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1.  Incidence of diabetic retinopathy in people with type 2 diabetes mellitus attending the Diabetic Retinopathy Screening Service for Wales: retrospective analysis  
Objectives To determine the incidence of any and referable diabetic retinopathy in people with type 2 diabetes mellitus attending an annual screening service for retinopathy and whose first screening episode indicated no evidence of retinopathy.
Design Retrospective four year analysis.
Setting Screenings at the community based Diabetic Retinopathy Screening Service for Wales, United Kingdom.
Participants 57 199 people with type 2 diabetes mellitus, who were diagnosed at age 30 years or older and who had no evidence of diabetic retinopathy at their first screening event between 2005 and 2009. 49 763 (87%) had at least one further screening event within the study period and were included in the analysis.
Main outcome measures Annual incidence and cumulative incidence after four years of any and referable diabetic retinopathy. Relations between available putative risk factors and the onset and progression of retinopathy.
Results Cumulative incidence of any and referable retinopathy at four years was 360.27 and 11.64 per 1000 people, respectively. From the first to fourth year, the annual incidence of any retinopathy fell from 124.94 to 66.59 per 1000 people, compared with referable retinopathy, which increased slightly from 2.02 to 3.54 per 1000 people. Incidence of referable retinopathy was independently associated with known duration of diabetes, age at diagnosis, and use of insulin treatment. For participants needing insulin treatment with a duration of diabetes of 10 years or more, cumulative incidence of referable retinopathy at one and four years was 9.61 and 30.99 per 1000 people, respectively.
Conclusions Our analysis supports the extension of the screening interval for people with type 2 diabetes mellitus beyond the currently recommended 12 months, with the possible exception of those with diabetes duration of 10 years or more and on insulin treatment.
PMCID: PMC3284424  PMID: 22362115
2.  Identification of signalling cascades involved in red blood cell shrinkage and vesiculation 
Bioscience Reports  2015;35(2):e00187.
Even though red blood cell (RBC) vesiculation is a well-documented phenomenon, notably in the context of RBC aging and blood transfusion, the exact signalling pathways and kinases involved in this process remain largely unknown. We have established a screening method for RBC vesicle shedding using the Ca2+ ionophore ionomycin which is a rapid and efficient method to promote vesiculation. In order to identify novel pathways stimulating vesiculation in RBC, we screened two libraries: the Library of Pharmacologically Active Compounds (LOPAC) and the Selleckchem Kinase Inhibitor Library for their effects on RBC from healthy donors. We investigated compounds triggering vesiculation and compounds inhibiting vesiculation induced by ionomycin. We identified 12 LOPAC compounds, nine kinase inhibitors and one kinase activator which induced RBC shrinkage and vesiculation. Thus, we discovered several novel pathways involved in vesiculation including G protein-coupled receptor (GPCR) signalling, the phosphoinositide 3-kinase (PI3K)–Akt (protein kinase B) pathway, the Jak–STAT (Janus kinase–signal transducer and activator of transcription) pathway and the Raf–MEK (mitogen-activated protein kinase kinase)–ERK (extracellular signal-regulated kinase) pathway. Moreover, we demonstrated a link between casein kinase 2 (CK2) and RBC shrinkage via regulation of the Gardos channel activity. In addition, our data showed that inhibition of several kinases with unknown functions in mature RBC, including Alk (anaplastic lymphoma kinase) kinase and vascular endothelial growth factor receptor 2 (VEGFR-2), induced RBC shrinkage and vesiculation.
After screening two libraries of small bioactive molecules and kinase inhibitors, we identified several signalling pathways to be involved in red blood cell (RBC) shrinkage and vesiculation. These include the Jak (Janus kinase)–STAT (signal transducer and activator of transcription) pathway, phosphoinositide 3-kinase (PI3K)–Akt pathway, the Raf–MEK (mitogen-activated protein kinase kinase)–ERK (extracellular signal-regulated kinase) pathway and GPCR (G protein-coupled receptor) signalling.
PMCID: PMC4400636  PMID: 25757360
bioactive small molecule; compound screen; kinase inhibitor; red blood cell; vesiculation; AMPK, AMP-activated kinase; ATA, aurintricarboxylic acid; BCR-ABL, breakpoint cluster region protein–Abelson murine leukaemia viral oncogene homologue 1; CaM, calmodulin; CK2, casein kinase 2; Epo, erythropoietin; ERK, extracellular signal-regulated kinase; GPCR, G protein-coupled receptor; Jak, Janus kinase; LOPAC, Library of Pharmacologically Active Compounds; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; NO, nitric oxide; nRTK, non-receptor tyrosine kinase; PC, phosphatidylcholine; PDGFR, platelet-derived growth factor receptor; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; PLC, phospholipase C; PS, phosphatidylserine; RBC, red blood cell; RTK, receptor tyrosine kinase; SAGM, saline-adenine-glucose-mannitol; SCD, sickle cell disease; SMase, acid sphingomyelinase; STAT, signal transducer and activator of transcription; VEGFR, vascular endothelial growth factor receptor; β-AR, β-adrenergic receptor
3.  Bnip3 impairs mitochondrial bioenergetics and stimulates mitochondrial turnover 
Cell Death and Differentiation  2010;18(4):721-731.
Bnip3 (Bcl-2/adenovirus E1B 19-kDa-interacting protein 3) is a mitochondrial BH3-only protein that contributes to cell death through activation of the mitochondrial pathway of apoptosis. Bnip3 is also known to induce autophagy, but the functional role of autophagy is unclear. In this study, we investigated the relationship between mitochondrial dysfunction and upregulation of autophagy in response to Bnip3 in cells lacking Bax and Bak. We found that Bnip3 induced mitochondrial autophagy in the absence of mitochondrial membrane permeabilization and Bax/Bak. Also, co-immunoprecipitation experiments showed that Bnip3 interacted with the autophagy protein LC3 (microtubule-associated protein light chain 3). Although Bax-/Bak-deficient cells were resistant to Bnip3-mediated cell death, inhibition of mitochondrial autophagy induced necrotic cell death. When investigating why these mitochondria had to be removed by autophagy, we discovered that Bnip3 reduced both nuclear- and mitochondria-encoded proteins involved in oxidative phosphorylation. Interestingly, Bnip3 had no effect on other mitochondrial proteins, such as Tom20 and MnSOD, or actin and tubulin in the cytosol. Bnip3 did not seem to reduce transcription or translation of these proteins. However, we found that Bnip3 caused an increase in mitochondrial protease activity, suggesting that Bnip3 might promote degradation of proteins in the mitochondria. Thus, Bnip3-mediated impairment of mitochondrial respiration induces mitochondrial turnover by activating mitochondrial autophagy.
PMCID: PMC3058880  PMID: 21278801
Bnip3; Bcl-2; autophagy; apoptosis; mitochondria; oxidative phosphorylation
7.  A six year longitudinal study of the occupational consequences of drinking over "safe limits" of alcohol. 
Although much research has focused on the psychological, social, and economic consequences of heavy problem drinking, there has been far less attention paid to the consequences of "moderate" drinking. This study used a unique opportunity to carry out a six year follow up of a cohort of male and female white collar workers in whom there was baseline information on alcohol consumption and access to details on sickness absence, labour turnover, and promotion. It has provided evidence that even moderate alcohol consumption in the working population is associated with social costs for the employer and the employee, including substantial sickness absence, and lack of promotion in men, although the increase in labour turnover was not statistically significant. The longitudinal examination of consumption in this study suggests that early intervention in a drinking career may reduce alcohol consumption and consequently avoid years of morbidity and sickness absence, as well as having a favourable influence on performance and labour turnover.
PMCID: PMC1039257  PMID: 1599875
8.  CMA in action. 
California Medicine  1973;119(6):18-37.
PMCID: PMC1455356  PMID: 4759816

Results 1-10 (10)