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1.  A photochemical method for determining plasma homocysteine with limited sample processing 
The photolytic formation of thiyl radicals allows for the selective detection of total homocysteine (tHcy) in plasma after reduction and filtering. The mechanism is based on the reduction of viologens by the α-amino carbon centred radical of Hcy generated by intramolecular hydrogen atom transfer (HAT) of its thiyl radical.
PMCID: PMC3979965  PMID: 24513922
2.  Determinants of Successful Glycemic Control among Participants in the BARI 2D Trial: A Post-hoc Analysis 
The BARI 2D trial compared insulin provision (IP) versus insulin sensitization (IS) for the primary outcome of total mortality in participants with T2DM and cardiovascular disease (CVD). In this analysis we examine baseline characteristics that are associated with successful long-term glycemic control.
Research Design and Methods
In a 2×2 factorial design, 2,368 participants were randomized to either IP or IS therapy, and to either prompt revascularization with medical therapy or medical therapy alone. Successful long-term glycemic control (success) was defined by simultaneously meeting 1) a mean HbA1c level of <7.0% after each participant's third year of follow-up period, and 2) adherence with medications only from the assigned glycemic treatment arm during >80% of the BARI 2D follow-up. The association between baseline variables and success was determined using unadjusted and adjusted logistic regression models.
1,917 participants (962 IP and 955 IS participants) had sufficiently long follow-up and data for this analysis. Among these IP and IS participants, 235 and 335 participants met both criteria of success, respectively (p <0.001). Those not on insulin at entry had higher odds of success (OR 2.25; CI 1.79-2.82) when treated with IS versus IP medications, irrespective of baseline HbA1c levels. Younger age, shorter duration of T2DM, and lower HbA1c at baseline were also each independently associated with higher success when treated with IS versus IP medications.
Patients similar to those in the BARI 2D trial may have a higher chance of achieving success with IS versus IP medications if they are younger, have shorter duration of T2DM, have lower HbA1c levels, have moderate or strenuous physically activity, and are not on insulin. In contrast, increasing age, longer duration of T2DM, higher HbA1c, and insulin therapy are associated with increased chance of success if treated with IP medications.
PMCID: PMC4156479  PMID: 23478173
Cardiovascular Disease; Plasma Insulin levels; Predictors of Glycemic Control
3.  Simple enrichment and analysis of plasma lysophosphatidic acids 
The Analyst  2013;138(22):6852-6859.
A simple and highly efficient technique for the analysis of lysophosphatidic acid (LPA) subspecies in human plasma is described. The streamlined sample preparation protocol furnishes the five major LPA subspecies with excellent recoveries. Extensive analysis of the enriched sample reveals only trace levels of other phospholipids. This level of purity not only improves MS analyses, but enables HPLC post-column detection in the visible region with a commercially available fluorescent phospholipids probe. Human plasma samples from different donors were analyzed using the above method and validated by ESI/MS/MS.
PMCID: PMC3929374  PMID: 24067566
4.  Impact of Glycemic Control Strategies on the Progression of Diabetic Peripheral Neuropathy in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Cohort 
Diabetes Care  2013;36(10):3208-3215.
The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial demonstrated similar long-term clinical effectiveness of insulin-sensitizing (IS) versus insulin-providing (IP) treatments for type 2 diabetes on cardiovascular outcomes in a cohort with documented coronary artery disease. We evaluated the effects of randomized glycemic control strategy (IS vs. IP) on the prevalence and incidence of diabetic peripheral neuropathy (DPN).
DPN (defined as Michigan Neuropathy Screening Instrument [MNSI] clinical examination score >2) was assessed at baseline and yearly for 4 years. DPN prevalence and incidence were compared by intention-to-treat modeling by logistic generalized estimating equation models for prevalence and Kaplan-Meier estimates and Cox regression models for incidence rates.
Results are reported for 2,159 BARI 2D participants (70% males) with valid baseline and at least one follow-up MNSI score (mean age 62 ± 9 years, mean HbA1c 7.7 ± 1.6%, diabetes duration 10 ± 9 years). There were no differences in the prevalence of DPN between the IS and the IP groups throughout the 4 years of follow-up. In 1,075 BARI 2D participants with no DPN at baseline, the 4-year cumulative incidence rate of DPN was significantly lower in the IS (66%) than in the IP (72%) strategy group (P = 0.02), which remained significant after adjusting for the in-trial HbA1c (P = 0.04). In subgroup analyses, IS strategy had a greater benefit in men (hazard ratio 0.75 [99% CI 0.58–0.99], P < 0.01).
Among patients with type 2 diabetes followed for up to 4 years during BARI 2D, a glycemic control therapy with IS significantly reduced the incidence of DPN compared with IP therapy and may add further benefit for men.
PMCID: PMC3781573  PMID: 23757426
5.  Change in enrollment patterns, patient selection, and clinical outcomes with the availability of drug-eluting stents in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial 
American heart journal  2013;166(3):10.1016/j.ahj.2013.05.017.
In the BARI 2D trial, patients with type 2 diabetes and stable coronary artery disease were randomized to prompt revascularization versus intensive medical therapy (IMT). This analysis sought to evaluate how the availability of drug-eluting stents (DESs) has changed practice and outcomes.
In BARI 2D, 1,605 patients were in the percutaneous coronary intervention (PCI)–intended stratum. As DES became available midway through recruitment, we report clinical outcomes among patients who underwent IMT versus prompt PCI with bare-metal stents (BMSs) or DES up to 4 years.
In North America, after DES became available, selection for the PCI-intended stratum increased from 73% to 79% (P = .003). Fewer BMS than DES patients had total occlusions treated or underwent rotational atherectomy (5.6% vs 9.7%, P = .02, and 1.2% vs 3.7%, P < .01, respectively). Subsequent revascularization (IMT 39%, BMS 29%, DES 21%, P < .01) and target vessel revascularization (BMS 16.1% vs DES 9.6%, P = .03) were lower with DES. Angina at 2 years tended to be less common with DES (IMT 39%, BMS 37%, DES 29%, P = .04, for 3 groups, P = .07 for DES vs BMS). The composite of death, myocardial infarction, or stroke was IMT 16.0%, BMS 20.5%, DES 17.5%; P = .80.
When DES became available in North America, patients were more likely to be selected into the PCI-intended stratum. Compared with patients receiving BMS, those receiving DES tended to have less target vessel revascularization and angina.
PMCID: PMC3867930  PMID: 24016502
6.  Prognostic Impact of the Presence and Absence of Angina on Mortality and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Stable Coronary Artery Disease 
The purpose of this analysis was to assess in patients with type 2 diabetes and stable coronary artery disease (CAD) whether the risk of all-cause mortality and cardiovascular events varied according to the presence or absence of angina and angina equivalent symptoms.
Data on the prognostic value of symptoms in these patients are limited.
Post-hoc analysis was performed in 2,364 patients with type 2 diabetes and documented CAD enrolled in the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial to determine the occurrence of death and composite of death, myocardial infarction, and stroke during a 5-year follow-up according to cardiac symptoms at baseline.
There were 1,434 patients with angina (A), 506 with angina equivalents (E), and 424 with neither of these (N). The cumulative death rates (total 316) were 12% in A, 14% in E, and 10% in N (p = 0.3), and cardiovascular composite rates (total 548) were 24% in A, 24% in E, and 21% in N (p =0.5). Compared with N, the hazard ratios adjusted for confounders were not different for death in A (1.11; 99% CI: 0.81 to 1.53) and E (1.17; 99% CI: 0.81 to 1.68) or for cardiovascular events in A (1.17; 99% CI: 0.92 to 1.50) and E (1.11; 99% CI: 0.84 to 1.48).
Whatever their symptom status, patients with type 2 diabetes and stable CAD were at similar risk of cardiovascular events and death. These findings suggest that these patients may be similarly managed in terms of risk stratification and preventive therapies. (Bypass Angioplasty Revascularization Investigation 2 Diabetes [BARI 2D]; NCT00006305)
PMCID: PMC3701296  PMID: 23410541
angina; coronary artery disease; silent ischemia; type 2 diabetes
7.  Field effects induce bathochromic shifts in xanthene dyes 
Journal of the American Chemical Society  2012;134(25):10502-10508.
There is ongoing interest in near infrared (NIR) absorbing and emitting dyes for a variety of biomedical and materials applications. Simple and efficient synthetic procedures enable the judicious tuning of through-space polar (field) effects as well as low barrier hydrogen bonding to modulate the HOMO-LUMO gap in xanthene dyes. This affords unique NIR-absorbing xanthene chromophores.
PMCID: PMC3384756  PMID: 22642754
xanthenes; near-infrared; large Stokes shift
8.  Progress toward red and near-infrared (NIR) emitting saccharide sensors* 
Red-shifted and near-infrared (NIR)-active rhodamine analogs and their boronic acid derivatives were synthesized and studied. These latter compounds function as fluorogenic NIR active substrates for sugar sensing. The effects of benzannulation and boronic acid functionalization on fluorophore optical and sensing properties are described.
PMCID: PMC3596891  PMID: 23504507
boronic acids; fluorescent indicators; naphthorhodamines; near infrared; semi-naphthorhodamines; sugar sensing; xanthenes
9.  BMI and Health Status in the Bypass Angioplasty Revascularization Investigation 2 Diabetes Trial (BARI 2D) 
American heart journal  2011;162(1):184-192.e3.
The longitudinal association between obesity, weight variability and health status outcomes is important for patients with coronary disease and diabetes.
The Bypass Angioplasty Revascularization Investigation 2 Diabetes trial (BARI 2D) was a multi-center randomized clinical trial to evaluate the best treatment strategy for patients with both documented stable ischemic heart disease and type 2 diabetes. We examined BARI 2D participants for four years to study how BMI was associated with health status outcomes. Health status was evaluated by the Duke Activity Status Index (DASI), RAND Energy/fatigue, Health Distress, and Self-rated health. BMI was measured quarterly throughout follow-up years, and health status was assessed at each annual follow-up visit. Variation in BMI measures was separated into between-person and within-person change in longitudinal analysis.
Higher mean BMI over follow-up years (the between-person BMI) was associated with poorer health status outcomes. Decreasing BMI (the within-person BMI change) was associated with better Self-rated health. The relationships between BMI variability and DASI or Energy appeared to be curvilinear, and differed by baseline obesity status. Decreasing BMI was associated with better outcomes if patients were obese at baseline, but was associated with poorer DASI and Energy outcomes if patients were non-obese at baseline.
For patients with stable ischemic heart disease and diabetes, weight gain was associated with poorer health status outcomes, independent of obesity-related comobidities. Weight reduction is associated with better functional capacity and perceived energy for obese patients but not for non-obese patients at baseline.
PMCID: PMC3141323  PMID: 21742107
BMI; obesity; coronary disease; diabetes mellitus; health status
10.  Chromophore Formation in Resorcinarene Solutions and the Visual Detection of Mono- and Oligosaccharides 
The colorimetric properties of resorcinarene solutions had not been investigated since Baeyer’s initial synthesis. We recently reported that solutions containing resorcinarene macrocycles develop color upon heating or standing. In the presence of saccharides, these solutions exhibit significant color changes which are easily seen. We herein present strong evidence that the solution color is due to macrocycle ring opening and oxidation. The optical responses to saccharides are due to complexation of the sugar with the acyclic chromophores. We apply these mechanistic insights toward the challenging problem of the visual detection of neutral oligosaccharides by simple chromogens. In addition, we also report the first single-crystal X-ray crystal structure determination of a rarely observed “diamond” resorcinarene stereoisomer.
PMCID: PMC3386614  PMID: 11982364
11.  Detection of Homocysteine and Cysteine 
Journal of the American Chemical Society  2005;127(45):15949-15958.
At elevated levels, homocysteine (Hcy, 1) is a risk factor for cardiovascular diseases, Alzheimer’s disease, neural tube defects, and osteoporosis. Both 1 and cysteine (Cys, 3) are linked to neurotoxicity. The biochemical mechanisms by which 1 and 3 are involved in disease states are relatively unclear. Herein, we describe simple methods for detecting either Hcy or Cys in the visible spectral region with the highest selectivity reported to date without using biochemical techniques or preparative separations. Simple methods and readily available reagents allow for the detection of Cys and Hcy in the range of their physiologically relevant levels. New HPLC postcolumn detection methods for biological thiols are reported. The potential biomedical relevance of the chemical mechanisms involved in the detection of 1 is described.
PMCID: PMC3386615  PMID: 16277539
12.  A Supramolecular Approach to Protein Labeling. A Novel Fluorescent Bioassay for Concanavalin A Activity 
Organic Letters  2004;6(9):1373-1376.
A new method for the bioassay of concanavalin A is based on the interaction of saccharide-substituted oligopyrrolic macrocycles with lectins. A general sensing mechanism involves the interaction of aggregated and primarily nonfluorescent labels with the target protein, label deaggregation, site-specific binding, and fluorescence signaling. Addition of saccharides to the fluorescent lectin–macrocycle complex leads to the release of the label and partial quenching of fluorescence due to reaggregation. Specificity of the protein–probe binding is discussed.
PMCID: PMC3384776  PMID: 15101745
13.  A Convenient Preparation of Xanthene Dyes 
The Journal of Organic Chemistry  2005;70(17):6907-6912.
A facile synthetic route utilizing readily available reagents affords a series of regioisomerically pure xanthene dye derivatives. Advantages include relatively mild conditions and good to excellent yields. Nonpolar, highly crystalline intermediates are isolable by standard chromatographic techniques. The intermediates are in the requisite xanthene oxidation state, thus avoiding the need for relatively inefficient oxidation chemistry and/or harsh conditions. During the course of this work, a new boron-mediated 1,2-aryl migration reaction was discovered.
PMCID: PMC3376412  PMID: 16095313
14.  Direct Detection of Homocysteine 
PMCID: PMC3376413  PMID: 15025448
16.  Detecting specific saccharides via a single indicator†‡ 
An improved synthesis of a rhodamine boronic acid indicator is reported. This compound is used in an optimized data collection protocol for wavelength- and time-dependent selectivity of sugars such as fructose and ribose derivatives. One indicator is thus used to selectively distinguish structurally related sugar analytes.
PMCID: PMC3377375  PMID: 21643594
17.  Selective fluorescence detection of cysteine and N-terminal cysteine peptide residues† 
A new fluorogenic fluorescein derivative containing an α,β-unsaturated aldehyde moiety produces a selective fluorescent signal enhancement in the presence of cysteine or peptides containing N-terminal cysteine residues. The mechanism is based on synergistic covalent and supramolecular interactions.
PMCID: PMC3376164  PMID: 20617237
18.  Live Cell Imaging of a Fluorescent Gentamicin Conjugate 
Natural Product Communications  2012;7(3):317-320.
Understanding cellular mechanisms of ototoxic and nephrotoxic drug uptake, intracellular distribution, and molecular trafficking across cellular barrier systems aids the study of potential uptake blockers that preserve sensory and renal function during critical life-saving therapy. Herein we report the design, synthesis characterization and evaluation of a fluorescent conjugate of the aminoglycoside antibiotic gentamicin. Live cell imaging results show the potential utility of this new material. Related gentamicin conjugates studied to date quench in live kindney cells, and have been largely restricted to use in fixed (delipidated) cells.
PMCID: PMC3376166  PMID: 22545403
Aminoglycosides; Gentamicin; Ototoxic drugs
19.  Macrocycle-Derived Functional Xanthenes and Progress Towards Concurrent Detection of Glucose and Fructose 
Journal of Fluorescence  2004;14(5):611-615.
The detection of saccharides in biological media is of great current importance for the monitoring of disease states. We have previously reported that solutions of boronic acid-functionalized macrocycles form acyclic oligomeric materials in situ. The oligomers contain fluorescent xanthene moieties. Current efforts are aimed at modulating the spectroscopic responses of these materials for the analysis of specific sugars. We describe conditions whereby the xanthene boronic acids exhibit high colorimetric fructose selectivity. In contrast, at physiological levels selective glucose monitoring can be achieved via fluorescence. Additionally, we describe a method which exhibits promise for detecting both glucose and fructose at dual wavelengths in the UV-Vis region. Mechanistic rationale for each of these findings is presented.
PMCID: PMC3376174  PMID: 15617268
Glucose; fructose; resorcinarene; boronic acid; xanthene
20.  Postcolumn HPLC Detection of Mono- and Oligosaccharides with a Chemosensor 
Organic Letters  2003;5(26):5007-5010.
Novel chromophoric compound 1 promotes the HPLC postcolumn detection of mono- and oligosaccharides. The detection of chromatographic peaks in the visible region for glucose, fructose, maltodextrins, sialic acid, and a ganglioside can be accomplished with a standard UV–vis detector. The use of selective, reversible binding agents in automated HPLC assays should allow for improved monitoring of specific analytes as well as material recovery.
PMCID: PMC3376175  PMID: 14682751
21.  Evaluating quality of care for patients with type 2 diabetes using electronic health record information in Mexico 
Several low and middle-income countries are implementing electronic health records (EHR). In the near future, EHRs could become an efficient tool to evaluate healthcare performance if appropriate indicators are developed. The aims of this study are: a) to develop quality of care indicators (QCIs) for type 2 diabetes (T2DM) in the Mexican Institute of Social Security (IMSS) health system; b) to determine the feasibility of constructing QCIs using the IMSS EHR data; and c) to evaluate the quality of care (QC) provided to IMSS patients with T2DM.
We used a three-stage mixed methods approach: a) development of QCIs following the RAND-UCLA method; b) EHR data extraction and construction of indicators; c) QC evaluation using EHR data from 25,130 T2DM patients who received care in 2009.
We developed 18 QCIs, of which 14 were possible to construct using available EHR data. QCIs comprised both process of care and health outcomes. Several flaws in the EHR design and quality of data were identified. The indicators of process and outcomes of care suggested areas for improvement. For example, only 13.0% of patients were referred to an ophthalmologist; 3.9% received nutritional counseling; 63.2% of overweight/obese patients were prescribed metformin, and only 23% had HbA1c <7% (or plasma glucose ≤130 mg/dl).
EHR data can be used to evaluate QC. The results identified both strengths and weaknesses in the electronic information system as well as in the process and outcomes of T2DM care at IMSS. This information can be used to guide targeted interventions to improve QC.
PMCID: PMC3437217  PMID: 22672471
22.  Development of a Panel of Genome-Wide Ancestry Informative Markers to Study Admixture Throughout the Americas 
PLoS Genetics  2012;8(3):e1002554.
Most individuals throughout the Americas are admixed descendants of Native American, European, and African ancestors. Complex historical factors have resulted in varying proportions of ancestral contributions between individuals within and among ethnic groups. We developed a panel of 446 ancestry informative markers (AIMs) optimized to estimate ancestral proportions in individuals and populations throughout Latin America. We used genome-wide data from 953 individuals from diverse African, European, and Native American populations to select AIMs optimized for each of the three main continental populations that form the basis of modern Latin American populations. We selected markers on the basis of locus-specific branch length to be informative, well distributed throughout the genome, capable of being genotyped on widely available commercial platforms, and applicable throughout the Americas by minimizing within-continent heterogeneity. We then validated the panel in samples from four admixed populations by comparing ancestry estimates based on the AIMs panel to estimates based on genome-wide association study (GWAS) data. The panel provided balanced discriminatory power among the three ancestral populations and accurate estimates of individual ancestry proportions (R2>0.9 for ancestral components with significant between-subject variance). Finally, we genotyped samples from 18 populations from Latin America using the AIMs panel and estimated variability in ancestry within and between these populations. This panel and its reference genotype information will be useful resources to explore population history of admixture in Latin America and to correct for the potential effects of population stratification in admixed samples in the region.
Author Summary
Individuals from Latin America are descendants of multiple ancestral populations, primarily Native American, European, and African ancestors. The relative proportions of these ancestries can be estimated using genetic markers, known as ancestry informative markers (AIMs), whose allele frequency varies between the ancestral groups. Once determined, these ancestral proportions can be correlated with normal phenotypes, can be associated with disease, can be used to control for confounding due to population stratification, or can inform on the history of admixture in a population. In this study, we identified a panel of AIMs relevant to Latin American populations, validated the panel by comparing estimates of ancestry using the panel to ancestry determined from genome-wide data, and tested the panel in a diverse set of populations from the Americas. The panel of AIMs produces ancestry estimates that are highly accurate and appropriately controlled for population stratification, and it was used to genotype 18 populations from throughout Latin America. We have made the panel of AIMs available to any researcher interested in estimating ancestral proportions for populations from the Americas.
PMCID: PMC3297575  PMID: 22412386
23.  A Fast Response Highly Selective Probe for the Detection of Glutathione in Human Blood Plasma 
Sensors (Basel, Switzerland)  2012;12(5):5940-5950.
A fluorescent probe for glutathione (GSH) detection was developed. Our study indicates a possible mechanism which couples a conjugate addition and micelle-catalyzed large membered ring formation/elimination sequence. This method enables excellent selectivity towards GSH over other biological thiols such as cysteine (Cys) and homocysteine (Hcy). The proposed method is precise with a relative standard deviation (R.S.D) lower than 6% (n = 3) and has been successfully applied to determine GSH in human plasma with recoveries between 99.2% and 102.3%.
PMCID: PMC3386722  PMID: 22778623
fluorescent probe; glutathione; micelle-catalyzed; selectivity
24.  Health Status after Treatment for Coronary Artery Disease and Type 2 Diabetes in the BARI 2D Trial 
Circulation  2010;122(17):1690-1699.
Health status is a key outcome for comparing treatments, particularly when mortality does not differ significantly.
Methods and Results
BARI 2D randomized 2368 patients with type 2 diabetes and stable ischemic heart disease to 1) prompt revascularization versus medical therapy and 2) insulin sensitization versus insulin provision. Randomization was stratified by the intended method of revascularization, coronary artery bypass graft surgery (CABG) or percutaneous coronary intervention (PCI). The Duke Activity Status Index (DASI) and RAND Energy, Health Distress and Self-rated Health were assessed at study entry and annually thereafter; linear mixed models were used to evaluate the effect of randomized treatment on these measures. Health status improved significantly from baseline to one-year (p<0.001) in each randomized treatment group. Compared with medical therapy, prompt revascularization was associated with significantly greater improvements in DASI (1.32 points, p<0.001), Energy (1.36 points, p=0.02) and Self-rated Health (1.77 points, p=0.007) but not Health Distress (−0.47, p=0.46). These treatment effects were largely maintained over four years of follow-up. The effect of revascularization on DASI was significantly larger in the subgroup of patients intended for CABG compared with the subgroup intended for PCI. Health status did not differ significantly on any of the four measures between the insulin provision and insulin sensitization strategies.
Prompt coronary revascularization was associated with small yet statistically significant improvements in health status compared with initial medical therapy among patients with diabetes and stable ischemic heart disease.
PMCID: PMC2964421  PMID: 20937978
coronary disease; diabetes mellitus; revascularization; health status
25.  NIR Dyes for Bioimaging Applications 
Summary of recent advances
Fluorescent dyes based on small organic molecules that function in the near infra red (NIR) region are of great current interest in chemical biology. They allow for imaging with minimal autofluorescence from biological samples, reduced light scattering and high tissue penetration. Herein, examples of ongoing NIR fluorophore design strategies as well as their properties and anticipated applications relevant to the bioimaging are presented.
PMCID: PMC2819555  PMID: 19926332

Results 1-25 (32)