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E Albert Reece

Publications and source records attributed to E Albert Reece.

At least 19 recordsLinked to original sources
PubMed2006

Effects of pioglitazone and metformin on beta-cell function in nondiabetic subjects at high risk for type 2 diabetes.

Thiazolidinediones (TZDs) and metformin decreased the incidence of diabetes in subjects at risk for developing diabetes and improved peripheral or hepatic insulin sensitivity, respectively. Whether they also directly improved beta-cell function is not clear. In vitro studies showed improved beta-cell function in response to TZDs and metformin; however, the effects of TZDs or metformin on beta-cell function in humans are still uncertain. We hypothesized that both TZDs and metformin directly affect beta-cell function. We evaluated beta-cell function and insulin sensitivity (S(I)) in subjects with impaired glucose tolerance or a history of gestational diabetes using oral and intravenous glucose tolerance tests in addition to the glucose-potentiated arginine stimulation test. In contrast to metformin, pioglitazone improved S(I), glucose tolerance, and insulin-independent glucose disposal [glucose effectiveness (S(G))]. Neither pioglitazone nor metformin significantly improved beta-cell compensation for insulin resistance [disposition index (DI)], but the change in DI significantly correlated with baseline S(I). Insulin secretion in response to arginine at maximally potentiating glucose levels (AIR(max)) tended to increase after metformin and to decrease after pioglitazone; however, when adjusted for S(I), the changes were not significant. Our results demonstrate that, in nondiabetic subjects at risk for diabetes, pioglitazone, but not metformin, significantly improved glucose tolerance by improving S(I) and S(G). We did not find any evidence that either pioglitazone or metformin improved beta-cell function. Improved beta-cell compensation was observed primarily in the subgroup of subjects that had the lowest S(I) at baseline.

Adult↗
PubMed2006

Dietary vitamin and lipid therapy rescues aberrant signaling and apoptosis and prevents hyperglycemia-induced diabetic embryopathy in rats.

OBJECTIVE: Maternal diabetes causes developmental malformations in the embryo. Dietary supplementation with antioxidants can reduce the malformation rates in animal models. To investigate the molecular mechanisms underlying diabetes-induced embryonic abnormalities and dietary interventions, activity of mitogen-activated protein kinases and factors associated with apoptotic pathways were examined in the maternal diabetic rat model. STUDY DESIGN: Diabetes was induced in pregnant rats using streptozotocin. In the yolk sacs of the embryos, activity of the extracellular signal-regulated kinases, Raf-1, and Akt was dramatically reduced in diabetic rats, whereas that of c-jun N-terminal kinases/stress-activated protein kinases was increased. RESULTS: When the diabetic dams were fed with arachidonic acid, vitamin E, or a combination of arachidonic acid, vitamin E, and myoinositol, the changes in the expression of these kinases were reversed and correlated with the decreases in the rates of apoptosis and embryonic malformations. CONCLUSION: These results suggest that mitogen-activated protein kinases are involved in diabetic embryopathy, and dietary supplementations can rescue the aberrant signaling pathways and reduce embryonic malformation rate.

Animals↗
PubMed2006

Characterization of differential gene expression profiles in diabetic embryopathy using DNA microarray analysis.

OBJECTIVE: The molecular mechanisms by which maternal diabetes impairs embryogenesis are not established. This study aimed to determine the developmental genes and molecular pathways that are involved in diabetic embryopathy, by comparing gene expression profiles in the yolk sacs between the embryos of diabetic and control rats by using DNA microarray analysis. STUDY DESIGN: Diabetes was induced in female rats by injecting streptozotocin (65 mg/kg) intravenously. Glucose levels were controlled by subcutaneously implanting insulin pellets. The female rats were mated with normal male rats. At gestation day 4, the insulin pellets were removed from a group of animals, making them hyperglycemic. The animals with insulin pellets served as controls. At gestational day 12, embryos were explanted, and yolk sacs were collected. Total RNA, free of DNA contamination, was extracted from the yolk sacs. Complementary DNA probes were synthesized, labeled with Cy3 and Cy5 fluorescent dyes, and used to hybridize rat oligo-array containing 10,000 genes. Data were analyzed by using 1-sample t test on log2 ratios, with P < .05 representing a significant difference. The changes in expression levels of important genes were verified with the use of a real-time polymerase chain reaction (PCR). RESULTS: Five microarray experiments produced consistent results. A total of 101 genes were found to be differentially expressed between the embryos of diabetic and control rats. Analyses that used PathwayAssist (Ariadne Genomics, Rockville, MD) revealed a number of potential signaling pathways and genes involved in insulin signaling and stress response (insulin 2, insulin-binding protein 1, GST pi1), cell growth (GAP43, CSF1R, HGF), calcium signaling (calbindin 3, CBP A6), and PKC signaling (PKCBP beta15, FABP5), in concert with prior biochemical and molecular findings. CONCLUSION: These observations show significant alterations in expression of developmental and stress response genes in diabetic embryopathy, and demonstrate, for the first time, that the yolk sac cells express insulin during early development. In addition, these data also demonstrate that hyperglycemia induces altered gene expression, resulting in aberrant cell signaling, morphogenesis, and embryopathy.

Animals↗
PubMed2006

Insulins and oral hypoglycemic agents in pregnancy.

Numerous studies have established a direct relationship between maternal levels of glycemic control and neonatal outcomes for pregnancies complicated by diabetes. The past several years have seen the addition of insulin analogues as well as many new oral agents to the pharmacological armamentarium available to treat diabetes. Insulin analogs (both rapid and long acting) are of potential interest for women with insulin-requiring diabetes because of the improved control reported in non-pregnant individuals. Insulin lispro is the only insulin analog to be systematically studied in pregnancy. At this time, the majority of evidence suggests that insulin lispro does not cross the placenta and does not have adverse maternal or fetal effects during pregnancy in women with diabetes. For women with gestational diabetes mellitus (GDM) and type 2 diabetes, which are characterized by insulin resistance and relatively decreased insulin secretion, treatment with oral hypoglycemic agents is generating much excitement. Most retrospective studies and the published clinical experience have failed to demonstrate an increased risk of neonatal hypoglycemia and other neonatal morbidities with glyburide or metformin. To date there has been only one randomized controlled trial utilizing glyburide, which found it to be safe and effective in the management of GDM. More intensive investigation regarding the safety and feasibility of oral agents in pregnancies complicated by type 2 diabetes is necessary.

Abnormalities, Drug-Induced↗
PubMed2006

Meeting the challenges facing clinical research: solutions proposed by leaders of medical specialty and clinical research societies.

The development of a robust national clinical research enterprise is needed to improve health care, but faces formidable challenges. To define the impediments and formulate solutions, the Institute of Medicine's Clinical Research Roundtable convened leaders from medical specialty and clinical research societies in 2003. Participants considered how to influence clinical research funding priorities, promote mechanisms to train physicians and other health care professionals to conduct clinical research, and how to encourage health care providers to follow evidence-based medical practice. Consensus emerged on multiple issues, including intersociety collaboration, the need for a core clinical research curriculum for training the new cadre of clinical researchers, joint advocacy for increased funding of clinical research and for the education of policymakers and the public on the benefits of clinical research. Specific recommendations were made on mechanisms for recruitment, training, and retention of clinical research trainees and mentors. Steps were outlined (1) to overcome career disincentives and develop appropriate reward systems for mentors and trainees, (2) to encourage use of web-based and continuing-medical-education-based mechanisms to bring practitioners up to date on issues in and results of clinical research, and (3) to create incentives for individuals, clinics, and hospitals to practice evidence-based medicine (EBM). Collectively, the response and proposed strategies can serve as a roadmap to improve clinical research funding and training, evidence-based medical practice, and health care quality.

Biomedical Research↗
PubMed2005

Nicotine-induced embryonic malformations mediated by apoptosis from increasing intracellular calcium and oxidative stress.

BACKGROUND: Tobacco smoking by women during pregnancy increases the risk of congenital birth defects in the infants. Among the smoke products, nicotine is believed to be the major teratogenic factor that perturbs embryonic development. However, the role of nicotine in embryonic malformations has not been addressed, and the mechanisms by which nicotine affects embryonic development remain to be delineated. METHODS: To investigate the effects of nicotine on early embryogenesis, murine embryos at embryonic day (E) 8.5 were dissected out of the uteri, cultured in a roller bottle system, and treated with nicotine (0.6-6 microM) or vehicle. Embryonic morphogenesis and growth were examined in terms of structural morphology and crown/rump length, respectively. Programmed cell death (apoptosis) was assessed using LysoTracker Red staining of whole mount embryos and TUNEL assay of tissue sections. Changes in intracellular calcium concentration ([Ca2+]i) and reactive oxygen species (ROS) production were assessed using fluorescent dyes (Flu-4, AM; H2DCFDA, respectively) under a confocal microscope. To further investigate the role of intracellular calcium and ROS in nicotine-induced embryopathy, embryos were treated with BAPTA-AM (2 microM) to inhibit [Ca2+]i elevation and ascorbic acid (vitamin C; 100 microg/ml) to scavenge ROS in presence of nicotine (6 microM). RESULTS: The embryos treated with nicotine in 3-6 microM were smaller than those treated with vehicle. Most of the embryos had open neural tube in the anterior (brain) regions. The embryos treated with 6 microM nicotine also exhibited severe defects in the posterior trunk, resembling caudal dysplasia. Excessive apoptosis was observed in the deformed structures. Significant increases in [Ca2+]i and ROS were seen in the tissues that had higher levels of apoptosis. Furthermore, inhibition of [Ca2+]i and scavenging of ROS significantly reduced embryonic malformation and apoptotic rates in the embryos. CONCLUSIONS: Nicotine affects embryonic development in a concentration-dependent manner. The nicotine-induced embryonic malformations are, in part, a result of excessive cell death. Nicotine increases [Ca2+]i and ROS level, which play a role in nicotine-induced embryonic apoptosis and malformations. These studies identify the molecular pathway of nicotine action in embryonic apoptosis and malformations, and provide a promising approach for ameliorating the teratogenic effects of nicotine.

Abnormalities, Drug-Induced↗
PubMed2005

Aberrant patterns of cellular communication in diabetes-induced embryopathy in rats: II, apoptotic pathways.

OBJECTIVE: The objective was to test the hypothesis that hyperglycemia-induced injury of yolk sac cell membranes is associated with disruption of cellular apoptotic signaling pathways. STUDY DESIGN: Pregnant rats were induced to become diabetic by injection of streptozotocin. Fourteen normal control and 24 diabetic rats were killed on day 12 of gestation. Yolk sac membranes in 3 conceptus groups (nondiabetic, diabetic with normal, or diabetic with malformed conceptus) were collected for study. DNA was extracted from yolk sac cells and assayed for fragmentation by using gel electrophoresis, which indicates apoptosis. Protein expression was evaluated by Western blot assays. Statistical analyses were performed with the Student t -test. RESULTS: The level of phosphorylated Akt was significantly decreased, whereas that of the proapoptotic protein Bax was increased. These changes were correlated with the presence of DNA fragmentation in yolk sac cells of the diabetic malformed conceptuses. CONCLUSION: Hyperglycemia-induced embryopathy involves apoptosis, during which the expression of proapoptotic protein Bax is upregulated and the activity of the cell-survival factor, Akt kinase, is decreased in yolk sac cells. These observations suggest that hyperglycemia of maternal diabetes triggers apoptotic signaling pathways and inhibits cell survival pathways, leading to embryonic malformations.

Animals↗
PubMed2005

Research agenda for preterm birth: recommendations from the March of Dimes.

Preterm birth (PTB) is a common, serious, and costly health problem affecting nearly 1 in 8 births in the United States. Burdens from PTB are especially severe for the very preterm infant (<32 weeks' gestation), comprising 2% of all US births. Successful prevention needs to include newly focused and adequately funded research, incorporating new technologies and recognition that genetic, environmental, social, and behavioral factors interact in complex pathogeneses and multiple pathways leading to PTB. The March of Dimes Scientific Advisory Committee created this prioritized research agenda, which is aimed at garnering serious attention and expanding resources to make major inroads into the prevention of PTB, targeting six major, overlapping categories: epidemiology, genetics, disparities, inflammation, biologic stress, and clinical trials. Analogous to other common, complex disorders, progress in prevention will require incorporating multipronged risk reduction strategies that are based on sound scientific discovery, as well as on effective translation into clinical care.

Charities↗
PubMed2005

Experimental mechanisms of diabetic embryopathy and strategies for developing therapeutic interventions.

A high frequency of birth defects is seen in infants born to diabetic mothers. The mechanisms by which maternal hyperglycemia, the major teratogenic factor, induces embryonic malformations remain to be addressed. It has been shown that increases in programmed cell death are one of the factors causing embryonic malformations. Hyperglycemia-induced apoptosis is associated with oxidative stress, lipid peroxidation, and decreased antioxidant defense capacity in the embryos. Recent studies have revealed that mitogen-activated protein kinases as intracellular signaling factors are involved in hyperglycemia-induced embryopathy. Based on the findings, interventions to prevent embryonic malformations have been explored. Strategies include supplementation of molecules that are deficient in the embryos under hyperglycemic conditions and antioxidants to alleviate the adverse effects of oxidative stress. The ultimate goal is to develop multi-nutrient dietary supplements to eliminate embryonic abnormalities induced by maternal diabetes.

Animals↗
PubMed2005

Creating a new structure for research on health care effectiveness.

Effectiveness research (a term we use in preference to the more confining and difficult health services or outcomes research) evaluates the clinical setting and the health care system on which it depends. It uses a variety of health care assessment techniques and the practical clinical trial to inform clinical practice, quality interventions, and health policy decisions. Effectiveness research had not had sufficient public or private funding to produce the information needed to facilitate evidence-based health care improvement. However, recent trends, such as the likelihood for continued substantial increases in health care costs and concern regarding the quality and safety of the US health care system, are among the important arguments for increasing its funding and capacity. We propose a new entity, a public-private consortium to expand and offer new capability and resources in this area. The consortium would consist of all relevant public and private entities. It would be organized into an executive committee, which would identify research priorities and panels to design requests for proposals. Competitive peer-reviewed proposals, transparency and balance of forces in choice of topics, conduct of research, and interpretation of results would be important features. Metrics for success would be use of the data derived from consortium projects in medical decision making and benefit design. The consortium would provide balance and potential mediation of conflicting or competing interests in which all stakeholders will be present to establish the rules. Broad representation of all interests would serve to avoid the economic, policy, and political issues that have bedeviled past efforts. Models for the consortium include the Health Effectiveness Institute, the Centers for Education and Research on Therapeutics, and the Transportation Research Board.

Clinical Competence↗
PubMed2004

Clinical research in the United States at a crossroads: proposal for a novel public-private partnership to establish a national clinical research enterprise.

The clinical research infrastructure of the United States is currently at a critical crossroads. To leverage the enormous biomedical research gains made in the past century efficiently, a drastic need exists to reengineer this system into a coordinated, safe, and more efficient and effective enterprise. To accomplish this task, clinical research must be transformed from its current state as a cottage industry to an enterprise-wide health care pipeline whose function is to bring the novel research from both government and private entities to the US public. We propose the establishment of a unique public-private partnership termed the National Clinical Research Enterprise (NCRE). Its agenda should consist of informed public participation, supportive information technologies, a skilled workforce, and adequate funding in clinical research. Devoting only 0.25% of the budgets from all health care stakeholders to support the NCRE would permit adequate funding to build the infrastructure required to address these problems in an enterprise fashion. All participants in the US health care delivery system must come together to focus on system-wide improvements that will benefit the public.

Academic Medical Centers↗
PubMed2004

[MAP kinase signal pathway in hyperglycemia-induced congenital neural tube defects].

The aim of the present study was to determine molecular mechanism in hyperglycemia-induced congenital neural tube defects and the its potential pharmacologic rescuing agents. In order to explore these questions, six study groups of Sprague-Dawley rats were employed: Group 1 was normal control rats with normal diet; group 2 represented streptozotocin (STZ) -induced diabetic rats with congenital neural tube defects in offspring; group 3 included STZ-induced diabetic rats with normal offspring; groups 4,5 and 6 included rats exposed to the same STZ-induced diabetic condition, but receiving daily oral supplementation of 80 microg/mL of the sodium salt of arachidonic acid (AA), 400mg of vitamin E and a cocktail of a polyunsaturated fatty acid (safflower oil) plus an antioxidant ( vitamin E) respectively. Yolk sac cells were harvested at gestational day 12 from each rat group. Changes in MAPK signaling pathways were detected by western blot analysis using special antibodies directed against phosphorylated forms of extracellular signal regulated kinase (ERK), Jun N-terminal/stress-activated protein kinase (JNK/SAPK). Furthermore, activity of RAF-1, an upstream kinase in ERK1/2 signaling cascade, was evaluated by immunoprecipitation assay. The results showed that in yolk sac cells in embryopathic offspring from experimentally-induced diabetic rats, activities of ERK1/2 were dramatically decreased (group 2). Consisted with these observation, reduction in RAF-1 kinase activity could be discerned in these diabetic yolk sac cells. In contrast, activities of JNK1/2 were significantly increased in yolk sac cells of group 2. Under rescuing circumstance,activations of ERK1/2 and RAF-1 were increased, and JNK1/2 were decreased. MAP kinase signal pathway plays a very important role in hyperglycemia induced neural tube defects. The supplementation of polyunsaturated fatty acid arachidonic acid, and antioxidant vitamin E rescued conceptuses from diabetic embryopathy by triggering a restoration of normal membrane signaling pathways.

Animals↗
PubMed2003

Central challenges facing the national clinical research enterprise.

Medical scientists and public health policy makers are increasingly concerned that the scientific discoveries of the past generation are failing to be translated efficiently into tangible human benefit. This concern has generated several initiatives, including the Clinical Research Roundtable at the Institute of Medicine, which first convened in June 2000. Representatives from a diverse group of stakeholders in the nation's clinical research enterprise have collaborated to address the issues it faces. The context of clinical research is increasingly encumbered by high costs, slow results, lack of funding, regulatory burdens, fragmented infrastructure, incompatible databases, and a shortage of qualified investigators and willing participants. These factors have contributed to 2 major obstacles, or translational blocks: impeding the translation of basic science discoveries into clinical studies and of clinical studies into medical practice and health decision making in systems of care. Considering data from across the entire health care system, it has become clear that these 2 translational blocks can be removed only by the collaborative efforts of multiple system stakeholders. The goal of this article is to articulate the 4 central challenges facing clinical research at present--public participation, information systems, workforce training, and funding; to make recommendations about how they might be addressed by particular stakeholders; and to invite a broader, participatory dialogue with a view to improving the overall performance of the US clinical research enterprise.

Biomedical Research↗