bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulating insulin signaling and β-cell function through IRS proteinsThis paper is one of a selection of papers published in this Special Issue, entitled Second Messengers and Phosphoproteins—12th International Conference.
Authors: White Morris F.
Published: September 2006

Diabetes mellitus is a complex disorder that arises from various causes, including dysregulated glucose sensing and impaired insulin secretion (maturity onset diabetes of youth, MODY), autoimmune-mediated β-cell destruction (type 1), or insufficient compensation for peripheral insulin resistance (type 2). Type 2 diabetes is the most prevalent form that usually occurs at middle age; it afflicts more than 30 million people over the age of 65, but is appearing with greater frequency in children and adolescents. Dysregulated insulin signaling exacerbated by chronic hyperglycemia promotes a cohort of systemic disorders—including dyslipidemia, hypertension, cardiovascular disease, and female infertility. Understanding the molecular basis of insulin resistance can prevent these disorders and their inevitable progression to type 2 diabetes.
Altered glucose homeostasis in mice lacking the receptor protein tyrosine phosphatase sigmaThis paper is one of a selection of papers published in this Special issue, entitled Second Messengers and Phosphoproteins—12th International Conference.
Authors: Chagnon Mélanie J. , Elchebly Mounib , Uetani Noriko , Dombrowski Luce , Cheng Alan , Mooney Robert A. , Marette André , Tremblay Michel L.
Published: September 2006

Several protein tyrosine phosphatases (PTPs) expressed in insulin sensitive-tissues are proposed to attenuate insulin action and could act as key regulators of the insulin receptor (IR) signaling pathway. Among these PTPs, RPTPσ is expressed in relatively high levels in insulin-target tissues. We show that RPTPσ−/− knockout mice have reduced plasma glucose and insulin concentrations in the fasted state compared with their wild-type siblings. The knockout animals were also more sensitive to exogenous insulin as assayed by insulin-tolerance tests. Despite increased whole-body insulin sensitivity, tyrosine phosphorylation of the IR was not increased in muscle of RPTPσ−/− animals, as would be expected in insulin-sensitive animals. Instead, the levels of IR tyrosine phosphorylation and PI3-kinase activity were reduced in the muscle of knockout animals stimulated with insulin in vivo. However, insulin-stimulated Akt serine phosphorylation was essentially identical between both groups of mice. Accordingly, muscles isolated from RPTPσ−/− mice did not have a significant increase in glucose uptake in response to insulin, suggesting that RPTPσ did not play a direct role in this process. Taken together, our results suggest an indirect modulation of the IR signaling pathways by RPTPσ. Since low dose injection of growth hormone (GH) normalized the response to exogenous insulin in RPTPσ−/− mice, we propose that the insulin hypersensitivity observed in RPTPσ−/− mice is secondary to their neuroendocrine dysplasia and GH/IGF-1 deficiency.
A QUASI-LATTICE THEORY FOR COMPOUND FORMING TERNARY LIQUID ALLOYS
Authors: AWE O. E. , AKINLADE O. , HUSSAIN L. A.
Published: September 2006

A Quasi-lattice model of liquid binary mixtures has been used to establish a model for calculating some thermodynamic properties of compound forming ternary liquid alloys. The effect of varying Z on the concentration fluctuations was also investigated. Results obtained for limiting case of the model are presented and compared with that obtained by Bhatia and Singh for binary liquid alloys. A framework for calculating the Warren Cowley short range order for ternary liquid alloys as a function of Z is also formulated.
THE MODIFIED TODA LATTICE IN (2+1)-DIMENSIONS AND INTEGRABLE COUPLING SYSTEMS
Authors: YANG HONGXIANG , XU XIXIANG , LI XIUZHEN , LI CHANGSHENG
Published: September 2006

By considering a discrete isospectral problem [H.-X. Yang et al., Phys. Lett. A338, 117 (2005)], integrable positive and negative lattice equations are derived, from which the modified (2+1)-dimensional Toda lattice is obtained. The method of enlarging spectral problems to construct the integrable couplings for lattice soliton equations is extended to higher-dimensional systems. Illustrating by examples, the positive and negative integrable couplings of the resulting lattice hierarchy and three classes of integrable couplings of (2+1)-dimensional mToda lattice are discussed.
ON THE ORIGIN OF d-WAVE PAIR FUNCTIONS IN HIGH-Tc SUPERCONDUCTIVITY
Authors: MATTIS DANIEL C.
Published: September 2006

We argue that the usual Hubbard's model produces only s-wave pairing functions and, even then, only at unphysically large values of the lumped parameter J≡4t2/U. It follows that a reliable theory of high-Tc superconductivity has to include additional features if it is to reproduce the d-wave gap. We test the effects of an alternating potential caused by a charge stripe, on the ground state of the Hubbard model in strong-coupling. If we "fine tune" we do find the d-waves. However, a better-formulated version of a three-band model yields a sturdier theory of pair formation in high-Tc superconductivity. The coupling constant g1=t2/V factors out, hence it serves only to establish the unit of energy; the underlying Hamiltonian is universal. We outline the principal properties of this model, including the intimate relation between charge-density stripes and the d-wave pair function, its rejection of 45° stripes (checkerboard pattern), and other concerns.
PI3K is involved in PDGF-β receptor upregulation post-PDGF-BB treatment in mouse HSC
Authors: Lechuga Carmen G. , Hernández-Nazara Zamira H. , Hernández Elizabeth , Bustamante Marcia , Desierto Gregory , Cotty Adam , Dharker Nachiket , Choe Moran , Rojkind Marcos
Published: September 2006

Increased expression of PDGF-β receptors is a landmark of hepatic stellate cell activation and transdifferentiation into myofibroblasts. However, the molecular mechanisms that regulate the fate of the receptor are lacking. Recent studies suggested that N-acetylcysteine enhances the extracellular degradation of PDGF-β receptor by cathepsin B, thus suggesting that the absence of PDGF-β receptors in quiescent cells is due to an active process of elimination and not to a lack of expression. In this communication we investigated further molecular mechanisms involved in PDGF-β receptor elimination and reappearance after incubation with PDGF-BB. We showed that in culture-activated hepatic stellate cells there is no internal protein pool of receptor, that the protein is maximally phosphorylated by 5 min and completely degraded after 1 h by a lysosomal-dependent mechanism. Inhibition of receptor autophosphorylation by tyrphostin 1296 prevented its degradation, but several proteasomal inhibitors had no effect. We also showed that receptor reappearance is time and dose dependent, being more delayed in cells treated with 50 ng/ml (48 h) compared with 10 ng/ml (24 h).
Daily restricted feeding resets the circadian clock in the suprachiasmatic nucleus of CS mice
Authors: Abe Hiroshi , Honma Sato , Honma Ken-ichi
Published: September 2006

Circadian rhythms in clock gene expressions in the suprachiasmatic nucleus (SCN) of CS mice and C57BL/6J mice were measured under a daily restricted feeding (RF) schedule in continuous darkness (DD), and entrainment of the SCN circadian pacemaker to RF was examined. After 2–3 wk under a light-dark cycle with free access to food, animals were released into DD and fed for 3 h at a fixed time of day for 3–4 wk. Subsequently, they returned to having free access to food for 2–3 wk. In CS mice, wheel-running rhythms entrained to RF with a stable phase relationship between the activity onset and feeding time, and the rhythms started to free run from the feeding time after the termination of RF. mPer1, mPer2, and mBMAL1 mRNA rhythms in the SCN showed a fixed phase relationship with feeding time, indicating that the circadian pacemaker in the SCN entrained to RF. On the other hand, in C57BL/6J mice, wheel-running rhythms free ran under RF, and clock gene expression rhythms in the SCN showed a stable phase relation not to feeding time but to the behavioral rhythms, indicating that the circadian pacemaker in the SCN did not entrain. These results indicate that the SCN circadian pacemaker of CS mice is entrainable to RF under DD and suggest that CS mice have a circadian clock system that can be reset by a signal associated with feeding time.
Mechanisms of renal blood flow autoregulation: dynamics and contributions
Authors: Just Armin
Published: September 2006

Autoregulation of renal blood flow (RBF) is caused by the myogenic response (MR), tubuloglomerular feedback (TGF), and a third regulatory mechanism that is independent of TGF but slower than MR. The underlying cause of the third regulatory mechanism remains unclear; possibilities include ATP, ANG II, or a slow component of MR. Other mechanisms, which, however, exert their action through modulation of MR and TGF are pressure-dependent change of proximal tubular reabsorption, resetting of RBF and TGF, as well as modulating influences of ANG II and nitric oxide (NO). MR requires < 10 s for completion in the kidney and normally follows first-order kinetics without rate-sensitive components. TGF takes 30–60 s and shows spontaneous oscillations at 0.025–0.033 Hz. The third regulatory component requires 30–60 s; changes in proximal tubular reabsorption develop over 5 min and more slowly for up to 30 min, while RBF and TGF resetting stretch out over 20–60 min. Due to these kinetic differences, the relative contribution of the autoregulatory mechanisms determines the amount and spectrum of pressure fluctuations reaching glomerular and postglomerular capillaries and thereby potentially impinge on filtration, reabsorption, medullary perfusion, and hypertensive renal damage. Under resting conditions, MR contributes ∼50% to overall RBF autoregulation, TGF 35–50%, and the third mechanism < 15%. NO attenuates the strength, speed, and contribution of MR, whereas ANG II does not modify the balance of the autoregulatory mechanisms.
Molecular characterization of water-selective AQP (EbAQP4) in hagfish: insight into ancestral origin of AQP4
Authors: Nishimoto Goro , Sasaki Go , Yaoita Eishin , Nameta Masaaki , Li Huiping , Furuse Kyoko , Fujinaka Hidehiko , Yoshida Yutaka , Mitsudome Akihisa , Yamamoto Tadashi
Published: September 2006

Hagfish ( Eptatretus burgeri) are agnathous and are the earliest vertebrates still in existence. Pavement cells adjacent to the mitochondria-rich cells show orthogonal arrays of particles (OAPs) in the gill of hagfish, a known ultrastructural morphology of aquaporin (AQP) in mammalian freeze-replica studies, suggesting that an AQP homolog exists in pavement cells. We therefore cloned water channels from hagfish gill and examined their molecular characteristics. The cloned AQP [ E. burgeri AQP4 (EbAQP4)] encodes 288 amino acids, including two NPA motifs and six transmembrane regions. The deduced amino acid sequence of EbAQP4 showed high homology to mammalian and avian AQP4 (rat, 44%; quail, 43%) and clustered with AQP4 subsets by the molecular phylogenetic tree. The osmotic water permeability of Xenopus oocytes injected with EbAQP4 cRNA increased eightfold compared with water-injected controls and was not reversibly inhibited by 0.3 mM HgCl2. EbAQP4 mRNA expression in the gill was demonstrated by the RNase protection assay; antibody raised against the COOH terminus of EbAQP4 also detected (by Western blot analysis) a major ∼31-kDa band in the gill. Immunohistochemistry and immunoelectron microscopy showed EbAQP4 localized along the basolateral membranes of gill pavement cells. In freeze-replica studies, OAPs were detected on the protoplasmic face of the split membrane comprising particles 5–6 nm long on the basolateral side of the pavement cells. These observations suggest that EbAQP4 is an ancestral water channel of mammalian AQP4 and plays a role in basolateral water transport in the gill pavement cells.
Interactive modulation of renal myogenic autoregulation by nitric oxide and endothelin acting through ET-B receptors
Authors: Shi Ying , Lau Catherine , Cupples William A.
Published: September 2006

In rats, nitric oxide modulates renal autoregulation in steady-state experiments and the myogenic mechanism in dynamic studies. Interactive modulation of autoregulation by nitric oxide and endothelin-1, predominantly involving endothelin B receptors, has been reported although it remains unclear whether the interaction is synergistic or obligatory or whether it affects the myogenic component of autoregulation. Nonselective inhibition of nitric oxide synthase (Lω-nitro-l-arginine methyl-ester; l-NAME) with endothelin A and B selective receptor antagonists BQ-123 and BQ-788, all infused into the renal artery, plus time series analysis were used to test the interactive actions of nitric oxide and endothelin on renal vascular conductance and on autoregulation. Nonselective endothelin receptor antagonism blunted the constrictor response to subsequent l-NAME but had no effect on previously established l-NAME-induced vasoconstriction. BQ-123 did not affect conductance and caused only minor reduction in myogenic autoregulatory efficiency. Responses to BQ-123 and l-NAME were additive and not interactive. BQ-788 and l-NAME each caused strong vasoconstriction alone and in the presence of the other, indicating that coupling between nitric oxide- and endothelin B-mediated events is not obligatory. l-NAME augmented myogenic autoregulation, and subsequent BQ-788 did not alter this response. However, BQ-788 infused alone also enhanced myogenic autoregulation but resulted in significant impairment of myogenic autoregulation by subsequent l-NAME. Thus the interaction between nitric oxide and endothelin is clearly nonadditive and, because it is asymmetrical, cannot be explained simply by convergence on a common signal pathway. Instead one must postulate some degree of hierarchical organization and that nitric oxide acts downstream to endothelin B activation.
A reevaluation of the effects of stimulation of the dorsal motor nucleus of the vagus on gastric motility in the rat
Authors: Cruz Maureen T. , Murphy Erin C. , Sahibzada Niaz , Verbalis Joseph G. , Gillis Richard A.
Published: September 2006

Our primary purpose was to characterize vagal pathways controlling gastric motility by microinjecting l-glutamate into the dorsal motor nucleus of the vagus (DMV) in the rat. An intragastric balloon was used to monitor motility. In 39 out of 43 experiments, microinjection of l-glutamate into different areas of the DMV rostral to calamus scriptorius (CS) resulted in vagally mediated excitatory effects on motility. We observed little evidence for inhibitory effects, even with intravenous atropine or with activation of gastric muscle muscarinic receptors by intravenous bethanechol. Inhibition of nitric oxide synthase with Nω-nitro-l-arginine methyl ester (l-NAME) HCl did not augment DMV-evoked excitatory effects on gastric motility. Microinjection of l-glutamate into the DMV caudal to CS produced vagally mediated gastric inhibition that was resistant to l-NAME. l-Glutamate microinjected into the medial subnucleus of the tractus solitarius (mNTS) also produced vagally mediated inhibition of gastric motility. Motility responses evoked from the DMV were always blocked by ipsilateral vagotomy, while responses evoked from the mNTS required bilateral vagotomy to be blocked. Microinjection of oxytocin into the DMV inhibited gastric motility, but the effect was never blocked by ipsilateral vagotomy, suggesting that the effect may have been due to diffusion of oxytocin to the mNTS. Microinjection of substance P and N-methyl-d-aspartate into the DMV also produced inhibitory effects attributable to excitation of nearby mNTS neurons. Our results do not support previous studies indicating parallel vagal excitatory and inhibitory pathways originating in the DMV rostral to CS. Our results do support previous findings of vagal inhibitory pathways originating in the DMV caudal to CS.
Exercise affects the gene expression profiles of human white blood cells
Authors: Büttner Petra , Mosig Sandy , Lechtermann Anja , Funke Harald , Mooren Frank C.
Published: September 2006

White blood cells (WBCs) express tens of thousands of genes, whose expression levels are modified by genetic and external factors. The purpose of the present study was to investigate the effects of acute exercise on gene expression profiles (GEPs) of WBCs and to identify suitable genes that may serve as surrogate markers for monitoring exercise and training load. Five male participants performed an exhaustive treadmill test (ET) at 80% of their maximal O2uptake (V̇o2 max) and a moderate treadmill test (MT) at 60% V̇o2 maxfor exactly the same time ∼2 wk later. WBCs were isolated by the erythrocyte lysis method. GEPs were measured using the Affymetrix GeneChip technology. After scaling, normalization, and filtering, groupwise comparisons of gene expression intensities were performed, and several measurements were validated by real-time PCR. We found 450 genes upregulated and 150 downregulated (>1.5-fold change; ANOVA with Benjamini-Hochberg correction, P < 0.05) after ET that were closely associated with the gene ontology lists “response to stress” and “inflammatory response”. Analysis of mean expression levels after MT showed that the extent of up- and downregulation was workload dependent. The genes for the stress (heat shock) proteins HSPA1A and HSPH1 and for the matrix metalloproteinase MMP-9 showed the most prominent increases, whereas the YES1 oncogene (YES1) and CD160 (BY55) were most strongly reduced. Despite different methodological approaches used, the consistency of our results with the expression data of another study (Connolly PH, Caiozzo VJ, Zaldivar F, Nemet D, Larson J, Hung SP, Heck JD, Hatfield GW, Cooper DM. J Appl Physiol 97: 1461–1469, 2004) suggests that expression fingerprints are useful tools for monitoring exercise and training loads and thereby help to avoid training-associated health risks.
Fatigue and functional performance of human biceps muscle following concentric or eccentric contractions
Authors: Smith I. Christopher H. , Newham Di J.
Published: September 2006

A long-lasting fatigue was measured in human biceps muscle, following 40 maximal isokinetic concentric or eccentric contractions of the forearm, as the response to single-shock stimuli every minute for 4 h. This protocol allowed new observations on the early time course of long-lasting fatigue. Concentric contractions induced a novel progressive decline to 30.2% (SE 7.8, n = 7) of control at 23 min with complete recovery by 120 min. Eccentric contractions lead initially to a smaller force reduction of similar time course followed by a slower decline to 40.0% (SE 5.1, n = 7) control at 120 min with recovery less than half complete at 4 h. A 50-Hz test stimuli overcame both fatigues, identifying low-frequency fatigue. EMG recordings from the biceps muscle showed moderate (<20%) changes during the fatigue. A visual-tracking task showed no decrement in performance at the time of maximal fatigue of the single-shock response. Because the eccentric contractions have a similar activation, a larger force, but much smaller metabolic usage than concentric contractions, it is concluded that the initial decline is related to the effects of metabolites, whereas the slower phase after eccentric contractions is associated with higher mechanical stress.
Excitability of human motor and visual cortex before, during, and after hyperventilation
Authors: Sparing Roland , Dafotakis Manuel , Buelte Dorothee , Meister Ingo G. , Noth Johannes
Published: September 2006

In humans, hyperventilation (HV) has various effects on systemic physiology and, in particular, on neuronal excitability and synaptic transmission. However, it is far from clear how the effects of HV are mediated at the cortical level. In this study we investigated the effects of HV-induced hypocapnia on primary motor (M1) and visual cortex (V1) excitability. We used 1) motor threshold (MT) and phosphene threshold (PT) and 2) stimulus-response (S-R) curves (i.e., recruitment curves) as measures of excitability. In the motor cortex, we additionally investigated 3) the intrinsic inhibitory and facilitatory neuronal circuits using a short-interval paired-pulse paradigm. Measurements were performed before, during, and after 10 min of HV (resulting in a minimum end-tidal Pco2 of 15 Torr). HV significantly increased motor-evoked potential (MEP) amplitudes, particularly at lower transcranial magnetic stimulation (TMS) intensities. Paired-pulse stimulation indicated that HV decreases intracortical inhibition (ICI) without changing intracortical facilitation. The results suggestthat low Pco2 levels modulate, in particular, the intrinsic neuronal circuits of ICI, which are largely mediated by neurons containing γ-aminobutyric acid. Modulation of MT probably resulted from alterations of Na+ channel conductances. A significant decrease of PT, together with higher intensity of phosphenes at low stimulus intensities, furthermore suggested that HV acts on the excitability of M1 and V1 in a comparable fashion. This finding implies that HV also affects other brain structures besides the corticospinal motor system. The further exploration of these physiological mechanisms may contribute to the understanding of the various HV-related clinical phenomenona.
Bruck Syndrome: Second Antenatal Diagnosis
Authors: Cuillier F. , Alessandri J.L. , Lemaire P. , Fritel X. , Harper L.
Published: September 2006

Bruck syndrome is characterized by the association of arthrogryposis and osteogenesis imperfecta. It is a distinct autosomal recessive disorder associated with normal collagen I. The main features are osteoporosis, long bone bowing and scoliosis due to vertebral deformities and congenital joint contractures. We describe a French girl who was born with ankle and wrist contractures (second antenatal discovery).
Reversed Pulmonary Artery Flow in Isolated Noncompaction of the Ventricular Myocardium
Authors: Grebe Sandra , Ichida Fukiko , Grabitz Ralph , Bültmann Burkhard , Heideman Simone , von Kaisenberg Constantin S.
Published: September 2006

Objective: To investigate the morphology and genetics of a fetus at 22 weeks. This fetus demonstrated progressive fetal hydrops and cardiomegaly with retrograde flow in the pulmonary artery and progressive myocardial deterioration and heart failure. Methods: Postmortem examination, light and electron microscopy of the myocardium, karyotyping, fetal DNA analysis, screening for mutations in the G4.5 gene, α-dystrobrevin gene, FKBP 12 gene, Desmin, Syntrophin and Cypher/ZASP genes, which have been described as being associated with noncompaction ventricular myocardium, using single-strand DNA conformation polymorphism analysis and DNA sequencing. Results: The morphological diagnosis was compatible with noncompaction ventricular myocardium or spongyforme myopathy. The karyotype was normal. Mutation analysis in exons and introns of all six genes did not show any known mutation. Conclusion: Noncompaction ventricular myocardium or spongyforme myopathy may be associated with mutations in genes which have previously not been thought to be associated with this phenotype. Alternatively, this disease could be the result of abnormal cardiac hemodynamics.
Intrauterine Intestinal Obstruction due to Fetal Midgut Volvulus: A Report of Two Cases
Authors: Molvarec Attila , Bábinszki Ágota , Kovács Kálmán , Tóth Ferenc , Szalay János
Published: September 2006

Fetal midgut volvulus is quite rare, and few surviving infants – particularly cases with meconium peritonitis – have been reported in the literature. We report two cases of intrauterine intestinal obstruction due to fetal midgut volvulus associated with intestinal malrotation. In both cases, the infant survived after cesarean section delivery and appropriate surgical intervention, and they both continue to be in good overall condition. We discuss the prenatal signs and outcome of in utero intestinal volvulus. Close prenatal follow-up and appropriate timing of delivery in cases where ultrasound examination shows signs of fetal intestinal obstruction, as well as optimal postnatal treatment, are essential to reduce the morbidity and mortality associated with fetal midgut volvulus.
First Trimester Down’s Syndrome Screening Shows High Detection Rate for Trisomy 21, but Poor Performance in Structural Abnormalities – Regional Outcome Results
Authors: Rissanen Anne , Niemimaa Marko , Suonpää Mikko , Ryynänen Markku , Heinonen Seppo
Published: September 2006

Objective: To evaluate whether first trimester screening markers are altered in pregnancies affected both by other chromosomal defects than trisomy 21 and structural anomalies and whether it is possible to detect these pregnancies by combined ultrasound and biochemical screening test. Methods: Altogether 4,776 singleton pregnancies underwent first trimester screening. Of them, 3,101 women were screened using a combination of maternal serum free hCG, pregnancy-associated plasma protein A and nuchal translucency and 1,361 women with first trimester biochemistry without ultrasound. Nuchal translucency screening was performed between the 11th and 13+6th gestational weeks, and biochemistry 1–2 weeks earlier. Results: Using a fixed cut-off rate of 1:250 for Down’s syndrome, the detection rate of trisomies 21, 18 and 13 were 92, 67 and 0%, respectively. All open defects, 85% of cardiac defects and other minor defects were not detected in first trimester screening. Majority of these structural abnormalities occurred in women under 35 years of age. Conclusion: First trimester Down’s syndrome screening is effective in trisomy screening, but its performance in structural abnormalities is low, when used as a part of routine clinical practice. We conclude that it is too early to drop second trimester screening ultrasound entirely from antenatal care programs if a high detection rate is to be achieved also in structural defects.
Validation of the Seven-Minute Screen Neurocognitive Battery for the Diagnosis of Dementia in a Spanish Population-Based Sample
Authors: Del Ser Teodoro , Sánchez-Sánchez Fernando , García de Yébenes María Jesús , Otero Angel , Munoz David G.
Published: September 2006

Objective: To validate the Seven-Minute Screen Neurocognitive Battery (7MS) in an elderly population-based sample to identify dementia using a new scoring method. Methods: Five hundred and twenty-seven home-dwelling elderly were assessed with a neurological and neuropsychological exam. The total score of the 7MS was the sum of z scores of its subtests. Dementia was diagnosed according to DSM-IV. The ROC curve and the diagnostic parameters of the 7MS were calculated. Results: The 7MS could be fully applied in 416 cases (78.9%), and 48 were diagnosed as demented independently of the 7MS. The four 7MS subtests correctly classified 97.6% of cases by discriminant analysis; orientation and memory were the most discriminative. Factorial analysis showed a single dimension in the 7MS. The ROC curve area for diagnosis of dementia was 0.996 (95% CI 0.992–1), sensitivity 100%, specificity 95.1%, and diagnostic accuracy 96.8%. All these parameters were higher than those of other cognitive screening tests. Dementia explained 54.9% of the variance of the 7MS, and age 3.1%; sex and education did not have a significant effect. Conclusions: The 7MS is a valid tool for the diagnosis of dementia, even when cognitive decline is mild, although it may not be appropriate for extensive epidemiological surveys.
Inner Ear Therapy for Neural Preservation
Authors: Richardson Rachael T. , Noushi Farnoush , O’Leary Stephen
Published: September 2006

A gradual loss of auditory neurons often occurs following sensorineural hearing loss. Since the cochlear implant must stimulate the remaining auditory neuron population, it would be beneficial to preserve as many auditory neurons as possible. Neurotrophic factors protect auditory neurons from degradation after sensorineural hearing loss in experimental animals, but have not yet been translated into the clinical setting. Current experimental and clinical techniques for drug delivery to the inner ear are examined in this review, covering the routes for drug delivery to the cochlea and the delivery systems used to introduce them. Duration of treatment, drug diffusion, effectiveness and safety are discussed with references to how they may be translated to the implementation of neurotrophic factor treatment for neural preservation.
Characteristics of Hearing Loss in HDR (Hypoparathyroidism, Sensorineural Deafness, Renal Dysplasia) Syndrome
Authors: van Looij Marjolein A.J. , Meijers-Heijboer Hanne , Beetz Rolf , Thakker Rajesh V. , Christie Paul T. , Feenstra Lou W. , van Zanten Bert G.A.
Published: September 2006

Haploinsufficiency of the zinc finger transcription factor GATA3 causes the triad of hypoparathyroidism, deafness and renal dysplasia, known by its acronym HDR syndrome. The purpose of the current study was to describe in detail the auditory phenotype in human HDR patients and compare these to audiometrical and histological data previously described in a mouse model of this disease. Pure tone audiometry, speech audiometry, speech in noise, auditory brainstem responses and transiently evoked otoacoustic emissions were measured in 2 patients affected by HDR syndrome. Both patients were affected by a moderate-to-severe sensorineural hearing loss. Speech reception thresholds were shifted and speech recognition in noise was disturbed. No otoacoustic emissions could be generated in either patient. Auditory brainstem response interpeak intervals were normal. The human and murine audiological phenotypes seem to correspond well. Hearing loss in HDR syndrome is moderate to severe, seems to be slightly worse at the higher end of the frequency spectrum and may be progressive with age. The absence of otoacoustic emissions and the loss of frequency selectivity suggest an important role for outer hair cells in causing the hearing loss.
Increased Levels of Soluble TNF-α Receptors and Cellular Adhesion Molecules in Patients Undergoing Bioincompatible Hemodialysis
Authors: Rysz Jacek , Majewska Ewa , Stolarek Robert A. , Banach Maciej , Ciałkowska-Rysz Aleksandra , Baj Zbigniew
Published: September 2006

Background: The study aimed to differentiate the effects of hemodialysis (HD) and chronic renal failure (CRF) on the levels of circulating tumor necrosis factor-α (TNF-α) and TNF-α receptors p55 and p75, soluble vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), soluble endothelial-leukocyte adhesion molecule-1 (sE-selectin) and sP-selectin in 18 patients on regular HD treatment with cuprophane membrane in relation to 15 non-dialyzed CRF patients and 15 healthy controls. Methods: The serum concentrations were determined with standard ELISA assays. Results: Blood serum p75 and p55 were approximately tenfold increased in CRF (36.7 ± 6.2 and 27.1 ± 5.6 ng/ml) and HD patients (45.6 ± 18.4 and 28.7 ± 5.9 ng/ml) before the HD session (HD 0), during (HD 20) the session (45.7 ± 18.4 and 28.5 ± 7.3 ng/ml) and after (HD 240) the HD session (52.1 ± 17.4 and 30.9 ± 8.2 ng/ml) in comparison to control values (5.6 ± 1.3 and 2.4 ± 0.8 ng/ml, respectively) (p < 0.01). The highest increment of p75 at the end of HD session (HD 240) was also significantly higher than at preceding time points (HD 0 and 20) (p < 0.05). However, the remaining study parameters did not change during an HD session. Also, there were no relevant changes in TNF-α levels if (HD 0) 22.7 ± 21.5 ng/ml and (HD 240) 21.1 ± 18.9 ng/ml were compared. Chronic HD status was related to the increase of sVCAM-1 and sICAM-1 levels. Prior to HD, T0 sVCAM-1 and sICAM-1 concentrations were 2,180.4 ± 761.8 and 567.3 ± 218.8 ng/ml, during HD (T20): 2,172.7 ± 759.2 and 602.3 ± 379.9 ng/ml, and after HD (T240): 2,401.6 ± 756.4 and 648.3 ± 183.5 ng/ml, respectively (p < 0.05 vs. controls and CRF patients). sVCAM-1 and sICAM-1 serum levels (1,262.2 ± 472.9 and 165.6 ± 50.4 ng/ml) were similar in CRF patients and healthy controls (854.4 ± 241.5 and 217.6 ± 74.2 ng/ml, respectively). Even though serum sE- and sP-selectin in CRF patients did not differ from the control (39.8 ± 21.3 vs. 42.1 ± 18.9 ng/ml and 187.9 ± 66.9 vs. 198.8 ± 62.2 ng/ml, respectively), their levels were increased in HD patients up to 111.9 ± 54.6 and 453.2 ± 231.1 ng/ml in patients prior to HD, 118.7 ± 66.2 and 350.8 ± 114.8 ng/ml during the HD session and then 132.3 ± 61.1 and 368.3 ± 126.6 ng/ml, respectively, after its completion (p < 0.05 in comparison with CRF patients and controls). Conclusions: The increased circulating TNF-α receptors appear more associated with the uremic milieu than HD-related systemic inflammation, whereas increased soluble cellular adhesion molecules in patients undergoing bioincompatible HD may be related to the enhanced systemic inflammation specifically due to maintenance HD.
Critical Role of Inducible Costimulator Signaling in the Development of Arteriosclerosis
Authors: Kosuge Hisanori , Suzuki Jun-ichi , Haraguchi Go , Koga Noritaka , Maejima Yasuhiro , Inobe Manabu , Isobe Mitsuaki , Uede Toshimitsu
Published: September 2006

Objective—

Proliferation and migration of smooth muscle cells (SMCs) and migration and accumulation of monocytes and T cells are landmark events in the development of arteriosclerosis. SMC proliferation in the intima induces interruption of blood flow and results in ischemia and graft rejection. Inducible costimulator (ICOS) is a major costimulator of T cell activation. However, the effect of costimulatory molecules on the formation of neointimal hyperplasia has not been fully elucidated. We examined the role of the ICOS pathway in SMC proliferation.

Methods and Results—

ICOS ligand (ICOSL) was detected in SMCs stimulated by interleukin (IL)-1β, and coculture of stimulated SMCs and activated T cells induced SMC proliferation. Inhibition of the ICOS pathway resulted in inhibition of SMC proliferation. In models of transplantation and vascular injury, ICOSL was induced in SMCs in the neointima. Expression of IL-1β, a key inducer of ICOSL expression, was significantly reduced in mice treated with anti-ICOS antibody or soluble form of ICOS (ICOSIg) and in ICOS-deficient mice. Inhibition of the ICOS pathway significantly suppressed neointimal thickening.

Conclusions—

These results indicate that ICOS on activated T cells contributes to neointimal formation through the regulation of SMC proliferation. These findings provide insights into new therapeutic strategies for arteriosclerosis.
cNGR: A Novel Homing Sequence for CD13/APN Targeted Molecular Imaging of Murine Cardiac Angiogenesis In Vivo
Authors: Buehler Alexandra , van Zandvoort Marc A.M.J. , Stelt Bram J. , Hackeng Tilman M. , Schrans-Stassen Bianca H.G.J. , Bennaghmouch Abdelkader , Hofstra Leo , Cleutjens Jack P.M. , Duijvestijn Adriaan , Smeets Mirjam B. , de Kleijn Dominique P.V. , Post Mark J. , de Muinck Ebo D.
Published: September 2006

Objective—

Previously, the peptide sequence cNGR has been shown to home specifically to CD13/APN (aminopeptidase N) on tumor endothelium. Here, we investigated the feasibility of selective imaging of cardiac angiogenesis using the cNGR-CD13/APN system.

Methods and Results—

CD13/APN induction and cNGR homing were studied in the murine myocardial infarction (MI) model. By real-time polymerase chain reaction (PCR) at 7 days after MI, CD13/APN expression was 10- to 20-fold higher in the angiogenic infarct border zone and the MI area than in non-MI areas. In vivo fluorescence microscopy confirmed specific homing of fluorophore-tagged cNGR to the border zone and MI territory at 4 and 7 days after MI with a local advantage of 2.3, but not at 1 or 14 days after MI. Tissue residence half-life was 9.1±0.3 hours, whereas the half-life in plasma was 15.4±3.4 minutes. Pulse chase experiments confirmed reversible binding of cNGR in the infarct area. Fluorescent labeled cNGR conjugates or antibodies were injected in vivo, and their distribution was studied ex vivo by 2-photon laser scanning microscopy (TPLSM). cNGR co-localized exclusively with CD13/APN and the endothelial marker CD31 on vessels.

Conclusions—

In cardiac angiogenesis endothelial CD13/APN is upregulated. It can be targeted specifically with cNGR conjugates. In the heart cNGR binds its endothelial target only in angiogenic areas.
Hereditary Postprandial Hypertriglyceridemic Rabbit Exhibits Insulin Resistance and Central Obesity
Authors: Kawai Takashi , Ito Tsunekata , Ohwada Kazuo , Mera Yasuko , Matsushita Mutsuyoshi , Tomoike Hitonobu
Published: September 2006

Objective—

We have established a hereditary postprandial hypertriglyceridemic (PHT) rabbit. The present study was designed to define whether this rabbit model represents both insulin resistance and central obesity.

Methods and Results—

Body weight, abdominal circumference, visceral fat weight, and glucose tolerance were compared between PHT and Japanese white (JW) rabbit. Plasma levels of triglycerides (TG), total cholesterol (TC), glucose, and insulin were measured before and after feeding. Abdominal circumference of PHT rabbit was larger than that of JW rabbit, with no difference in body mass index. Visceral fat accumulation was noted as obvious in mesenterium, retroperitoneal space, and epididymal area. Plasma TG and TC levels were high preprandially and markedly increased postprandially in PHT rabbit compared with JW rabbit. Although plasma glucose levels were comparable in both groups, plasma insulin levels were elevated in PHT rabbit. Glucose tolerance tests indicated that plasma insulin levels in PHT rabbit were consistently higher than in JW rabbit. A positive correlation was observed between plasma insulin levels and visceral fat weight in PHT rabbit.

Conclusions—

PHT rabbit shows insulin resistance along with central obesity. PHT rabbit will serve as a model for elucidating genetic predisposition and pathophysiology in metabolic syndrome.
Improvement of Endothelial Function by Systemic Transfusion of Vascular Progenitor Cells
Authors: Wassmann Sven , Werner Nikos , Czech Thomas , Nickenig Georg
Published: September 2006

Endothelial dysfunction is characterized by abnormalities in vasoreactivity and is a marker of the extent of atherosclerosis. Cellular repair by circulating progenitor cells of ongoing vascular injury may be essential for vascular integrity and function and may limit abnormalities in vasoreactivity. Apolipoprotein E–deficient (apoE
−/−
) mice were splenectomized and treated with high-cholesterol diet for 5 weeks, resulting in marked impairment of endothelium-dependent vasodilation of aortic segments as compared with wild-type mice. Intravenous transfusion of 2×10
7
spleen-derived mononuclear cells (MNCs) isolated from wild-type mice on 3 consecutive days restored endothelium-dependent vasodilation in the apoE
−/−
mice, as measured 7, 14, and 45 days after transfusion. Histological analyses of aortic tissue identified fluorescent-labeled, exogenously applied progenitor cells that expressed the endothelial cell marker CD31 in the endothelial cell layer of atherosclerotic lesions. Progenitor cell treatment led to increased vascular nitric oxide synthase activity. Transfusion of either in vitro-differentiated Dil-Ac-LDL/lectin-positive endothelial progenitor cells, CD11b-positive (monocyte marker), CD45R-positive (B-cell marker), or Sca-1–positive (stem cell marker) MNC subpopulations significantly improved endothelium-dependent vasodilation, although these treatments were not as effective as transfusion of total MNCs. Depletion of MNCs of either CD11b-positive, CD45R-positive, or Sca-1–positive cells resulted in significant attenuation of endothelium-dependent vasodilation as compared with nondepleted MNCs; however, vasoreactivity was still significantly improved as compared with saline-treated apoE
−/−
mice. Intravenous transfusion of spleen-derived MNCs improves endothelium-dependent vasodilation in atherosclerotic apoE
−/−
mice, indicating an important role of circulating progenitor cells for the repair of ongoing vascular injury. More than 1 subpopulation of the MNC fraction seems to be involved in this effect.
ROCK Controls Matrix Synthesis in Vascular Smooth Muscle Cells
Authors: Chapados Rene , Abe Khotaro , Ihida-Stansbury Kaori , McKean David , Gates Adam T. , Kern Michael , Merklinger Sandra , Elliott John , Plant Anne , Shimokawa Hiroaki , Jones Peter Lloyd
Published: September 2006

Tenascin-C (TN-C) is an extracellular matrix (ECM) protein expressed within remodeling systemic and pulmonary arteries (PAs), where it supports vascular smooth muscle cell (SMC) proliferation. Previously, we showed that A10 SMCs cultivated on native type I collagen possess a spindle-shaped morphology and do not express TN-C, whereas those on denatured collagen possess a well-defined F-actin stress fiber network, a spread morphology, and they do express TN-C. To determine whether changes in cytoskeletal architecture control TN-C, SMCs on denatured collagen were treated with cytochalasin D, which decreased SMC spreading and activation of extracellular signal-regulated kinase 1/2 (ERK1/2), signaling effectors required for TN-C transcription. Next, to determine whether cell shape, dictated by the F-actin cytoskeleton, regulates TN-C, different geometries of SMCs (ranging from spread to round) were engineered on denatured collagen: as SMCs progressively rounded, ERK1/2 activity and TN-C transcription declined. Because RhoA and Rho kinase (ROCK) regulate cell morphology by controlling cytoskeletal architecture, we reasoned that these factors might also regulate TN-C. Indeed, SMCs on denatured collagen possessed higher levels of RhoA activity than those on native collagen, and blocking RhoA or ROCK activities attenuated SMC spreading, ERK1/2 activity, and TN-C expression in SMCs on denatured collagen. Thus, ROCK controls the configuration of the F-actin cytoskeleton and SMC shape in a manner that is permissive for ERK1/2-dependent production of TN-C. Finally, we showed that inhibition of ROCK activity suppresses SMC TN-C expression and disease progression in hypertensive rat PAs. Thus, in addition to its role in regulating vasoconstriction, ROCK also controls matrix production.
Risk Score for Peri-Interventional Complications of Carotid Artery Stenting
Authors: Hofmann Robert , Niessner Alexander , Kypta Alexander , Steinwender Clemens , Kammler Jürgen , Kerschner Klaus , Grund Michael , Leisch Franz , Huber Kurt
Published: September 2006

Background and Purpose—

Routinely available independent risk factors for the peri-interventional outcome of patients undergoing elective carotid artery stenting (CAS) are lacking. The rationale of the study was to create a risk score identifying high-risk patients.

Methods—

We prospectively enrolled 606 consecutive patients assigned to CAS at a secondary care hospital. Various biochemical, clinical, and lesion-related risk factors were prospectively defined. The primary end point reflecting periprocedural complications encompassed minor and major stroke, nonfatal myocardial infarction and all-cause mortality within 30 days.

Results—

Three percent of patients (n=18) experienced a nonfatal minor (n=13) or major (n=5) stroke. 1.3% of patients (n=8) died from fatal stroke (n=4) or other causes (n=4). No myocardial infarction was observed within 30 days after stenting. Multivariable analysis revealed diabetes mellitus with inadequate glycemic control (HbA
1c
>7%), age ≥80 years, ulceration of the carotid artery stenosis, and a contralateral stenosis ≥50% as independent risk factors. A risk score formed with these variables showed a superior predictive value (C-statistic=0.73) compared with single risk factors. The presence of 2 or more of these risk factors identified patients with a risk of 11% for a periprocedural complication compared with 2% in patients with a score of 0 or 1.

Conclusions—

In patients undergoing elective CAS, a risk score based on routinely accessible variables was able to identify patients at high-risk for atherothrombotic events and all-cause death within 30 days after the intervention.
High von Willebrand Factor Levels Increase the Risk of First Ischemic Stroke
Authors: Bongers Tamara N. , de Maat Moniek P.M. , van Goor Mary-Lou P.J. , Bhagwanbali Vinod , van Vliet Huub H.D.M. , Gómez García Encarna B. , Dippel Diederik W.J. , Leebeek Frank W.G.
Published: September 2006

Background and Purpose—

Elevated von Willebrand factor (vWF) concentrations are associated with an increased risk of ischemic heart disease. Several factors influence vWF antigen levels and activity, including blood group, genetic variability, acute-phase response, and proteolysis by
A
D
isintegrin
a
nd
M
etalloprotease with
T
hrombo
S
pondin motif (ADAMTS13), a determinant of proteolytic cleavage of vWF. We assessed how these factors affect the relation between vWF and the occurrence of stroke to understand the underlying mechanism.

Methods—

In a case-control study of 124 first-ever ischemic stroke patients and 125 age- and sex-matched controls, we studied vWF antigen (vWF:Ag), vWF ristocetin cofactor activity (vWF:RCo), ADAMTS13 activity, the −1793
C/G
polymorphism in the
vWF
gene, and C-reactive protein.

Results—

vWF antigen and activity levels were significantly higher in cases than in controls. The relative risk of ischemic stroke was highest in individuals in the upper quartile of vWF:Ag (odds ratio, 3.2; 95% CI, 1.4 to 7.5) and vWF:RCo (odds ratio, 2.1; 95% CI, 0.9 to 4.8) compared with individuals in the lowest quartiles. In individuals with ADAMTS13 in the lowest quartile, the relative risk of stroke was 1.7 (95% CI, 0.7 to 3.9) compared with the highest quartile. C-reactive protein, ADAMTS13, and genetic variation did not affect the association between vWF and the relative risk of stroke, whereas blood group did affect the association.

Conclusions—

vWF antigen and activity are associated with the occurrence of acute ischemic stroke. This relation is unaffected by the severity of the acute-phase response or by genetic variation or degradation.
The Gene Encoding Transforming Growth Factor β1 Confers Risk of Ischemic Stroke and Vascular Dementia
Authors: Kim Younyoung , Lee Chaeyoung
Published: September 2006

Background and Purpose—

Transforming growth factor-β1 (TGF-β1) is an anti-inflammatory cytokine that plays an important role in cerebrovascular pathophysiology with protective activity against ischemia-induced neuronal death. We investigated the association of the polymorphism in
TGFB1
with ischemic stroke and vascular dementia.

Methods—

Three sequence variants in and around promoter and exons of
TGFB1
gene were identified in 30 Koreans. Pro10Leu was selected for association study, and then control subjects (n=207) and patients with ischemic stroke (n=271) and vascular dementia (n=207) were screened.

Results—

Subjects carrying Leu/Leu were susceptible to both ischemic stroke (odds ratio [OR]=1.63;
P
<0.05) and vascular dementia (OR=1.88;
P
<0.01). Analyses with stroke subtypes showed a strong association with small vessel occlusion (SVO, n=110; OR=2.07;
P
<0.01). Further analysis of SVO data partitioned by gender revealed the female-specific association with Pro10Leu (OR=2.70;
P
<0.05).

Conclusions—

The Pro10Leu of
TGFB1
might be a risk factor of ischemic stroke and vascular dementia, especially for SVO in females.