bluuebunny/crossref_metadata_2025 huggingface dataset:
Rhetoric as Character-Fashioning: The Implications of Delivery's “Places” in the British Renaissance Paideia
Authors: Christiansen Nancy L.
Published: February 2007

Abstract: Pronuntiatio teaches charaeter creation and analysis. Because the rhetorical curriculum in the British Renaissance considers pronuntiatio essential, retains the educational goal of facilitas, treats every “text” as a declamation, and depicts inventio, dispositio, elocutio, and memoria in behavioral metaphors with rules mirroring those of pronuntiatio, Renaissance rhetoric is in practice an art of behavior centrally concerned with decorum. This connection between Renaissance rhetoric and ethics suggests a defense for the claim that the good orator is the good man and expands the domain of rhetoric from an art of expression, composition, or persuasion to an art of character-fashioning.
Cicero, On Invention 1.51–77 Hypothetical Syllogistic and the Early Peripatetics
Authors: Fortenbaugh William W.
Published: February 2007

Abstract: In On Invention, Cicero discusses both induction and deduction. In regard to the latter, Cicero presents a controversy between those who advocate a five-part analysis of deductive reasoning and those who prefer three parts. The issue is not practical or pedagogical, but conceptual in nature. Cicero himself prefers analysis into five parts, and rather confusingly he presents the argument of the advocates of five parts as if it were his own. The argument is striking in that it makes elaborate use of mixed hypothetical syllogisms in order to argue for five parts. Cicero claims that the five-part analysis has been preferred by all who take their start from Aristotle and Theophrastus. A survey of what Theophrastus is reported to have said concerning the hypothetical syllogism renders Cicero's claim intelligible. That is not to say that Theophrastus himself advocated a five-part analysis. Most likely the association with him derives from his known interest in hypothetical syllogistic. Later rhetoricians who identified themselves with the Peripatos made the cormection with the founders of the school, thereby gaining authority for a controversial analysis.
“Non solum sibi sed aliis etiam”: Neoplatonism and Rhetoric in Saint Augustine's De doctrina Christiana
Authors: Camargo Martin
Published: February 2007

Abstract: In the Confessions (397-401) and On Christian Doctrine (396; 426), St. Augustine brackets Neoplatonic philosophy with Ciceronian rhetoric, finding the acknowledged value of each to be limited by an emphasis on individual achievement that is conducive to pride. His personal struggle to overcome such pride shaped his conception of Christian eloquence, which stresses humility through subordination to the scriptural text and service to others. The Christian orator, as defined by Augustine, is above all a teacher who embodies the biblical text, whether by using the “rule of charity” to paraphrase the truths found in Scripture, by simply repeating the actual words of the Bible, or by leading a life of charity that constitutes a kind of speech without words.
Cassiodorus's Commentary on the Psalms as an Ars rhetorica
Authors: Astell Ann W.
Published: February 2007

Abstract: The Commentary on the Psalms is the least studied of Cassiodorus's sixth-century works. Close knowledge of it significantly alters our understanding of the Introduction to Divine and Human Readings, with which it should be paired. The Commentary serves to establish the Bible as the source for all the liberal arts and a model for rhetorical imitation. This essay examines the eloquence Cassiodorus discovers in the Psalter, focussing in particular on those passages which he marked with the marginal notation for Rhetoric: RT. Cassiodorus finds examples of deliberative, demonstrative, and judicial oration in the Psalter. His elucidation of them does not simply preserve classical lore,but rather presents a sophisticated alternative to pagan theory and practice. A fuller understanding of Cassiodorus's view helps us to grasp his formative influence on medieval culture, rhetoric, and poetics.
Parrhesia: The Rhetoric of Free Speech in Early Modern England
Authors: Colclough David
Published: February 2007

Abstract: The understanding of free speech was, from fifth century Athens onwards, rhetorically coloured, and Greek uses of parrhesia and the definitions of licentia later set out in Roman handbooks are highly influential to sixteenth- and seventeenth-century English works on rhetoric and political advice. Consequently, discussions of liberty of speech in Elizabethan and Jacobean England can often be understood best if read with an eye to the conditions of deliberative rhetoric. Authors of rhetorical works in the sixteenth and seventeenth centuries were engaged in a complicated relationship of negotiation with sometimes apparentiy contradictory traditions when they defined parrhesia. Both traditions were used by speakers and writers concerned find ways of offering frank counsel to their superiors in the late sixteenth and early seventeenth centuries.
The “Perplexity” of George Campbell's Rhetoric: The Epistemic Function of Common Sense
Authors: Agnew Lois
Published: February 2007

Abstract: George Campbell's rhetorical theory is based upon a philosophical tradition that has ancient roots—common sense philosophy. Campbell's interest in common sense emerged through his association with Scottish Enlightenment philosophers such as Thomas Reid. However, Campbell's beliefs about the relationship between individual perception and social knowledge at the same time reveal a philosophical affinity with Aristotie and the Stoics. For Campbell, as for the ancients, common sense represents both the intuitive ability that individuals use in apprehending the reality of the external world and the shared human capacity to make necessary collective judgments. Although Campbell believes that there is objective truth that is apprehended through coinmon sense, he at the same time perceives common sense as providing a foundation for making decisions about the contingent circumstances that people face from day to day. Campbell's rhetoric has frequentiy been described as managerial, but his interest in common sense creates an epistemic function for rhetoric, as it provides the means for negotiating the principles of moral evidence in order to resolve the specific questions that arise in the life of the community.
Childhood Helicobacter pylori Infection and Growth Impairment in Developing Countries: A Vicious Cycle?
Authors: Windle Henry J. , Kelleher Dermot , Crabtree Jean E.
Published: February 2007

We hypothesize that infection with the gastric pathogen Helicobacter pylori in children in developing countries is the initiator of a vicious cycle of events that result ultimately in malnutrition and growth impairment. Acute infection with H pylori is accompanied by hypochlorhydria, which facilitates the acquisition of other enteropathogens because of removal of the gastric acid barrier, which then results in diarrheal disease and iron-deficiency anemia. This is likely to occur most frequently in developing regions where the prevalence of H pylori infection is disproportionately high and multiple enteric coinfections are common. The consequent synergistic impact of diarrheal disease and micronutrient deficiency on growth and cognitive function in children has significant public health implications for socioeconomic development in these countries.
An experimental investigation into the mechanical behaviour of a structured stiff clay
Authors: Amorosi A. , Rampello S.
Published: February 2007

In recent years, fundamental research has been carried out into the properties of some natural stiff clays and the corresponding reconstituted materials, highlighting the role of microstructural features in the observed differences. In this paper the results of an experimental investigation into the mechanical behaviour of an Italian stiff clay of marine origin are presented. Medium-pressure and high-pressure stress-controlled triaxial cells were used in which natural samples underwent isotropic and anisotropic compression and swelling before drained or undrained shearing. Comparison of soil behaviour observed after different compression histories up to different values of maximum effective stress allowed the following aspects to be discussed: the effects of the initially structured state on the medium to large strain response and shear strength characteristics of the soil; the relevance of volumetric and deviatoric plastic strain to the structure degradation; the role and implications of the imposed non-isotropic stress histories; the permanent differences between reconstituted samples and fully destructured natural samples; and the uniqueness of the critical state condition.
Structure and mechanical response of sub-Apennine Blue Clays in relation to their geological and recent loading history
Authors: Cotecchia F. , Cafaro F. , Aresta B.
Published: February 2007

The paper discusses the intrinsic properties, geological history, natural structure and mechanical behaviour of stiff Italian clays, part of the sub-Apennine Blue Clay formation, which are located at different sites within the marine basin where the clay formation was deposited in the early Pleistocene. For all the clay deposits being considered, diagenesis, unloading due to erosion, and weathering of the top strata represent the main stages of the geological history. However, the clays have undergone different levels of unloading, and have developed different levels of structure due to their different locations in the basin. These differences are accounted for in the analysis of their current states and behaviour. Based upon a large experimental database, the structure and mechanical behaviour of the clay samples from the different sites are compared and related to the clay history. In particular, the soil structure is characterised based upon SEM analysis results and compression–swelling test results. The comparison of the response to compression–swelling cycles of the natural clay with that of the same clay when reconstituted leads to the evaluation of parameters such as the stress sensitivity Sσ and the swell sensitivity C*s/Cs, which are used to assess the structural strength of the natural clay with respect to that of the reconstituted clay. The stress–strain behaviour of the different clays along different constant stress-ratio compression paths and shear paths (from low to high pressures) is discussed in detail. The variations in stress–strain response of samples subjected to different pre-shear consolidation paths are outlined. The corresponding trends of the plastic strain increment ratios are investigated. As a result of the analysis, the features of the gross yield curves of the different clay horizons are also assessed. Finally, the study provides elements for the characterisation of the hardening properties of stiff clays, and therefore of the evolution of the material anisotropy during plastic deformation.
In situ behaviour of a stiff layered clay subject to thermal loading: observations and interpretation
Authors: Gens A. , Vaunat J. , Garitte B. , Wileveau Y.
Published: February 2007

The paper presents an interpretation of an in situ heating test carried out on Opalinus clay in the Mont Terri underground laboratory. Opalinus clay is a stiff, strongly bedded, Mesozoic clay of marine origin. When subjected to thermal loading, saturated stiff clays exhibit a strong pore pressure response that significantly affects the hydraulic and mechanical behaviour of the material. The observations gathered in the in situ test have provided an opportunity to examine the integrated thermo-hydro-mechanical (THM) response of this sedimentary clay. Coupled THM numerical analyses have been carried out to provide a structured framework for interpretation, and to enhance understanding of THM clay behaviour. Numerical analyses have been based on a coupled theoretical formulation that incorporates a constitutive law especially developed for this type of material. The law includes degradation of bonding by damage. By performing three-dimensional computations, it has been possible to incorporate anisotropy of material parameters and of in situ stresses. The 3D simulation has proved able to furnish a satisfactory representation of the development of the in situ test and of the main observed patterns of behaviour. A sensitivity analysis has also been carried out to examine the potential effect of various key or uncertain parameters. The critical examination of test observations and the results of the numerical analyses have allowed the classification, by differing degrees of significance, of the various coupled phenomena present in the problem.
AMP-Activated Protein Kinase α2 Deficiency Affects Cardiac Cardiolipin Homeostasis and Mitochondrial Function
Authors: Athéa Yoni , Viollet Benoît , Mateo Philippe , Rousseau Delphine , Novotova Marta , Garnier Anne , Vaulont Sophie , Wilding James R. , Grynberg Alain , Veksler Vladimir , Hoerter Jacqueline , Ventura-Clapier Renée
Published: February 2007

AMP-activated protein kinase (AMPK) plays an important role in controlling energy homeostasis and is envisioned as a promising target to treat metabolic disorders. In the heart, AMPK is involved in short-term regulation and in transcriptional control of proteins involved in energy metabolism. Here, we investigated whether deletion of AMPKα2, the main cardiac catalytic isoform, alters mitochondrial function and biogenesis. Body weight, heart weight, and AMPKα1 expression were similar in control littermate and AMPKα2−/− mice. Despite normal oxygen consumption in perfused hearts, maximal oxidative capacity, measured using saponin permeabilized cardiac fibers, was ∼30% lower in AMPKα2−/− mice with octanoate, pyruvate, or glutamate plus malate but not with succinate as substrates, showing an impairment at complex I of the respiratory chain. This effect was associated with a 25% decrease in mitochondrial cardiolipin content, the main mitochondrial membrane phospholipid that is crucial for complex I activity, and with a 13% decrease in mitochondrial content of linoleic acid, the main fatty acid of cardiolipins. The decrease in cardiolipin content could be explained by mRNA downregulation of rate-limiting enzymes of both cardiolipin synthesis (CTP:PA cytidylyltransferase) and remodeling (acyl-CoA:lysocardiolipin acyltransferase 1). These data reveal a new role for AMPKα2 subunit in the regulation of cardiac muscle oxidative capacity via cardiolipin homeostasis.
Family History of Diabetes Links Impaired Substrate Switching and Reduced Mitochondrial Content in Skeletal Muscle
Authors: Ukropcova Barbara , Sereda Olga , de Jonge Lilian , Bogacka Iwona , Nguyen Tuong , Xie Hui , Bray George A. , Smith Steven R.
Published: February 2007

Insulin resistance is associated with metabolic inflexibility, impaired switching of substrate oxidation from fatty acids to glucose in response to insulin. Impaired switching to fat oxidation in response to a high-fat diet (HFD) is hypothesized to contribute to insulin resistance. The objective of this study was to test the hypothesis that defects in substrate switching in response to insulin and a HFD are linked to reduced mitochondrial biogenesis and occur before the development of diabetes. Metabolic flexibility was measured in young sedentary men with (n = 16) or without (n = 34) a family history of diabetes by euglycemic-hyperinsulinemic clamp. Flexibility correlated with fat oxidation measured in a respiratory chamber after a 3-day HFD. Muscle mitochondrial content was higher in flexible subjects with high fat oxidation after a HFD and contributed 49% of the variance. Subjects with a family history of diabetes were inflexible and had reduced HFD-induced fat oxidation and muscle mitochondrial content but did not differ in the amount of body or visceral fat. Metabolic inflexibility, lower adaptation to a HFD, and reduced muscle mitochondrial mass cluster together in subjects with a family history of diabetes, supporting the role of an intrinsic metabolic defect of skeletal muscle in the pathogenesis of insulin resistance.
Rapid Turnover of Phosphatidylinositol-4,5-Bisphosphate in Insulin-Secreting Cells Mediated by Ca2+ and the ATP-to-ADP Ratio
Authors: Thore Sophia , Wuttke Anne , Tengholm Anders
Published: February 2007

Phosphatidylinositol-4,5-bisphosphate (PIP2) is important for a variety of cellular processes as a precursor for second messengers and by regulating ion channels, the cytoskeleton, and vesicle traffic in many types of cells, including insulin-secreting β-cells. Here, we applied evanescent wave microscopy and the PIP2-binding pleckstrin homology domain from phospholipase C (PLC)-δ fused to the green fluorescent protein to characterize the regulation of plasma membrane PIP2 in individual insulin-secreting MIN6 β-cells. Elevation of the glucose concentration from 3 to 11 mmol/l evoked antisynchronous oscillations of [PIP2] and cytoplasmic Ca2+concentration, consistent with PLC being periodically activated by the voltage-dependent Ca2+ influx. The effect of adenine nucleotides on [PIP2] was studied in cells permeabilized with α-toxin. ATP dose- dependently stimulated PIP2 synthesis with half-maximal effect at 300 μmol/l. Omission of the nucleotide resulted in rapid loss of PIP2 with t1/2 < 40 s. ADP also stimulated PIP2 formation, but this effect reflected local ATP formation and was prevented by the adenylate kinase inhibitor diadenosine-pentaphosphate. The ATP-induced PIP2 synthesis was counteracted by the ADP analog adenosine-5′-O-2-thiodiphosphate. We conclude that plasma membrane PIP2 is dynamically regulated by intracellular Ca2+ and the ATP-to-ADP ratio in insulin-secreting cells. The rapid turnover allows maintenance of PIP2 levels while generating second messengers of critical importance for insulin secretion.
Anti-Inflammatory Effects of the Advanced Glycation End Product Inhibitor LR-90 in Human Monocytes
Authors: Figarola James L. , Shanmugam Narkunaraja , Natarajan Rama , Rahbar Samuel
Published: February 2007

Ligation of advanced glycation end products (AGEs) with their receptor (RAGE) plays an important role in the development of various diabetes complications, including atherosclerosis. Monocyte activation, adhesion, and migration are key events in the pathogenesis of atherosclerosis. Previous studies showed that AGEs and S100b, a specific RAGE ligand, could augment monocyte inflammatory responses via RAGE. In this study, we examined whether LR-90, a compound belonging to a new class of AGE inhibitor, could inhibit inflammatory responses in human monocytes. Human THP-1 cells were pretreated with LR-90 and then stimulated with S100b. LR-90 significantly inhibited S100b-induced expression of RAGE and other proinflammatory genes including monocyte chemoattractant protein-1, interferon-γ–inducible protein-10, and cyclooxygenase-2 in a dose-dependent manner. These inhibitory effects may be exerted via inhibition of nuclear factor-κB (NF-κB) activation, as LR-90 suppressed both S100b–and tumor necrosis factor-α–induced IκB-α degradation as well as NF-κB promoter transcriptional activity. LR-90 also prevented oxidative stress in activated monocytes, as demonstrated by its inhibitory effects on S100b-induced expression of NADPH oxidase and intracellular superoxide production. In addition, LR-90 blocked S100b-induced monocyte adhesion to human umbilical vein endothelial cell. These new data show that, in addition to its AGE inhibitory effects, LR-90 has novel anti-inflammatory properties and might therefore have additional protective effects against diabetic vascular complications.
Meta-Analysis of Genome-Wide Linkage Studies of Quantitative Lipid Traits in Families Ascertained for Type 2 Diabetes
Authors: Malhotra Alka , Elbein Steven C. , Ng Maggie C.Y. , Duggirala Ravindranath , Arya Rector , Imperatore Giuseppina , Adeyemo Adebowale , Pollin Toni I. , Hsueh Wen-Chi , Chan Juliana C.N. , Rotimi Charles , Hanson Robert L. , Hasstedt Sandra J. , Wolford Johanna K. ,   and the American Diabetes Association GENNID Study Group
Published: February 2007

Dyslipidemia is a major risk factor for coronary heart disease, which is the predominant cause of mortality in individuals with type 2 diabetes. To date, nine linkage studies for quantitative lipid traits have been performed in families ascertained for type 2 diabetes, individually yielding linkage results that were largely nonoverlapping. Discrepancies in linkage findings are not uncommon and are typically due to limited sample size and heterogeneity. To address these issues and increase the power to detect linkage, we performed a meta-analysis of all published genome scans for quantitative lipid traits conducted in families ascertained for type 2 diabetes. Statistically significant evidence (i.e., P < 0.00043) for linkage was observed for total cholesterol on 7q32.3-q36.3 (152.43–182 cM; P = 0.00004), 19p13.3-p12 (6.57–38.05 cM; P = 0.00026), 19p12-q13.13 (38.05–69.53 cM; P = 0.00001), and 19q13.13-q13.43 (69.53–101.1 cM; P = 0.00033), as well as LDL on 19p13.3-p12 (P = 0.00041). Suggestive evidence (i.e., P < 0.00860) for linkage was also observed for LDL on 19p12-q13.13, triglycerides on 7p11-q21.11 (63.72–93.29 cM), triglyceride/HDL on 7p11-q21.11 and 19p12-q13.13, and LDL/HDL on 16q11.2-q24.3 (65.2–130.4 cM) and 19p12-q13.13. Linkage for lipid traits has been previously observed on both chromosomes 7 and 19 in several unrelated studies and, together with the results of this meta-analysis, provide compelling evidence that these regions harbor important determinants of lipid levels in individuals with type 2 diabetes.
No Alterations in the Frequency of FOXP3+ Regulatory T-Cells in Type 1 Diabetes
Authors: Brusko Todd , Wasserfall Clive , McGrail Kieran , Schatz Richard , Viener Hilla Lee , Schatz Desmond , Haller Michael , Rockell Jennifer , Gottlieb Peter , Clare-Salzler Michael , Atkinson Mark
Published: February 2007

Regulatory T-cells (Tregs) play a critical role in maintaining dominant peripheral tolerance. Previous characterizations of Tregs in type 1 diabetes have used antibodies against CD4 and α-chain of the interleukin-2 receptor complex (CD25). This report extends those investigations by the addition of a more lineage-specific marker for Tregs, transcription factor forkhead box P3 (FOXP3), in subjects with type 1 diabetes, their first-degree relatives, and healthy control subjects. With inclusion of this marker, two predominant populations of CD4+CD25+ T-cells were identified: CD4+CD25+FOXP3+ as well as CD4+FOXP3− T-cells expressing low levels of CD25 (CD4+CD25LOWFOXP3−). In all study groups, the frequency of CD4+CD25+FOXP3+ cells was age independent, whereas CD4+CD25LOWFOXP3− cell frequencies strongly associated with age. In terms of additional markers for delineating cells of Treg lineage, FOXP3+ cells were CD127− to CD127LOW whereas CD25+ cells were less restricted in their expression of this marker, with CD127 expressed across a continuum of levels. Importantly, no differences were observed in the frequency of CD4+CD25+FOXP3+ T-cells in individuals with or at varying degrees of risk for type 1 diabetes. These investigations suggest that altered peripheral blood frequencies of Tregs, as defined by the expression of FOXP3, are not specifically associated with type 1 diabetes and continue to highlight age as an important variable in analysis of immune regulation.
Activating Transcription Factor 6 (ATF6) Sequence Polymorphisms in Type 2 Diabetes and Pre-Diabetic Traits
Authors: Chu Winston S. , Das Swapan Kumar , Wang Hua , Chan Juliana C. , Deloukas Panos , Froguel Philippe , Baier Leslie J. , Jia Weiping , McCarthy Mark I. , Ng Maggie C.Y. , Damcott Coleen , Shuldiner Alan R. , Zeggini Eleftheria , Elbein Steven C.
Published: February 2007

Activating transcription factor 6 (ATF6) is located within the region of linkage to type 2 diabetes on chromosome 1q21-q23 and is a key activator of the endoplasmic reticulum stress response. We evaluated 78 single nucleotide polymorphisms (SNPs) spanning >213 kb in 95 people, from which we selected 64 SNPs for evaluation in 191 Caucasian case subjects from Utah and between 165 and 188 control subjects. Six SNPs showed nominal associations with type 2 diabetes (P = 0.001–0.04), including the nonsynonymous SNP rs1058405 (M67V) in exon 3 and rs11579627 in the 3′ flanking region. Only rs1159627 remained significant on permutation testing. The associations were not replicated in 353 African-American case subjects and 182 control subjects, nor were ATF6 SNPs associated with altered insulin secretion or insulin sensitivity in nondiabetic Caucasian individuals. No association with type 2 diabetes was found in a subset of 44 SNPs in Caucasian (n = 2,099), Pima Indian (n = 293), and Chinese (n = 287) samples. Allelic expression imbalance was found in transformed lymphocyte cDNA for 3′ untranslated region variants, thus suggesting cis-acting regulatory variants. ATF6 does not appear to play a major role in type 2 diabetes, but further work is required to identify the cause of the allelic expression imbalance.
Endothelin Limits Insulin Action in Obese/Insulin-Resistant Humans
Authors: Lteif Amale , Vaishnava Prashant , Baron Alain D. , Mather Kieren J.
Published: February 2007

The normal action of insulin to vasodilate and redistribute blood flow in support of skeletal muscle metabolism is impaired in insulin-resistant states. Increased endogenous endothelin contributes to endothelial dysfunction in obesity and diabetes. Here, we test the hypothesis that increased endogenous endothelin action also contributes to skeletal muscle insulin resistance via impairments in insulin-stimulated vasodilation. We studied nine lean and seven obese humans, measuring the metabolic and hemodynamic effects of insulin (300 mU · m−2 · min−1) alone and during femoral artery infusion of BQ123 (an antagonist of type A endothelin receptors, 1 μmol/min). Endothelin antagonism augmented skeletal muscle responses to insulin in obese subjects through changes in both leg blood flow (LBF) and glucose extraction. Insulin-stimulated LBF was significantly increased in obese subjects only. These changes, combined with differential effects on glucose extraction, resulted in augmented insulin-stimulated leg glucose uptake in obese subjects (54.7 ± 5.7 vs. 107.4 ± 18.9 mg/min with BQ123), with no change in lean subjects (103.7 ± 11.4 vs. 88.9 ± 16.3, P = 0.04 comparing BQ123 across groups). BQ123 allowed augmented leg glucose extraction in obese subjects even in the face of NOS antagonism. These findings suggest that increased endogenous endothelin action contributes to insulin resistance in skeletal muscle of obese humans, likely through both vascular and tissue effects.
CD8+ T-Cell Responses Identify β-Cell Autoimmunity in Human Type 1 Diabetes
Authors: Mallone Roberto , Martinuzzi Emanuela , Blancou Philippe , Novelli Giulia , Afonso Georgia , Dolz Manuel , Bruno Graziella , Chaillous Lucy , Chatenoud Lucienne , Bach Jean-Marie , van Endert Peter
Published: February 2007

Despite the understanding that type 1 diabetes pathogenesis is mediated by T-cells, detection of these rare lymphocytes remains largely elusive. Suitable T-cell assays are highly needed, since they could offer preclinical diagnoses and immune surrogate end points for clinical trials. Although CD4+ T-cell assays have met with limited success, CD8+ T-cells are increasingly recognized as key actors in the diabetes of the NOD mouse. CD8+ T-cells are likely to play a role also in humans and may provide new markers of β-cell autoimmunity. Taking advantage of a panel of HLA-A2–restricted β-cell epitopes derived from preproinsulin, GAD, and islet glucose-6-phosphatase catalytic subunit-related protein (IGRP), we have implemented an islet-specific CD8+ T-cell interferon-γ enzyme-linked immunospot (ISL8Spot) assay. The ISL8Spot assay is capable of detecting and quantifying β-cell–reactive CD8+ T-cells directly ex vivo, without any preliminary expansion, using either fresh or frozen samples. Positive ISL8Spot responses separate new-onset diabetic and healthy samples with high accuracy (86% sensitivity, 91% specificity), using as few as five immunodominant epitopes. Moreover, sensitivity reaches 100% when the ISL8Spot assay is complemented by antibody determinations. Combination of CD8+ T-cell measurements with immune intervention strategies may open new avenues toward type 1 diabetes prediction and prevention.
No Evidence for Mouse Pancreatic β-Cell Epithelial-Mesenchymal Transition In Vitro
Authors: Atouf Fouad , Park Cheol Hong , Pechhold Klaus , Ta Malancha , Choi Yong , Lumelsky Nadya L.
Published: February 2007

We used cre/loxP-based genetic lineage tracing analysis to test a previously proposed hypothesis that in vitro cultured adult pancreatic β-cells undergo epithelial-mesenchymal transition (EMT) to generate a highly proliferative, differentiation-competent population of mesenchymal islet “progenitor” cells. Our results in the mouse that are likely to be directly relevant to the human system show that adult mouse β-cells do not undergo EMT in vitro and that the mesenchymal cells that arise in cultures of adult pancreas are not derived from β-cells. We argue that these cells most likely originate from expansion of mesenchymal cells integral to the heterogeneous pancreatic islet preparations. As such, these mesenchymal “progenitors” might not represent the best possible source for generation of physiologically competent β-cells for treatment of diabetes.
Limited Capacity of Human Adult Islets Expanded In Vitro to Redifferentiate Into Insulin-Producing β-Cells
Authors: Kayali Ayse G. , Flores Luis E. , Lopez Ana D. , Kutlu Burak , Baetge Emmanuel , Kitamura Ryuichi , Hao Ergeng , Beattie Gillian M. , Hayek Alberto
Published: February 2007

Limited organ availability is an obstacle to the widespread use of islet transplantation in type 1 diabetic patients. To address this problem, many studies have explored methods for expanding functional human islets in vitro for diabetes cell therapy. We previously showed that islet cells replicate after monolayer formation under the influence of hepatocyte growth factor and selected extracellular matrices. However, under these conditions, senescence and loss of insulin expression occur after >15 doublings. In contrast, other groups have reported that islet cells expanded in monolayers for months progressed through a reversible epithelial-to-mesenchymal transition, and that on removal of serum from the cultures, islet-like structures producing insulin were formed (1). The aim of the current study was to compare the two methods for islet expansion using immunostaining, real-time quantitative PCR, and microarrays at the following time points: on arrival, after monolayer expansion, and after 1 week in serum-free media. At this time, cell aliquots were grafted into nude mice to study in vivo function. The two methods showed similar results in islet cell expansion. Attempts at cell differentiation after expansion by both methods failed to consistently recover a β-cell phenotype. Redifferentiation of β-cells after expansion is still a challenge in need of a solution.
Effects of Medical Therapy on Insulin Resistance and the Cardiovascular System in Polycystic Ovary Syndrome
Authors: Meyer Caroline , McGrath Barry P. , Teede Helena Jane
Published: February 2007

OBJECTIVE—We aimed to determine the impact of medical therapy for symptom management on insulin resistance, metabolic profiles, and surrogate markers of cardiovascular disease in polycystic ovary syndrome (PCOS), an insulin-resistant pre-diabetes condition.

RESEARCH DESIGN AND METHODS—One hundred overweight women (BMI >27 kg/m2), average age 31 years, who were nonsmokers, were not pregnant, did not have diabetes, and were off relevant medications for 3 months completed this 6-month open-label controlled trial. Randomization was to a control group (higher-dose oral contraceptive [OCP] 35 μg ethinyl estradiol [EE]/2 mg cyproterone acetate, metformin [1 g b.d.] or low-dose OCP [20 μg EE/100 μg levonorgestrel + aldactone 50 mg b.d.]). Primary outcome measures were insulin resistance (area under curve on oral glucose tolerance test) and surrogate markers of cardiovascular disease including arterial stiffness (pulse wave velocity [PWV]) and endothelial function.

RESULTS—All treatments similarly and significantly improved symptoms including hirsutism and menstrual cycle length. Insulin resistance was improved by metformin and worsened by the high-dose OCP. Arterial stiffness worsened in the higher-dose OCP group (PWV 7.46 vs. 8.03 m/s, P < 0.05), related primarily to the increased insulin resistance.

CONCLUSIONS—In overweight women with PCOS, metformin and low- and high-dose OCP preparations have similar efficacy but differential effects on insulin resistance and arterial function. These findings suggest that a low-dose OCP preparation may be preferable if contraception is needed and that metformin should be considered for symptomatic management, particularly in women with additional metabolic and cardiovascular risk factors.
Circulating Soluble Transferrin Receptor According to Glucose Tolerance Status and Insulin Sensitivity
Authors: Fernández-Real José Manuel , Moreno José Maria , López-Bermejo Abel , Chico Berta , Vendrell Joan , Ricart Wifredo
Published: February 2007

OBJECTIVE—The relationships between iron metabolism and type 2 diabetes are bidirectional: iron affects glucose metabolism and glucose metabolism impinges on several iron metabolic pathways. The mechanisms of these interactions depend on poorly known factors. We aimed to study the contribution of the serum soluble transferrin receptor (sTfR).

RESEARCH DESIGN AND METHODS—Circulating sTfR was evaluated in 221 men (97 with normal glucose tolerance [NGT], 36 with impaired glucose tolerance, and 88 with type 2 diabetes). In a subset of these subjects, glucose tolerance (oral glucose tolerance test [OGTT]), minimal model–derived insulin sensitivity, and sTfR during the OGTT were also evaluated.

RESULTS—Men with altered glucose tolerance showed significantly increased sTfR (9.4 ± 4.4 vs. 8.2 ± 2.6 μg/ml, P = 0.02) and higher serum ferritin than men with NGT. Serum sTfR was negatively associated with serum ferritin (r = −0.16, P = 0.02). sTfR correlated with several clinical and metabolic variables such as systolic blood pressure, glycated hemoglobin, and glucose and insulin values during OGTT. Insulin sensitivity was also negatively associated with sTfR in NGT and nonobese subjects. BMI (P = 0.01), serum ferritin (P = 0.025), and insulin sensitivity (P < 0.0001) contributed independently to 21% of sTfR variance. Serum sTfR concentration did not significantly change during the OGTT.

CONCLUSIONS—Both insulin sensitivity and glucose tolerance status are significantly associated with serum sTfR concentrations, although insulin sensitivity predicts independently circulating sTfR, mainly in subjects with NGT. The implications of the interrelationships between iron and glucose metabolism should be investigated further.
Does Dairy Calcium Intake Enhance Weight Loss Among Overweight Diabetic Patients?
Authors: Shahar Danit R. , Abel Relly , Elhayany Asher , Vardi Hillel , Fraser Drora
Published: February 2007

OBJECTIVE—To examine the effect of dairy calcium consumption on weight loss and improvement in cardiovascular disease (CVD) and diabetes indicators among overweight diabetic patients.

RESEARCH DESIGN AND METHODS—This was an ancillary study of a 6-month randomized clinical trial assessing the effect of three isocaloric diets in type 2 diabetic patients: 1) mixed glycemic index carbohydrate diet, 2) low–glycemic index diet, and 3) modified Mediterranean diet. Low-fat dairy product consumption varied within and across the groups by personal choice. Dietary intake, weight, CVD risk factors, and diabetes indexes were measured at baseline and at 6 months.

RESULTS—A total of 259 diabetic patients were recruited with an average BMI >31 kg/m2 and mean age of 55 years. No difference was found at baseline between the intervention groups in CVD risk factors, diabetes indicators, macronutrient intake, and nutrient intake from dairy products. Dairy calcium intake was associated with percentage of weight loss. Among the high tertile of dairy calcium intake, the odds ratio for weight loss of >8% was 2.4, P = 0.04, compared with the first tertile, after controlling for nondairy calcium intake, diet type, and the change in energy intake from baseline. No association was noted between dairy calcium and other health indexes except for triglyceride levels.

CONCLUSIONS—A diet rich in dairy calcium intake enhances weight reduction in type 2 diabetic patients. Such a diet could be tried in diabetic patients, especially those with difficulty adhering to other weight reduction diets.
Circulating Visfatin Is Associated With Parameters of Iron Metabolism in Subjects With Altered Glucose Tolerance
Authors: Fernández-Real José Manuel , Moreno José María , Chico Berta , López-Bermejo Abel , Ricart Wifredo
Published: February 2007

OBJECTIVE—Visfatin is a novel adipokine that is predominantly secreted by visceral adipose tissue. Accumulation of visceral adipose tissue is also associated with iron metabolism. Despite the coincidence of visfatin expression in iron-rich tissues, no study has investigated the possible interaction of visfatin with parameters of iron metabolism.

RESEARCH DESIGN AND METHODS—We evaluated insulin sensitivity and parameters of iron metabolism in 95 men with normal glucose tolerance (NGT) and 43 men with altered glucose tolerance.

RESULTS—Men with newly diagnosed type 2 diabetes had significantly increased serum visfatin in parallel with increased serum prohepcidin and serum ferritin compared with the other groups. In all subjects as a whole, circulating visfatin was not found to be significantly linked to insulin sensitivity (r = 0.07, P = 0.4) but was significantly associated with serum prohepcidin concentration (r = 0.40, P < 0.0001). Obesity status and glucose tolerance status influenced the relationships among visfatin, insulin sensitivity, and parameters of iron metabolism. Among men with altered glucose tolerance, serum visfatin was strongly associated with serum prohepcidin (r = 0.61, P < 0.0001) and serum soluble transferrin receptor (sTfR) (r = −0.51, P < 0.0001). In nonobese subjects, sTfR (P = 0.02) and prohepcidin (P = 0.04) contributed independently to visfatin variance after controlling for age and BMI. When insulin sensitivity was added to the model, only the latter (P = 0.006) contributed to 17% of visfatin variance. In obese men, however, only sTfR (P = 0.04) contributed independently to visfatin variance in this latter model.

CONCLUSIONS—Serum visfatin concentration is significantly associated with parameters of iron metabolism, especially in subjects with altered glucose tolerance.
Randomized Trial of Behavioral Family Systems Therapy for Diabetes
Authors: Wysocki Tim , Harris Michael A. , Buckloh Lisa M. , Mertlich Debbie , Lochrie Amanda S. , Mauras Nelly , White Neil H.
Published: February 2007

OBJECTIVE—Studies showing that family communication and conflict resolution are critical to effective management of type 1 diabetes in adolescents have stimulated interest in evaluating psychological treatments targeting these processes. Previous trials have shown that Behavioral Family Systems Therapy (BFST) improved parent-adolescent relationships but not treatment adherence or glycemic control. This study evaluates a revised intervention, BFST for Diabetes (BFST-D), modified to achieve greater impact on diabetes-related family conflict, treatment adherence, and metabolic control.

RESEARCH DESIGN AND METHODS—A sample of 104 families of adolescents with inadequate control of type 1 diabetes was randomized to either remain in standard care (SC) or to augmentation of that regimen by 12 sessions of either a multifamily educational support (ES) group or 12 sessions of BFST-D over 6 months. Pertinent measures were collected at baseline and at follow-up evaluations at 6, 12, and 18 months.

RESULTS—BFST-D was significantly superior to both SC and ES in effects on A1C, while effects on treatment adherence and family conflict were equivocal. Improvement in A1C appeared to be mediated by improvement in treatment adherence. A significantly higher percentage of BFST-D youth achieved moderate or greater improvement (>0.5 SD) in treatment adherence compared with the SC group at each follow-up and the ES group at 6 and 18 months. Change in treatment adherence correlated significantly with change in A1C at each follow-up.

CONCLUSIONS—These results support the efficacy of BFST-D in improving A1C, but further research is needed to identify the mechanisms of this effect and to achieve cost-effective dissemination of the intervention.
Clinical Depression Versus Distress Among Patients With Type 2 Diabetes
Authors: Fisher Lawrence , Skaff Marilyn M. , Mullan Joseph T. , Arean Patricia , Mohr David , Masharani Umesh , Glasgow Russell , Laurencin Grace
Published: February 2007

OBJECTIVE—We sought to determine differences between structured interviews, symptom questionnaires, and distress measures for assessment of depression in patients with diabetes.

RESEARCH DESIGN AND METHODS—We assessed 506 diabetic patients for major depressive disorder (MDD) by a structured interview (Composite International Diagnostic Interview [CIDI]), a questionnaire for depressive symptoms (Center for Epidemiological Studies Depression Scale [CESD]), and on the Diabetes Distress Scale. Demographic characteristics, two biological variables (A1C and non-HDL cholesterol), and four behavioral management measures (kilocalories, calories of saturated fat, number of fruit and vegetable servings, and minutes of physical activity) were assessed. Comparisons were made between those with and without depression on the CIDI and the CESD.

RESULTS—Findings showed that 22% of patients reached CESD ≥16, and 9.9% met a CIDI diagnosis of MDD. Of those above CESD cut points, 70% were not clinically depressed, and 34% of those who were clinically depressed did not reach CESD scores ≥16. Those scoring ≥16, compared with those <16 on the CESD, had higher A1C, kilocalories, and calories of saturated fat and lower physical activity. No differences were found using the CIDI. Diabetes distress was minimally related to MDD but substantively linked to CESD scores and to outcomes.

CONCLUSIONS—Most patients with diabetes and high levels of depressive symptoms are not clinically depressed. The CESD may be more reflective of general emotional and diabetes-specific distress than clinical depression. Most treatment of distress, however, is based on the depression literature, which suggests the need to consider different interventions for distressed but not clinically depressed diabetic patients.
Serum Zinc Level and Coronary Heart Disease Events in Patients With Type 2 Diabetes
Authors: Soinio Minna , Marniemi Jukka , Laakso Markku , Pyörälä Kalevi , Lehto Seppo , Rönnemaa Tapani
Published: February 2007

OBJECTIVE—Low serum zinc level may predispose nondiabetic subjects to cardiovascular diseases. Our aim was to investigate whether serum zinc level predicts coronary heart disease (CHD) events in subjects with type 2 diabetes

RESEARCH DESIGN AND METHODS—The original study population consisted of 1,059 patients with type 2 diabetes, aged 45–64 years. Mean duration of diabetes was 8 years. Serum zinc values were available from 1,050 subjects. CHD mortality and the incidence of nonfatal myocardial infarction (MI) were assessed in a 7-year follow-up.

RESULTS—During the follow-up, 156 patients died from CHD and 254 patients had a fatal or nonfatal MI. Patients with serum zinc concentration ≤14.1 μmol/l at baseline had a higher risk for death from CHD than patients with serum zinc level >14.1 μmol/l (20.8 and 12.8%, respectively; P = 0.001) The risks for fatal or nonfatal MI were 30.5 and 22.0%, respectively (P = 0.005). In Cox regression analyses, low serum zinc concentration was significantly associated with CHD mortality (relative risk [RR] 1.7, P = 0.002) and all CHD events (RR 1.37, P = 0.030), even after adjustment for confounding variables.

CONCLUSIONS—In this large cohort of type 2 diabetic patients, low serum zinc level was an independent risk factor for CHD events.
Perceptions of Psychosocial Factors and the Insulin Pump
Authors: Ritholz Marilyn D. , Smaldone Arlene , Lee Jarim , Castillo Astrid , Wolpert Howard , Weinger Katie
Published: February 2007

OBJECTIVE—The purpose of this study was to identify psychosocial issues related to diabetes, approaches to self-care, self-perceptions, and social interactions among insulin pump users with type 1 diabetes.

RESEARCH DESIGN AND METHODS—Adult insulin pump users participated in focus groups loosely formed on the basis of A1C level. Transcripts of focus group meetings were coded into themes by five reviewers using NVivo2 qualitative software.

RESULTS—Thirty adults with long-term diabetes participated in five focus groups: two with low mean ±SD A1C (6.8 ± 0.4%), one with mid A1C (7.80 ± 0.3%), and two with high A1C (9.1 ± 0.5%). Three major themes were identified: impact on diabetes self-care, emotional reactions to the insulin pump, body image, and social acceptance. Participants who described the pump as a tool to meet glycemic goals also described a more active approach to diabetes and had better glycemic control; those who discussed the pump as a panacea described more passive self-care and had poorer glycemic control. Low A1C groups reported that starting the insulin pump reminded them of feelings they experienced at their initial diabetes diagnosis, whereas the high A1C groups did not report these feelings. Women were more concerned than men about body image and social acceptance with pump use.

CONCLUSIONS—Active participation in self-care, realistic expectations of pump use, and emotional recall of diabetes diagnosis were associated with better glycemic control. Interventions to improve diabetes management with pump use should include evaluation and discussion of active versus passive approaches to self-care, recall of diabetes diagnosis, expectations of the pump, and pump-related self-consciousness and body image concerns. The roles of these factors in optimal diabetes management warrant further investigation.
Progressive Loss of β-Cell Function Leads to Worsening Glucose Tolerance in First-Degree Relatives of Subjects With Type 2 Diabetes
Authors: Cnop Miriam , Vidal Josep , Hull Rebecca L. , Utzschneider Kristina M. , Carr Darcy B. , Schraw Todd , Scherer Philipp E. , Boyko Edward J. , Fujimoto Wilfred Y. , Kahn Steven E.
Published: February 2007

OBJECTIVE—The relative roles of insulin resistance and β-cell dysfunction in the pathogenesis of impaired glucose tolerance (IGT) and type 2 diabetes are debated. First-degree relatives of individuals with type 2 diabetes are at increased risk of developing hyperglycemia.

RESEARCH DESIGN AND METHODS—We evaluated the evolution of insulin sensitivity, β-cell function, glucose effectiveness, and glucose tolerance over 7 years in 33 nondiabetic, first-degree relatives of type 2 diabetic individuals using frequently sampled tolbutamide-modified intravenous and oral glucose tolerance tests.

RESULTS—Subjects gained weight, and their waist circumference increased (P < 0.05). Insulin sensitivity, the acute insulin response to glucose, and glucose effectiveness did not change significantly. However, when we accounted for the modulating effect of insulin sensitivity on insulin release, β-cell function determined as the disposition index decreased by 22% (P < 0.05). This decrease was associated with declines in intravenous and oral glucose tolerance (P < 0.05 and P < 0.001, respectively). Of the subjects with normal glucose tolerance at the first assessment, we compared those who progressed to IGT with those who did not. The disposition index was 50% lower in the progressors than in the nonprogressors at follow-up (P < 0.05).

CONCLUSIONS—The decline in glucose tolerance over time in first-degree relatives of type 2 diabetic individuals is strongly related to the loss of β-cell function. Thus, early interventions to slow the decline in β-cell function should be considered in high-risk individuals.