41 research outputs found
Interference of Compensatory Strategies in Oral Production of English Language Student in an ESL Classroom: Does Compensatory Strategy Play a Role in Academic Performance?
The study aims to identify the compensatory strategies predominantly used by fifty-four ESL High school student, its relation to language proficiency level in terms of accuracy, fluency, and comprehensibility and to its role in academic performance of the participants. Two oral task namely oral interview and pictured-cued narration were used as primary source of data. The picture-cued narration was applied to determine the oral language proficiency level and compensatory strategies of the participants. Finding shows the eight compensatory strategies were employed in their production, namely, switching to mother tongue, getting help, using mime, selecting the topic, adjusting the message, coining words, avoiding communication partially and totally, and using circumlocution or synonyms. It was also found out that switching to mother tongue was predominantly employed in their oral production. There is, however, negative relationship between compensatory strategies used and academic performance of ESL learners. Pedagogical implications are discussed discussed in the paper.
Keywords: communicative competence, compensatory strategies, language classroom, oral productio
Strain-dependent mutational effects for Pepino mosaic virus in a natural host
[EN] Pepino mosaic virus (PepMV) is an emerging plant pathogen that infects tomatoes worldwide.
Understanding the factors that influence its evolutionary success is essential for developing new control strategies that
may be more robust against the evolution of new viral strains. One of these evolutionary factors is the distribution of
mutational fitness effect (DMFE), that is, the fraction of mutations that are lethal, deleterious, neutral, and beneficial on
a given viral strain and host species. The goal of this study was to characterize the DMFE of introduced
nonsynonymous mutations on a mild isolate of PepMV from the Chilean 2 strain (PepMV-P22). Additionally, we also
explored whether the fitness effect of a given mutation depends on the gene where it appears or on epistatic
interactions with the genetic background. To address this latter possibility, a subset of mutations were also introduced
in a mild isolate of the European strain (PepMV-P11) and the fitness of the resulting clones measured.This study was financially supported by grant 2011/01/D/NZ9/00279, from the Poland National Science Center, to B.H.J and by grants BFU2015-65037-P, from Spain Ministry of Economy and Competitiveness-FEDER, and PROMETEOII/2014/021, from Generalitat Valenciana, to S.F.E.Minicka, J.; Elena Fito, SF.; Borodynko-Filas, N.; Rubis, B.; Hasiów-Jaroszewska, B. (2017). Strain-dependent mutational effects for Pepino mosaic virus in a natural host. BMC Evolutionary Biology. 17:1-11. https://doi.org/10.1186/s12862-017-0920-4S11117Steinhauer DA, Domingo E, Holland JJ. Lack of evidence for proofreading mechanisms associated with an RNA virus polymerase. Gene. 1992;122:281–8.Sanjuán R, Nebot MR, Chirico N, Mansky LM, Belshaw R. Viral mutation rates. J Virol. 2010;84:9733–48.Domingo E. Viruses at the edge of adaptation. Virology. 2000;270:251–3.Chao L. Fitness of RNA virus decreased by muller ratchet. Nature. 1990;348:454–5.Duarte E, Clarke D, Moya A, Domingo E, Holland J. Rapid fitness losses in mammalian RNA virus clones due to Muller ratchet. Proc Natl Acad Sci U S A. 1992;89:6015–9.De la Iglesia F, Elena SF. Fitness declines in Tobacco etch virus upon serial bottleneck transfers. J Virol. 2007;81:4941–7.Elena SF, Carrasco P, Daròs JA, Sanjuán R. Mechanisms of genetic robustness in RNA viruses. EMBO Rep. 2006;7:168–73.Elena SF, Moya A. Rate of deleterious mutation and the distribution of its effects on fitness in Vesicular stomatitis virus. J Evol Biol. 1999;12:1078–88.Sanjuán R, Moya A, Elena SF. The distribution of fitness effects caused by single-nucleotide substitutions in an RNA virus. Proc Natl Acad Sci U S A. 2004;101:8396–401.Acevedo A, Brodsky L, Andino R. Mutational and fitness landscapes of an RNA virus revealed through population sequencing. Nature. 2014;505:686–90.Visher E, Whitefield SE, McCrone JT, Fitzsimmons W, Lauring AS. The mutational robustness of Influenza A virus. PLoS Pathog. 2016;12, e1005856.Carrasco P, de la Iglesia F, Elena SF. Distribution of fitness and virulence effects caused by single-nucleotide substitutions in Tobacco etch virus. J Virol. 2007;81:12979–84.Bernet GP, Elena SF. Distribution of mutational fitness effects and of epistasis in the 5′ untranslated region of a plant RNA virus. BMC Evol Biol. 2015;15:274.Domingo-Calap P, Cuevas JM, Sanjuán R. The fitness effects of random mutations in single-stranded DNA and RNA bacteriophages. PLoS Genet. 2009;5, e1000742.Peris JB, Davis P, Cuevas JM, Nebot MR, Sanjuán R. Distribution of fitness effects caused by single-nucleotide substitutions in bacteriophage f1. Genetics. 2010;185:603–9.Keightley PD, Ohnishi O. EMS-induced polygenic mutation rates for nine quantitative characters in Drosophila melanogaster. Genetics. 1998;148:753–66.Keightley PD, Davies EK, Peters AD, Shaw RG. Properties of ethylmethane sulfonate-induced mutations affecting life-history traits in Caenorhabditis elegans and inferences about bivariate distributions of mutation effects. Genetics. 2000;156:143–54.Koufopanou V, Lomas S, Tsai IJ, Burt A. Estimating the fitness effects of new mutations in the wild yeast Saccharomyces paradoxus. Genome Biol Evol. 2015;7:1887–95.Sanjuán R. Mutational fitness effects in RNA and single-stranded DNA viruses: common patterns revealed by site-directed mutagenesis. Philos Trans R Soc B. 2010;365:1975–82.Keightley PD, Lynch M. Toward a realistic model of mutations affecting fitness. Evolution. 2003;57:683–5.Orr HA. The distribution of fitness effects among beneficial mutations. Genetics. 2003;163:1519–26.Miralles R, Gerrish PJ, Moya A, Elena SF. Clonal interference and the evolution of RNA viruses. Science. 1999;285:1745–7.Escarmís C, Dávila M, Charpentier N, Bracho A, Moya A, Domingo E. Genetic lesions associated with Muller’s ratchet in an RNA virus. J Mol Biol. 1996;264:255–67.Phillips PC. Epistasis - the essential role of gene interactions in the structure and evolution of genetic systems. Nat Rev Genet. 2008;9:855–67.De Visser JAGM, Krug J. Empirical fitness landscapes and the predictability of evolution. Nat Rev Genet. 2014;15:480–90.Lalić J, Elena SF. Magnitude and sign epistasis among deleterious mutations in a positive-sense plant RNA virus. Heredity. 2012;109:71–7.Lalić J, Elena SF. The impact of higher-order epistasis in the within-host fitness of a positive-sense plant RNA virus. J Evol Biol. 2015;28:2236–47.Hillung J, Cuevas JM, Elena SF. Evaluating the within-host fitness effects of mutations fixed during virus adaptation to different ecotypes of a new host. Philos Trans R Soc B. 2015;370:20140292.Cervera H, Lalić J, Elena SF. Effect of host species on the topography of the fitness landscape for a plant RNA virus. J Virol. 2016;90:10160–9.Cervera H, Lalić J, Elena SF. Efficient escape from local optima in a highly rugged fitness landscape by evolving RNA virus populations. Proc R Soc B. 2016;283:20160984.Blystad DR, van der Vlugt R, Alfaro-Fernandez A, Cordoba MD, Bese G, Hristova D, Pospieszny H, Mehle N, Ravnikar M, Tomassoli L, Varveri C, Nielsen SL. Host range and symptomatology of Pepino mosaic virus strains occurring in Europe. Eur J Plant Pathol. 2015;143:43–56.Mumford RA, Metcalfe EJ. The partial sequencing of the genomic RNA of a UK isolate of Pepino mosaic virus and the comparison of the coat protein sequence with other isolates from Europe and Peru. Arch Virol. 2001;146:2455–60.Roggero P, Masenga V, Lenzi R, Coghe F, Ena S, Winter S. First report of Pepino mosaic virus in tomato in Italy. Plant Dis. 2001;3:8.Cotillon AC, Girard M, Ducouret S. Complete nucleotide sequence of the genomic RNA of a French isolate of Pepino mosaic virus (PepMV). Arch Virol. 2002;147:2231–8.Maroon-Lango CJ, Guaragna MA, Jordan RL, Hammond J, Bandla M, Marquardt SK. Two unique US isolates of Pepino mosaic virus from a limited source of pooled tomato tissue are distinct from a third (European-like) US isolate. Arch Virol. 2005;150:1187–201.Pagán I, Córdoba-Selles MD, Martínez-Priego L, Fraile A, Malpica JM, Jorda C, García-Arenal F. Genetic structure of the population of Pepino mosaic virus infecting tomato crops in Spain. Phytopathology. 2006;96:274–9.Ling KS. Molecular characterization of two Pepino mosaic virus variants from imported tomato seed reveals high levels of sequence identity between Chilean and US isolates. Virus Genes. 2007;34:1–8.Hanssen IM, Paeleman A, Wittemans L, Goen K, Lievens B, Bragard C, Vanachter A, Thomma B. Genetic characterization of Pepino mosaic virus isolates from Belgian greenhouse tomatoes reveals genetic recombination. Eur J Plant Pathol. 2008;121:131–46.Hasiów B, Borodynko N, Pospieszny H. Complete genomic RNA sequence of the Polish Pepino mosaic virus isolate belonging to the US2 strain. Virus Genes. 2008;36:209–14.Hanssen IM, Paeleman A, Vandewoestijne E, Van Bergen L, Bragard C, Lievens B, Vanacher ACRC, Thomma BPHJ. Pepino mosaic virus isolates and differential symptomatology in tomato. Plant Pathol. 2009;58:450–60.Moreno-Pérez MG, Pagán I, Aragón-Caballero L, Cáceres F, Fraile A, García-Arenal F. Ecological and genetic determinants of Pepino mosaic virus emergence. J Virol. 2014;88:3359–68.Ling K, Li R, Bledsoe M. Pepino mosaic virus genotype shift in North America and development of a loop-mediated isothermal amplification for rapid genotype identification. Virol J. 2013;10:117.Hasiów-Jaroszewska B, Paeleman A, Ortega-Parra N, Borodynko N, Minicka J, Czerwoniec A, Thomma BP, Hanssen IM. Ratio of mutated versus wild-type coat protein sequences in Pepino mosaic virus determines the nature and severity of yellowing symptoms on tomato plants. Mol Plant Pathol. 2013;14:923–33.Sempere RN, Gómez-Aix C, Ruiz-Ramon F, Gómez P, Hasiów-Jaroszewska B, Sánchez-Pina MA, Aranda MA. Pepino mosaic virus RNA-dependent RNA polymerase POL domain is a hypersensitive response-like elicitor shared by necrotic and mild isolates. Phytopathology. 2016;106:395–406.Hasiów-Jaroszewska B, Borodynko N, Jackowiak P, Figlerowicz M, Pospieszny H. Single mutation converts mild pathotype of the Pepino mosaic virus into necrotic one. Virus Res. 2011;159:57–61.Minicka J, Rymelska N, Elena SF, Czerwoniec A, Hasiów-Jaroszewska B. Molecular evolution of Pepino mosaic virus during long-term passaging in different hosts and its impact on virus virulence. Ann Appl Biol. 2015;166:389–401.Hasiów-Jaroszewska B, Jackowiak P, Borodynko N, Figlerowicz M, Pospieszny H. Quasispecies nature of Pepino mosaic virus and its evolutionary dynamics. Virus Genes. 2010;41:260–7.Eigen M, McCaskill J, Schuster P. Molecular quasi-species. J Phys Chem. 1988;92(24):6881–91.Schneider WL, Roossinck MJ. Evolutionarily related Sindbis-like plant viruses maintain different levels of population diversity in a common host. J Virol. 2000;74:3130–4.Legg JP, Thresh JM. Cassava mosaic virus disease in East Africa: a dynamic disease in a changing environment. Virus Res. 2000;71:135–49.Hasiów-Jaroszewska B, Borodynko N, Pospieszny H. Infectious RNA transcripts derived from cloned cDNA of a Pepino mosaic virus isolate. Arch Virol. 2009;154:853–6.Hasiów-Jaroszewska B, Komorowska B. A new method for detection and discrimination of Pepino mosaic virus isolates using high resolution melting analysis of the triple gene block 3. J Virol Methods. 2013;193:1–5.Poelwijk FJ, Tanase-Nicola S, Kiviet DJ, Tans SJ. Reciprocal sign epistasis is a necessary condition for multi-peaked fitness landscapes. J Theor Biol. 2011;272:141–4.Dean AM, Thornton JW. Mechanistic approaches to the study of evolution: the functional synthesis. Nat Rev Genet. 2007;8:675–88.Lalić J, Cuevas JM, Elena SF. Effect of host species on the distribution of mutational fitness effects for an RNA virus. PLoS Genet. 2011;7, e1002378.Vale PF, Choisy M, Froissart R, Sanjuán R, Gandon S. The distribution of mutational fitness effects of phage ϕX174 on different hosts. Evolution. 2012;66:3495–507.Hasiów-Jaroszewska B, Minicka J, Pospieszny H. Cross-protection between different pathotypes of Pepino mosaic virus representing chilean 2 genotype. Acta Sci Pol Hortoru. 2014;13:177–85.Minicka J, Otulak K, Garbaczewska G, Pospieszny H, Hasiów-Jaroszewska B. Ultrastructural insights into tomato infections caused by three different pathotypes of Pepino mosaic virus and immunolocalization of viral coat proteins. Micron. 2015;79:84–92.Gómez P, Sempere RN, Aranda MA, Elena SF. Phylodynamics of Pepino mosaic virus in Spain. Eur J Plant Pathol. 2012;134:445–9.Vignuzzi M, Stone JK, Arnold JJ, Cameron CE, Andino R. Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population. Nature. 2006;439:344–8.Domingo E, Martíb V, Perales C, Grande-Pérez A, García-Arriaza Arias J. Viruses as quasispecies: biological implications. Curr Top Microbiol Immunol. 2006;299:51–82.Jones RAC, Koenig R, Lesemann DE. Pepino mosaic virus, a new potexvirus from pepino (Solanum muricatum). Ann Appl Biol. 1980;94:61–8.Domingo E, Sheldon J, Perales C. Viral quasispecies evolution. Microbiol Mol Biol Rev. 2012;76:159–216.Lough TJ, Emerson SJ, Lucas WJ, Forster RLS. Trans-complementation of long-distance movement of White clover mosaic virus triple gene block (TGB) mutants: Phloem-associated movement of TGBp1. Virology. 2001;288:18–28.Pospieszny H, Hasiów B, Borodynko N. Characterization of two distinct Polish isolates of Pepino mosaic virus. Eur J Plant Pathol. 2008;122:443–5.Gómez P, Sempere RN, Elena SF, Aranda MA. Mixed infections of Pepino mosaic virus strains modulate the evolutionary dynamics of this emergent virus. J Virol. 2009;83:12378–87.Elena SF, Solé RV, Sardanyés J. Simple genomes, complex interactions: epistasis in RNA virus. Chaos. 2010;20:026106.Sanjuán R, Moya A, Elena SF. The contribution of epistasis to the architecture of fitness in an RNA virus. Proc Natl Acad Sci USA. 2004;101:15376–9.Elena SF. RNA virus genetic robustness: possible causes and some consequences. Curr Opin Virol. 2012;2:525–30.Stern A, Bianco S, Yeh MT, Wright CF, Butcher K, Tang C, Nielsen R, Andino R. Costs and benefits of mutational robustness in RNA viruses. Cell Rep. 2014;8:1–11.Elena SF, Lalić J. Plant RNA virus fitness predictability: contribution of genetic and environmental factors. Plant Pathol. 2013;62:10–8
Blood pressure and metabolic effects of acetyl-L-carnitine in type 2 diabetes: DIABASI randomized controlled trial
Context: Acetyl-L-carnitine (ALC), a mitochondrial carrier involved in lipid oxidation and glucose metabolism, decreased systolic blood pressure (SBP), and ameliorated insulin sensitivity in hypertensive nondiabetic subjects at high cardiovascular risk. Objective: To assess the effects of ALC on SBP and glycemic and lipid control in patients with hypertension, type 2 diabetes mellitus (T2D), and dyslipidemia on background statin therapy. Design: After 4-week run-in period and stratification according to previous statin therapy, patients were randomized to 6-month, double-blind treatment with ALC or placebo added-on simvastatin. Setting: Five diabetology units and one clinical research center in Italy. Patients: Two hundred twenty-nine patients with hypertension and dyslipidemic T2D > 40 years with stable background antihypertensive, hypoglycemic, and statin therapy and serum creatinine < 1.5 mg/ dL. Interventions: Oral ALC 1000 mg or placebo twice daily on top of stable simvastatin therapy. Outcome and Measures: Primary outcome was SBP. Secondary outcomes included lipid and glycemic profiles. Total-body glucose disposal rate and glomerular filtration rate were measured in subgroups by hyperinsulinemic-euglycemic clamp and iohexol plasma clearance, respectively. Results: SBP did not significantly change after 6-month treatment with ALC compared with placebo (-2.09mmHg vs-3.57mmHg, P = 0.9539). Serum cholesterol, triglycerides, and lipoprotein(a), as well as blood glucose, glycated hemoglobin, fasting insulin levels, homeostatic model assessment of insulin resistance index, glucose disposal rate, and glomerular filtration rate did not significantly differ between treatments. Adverse events were comparable between groups. Conclusions: Six-month oral ALC supplementation did not affect blood pressure, lipid and glycemic control, insulin sensitivity and kidney function in hypertensive normoalbuminuric and microalbuminuric T2D patients on background statin therapy
Human telomerase activity regulation
Telomerase has been recognized as a relevant factor distinguishing cancer cells from normal cells. Thus, it has become a very promising target for anticancer therapy. The cell proliferative potential can be limited by replication end problem, due to telomeres shortening, which is overcome in cancer cells by telomerase activity or by alternative telomeres lengthening (ALT) mechanism. However, this multisubunit enzymatic complex can be regulated at various levels, including expression control but also other factors contributing to the enzyme phosphorylation status, assembling or complex subunits transport. Thus, we show that the telomerase expression targeting cannot be the only possibility to shorten telomeres and induce cell apoptosis. It is important especially since the transcription expression is not always correlated with the enzyme activity which might result in transcription modulation failure or a possibility for the gene therapy to be overcome. This review summarizes the current state of knowledge of numerous telomerase regulation mechanisms that take place after telomerase subunits coding genes transcription. Thus we show the possible mechanisms of telomerase activity regulation which might become attractive anticancer therapy targets
Cardiopoietic cell therapy for advanced ischemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial
Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort
NANOMEDICINE AND MEDICINAL PLANTS: EMERGING SYMBIOSIS IN MANAGING LUNG DISEASES AND ASSOCIATED INFECTIONS
Prognostic impact of tumour-infiltrating lymphocytes and cancer-associated fibroblasts in patients with pancreatic adenocarcinoma of the body and tail undergoing resection
International audienceBackground: The prognosis of patients with pancreatic cancer remains poor and novel therapeutic targets are required urgently. Treatment resistance could be due to the tumour microenvironment, a desmoplastic stroma consisting of cancer-associated fibroblasts and tumour-infiltrating lymphocytes (TILs). The aim of the study was to evaluate the prognostic value of TILs and cancer-associated fibroblasts (CAFs) in pancreatic cancer of the body and tail.Methods: Using tissue microarray from resected left-sided pancreatic cancer specimens, the immunohistochemistry of TILs (cluster of differentiation (CD) 45, CD3, CD4, FoxP3 and CD8), CAFs (vimentin and α-smooth muscle actin (αSMA)) and functional markers (PD-L1 and Ki-67) was examined, and the association with disease-free (DFS) and overall (OS) survival investigated using a computer-assisted quantitative analysis. Patients were classified into two groups, with low or high levels or ratios, using the 75th percentile value as the cut-off.Results: Forty-three patients were included in the study. Their median DFS and OS were 9 and 27 months respectively. A high CD4/CD3 lymphocyte ratio was associated with poorer DFS (8 months versus 11 months for a low ratio) (hazard ratio (HR) 2·23, 95 per cent c.i. 1·04 to 4·61; P = 0·041) and OS (13 versus 27 months respectively) (HR 2·62, 1·11 to 5·88; P = 0·028). A low αSMA/vimentin ratio together with a high CD4/CD3 ratio was correlated with poorer outcomes. No significant association was found between Ki-67, PD-L1 and survival.Conclusion: In patients with resected left-sided pancreatic cancer, a tumour microenvironment characterized by a high CD4/CD3 lymphocyte ratio along with a low αSMA/vimentin ratio is correlated with poorer survival
Long-term Effects of Octreotide on Liver Volume in Patients With Polycystic Kidney and Liver Disease
Background & aims: Short-term studies have shown that somatostatin analogues are effective in patients with polycystic kidney and liver disease. We evaluated the long-term effects of long-acting release octreotide (octreotide LAR), a somatostatin inhibitor, vs placebo in these patients.Methods: We performed a controlled study of adults with polycystic kidney and liver disease (estimated glomerular filtration rate, 40 mL/min/1.73m(2) or more) at a single center in Italy. We analyzed data from 27 patients randomly assigned to groups given octreotide LAR (40 mg, n = 14) or placebo (n = 13) each month for 3 years. The primary outcome was absolute and percentage change in total liver volume (TLV), which was measured by magnetic resonance imaging at baseline, after 3 years of treatment, and then 2 years after treatment ended.Results: Baseline characteristics were similar between groups. After 3 years, TLV decreased by 130.2 ± 133.2 mL in patients given octreotide LAR (7.8% ± 7.4%) (P = .003) but increased by 144.3 ± 316.8 mL (6.1% ± 14.1%) in patients given placebo. Change vs baseline differed significantly between groups (P = .004). Two years after treatment ended, TLV had decreased 14.4 ± 138.4 mL (0.8% ± 9.7%) from baseline in patients given octreotide LAR but increased by 224.4 ± 331.7 mL (11.0% ± 14.4%) in patients given placebo. Changes vs baseline still differed significantly between groups (P = .046). Decreases in TLV were similar in each sex; the change in TLV was greatest among subjects with larger baseline TLV. No patient withdrew because of side effects.Conclusions: In a placebo-controlled study of patients with polycystic kidney and liver disease, 3 years of treatment with octreotide LAR significantly reduced liver volume; reductions were maintained for 2 years after treatment ended. Octreotide LAR was well-tolerated. ClinicalTrials.gov number: NCT02119052
Developing Regulatory-compliant Electronic Case Report Forms for Clinical Trials: Experience with The Demand Trial
The use of electronic case report forms (CRF) to gather data in randomized clinical trials has grown to progressively replace paper-based forms. Computerized form designs must ensure the same data quality expected of paper CRF, by following Good Clinical Practice rules. Electronic data capture (EDC) tools must also comply with applicable statutory and regulatory requirements. Here the authors focus on the development of computerized systems for clinical trials implementing FDA and EU recommendations and regulations, and describe a laptop-based electronic CRF used in a randomized, multicenter clinical trial
Measurable urinary albumin predicts cardiovascular risk among normoalbuminuric patients with type 2 diabetes
Micro- or macroalbuminuria is associated with increased cardiovascular risk factors among patients with type 2 diabetes, but whether albuminuria within the normal range predicts long-term cardiovascular risk is unknown. We evaluated the relationships between albuminuria and cardiovascular events in 1208 hypertensive, normoalbuminuric patients with type 2 diabetes from the BErgamo NEphrologic Diabetes Complication Trial (BENEDICT), all of whom received angiotensin-converting enzyme inhibitor (ACEI) therapy at the end of the trial and were followed for a median of 9.2 years. The main outcome was time to the first of fatal or nonfatal myocardial infarction; stroke; coronary, carotid, or peripheral artery revascularization; or hospitalization for heart failure. Overall, 189 (15.6%) of the patients experienced a main outcome event (2.14 events/100 patient-years); 24 events were fatal. Albuminuria independently predicted events (hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.02-1.08). Second-degree polynomial multivariable analysis showed a continuous nonlinear relationship between albuminuria and events without thresholds. Considering the entire study population, even albuminuria at 1-2 \u3bcg/min was significantly associated with increased risk compared with albuminuria <1 \u3bcg/min (HR, 1.04; 95%CI, 1.02-1.07). This relationship was similar in the subgroup originally randomly assigned to non-ACEI therapy. Among those originally receiving ACEI therapy, however, the event rate was uniformly low and was not significantly associated with albuminuria. Taken together, among normoalbuminuric patients with type 2 diabetes, any degree of measurable albuminuria bears significant cardiovascular risk. The association with risk is continuous but is lost with early ACEI therapy