bluuebunny/crossref_metadata_2025 huggingface dataset:
Large Unrepaired Aortopulmonary Window—Survival into the Seventh Decade
Authors: Su‐Mei Angela Koh , Ju‐Le Tan
Published: November 2006

Aortopulmonary (AP) window is a rare cardiac malformation. We report a patient with Eisenmenger syndrome secondary to a large unrepaired AP window who gave birth to three children in her thirties, survived into her fifties with relatively preserved quality of life, and died at age 60.
Unusual Superior Vena Cava Thrombus (Partly Obstructive) Extending through Right Atrium to Eustachian Valve
Authors: Munir Ahmad , Minderman Daniel , D'Cruz Ivan
Published: November 2006

A 50‐year‐old patient with end‐stage renal disease who was being dialyzed with an internal jugular catheter presented with fever. Transthoracic and transesophageal echo demonstrated a thrombus in the inferior venacava, protruding into the right atrium and extending to the eustachian valve to which it was adherent. Multiple organisms grew from the blood as well as the catheter tip. Antibiotic therapy was started with Vancomycin and Gentamicin but later changed to other combinations according to sensitivity studies. Coumadin was also given.
Echocardiographic Evaluation of Ventricular Function in Mice
Authors: Rottman Jeffrey N. , Ni Gemin , Brown Michael
Published: November 2006

Ventricular dysfunction remains a hallmark of most cardiac disease. The mouse has become an essential model system for cardiovascular biology, and echocardiography an established tool in the study of normal and genetically altered mice. This review describes the measurement of ventricular function, most often left ventricular function, by echocardiographic methods in mice. Technical limitations related to the small size and rapid heart rate in the mouse initially argued for the performance of echocardiography under anesthesia. More recently, higher frame rates and smaller probes operating at higher frequencies have facilitated imaging of conscious mice in some, but not all, experimental protocols and conditions. Ventricular function may be qualitatively and quantitatively evaluated under both conditions. Particular detail is provided for measurement under conscious conditions, and measurement under conscious and sedated or anesthestized conditions are contrasted. Normal values for echocardiographic indices for the common C57BL/6 strain are provided. Diastolic dysfunction is a critical pathophysiologic component of many disease states, and progress in the echocardiographic evaluation of diastolic function is discussed. Finally, echocardiography exists among several competing imaging technologies, and these alternatives are compared.
Doppler Ultrasound in Mice
Authors: Stypmann Jörg
Published: November 2006

Color, power, spectral, and tissue Doppler have been applied to mice. Due to the noninvasive nature of the technique, serial intraindividual Doppler measurements of cardiovascular function are feasible in wild‐type and genetically altered mice before and after microsurgical procedures or to follow age‐related changes. Fifty‐megahertz ultrasound biomicroscopy allows to record the first beats of the embryonic mouse heart at somite stage 5, and the first Doppler‐flow signals can be recorded after the onset of intrauterine cardiovascular function at somite stage 7. Using 10‐ to 20‐MHz ultrasound transducers in the mouse embryo, cardiac, and circulatory function can be studied as early as 7.5 days after postcoital mucous plug. Postnatal Doppler ultrasound examinations in mice are possible from birth to senescent age. Several strain‐, age‐, and gender‐related differences of Doppler ultrasound findings have been reported in mice. Results of Doppler examinations are influenced by the experimental settings as stress testing or different forms of anesthesia. This review summarizes the present status of Doppler ultrasound examinations in mice and animal handling in the framework of a comprehensive phenotype characterization of cardiac contractile and circulatory function.
Low‐level Exercise Echocardiography Fails to Elicit Left Ventricular Contractile Reserve in Patients with Aortic Stenosis, Reduced Ejection Fraction, and Low Transvalvular Gradient
Authors: Ennezat Pierre V. , Toussaint Juliette , Maréchaux Sylvestre , Le Tourneau Thierry , Aubert Jean Marc , Asseman Philippe , LeJemtel Thierry H. , Deklunder Ghislaine
Published: November 2006

Background: Low‐level exercise echocardiography is useful to assess left ventricular (LV) contractile reserve after an acute myocardial infarction. Whether low‐level exercise can elicit LV contractile reserve in patients with severe aortic stenosis, reduced LV systolic function and low transvalvular gradient are unknown. Accordingly, the value of low‐level exercise to elicit contractile reserve was assessed in these patients using dobutamine administration as the gold standard method. Methods and Results: Seventeen patients with severely decreased aortic valve area (0.75 ± 0.03 cm2), reduced LV ejection fraction (35 ± 2%) and low mean transvalvular gradient (23 ± 3 mmHg) underwent low‐level exercise and dobutamine echocardiography. Ejection fraction increased by 23% (P < 0.001) with dobutamine and decreased by 8% (P = 0.2) with low‐level exercise. Left ventricular outflow tract velocity time integral increased from 13 ± 1 to 16.7 ± 1 cm (P < 0.001) with dobutamine but did not change with low‐level exercise (13 ± 1 vs. 13.5 ± 1, P = 0.5). Conclusion: Low‐level exercise fails to elicit LV contractile reserve in patients with severe aortic stenosis, reduced LV systolic function, and low transvalvular gradient.
Melatonin reduces mortality and oxidatively mediated hepatic and renal damage due to diquat treatment
Authors: Xu Jingming , Sun Shichun , Wei Wei , Fu Jianmin , Qi Wenbo , Manchester Lucien C. , Tan Dun‐Xian , Reiter Russel J.
Published: November 2006

Abstract:  The bipyridyl herbicide, diquat, is a potent prooxidant that generates superoxide anions through redox cycling in vivo. Exposure to elevated levels of this compound causes acute hepatic and renal toxicity as well as death in rodents. In the present study, we investigated whether melatonin, a free radical scavenger and antioxidant, could protect against diquat‐induced hepatic and renal damage and whether the indole would improve survival of Kunming mice given a lethal dose of diquat. When mice were intraperitoneally (i.p.) given a single dose of diquat (50 mg/kg body weight), liver and kidney injuries were observed at 6 hr as indicated by elevated serum levels of both alanine aminotransferase (ALT) activity and blood urea nitrogen (BUN). In addition, lipid peroxidation levels in both liver and kidney showed significant increases as shown by elevated concentrations of F2‐isoprostanes. The administration of melatonin (20 mg/kg) 30 min before the diquat injection resulted in a significant reduction in serum levels of ALT and BUN as well as hepatic and renal F2‐isoprostanes levels. For the survival study, 75 mg/kg diquat was administered i.p. into mice to induce acute death. Without melatonin treatment, 10 of 23 (43.5%) mice died within 24 hr after diquat injection. Pretreatment with melatonin (20 mg/kg) 30 min prior to the injection of diquat and thereafter at 4‐hr intervals until the end of the observation period (24 hr), reduced the death rate to two of 22 (9.1%) mice. Chi‐squared test revealed a significant difference with P ≤ 0.05. In conclusion, melatonin, a broad spectrum antioxidant, reduces hepatic and renal damage and lowers the death rate in diquat‐treated mice.
Phosphatidylserine induces functional and structural alterations of the membrane‐associated pleckstrin homology domain of phospholipase C‐δ1
Authors: Uekama Naoko , Sugita Takio , Okada Masashi , Yagisawa Hitoshi , Tuzi Satoru
Published: November 2006

The membrane binding affinity of the pleckstrin homology (PH) domain of phospholipase C (PLC)‐δ1 was investigated using a vesicle coprecipitation assay and the structure of the membrane‐associated PH domain was probed using solid‐state 13C NMR spectroscopy. Twenty per cent phosphatidylserine (PS) in the membrane caused a moderate but significant reduction of the membrane binding affinity of the PH domain despite the predicted electrostatic attraction between the PH domain and the head groups of PS. Solid‐state NMR spectra of the PH domain bound to the phosphatidylcholine (PC)/PS/phosphatidylinositol 4,5‐bisphosphate (PIP2) (75 : 20 : 5) vesicle indicated loss of the interaction between the amphipathic α2‐helix of the PH domain and the interface region of the membrane which was previously reported for the PH domain bound to PC/PIP2 (95 : 5) vesicles. Characteristic local conformations in the vicinity of Ala88 and Ala112 induced by the hydrophobic interaction between the α2‐helix and the membrane interface were lost in the structure of the PH domain at the surface of the PC/PS/PIP2 vesicle, and consequently the structure becomes identical to the solution structure of the PH domain bound to d‐myo‐inositol 1,4,5‐trisphosphate. These local structural changes reduce the membrane binding affinity of the PH domain. The effects of PS on the PH domain were reversed by NaCl and MgCl2, suggesting that the effects are caused by electrostatic interaction between the protein and PS. These results generally suggest that the structure and function relationships among PLCs and other peripheral membrane proteins that have similar PH domains would be affected by the local lipid composition of membranes.
Modular metabolic control analysis of large responses
Authors: Acerenza Luis , Ortega Fernando
Published: November 2006

Deciphering the laws that govern metabolic responses of complex systems is essential to understand physiological functioning, pathological conditions and the outcome of experimental manipulations of intact cells. To this aim, a theoretical and experimental sensitivity analysis, called modular metabolic control analysis (MMCA), was proposed. This field was previously developed under the assumptions of infinitesimal changes and/or proportionality between parameters and rates, which are usually not fulfilled in vivo. Here we develop a general MMCA for two modules, not relying on those assumptions. Control coefficients and elasticity coefficients for large changes are defined. These are subject to constraints: summation and response theorems, and relationships that allow calculating control from elasticity coefficients. We show how to determine the coefficients from top‐down experiments, measuring the rates of the isolated modules as a function of the linking intermediate (there is no need to change parameters inside the modules). The novel formalism is applied to data of two experimental studies from the literature. In one of these, 40% increase in the activity of the supply module results in less than 4% increase in flux, while infinitesimal MMCA predicts more than 30% increase in flux. In addition, it is not possible to increase the flux by manipulating the activity of demand. The impossibility of increasing the flux by changing the activity of a single module is due to an abrupt decrease of the control of the modules when their corresponding activities are increased. In these cases, the infinitesimal approach can give highly erroneous predictions.
Two splicing isoforms of the Y‐box protein ctYB‐1 appear on the same mRNA molecule
Authors: Nashchekin Dmitry , Masich Sergej , Soop Teresa , Kukalev Alexander , Kovrigina Elizaveta , Nashchekina Oxana , Daneholt Bertil
Published: November 2006

Y‐box proteins constitute an evolutionarily conserved family of DNA‐ and RNA‐binding proteins involved in the regulation of transcription and translation. In the dipteran Chironomus tentans, a homologue to the vertebrate Y‐box protein YB‐1 was recently characterized and designated ctYB‐1. It is transferred from nucleus to cytoplasm bound to mRNA and is likely to affect translation. It appears in two size variants, p40 and p50. We further analysed the two size variants and their interaction with mRNA. Southern blot analysis, in situ hybridization and RT‐PCR analysis suggested that there is just one YB‐1 gene, and that the two size variants represent splicing isoforms. In a C. tentans epithelial cell line, only p40 is present, whereas both variants appear together in eight tissues from fourth‐instar larvae, although in somewhat different proportions. Furthermore, the appearance of the two isoforms was studied in relation to a specific 35–40 kb mRNA transcript in the salivary glands, the Balbiani ring mRNA. Because of their exceptional size, Balbiani ring messenger ribonucleoprotein particles in nucleoplasm and Balbiani ring polysomes in cytoplasm could be identified and selectively studied. We were able to establish that both isoforms are associated with both nuclear and cytoplasmic Balbiani ring mRNA. In addition, a p50‐specific antibody coimmunoprecipitated p40 from Balbiani ring polysomes, suggesting that the two splicing isoforms are located along the same Balbiani ring mRNA molecule. The functional significance of the two isoforms is being discussed.
Induction of uPA gene expression by the blockage of E‐cadherin via Src‐ and Shc‐dependent Erk signaling
Authors: Kleiner Sandra , Faisal Amir , Nagamine Yoshikuni
Published: November 2006

Loss of E‐cadherin‐mediated cell–cell adhesion and expression of proteolytic enzymes characterize the transition from benign lesions to invasive, metastatic tumor, a rate‐limiting step in the progression from adenoma to carcinoma in vivo. A soluble E‐cadherin fragment found recently in the serum and urine of cancer patients has been shown to disrupt cell–cell adhesion and to drive cell invasion in a dominant‐interfering manner. Physical disruption of cell–cell adhesion can be mimicked by the function‐blocking antibody Decma. We have shown previously in MCF7 and T47D cells that urokinase‐type plasminogen activator (uPA) activity is up‐regulated upon disruption of E‐cadherin‐dependent cell–cell adhesion. We explored the underlying molecular mechanisms and found that blockage of E‐cadherin by Decma elicits a signaling pathway downstream of E‐cadherin that leads to Src‐dependent Shc and extracellular regulated kinase (Erk) activation and results in uPAgene activation. siRNA‐mediated knockdown of endogenous Src‐homology collagen protein (Shc) and subsequent expression of single Shc isoforms revealed that p46Shc and p52Shc but not p66Shc were able to mediate Erk activation. A parallel pathway involving PI3K contributed partially to Decma‐induced Erk activation. This report describes that disruption of E‐cadherin‐dependent cell–cell adhesion induces intracellular signaling with the potential to enhance tumorigenesis and, thus, offers new insights into the pathophysiological mechanisms of tumor development.
Genotypic variation in cold tolerance influences the yield of Miscanthus
Authors: Farrell A.D. , Clifton‐Brown J.C. , Lewandowski I. , Jones M.B.
Published: November 2006

When grown in Europe, Miscanthus genotypes often produce yields lower than their potential due to late emergence of shoots in the spring or to damage from late frosts when shoots emerge too early. Here, we investigate genotypic variation in the base temperature (Tb) for shoot emergence and in the lethal temperature for shoots (LT50) in four Miscanthus genotypes. In all genotypes, lowering temperature increased the time to shoot emergence, with Tb ranging from 8.6°C in Sac‐5 to 6°C in Sin‐H9. Frost treatments below −8°C resulted in a marked reduction in growth in all four genotypes. Sin‐H9 was the most frost tolerant with an LT50 of −9.3°C. There was little variation found in leaf osmotic potential, but leaf moisture content was significantly lower in Sin‐H9 than in the other genotypes. The lower thermal requirement for emergence and lower LT50 seen in Sin‐H9 was incorporated into a model of Miscanthus production. The model showed an extended growing season that was predicted to increase yields by up to 25%.
Localisation of hydrogen peroxide and peroxidase in gametophytes of Ceratopteris richardii (C‐fern) grown in the presence of pathogenic fungi in a gnotobiotic system
Authors: Urs R.R. , Roberts P.D. , Schultz D.C.
Published: November 2006

The endogenous localisation of peroxidase and hydrogen peroxide (H2O2) was detected when gametophytes of the fern, Ceratopteris richardii, were exposed to the plant pathogenic fungi Sclerotium rolfsii and Sclerotinia sclerotiorum and Phytophthora infestans, an oomycete, in a gnotobiotic system. This was accomplished by light microscopy using 3,3′‐diaminobenzidine, guaiacol and H2O2 and starch potassium iodide (KI) staining procedures, which facilitated the observation of the reaction in vivo and in situ, without physically damaging the tissues. All three staining methods promoted staining at the rhizoid regions. Although most of the cells were destroyed when gametophytes were exposed to S. rolfsii and S. sclerotiorum, there was staining where mycelial growth was confluent with cell walls. A qualitative test confirmed that the colour change in starch KI agar medium, as well as in the histochemical test with starch KI, was because of H2O2 secreted by S. rolfsii or S. sclerotiorum and not because of oxalic acid. When gametophytes were exposed to P. infestans, no infection occurred, but localisation of H2O2 and peroxidase was detected irrespective of staining methods tested. Based on the observation on gametophytes grown in presence of P. infestans, it is possible that the peroxidase in plants coupled with H2O2 may prevent the invasion of nonpathogens by functioning as a barrier. This fern–pathogen model system has potential for application as a tool to study the host–parasite interaction in a gnotobiotic system.
Detection, characterisation and transmission by Macrosteles leafhoppers of watercress yellows phytoplasma in Hawaii
Authors: Borth W.B. , Fukuda S.K. , Hamasaki R.T. , Hu J.S. , Almeida R.P.P.
Published: November 2006

A new yellows disease of watercress (Nasturtium officinale) in Hawaii has symptoms of reduced leaf size, leaf yellowing and crinkling, and occasionally witches’ brooms. This disease is found on all watercress farms on Oahu but has not yet been found on other Hawaiian islands. Watercress plants were tested for phytoplasma infection by polymerase chain reaction assays using phytoplasma‐specific primers. Amplicons of the expected sizes were produced from all symptomatic plants but not from healthy plants raised from seed. Phylogenetic analysis of the 16S rRNA gene indicated that watercress yellows was caused by a phytoplasma in the aster yellows group, with sequence similarity to onion yellows from Japan. Six weed species collected from the vicinity of affected watercress farms, Amaranth sp., Eclipta prostrata, Emilia sonchifolia, Plantago major, Myriophyllum aquaticum and Sonchus oleraceus, were also determined to be hosts of this phytoplasma. Leafhoppers, identified as Macrosteles sp. (Hemiptera, Cicadellidae), collected from symptomatic watercress transmitted this phytoplasma to watercress, plantain and lettuce (Lactuca sativa) in greenhouse experiments.
The Indirect Generation of Long‐distance Structural Changes in Antibodies upon their Binding to Antigen
Authors: Piekarska Barbara , Drozd Anna , Konieczny Leszek , Król Marcin , Jurkowski Wiktor , Roterman Irena , Spólnik Paweł , Stopa Barbara , Rybarska Janina
Published: November 2006

An allosteric mechanism for the generation of long‐distance structural alterations in Fab fragments of antibodies in immune complexes has been postulated and tested in theoretical and experimental analysis. The flexing and/or torsion‐derived forces exerted on the elbow region in Fab arms of bivalent antibodies upon binding to antigen were assumed to drive the disruption of hydrogen bonds which stabilize N‐ and C‐terminal chain fragments in V‐domains. This allows an extra movement in the elbow followed by a relaxation in the Fab arm and may generate long‐distance effects if, in particular, the structural changes are generated asymmetrically involving one chain of the Fab arm only. This mechanism was studied by simulation of molecular dynamics. The local instability in the area involving the site of packing of the N‐terminal chain fragment allows penetration and binding of the supramolecular dye Congo red that hence becomes an indicator of the initiated relaxation process and is also the prospective ligand in studies of designing drugs. The susceptibility to dye binding was observed in complexation of bivalent antibodies only, supplying the evidence that constraints associating the interaction with randomly distributed antigenic determinants drive the local structural changes in the V‐domain followed by long‐distance effects.
Moral Rationalism vs. Moral Sentimentalism: Is Morality More Like Math or Beauty?
Authors: Gill Michael B.
Published: November 2006

One of the most significant disputes in early modern philosophy was between the moral rationalists and the moral sentimentalists. The moral rationalists – such as Ralph Cudworth, Samuel Clarke, and John Balguy – held that morality originated in reason alone. The moral sentimentalists – such as Anthony Ashley Cooper, the third Earl of Shaftesbury, Francis Hutcheson, and David Hume – held that morality originated at least partly in sentiment. In addition to other arguments, the rationalists and sentimentalists developed rich analogies. The most significant analogy the rationalists developed was between morality and mathematics. The most significant analogy the sentimentalists developed was between morality and beauty. These two analogies illustrate well the main ideas, underlying insights, and accounts of moral phenomenology the two positions have to offer. An examination of the two analogies will thus serve as a useful introduction to the debate between moral rationalism and moral sentimentalism as a whole.
Hobbes's Reply to the Fool
Authors: LeBuffe Michael
Published: November 2006

The objection Hobbes raises in the voice of the Fool against his own argument is, apparently, that it is sometimes rational to break covenant. Hobbes's answer is puzzling, both because it seems implausible and also because it seems at odds with some of his own views. This article reviews several strategies critics have taken in trying to show that Hobbes's answer is more plausible than it seems and one attempt to show that the Fool's objection concerns the action of breaking covenant only indirectly.
Religious Literature of Late Period and Greco‐Roman Egypt
Authors: Jay Jacqueline E.
Published: November 2006

Although Egypt was ruled by foreigners during most of the Late and Greco‐Roman periods, native religious traditions remained strong and the period witnessed the production of a wide variety of religious texts written in the Egyptian language. This article presents many of the major religious texts of Egypt's Late and Greco‐Roman periods and comments on the trends of continuity and change that they suggest. It is divided into three sections. The first discusses texts written on temple walls or on papyri stored in temple scriptoria which speak to the ritual and theological activities of the priesthood. The second examines different types of oracle requests and divinatory texts which represent the practical religion of the living. The third focuses on mortuary texts recited over the deceased and funerary texts placed in the grave.1
Immunosuppressive Strategies that are Mediated by Tumor Cells
Authors: Rabinovich Gabriel A. , Gabrilovich Dmitry , Sotomayor Eduardo M.
Published: November 2006

Despite major advances in understanding the mechanisms leading to tumor immunity, a number of obstacles hinder the successful translation of mechanistic insights into effective tumor immunotherapy. Such obstacles include the ability of tumors to foster a tolerant microenvironment and the activation of a plethora of immunosuppressive mechanisms, which may act in concert to counteract effective immune responses. Here we discuss different strategies employed by tumors to thwart immune responses, including tumor-induced impairment of antigen presentation, the activation of negative costimulatory signals, and the elaboration of immunosuppressive factors. In addition, we underscore the influence of regulatory cell populations that may contribute to this immunosuppressive network; these include regulatory T cells, natural killer T cells, and distinct subsets of immature and mature dendritic cells. The current wealth of preclinical information promises a future scenario in which the synchronized blockade of immunosuppressive mechanisms may be effective in combination with other conventional strategies to overcome immunological tolerance and promote tumor regression.
Structure and Dynamics of Conjugated Polymers in Liquid Crystalline Solvents
Authors: Barbara P.F. , Chang W.-S. , Link S. , Scholes G.D. , Yethiraj Arun
Published: November 2006

A combination of single-molecule spectroscopy and analysis with simulations is used to provide detailed information about the structural and dynamic properties of a fluorescent polymer MEH-PPV (poly[2-methoxy-5-(2′-ethylhexyloxy)-1,4-phenylenevinylene]) immersed in a nematic and smectic solvent. In nematic solvents, single-polymer molecules are oriented strongly along the solvent director, much more so than the solvent molecules, confirming Onsager's old prediction. The diffusion anisotropy parallel and perpendicular to the solvent director, however, is less than two, which is similar to that of a spherical colloid in a nematic solvent. In smectic solvents, there is a second orientation of the dissolved polymer perpendicular to the solvent director, which we hypothesize is caused by the polymer occupying the interlayer volume. The research discussed here emphasizes the importance of organization in complex fluids and suggests that the interplay of order on different length scales could be exploited to fabricate novel nanostructured materials.
Measurement of Single-Molecule Conductance
Authors: Chen Fang , Hihath Joshua , Huang Zhifeng , Li Xiulan , Tao N.J.
Published: November 2006

What is the conductance of a single molecule? This basic and seemingly simple question has been a difficult one to answer for both experimentalists and theorists. To determine the conductance of a molecule, one must wire the molecule reliably to at least two electrodes. The conductance of the molecule thus depends not only on the intrinsic properties of the molecule, but also on the electrode materials. Furthermore, the conductance is sensitive to the atomic-level details of the molecule-electrode contact and the local environment of the molecule. Creating identical contact geometries has been a challenging experimental problem, and the lack of atomic-level structural information of the contacts makes it hard to compare calculations with measurements. Despite the difficulties, researchers have made substantial advances in recent years. This review provides an overview of the experimental advances, discusses the advantages and drawbacks of different techniques, and explores remaining issues.
Glucagon chronically impairs hepatic and muscle glucose disposal
Authors: Chen Sheng-Song , Zhang Yiqun , Santomango Tammy S. , Williams Phillip E. , Lacy D. Brooks , McGuinness Owen P.
Published: November 2006

Defects in insulin secretion and/or action contribute to the hyperglycemia of stressed and diabetic patients, and we hypothesize that failure to suppress glucagon also plays a role. We examined the chronic impact of glucagon on glucose uptake in chronically catheterized conscious depancreatized dogs placed on 5 days of nutritional support (NS). For 3 days of NS, a variable intraportal infusion of insulin was given to maintain isoglycemia (∼120 mg/dl). On day 3 of NS, animals received a constant low infusion of insulin (0.4 mU·kg−1·min−1) and either no glucagon (CONT), basal glucagon (0.7 ng·kg−1·min−1; BasG), or elevated glucagon (2.4 ng·kg−1·min−1; HiG) for the remaining 2 days. Glucose in NS was varied to maintain isoglycemia. An additional group (HiG + I) received elevated insulin (1 mU·kg−1·min−1) to maintain glucose requirements in the presence of elevated glucagon. On day 5 of NS, hepatic substrate balance was assessed. Insulin and glucagon levels were 10 ± 2, 9 ± 1, 7 ± 1, and 24 ± 4 μU/ml, and 24 ± 5, 39 ± 3, 80 ± 11, and 79 ± 5 pg/ml, CONT, BasG, HiG, and HiG + I, respectively. Glucagon infusion decreased the glucose requirements (9.3 ± 0.1, 4.6 ± 1.2, 0.9 ± 0.4, and 11.3 ± 1.0 mg·kg−1·min−1). Glucose uptake by both hepatic (5.1 ± 0.4, 1.7 ± 0.9, −1.0 ± 0.4, and 1.2 ± 0.4 mg·kg−1·min−1) and nonhepatic (4.2 ± 0.3, 2.9 ± 0.7, 1.9 ± 0.3, and 10.2 ± 1.0 mg·kg−1·min−1) tissues decreased. Additional insulin augmented nonhepatic glucose uptake and only partially improved hepatic glucose uptake. Thus, glucagon impaired glucose uptake by hepatic and nonhepatic tissues. Compensatory hyperinsulinemia restored nonhepatic glucose uptake and partially corrected hepatic metabolism. Thus, persistent inappropriate secretion of glucagon likely contributes to the insulin resistance and glucose intolerance observed in obese and diabetic individuals.
Abdominal obesity in BTBR male mice is associated with peripheral but not hepatic insulin resistance
Authors: Flowers Jessica B. , Oler Angie T. , Nadler Samuel T. , Choi YounJeong , Schueler Kathryn L. , Yandell Brian S. , Kendziorski Christina M. , Attie Alan D.
Published: November 2006

Insulin resistance is a common feature of obesity. BTBR mice have more fat mass than most other inbred mouse strains. On a chow diet, BTBR mice have elevated insulin levels relative to the C57BL/6J (B6) strain. Male F1 progeny of a B6 × BTBR cross are insulin resistant. Previously, we reported insulin resistance in isolated muscle and in isolated adipocytes in this strain. Whereas the muscle insulin resistance was observed only in male F1 mice, adipocyte insulin resistance was also present in male BTBR mice. We examined in vivo mechanisms of insulin resistance with the hyperinsulinemic euglycemic clamp technique. At 10 wk of age, BTBR and F1 mice had a >30% reduction in whole body glucose disposal primarily due to insulin resistance in heart, soleus muscle, and adipose tissue. The increased adipose tissue mass and decreased muscle mass in BTBR and F1 mice were negatively and positively correlated with whole body glucose disposal, respectively. Genes involved in focal adhesion, actin cytoskeleton, and inflammation were more highly expressed in BTBR and F1 than in B6 adipose tissue. The BTBR and F1 mice have higher levels of testosterone, which may be related to the pathological changes in adipose tissue that lead to systemic insulin resistance. Despite profound peripheral insulin resistance, BTBR and F1 mice retained hepatic insulin sensitivity. These studies reveal a genetic difference in body composition that correlates with large differences in peripheral insulin sensitivity.
Flow increases superoxide production by NADPH oxidase via activation of Na-K-2Cl cotransport and mechanical stress in thick ascending limbs
Authors: Hong Nancy J. , Garvin Jeffrey L.
Published: November 2006

Superoxide (O2−) regulates renal function and is implicated in hypertension. O2−production increases in response to increased ion delivery in thick ascending limbs (TALs) and macula densa and mechanical strain in other cell types. Tubular flow in the kidney acutely varies causing changes in ion delivery and mechanical stress. We hypothesized that increasing luminal flow stimulates O2−production by NADPH oxidase in TALs via activation of Na-K-2Cl cotransport. We measured intracellular O2−in isolated rat TALs using dihydroethidium in the presence and absence of luminal flow and inhibitors of NADPH oxidase, Na-K-2Cl cotransport, and Na/H exchange. In the absence of flow, the rate of O2−production was 5.8 ± 1.4 AU/s. After flow was initiated, it increased to 29.7 ± 4.3 AU/s ( P < 0.001). O2−production was linearly related to flow. Tempol alone and apocynin alone blocked the flow-induced increase in O2−production (3.5 ± 1.7 vs. 4.5 ± 2.8 AU/s and 8.2 ± 2.1 vs. 10.6 ± 2.8 AU/s, respectively). Furosemide decreased flow-induced O2−production by 55% (37.3 ± 5.2 to 16.8 ± 2.8 AU/s; P < 0.002); however, dimethylamiloride had no effect. Finally, we examined whether changes in mechanical forces are involved in flow-induced O2−production by using a Na-free solution to perfuse TALs. In the absence of NaCl, luminal flow enhanced O2−production (1.5 ± 0.5 to 13.5 ± 1.1 AU/s; P < 0.001), ∼50% less stimulation than when flow was increased in the presence of luminal NaCl. We conclude that flow stimulates O2−production in TALs via activation of NADPH oxidase and that NaCl absorption due to Na-K-2Cl cotransport and flow-associated mechanical factors contribute equally to this process.
Frontal Eye Field Contributions to Rapid Corrective Saccades
Authors: Murthy Aditya , Ray Supriya , Shorter Stephanie M. , Priddy Elizabeth G. , Schall Jeffrey D. , Thompson Kirk G.
Published: November 2006

Visually guided movements can be inaccurate, especially if unexpected events occur while the movement is programmed. Often errors of gaze are corrected before external feedback can be processed. Evidence is presented from macaque monkey frontal eye field (FEF), a cortical area that selects visual targets, allocates attention, and programs saccadic eye movements, for a neural mechanism that can correct saccade errors before visual afferent or performance monitoring signals can register the error. Macaques performed visual search for a color singleton that unpredictably changed position in a circular array as in classic double-step experiments. Consequently, some saccades were directed in error to the original target location. These were followed frequently by unrewarded, corrective saccades to the final target location. We previously showed that visually responsive neurons represent the new target location even if gaze shifted errantly to the original target location. Now we show that the latency of corrective saccades is predicted by the timing of movement-related activity in the FEF. Preceding rapid corrective saccades, the movement-related activity of all neurons began before explicit error signals arise in the medial frontal cortex. The movement-related activity of many neurons began before visual feedback of the error was registered and that of a few neurons began before the error saccade was completed. Thus movement-related activity leading to rapid corrective saccades can be guided by an internal representation of the environment updated with a forward model of the error.
Visual fMRI Responses in Human Superior Colliculus Show a Temporal–Nasal Asymmetry That Is Absent in Lateral Geniculate and Visual Cortex
Authors: Sylvester Richard , Josephs Oliver , Driver Jon , Rees Geraint
Published: November 2006

Eye patching has revealed enhanced saccadic latencies or attention effects when orienting toward visual stimuli presented in the temporal versus nasal hemifields of humans. Such behavioral advantages have been tentatively proposed to reflect possible temporal–nasal differences in the retinotectal pathway to the superior colliculus, rather than in the retinogeniculate pathway or visual cortex. However, this has not been directly tested with physiological measures in humans. Here, we examined responses of the human superior colliculus (SC) to contralateral visual field stimulation, using high spatial resolution fMRI, while manipulating which hemifield was stimulated and orthogonally which eye was patched. The SC responded more strongly to visual stimulation when eye-patching made this stimulation temporal rather than nasal. In contrast, the lateral geniculate nucleus (LGN) plus retinotopic cortical areas V1–V3 did not show any temporal–nasal differences and differed from the SC in this respect. These results provide the first direct physiological demonstration in humans that SC shows temporal–nasal differences that LGN and early visual cortex apparently do not. This may represent a temporal hemifield bias in the strength of the retinotectal pathway, leading to a preference for the contralateral hemifield in the contralateral eye.
Warning Signals Influence Motor Processing
Authors: Fecteau Jillian H. , Munoz Douglas P.
Published: November 2006

When observers initiate responses to visual targets, they do so sooner when a preceding stimulus indicates that the target will appear shortly. This consequence of a warning signal may change neural activity in one of four ways. On the sensory side, the warning signal may speed up the rate at which the target is registered by the brain or enhance the magnitude of its signal. On the motor end, the warning signal may lower the threshold required to initiate a response or speed up the rate at which activity accumulates to reach threshold. Here, we describe which explanation is better supported. To accomplish this end, monkeys performed different versions of a cue-target task while we monitored the activity of visuomotor and motor neurons in the superior colliculus. Although the cue target task was designed to measure the properties of reflexive spatial attention, there are two events in this task that produce nonspecific warning effects: a central reorienting event (brightening of central fixation marker) that is used to direct attention away from the cue, and the presentation of the cue itself. Monopolizing on these tendencies, we show that warning effects are associated with several changes in neural activity: the target-related response is enhanced, the threshold for initiating a saccade is lowered, and the rate at which activity accumulates toward threshold rises faster. Ultimately, the accumulation of activity toward threshold predicted behavior most closely. In the discussion, we describe the implications and limitations of these data for theories of warning effects and potential avenues for future research.
Neural and Electromyographic Correlates of Wrist Posture Control
Authors: Suminski Aaron J. , Rao Stephen M. , Mosier Kristine M. , Scheidt Robert A.
Published: November 2006

In identical experiments in and out of a MR scanner, we recorded functional magnetic resonance imaging and electromyographic correlates of wrist stabilization against constant and time-varying mechanical perturbations. Positioning errors were greatest while stabilizing random torques. Wrist muscle activity lagged changes in joint angular velocity at latencies suggesting trans-cortical reflex action. Drift in stabilized hand positions gave rise to frequent, accurately directed, corrective movements, suggesting that the brain maintains separate representations of desired wrist angle for feedback control of posture and the generation of discrete corrections. Two patterns of neural activity were evident in the blood-oxygenation-level-dependent (BOLD) time series obtained during stabilization. A cerebello-thalamo-cortical network showed significant activity whenever position errors were present. Here, changes in activation correlated with moment-by-moment changes in position errors (not force), implicating this network in the feedback control of hand position. A second network, showing elevated activity during stabilization whether errors were present or not, included prefrontal cortex, rostral dorsal premotor and supplementary motor area cortices, and inferior aspects of parietal cortex. BOLD activation in some of these regions correlated with positioning errors integrated over a longer time-frame consistent with optimization of feedback performance via adjustment of the behavioral goal (feedback setpoint) and the planning and execution of internally generated motor actions. The finding that nonoverlapping networks demonstrate differential sensitivity to kinematic performance errors over different time scales supports the hypothesis that in stabilizing the hand, the brain recruits distinct neural systems for feedback control of limb position and for evaluation/adjustment of controller parameters in response to persistent errors.
Population and systems genetics analyses of cortisol in pigs divergently selected for stress
Authors: Kadarmideen Haja N. , Janss Luc L. G.
Published: November 2006

This study presents a systems genetic analysis on the physiology of cortisol in mice and pigs with an aim to show the potential of a comprehensive computational approach to quickly identify candidate genes and avoid a costly whole-genome quantitative trait locus (QTL) mapping. Population genetics analyses were performed on measurements of cortisol from a pig selection experiment. Expression QTL were mapped and gene networks were built using gene expressions for Crhr1 (corticotrophin-releasing hormone receptor) gene and single nucleotide polymorphisms from public mouse data. Results from mouse data were used to infer potential candidate regulatory genes involved in pig cortisol regulation, using a comparative or translational systems genetics approach. The pig data used were from a 10-yr divergent genetic selection experiment, providing data on 417 individuals. Population genetics analysis showed that cortisol is highly genetically determined with heritabilities of 0.40–0.70. Furthermore, a major gene with an additive effect of 86 ng/ml is segregating. Genetical-genomics investigations revealed two trans-acting eQTL for Crhr1 gene expression on chromosomes 2 and 13. Candidate gene search under trans-eQTL peaks yielded 63 genes for Crhr1 expression phenotypes. Functional links for Crhr1 genes with other genes/proteins in the gene network using mouse data were shown for the first 10 statistically significant genes involved. Results show translational or comparative systems genetics approaches reduce costs and time in large-scale genetics and “-omics” investigations. This is the first study to report a strong genetic basis for cortisol physiology using a systems approach.
Characterization of circulatory disorders in β-thalassemic mice by noninvasive ultrasound biomicroscopy
Authors: Stoyanova Ekatherina , Trudel Marie , Felfly Hady , Garcia Damien , Cloutier Guy
Published: November 2006

β-Thalassemia is an inherited hematological disease caused by a decrease or absence of production of β-globin that requires chronic therapeutic interventions. This condition leads to important arterial and venous thromboembolic events, transitory ischemic attacks, and microcirculatory obstructions, indicative of circulatory disturbances. To investigate the presence of microcirculatory disorders without the confounding effect of treatments, we used β-thalassemic mice with typical clinical characteristics of human β-thalassemia major. One impediment to the understanding of microcirculatory physiology, in particular for β-thalassemic mice, has been the lack of an appropriate noninvasive imaging approach. We thus developed a novel noninvasive high-frequency ultrasound imaging method to evaluate murine vascular hemodynamic properties. In our β-thalassemic mice, total peripheral vascular resistance was significantly increased ( P < 0.01) compared with wildtype littermates, whereas mean blood pressure, heart rate, and cardiac output were similar ( P = nonsignificant). Importantly, the vascular hemodynamics in β-thalassemic mice were significantly affected according to the Pourcelot indexes measured in the common carotid artery and abdominal aorta ( P < 0.01 and P < 0.05, respectively). Hence, our β-thalassemia characterization of vascular hemodynamics by noninvasive ultrasonic approaches proves the existence and provides unique quantitative assessment of microcirculatory flow disturbances in those mice.
Lung cancer genetics and pharmacogenomics
Authors: Joshi V.A. , Kucherlapati R.
Published: November 2006

Epidermal growth factor receptor (EGFR)-targeted therapies have demonstrated remarkable success in a small subset of non-small cell lung cancer patients. The mechanism of response has been an area of active research, with somatic mutation in a number of genes in the EGFR signal transduction pathway and copy number alterations of genes of the EGFR family as candidates contributing towards response. Continuing studies should help determine an appropriate biomarker or combination of biomarkers that can be used to predict response to this class of therapy.
Medical applications of array CGH and the transformation of clinical cytogenetics
Authors: Shaffer L.G. , Bejjani B.A.
Published: November 2006

Microarray-based comparative genomic hybridization (array CGH) merges molecular diagnostics with traditional chromosome analysis and is transforming the field of cytogenetics. Prospective studies of individuals with developmental delay and dysmorphic features have demonstrated that array CGH has the ability to detect any genomic imbalance including deletions, duplications, aneuploidies and amplifications. Detection rates for chromosome abnormalities with array CGH range from 5–17% in individuals with normal results from prior routine cytogenetic testing. In addition, copy number variants (CNVs) were identified in all studies. These CNVs may include large-scale variation and can confound the diagnostic interpretations. Although cytogeneticists will require additional training and laboratories must become appropriately equipped, array CGH holds the promise of being the initial diagnostic tool in the identification of visible and submicroscopic chromosome abnormalities in mental retardation and other developmental disabilities.
Incontinence Induces Stratum Corneum Vulnerability and Impairs the Skin Barrier Function in the Perianal Region
Authors: Nakagami Gojiro , Sanada Hiromi , Kitagawa Atsuko , Tadaka Etsuko , Maekawa Takeo , Nagase Takashi , Konya Chizuko
Published: November 2006

Background: Incontinence leads to a reduced skin barrier function, while also increasing the risk of skin breakdown. Aim: To investigate the perianal skin barrier function of elderly patients with or without incontinence. Methods: We compared the skin barrier function by investigating the skin hydration, the skin pH, the amount of ceramide and by making a dermatological skin inspection of the perianal region in patients with and without incontinence. Results: Twenty-one incontinent patients (70.0%) showed a glossy skin, which indicates impairment of the skin barrier while none of the patients in the continence group did so. In the incontinence group, those who had a glossy skin showed a significantly greater skin pH and total amount of ceramide than those with a normal skin (p = 0.0099, p = 0.0179, respectively). Conclusions: These results demonstrate that a glossy skin may be a useful indicator of a reduced perianal skin barrier function.
Surgery for Foreign Body Reactions due to Injectable Fillers
Authors: Wolfram Dolores , Tzankov Alexandar , Piza-Katzer Hildegunde
Published: November 2006

Background: An increasing number of soft tissue fillers have been introduced to the beauty market and these filler substances are widely used as non-toxic, non-immunogenic and relatively harmless injectable alternatives to surgical rejuvenation. Generally, facial fillers are injectable – or surgically insertable – products that are used to fill up the volume loss in the aging face. Depending on bioavailability, chemical composition and degradation, fillers can be classified as temporary or permanent, organic or inorganic and autologous or heterologous. Objective: A plethora of new products has swamped the beauty market since face rejuvenation has become socially acceptable as well as affordable to a wider population, but adverse reactions cannot be excluded. We present 4 patients with complications after injection of facial fillers [including Artecoll®(polymethylmethacrylate microspheres), Restylane® (hyaluronic acid), DermaLive® (hyaluronic acid plus acrylic hydrogel particles) and Newfill® (polylactic acid)] and surgical correction. Results: Surgical intervention led to good aesthetic and functional results after multiple unsuccessful conservative therapies. Conclusion: We recommend that only physicians familiar with the injection techniques and the biological and chemical characteristics of the various injectable products should perform such interventions. Especially permanent fillers should be used with utmost reticence in cosmetic surgery and we would recommend their application only in reconstructive procedures. Additionally, documentation and reporting of all adverse effects must be mandatory.