Biomedical subjects

Sarah Ross

Publications and source records attributed to Sarah Ross.

9 recordsLinked to original sources

PubMed2007

Substrate specificity and acute regulation of the tumour suppressor phosphatase, PTEN.

PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a tumour suppressor that functions as a PtdIns(3,4,5)P3 3-phosphatase to inhibit cell proliferation, survival and growth by antagonizing PI3K (phosphoinositide 3-kinase)-dependent signalling. Recent work has begun to focus attention on potential biological functions of the protein phosphatase activity of PTEN and on the possibility that some of its functions are phosphatase-independent. We discuss here the structural and regulatory mechanisms that account for the remarkable specificity of PTEN with respect to its PtdIns substrates and how it avoids the soluble headgroups of PtdIns that occur commonly in cells. Secondly we discuss the concept of PTEN as a constitutively active enzyme that is subject to negative regulation both physiologically and pathologically. Thirdly, we review the evidence that PTEN functions as a dual specificity phosphatase with discrete lipid and protein substrates. Lastly we present a current model of how PTEN may participate in the control of cell migration.

Allosteric Regulation↗

PubMed2006

Smads orchestrate specific histone modifications and chromatin remodeling to activate transcription.

Smads are intracellular transducers for TGF-beta superfamily ligands, but little is known about the mechanism by which complexes of receptor-phosphorylated Smad2 and Smad4 regulate transcription. Using an in vitro transcription system, we have discovered that, unlike most transcription factors that are sufficient to recruit the basal transcription machinery and therefore activate transcription on both naked DNA and chromatin templates, the Smads only activate transcription from chromatin templates. We demonstrate that Smad2-mediated transcription requires the histone acetyltransferase, p300. Smad2-recruited p300 exhibits an altered substrate specificity, specifically acetylating nucleosomal histone H3 at lysines 9 and 18, and these modifications are also detected on an endogenous Smad2-dependent promoter in a ligand-induced manner. Furthermore, we show that endogenous Smad2 interacts with the SWI/SNF ATPase, Brg1, in a TGF-beta-dependent manner, and demonstrate that Brg1 is recruited to Smad2-dependent promoters and is specifically required for TGF-beta-induced expression of endogenous Smad2 target genes. Our data indicate that the Smads define a new class of transcription factors that absolutely require chromatin to assemble the basal transcription machinery and activate transcription.

Acetylation↗

PubMed2006

Homoeopathic and herbal prescribing in general practice in Scotland.

AIMS: To investigate the current levels of homoeopathic and herbal prescribing in Scottish general practice. METHODS: Prescribing of homoeopathic and herbal remedies in primary care was assessed in 1891 669 patients for the year 2003-2004, using computerized prescribing data retrieved from 323 general practices in Scotland. RESULTS: Forty-nine percent of practices prescribed homoeopathic and 32% herbal remedies. A total of 193 homoeopathic and 17 herbal remedies were prescribed, with 5% of practices accounting for 46% of patients and 50% of remedies. Four thousand one hundred and sixty patients (2.2/1000 registered patients) were prescribed at least one homoeopathic remedy during the study period, with the highest prevalence to children under 12 months of age (9.5/1000 children of that age). Children under the age of 16 made up 16% of the population prescribed homoeopathic remedies (2.2/1000 registered patients of that age). Three hundred and sixty-one patients (0.2/1000 registered patients) were prescribed at least one herbal remedy during the study period, 44 of whom were children < 16 years old. Patients prescribed a homoeopathic or herbal remedy were also prescribed a median of four and five conventional medicines, respectively. Of patients prescribed an oral herbal remedy, 4% were also concomitantly prescribed a conventional medicine with which a drug-herb interaction has been documented. CONCLUSIONS: Our study reports that a substantial number of Scottish general practitioners prescribe homoeopathic and herbal remedies, with an approximate doubling in the number of children prescribed homoeopathic remedies. The level of homoeopathic and herbal prescribing raises questions about homoeopathic/herbal provision in the National Health Service and should prompt critical review.

Adolescent↗

PubMed2006

Experimental efficacy of an everolimus eluting cobalt chromium stent.

INTRODUCTION: Rapamycin and its analogs are now being coated on different stent platforms, using different polymer matrices to prevent restenosis by impairing vascular smooth muscle cell proliferation and neointimal formation. METHODS: We evaluated the feasibility and compared the efficacy of biostable polymeric everolimus and sirolimus (CYPHER, Cordis) eluting stents in a porcine coronary model. Cobalt chromium balloon expandable stents (ML VISION, Guidant) were coated with a polymer containing everolimus (190 mug/cm(2)). Twelve pigs underwent placement of 36 oversized sirolimus (n = 12), everolimus (n = 12), and bare metal (cobalt chromium, n = 12) stents in the coronary arteries. RESULTS: At day 28, vessel injury scores were low (<0.25) and similar between each of the three test groups. The mean neointimal thickness was significantly lower in the everolimus- (0.13 +/- 0.07 mm, P = 0.02) and sirolimus-eluting stents (0.13 +/- 0.08 mm, P = 0.04) versus the bare metal stents (0.20 +/- 0.07 mm). The mean percent area stenosis was similar for the everolimus-eluting stents [(20.8 +/- 6.9)%] and the sirolimus-eluting stents [(20.8 +/- 7.6)%], and each was significantly less than that of bare metal stents [(26.1 +/- 7.8)%, P = 0.05]. CONCLUSION: Stent-based delivery of sirolimus and everolimus delivered via durable polymeric matrices are equally effective in the suppression of neointimal formation at day 28 in the porcine coronary model. Further study is necessary to document dose response and long-term comparative effects of these drug-eluting stents.

Animals↗

PubMed2006

Stress, debt and undergraduate medical student performance.

INTRODUCTION: Against the background of current debate over university funding and widening access, we aimed to examine the relationships between student debt, mental health and academic performance. METHODS: We carried out an electronic survey of all medical undergraduate students at the University of Aberdeen during May-June 2004. The questionnaire contained items about demographics, debt, income and stress. Students were also asked for consent to access their examination results, which were correlated with their answers. Statistical analyses of the relationships between debt, performance and stress were performed. RESULTS: The median total outstanding debt was pound 7300 (interquartile range 2000-14 762.50). Students from lower socioeconomic backgrounds and postgraduate students had higher debts. There was no direct correlation between debt, class ranking or General Health Questionnaire (GHQ) score; however, a subgroup of 125 students (37.7%), who said that worrying about money affected their studies, did have higher debt and were ranked lower in their classes. Some of these students were also cases on the GHQ-12. Overall, however, cases on the GHQ had lower levels of debt and lower class ranking, suggesting that financial worries are only 1 cause of mental health difficulties. DISCUSSION: Students' perceptions of their own levels of debt rather than level of debt per se relates to performance. Students who worry about money have higher debts and perform less well than their peers in degree examinations. Some students in this subgroup were also identified by the GHQ and may have mental health problems. The relationships between debt, mental health and performance in undergraduate medical students are complex but need to be appreciated by medical education policy makers.

Clinical Competence↗

PubMed2005

Antihypertensive drug prescribing in Grampian.

AIMS: To assess the cost implications of changing prescribing patterns for antihypertensive drugs and to analyse adherence to guidelines and formulary in Grampian region over a 1 year period. METHODS: Data on all prescriptions for antihypertensive medicines between November 2001 and October 2002 were obtained from Grampian Health Board. The total quantity and cost of each drug prescribed was calculated and compared with November 1998 to October 1999. Adherence to the local formulary and 1999 British Hypertension Society guidelines for first line agents and prescribing of generic drug names were analyzed for each practice. RESULTS: There was an increase in the total number of prescriptions for antihypertensive drugs from 504929 in 1998/99 to 741620 in 2001/02, and a corresponding increase in total cost from pound 4.52 million to pound 6.79 million. Increases were seen in all drug classes, particularly angiotensin II antagonists (246.27%). Adherence to the local formulary was good, with an average of 91.25% (SD 5.94%) of prescribing consistent with recommended agents. This fell to 71.70% (SD 23.10%) for angiotensin II antagonists. Prescription using generic name was related to whether the practice dispensed medication or not: the mean level of generic prescribing in dispensing practices was 75.25% and in nondispensing practices was 89.02% (mean difference 13.76 (9.27, 18.26), P < 0.001). CONCLUSIONS: There was a substantial increase in prescribing volume and cost of antihypertensives between 1998/99 and 2001/02. This trend is likely to have continued, given changing targets and indications for therapy. Although practices generally showed high concordance with formulary recommendations, newer agents such as angiotensin II antagonists were less consistent, possibly related to pharmaceutical influences on prescribing. Dispensing practices were more likely to prescribe branded drugs which may reflect current reimbursement policies. Changing prescribing practices by encouraging formulary based prescribing and prescribing of generic agents may help offset the cost implications of guideline driven increases in antihypertensive drug prescribing. Education, and reviewing payment practices in dispensing and smaller practices, may also have a role.

Antihypertensive Agents↗

PubMed2005

Bupropion: risks and benefits.

Cigarette smoking represents one of the most preventable causes of death worldwide. However, success rates for stopping smoking are disappointingly low and are associated with high relapse rates. There is a need for a successful form of smoking cessation therapy. Bupropion is an effective therapy for smoking cessation and is recommended as first-line treatment in both US and UK guidelines. Its mechanism of action in smoking cessation is unclear, although it is thought that dopaminergic pathways are involved in the 'reward' circuit of drug dependence. Seizures are an important adverse effect of bupropion and care is needed when used in other conditions or with other medication that can lower the seizure threshold. Bupropion has been shown to be a cost-effective therapy for smoking cessation.

Bupropion↗

PubMed2002

SUMO-1 modification represses Sp3 transcriptional activation and modulates its subnuclear localization.

The GC box binding transcription factor Sp3 both activates and represses transcription. We have found that Sp3 activity is regulated by SUMO-1 modification. Endogenous Sp3 is sumoylated and localized to the nuclear periphery and in nuclear dots. Removal of SUMO-1 from Sp3 by mutation of the SUMO acceptor lysines or expression of the SUMO-1 protease SuPr-1 converted Sp3 to a strong activator with a diffuse nuclear localization. Covalent attachment of SUMO-1 to Sp3 by gene fusion was sufficient to repress Sp3-dependent transcription and relocalize Sp3 to the nuclear periphery and nuclear dots. These studies reveal a direct effect of SUMO-1 modification on activity of a dual function transcription factor and provide a mechanism for functional specificity within the Sp transcription factor family.

Binding Sites↗

PubMed2001

GC box-binding transcription factors control the neuronal specific transcription of the cyclin-dependent kinase 5 regulator p35.

Cyclin-dependent kinase 5 (cdk5)/p35 kinase activity is highest in post-mitotic neurons of the central nervous system and is critical for development and function of the brain. The neuronal specific activity of the cdk5/p35 kinase is achieved through the regulated expression of p35 mRNA. We have identified a small 200-bp fragment of the p35 promoter that is sufficient for high levels of neuronal specific expression. Mutational analysis of this TATA-less promoter has identified a 17-bp GC-rich element, present twice, that is both required for promoter activity and sufficient for neuronal specific transcription. A GC box within the 17-bp element is critical for both promoter activity and protein-DNA complex formation. The related transcription factors Sp1, Sp3, and Sp4 constitute most of the GC box DNA binding activity in neurons. We have found that both the relative contribution of the Sp family proteins to GC box binding and the transcriptional activity of these proteins is regulated during neuronal differentiation. Thus, our data show that the GC box-binding Sp proteins contribute to the regulation of p35 expression in neurons, suggesting changes in the Sp transcription factors level and activity may contribute to cell type-specific expression of many genes in the central nervous system.

Animals↗