bluuebunny/crossref_metadata_2025 huggingface dataset:
Glycogen Phosphorylase Inhibition in Type 2 Diabetes Therapy
Authors: Baker David J. , Timmons James A. , Greenhaff Paul L.
Published: March 2007

Inhibition of hepatic glycogen phosphorylase is a promising treatment strategy for attenuating hyperglycemia in type 2 diabetes. Crystallographic studies indicate, however, that selectivity between glycogen phosphorylase in skeletal muscle and liver is unlikely to be achieved. Furthermore, glycogen phosphorylase activity is critical for normal skeletal muscle function, and thus fatigue may represent a major development hurdle for this therapeutic strategy. We have carried out the first systematic evaluation of this important issue. The rat gastrocnemius-plantaris-soleus (GPS) muscle was isolated and perfused with a red cell suspension, containing 3 μmol/l glycogen phosphorylase inhibitor (GPi) or vehicle (control). After 60 min, the GPS muscle was snap-frozen (rest, n = 11 per group) or underwent 20 s of maximal contraction (n = 8, control; n = 9, GPi) or 10 min of submaximal contraction (n = 10 per group). GPi pretreatment reduced the activation of the glycogen phosphorylase a form by 16% at rest, 25% after 20 s, and 44% after 10 min of contraction compared with the corresponding control. AMP-mediated glycogen phosphorylase activation was impaired only at 10 min (by 21%). GPi transiently reduced muscle lactate production during contraction, but other than this, muscle energy metabolism and function remained unaffected at both contraction intensities. These data indicate that glycogen phosphorylase inhibition aimed at attenuating hyperglycaemia is unlikely to negatively impact muscle metabolic and functional capacity.
Galanin-Like Peptide Rescues Reproductive Function in the Diabetic Rat
Authors: Stoyanovitch Angela G. , Johnson Marlie A. , Clifton Donald K. , Steiner Robert A. , Fraley Gregory S.
Published: March 2007

Galanin-like peptide (GALP) is expressed in the hypothalamic arcuate nucleus and is regulated by leptin and insulin. Centrally administered GALP stimulates gonadotropin secretion and sexual behavior in the rat. Type 1 diabetes is associated with reduced expression of GALP, as well as an overall decline in reproductive function. We postulated that tonic activity of GALP in the brain is required to sustain normal reproductive activity. To test this hypothesis, we examined whether central (intracerebroventricular) immunoblockade of GALP would reduce sexual behaviors and serum levels of luteinizing hormone (LH) in normal adult male rats. We found that GALP antibody reversibly reduced serum levels of LH and abolished male sexual behaviors (P < 0.05 and 0.001, respectively). Second, we tested whether intracerebroventricular GALP could restore normal plasma LH levels and sexual behavior in diabetic animals. We compared groups of diabetic rats that received intracerebroventricular GALP or vehicle and found that GALP increased serum levels of LH and sexual behavior. Third, we examined whether intracerebroventricular administration of affinity-purified GALP antibody could block the effect of insulin and leptin in reversing the effects of diabetes on LH and sexual behavior. We found that treatment of diabetic animals with insulin and leptin nearly normalized LH levels and sexual behaviors; however, this effect was attenuated by intracerebroventricular administration of GALP antibody (P < 0.05). These observations demonstrate that endogenous GALP provides trophic support to the neuroendocrine reproductive axis, including sexual behavior.
A Large-Scale Association Analysis of Common Variation of the HNF1α Gene With Type 2 Diabetes in the U.K. Caucasian Population
Authors: Weedon Michael N. , Owen Katharine R. , Shields Beverley , Hitman Graham , Walker Mark , McCarthy Mark I. , Hattersley Andrew T. , Frayling Timothy M.
Published: March 2007

HNF1α (TCF1) is a key transcription factor that is essential for pancreatic β-cell development and function. Rare mutations of HNF1α cause maturity-onset diabetes of the young. A common variant, G319S, private to the Oji-Cree population, predisposes to type 2 diabetes, but the role of common HNF1α variation in European populations has not been comprehensively assessed. We determined the linkage disequilibrium and haplotype structure across the HNF1α gene region using 29 single nucleotide polymorphisms (SNPs). Eight tagging SNPs (tSNPs) that efficiently capture common haplotypes and the amino acid–changing variant, A98V, were genotyped in 5,307 subjects (2,010 type 2 diabetic case subjects, 1,643 control subjects, and 1,654 members of 521 families). We did not find any evidence of association between the tSNPs or haplotypes and type 2 diabetes. We could exclude odds ratios (ORs) >1.25 for all tSNPs. The rare V98 allele (∼3% frequency) showed possible evidence of association with type 2 diabetes (OR 1.23 [95% CI 0.99–1.54], P = 0.07), a result that was supported by meta-analysis of this and published studies (OR 1.31 [1.08–1.59], P = 0.007). Further studies are required to investigate this association, demonstrating the difficulty of defining the role of rare (<5%) alleles in type 2 diabetes risk.
Essential Role for Membrane Lipid Rafts in Interleukin-1β−Induced Nitric Oxide Release From Insulin-Secreting Cells
Authors: Veluthakal Rajakrishnan , Chvyrkova Irina , Tannous Marie , McDonald Phillip , Amin Rajesh , Hadden Timothy , Thurmond Debbie C. , Quon Michael J. , Kowluru Anjaneyulu
Published: March 2007

We recently reported that the activation of H-Ras represents one of the signaling steps underlying the interleukin-1β (IL-1β)−mediated metabolic dysfunction of the islet β-cell. In the present study, we examined potential contributory roles of membrane-associated, cholesterol-enriched lipid rafts/caveolae and their constituent proteins (e.g., caveolin-1 [Cav-1]) as potential sites for IL-1β−induced nitric oxide (NO) release in the isolated β-cell. Disruption of lipid rafts (e.g., with cyclodextrin) markedly reduced IL-1β−induced gene expression of inducible NO synthase (iNOS) and NO release from β-cells. Immunologic and confocal microscopic evidence also suggested a transient but significant stimulation of tyrosine phosphorylation of Cav-1 in β-cells briefly (for 15 min) exposed to IL-1β that was markedly attenuated by three structurally distinct inhibitors of protein tyrosine phosphorylation. Overexpression of an inactive mutant of Cav-1 lacking the tyrosine phosphorylation site (Y14F) or an siRNA-mediated Cav-1 knock down also resulted in marked attenuation of IL-1β–induced iNOS gene expression and NO release from these cells, thus further implicating Cav-1 in this signaling cascade. IL-1β treatment also increased (within 20 min) the translocation of H-Ras into lipid rafts. Here we provide the first evidence to suggest that tyrosine phosphorylation of Cav-1 and subsequent interaction among members of the Ras signaling pathway within the membrane lipid microdomains represent early signaling mechanisms of IL-1β in β-cells.
Combination Therapy With Epidermal Growth Factor and Gastrin Increases β-Cell Mass and Reverses Hyperglycemia in Diabetic NOD Mice
Authors: Suarez-Pinzon Wilma L. , Yan Yanhua , Power Robert , Brand Stephen J. , Rabinovitch Alex
Published: March 2007

Combination therapy with epidermal growth factor (EGF) and gastrin induces β-cell regeneration in rodents with chemically induced diabetes. We investigated whether EGF plus gastrin could correct hyperglycemia in NOD mice with autoimmune diabetes. Combined treatment with EGF (1 μg/kg) and gastrin (3 μg/kg) for 2 weeks restored normoglycemia after diabetes onset in NOD mice, whereas EGF or gastrin alone did not. Fasting blood glucose remained normal (3.5–6.5 mmol/l) or mildly elevated (<11 mmol/l) in five of six mice (83%) for 10 weeks after EGF plus gastrin treatment was stopped, whereas all mice treated with vehicle or EGF or gastrin alone became severely hyperglycemic (12–35 mmol/l). Pancreatic β-cell mass was increased threefold and insulin content was increased eightfold in mice treated with EGF plus gastrin compared with pretreatment values. The correction of hyperglycemia correlated significantly with increases in pancreatic β-cell mass and insulin content. In addition, splenic cells from mice treated with EGF plus gastrin delayed diabetes induction by adoptive transfer of diabetogenic cells into immunodeficient NOD-scid mice, suggesting the induction of immunoregulatory cells in NOD mice treated with EGF plus gastrin. We conclude that a short course of combined EGF and gastrin therapy increases pancreatic β-cell mass and reverses hyperglycemia in acutely diabetic NOD mice; the impact of this combined therapy may result from the effects of EGF and gastrin on β-cells, immune cells, or both.
Matrix Metalloproteinases Contribute to Insulin Insufficiency in Zucker Diabetic Fatty Rats
Authors: Zhou Yun-Ping , Madjidi Azadeh , Wilson Maria E. , Nothhelfer David A. , Johnson John H. , Palma John F. , Schweitzer Anthony , Burant Charles , Blume John E. , Johnson Jeffrey D.
Published: March 2007

To assess the molecular changes associated with pancreatic β-cell dysfunction occurring during the onset of type 2 diabetes, we profiled pancreatic islet mRNAs from diabetic male and high-fat–fed female Zucker diabetic fatty (ZDF) rats and their nondiabetic lean counterparts on custom islet-specific oligonucleotide arrays. The most prominent changes in both the male and female models of type 2 diabetes were increases in the mRNAs encoding proteases and extracellular matrix components that are associated with tissue remodeling and fibrosis. The mRNAs for metalloproteinase (MMP)-2, -12, and -14 were sharply increased with the onset of islet dysfunction and diabetes. Zymography of islet extracts revealed a concurrent, >10-fold increase in MMP-2 protease activity in islets from 9-week-old male ZDF rats. Treatment of female ZDF rats receiving a diabetogenic diet with PD166793, a broad-spectrum MMP inhibitor, substantially prevented diabetes. The effect of this compound was due in part to marked β-cell expansion. These studies indicate that MMPs contribute to islet fibrosis and insulin insufficiency in ZDF rats. Class-targeted protease inhibitors should be explored for their potential therapeutic utility in preservation of β-cell mass in type 2 diabetes.
Type 2 Diabetes Causes Remodeling of Cerebrovasculature via Differential Regulation of Matrix Metalloproteinases and Collagen Synthesis
Authors: Harris Alex K. , Hutchinson Jim R. , Sachidanandam Kamakshi , Johnson Maribeth H. , Dorrance Anne M. , Stepp David W. , Fagan Susan C. , Ergul Adviye
Published: March 2007

The risk of cerebrovascular disease is four- to sixfold higher in patients with diabetes. Vascular remodeling, characterized by extracellular matrix deposition and an increased media-to-lumen ratio, occurs in diabetes and contributes to the development of complications. However, diabetes-induced changes in the cerebrovascular structure remain unknown. Endothelin-1 (ET-1), a potent vasoconstrictor with profibrotic properties, is chronically elevated in diabetes. To determine diabetes-mediated changes in the cerebrovasculature and the role of ET-1 in this process, type 2 diabetic Goto-Kakizaki (GK) rats were administered an ETA receptor antagonist for 4 weeks. Middle cerebral arteries were harvested and studies were performed to determine vascular structure. Tissue and plasma ET-1 levels were increased in GK rats compared with controls. Significant medial hypertrophy and collagen deposition resulted in an increased wall-to-lumen ratio in diabetic rats that was reduced by ETA receptor antagonism. Vascular matrix metalloproteinase (MMP)-2 activity was higher, but MMP-1 levels were significantly reduced in GK rats, and MMP levels were restored to control levels by ETA receptor antagonism. We conclude that ET-1 promotes cerebrovascular remodeling in type 2 diabetes through differential regulation of MMPs. Augmented cerebrovascular remodeling may contribute to an increased risk of stroke in diabetes, and ETA receptor antagonism may offer a novel therapeutic target.
Expression of Mfn2, the Charcot-Marie-Tooth Neuropathy Type 2A Gene, in Human Skeletal Muscle
Authors: Bach Daniel , Naon Deborah , Pich Sara , Soriano Francesc X. , Vega Nathalie , Rieusset Jennifer , Laville Martine , Guillet Christelle , Boirie Yves , Wallberg-Henriksson Harriet , Manco Melania , Calvani Menotti , Castagneto Marco , Palacín Manuel , Mingrone Geltrude , Zierath Juleen R. , Vidal Hubert , Zorzano Antonio
Published: March 2007

The primary gene mutated in Charcot-Marie-Tooth type 2A is mitofusin-2 (Mfn2). Mfn2 encodes a mitochondrial protein that participates in the maintenance of the mitochondrial network and that regulates mitochondrial metabolism and intracellular signaling. The potential for regulation of human Mfn2 gene expression in vivo is largely unknown. Based on the presence of mitochondrial dysfunction in insulin-resistant conditions, we have examined whether Mfn2 expression is dysregulated in skeletal muscle from obese or nonobese type 2 diabetic subjects, whether muscle Mfn2 expression is regulated by body weight loss, and the potential regulatory role of tumor necrosis factor (TNF)α or interleukin-6. We show that mRNA concentration of Mfn2 is decreased in skeletal muscle from both male and female obese subjects. Muscle Mfn2 expression was also reduced in lean or in obese type 2 diabetic patients. There was a strong negative correlation between the Mfn2 expression and the BMI in nondiabetic and type 2 diabetic subjects. A positive correlation between the Mfn2 expression and the insulin sensitivity was also detected in nondiabetic and type 2 diabetic subjects. To determine the effect of weight loss on Mfn2 mRNA expression, six morbidly obese subjects were subjected to weight loss by bilio-pancreatic diversion. Mean expression of muscle Mfn2 mRNA increased threefold after reduction in body weight, and a positive correlation between muscle Mfn2 expression and insulin sensitivity was again detected. In vitro experiments revealed an inhibitory effect of TNFα or interleukin-6 on Mfn2 expression in cultured cells. We conclude that body weight loss upregulates the expression of Mfn2 mRNA in skeletal muscle of obese humans, type 2 diabetes downregulates the expression of Mfn2 mRNA in skeletal muscle, Mfn2 expression in skeletal muscle is directly proportional to insulin sensitivity and is inversely proportional to the BMI, TNFα and interleukin-6 downregulate Mfn2 expression and may participate in the dysregulation of Mfn2 expression in obesity or type 2 diabetes, and the in vivo modulation of Mfn2 mRNA levels is an additional level of regulation for the control of muscle metabolism and could provide a molecular mechanism for alterations in mitochondrial function in obesity or type 2 diabetes.
Experimental Diabetes Attenuates Cerebral Cortical−Evoked Forelimb Motor Responses
Authors: Emerick April J. , Richards Michael P. , Kartje Gwendolyn L. , Neafsey Edward J. , Stubbs Evan B.
Published: March 2007

Poorly controlled diabetes leads to debilitating peripheral complications, including retinopathy, nephropathy, and neuropathy. Chronic diabetes also impairs the central nervous system (CNS), leading to measurable deficits in cognition, somatosensory, and motor function. The cause of diabetes-associated CNS impairment is unknown. In this study, sustained hyperglycemia resulting from insulin deficiency was shown to contribute to CNS motor dysfunction. Experimental diabetes was induced in rats by streptozotocin (STZ) injection. CNS motor function was assessed by intracortical microstimulation of the sensorimotor cortex. Experimental diabetes significantly (P < 0.01; n = 14) attenuated the number of motor cortical sites eliciting forelimb movements. The net area of the motor cortex representing the forelimb in diabetic rats was significantly reduced (4.0 ± 0.5 [control] vs. 2.4 ± 0.4 [STZ] mm2; P < 0.05). Experimental diabetes attenuated the activation of some, but not all, forelimb motor cortical neurons. Insulin treatment of diabetic rats prevented the attenuation of cortical-evoked forelimb responses. Peripheral nerve−evoked responses were unaffected by this short period of diabetes, suggesting the absence of peripheral nerve dysfunction. This study showed that metabolic imbalance resulting from insulin deficiency elicits a marked attenuation of cortical-evoked motor function. Uncontrolled hyperglycemia, deficiencies of central insulin, or both may contribute to corticospinal motor dysfunction.
Rosiglitazone Improves Myocardial Glucose Uptake in Patients With Type 2 Diabetes and Coronary Artery Disease
Authors: Lautamäki Riikka , Airaksinen K.E. Juhani , Seppänen Marko , Toikka Jyri , Luotolahti Matti , Ball Elizabeth , Borra Ronald , Härkönen Risto , Iozzo Patricia , Stewart Murray , Knuuti Juhani , Nuutila Pirjo
Published: March 2007

Rosiglitazone therapy improves insulin sensitivity and glucose uptake in patients with uncomplicated type 2 diabetes. In coronary artery disease (CAD), glucose is an important source of energy and preserved myocardial glucose uptake is essential for the viability of jeopardized myocardium. The aim was to test whether rosiglitazone changes myocardial metabolism in type 2 diabetic patients with CAD. We studied 54 patients (38 men and 16 women) with type 2 diabetes (HbA1c 7.2 + 0.9%) and CAD. Myocardial glucose uptake was measured with [18F]fluoro-2-deoxy-d-glucose positron emission tomography in ischemic (evaluated by single-photon emission tomography and coronary angiography) and nonischemic regions during euglycemic-hyperinsulinemic clamp before and after a 16-week intervention period with rosiglitazone (n = 27) or placebo (n = 27). Rosiglitazone significantly improved glycemic control (P < 0.0001) and whole-body insulin sensitivity (P < 0.0001). Rosiglitazone increased myocardial glucose uptake from 20.6 ± 11.8 to 25.5 ± 12.4 μmol · 100 g−1 · min−1 (P = 0.038 vs. baseline, P = 0.023 vs. placebo) in ischemic regions and from 21.7 ± 12.1 to 28.0 ± 12.7 μmol · 100 g−1 · min−1 (P = 0.014 vs. baseline, P = 0.003 vs. placebo) in nonischemic regions. The increase in myocardial glucose uptake was partly explained by the suppression of free fatty acid levels during clamp. Rosiglitazone therapy significantly increased insulin sensitivity and improved myocardial glucose uptake in type 2 diabetic patients with CAD. These results suggest that rosiglitazone therapy may facilitate myocardial glucose storage and utilization in these patients.
Colocalization of Mouse Autoimmune Diabetes Loci Idd21.1 and Idd21.2 With IDDM6 (Human) and Iddm3 (Rat)
Authors: Hollis-Moffatt Jade E. , Hook Sarah M. , Merriman Tony R.
Published: March 2007

Comparative mapping between the human and rodent genomes is one approach for positional cloning of complex disease loci. The human type 1 diabetes susceptibility locus IDDM6 has orthology with distal rodent chromosome 18, to which Iddm3 has been mapped in rat. Previously, we mapped Idd21 to mouse chromosome 18. Here, the primary aim was to determine whether Idd21 mapped to distal mouse chromosome 18. We constructed novel congenic strains from the consomic NOD-Chr 18ABH strain and mapped two loci (Idd21.1 and Idd21.2) to the distal 29.3-Mb portion of mouse chromosome 18, orthologous to IDDM6 (human) and Iddm3 (rat). Idd21.3 was mapped to proximal mouse chromosome 18 (0–21.9 Mb). Although Idd21.1 did not influence β-islet inflammation, splenocytes from pre-diabetic Idd21.1-congenic mice were less efficient at transferring diabetes to immunodeficient NOD-scid mice. This suggests that Idd21.1 may act by reducing the pathogenicity of islet-infiltrating immune cells. For the first time, the presence of a non–major histocompatibility complex autoimmune diabetes locus colocalizing in three species has been demonstrated; IDDM6 (human), Iddm3 (rat), and now Idd21.1–21.2 in mouse. Further genetic localization of Idd21.1 and Idd21.2 could expedite characterization of the human IDDM6 region.
Fetal and Infant Growth and Glucose Tolerance in the Hertfordshire Cohort Study
Authors: Phillips David I.W. , Goulden Peter , Syddall Holly E. , Aihie Sayer Avan , Dennison Elaine M. , Martin Helen , Cooper Cyrus ,   the Hertfordshire Cohort Study Group
Published: March 2007

The Hertfordshire Cohort Study based in the U.K. was the first to report associations between fetal or infant growth and the prevalence of adult glucose intolerance and diabetes. Many studies have replicated the findings with respect to birth weight, but there have been fewer observations in relationship to infant growth, because this is infrequently recorded in routine datasets. Recently, we carried out glucose tolerance tests in a more recently born group of men and women from the Hertfordshire Cohort Study. The objective was to determine whether the associations with weights at birth and 1 year of age reported in the original study of people born between 1920 and 1930 were observed in people born between 1931 and 1939. Birth weight was inversely related to the overall prevalence of diabetes (comprising newly diagnosed as well as existing cases) in men and women. However, weight at 1 year of age was not associated with diabetes in either sex. Analysis of data from the glucose tolerance tests showed that both sexes had evidence of higher insulin and glucose concentrations in people who were small at birth or during infancy. Finally, direct comparison of 2-h plasma glucose concentrations in the previous and current Hertfordshire study suggested that both surveys showed broad similarity of the trends in glucose tolerance with birth or infant weights; most differences arose at the extremes of the birth weight, possibly because of the small numbers of subjects studied in these groups.
Mouse Models and the Genetics of Diabetes
Authors: Leiter Edward H. , Lee Chul-Ho
Published: March 2007

In humans, both type 1 and type 2 diabetes exemplify genetically heterogeneous complex diseases in which epigenetic factors contribute to underlying genetic susceptibility. Extended human pedigrees often show inheritance of both diabetes types. A common pathophysiological denominator in both disease forms is pancreatic β-cell exposure to proinflammatory cytokines. Hence, it is intuitive that systemically expressed genes regulating β-cell ability to withstand chronic diabetogenic stress may represent a component of shared susceptibility to both major disease forms. In this review, the authors assemble evidence from genetic experiments using animal models developing clearly distinct diabetes syndromes to inquire whether some degree of overlap in genes contributing susceptibility can be demonstrated. The conclusion is that although overlap exists in the pathophysiological insults leading to β-cell destruction in the currently studied rodent models, the genetic bases seem quite distinct.
Autoantibodies in Diabetes
Authors: Pihoker Catherine , Gilliam Lisa K. , Hampe Christiane S. , Lernmark Åke
Published: March 2007

Islet cell autoantibodies are strongly associated with the development of type 1 diabetes. The appearance of autoantibodies to one or several of the autoantigens—GAD65, IA-2, or insulin—signals an autoimmune pathogenesis of β-cell killing. A β-cell attack may be best reflected by the emergence of autoantibodies dependent on the genotype risk factors, isotype, and subtype of the autoantibodies as well as their epitope specificity. It is speculated that progression to β-cell loss and clinical onset of type 1 diabetes is reflected in a developing pattern of epitope-specific autoantibodies. Although the appearance of autoantibodies does not follow a distinct pattern, the presence of multiple autoantibodies has the highest positive predictive value for type 1 diabetes. In the absence of reliable T-cell tests, dissection of autoantibody responses in subjects of genetic risk should prove useful in identifying triggers of islet autoimmunity by examining seroconversion and maturation of the autoantibody response that may mark time to onset of type 1 diabetes. The complexity of the disease process is exemplified by multiple clinical phenotypes, including autoimmune diabetes masquerading as type 2 diabetes in youth and adults. Autoantibodies may also provide prognostic information in clinically heterogeneous patient populations when examined longitudinally.
Transcriptional profiling of lymphoblast lines from subjects with panic disorder
Authors: Philibert Robert A. , Crowe Raymond , Ryu Gi‐Yung , Yoon Jae‐Geun , Secrest Dianna , Sandhu Harinder , Madan Anup
Published: March 2007

In attempts to isolate genetic vulnerability factors for panic disorder (PD), a number of investigators have used genome‐wide linkage or association analyses. But these attempts have been only modestly successful which suggests that alternative approaches may be needed to define the biology of PD. Therefore, using recently developed genome‐wide gene expression profiling, we explored whether transcriptional signatures associated with PD are present in lymphoblast cell line. The expression of 2,469 transcripts in lymphoblast cell lines from 16 subjects was arithmetically increased in every line and significantly increased overall and 354 transcripts was arithmetically decreased in every cell line and significantly decreased overall as compared to those lymphoblast lines from 17 subjects without a history of behavioral illness. Further sex specific analyses showed that in those 10 lines derived from female probands, the expression of a further 67 transcripts was arithmetically increased in every line and significantly increased overall and a further 332 transcripts was arithmetically decreased in every cell line and significantly decreased. Conversely, in cell lines from the six male probands, the expression of an additional 212 was arithmetically increased in every line and significantly increased overall and a further 332 transcripts was arithmetically decreased in every cell line. We conclude that lymphoblast cell lines derived from subjects with PD have significant, partially sex dependent changes in gene transcription. Further studies are necessary to correlate these changes in these hemopoetically derived cells with those changes postulated to occur in the CNS in association with PD. © 2007 Wiley‐Liss, Inc.
Dicarbonylrhodium(I) complexes of aminophenols and their catalytic carbonylation reaction
Authors: Sharma Manab , Sarmah Bhaskar J. , Bhattacharyya Pradip , Deka Ramesh C. , Dutta Dipak K.
Published: March 2007

The complexes [Rh(CO)2ClL](1), where L = 2‐aminophenol (a), 3‐aminophenol (b) and 4‐aminophenol (c), have been synthesized and characterized. The ligands are coordinated to the metal centre through an N‐donor site. The complexes 1 undergo oxidative addition (OA) reactions with various alkyl halides (RX) like CH3I, C2H5I and C6H5CH2Cl to produce Rh(III) complexes of the type [Rh(CO)(COR)XClL], where R = CH3(2), C2H5(3), X = I; R = C6H5CH2 and X = Cl (4). The OA reaction with CH3I follows a two‐stage kinetics and shows the order of reactivity as 1b > 1c > 1a. The minimum energy structure and Fukui function values of the complexes 1a–1c were calculated theoretically using a DND basis set with the help of Dmol3 program to substantiate the observed local reactivity trend. The catalytic activity of the complexes 1 in carbonylation of methanol, in general, is higher (TON 1189–1456) than the species [Rh(CO)2I2]− (TON 1159). Copyright © 2007 John Wiley & Sons, Ltd.
Solvent effects on complexation of thallium(I) with guanosine 5′‐monophosphate in methanol–water mixtures
Authors: Gharib Farrokh , Sadeghi Fatemeh
Published: March 2007

The interaction of guanosine 5′‐monophosphate, GMP, with the thallium(I) ion was studied by UV–vis and potentiometric titration methods and 31P NMR spectroscopy. Both NMR spectra and UV–vis titration data have shown that GMP coordinates via guanine to the thallium(I) ion in the pH range 1.5–10. Our study of the system Tl(I) + GMP was performed in water–methanol mixtures with different volume ratios of methanol. The complexation equilibrium in the pH range of study led to the following mononuclear species: TlH2(GMP)+, TlH(GMP) and Tl(GMP)−, where (GMP)2− represents the fully dissociated ligand. The formation constants of the species were calculated in the various media at constant temperature (25 °C) and constant ionic strength of sodium perchlorate (0.1 mol dm−3) using a suitable computer program. The formation constants were analyzed in terms of Kamlet and Taft's parameters. A single‐parameter correlation of the formation constants, β121, β111 and β101 vs α (hydrogen‐bond donor acidity), β (hydrogen‐bond acceptor basicity) and for π* (dipolarity/polarizability) are relatively poor in all solutions, but multi‐parameter correlations represent significant improvements with regard to the single‐parameter model. In this work, we have also used the normalized polarity parameter, ETN, alone and in combination with some of the Kamlet–Taft parameters to find a better correlation of the formation constants in different methanol–water mixtures. Copyright © 2007 John Wiley & Sons, Ltd.
Development of an animal model for ovotoxicity using 4‐vinylcyclohexene: a case study
Authors: Hoyer Patricia B. , Sipes I. Glenn
Published: March 2007

BACKGROUNDThe occupational chemical 4‐vinylcyclohexene (VCH) has been shown to cause destruction of small pre‐antral follicles in ovaries of mice. Further, its monoepoxide metabolites, 1,2‐VCH epoxide, 7,8‐VCH epoxide, and the diepoxide, VCD, have been shown to cause pre‐antral follicle loss in rats as well as mice. Chemicals that destroy small pre‐antral follicles are of concern to women because exposure can result in premature ovarian failure (early menopause).METHODSStudies working with these chemicals over the past decade have determined a number of aspects of the mechanism(s) of small pre‐antral destruction, and a variety of questions have been answered.RESULTSSpecifically, it has been determined that the diepoxide (VCD) is the bioactive form and it directly targets the ovary in mice and rats. Mice are more susceptible to VCH than rats because they are capable of its metabolic bioactivation. Follicle destruction by VCD is selective for primordial and primary follicles. Mechanistic studies in rats have determined that VCD causes ovotoxicity by accelerating the natural process of atresia (apoptosis) and this requires repeated exposures. Pro‐apoptotic signaling events in the Bcl‐2 and mitogen activated protein kinase families have been shown to be selectively activated in fractions of small pre‐antral follicles (targets for VCD). Finally, a whole ovarian culture system using neonatal mouse and rat ovaries has been developed to expand the potential for more in depth investigations into ovotoxicity caused by VCD.CONCLUSIONSThis article provides an overview of the questions asked and the approaches taken in studying VCH and VCD to support these conclusions.Birth Defects Res (Part B), 2007. © 2007 Wiley‐Liss, Inc.
Stereoselective Ring‐Opening Polymerization of a Racemic Lactide by Using Achiral Salen– and Homosalen–Aluminum Complexes
Authors: Nomura Nobuyoshi , Ishii Ryohei , Yamamoto Yoshihiko , Kondo Tadao
Published: March 2007

Highly isotactic polylactide or poly(lactic acid) is synthesized in a ring‐opening polymerization (ROP) of racemic lactide with achiral salen– and homosalen–aluminum complexes (salenH2=N,N′‐bis(salicylidene)ethylene‐1,2‐diamine; homosalenH2=N,N′‐bis(salicylidene)trimethylene‐1,3‐diamine). A systematic exploration of ligands demonstrates the importance of the steric influence of the Schiff base moiety on the degree of isotacticity and the backbone for high activity. The complexes prepared in situ are pure enough to apply to the polymerizations without purification. The crystal structures of the key complexes are elucidated by X‐ray diffraction, which confirms that they are chiral. However, analysis of the 1H and 13C NMR spectra unambiguously demonstrates that their conformations are so flexible that the chiral environment of the complexes cannot be maintained in solution at 25 °C and that the complexes are achiral under the polymerization conditions. The flexibility of the backbone in the propagation steps is also documented. Hence, the isotacticity of the polymer occurs due to a chain‐end control mechanism. The highest reactivity in the present system is obtained with the homosalen ligand with 2,2‐dimethyl substituents in the backbone (ArCHNCH2CMe2CH2NCHAr), whereas tBuMe2Si substituents at the 3‐positions of the salicylidene moieties lead to the highest selectivity (Pmeso=0.98; Tm=210 °C). The ratio of the rate constants in the ROPs of racemic lactide and L‐lactide is found to correlate with the stereoselectivity in the present system. The complex can be utilized in bulk polymerization, which is the most attractive in industry, although with some loss of stereoselectivity at high temperature, and the afforded polymer shows a higher melting temperature (Pmeso=0.92, Tm up to 189 °C) than that of homochiral poly(L‐lactide) (Tm=162–180 °C). The “livingness” of the bulk polymerization at 130 °C is maintained even at a high conversion (97–98 %) and for an extended polymerization time (1–2 h).
Fat and water differentiation by nuclear magnetic resonance imaging
Authors: Kaldoudi Eleni , Williams Steve C. R.
Published: March 2007

Following our article entitled „Fat and Water Differentiation by Nuclear Magnetic Resonance Imaging”︁ (1), it was suggested that it would be helpful to summarize our findings in tabular form. The table presented here highlights the advantages and disadvantages of numerous techniques that have been used in MRI for fat and water differentiation. Our „title”︁ for each subcategory is followed by the original references relating to that method. This table is intended to be used as a quick reference guide. For a more elaborate treatment of the subject, we suggest that the reader refer to the full paper.
Parameterized description of NMR signal reception systems. Part II: S/N of NMR signal reception systems
Authors: Cho Shin‐Il , Sullivan Neil S.
Published: March 2007

The mathematical tools that were developed in Part I are used to show quantitatively how the signal‐to‐noise ratio and the ringing time depend on Q factors, and thus how overall performance can be improved. The noise factor of a model preamplifier also is considered, and the minimum noise factor is derived in terms of the impedances of the probe and of the preamplifier. The optimization of the noise factor in realistic signal reception systems is discussed.
NMR rotating‐frame relaxation measurements of conformational exchanges on the microsecond time scale. Part II: Verification of the T1p method and analysis of experimental results
Authors: Wang Yu‐Sen
Published: March 2007

Part I of this paper describes an on‐resonance, rotating‐frame relaxation method and proposes a procedure for the accurate evaluation of the contribution of chemical exchange to rotating‐frame spin‐lattice relaxation (T1p). Dynamic information, such as exchange lifetimes and chemical shift differences between exchange sites, can be extracted from the exchange contribution. The procedure extends the T1p method to medium‐sized and large molecules. Part II presents a verification of the T1p method and an analysis of experimental results. The accuracy of these dynamic parameters has been examined using simple, well‐characterized conformational exchange systems. The examination shows that T1p is convenient for studying molecular dynamics on the microsecond time scale. The application of the method to peptides and to right‐ and left‐handed DNA oligomers gives unique dynamic information on the conformational exchange processes in these molecules.
Rotational resonance NMR of biological membranes
Authors: Peersen Olve B. , Smith Steven O.
Published: March 2007

Rotational resonance (RR) NMR is a magic angle spinning‐based method for measuring internuclear distances through homonuclear dipolar couplings. RR NMR data obtained from crystals of a hydrophobic α‐helical peptide are used to illustrate general experimental considerations in generating RR magnetization exchange curves and in translating the observed exchange rates into internuclear distances. The extension of RR methods to structural studies of membranes is demonstrated by intramolecular measurements within the transmembrane domain of glycophorin A and between 13C‐labeled sites in lipid bilayers.
Quadrupole effects in solid‐state NMR spectra of spin‐½ Nuclei: A perturbation approach
Authors: Grondona Patricia , Olivieri Alejandro C.
Published: March 2007

In solution, the effect of quadrupolar nuclei on the resonances of spin‐% nuclei are confined to relaxation processes and, in favorable cases, to J‐coupling interactions. In the solid state, however, an interesting phenomenon takes place: the appearance of unexpected field‐dependent multiplicities. The application of a perturbation approach to the understanding of these multiplicities is discussed; particular attention is given to the 13C, l4N spin pair.
Magnetization transfer via isotropic mixing: An introduction to the HOHAHA experiment
Authors: Hicks Rickey P. , Young John K. , Moskau Detlef
Published: March 2007

The theory of the cross‐polarization two‐dimensional homonuclear Hartmann‐Hahn experiment is introduced. The product operator formalism is used to develop expressions to explain the transfer of magnetization under the influence of the isotropic Hamiltonian. The various modifications of the HOHAHA/TOCSY experiment are presented. The MLEV‐17 pulse cycle for generation of the spin‐lock pulse is discussed in detail. The intensity of magnetization transfer is shown both mathematically and graphically to be dependent on the relationship mixing time 1/(2JAX). The HOHAHA experiment is also discussed in relation to the other spin‐lock experiments, ROESY and CAMELSPIN.
Superconducting NMR magnet design
Authors: Laukien Dirk D. , Tschopp Werner H.
Published: March 2007

General information is given about solenoidal superconducting magnets and an overview is given of the design principles and theories for superconducting magnets. Issues relevant to NMR are reviewed in detail. Advantages and disadvantages of different superconducting wire, construction methods, and mathematical concepts necessary for the main components of a superconducting magnet applicable to high‐resolution NMR are surveyed. Major components such as joints, dump resistors, heat shields, and magnet dewars are illustrated and described.
Product operators, coherence pathways, and phase cycling part i: product operators, spin‐spin coupling, and coherence pathways
Authors: Kingsley Peter B.
Published: March 2007

The vector model is compared with product operator descriptions of NMR pulse sequences. For coupled spins, the relationship between the counter‐rotating vectors of the vector model and antiphase product operators is explained. Coherence pathways for an uncoupled spin I = ½ are explained in vector terms. The compact Cartesian coordinate product operator (C3PO) formalism is shown to provide complete coherence pathway information with vector pictures.
A pictorial representation for multispin evolutions
Authors: Wei Guowei , Snider R. F.
Published: March 2007

Modern NMR techniques involve keeping track of the evolutions of two or more coupled spins. A new multivector representation adequate for visualizing such evolutions is presented. This representation can be put in one‐one correspondence with product operators, and has the advantage that it retains all possible orientations of each spin in the product operator. Thus, as the spins evolve, faithful pictures can be drawn both to indicate the directional change of the spins magnetizations and to deduce the detailed signals that arise from their evolution. The results are in full agreement with density matrix calculations. In particular, one can visualize multiple‐quantum coherence transfer. Evolutions due to chemical shift, J coupling, and the effect of radio frequency (rf) pulses are pictured. A simple heteronuclear chemical shift correlation pulse sequence is used to illustrate how the multivector representation can follow through a combination of spin evolutions and how the signals can be correctly deduced entirely from pictures without the need to refer to density matrix or operator algebra calculations.
Product operators, coherence pathways, and phase cycling. Part III: phase cycling
Authors: Kingsley Peter B.
Published: March 2007

The coherence pathway approach allows the systematic design of phase cycles to eliminate unwanted coherence pathway signals in multipulse NMR sequences. Some quadrature receiver imperfections are shown to be equivalent to detection of magnetization in coherence level p = + 1 in addition to the normally observable p = −1. Other receiver artifacts do not correspond to p = +1 but also can be removed by phase cycling. Selection of signals in one‐, two‐, and three‐pulse sequences is described for uncoupled and coupled spins.
New method to quantify erythrophagocytosis by autologous monocytes
Authors: Fendel Rolf , Mordmüller Benjamin , Kreidenweiss Andrea , Rudat Annika , Steur Claudia , Ambrosch Christian , Kirstein Max , Berdel Wolfgang E. , Kremsner Peter G. , Brandts Christian
Published: March 2007

Background:

Anemia is the net result of decreased red blood cell (RBC) production and increased removal of RBCs. Replication and maturation of erythroid precursors and RBC lysis can be measured by standardized in vitro methods and surrogate markers, respectively. In contrast, erythrophagocytosis by autologous phagocytes is more difficult to quantify.

Methods:

We developed a method to assess erythrophagocytosis by autologous monocytes from 5 ml of whole blood. RBCs were labeled with carboxyfluorescein‐diacetate‐succinimidyl ester (CFDA‐SE) and subsequently coincubated with autologous CD14+ monocytes. Phagocytosis was quantified using flow cytometry. After standardization, the assay was validated in patients with severe malarial anemia (SMA), a condition that is associated with increased erythrophagocytosis.

Results:

After labeling, CFDA‐SE was stably incorporated into RBCs and no significant leakage leading to contamination of nonlabeled cells was observed. Monocytes ingested opsonized, labeled RBCs seven times more than nonopsonized controls. Erythrophagocytosis was significantly higher in SMA than in healthy controls.

Conclusions:

The established assay showed enhanced autoerythrophagocytosis associated with SMA and hence was able to detect clinically relevant erythrophagocytosis. This novel assay is well suited for rapid quantification of in vitro erythrophagocytosis by autologous monocytes. © 2007 International Society for Analytical Cytology.
Androgenic, but not estrogenic, protection of motoneurons from somal and dendritic atrophy induced by the death of neighboring motoneurons
Authors: Fargo Keith N. , Sengelaub Dale R.
Published: March 2007

Motoneuron loss is a significant medical problem, capable of causing severe movement disorders or even death. We have been investigating the effects of motoneuron loss on surviving motoneurons in a lumbar motor nucleus, the spinal nucleus of the bulbocavernosus (SNB). SNB motoneurons undergo marked dendritic and somal atrophy following the experimentally induced death of other nearby SNB motoneurons. However, treatment with testosterone at the time of lesioning attenuates this atrophy. Because testosterone can be metabolized into the estrogen estradiol (as well as other physiologically active steroid hormones), it was unknown whether the protective effect of testosterone was an androgen effect, an estrogen effect, or both. In the present experiment, we used a retrogradely transported neurotoxin to kill the majority of SNB motoneurons on one side of the spinal cord only in adult male rats. Some animals were also treated with either testosterone, the androgen dihydrotestosterone (which cannot be converted into estradiol), or the estrogen estradiol. As seen previously, partial motoneuron loss led to reductions in soma area and in dendritic length and extent in surviving motoneurons. Testosterone and dihydrotestosterone attenuated these reductions, but estradiol had no protective effect. These results indicate that the neuroprotective effect of testosterone on the morphology of SNB motoneurons following partial motoneuron depletion is an androgen effect rather than an estrogen effect. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007.
Zinc, Cadmium and Mercury Dithiocarboxylates: Synthesis, Characterization, Structure and Their Transformation to Metal Sulfide Nanoparticles
Authors: Kedarnath Gotluru , Jain Vimal K. , Ghoshal Shamik , Dey Gautam K. , Ellis Carol A. , Tiekink Edward R. T.
Published: March 2007

Reactions of M(OAc)2·nH2O and M(OAc)2(tmeda) with dithiocarboxylic acids gave [M(S2CTol)2]n (1) (M = Zn or Cd; Tol = C6H4Me‐4) and [M(S2CAr)2(tmeda)] (3) (M = Zn, Cd, Hg; Ar = Ph or Tol), respectively, in high yields as deep‐colored crystalline solids. The former are soluble in pyridine to give pyridine adducts [M(S2CTol)2(py)] (2). These complexes were characterized by elemental analysis, UV/Vis and NMR (1H, 13C) spectroscopy. The absorptions in the electronic spectra have been assigned to ligand‐to‐ligand charge‐transfer transitions. The crystal and molecular structures of the monomeric species [Zn(S2CTol)2(py)] (2), [Zn(S2CPh)2(tmeda)] (3a), [Zn(S2CTol)2(tmeda)] (3b) and [Cd(S2CTol)2(tmeda)] (3d) have been established by X‐ray crystallography. In [Zn(S2CTol)2(py)], chelating dithiocarboxylate ligands and pyridine define a coordination geometry intermediate between square pyramidal and trigonal bipyramidal. In each of 3a and 3b, tetrahedral N2S2 coordination geometries are found as the dithiocarboxylate ligands are effectively monodentate; evidence for the greater coordination potential is found for –S2CTol over –S2CPh. Chelating dithiocarboxylate ligands in [Cd(S2CTol)2(tmeda)] (3d) lead to an octahedral geometry. Thermal behavior has been studied by thermogravimetric analysis. The [M(S2CAr)2(tmeda)] complexes underwent a three‐step decomposition. Pyrolysis in the temperature range 300–500 °C and solvothermal decomposition in ethylenediamine and hexadecylamine (HDA) gave metal sulfide nanoparticles. The MS (M = Zn, Cd, Hg) nanoparticles were characterized by XRD, EDAX, absorption/emission spectroscopy and electron microscopy (TEM). Solvothermal decomposition gave hexagonal phases of nanoparticles whereas heating in a furnace gave cubic ZnS and HgS, and hexagonal CdS. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)
Multi‐scale modelling approach for the pushover analysis of existing RC shear walls—Part II: Experimental verification
Authors: Mulas Maria Gabriella , Coronelli Dario , Martinelli Luca
Published: March 2007

In a companion paper two different modelling approaches have been described, operating at the meso‐scale of the fibre elements and at the micro‐scale of the finite element (FE) method. The aim of this paper is to explore the efficiency of these models in the pushover analysis for the seismic assessment of existing reinforced concrete (RC) structures. To this purpose a prototype reference structure, one of the RC shear walls designed according to the multi‐fuse concept and tested on shaking table for the CAMUS Project, is modelled at different levels of refinement. At the micro‐scale the reinforcement and anchorage details are described with increasing accuracy in separate models, whereas at the meso‐scale one single model is used, where each element represents a large part of the structure. Static incremental non‐linear analyses are performed with both models to derive a capacity curve enveloping the experimental results and to reproduce the damage pattern at the displacement level where failure is reached. The comparison between experimental and numerical results points out the strong and weak points of the different models inside the procedure adopted, and the utility of an integration of results from both approaches. This study confirms, even for the rather difficult case at study, the capability of the pushover in reproducing the non‐linear dynamic response, both at a global and a local level, and opens the way to the use of the models within a displacement‐based design and assessment procedure. Copyright © 2007 John Wiley & Sons, Ltd.