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1.  Improving medication adherence in hypercholesterolemia: challenges and solutions 
Medication nonadherence is a prevalent public health issue that contributes to significant medical costs and detrimental health outcomes. This is especially true in patients with hypercholesterolemia, a condition affecting millions of American adults and one that is associated with increased risk for coronary and cerebrovascular events. Considering the magnitude of outcomes related to this disease, the medical community has placed significant emphasis on addressing the treatment for high cholesterol, and progress has been made in recent years. However, poor adherence to therapy continues to plague health outcomes and more must be understood and done to address suboptimal medication taking. Here we provide an overview of the reasons for poor medication adherence in patients with hypercholesterolemia and describe recent efforts to curb nonadherence. Suggested approaches for improving medication taking in patients with high cholesterol are also provided to guide practitioners, patients, and payers.
Video abstract
PMCID: PMC4226449  PMID: 25395859
medication use; lipid management; cardiovascular disease
2.  Does Health Information Exchange Reduce Unnecessary Neuroimaging and Improve Quality of Headache Care in the Emergency Department? 
Health information exchange (HIE) is advocated as an approach to reduce unnecessary testing and improve quality of emergency department (ED) care, but little evidence supports its use. Headache is a specific condition for which HIE has theoretical benefits.
To determine whether health information exchange (HIE) reduces potentially unnecessary neuroimaging, increases adherence with evidence-based guidelines, and decreases costs in the emergency department (ED) evaluation of headache.
Longitudinal data analysis
All repeat patient-visits (N = 2,102) by all 1,252 adults presenting with headache to a Memphis metropolitan area ED two or more times between August 1, 2007 and July 31, 2009.
Use of a regional HIE connecting the 15 major adult hospitals and two regional clinic systems by authorized ED personnel to access the patient’s record during the time period in which the patient was being seen in the ED.
Main Measures
Diagnostic neuroimaging (CT, CT angiography, MRI or MRI angiography), evidence-based guideline adherence, and total patient-visit estimated cost.
Key Results
HIE data were accessed for 21.8 % of ED patient-visits for headache. 69.8 % received neuroimaging. HIE was associated with decreased odds of diagnostic neuroimaging (odds ratio [OR] 0.38, confidence interval [CI] 0.29–0.50) and increased adherence with evidence-based guidelines (OR 1.33, CI 1.02–1.73). Administrative/nursing staff HIE use (OR 0.24, CI 0.17–0.34) was also associated with decreased neuroimaging after adjustment for confounding factors. Overall HIE use was not associated with significant changes in costs.
HIE is associated with decreased diagnostic imaging and increased evidence-based guideline adherence in the emergency evaluation of headache, but was not associated with improvements in overall costs. Controlled trials are needed to test whether specific HIE enhancements to increase HIE use can further reduce potentially unnecessary diagnostic imaging and improve adherence with guidelines while decreasing costs of care.
PMCID: PMC3614141  PMID: 22648609
health information exchange; medical informatics; headache; headache disorders; migraine disorders; delivery of health care; emergency medicine; quality of health care; health services research
3.  Hypertension Awareness and Associated Factors among Older Chinese Adults 
Hypertension is one of the most preventable chronic conditions. Improving hypertension awareness is a critical first step to reducing morbidity and mortality from hypertension in the elderly, yet the factors associated with hypertension awareness in China are poorly understood. The objective of this paper is to examine the extent to which older Chinese adults are aware of their hypertension, and factors associated with this awareness. We included 2404 adults aged 60 years or older clinically identified as hypertensive from panel data surveyed in 1997, 2000, 2004, and 2006 as part of the China Health and Nutrition Survey. Comparing this data with respondents’ self-reported diagnosis of hypertension enabled us to characterize hypertension awareness. Covariates included socio-demographic, health status, functional disability, and behavioral factors. Generalized estimating equations were used to identify factors for hypertension awareness. We found 22.9% in 1997 and 42.7% in 2006 of study participants were aware of their hypertensive status. Lower awareness was found among those who lived in rural areas [odds ratio (OR) = 0.64, 95% Confidence Interval (CI), 0.47–0.88]. Higher awareness was noted for persons who were aware of their hypertensive status in a previous survey wave (OR = 7.43, 95% CI, 5.45–10.13), had high income (OR = 1.55, 95% CI, 1.05–2.28), had stage two hypertension (OR = 2.28, 95% CI, 1.69–3.06), had acute condition (OR = 2.54, 95% CI, 1.89–3.42), and had greater activities of daily living limitations (OR = 1.24, 95% CI, 1.08–1.43). Studying dynamics of hypertension awareness can help inform both clinical and public health approaches to improve healthcare.
PMCID: PMC3859975  PMID: 24350235
hypertension; awareness; elderly care; rural; Asia; Chinese
5.  Antihypertensive Medication Adherence, Ambulatory Visits, and Risk of Stroke and Death 
This study seeks to determine whether antihypertensive medication refill adherence, ambulatory visits, and type of antihypertensive medication exposures are associated with decreased stroke and death for community-dwelling hypertensive patients.
This retrospective cohort study included all chronic medication-treated hypertensives enrolled in Tennessee’s Medicaid program (TennCare) for 3–7 years during the period 1994–2000 (n = 49,479). Health care utilization patterns were evaluated using administrative data linked to vital records during a 2-year run-in period and 1- to 5-year follow-up period. Antihypertensive medication refill adherence was calculated using pharmacy records.
Associations with stroke and death were assessed using Cox proportional hazards modeling. Stroke occurred in 619 patients (1.25%) and death in 2,051 (4.15%). Baseline antihypertensive medication refill adherence was associated with decreased multivariate hazards of stroke [hazard ratio (HR) 0.91; 95% confidence interval (CI), 0.86–0.97 for 15% increase in adherence]. Adherence in the follow-up period was associated with decreased hazards of stroke (HR 0.92; CI 0.87–0.96) and death (HR 0.93; CI 0.90–0.96). Baseline ambulatory visits were associated with decreased death (HR 0.99; CI 0.98–1.00). Four major classes of antihypertensive agents were associated with mortality reduction. Only thiazide-type diuretic use was associated with decreased stroke (HR 0.89; CI 0.85–0.93).
Ambulatory visits and antihypertensive medication exposures are associated with reduced mortality. Increasing adherence by one pill per week for a once-a-day regimen reduces the hazard of stroke by 8–9% and death by 7%.
PMCID: PMC2869423  PMID: 20165989
hypertension; ambulatory care; adherence; stroke; thiazide diuretics
7.  Intracellular Carbon Fluxes in Riboflavin-Producing Bacillus subtilis during Growth on Two-Carbon Substrate Mixtures 
Metabolic responses to cofeeding of different carbon substrates in carbon-limited chemostat cultures were investigated with riboflavin-producing Bacillus subtilis. Relative to the carbon content (or energy content) of the substrates, the biomass yield was lower in all cofeeding experiments than with glucose alone. The riboflavin yield, in contrast, was significantly increased in the acetoin- and gluconate-cofed cultures. In these two scenarios, unusually high intracellular ATP-to-ADP ratios correlated with improved riboflavin yields. Nuclear magnetic resonance spectra recorded with amino acids obtained from biosynthetically directed fractional 13C labeling experiments were used in an isotope isomer balancing framework to estimate intracellular carbon fluxes. The glycolysis-to-pentose phosphate (PP) pathway split ratio was almost invariant at about 80% in all experiments, a result that was particularly surprising for the cosubstrate gluconate, which feeds directly into the PP pathway. The in vivo activities of the tricarboxylic acid cycle, in contrast, varied more than twofold. The malic enzyme was active with acetate, gluconate, or acetoin cofeeding but not with citrate cofeeding or with glucose alone. The in vivo activity of the gluconeogenic phosphoenolpyruvate carboxykinase was found to be relatively high in all experiments, with the sole exception of the gluconate-cofed culture.
PMCID: PMC123836  PMID: 11916694
8.  Streptogramin- and tetracycline-responsive dual regulated expression of p27Kip1 sense and antisense enables positive and negative growth control of Chinese hamster ovary cells 
Nucleic Acids Research  2001;29(4):e19.
We constructed a dual regulated expression vector cassette (pDuoRex) whereby two heterologous genes can be independently regulated via streptogramin- and tetracycline-responsive promoters. Two different constructs containing growth-promoting and growth-inhibiting genes were stably transfected in recombinant Chinese hamster ovary (CHO) cells that express the streptogramin- and tetracycline-dependent transactivators in a dicistronic configuration. An optimally balanced heterologous growth control scenario was achieved by reciprocal expression of the growth-inhibiting human cyclin-dependent kinase inhibitor p27Kip1 in sense (p27Kip1S) and antisense (p27Kip1AS) orientation. Exclusive expression of p27Kip1S resulted in complete G1-phase-specific growth arrest, while expression of only p27Kip1AS showed significantly increased proliferation compared to control cultures (both antibiotics present), presumably by decreasing host cell p27Kip1 expression. In a second system, a derivative of pDuoRex encoding streptogramin-responsive expression of the growth-promoting SV40 small T antigen (sT) and tetracycline-regulated expression of p27Kip1 was stably transfected into CHO cells. Expression of sT alone resulted in an increase in cell proliferation, but the expression of p27Kip1 failed to provide the expected G1-specific growth arrest despite having demonstrated expression of the protein. This illustrates the difficulty in balancing the complex pathways underlying cell proliferation control through the expression of two functionally distinct genes involved in those pathways, and how a single-gene sense/antisense approach using pDuoRex can overcome this barrier to complete metabolic engineering control.
PMCID: PMC29626  PMID: 11160939
9.  Dissection of Central Carbon Metabolism of Hemoglobin-Expressing Escherichia coli by 13C Nuclear Magnetic Resonance Flux Distribution Analysis in Microaerobic Bioprocesses 
Escherichia coli MG1655 cells expressing Vitreoscilla hemoglobin (VHb), Alcaligenes eutrophus flavohemoprotein (FHP), the N-terminal hemoglobin domain of FHP (FHPg), and a fusion protein which comprises VHb and the A. eutrophus C-terminal reductase domain (VHb-Red) were grown in a microaerobic bioreactor to study the effects of low oxygen concentrations on the central carbon metabolism, using fractional 13C-labeling of the proteinogenic amino acids and two-dimensional [13C, 1H]-correlation nuclear magnetic resonance (NMR) spectroscopy. The NMR data revealed differences in the intracellular carbon fluxes between E. coli cells expressing either VHb or VHb-Red and cells expressing A. eutrophus FHP or the truncated heme domain (FHPg). E. coli MG1655 cells expressing either VHb or VHb-Red were found to function with a branched tricarboxylic acid (TCA) cycle. Furthermore, cellular demands for ATP and reduction equivalents in VHb- and VHb-Red-expressing cells were met by an increased flux through glycolysis. In contrast, in E. coli cells expressing A. eutrophus hemeproteins, the TCA cycle is running cyclically, indicating a shift towards a more aerobic regulation. Consistently, E. coli cells displaying FHP and FHPg activity showed lower production of the typical anaerobic by-products formate, acetate, and d-lactate. The implications of these observations for biotechnological applications are discussed.
PMCID: PMC92635  PMID: 11157231
10.  Regulated overexpression of the survival factor bcl-2 in CHO cells increases viable cell density in batch culture and decreases DNA release in extended fixed-bed cultivation 
Cytotechnology  2000;32(1):45-61.
Using multicistronic expression technology we generated a stable Chinese hamster ovary (CHO) cell line (MG12) expressing a model secreted heterologous glycoprotein, the secreted form of the human placental alkaline phosphatase (SEAP), and bcl-2, best known as an apoptosis inhibitor, in a tetracycline-repressible dicistronic configuration. In batch cultivations in serum-containing medium, MG12 cells reached twice the final viable cell density when Bcl-2 was overexpressed (in the absence oftetracycline) compared to MG12 populations culturedunder tetracycline-containing conditions (bcl-2repressed). However, bcl-2-expressing MG12 cellsshowed no significant retardation of the decline phasecompared to batch cultures in which the dicistronicexpression unit was repressed.Genetic linkage of bcl-2 expression with the reporter protein SEAP in our multicistronic construct allowed online monitoring of Bcl-2 expression over an extended, multistage fixed-bed bioreactor cultivation. The cloned multicistronic expression unit proved to be stable over a 100 day bioreactor run. CHO MG12 cells in the fixed-bed reactor showed a drastic decrease in the release of DNA into the culture supernatant under conditions of reduced tetracycline (and hencederepressed SEAP and bcl-2 overexpression). This observation indicated enhanced robustness associated with bcl-2 overexpression, similar to recent findings for constitutive Bcl-2-overexpressing hybridoma cells under the same bioprocess conditions. These findings indicate, in these serum-containing CHO cell cultures, that overexpression of Bcl-2 results in desirable modifications in culture physiology.
PMCID: PMC3449443  PMID: 19002966
apoptosis; Bcl-2; fixed-bed reactor; regulated gene expression
11.  Expression of Alcaligenes eutrophus Flavohemoprotein and Engineered Vitreoscilla Hemoglobin-Reductase Fusion Protein for Improved Hypoxic Growth of Escherichia coli 
Expression of the vhb gene encoding hemoglobin from Vitreoscilla sp. (VHb) in several organisms has been shown to improve microaerobic cell growth and enhance oxygen-dependent product formation. The amino-terminal hemoglobin domain of the flavohemoprotein (FHP) of the gram-negative hydrogen-oxidizing bacterium Alcaligenes eutrophus has 51% sequence homology with VHb. However, like other flavohemoglobins and unlike VHb, FHP possesses a second (carboxy-terminal) domain with NAD(P)H and flavin adenine dinucleotide (FAD) reductase activities. To examine whether the carboxy-terminal redox-active site of flavohemoproteins can be used to improve the positive effects of VHb in microaerobic Escherichia coli cells, we fused sequences encoding NAD(P)H, FAD, or NAD(P)H-FAD reductase activities of A. eutrophus in frame after the vhb gene. Similarly, the gene for FHP was modified, and expression cassettes encoding amino-terminal hemoglobin (FHPg), FHPg-FAD, FHPg-NAD, or FHP activities were constructed. Biochemically active heme proteins were produced from all of these constructions in Escherichia coli, as indicated by their ability to scavenge carbon monoxide. The presence of FHP or of VHb-FAD-NAD reductase increased the final cell density of transformed wild-type E. coli cells approximately 50 and 75%, respectively, for hypoxic fed-batch culture relative to the control synthesizing VHb. Approximately the same final optical densities were achieved with the E. coli strains expressing FHPg and VHb. The presence of VHb-FAD or FHPg-FAD increased the final cell density slightly relative to the VHb-expressing control under the same cultivation conditions. The expression of VHb-NAD or FHPg-NAD fusion proteins reduced the final cell densities approximately 20% relative to the VHb-expressing control. The VHb-FAD-NAD reductase-expressing strain was also able to synthesize 2.3-fold more recombinant β-lactamase relative to the VHb-expressing control.
PMCID: PMC91791  PMID: 10618209
12.  Regulated multicistronic expression technology for mammalian metabolic engineering 
Cytotechnology  1998;28(1-3):111-126.
Contemporary basic research is rapidly revealing increasingly complex molecular regulatory networks which are often interconnected via key signal integrators. These connections among regulatory and catalytic networks often frustrate bioengineers as promising metabolic engineering strategies are bypassed by compensatory metabolic responses or cause unexpected, undesired outcomes such as apoptosis, product protein degradation or inappropriate post- translational modification. Therefore, for metabolic engineering to achieve greater success in mammalian cell culture processes and to become important for future applications such as gene therapy and tissue engineering, this technology must be enhanced to allow simultaneous, in cases conditional, reshaping of metabolic pathways to access difficult-to-attain cell states. Recent advances in this new territory of multigene metabolic engineering are intimately linked to the development of multicistronic expression technology which allows the simultaneous, and in some cases, regulated expression of several genes in mammalian cells. Here we review recent achievements in multicistronic expression technology in view of multigene metabolic engineering.
PMCID: PMC3449837  PMID: 19003413
autoregulation; cell-cycle engineering; eukaryotic operon; IRES; multigene engineering; picornavirus; pTRIDENT; regulated expression
13.  pQuattro vectors allow one-step multigene metabolic engineering and auto-selection of quattrocistronic artificial mammalian operons 
Cytotechnology  1998;28(1-3):229-235.
Based on internal ribosomal entry sites (IRES) of picornaviral origin we constructed a novel family of mammalian expression vectors. pQuattro vectors contain quattrocistronic artificial eukaryotic operons which link, in a single transcript, the simultaneous and coordinated as well as adjustable expression of up to three independent genes of interest to a terminal neomycin (neo) resistance marker. Due to the strict genetic linkage of the transgenes and the terminal selection marker, this genetic configuration enables, by the selection on neomycin, multigene metabolic engineering of mammalian cells in a single step (one-step metabolic engineering). Furthermore, selection on the terminal cistron of multicistronic expression units enforces cocistronic expression of all upstream encoded genes and maximises genetic integrity of the eukaryotic operon in stable mammalian cell lines, since clones harbouring damaged multicistronic expression units become neomycin-sensitive and are automatically counterselected (auto-selection). The modular set-up and the abundance of restriction sites in pQuattro vectors facilitate the movement of individual genes between multicistronic expression vectors and guarantees high compatibility with genetic elements of a wide variety of existing mammalian expression vectors.
PMCID: PMC3449843  PMID: 19003423
CITE; EMCV; GFP; IRES; picornavirus
14.  Metabolic Flux Ratio Analysis of Genetic and Environmental Modulations of Escherichia coli Central Carbon Metabolism 
Journal of Bacteriology  1999;181(21):6679-6688.
The response of Escherichia coli central carbon metabolism to genetic and environmental manipulation has been studied by use of a recently developed methodology for metabolic flux ratio (METAFoR) analysis; this methodology can also directly reveal active metabolic pathways. Generation of fluxome data arrays by use of the METAFoR approach is based on two-dimensional 13C-1H correlation nuclear magnetic resonance spectroscopy with fractionally labeled biomass and, in contrast to metabolic flux analysis, does not require measurements of extracellular substrate and metabolite concentrations. METAFoR analyses of E. coli strains that moderately overexpress phosphofructokinase, pyruvate kinase, pyruvate decarboxylase, or alcohol dehydrogenase revealed that only a few flux ratios change in concert with the overexpression of these enzymes. Disruption of both pyruvate kinase isoenzymes resulted in altered flux ratios for reactions connecting the phosphoenolpyruvate (PEP) and pyruvate pools but did not significantly alter central metabolism. These data indicate remarkable robustness and rigidity in central carbon metabolism in the presence of genetic variation. More significant physiological changes and flux ratio differences were seen in response to altered environmental conditions. For example, in ammonia-limited chemostat cultures, compared to glucose-limited chemostat cultures, a reduced fraction of PEP molecules was derived through at least one transketolase reaction, and there was a higher relative contribution of anaplerotic PEP carboxylation than of the tricarboxylic acid (TCA) cycle for oxaloacetate synthesis. These two parameters also showed significant variation between aerobic and anaerobic batch cultures. Finally, two reactions catalyzed by PEP carboxykinase and malic enzyme were identified by METAFoR analysis; these had previously been considered absent in E. coli cells grown in glucose-containing media. Backward flux from the TCA cycle to glycolysis, as indicated by significant activity of PEP carboxykinase, was found only in glucose-limited chemostat culture, demonstrating that control of this futile cycle activity is relaxed under severe glucose limitation.
PMCID: PMC94132  PMID: 10542169
15.  The Prognostic Significance of Asymptomatic Carotid Bruits in the Elderly 
To determine the association between asymptomatic carotid bruits and the development of subsequent stroke in older adults with isolated systolic hypertension.
Retrospective cohort study.
The Systolic Hypertension in the Elderly Program (SHEP), a 5-year randomized trial testing the efficacy of treating systolic hypertension in noninstitutionalized persons aged 60 years or older. From the original 4,736 SHEP participants, we identified a cohort of 4,442 persons who had no prior history of stroke, transient ischemic attack, or myocardial infarction at randomization.
The end point for this ancillary study was the development of a stroke. The average follow-up was 4.2 years. Carotid bruits were found in 284 (6.4%) of the participants at baseline. Strokes developed in 21 (7.4%) of those with carotid bruits and in 210 (5.0%) of those without carotid bruits. The unadjusted risk of stroke among persons with carotid bruits was 1.53 (95% confidence interval [CI] 0.98, 2.40). Adjusting for age, gender, race, blood pressure, smoking, lipid levels, self-reported aspirin use, and treatment group assignment, the relative risk of stroke among persons with asymptomatic carotid bruits was 1.29 (95% CI 0.80, 2.06). Among SHEP enrollees aged 60 to 69 years, there was a trend (p=.08) toward increased risk (relative risk [RR] 2.05; 95% CI 0.92, 4.68) of subsequent stroke in persons with, compared to those without, carotid bruits. However, among enrollees aged 70 years or over, there was no relation between carotid bruit and subsequent stroke (RR 0.98; 95% CI 0.55, 1.76). In no other subgroup of SHEP enrollees did the presence of carotid bruit independently predict stroke.
Although we cannot rule out a small increased risk of stroke associated with bruits in asymptomatic SHEP enrollees aged 60 to 69 years, the utility of carotid bruits as a marker for increased risk of stroke among asymptomatic elderly with isolated systolic hypertension aged 70 years or older is limited.
PMCID: PMC1496903  PMID: 9502367
carotid bruits; asymptomatic; stroke; elderly; Systolic Hypertension in the Elderly Program (SHEP)

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