bluuebunny/crossref_metadata_2025 huggingface dataset:
SPIN DEPENDENT WIGNER FUNCTION SIMULATIONS OF DILUTED MAGNETIC SEMICONDUCTOR SUPERLATTICES – B FIELD TUNING
Authors: GRUBIN H. L.
Published: October 2007

Two terminal devices have traditionally provided band-structure based high frequency operation. Third terminal control often involves hybrid design approaches. The presence of diluted magnetic semiconductor layers in device fabrication should permit the magnetic field to function as a pseudothird terminal. This is discussed for single barrier, double barrier and superlattice structures, where control is demonstrated. The limits of high frequency operation are discussed in general terms with application to barrier devices and superlattices containing DMS layers.
Clockmutation facilitates accumulation of cholesterol in the liver of mice fed a cholesterol and/or cholic acid diet
Authors: Kudo Takashi , Kawashima Mihoko , Tamagawa Toru , Shibata Shigenobu
Published: October 2007

Cholesterol (CH) homeostasis in the liver is regulated by enzymes of CH synthesis such as 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and catabolic enzymes such as cytochrome P-450, family 7, subfamily A, and polypeptide 1 (CYP7A1). Since a circadian clock controls the gene expression of these enzymes, these genes exhibit circadian rhythm in the liver. In this study, we examined the relationship between a diet containing CH and/or cholic acid (CA) and the circadian regulation of Hmgcr, low-density lipoprotein receptor ( Ldlr), and Cyp7a1 gene expression in the mouse liver. A 4-wk CA diet lowered and eventually abolished the circadian expression of these genes. Not only clock genes such as period homolog 2 (Drosophila) ( Per2) and brain and muscle arnt-like protein-1 ( Bmal1) but also clock-controlled genes such as Hmgcr, Ldlr, and Cyp7a1 showed a reduced and arrhythmic expression pattern in the liver of Clock mutant mice. The reduced gene expression of Cyp7a1 in mice fed a diet containing CA or CH + CA was remarkable in the liver of Clock mutants compared with wild-type mice, and high liver CH accumulation was apparent in Clock mutant mice. In contrast, a CH diet without CA only elevated Cyp7a1 expression in both wild-type and Clock mutant mice. The present findings indicate that normal circadian clock function is important for the regulation of CH homeostasis in the mouse liver, especially in conjunction with a diet containing high CH and CA.
Thyroid hormone is required for the phenotype transitions induced by the pharmacological inhibition of calcineurin in adult soleus muscle of rats
Authors: Koulmann Nathalie , Bahi Lahoucine , Ribera Florence , Sanchez Hervé , Serrurier Bernard , Chapot Rachel , Peinnequin André , Ventura-Clapier Renée , Bigard Xavier
Published: October 2007

The present experiment was designed to examine the effects of hypothyroidism and calcineurin inhibition induced by cyclosporin A (CsA) administration on both contractile and metabolic soleus muscle phenotypes, with a novel approach to the signaling pathway controlling mitochondrial biogenesis. Twenty-eight rats were randomly assigned to four groups, normothyroid, hypothyroid, and orally treated with either CsA (25 mg/kg, N-CsA and H-CsA) or vehicle (N-Vh and H-Vh), for 3 wk. Muscle phenotype was estimated by the MHC profile and activities of oxidative and glycolytic enzymes. We measured mRNA levels of the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), the major regulator of mitochondrial content. We also studied the expression of the catalytic A-subunit of calcineurin (CnA) both at protein and transcript levels and mRNA levels of modulatory calcineurin inhibitor proteins (MCIP)-1 and -2, which are differentially regulated by calcineurin activity and thyroid hormone, respectively. CsA-administration induced a slow-to-fast MHC transition limited to the type IIA isoform, which is associated with increased oxidative capacities. Hypothyroidism strongly decreased both the expression of fast MHC isoforms and oxidative capacities. Effects of CsA administration on muscle phenotype were blocked in conditions of thyroid hormone deficiency. Changes in the oxidative profile were strongly related to PGC-1α changes and associated with phosphorylation of p38 MAPK. Calcineurin and MCIPs mRNA levels were decreased by both hypothyroidism and CsA without additive effects. Taken together, these results suggest that adult muscle phenotype is primarily under the control of thyroid state. Physiological levels of thyroid hormone are required for the effects of calcineurin inhibition on slow oxidative muscle phenotype.
Berberine improves glucose metabolism through induction of glycolysis
Authors: Yin Jun , Gao Zhanguo , Liu Dong , Liu Zhijun , Ye Jianping
Published: October 2007

Berberine, a botanical alkaloid used to control blood glucose in type 2 diabetes in China, has recently been reported to activate AMPK. However, it is not clear how AMPK is activated by berberine. In this study, activity and action mechanism of berberine were investigated in vivo and in vitro. In dietary obese rats, berberine increased insulin sensitivity after 5-wk administration. Fasting insulin and HOMA-IR were decreased by 46 and 48%, respectively, in the rats. In cell lines including 3T3-L1 adipocytes, L6 myotubes, C2C12myotubes, and H4IIE hepatocytes, berberine was found to increase glucose consumption, 2-deoxyglucose uptake, and to a less degree 3- O-methylglucose (3-OMG) uptake independently of insulin. The insulin-induced glucose uptake was enhanced by berberine in the absence of change in IRS-1 (Ser307/312), Akt, p70 S6, and ERK phosphorylation. AMPK phosphorylation was increased by berberine at 0.5 h, and the increase remained for ≥16 h. Aerobic and anaerobic respiration were determined to understand the mechanism of berberine action. The long-lasting phosphorylation of AMPK was associated with persistent elevation in AMP/ATP ratio and reduction in oxygen consumption. An increase in glycolysis was observed with a rise in lactic acid production. Berberine exhibited no cytotoxicity, and it protected plasma membrane in L6 myotubes in the cell culture. These results suggest that berberine enhances glucose metabolism by stimulation of glycolysis, which is related to inhibition of glucose oxidation in mitochondria. Berberine-induced AMPK activation is likely a consequence of mitochondria inhibition that increases the AMP/ATP ratio.
The gastroduodenal branch of the common hepatic vagus regulates voluntary lard intake, fat deposition, and plasma metabolites in streptozotocin-diabetic rats
Authors: Warne James P. , Foster Michelle T. , Horneman Hart F. , Pecoraro Norman C. , de Jong Hanna K. , Ginsberg Abigail B. , Akana Susan F. , Dallman Mary F.
Published: October 2007

The common hepatic branch of the vagus nerve negatively regulates lard intake in rats with streptozotocin (STZ)-induced, insulin-dependent diabetes. However, this branch consists of two subbranches: the hepatic branch proper, which serves the liver, and the gastroduodenal branch, which serves the distal stomach, pancreas, and duodenum. The aim of this study was to determine whether the gastroduodenal branch specifically regulates voluntary lard intake. We performed a gastroduodenal branch vagotomy (GV) on nondiabetic, STZ-diabetic, and STZ-diabetic insulin-treated groups of rats and compared them with sham-operated counterparts. All rats had high steady-state corticosterone levels to maximize lard intake. Five days after surgery, all rats were provided with the choice of chow or lard to eat for another 5 days. STZ-diabetes resulted in a reduction in lard intake that was partially rescued by either GV or insulin treatment. Patterns of white adipose tissue (WAT) deposition differed after GV- and insulin-induced lard intake, with subcutaneous WAT increasing exclusively after the former and mesenteric WAT increasing exclusively in the latter. GV also prevented the insulin-induced reduction in the STZ-elevated plasma glucagon, triglycerides, free fatty acids, and total ketone bodies but did not alter the effect of insulin-induced reduction of plasma glucose levels. These data suggest that the gastroduodenal branch of the vagus inhibits lard intake and regulates WAT deposition and plasma metabolite levels in STZ-diabetic rats.
A novel GIP receptor splice variant influences GIP sensitivity of pancreatic β-cells in obese mice
Authors: Harada Norio , Yamada Yuichiro , Tsukiyama Katsushi , Yamada Chizumi , Nakamura Yasuhiko , Mukai Eri , Hamasaki Akihiro , Liu Xibao , Toyoda Kentaro , Seino Yutaka , Inagaki Nobuya
Published: October 2007

Gastric inhibitory polypeptide (GIP) is an incretin that potentiates insulin secretion from pancreatic β-cells by binding to GIP receptor (GIPR) and subsequently increasing the level of intracellular adenosine 3′,5′-cyclic monophosphate (cAMP). We have identified a novel GIPR splice variant in mouse β-cells that retains intron 8, resulting in a COOH-terminal truncated form (truncated GIPR). This isoform was coexpressed with full-length GIPR (wild-type GIPR) in normal GIPR-expressing tissues. In an experiment using cells transfected with both GIPRs, truncated GIPR did not lead to cAMP production induced by GIP but inhibited GIP-induced cAMP production through wild-type GIPR ( n = 3–4, P < 0.05). Wild-type GIPR was normally located on the cell surface, but its expression was decreased in the presence of truncated GIPR, suggesting a dominant negative effect of truncated GIPR against wild-type GIPR. The functional relevance of truncated GIPR in vivo was investigated. In high-fat diet-fed obese mice (HFD mice), blood glucose levels were maintained by compensatory increased insulin secretion ( n = 8, P < 0.05), and cAMP production ( n = 6, P < 0.01) and insulin secretion ( n = 10, P < 0.05) induced by GIP were significantly increased in isolated islets, suggesting hypersensitivity of the GIPR. Total GIPR mRNA expression was not increased in the islets of HFD mice, but the expression ratio of truncated GIPR to total GIPR was reduced by 32% compared with that of control mice ( n = 6, P < 0.05). These results indicate that a relative reduction of truncated GIPR expression may be involved in hypersensitivity of GIPR and hyperinsulinemia in diet-induced obese mice.
Oxyntomodulin ameliorates glucose intolerance in mice fed a high-fat diet
Authors: Parlevliet Edwin T. , Heijboer Annemieke C. , Schröder-van der Elst Janny P. , Havekes Louis M. , Romijn Johannes A. , Pijl Hanno , Corssmit Eleonora P. M.
Published: October 2007

We evaluated the acute effects of OXM on glucose metabolism in diet-induced insulin-resistant male C57Bl/6 mice. To determine the effects on glucose tolerance, mice were intraperitoneally injected with OXM (0.75, 2.5, or 7.5 nmol) or vehicle prior to an ip glucose tolerance test. OXM (0.75 nmol/h) or vehicle was infused during a hyperinsulinemic euglycemic clamp to quantify insulin action on glucose production and disposal. OXM dose-dependently improved glucose tolerance as estimated by AUC for glucose (OXM: 7.5 nmol, 1,564 ± 460, P < 0.01; 2.5 nmol, 1,828 ± 684, P < 0.01; 0.75 nmol, 2,322 ± 303, P < 0.05; control: 2,790 ± 222 mmol·l−1·120 min). Insulin levels in response to glucose administration were higher in 7.5 nmol OXM-treated animals compared with controls. In basal clamp conditions, OXM increased EGP (82.2 ± 14.7 vs. 39.9 ± 5.7 μmol·min−1·kg−1, P < 0.001). During insulin infusion, insulin levels were twice as high in OXM-treated mice compared with controls (10.6 ± 2.8 vs. 4.4 ± 2.2 ng/ml, P < 0.01). Consequently, glucose infusion rate (118.6 ± 30.8 vs. 38.8 ± 26.4 μl/h, P < 0.001) and glucose disposal (88.1 ± 13.0 vs. 45.2 ± 6.9 μmol·min−1·kg−1, P < 0.001) were enhanced in mice that received OXM. In addition, glucose production was more suppressed during OXM infusion (35.7 ± 15.5 vs. 15.8 ± 11.4% inhibition, P < 0.05). However, if these data were expressed per unit concentration of circulating insulin, OXM did not affect insulin action on glucose disposal and production. These results indicate that OXM beneficially affects glucose metabolism in diet-induced insulin-resistant C57Bl/6 mice. It ameliorates glucose intolerance, most likely because it elevates glucose-induced plasma insulin concentrations. OXM does not appear to impact on insulin action.
GABAB receptors and glucose homeostasis: evaluation in GABAB receptor knockout mice
Authors: Bonaventura M. M. , Catalano P. N. , Chamson-Reig A. , Arany E. , Hill D. , Bettler B. , Saravia F. , Libertun C. , Lux-Lantos V. A.
Published: October 2007

GABA has been proposed to inhibit insulin secretion through GABAB receptors (GABABRs) in pancreatic β-cells. We investigated whether GABABRs participated in the regulation of glucose homeostasis in vivo. The animals used in this study were adult male and female BALB/C mice, mice deficient in the GABAB1 subunit of the GABABR (GABAB−/−), and wild types (WT). Blood glucose was measured under fasting/fed conditions and in glucose tolerance tests (GTTs) with a Lifescan Glucose meter, and serum insulin was measured by ELISA. Pancreatic insulin content and islet insulin were released by RIA. Western blots for the GABAB1 subunit in islet membranes and immunohistochemistry for insulin and GABAB1 were performed in both genotypes. BALB/C mice preinjected with Baclofen (GABABR agonist, 7.5 mg/kg ip) presented impaired GTTs and decreased insulin secretion compared with saline-preinjected controls. GABAB−/− mice showed fasting and fed glucose levels similar to WT. GABAB−/− mice showed improved GTTs at moderate glucose overloads (2 g/kg). Baclofen pretreatment did not modify GTTs in GABAB−/− mice, whereas it impaired normal glycemia reinstatement in WT. Baclofen inhibited glucose-stimulated insulin secretion in WT isolated islets but was without effect in GABAB−/− islets. In GABAB−/− males, pancreatic insulin content was increased, basal and glucose-stimulated insulin secretion were augmented, and impaired insulin tolerance test and increased homeostatic model assessment of insulin resistance index were determined. Immunohistochemistry for insulin demonstrated an increase of very large islets in GABAB−/− males. Results demonstrate that GABABRs are involved in the regulation of glucose homeostasis in vivo and that the constitutive absence of GABABRs induces alterations in pancreatic histology, physiology, and insulin resistance.
Differential energetic response of brain vs. skeletal muscle upon glycemic variations in healthy humans
Authors: Oltmanns Kerstin M. , Melchert Uwe H. , Scholand-Engler Harald G. , Howitz Maria C. , Schultes Bernd , Schweiger Ulrich , Hohagen Fritz , Born Jan , Peters Achim , Pellerin Luc
Published: October 2007

The brain regulates all metabolic processes within the organism, and therefore, its energy supply is preserved even during fasting. However, the underlying mechanism is unknown. Here, it is shown, using 31P-magnetic resonance spectroscopy that during short periods of hypoglycemia and hyperglycemia, the brain can rapidly increase its high-energy phosphate content, whereas there is no change in skeletal muscle. We investigated the key metabolites of high-energy phosphate metabolism as rapidly available energy stores by 31P MRS in brain and skeletal muscle of 17 healthy men. Measurements were performed at baseline and during dextrose or insulin-induced hyperglycemia and hypoglycemia. During hyperglycemia, phosphocreatine (PCr) concentrations increased significantly in the brain ( P = 0.013), while there was a similar trend in the hypopglycemic condition ( P = 0.055). Skeletal muscle content remained constant in both conditions ( P > 0.1). ANOVA analyses comparing changes from baseline to the respective glycemic plateau in brain (up to +15%) vs. muscle (up to −4%) revealed clear divergent effects in both conditions ( P < 0.05). These effects were reflected by PCr/Pi ratio ( P < 0.05). Total ATP concentrations revealed the observed divergency only during hyperglycemia ( P = 0.018). These data suggest that the brain, in contrast to peripheral organs, can activate some specific mechanisms to modulate its energy status during variations in glucose supply. A disturbance of these mechanisms may have far-reaching implications for metabolic dysregulation associated with obesity or diabetes mellitus.
Exercise-heat acclimation in humans alters baseline levels and ex vivo heat inducibility of HSP72 and HSP90 in peripheral blood mononuclear cells
Authors: McClung James P. , Hasday Jeffrey D. , He Ju-ren , Montain Scott J. , Cheuvront Samuel N. , Sawka Michael N. , Singh Ishwar S.
Published: October 2007

The induction of cellular acquired thermal tolerance (ATT) during heat acclimation (HA) in humans is not well described. This study determined whether exercise-HA modifies the human heat shock protein (HSP)72 and HSP90 responses and whether changes are correlated with physiological adaptations to HA. Using a 10-day HA protocol comprising daily exercise (treadmill walking) in a hot environment ( Ta = 49°C, 20% RH), we analyzed baseline and ex vivo heat-induced expression of HSP72 and HSP90 in peripheral blood mononuclear cells (PBMCs) isolated prior to exercise from eight subjects on day 1 and 10 of the HA protocol. Classical physiological responses to HA were observed, including significantly reduced heart rate and core body temperature, and significantly increased sweating rate. Baseline levels of HSP72 and HSP90 were significantly increased following acclimation by 17.7 ± 6.1% and 21.1 ± 6.5%, respectively. Ex vivo induction of HSP72 in PBMCs exposed to heat shock (43°C) was blunted on day 10 compared with day 1. A correlation was identified ( r2 = 0.89) between changes in core temperature elevation and ex vivo HSP90 responses to heat shock between days 1 and 10, indicating that volunteers demonstrating the greatest physiological HA tended to exhibit the greatest blunting of ex vivo HSP induction in response to heat shock. In summary, 1) exercise-HA resulted in increased baseline levels of HSP72 and HSP90, 2) ex vivo heat inducibility of HSP72 was blunted after HA, and 3) volunteers demonstrating the greatest physiological HA tended to exhibit the greatest blunting of ex vivo HSP induction in response to heat shock. These data demonstrate that physiological adaptations in humans undergoing HA are accompanied by both increases in baseline levels and changes in regulation of cytoprotective HSPs.
Premotor Inhibitory Neurons Carry Signals Related to Saccade Adaptation in the Monkey
Authors: Kojima Yoshiko , Iwamoto Yoshiki , Robinson Farrel R. , Noto Christopher T. , Yoshida Kaoru
Published: October 2007

Cerebellar output changes during motor learning. How these changes cause alterations of motoneuron activity and movement remains an unresolved question for voluntary movements. To answer this question, we examined premotor neurons for saccadic eye movement. Previous studies indicate that cells in the fastigial oculomotor region (FOR) within the cerebellar nuclei on one side exhibit a gradual increase in their saccade-related discharge as the amplitude of ipsiversive saccades adaptively decreases. This change in FOR activity could cause the adaptive change in saccade amplitude because neurons in the FOR project directly to the brain stem region containing premotor burst neurons (BNs). To test this possibility, we recorded the activity of saccade-related burst neurons in the area that houses premotor inhibitory burst neurons (IBNs) and examined their discharge during amplitude-reducing adaptation elicited by intrasaccadic target steps. We specifically analyzed their activity for off-direction (contraversive) saccades, in which the IBN activity would increase to reduce saccade size. Before adaptation, 29 of 42 BNs examined discharged, at least occasionally, for contraversive saccades. As the amplitude of contraversive saccades decreased adaptively, half of BNs with off-direction spike activity showed an increase in the number of spikes (14/29) or an earlier occurrence of spikes (7/14). BNs that were silent during off-direction saccades before adaptation remained silent after adaptation. These results indicate that the changes in the off-direction activity of BNs are closely related to adaptive changes in saccade size and are appropriate to cause these changes.
Hemispheric Coordination Is Necessary for Song Production in Adult Birds: Implications for a Dual Role for Forebrain Nuclei in Vocal Motor Control
Authors: Ashmore Robin C. , Bourjaily Mark , Schmidt Marc F.
Published: October 2007

Precise coordination across hemispheres is a critical feature of many complex motor circuits. In the avian song system the robust nucleus of the arcopallium (RA) plays a key role in such coordination. It is simultaneously the major output structure for the descending vocal motor pathway, and it also sends inputs to structures in the brain stem and thalamus that project bilaterally back to the forebrain. Because all birds lack a corpus callosum and the anterior commissure does not interconnect any of the song control nuclei directly, these bottom-up connections form the only pathway that can coordinate activity across hemispheres. In this study, we show that unilateral lesions of RA in adult male zebra finches ( Taeniopigia guttata) completely and permanently disrupt the bird's stereotyped song. In contrast, lesions of RA in juvenile birds do not prevent the acquisition of normal song as adults. These results highlight the importance of hemispheric interdependence once the circuit is established but show that one hemisphere is sufficient for complex vocal behavior if this interdependence is prevented during a critical period of development. The ability of birds to sing with a single RA provides the opportunity to test the effect of targeted microlesions in RA without confound of functional compensation from the contralateral RA. We show that microlesions cause significant changes in song temporal structure and implicate RA as playing a major part in the generation of song temporal patterns. These findings implicate a dual role for RA, first as part of the program generator for song and second as part of the circuit that mediates interhemispheric coordination.
Tissue expression patterns identify mouse cilia genes
Authors: McClintock Timothy S. , Glasser Chad E. , Bose Soma C. , Bergman Daniel A.
Published: October 2007

In mammals, cilia are critical for development, sensation, cell signaling, sperm motility, and fluid movement. Defects in cilia are causes of several congenital syndromes, providing additional reasons to identify cilia-related genes. We hypothesized that mRNAs selectively abundant in tissues rich in highly ciliated cells encode cilia proteins. Selective abundance in olfactory epithelium, testes, vomeronasal organ, trachea, and lung proved to be an expression pattern uniquely effective in identifying documented cilia-related genes. Known and suspected cilia-related genes were statistically overrepresented among the 99 genes identified, but the majority encoded proteins of unknown function, thereby predicting new cilia-related proteins. Evidence of expression in a highly ciliated cell, the olfactory sensory neuron, exists for 73 of the genes. In situ hybridization for 17 mRNAs confirmed expression of all 17 in olfactory sensory neurons. Most were also detected in vomeronasal sensory neurons and in neighboring tissues rich in ciliated cells such as respiratory epithelium. Immunoreactivity for one of the proteins identified, Spa17, colocalized with acetylated tubulin in the cilia layer of the olfactory epithelium. In contrast, the ciliary rootlet protein, Crocc, was located in discrete structures whose position was consistent with the dendritic knobs of the olfactory sensory neurons. A compilation of >2,000 mouse genes predicted to encode cilia-related proteins revealed a strong correlation ( R = 0.99) between the number of studies predicting a gene's involvement in cilia and documented evidence of such involvement, a fact that simplifies the selection of genes for further study of the physiology of cilia.
Identification of Nogo as a novel indicator of heart failure
Authors: Bullard Tara A. , Protack Tricia L. , Aguilar Frédérick , Bagwe Suveer , Massey H. Todd , Blaxall Burns C.
Published: October 2007

Numerous genetically engineered animal models of heart failure (HF) exhibit multiple characteristics of human HF, including aberrant β-adrenergic signaling. Several of these HF models can be rescued by cardiac-targeted expression of the Gβγ inhibitory carboxy-terminus of the β-adrenergic receptor kinase (βARKct). We recently reported microarray analysis of gene expression in multiple animal models of HF and their βARKct rescue, where we identified gene expression patterns distinct and predictive of HF and rescue. We have further investigated the muscle LIM protein knockout model of HF (MLP−/−), which closely parallels human dilated cardiomyopathy disease progression and aberrant β-adrenergic signaling, and their βARKct rescue. A group of known and novel genes was identified and validated by quantitative real-time PCR whose expression levels predicted phenotype in both the larger HF group and in the MLP−/− subset. One of these novel genes is herein identified as Nogo, a protein widely studied in the nervous system, where it plays a role in regeneration. Nogo expression is altered in HF and normalized with rescue, in an isoform-specific manner, using left ventricular tissue harvested from both animal and human subjects. To investigate cell type-specific expression of Nogo in the heart, immunofluorescence and confocal microscopy were utilized. Nogo expression appears to be most clearly associated with cardiac fibroblasts. To our knowledge, this is the first report to demonstrate the relationship between Nogo expression and HF, including cell-type specificity, in both mouse and human HF and phenotypic rescue.
Estrogen Receptor Alpha Gene Polymorphisms and First-Ever Intracerebral Hemorrhage
Authors: Strand Magnus , Söderström Ingegerd , Wiklund Per-Gunnar , Hallmans Göran , Weinehall Lars , Söderberg Stefan , Olsson Tommy
Published: October 2007

Background: Signaling through estrogen receptor alpha (ERα) regulates vasodilatation and atherogenesis. Since hypertension and atherosclerosis are major mechanisms in stroke development, we hypothesized that genetic variants of the ERα gene (ESR1) are determinants of future ischemic stroke or intracerebral hemorrhage (ICH). Methods: In a population-based prospective nested case-control study, the relationships between ESR1 polymorphisms (c.454–397T>C and c.454–351A>G) and ischemic stroke and ICH were examined in univariate and multivariate models using conditional logistic regression, which included established risk factors.Definitive first-ever stroke events (n = 388), including ischemic stroke (n = 320), ICH (n = 61), and unspecified stroke (n = 7) cases, and controls without cardiovascular disease (n = 773), matched for age, sex, and geographical region were included. Results: Carriers of the c.454–397T/T genotype had a significantly (p = 0.017) increased risk of ICH (OR 2.31, 95% CI 1.16–4.60) in a univariate analysis. This association persisted (OR 3.94, 95% CI 1.54–10.03), after adjustment for stroke risk determinants. Carriers of c.454–397T/T or c.454–397T/C genotypeshad significantly (p = 0.002 and p = 0.004, respectively) higher mean systolic blood pressure (SBP), than carriers of c.454–397C/C, and a similar relationship was observed for diastolic blood pressure (DBP). The combinations of c.454–397T/T genotype and hypertension (OR 21.46, 95% CI 5.20–88.51), or high SBP (OR 18.17, 95% CI 4.91–67.31) or DBP (OR 11.94, 95% CI 3.75–38.03), were strongly associated with increased risk of ICH. Conclusions: In this population,the c.454–397T/T genotype associates with first-ever ICH, particularly in combination with hypertension. This implies that alterations in ERα-mediated signaling may be involved in the pathophysiology of this disease, with a putative impact on primary prevention.
Clinical MRI Cutoff Points for Predicting Lacunar Stroke May Not Exist: Need for a Grading rather than a Dichotomizing System
Authors: Bang Oh Young , Yeo Seung Hyeon , Yoon Jung Han , Seok Jung Im , Sheen Seung Soo , Yoon Sa Rah , Kim Gyeong Moon , Chung Chin Sang , Lee Kwang Ho
Published: October 2007

Background: Lacunar stroke has been defined as an infarct <15 mm in diameter in the presence of symptoms of lacunar syndromes. We investigated a new approach in predicting whether a deep infarct is caused by small arterial occlusion. Methods: A total of 319 consecutive patients with acute symptomatic infarcts within the striatocapsular territory underwent diffusion-weighted imaging (DWI) and diagnostic workups, including vascular and cardiological studies. Predictors for nonlacunar mechanisms were evaluated by logistic regression analysis, with the size of infarct (1-mm increase) and stroke syndrome (traditional vs. atypical lacunar syndrome vs. cortical syndrome) graded rather than dichotomized. Results: Amongst the 171 patients who did not meet the established criteria for lacunar stroke, that is, deep infarct of ≧15 mm or presenting symptoms of nontraditional lacunar syndrome, a documented etiology could not be determined in 97 (56.7%) patients. In contrast, amongst the 148 patients who met the criteria, 27 (18.2%) had nonlacunar mechanisms. Logistic regression analysis identified the variables that predicted nonlacunar stroke mechanisms with statistical significance as nontraditional lacunar syndromes (OR 2.19 for atypical lacunar syndrome, and OR 6.72 for cortical syndrome), infarct size on DWI (OR 1.05 per 1-mm increase), and unilateral multiple deep infarcts on DWI (OR 2.22, p < 0.05 in all cases). Receiver operating characteristic curves showed that discrimination power of the model derived from logistic regression analysis (grading system) was better than that of the previously established dichotomizing criterion in predicting nonlacunar mechanisms (p = 0.004). Conclusions: A clinically significant proportion of clinical MRI lacunae are associated with underlying nonlacunar mechanisms. Decisions regarding the extent of diagnostic procedures in patients with subcortical infarcts can be guided by the point value in terms of the stroke syndrome and infarct patterns, as well as the size of infarct.
Simultaneous Hybrid COronary Revascularization Using Totally Endoscopic Left Internal Mammary Artery Bypass Grafting and Placement of RapamycIN Eluting Stents in the SAme IntervenTIONal Session
Authors: Bonatti Johannes , Schachner Thomas , Bonaros Nikolaos , Jonetzko Patrycja , Öhlinger Armin , Ruetzler Elisabeth , Kolbitsch Christian , Feuchtner Gudrun , Laufer Guenther , Pachinger Otmar , Friedrich Guy
Published: October 2007

Objectives: Hybrid coronary revascularization procedures apply minimally invasive coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) for treatment of multivessel coronary artery disease. For logistic reasons simultaneous procedures would be desirable. In a pilot study the feasibility of simultaneous robotic totally endoscopic CABG and PCI using drug eluting stents was assessed. Patients and Methods: Five patients were scheduled to undergo simultaneous combined coronary inter- vention. A left internal mammary artery bypass graft was placed to the left anterior descending artery (LAD) in a completely endoscopic fashion using the daVinciTM telemanipulation system. PCI was carried out in the surgical operating room with the GE OEC9800 mobile coronary angiography C-arm. Rapamycin coated Cypher™ stents were placed into stenotic non-LAD targets. Results: The procedure was feasible in 4 patients, one patient was converted to a double CABG operation. There were no significant postoperative clinical complications and patients were discharged from intensive care unit and the hospital after 19 (18–61) hours and 6 (5–7) days respectively. At 6 months postoperatively all patients are free from angina. Conclusion: We conclude that simultaneous robotic totally endoscopic left internal mammary artery to LAD placement and PCI to non-LAD targets using drug eluting stents is feasible in one session.
Periprocedural Abciximab Administration in ST Elevation Myocardial Infarction Patients
Authors: Tarantini Giuseppe , Ramondo Angelo , Corbetti Francesco , Perazzolo Marra Martina , Cacciavillani Luisa , Napodano Massimo , Bilato Claudio , Razzolini Renato , Iliceto Sabino
Published: October 2007

Objectives: The impact of periprocedural (before primary percutaneous coronary angioplasty, PCI) abciximab administration on microvascular obstruction in patients with occluded infarct-related artery (IRA) is unknown. Methods: We studied 36 consecutive patients with first ST elevation myocardial infarction (STEMI) and occluded IRA treated with successful primary PCI within 12 h from symptom onset, who received intravenous abciximab immediately before PCI and 49 matched patients who did not receive abciximab as controls. All patients underwent delayed-enhanced magnetic resonance (DE-MR) 6 ± 2 days after PCI. Necrosis was judged as transmural when DE was extended to ≧75% of left ventricular (LV) segment thickness. Severe microvascular obstruction was identified as areas of late hypoenhancement surrounded by DE. Results: Time to treatment was comparable in the two groups (182 ± 60 vs. 188 ± 110 min, respectively). Transmurality and severe microvascular obstruction were present in 3.03 ± 2.8 versus 3.09 ± 2.9 (p = 0.9) and 1.05 ± 1.5 versus 1.06 ± 1.8 (p = 0.6) of LV segments, respectively, in the abciximab group versus controls. At multivariate analysis, severe microvascular obstruction was independently associated only with transmural necrosis (OR 1.5, p < 0.001) and age (OR 1.1, p = 0.02) but not with the use of abciximab. Conclusions: Severe microvascular obstruction after primary PCI of STEMI patients with occluded IRA is related to transmural necrosis but not to the use of abciximab.
Cardiopulmonary Exercise Testing in Mild Heart Failure: Impact of the Mode of Exercise on Established Prognostic Predictors
Authors: Maeder Micha Tobias , Wolber Thomas , Ammann Peter , Myers Jonathan , Brunner-La Rocca Hans Peter , Hack Dietrich , Riesen Walter , Rickli Hans
Published: October 2007

Objectives: In patients with heart failure (HF), peak oxygen consumption (peak VO2), the relationship between minute ventilation and carbon dioxide production (VE/VCO2 slope) and heart rate recovery (HRR) are established prognostic predictors. However, treadmill exercise has been shown to elicit higher peak VO2 values than bicycle exercise. We sought to assess whether the VE/VCO2 slope and HRR in HF also depend on the exercise mode. Methods: Twenty-one patients with mild HF on chronic β-blocker therapy underwent treadmill and bicycle cardiopulmonary exercise testing for measurement of peak VO2 and the VE/VCO2 slope. In patients with sinus rhythm (n = 16), HRR at 1 (HRR-1) and 2 min (HRR-2) after exercise termination was assessed. Results: Peak VO2 was higher during treadmill as compared with bicycle testing (21.7 ± 4.6 vs. 19.6 ± 3.4 ml/kg/min; p = 0.006). HRR-1 tended to be slower (15 bpm, interquartile range 8–19, vs. 18 bpm, interquartile range 11–22; p = 0.16), and HRR-2 was significantly slower after treadmill exercise (26 bpm, interquartile range 20–39, vs. 31 bpm, interquartile range 22–41; p = 0.04). In contrast, VE/VCO2 slope values did not differ between the test modes (32.9 ± 5.5 vs. 32.3 ± 5.0; p = 0.56). Conclusions: In contrast to peak VO2 and HRR, the VE/VCO2 slope is not affected by the exercise mode in patients with mild HF.
Immune Reconstitution Inflammatory Syndrome Presenting as Pericarditis and Pericardial Effusion
Authors: Rapose Alwyn , Sarvat Bilal , Sarria Juan C.
Published: October 2007

Immune reconstitution inflammatory syndrome (IRIS) affects 30–43% of HIV and tuberculosis (TB) co-infected patients after starting highly active antiretroviral therapy (HAART). Pericarditis and pericardial effusion are rare manifestations of IRIS. We report a case of HIV-TB related IRIS that developed pericardial involvement. This complication resolved after treatment with ibuprofen. Antituberculous treatment and HAART were not interrupted.
5-Fluorouracil, Leucovorin and Oxaliplatin plus Bevacizumab in the First-Line Treatment of Metastatic Colorectal Cancer: A Single-Institute Study
Authors: Bir Arvinder , Tan Wei , Wilding Gregory E. , Lombardo Jeffery , Fakih Marwan G.
Published: October 2007

Background: The addition of bevacizumab to 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) improved the time-to-progression (TTP) and overall survival (OS) in comparison to FOLFOX in the second-line treatment of metastatic colorectal cancer (MCRC). However, limited survival data are available to support FOLFOX plus bevacizumab in a first-line setting. We conducted a retrospective study of first-line FOLFOX plus bevacizumab to better characterize the safety and efficacy of this regimen in the first-line treatment of MCRC. Methods: Records of patients treated with first-line FOLFOX plus bevacizumab between January 2003 and March 2006 were reviewed. Grade 3 and 4 toxicity as well as efficacy data were collected. TTP and OS analyses were done using the Kaplan-Meier method. Results: 51 patients were treated with FOLFOX plus bevacizumab. Oxaliplatin treatment was interrupted prior to progression in 67% of patients. Grade 3 neuropathy, neutropenia and diarrhea occurred in 16, 8, and 8% of patients, respectively. The overall response rate, median TTP and median OS were 41%, 9.9 months and 23.2 months, respectively. Conclusions: First-line FOLFOX plus bevacizumab is associated with favorable TTP and OS. The definitive role of bevacizumab in the first-line setting in combination with FOLFOX chemotherapy should be explored further in randomized clinical trials.
A Novel Panel of Cerebrospinal Fluid Biomarkers for the Differential Diagnosis of Alzheimer’s Disease versus Normal Aging and Frontotemporal Dementia
Authors: Simonsen A.H. , McGuire J. , Podust V.N. , Hagnelius N.-O. , Nilsson T.K. , Kapaki E. , Vassilopoulos D. , Waldemar G.
Published: October 2007

Background: An early and accurate diagnosis of Alzheimer’s disease (AD) is important in order to initiate symptomatic treatment with currently approved drugs and will be of even greater importance with the advent of disease-modifying compounds. Methods: Protein profiles of human cerebrospinal fluid samples from patients with AD (n = 85), frontotemporal dementia (n = 20), and healthy controls (n = 32) were analyzed by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to verify previously discovered biomarkers. Results: We verified 15 protein biomarkers that were able to differentiate between AD and controls, and 7 of these 15 markers also differentiated AD from FTD. Conclusion: A panel of cerebrospinal fluid protein markers was verified by a proteomics technology which may potentially improve the accuracy of the AD diagnosis.
Screening for Frontotemporal Dementias and Alzheimer’s Disease with the Philadelphia Brief Assessment of Cognition: A Preliminary Analysis
Authors: Libon David J. , Massimo Lauren , Moore Peachie , Coslett H. Branch , Chatterjee Anjan , Aguirre Geoffrey K. , Rice Aaron , Vesely Luisa , Grossman Murray
Published: October 2007

Background: A neuropsychological screening instrument sensitive to neuropsychological deficits associated with Alzheimer’s disease (AD) and patients with frontotemporal dementia (FTD) would be valuable for diagnostic evaluation. Methods: The Philadelphia Brief Assessment of Cognition (PBAC) assesses working memory/executive control, language, visuospatial operations, verbal/visual episodic memory, and behavior/social comportment and can be administered and scored in 15–20 min. Participants included 149 patients with AD and four groups of FTD patients – i.e., patients with a decline in social comportment, personality, and executive functioning (SOC/EXEC), semantic dementia (SemD), progressive nonfluent aphasia (PNFA), and corticobasal syndrome (CBS). Results: The total PBAC score correlated with the Mini-Mental State Examination. Between-group analysis of PBAC subscales and the results of logistic regression analyses produced substantial between-group differences, emphasizing the sensitivity of the test to differentiate dementia subtypes. AD patients were impaired on tests of episodic memory, SOC/EXEC patients were impaired on a measure of social comportment/behavioral disturbance, PNFA patients obtained low scores on tests of working memory/executive control, SemD patients obtained lower scores on language-mediated measures, and CBS patients were impaired on visuospatial/visual memory tests. Conclusion: These data support the usefulness of the PBAC as a relatively brief screening test of overall dementia severity across a wide range of dementia patients.
Limited Costimulatory Molecule Expression on Renal Tubular Epithelial Cells Impairs T Cell Activation
Authors: Waeckerle-Men Ying , Starke Astrid , Wahl Patricia R. , Wüthrich Rudolf P.
Published: October 2007

Background/Aims: MHC molecules are upregulated on renal proximal tubular epithelial cells (TEC) under inflammatory conditions. This allows TEC to act as ‘non-professional’ antigen-presenting cells (APC). The aim of this study was to compare the costimulatory molecule expression pattern and the T cell activation capacity between renal TEC and professional APC, e.g. bone marrow-derived dendritic cells (BM-DC). Methods: Flow cytometry analysis was used to study the costimulatory molecule surface expression on TEC or BM-DC. Ovalbumin-specific CD4 and CD8 T cell activation induced by TEC or BM-DC was compared, in terms of T cell proliferation, cytokine production and CTL activity. Results: TEC did not constitutively express significant amounts of costimulatory molecules. Stimulation of TEC with IFN-β or IFN-γ, but not other tested cytokines, enhanced the expression of PD-L1, ICOS-L and CD40. Compared to BM-DC, TEC only induced suboptimal T cell activation. Blockade of PD-L1 on both APC strongly increased T cell activity. Furthermore, high PD-L1-expressing TEC were more resistant to the cytolysis by CTL. Conclusion: The low costimulatory molecule expression may explain the suboptimal T cell activation by TEC. The IFN-upregulated negative costimulatory molecule PD-L1 on TEC may play a protective role to limit tissue injury during renal parenchymal immune responses.
Effects of Repeated Annual Influenza Vaccination on Antibody Responses against Unchanged Vaccine Antigens in Elderly Frail Institutionalized Volunteers
Authors: Iorio A.M. , Camilloni B. , Basileo M. , Neri M. , Lepri E. , Spighi M.
Published: October 2007

Background: Concern about the possibility that annually repeated influenza immunizationmayinduce a lower antibody response than first vaccination. Objective: To ascertain the cumulative effects of yearly vaccination on serological response to unaltered vaccine antigens in the elderly. Methods: The haemagglutination-inhibiting (HI) antibody response was examined in 158 elderly institutionalized frail volunteers subdivided in 3 groups according to the sequential winters in which each subject received a trivalent inactivated influenza vaccine. The study, conducted over 5 consecutive winters (from 1998/99 to 2002/03), reports the antibody response only for sequential years (2 or 3) in which the vaccine strain examined was not altered. Results: Significant increases in the values of HI antibody titres were observed after vaccination in each year examined against the different influenza vaccine strains used, except against B antigen in the second of the 3 winters studied (1999/00). The antibody responses found were not always adequate, i.e. at levels above the currently requested values for commercial vaccines (post-vaccination seroprotection rate ≧1:40, increases in geometric mean titres ≧2, positive responses ≧30% compared with pre-vaccination), probably because of old age (mean age ≧81 years) and the presence of underlying diseases in a high percentage of volunteers (≧86%). The most frequent chronic diseases found werecardiovascular diseases (48%), endocrine disorders (19%), functional disability (10%) and pulmonary diseases (4%). The post-vaccination values observed in the sequential years were in general similar for A/H3N2 and A/H1N1 vaccine strains. A decrease, however, for some parameters at statistically significant levels, was observed against B antigen following repeated vaccine administrations. Conclusion: Our data seem to support the possibility of a slight impairment of HI antibody response against unaltered influenza vaccine antigens, especially for influenza strains that have circulated for prolonged periods of time. Indeed a tendency to a lower response was found only against B/Beijing antigen, introduced in the vaccine composition in the winter 1995/96, but not against the A/H3N2 and A/H1N1 vaccine strains, which weremore frequently changed.
Type B Fulminant Hepatitis Is Closely Associated with a Highly Mutated Hepatitis B Virus Strain
Authors: Kanada Aimi , Takehara Tetsuo , Ohkawa Kazuyoshi , Tatsumi Tomohide , Sakamori Ryotaro , Yamaguchi Shinjiro , Uemura Akio , Kohga Keisuke , Sasakawa Akira , Hikita Hayato , Hijioka Taizo , Katayama Kazuhiro , Deguchi Matsuo , Kagita Masanori , Kanto Tatsuya , Hiramatsu Naoki , Hayashi Norio
Published: October 2007

Objective: Genome-wide sequences of hepatitis B virus strain associated with type B fulminant hepatitis have not been compared with those of acute self-limited hepatitis. We carried out full-length sequencing analysis of viral strains derived from patients with type B acute liver injury. Methods: Nine acute self-limited hepatitis and 6 fulminant hepatitis patients were the subjects of this study. Full-length sequencing analysis of viral DNA was done by PCR-direct sequencing. Results: Higher frequencies in fulminant hepatitis strains compared with acute hepatitis ones were observed in the T1762/A1764 (p < 0.05), A1896 (p = 0.09) and M1753 (M = C or A) (p = 0.09) mutations. Viruses related to fulminant hepatitis possessed the higher number of nucleotide substitutions than those related to acute hepatitis in the whole virus genome (p < 0.01) and various regions including preS/S gene (p < 0.05), precore/core gene (p < 0.01), polymerase gene (p < 0.05) and basic core promoter/core upstream regulatory sequence (p < 0.01). The high number of nucleotide substitutions in viruses related to fulminant hepatitis was predominantly non-synonymous in the preS/S and precore/core genes. Conclusion: Development of type B fulminant hepatitis may be associated with a highly mutated hepatitis B virus strain.
Comparison of the Effectiveness of Geranylgeranylacetone with Cimetidine in Gastritis Patients with Dyspeptic Symptoms and Gastric Lesions: A Randomized, Double-Blind Trial in Japan
Authors: Sakamoto Choitsu , Ogoshi Kazuei , Saigenji Katsunori , Narisawa Rintarou , Nagura Hiroshi , Mine Tetsuya , Tada Masahiro , Umegaki Eiji , Maekawa Takama , Maekawa Ryuichiro , Maeda Kazuhiro
Published: October 2007

Background and Aim: Controversy remains regarding the treatment of choice for chronic gastritis patients with dyspeptic symptoms when Helicobacter pylori eradication is not indicated or fails for their gastric lesions. A multicenter, randomized, double-blind trial was performed to compare the effectiveness of geranylgeranylacetone (GGA), a mucoprotective drug, against cimetidine (CIT), an H2-receptor antagonist, on the treatment of erosions and petechial hemorrhage in H. pylori-infected patients with dyspeptic symptoms. Methods: 128 H. pylori-positive gastritis patients with mucosal erosions and/or petechial hemorrhage were randomized to receive 150 mg GGA t.i.d. or 400 mg CIT b.i.d. for 2 weeks. Improvement and cure rates on endoscopic findings, symptom disappearance rates, and changes in mucosal neutrophil infiltration were compared. Results: Endoscopic improvement rates were significantly higher in the GGA group (n = 50) than in the CIT group (n = 54; 86.0 vs. 64.8%, p = 0.014). Endoscopic cure rates were also significantly higher for GGA than for CIT (80.0 vs. 55.6%, p = 0.012). Symptom disappearance rates were 52.0% for GGA and 42.6% for CIT, but the difference was not significant. There was also no significant difference in mucosal neutrophil infiltration between the groups. Conclusion: GGA treatment appears to be more effective than CIT for chronic gastritis-associated erosion and petechial hemorrhage.