ORCID Profile
0000-0002-2566-9304
Current Organisations
Walter and Eliza Hall Institute of Medical Research
,
Monash University
,
University of Cambridge
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Publisher: Hindawi Limited
Date: 02-2007
Publisher: Oxford University Press (OUP)
Date: 22-04-2008
DOI: 10.1093/HMG/DDN128
Publisher: Wiley
Date: 12-11-2019
Abstract: Noscapine displays weak anticancer efficacy and numerous research efforts have attempted to generate more potent noscapine analogues. These modifications included the replacement of the N-methyl group in the 6'-position with a range of substituents, where N-ethylcarbamoyl substitution was observed to possess enhanced anticancer activity. Herein, we describe advances in this area, namely the synthesis and pharmacological evaluation of a series of N-sulfonyl and N-sulfamoyl noscapine derivatives. A number of these sulfonyl-containing noscapinoids demonstrated improved activities compared to noscapine. ((R)-5-((S)-4,5-Dimethoxy-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-((1-methyl-1H-imidazol-4-yl)sulfonyl)-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinoline) (14 q) displayed sub-micromolar activities of 560, 980, 271 and 443 nM against MCF-7, PANC-1, MDA-MB-435 and SK-MEL-5 cells, respectively. This antiproliferative effect was also maintained against drug-resistant NCI/Adr
Publisher: American Diabetes Association
Date: 14-06-2014
DOI: 10.2337/DB13-1777
Abstract: Diagnosis of the autoimmune disease type 1 diabetes (T1D) is preceded by the appearance of circulating autoantibodies to pancreatic islets. However, almost nothing is known about events leading to this islet autoimmunity. Previous epidemiological and genetic data have associated viral infections and antiviral type I interferon (IFN) immune response genes with T1D. Here, we first used DNA microarray analysis to identify IFN-β–inducible genes in vitro and then used this set of genes to define an IFN-inducible transcriptional signature in peripheral blood mononuclear cells from a group of active systemic lupus erythematosus patients (n = 25). Using this predefined set of 225 IFN signature genes, we investigated the expression of the signature in cohorts of healthy controls (n = 87), patients with T1D (n = 64), and a large longitudinal birth cohort of children genetically predisposed to T1D (n = 109 454 microarrayed s les). Expression of the IFN signature was increased in genetically predisposed children before the development of autoantibodies (P = 0.0012) but not in patients with established T1D. Upregulation of IFN-inducible genes was transient, temporally associated with a recent history of upper respiratory tract infections (P = 0.0064), and marked by increased expression of SIGLEC-1 (CD169), a lectin-like receptor expressed on CD14+ monocytes. DNA variation in IFN-inducible genes altered T1D risk (P = 0.007), as exemplified by IFIH1, one of the genes in our IFN signature for which increased expression is a known risk factor for disease. These findings identify transient increased expression of type I IFN genes in preclinical diabetes as a risk factor for autoimmunity in children with a genetic predisposition to T1D.
Publisher: American Chemical Society (ACS)
Date: 29-08-2018
DOI: 10.1021/ACS.JMEDCHEM.8B00986
Abstract: A series of 5-substituted tetrahydroisoquinolines was synthesized via a 10-step linear synthesis to assess whether replacement of noscapine's southern isobenzofuranone with other moieties resulted in retained cytotoxic activity. One such molecule, 18g, bearing a para-methoxybenzyl functionality with N-ethylcarbamoyl substitution, produced cell-cycle arrest at the G2/M phase with an EC
Publisher: Springer Science and Business Media LLC
Date: 05-02-2001
Abstract: Early detection of risk of microalbuminuria could prevent early renal damage. We investigated whether urine retinol binding protein and N-acetyl-glucosaminidase could predict the risk of microalbuminuria in a large cohort of children followed from diagnosis of Type I (insulin-dependent) diabetes mellitus. Subjects under 16 years of age within a georaphically defined region were recruited at diagnosis of Type I (insulin-dependent) diabetes mellitus. Annually, albumin-, retinol binding protein- and N-acetyl-glucosaminidase- to creatinine ratios were each measured in 3 urine s les. A total of 511 subjects were followed for a median of 6 years (range: 1-14). Microalbuminuria (males: > or = 3.5 mg/mmol females: > or = 4.0 mg/mmol, in 2 out of 3 urines) developed in 78 subjects (36 male). The cumulative probability of microalbuminuria was 40% after 12 years duration of diabetes. Retinol-binding-proteinuria (men: > or = 21 microg/mmol women > or = 33 microg/mmol) developed in 217 subjects (152 men). The cumulative probability of retinol-binding-proteinuria was 67 % after 12 years duration of diabetes. The cumulative probability of retinol-binding-proteinuria was 40 % before the onset of microalbuminuria and 59% in subjects who did not subsequently develop microalbuminuria. Retinol-binding-proteinuria developed at a higher rate with increasing HbA1c than microalbuminuria. N-acetyl-glucosaminidase-uria (males: > or = 56 micromol-pnp x h(-1) x mmol(-1) females: > or = 46 micromol-pnp h(-1) x mmol(-1)) developed in 477 subjects. The cumulative probability of N-acetylglucosaminidase-uria was 98 % after 10 years of diabetes duration. The cumulative probability of N-acetyl-glucosaminidase-uria was 73 % in the years before the onset of microalbuminuria and 97 % in subjects without microalbuminuria. The probability of Nacetyl-glucosaminidase-uria was 99 % with an HbA1c greater than or equal to 14.5 %. Raised amounts of urine retinol binding protein and N-acetyl-glycosaminidase are related to HbA1c and the duration of diabetes. They occur in the majority of subjects and are not early markers for the risk of microalbuminuria.
Publisher: Public Library of Science (PLoS)
Date: 10-01-2012
Publisher: Massachusetts Medical Society
Date: 02-11-2017
Publisher: Oxford University Press (OUP)
Date: 05-05-2009
DOI: 10.1093/HMG/DDP193
Publisher: Elsevier BV
Date: 10-2009
Publisher: American Chemical Society (ACS)
Date: 16-01-2015
DOI: 10.1021/JM501402X
Abstract: We have identified a class of molecules, known as 2-aminothiazoles (2-ATs), as frequent-hitting fragments in biophysical binding assays. This was exemplified by 4-phenylthiazol-2-amine being identified as a hit in 14/14 screens against a erse range of protein targets, suggesting that this scaffold is a poor starting point for fragment-based drug discovery. This prompted us to analyze this scaffold in the context of an academic fragment library used for fragment-based drug discovery (FBDD) and two larger compound libraries used for high-throughput screening (HTS). This analysis revealed that such "promiscuous 2-aminothiazoles" (PrATs) behaved as frequent hitters under both FBDD and HTS settings, although the problem was more pronounced in the fragment-based studies. As 2-ATs are present in known drugs, they cannot necessarily be deemed undesirable, but the combination of their promiscuity and difficulties associated with optimizing them into a lead compound makes them, in our opinion, poor scaffolds for fragment libraries.
Publisher: Hindawi Limited
Date: 09-2009
Publisher: American Diabetes Association
Date: 27-04-2018
DOI: 10.2337/DB17-0914
Abstract: Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication s les, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10−8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased s le sizes will continue to provide more robust inference regarding risk variant discovery for DKD.
Publisher: American Diabetes Association
Date: 27-02-2020
DOI: 10.2337/DC19-0884
Abstract: Suboptimal adherence to insulin treatment is a main issue in adolescents with type 1 diabetes. However, to date, there are no available data on adherence to adjunct noninsulin medications in this population. Our aim was to assess adherence to ACE inhibitors and statins and explore potential determinants in adolescents with type 1 diabetes. There were 443 adolescents with type 1 diabetes recruited into the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) and exposed to treatment with two oral drugs—an ACE inhibitor and a statin—as well as combinations of both or placebo for 2–4 years. Adherence was assessed every 3 months with the Medication Event Monitoring System (MEMS) and pill count. Median adherence during the trial was 80.2% (interquartile range 63.6–91.8) based on MEMS and 85.7% (72.4–92.9) for pill count. Adherence based on MEMS and pill count dropped from 92.9% and 96.3%, respectively, at the first visit to 76.3% and 79.0% at the end of the trial. The percentage of study participants with adherence ≥75% declined from 84% to 53%. A good correlation was found between adherence based on MEMS and pill count (r = 0.82, P & 0.001). Factors associated with adherence were age, glycemic control, and country. We report an overall good adherence to ACE inhibitors and statins during a clinical trial, although there was a clear decline in adherence over time. Older age and suboptimal glycemic control at baseline predicted lower adherence during the trial, and, predictably, reduced adherence was more prevalent in subjects who subsequently dropped out.
Publisher: Springer Science and Business Media LLC
Date: 07-06-2007
DOI: 10.1038/NATURE05911
Publisher: Hindawi Limited
Date: 12-07-2014
DOI: 10.1111/PEDI.12174
Publisher: BMJ
Date: 07-2002
DOI: 10.1136/ADC.87.1.10
Publisher: Informa UK Limited
Date: 17-02-2018
Publisher: Springer Science and Business Media LLC
Date: 27-04-2008
DOI: 10.1038/NG.145
Publisher: Springer Science and Business Media LLC
Date: 04-05-2008
DOI: 10.1038/NG.140
Publisher: The Endocrine Society
Date: 12-2010
DOI: 10.1210/JC.2010-1047
Publisher: Hindawi Limited
Date: 17-08-2020
DOI: 10.1111/PEDI.13095
Publisher: Massachusetts Medical Society
Date: 09-01-2014
Publisher: American Diabetes Association
Date: 05-2003
DOI: 10.2337/DIACARE.26.5.1456
Abstract: OBJECTIVE—To describe longitudinal variations in pubertal hormonal variables in subjects with and without microalbuminuria (MA). RESEARCH DESIGN AND METHODS—Blood s les collected annually from subjects recruited at diagnosis of type 1 diabetes and followed prospectively through puberty (median follow-up 9.3 years, range 4.7–12.8) were analyzed for total and free IGF-I, IGF binding protein-1, testosterone, sex hormone-binding globulin, and HbA1c. A total of 55 subjects who developed MA (MA+ group) were compared with 55 age-, sex-, and duration-matched control subjects who did not develop MA (MA− group). RESULTS—For female subjects, total IGF-I (MA+ 1.2 mU/l vs. MA− 1.4 mU/l, P = 0.03) and free IGF-I levels (MA+ 1,767 ng/l vs. MA− 2010 ng/l, P = 0.002) were lower, whereas the free androgen index (MA+ 2.4 vs. MA− 2.0, P = 0.03) was higher in those with MA. These changes were less pronounced in male subjects. For both sexes, in a Cox model after adjusting for puberty, the presence of MA was associated with lower free IGF-I levels, higher testosterone standard deviation score (SDS), and poor glycemic control. We found that 22 of 55 case subjects (40%) developed persistent MA, whereas 33 (60%) had transient MA. In the persistent MA group compared with the transient and control groups, total IGF-I levels were lower (1.1 vs. 1.3 vs. 1.4 mU/l, P = 0.002) as were free IGF-I levels (1,370.9 vs. 1,907.3 vs. 1,886.7 ng/l, P & 0.001), whereas HbA1c levels were higher (11.8 vs. 10.3 vs. 9.9%, P & 0.001). CONCLUSIONS—Poor glycemic control and differences in IGF-I levels and androgens, particularly in female subjects, accompany development of MA at puberty. These differences may in part account for the sexual dimorphism in MA risk during puberty and could relate to disease progression.
Publisher: Springer Science and Business Media LLC
Date: 14-09-2008
DOI: 10.1038/NG.218
Publisher: American Diabetes Association
Date: 23-04-2011
DOI: 10.2337/DB10-1656
Abstract: Vitamin D deficiency (25-hydroxyvitamin D [25(OH)D] & nmol/L) is commonly reported in both children and adults worldwide, and growing evidence indicates that vitamin D deficiency is associated with many extraskeletal chronic disorders, including the autoimmune diseases type 1 diabetes and multiple sclerosis. We measured 25(OH)D concentrations in 720 case and 2,610 control plasma s les and genotyped single nucleotide polymorphisms from seven vitamin D metabolism genes in 8,517 case, 10,438 control, and 1,933 family s les. We tested genetic variants influencing 25(OH)D metabolism for an association with both circulating 25(OH)D concentrations and disease status. Type 1 diabetic patients have lower circulating levels of 25(OH)D than similarly aged subjects from the British population. Only 4.3 and 18.6% of type 1 diabetic patients reached optimal levels (≥75 nmol/L) of 25(OH)D for bone health in the winter and summer, respectively. We replicated the associations of four vitamin D metabolism genes (GC, DHCR7, CYP2R1, and CYP24A1) with 25(OH)D in control subjects. In addition to the previously reported association between type 1 diabetes and CYP27B1 (P = 1.4 × 10−4), we obtained consistent evidence of type 1 diabetes being associated with DHCR7 (P = 1.2 × 10−3) and CYP2R1 (P = 3.0 × 10−3). Circulating levels of 25(OH)D in children and adolescents with type 1 diabetes vary seasonally and are under the same genetic control as in the general population but are much lower. Three key 25(OH)D metabolism genes show consistent evidence of association with type 1 diabetes risk, indicating a genetic etiological role for vitamin D deficiency in type 1 diabetes.
Publisher: Bioscientifica
Date: 04-1201
Abstract: The long term therapeutic potential of recombinant human (rh) IGF-I administration in insulin-dependent diabetes mellitus (IDDM) may be determined by changes in the IGF binding proteins (IGFBPs) and thus the bioavailability of IGF-I. We have therefore studied the effects of a single subcutaneous dose of rhIGF-I (40 micrograms/kg at 1800 h), when compared with an untreated control night, in 17 subjects with IDDM, on serum concentrations of IGF-I, IGF-II, IGFBP-3, acid labile subunit (ALS), and IGFBP-3 proteolysis. Mean (+/- S.E.M.) IGF-I levels increased from 242 +/- 30 ng/ml to 399 +/- 26 ng/ml (P = 0.01) after rhIGF-I whereas IGF-II levels declined from 600 +/- 45 ng/ml to 533 +/- 30 ng/ml. There was a small overnight reduction in baseline ALS levels from 48 +/- 2.8 to 44.5 +/- 3.2 micrograms/ml (P = 0.04) after rhIGF-I administration. An early fall in IGFBP-3 concentrations on the control night was not seen after rhIGF-I and overall mean levels were increased (5.2 +/- 0.2 micrograms/ml vs 4.9 +/- 0.2 micrograms/ml, P = 0.04, on the control night). On the baseline night, IGFBP-3 levels correlated with the sum of IGF-I and IGF-II (r = 0.73, P = 0.02) and with levels of the ALS (r = 0.7, P = 0.002). However after rhIGF-I, the sum of IGF-I and IGF-II no longer correlated with IGFBP-3, whereas the relationship with ALS was maintained. Immunoblot studies in six subjects indicated that 60%-70% of the IGFBP-3 was detected as a low molecular weight fragment at 1900 h on both study nights, but the amount of fragment declined to approximately 50% at 0100 h and 45% at 0700 h. In conclusion, despite a slight but significant fall in ALS, IGFBP-3 levels rise after rhIGF-I administration in IDDM. This cannot be explained by alterations in IGFBP-3 proteolysis, and may relate to the relative stability of ALS/IGFBP-3 when complexed principally with IGF-I rather than IGF-II.
Publisher: CSIRO Publishing
Date: 2013
DOI: 10.1071/CH13266
Abstract: Apical membrane antigen 1 (AMA1) is an essential component of the moving junction complex used by Plasmodium falciparum to invade human red blood cells. AMA1 has a conserved hydrophobic cleft that is the site of key interactions with the rhoptry neck protein complex. Our goal is to develop small molecule inhibitors of AMA1 with broad strain specificity, which we are pursuing using a fragment-based approach. In our screening c aign, we identified fragments that bind to the hydrophobic cleft with a hit rate of 5 %. The high hit rate observed strongly suggests that a druggable pocket is present within the cleft.
Publisher: American Diabetes Association
Date: 03-1999
Abstract: OBJECTIVE: The predictive value of microalbuminuria (MA) in children with type 1 diabetes has not been defined. We describe the natural history of MA in a large cohort of children recruited at diagnosis of type 1 diabetes. RESEARCH DESIGN AND METHODS: Between 1985 and 1996, 514 children (279 male) who developed type 1 diabetes before the age of 16 years (91% of those eligible from a region where ascertainment of new cases is 95%) were recruited for a longitudinal study with central annual assessment of HbAlc and albumin excretion (three urine s les). Dropout rates have been & 1% per year, and 287 children have been followed for & 4.5 years. RESULTS: MA (defined as albumin-to-creatinine ratio & or = 3.5 and & or = 4.0 mg/mmol in boys and girls, respectively) developed in 63 (12.8%) and was persistent in 22 (4.8%) of the subjects. The cumulative probability (based on the Kaplan-Meier method) for developing MA was 40% after 11 years. HbAlc was worse in those who developed MA than in others (mean difference +/- SEM: 1.1% +/- 0.2, P & 0.001). In subjects who had been 5-11 years of age when their diabetes was diagnosed, the appearance of MA was delayed until puberty, whereas of those whose age was & 5 years at diagnosis of diabetes, 5 of 11 (45%) developed MA before puberty. The adjusted proportional probability (Cox model) of MA was greater for female subjects (200%), after pubertal onset (310%), and with greater HbAlc (36% increase for every 1% increase in HbAlc). Despite earlier differences based on age at diagnosis of diabetes (& 5, 5-11, and & 11 years), the overall cumulative risks in these groups were similar (38 vs. 29 vs. 39%, respectively) after 10 years' duration of diabetes. CONCLUSIONS: Prepubertal duration of diabetes and prepubertal hyperglycemia contribute to the risk of postpubertal MA. The differences in rates of development of MA relating to HbAlc, sex, and age at diagnosis relative to puberty may have long-term consequences for the risk of subsequent nephropathy and for cardiovascular risk.
Publisher: National Institute for Health and Care Research
Date: 02-2014
DOI: 10.3310/HTA18140
Publisher: American Diabetes Association
Date: 08-01-2015
DOI: 10.2337/DC14-1848
Abstract: This study examined the association between cardiac autonomic dysfunction and high albumin-to-creatinine ratio (ACR) in adolescents with type 1 diabetes. Adolescents recruited as part of a multicenter screening study (n = 445, 49% female, aged 10–17 years, mean duration 6.9 years mean HbA1c 8.4%, 68 mmol/mol) underwent a 10-min continuous electrocardiogram recording for heart rate variability analysis. Time-domain heart rate variability measures included baseline heart rate, SD of the R-R interval (SDNN), and root mean squared difference of successive R-R intervals (RMSSD). Spectral analysis included sympathetic (low-frequency) and parasympathetic (high-frequency) components. Standardized ACR were calculated from six early morning urine collections using an established algorithm, reflecting age, sex, and duration, and stratified into ACR tertiles, where the upper tertile reflects higher nephropathy risk. The upper-tertile ACR group had a faster heart rate (76 vs. 73 bpm P & 0.01) and less heart rate variability (SDNN 68 vs. 76 ms, P = 0.02 RMSSD 63 vs. 71 ms, P = 0.04). HbA1c was 8.5% (69 mmol/mmol) in the upper tertile vs. 8.3% (67 mmol/mol) in the lower tertiles (P = 0.07). In multivariable analysis, upper-tertile ACR was associated with faster heart rate (β = 2.5, 95% CI 0.2–4.8, P = 0.03) and lower RMSSD (β = −9.5, 95% CI −18.2 to −0.8, P = 0.03), independent of age and HbA1c. Adolescents at potentially higher risk for nephropathy show an adverse cardiac autonomic profile, indicating sympathetic overdrive, compared with the lower-risk group. Longitudinal follow-up of this cohort will further characterize the relationship between autonomic and renal dysfunction and the effect of interventions in this population.
Publisher: American Diabetes Association
Date: 11-02-2014
DOI: 10.2337/DC13-1634
Abstract: We assessed the association between early increases in albumin excretion and cardiovascular (CV) and renal markers in a large cohort of young people with type 1 diabetes. As part of preliminary screening for a multicenter, randomized controlled trial of statins/ACE inhibitors, we measured albumin–creatinine ratio (ACR) in six early morning urine s les from 3,353 adolescents (10–16 years of age) and calculated tertiles based on an established algorithm. From those subjects deemed to be at higher risk (upper ACR tertile), we recruited 400 into the intervention study (trial cohort). From those subjects deemed to be at lower risk (middle–lower ACR tertiles), we recruited 329 to the observation cohort. At baseline, vascular measurements (carotid intima-media thickness, pulse wave velocity [PWV], flow-mediated dilatation, digital pulse litude tonometry), renal markers (symmetric dimethylarginine, cystatin C, creatinine), and CV disease markers (lipids and apolipoproteins [Apo] A-1 and B, C-reactive protein, asymmetric dimethylarginine) were assessed. Age- and sex-adjusted PWV was higher in the trial than in the observational cohort (5.00 ± 0.84 vs. 4.86 ± 0.70 m/s P = 0.021). Similarly, non-HDL cholesterol (2.95 ± 0.83 vs. 2.81 ± 0.78 mmol/L P = 0.02) and ApoB–ApoA-1 ratio (0.50 ± 0.14 vs. 0.47 ± 0.11 P = 0.04) were higher in the trial cohort. Cystatin C and creatinine were decreased (0.88 ± 0.13 vs. 0.90 ± 0.13 mg/L, P = 0.04 51.81 ± 10.45 vs. 55.35 ± 11.05 μmol/L, P & 0.001 respectively) and estimated glomerular filtration rate (137.05 ± 23.89 vs. 129.31 ± 22.41 mL/min/1.73 m2 P & 0.001) increased in the trial compared with the observational cohort. Our data demonstrate that in adolescents with type 1 diabetes, the group with the highest tertile of albumin excretion showed more evidence of early renal and CV disease than those in the lower tertiles.
Publisher: Wiley
Date: 22-11-2019
Publisher: Wiley
Date: 03-1994
DOI: 10.1111/J.1365-2362.1994.TB00982.X
Abstract: The effects of growth hormone (GH) administration to rats in vivo on the sensitivity of the rate of glucose utilization to insulin were studied in soleus muscles isolated from these rats. A single injection of GH did not increase the rate of glucose transport within 1-2 h. However, 12 h after, the rate of glucose transport was increased at 10 mU insulin l-1 and was accompanied by a similar increase in the rate of lactate formation but no change in the rate of glycogen synthesis. Prolonged treatment with GH decreased the rate of glucose transport and glycogen synthesis and increased the content of glucose 6-phosphate at physiological levels of insulin but did not affect the rate of lactate formation. These results suggest that: (a) GH does not increase the rate of glucose transport acutely however, after several hours, the sensitivity of glucose transport and glycolysis to insulin are increased (b) prolonged elevations of the level of GH in plasma decrease the sensitivity of the rate of glucose transport and glycogen synthesis to insulin. However, redirection of glucose residues away from the pathway of glycogen synthesis towards that of glycolysis and a possible increase in the rate of glycogenolysis maintain a normal rate of lactate formation, although the rate of glucose transport is decreased.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2020
DOI: 10.1161/HYPERTENSIONAHA.120.15721
Abstract: An increased albumin-creatinine ratio within the normal range can identify adolescents at higher risk of developing adverse cardio-renal outcomes as they progress into adulthood. Utilizing a parallel randomized controlled trial and observational cohort study, we characterized the progression of vascular phenotypes throughout this important period and investigated the effect of ACE (angiotensin-converting enzyme) inhibitors and statins in high-risk adolescents. Endothelial function (flow-mediated dilation and reactive hyperemia index) and arterial stiffness (carotid-femoral pulse wave velocity) were assessed in 158 high-risk participants recruited to a randomized, double-blind placebo-controlled 2×2 factorial trial (randomized, placebo-controlled trial) of ACE inhibitors and/or statins in adolescents with type 1 diabetes (AdDIT [Adolescent Type 1 Diabetes cardio-renal Intervention Trial]). Identical measures were also assessed in 215 lower-risk in iduals recruited to a parallel observational study. In the randomized, placebo-controlled trial, high-risk patients randomized to ACE inhibitors had improved flow-mediated dilation after 2 to 4 years of follow-up (mean [95% CI]: 6.6% [6.0–7.2] versus 5.3% [4.7–5.9] P =0.005), whereas no effect was observed following statin use (6.2% [5.5–6.8] versus 5.8% [5.1–6.4] P =0.358). In the observational study, patients classed as high-risk based on albumin-creatinine ratio showed evidence of endothelial dysfunction at the end of follow-up (flow-mediated dilation=4.8% [3.8–5.9] versus 6.3% [5.8–6.7] for high-risk versus low-risk groups P =0.015). Neither reactive hyperemia index nor pulse wave velocity were affected by either treatment ( P .05 for both), but both were found to increase over the duration of follow-up (0.07 [0.03–0.12] P =0.001 and 0.5 m/s [0.4–0.6] P .001 for reactive hyperemia index and pulse wave velocity, respectively). ACE inhibitors improve endothelial function in high-risk adolescents as they transition through puberty. The longer-term protective effects of this intervention at this early age remain to be determined. URL: www.clinicaltrials.gov Unique identifier NCT01581476.
Publisher: American Diabetes Association
Date: 03-2001
Abstract: OBJECTIVE—To examine whether a rise in blood pressure could be detected before the onset of microalbuminuria (MA) in a cohort of children followed from diagnosis of type 1 diabetes. RESEARCH DESIGN AND METHODS—The Oxford Regional Prospective Study is an incident cohort study of children with type 1 diabetes aged (mean ± SD) 9.8 ± 3.7 years at diagnosis. Subjects were assessed annually from diagnosis, with measurement of HbA1c, arterial blood pressure (random zero), and three urine s les for estimation of the albumin/creatinine ratio. During follow-up, 63 of 494 children developed MA at one or more annual assessments and were designated as cases for a nested case-control study. Each case was matched for sex and age at diagnosis with two normoalbuminuric control subjects. Blood pressure (BP) data were compared at corresponding years of diabetes duration. RESULTS—Cases with MA were similar to normoalbuminuric control subjects with respect to age and BMI, but they had higher mean HbA1c levels (mean difference 1.1%, P & 0.001). In the years before the onset of MA, the diastolic BP standard deviation score (SDS) was significantly higher than zero in cases (mean 0.49, P & 0.001) and in control subjects (0.50, P & 0.001). No difference could be detected between cases and control subjects before the onset of MA in either systolic or diastolic BP (mean difference systolic −1.2 mmHg [95% CI −4.7 to 2.7], mean difference diastolic 0.1 mmHg [−2.4 to 2.6]). However, within the cases, the onset of MA was associated with elevations in systolic and diastolic BP SDSs (F = 16.1, P & 0.001 and F = 18.0, P & 0.001). BMI, but not HbA1c, was associated with systolic and diastolic BP SDSs in the subjects with MA (F = 0.6, P = 0.4 and F = 12.3, P = 0.001). However, the association of BP with MA remained significant for systolic BP (P = 0.001) and for diastolic BP (P & 0.001) after adjusting for BMI. CONCLUSIONS—A rise in systemic BP cannot be detected before the first appearance of MA in children with type 1 diabetes. BP rises concurrently with the onset of MA and is also closely related to BMI.
Publisher: Wiley
Date: 07-1999
DOI: 10.1046/J.1464-5491.1999.00109.X
Abstract: To determine whether abnormal lipid levels in children with Type 1 diabetes mellitus are the result of poor metabolic control or may in part be determined by genetic factors. Non-fasting lipid levels were measured in 141 children with Type 1 diabetes (age range 7.7-19 years) 3 years after diagnosis, and in 192 of their parents. Glycosylated haemoglobin and the urinary albumin-creatinine ratio (three urine s les) were estimated in each child annually. The children had a mean total cholesterol of 4.46 +/- 1.25 mmol/l (+/- SD) and a median triacylglycerol of 1.18 mmol/l (range 0.32-4.7). A total of 15.3% of the population had a total cholesterol > 5.2 mmol/l and 17.9% had a triacylglycerol > 1.7 mmol/l in 5.6% both total cholesterol and triacylglycerol were greater than these cut-off points. Total cholesterol, triacylglycerol and very low density lipoprotein-cholesterol were significantly correlated to glycaemic control. However, total cholesterol was also significantly related to parental total cholesterol either as analysed separately or as mean parental total cholesterol (r = 0.37, P = 0.0001). In stepwise multiple regression analysis both mean parental total cholesterol (P = 0.001) and HbA1c (P = 0.015) were significant determinants of the child's total cholesterol. The children studied were being followed prospectively for the development of microalbuminuria and there was a weak association across tertiles of total cholesterol, linking higher levels to the development of microalbuminuria (P < 0.05). We conclude that both glycaemic control and familial factors may be important determinants of lipid levels in young people with diabetes. Both may contribute to the subsequent risk of cardiovascular disease and possibly the development of incipient diabetic nephropathy.
Publisher: Wiley
Date: 28-07-2015
Abstract: Antioxidants have not reduced the burden of cardiovascular disease, and current evidence suggests a beneficial role of oxidative stress, via NADPH oxidase (Nox) upregulation, in endothelial function. Homocysteine thiolactone (HcyT) induces blood vessel dysfunction and this correlates with increased vascular oxidative stress. This study aimed to determine if pharmacological inhibition of Nox could impair HcyT induced blood vessel dysfunction. Abdominal aorta were excised from New Zealand White rabbits (n = 6), cut into rings and sequentially mounted in organ baths. Rings were preincubated with 0.55 μmol/L homocysteine thiolactone for 1 h, or combinations of putative Nox inhibitors (plumbagin for Nox4, gp91ds-tat for Nox2, and ML090 for Nox1), 30 min prior to the addition of HcyT, followed by a dose response curve to acetylcholine on phenylephrine preconstricted rings. Plumbagin, ML090 + gp91ds-tat and HcyT reduced responses to acetylcholine, and Plumbagin + Hcyt caused constriction to acetylcholine, which was normalised to plumbagin by ML090. Plumbagin + ML090 or plumbagin + gp91ds-tat completely impaired the effect of acetylcholine. ML090 inhibited the effect of HcyT on reduced response to acetylcholine, whereas gp91ds-tat had no effect. This study concludes that inhibition of Nox1 prevents, whereas inhibition of Nox4 worsens, acetylcholine induced blood vessel relaxation caused by HcyT, while Nox2 inhibition has no effect. However combinations of Nox inhibitors worsen acetylcholine induced blood vessel relaxation. These results suggest that there is cross-talk between Nox isoforms during physiological and pathophysiological processes.
Publisher: Hindawi Limited
Date: 09-2009
Publisher: Wiley
Date: 26-01-2007
DOI: 10.1111/J.1464-5491.2006.02047.X
Abstract: To determine whether higher than average albumin excretion during early puberty identifies subjects who will subsequently develop microalbuminuria (MA) and clinical proteinuria. Longitudinal data from the Oxford Regional Prospective Study of Childhood Diabetes (ORPS n = 554, median duration of follow-up 10 years range 3.0-16.7) with assessment of albumin/creatinine ratios in three early morning urine s les collected annually. An albumin excretion phenotype was derived from longitudinal data, for each in idual, defining deviation from the mean of regression models, including covariates gender, age, duration of diabetes and age at assessment. Tracking of the phenotypes was confirmed in a second independent cohort from Perth, Australia. The albumin excretion phenotype showed reasonable correlation between age 11-15 years and age 16-18 years in both cohorts, indicative of good 'tracking'. In the ORPS cohort, tertiles of the albumin excretion phenotype at aged 11-15 years were predictive of subsequent risk for the development of MA. All of the subjects developing clinical proteinuria had an albumin excretion phenotype in the upper tertile or an HbA(1c) > 9% at aged 11-15 years. Identification of adolescents at risk of diabetic nephropathy using an albumin excretion phenotype is feasible. When combined with elevated HbA(1c), it may identify subjects for trial of early intervention with angiotensin-converting enzyme inhibitors/angiotensin-II receptor antagonists and statins to improve long-term prognosis in these subjects where sustained improvement in glycaemic control may be difficult to achieve.
Publisher: Wiley
Date: 13-02-2019
Abstract: Apical membrane antigen 1 (AMA1) is essential for the invasion of host cells by malaria parasites. Several small-molecule ligands have been shown to bind to a conserved hydrophobic cleft in Plasmodium falciparum AMA1. However, a lack of detailed structural information on the binding pose of these molecules has hindered their further optimisation as inhibitors. We have developed a spin-labelled peptide based on RON2, the native binding partner of AMA1, to probe the binding sites of compounds on PfAMA1. The crystal structure of this peptide bound to PfAMA1 shows that it binds at one end of the hydrophobic groove, leaving much of the binding site unoccupied and allowing fragment hits to bind without interference. In paramagnetic relaxation enhancement (PRE)-based NMR screening, the
Publisher: Wiley
Date: 04-2016
DOI: 10.1002/OBY.21487
Publisher: American Diabetes Association
Date: 10-10-2014
DOI: 10.2337/DC14-0700
Abstract: The origins of cardiovascular and renal disease in type 1 diabetes begin during childhood. We aimed to evaluate carotid (cIMT) and aortic intima-media thickness (aIMT) and their relationship with cardiovascular risk factors and urinary albumin excretion in adolescents with type 1 diabetes in the Adolescent Type 1 Diabetes cardio-renal Intervention Trial (AdDIT). A total of 406 adolescents with type 1 diabetes, who were 14.1 ± 1.9 years old with type 1 diabetes duration of 6.7 ± 3.7 years, and 57 age-matched control subjects provided clinical and biochemical data and ultrasound measurements of vascular structure (cIMT and aIMT). Vascular endothelial and smooth muscle function was also measured in 123 of 406 with type 1 diabetes and all control subjects. In type 1 diabetic subjects, mean/maximal aIMT (P & 0.006 & .008), but not mean/maximal cIMT, was greater than in control subjects. Mean/maximal aIMT related to urinary albumin-to-creatinine ratio (multiple regression coefficient [SE], 0.013 [0.006], P = 0.03 0.023 [0.007], P = 0.002), LDL cholesterol (0.019 [0.008], P = 0.02 0.025 [0.011], P = 0.02), and age (0.010 [0.004], P = 0.004 0.012 [0.005], P = 0.01), independent of other variables. Mean/maximal cIMT was greater in males (0.023 [0.006], P = 0.02 0.029 [0.007], P & 0.0001), and mean cIMT related independently to systolic blood pressure (0.001 [0.001], P = 0.04). Vascular smooth muscle function related to aIMT and cIMT but not to urinary albumin excretion. aIMT may be a more sensitive marker of atherosclerosis than cIMT in type 1 diabetes during mid-adolescence. Higher urinary albumin excretion, even within the normal range, is associated with early atherosclerosis and should direct clinical attention to modifiable cardiovascular risk factors.
Publisher: American Diabetes Association
Date: 12-2000
DOI: 10.2337/DIACARE.23.12.1811
Abstract: OBJECTIVE: The early detection of a rise in albumin excretion within the normal range could permit early intervention to prevent the development of microalbuminuria (MA) in genetically susceptible subjects with type 1 diabetes. In the Oxford Regional Prospective Study we prospectively examined urine albumin excretion during the first years after diagnosis of childhood type 1 diabetes. RESEARCH DESIGN AND METHODS: Between 1986 and 1995, 511 subjects aged & 16 years were recruited at diagnosis and followed for a median of 6 years (range 1-14). In 78 subjects (designated cases), an annual assessment of the albumin-to-creatinine ratio (ACR) in three morning first-void urine s les detected MA (males: ACR & or =3.5 mg/mmol, females: ACR & or =4.0 mg/mmol in two of three urine s les). In 63 of these subjects and 396 normoalbuminuric diabetic control subjects, rates of change of the ACR were calculated as the slope of the ACR over diabetes duration. RESULTS: The baseline ACR (median [interquartile (IQ) range]), as measured at 1-2.5 years' duration of diabetes, was higher in microalbuminuric subjects than in the normoalbuminuric subjects (1.0 mg/mmol [0.6-2.1], n = 52, vs. 0.8 mg/mmol [0.6-1.2], n = 303 P = 0.02). The rate of increase of the ACR in the years before the onset of MA was higher in the microalbuminuric subjects than in the normoalbuminuric subjects (70% per year [37-149], n = 63, vs. 1% per year [-9 to 13], n = 396 P & 0.001). The mean HbA1c level after the onset of puberty was weakly correlated with the rate of change of the ACR (r = 0.11, P = 0.024, n = 418). CONCLUSIONS: Higher levels of ACR within the first 2 years after diagnosis and a significantly higher rate of increase of the ACR within the first 5 years from diagnosis can be detected in subjects who subsequently develop MA. HbA1c is a determinant of risk for MA, but pubertal factors have a greater effect on rates of progression of urine albumin excretion during adolescence in this cohort.
Publisher: Hindawi Limited
Date: 04-2008
Publisher: American Diabetes Association
Date: 19-07-2018
DOI: 10.2337/DC18-1125
Abstract: Baseline data from the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) indicated that tertiles of urinary albumin-to-creatinine ratios (ACRs) in the normal range at age 10–16 years are associated with risk markers for diabetic nephropathy (DN) and cardiovascular disease (CVD). We aimed to determine whether the top ACR tertile remained associated with DN and CVD risk over the 2–4-year AdDIT study. One hundred fifty adolescents (mean age 14.1 years [SD 1.6]) with baseline ACR in the upper tertile (high-ACR group) recruited to the AdDIT trial, who remained untreated, and 396 (age 14.3 years [1.6]) with ACR in the middle and lower tertiles (low-ACR group), who completed the parallel AdDIT observational study, were evaluated prospectively with assessments of ACR and renal and CVD markers, combined with carotid intima-media thickness (cIMT) at baseline and end of study. After a median follow-up of 3.9 years, the cumulative incidence of microalbuminuria was 16.3% in the high-ACR versus 5.5% in the low-ACR group (log-rank P & 0.001). Cox models showed independent contributions of the high-ACR group (hazard ratio 4.29 [95% CI 2.08–8.85]) and HbA1c (1.37 [1.10–1.72]) to microalbuminuria risk. cIMT change from baseline was significantly greater in the high- versus low-ACR group (mean difference 0.010 mm [0.079], P = 0.006). Changes in estimated glomerular filtration rate, systolic blood pressure, and hs-CRP were also significantly greater in the high-ACR group (P & 0.05). ACR at the higher end of the normal range at the age of 10–16 years is associated with an increased risk of progression to microalbuminuria and future CVD risk, independently of HbA1c.
Publisher: Springer Science and Business Media LLC
Date: 10-05-2009
DOI: 10.1038/NG.361
Publisher: Wiley
Date: 2000
DOI: 10.1046/J.1464-5491.2000.00200.X
Abstract: Microalbuminuria and, to a lesser extent, renal tubular proteins are widely used in the early detection of incipient nephropathy in diabetes mellitus. Recent reports have indicated detrimental effects of storage at -20 degrees C on urine proteins. This study investigated the effects of storage on the measurement of urine proteins and discusses implications for the interpretation of data. Two-hundred and sixty-eight specimens, collected from children with Type 1 diabetes, split into duplicate aliquots and stored at -20 degrees C and -70 degrees C, respectively, for 6-8 months, were analysed for albumin, retinol binding protein, N-acetyl glucosaminidase and creatinine, in the same assays to eliminate inter-assay variability. Two independent non-diabetic cohorts of children provided urine specimens, which were stored at -20 degrees C for one cohort and -70 degrees C for the other, to determine normal ranges for urine proteins. Storage at -20 degrees C led to a variable underestimation of all three urine proteins in 20% of specimens. Creatinine was unaffected. This underestimation was greater in more concentrated urine (r2 = 0.38, P 2SD above the geometric mean in non-diabetic specimens stored at -20 degrees C) was 27% after storage at -70 degrees C vs. 24% after -20 degrees C. The prevalence of microalbuminuria (>2SD above the geometric mean in nondiabetic specimens stored at -70 degrees C) was 21% after storage at -70 degrees C vs. 17% after -20 degrees C. Urine proteins are significantly but variably underestimated after storage at -20 degrees C. These effects account for increased variance and differences in the normal range, but have less effect on the detection of microalbuminuria than might be predicted.
Publisher: Springer Science and Business Media LLC
Date: 17-04-2019
DOI: 10.1038/S41574-019-0198-2
Abstract: Diabetes vascular complications, including cardiovascular disease, diabetic nephropathy and retinopathy, have a negative effect on the long-term prognosis of young people with type 1 diabetes mellitus (T1DM). Poor glycaemic control and consequent increased HbA
Publisher: Springer Science and Business Media LLC
Date: 02-02-2018
Publisher: Wiley
Date: 17-02-2004
DOI: 10.1111/J.1464-5491.2004.01123.X
Abstract: Susceptibility to diabetic nephropathy has not yet been causally linked to any genetic factors. We investigated in nuclear families whether parental ambulatory blood pressure, lipids and urine albumin excretion were early markers of risk of microalbuminuria in young adults with Type 1 diabetes. A subset of 98 young adults from the Oxford Regional Prospective Study were followed from diagnosis until aged >or= 16 years and duration of diabetes >or= 5 years (probands). Of these subjects, 24 developed microalbuminuria (males >or= 3.5 mg/mmol females >or= 4 mg/mmol) and were designated cases, whereas 74 were controls. Family medical history, 24-h ambulatory blood pressure, urine albumin to creatinine ratio (ACR), non-fasting lipid profile and apolipoproteins (A1 and B) were measured in mothers and fathers. The prevalence of a parental hypertension (taking anti-hypertensive medication or daytime blood pressure > 140/90 mmHg), was similar in cases and controls (29% vs. 35% chi2 test, P = 0.3). The systolic blood pressure night to day ratio and also ACR were higher in the fathers of cases when compared with the fathers of controls [systolic 0.88 (0.08), n = 14 vs. 0.85 (0.12), n = 53, P = 0.041] [ACR median (IQ range) 0.6 mg/mmol (0.2-16.9) vs. 0.47 mg/mmol (0.3-3.7), P = 0.049]. Paternal night-time systolic blood pressure, night to day systolic blood pressure ratio and ACR were correlated with an index of susceptibility to albuminuria (r = 0.25, P = 0.042, n = 69 and r = 0.28, P = 0.022, n = 0.67 and r = 0.24, P = 0.029, n = 0.85, respectively). Higher paternal ACR and night to day ratio of ambulatory blood pressure, but not parental hypertension or maternal factors, are associated with microalbuminuria in young adults with Type 1 diabetes.
Publisher: American Diabetes Association
Date: 10-2007
DOI: 10.2337/DB07-0652
Abstract: OBJECTIVE—Epidemiological studies have linked vitamin D deficiency with the susceptibility to type 1 diabetes. Higher levels of the active metabolite 1α,25-dihydroxyvitamin D (1α,25(OH)2D) could protect from immune destruction of the pancreatic β-cells. 1α,25(OH)2D is derived from its precursor 25-hydroxyvitamin D by the enzyme 1α-hydroxylase encoded by the CYP27B1 gene and is inactivated by 24-hydroxylase encoded by the CYP24A1 gene. Our aim was to study the association between the CYP27B1 and CYP24A1 gene polymorphisms and type 1 diabetes. RESEARCH DESIGN AND METHODS—We studied 7,854 patients with type 1 diabetes, 8,758 control subjects from the U.K., and 2,774 affected families. We studied four CYP27B1 variants, including common polymorphisms −1260C& A (rs10877012) and +2838T& C (rs4646536) and 16 tag polymorphisms in the CYP24A1 gene. RESULTS—We found evidence of association with type 1 diabetes for CYP27B1 −1260 and +2838 polymorphisms, which are in perfect linkage disequilibrium. The common C allele of CYP27B1 −1260 was associated with an increased disease risk in the case-control analysis (odds ratio for the C/C genotype 1.22, P = 9.6 × 10−4) and in the fully independent collection of families (relative risk for the C/C genotype 1.33, P = 3.9 × 10−3). The combined P value for an association with type 1 diabetes was 3.8 × 10−6. For the CYP24A1 gene, we found no evidence of association with type 1 diabetes (multilocus test, P = 0.23). CONCLUSIONS—The present data provide evidence that common inherited variation in the vitamin D metabolism affects susceptibility to type 1 diabetes.
Publisher: Elsevier BV
Date: 04-2016
Location: Australia
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Professor David Dunger.