantoin. However, in addition there were some unexpected metabolic changes after treatment. Ascorbic acid levels were undetectable, glutathione levels fell and glutathione disulphide levels rose, methionine S-oxide levels rose and riboflavin levels fell. The origin of this oxidative stress was not immediately apparent; however, there was a strong suggestion that it might be related to a fall in NADPH levels linked to a reduction in glucose-6-phosphate dehydrogenase activity, resulting in reduced levels of some metabolites in the pentose phosphate pathway. In addition to producing oxidative stress there were marked effects on tryptophan metabolism with most of the metabolites in the kynurenine pathway being lowered by allopurinol treatment. The effects on the kynurenine pathway could be related to the established use of allopurinol in treating schizophrenia. © 2011 Springer Science+Business Media, LLC.


Croft D.R.,Beatson Institute for Cancer Research | Croft D.R.,Strathclyde Institute for Pharmacy and Biomedical science | Olson M.F.,Beatson Institute for Cancer Research
Transcription | Year: 2011

Signaling through the Rho family of small GTPases regulates a variety of cellular processes via changes in the actin cytoskeleton. Here we discuss recent fndings that show the transcription factor p53 regulates the expression of several Rho pathway signaling molecules, and how mutation of p53 in cancer dramatically alters signaling output through this pathway. © 2011 Landes Bioscience.


PubMed | Strathclyde Institute for Pharmacy and Biomedical science
Type: Journal Article | Journal: Quality in primary care | Year: 2013

There are on-going initiatives in Scotland to improve the quality and efficiency of prescribing in primary care. Activities to enhance prescribing of angiotensin-converting enzyme inhibitors (ACEIs) versus angiotensin receptor blockers (ARBs) include prescribing guidance, guidelines, benchmarking, prescribing targets and financial incentives. These measures stabilised reimbursed expenditure for renin-angiotensin inhibitor drugs between 2001 and 2007 despite a 159% increase in volumes. Generic losartan was included in the Drug Tariff from July 2010. As there is no appreciable difference between ARBs, and the prices of generic losartan are falling, health boards should be actively encouraging its prescribing.To primarily assess changes in utilisation patterns of losartan versus other ARBs after July 2010. Second, to assess the utilisation of generic versus originator losartan.We used an interrupted time series analysis of ARB utilisation, measured in defined daily doses (DDDs) before and after July 2010. Utilisation data were obtained from the NHS National Services Scotland Corporate Warehouse.There was no significant change in the utilisation pattern of losartan or other ARBs combined before or after the introduction of generic losartan. Losartan accounted for 32% of total ARBs 12 months after listing. Between 98 and 99% of losartan was prescribed generically. In March 2012, the price of losartan was 88% below prepatent prices with potential savings of ?8m per year.Specific measures are needed to change prescribing habits especially with complex messages. The cost of deriving savings must be weighed against other quality initiatives and other ARBs losing or shortly losing their patents.

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