bluuebunny/crossref_metadata_2025 huggingface dataset:
Trans-Atlantic correlation of the Palaeogene volcanic successions in the Faeroe Islands and East Greenland
Authors: LARSEN LOTTE M. , WAAGSTEIN REGIN , PEDERSEN ASGER K. , STOREY MICHAEL
Published: December 2007

Before continental break-up in the NE Atlantic, the Faeroe Islands and central East Greenland were within a distance of 100–120 km. Chemical and lithological data for complete sections through the 5 km thick piles of contemporaneous Palaeogene flood basalts in the Faeroe Islands and in the Nansen Fjord area in East Greenland show very similar basalt compositions and evolution patterns with time. The Faeroes lower basalt formation and the equivalent Nansen Fjord Formation in East Greenland form a pre-break-up succession overlain by a sediment horizon. A syn-break-up succession consists of the Faeroes middle and upper basalt formations and the equivalent Milne Land Formation in East Greenland in which five intervals can be correlated with a compositional evolution from Ti-rich magnesian basalts and picrites at the base to a dominance of
MORB
-like low-Ti basalts at the top. The successions were generated in the same mantle melting column beneath a thinning continent with a rift zone that eventually ruptured the continent. The evolution pattern is very similar to that seen on the SE Greenland margin, but spreading according to the Palmason model of 1973 was not yet established. The pre- and syn-break-up successions formed volcanic megasystems stretching across the rift zone with areal extents of 70 000 and 220 000 km
2
and volumes of 120 000 and 250 000 km
3
. Rocks from the pre- and syn-break-up successions can be discriminated based on a simple major-element plot. The overlying succession was 3–3.5 km thick in E Greenland but was thin or absent in the Faeroes; the energy source for the melting appears to have been concentrated on the Greenland side.
U-Pb zircon geochronology of migmatization in the northern Central Highlands: evidence for pre-Caledonian (Neoproterozoic) tectonometamorphism in the Grampian block, Scotland
Authors: HIGHTON A. J. , HYSLOP E. K. , NOBLE S. R.
Published: December 2007

The age and formation of zircons in Neoproterozoie migmatites from the northern Grampian Highlands are assessed using field observations, imaging and U-Pb isotope dilution techniques. Acicular zircons within monzogranitie leucosomes provide evidence for neocrystalline growth during localized anatexis. U-Pb zircon data show that formation of the regional gneissose fabric, melt generation and new zircon growth occurred at 840 ±11 Ma contemporaneous with peak metamorphism. These data and previously dated shear fabrics at
c.
800 Ma, confirm that a Neoproterozoic tectonometamorphic event affected at least part of the metasedimentary sequence southeast of the Great Glen Fault. Data from detrital zircons indicate a Palaeoproterozoic/Grenville province, rather than Archaean, as the most likely source for the sedimentary protolith. In the absence of identifiable orogenic discontinuities within the Scottish Highlands, we question current correlations with Laurentian passive margin sequences, and the inferences that the rocks of the Grampian Block only experienced a simple Caledonian (Palaeozoic) orogenic history.
A formally verified proof of the prime number theorem
Authors: Avigad Jeremy , Donnelly Kevin , Gray David , Raff Paul
Published: December 2007

The prime number theorem, established by Hadamard and de la Vallée Poussin independently in 1896, asserts that the density of primes in the positive integers is asymptotic to 1/ln
x
. Whereas their proofs made serious use of the methods of complex analysis, elementary proofs were provided by Selberg and Erdös in 1948. We describe a formally verified version of Selberg's proof, obtained using the Isabelle proof assistant.
Predicate abstraction with indexed predicates
Authors: Lahiri Shuvendu K. , Bryant Randal E.
Published: December 2007

Predicate abstraction provides a powerful tool for verifying properties of infinite-state systems using a combination of a decision procedure for a subset of first-order logic and symbolic methods originally developed for finite-state model checking. We consider models containing first-order state variables, where the system state includes mutable functions and predicates. Such a model can describe systems containing arbitrarily large memories, buffers, and arrays of identical processes. We describe a form of predicate abstraction that constructs a formula over a set of universally quantified variables to describe invariant properties of the first-order state variables. We provide a formal justification of the soundness of our approach and describe how it has been used to verify several hardware and software designs, including a directory-based cache coherence protocol.
Minimizing expected energy consumption in real-time systems through dynamic voltage scaling
Authors: Xu Ruibin , Mossé Daniel , Melhem Rami
Published: December 2007

Many real-time systems, such as battery-operated embedded devices, are energy constrained. A common problem for these systems is how to reduce energy consumption in the system as much as possible while still meeting the deadlines; a commonly used power management mechanism by these systems is dynamic voltage scaling (DVS). Usually, the workloads executed by these systems are variable and, more often than not, unpredictable. Because of the unpredictability of the workloads, one cannot guarantee to minimize the energy consumption in the system. However, if the variability of the workloads can be captured by the probability distribution of the computational requirement of each task in the system, it is possible to achieve the goal of
minimizing the expected energy consumption
in the system. In this paper, we investigate DVS schemes that aim at minimizing expected energy consumption for frame-based hard real-time systems. Our investigation considers various DVS strategies (i.e., intra-task DVS, inter-task DVS, and hybrid DVS) and both an ideal system model (i.e., assuming unrestricted continuous frequency, well-defined power-frequency relation, and no speed change overhead) and a realistic system model (i.e., the processor provides a set of discrete speeds, no assumption is made on power-frequency relation, and speed change overhead is considered). The highlights of the investigation are two
practical
DVS schemes: Practical PACE (PPACE) for a single task and Practical Inter-Task DVS (PITDVS2) for general frame-based systems. Evaluation results show that our proposed schemes outperform and achieve significant energy savings over existing schemes.
Up and coming SIGWEB supported conferences
Authors: Lunn Darren
Published: December 2007

SIGWEB supports several specialized conferences, short courses, and workshops, as well as the Annual Hypertext Conference. SIGWEB sponsored conferences focus on timely topics in applied and computational hypertext and Web disciplines and provide a place for members and the entire applied Hypermedia and Web community to exchange ideas and to meet with and expand their network of colleagues. In this article, we provide a brief overview of SIGWEB sponsored conferences for delegates and other interested parties.
Analyzing block locality in Morton-order and Morton-hybrid matrices
Authors: Lorton K. Patrick , Wise David S.
Published: December 2007

As the architectures of computers change, introducing more caches onto multicore chips, even more locality becomes necessary. With the bandwidth between caches and RAM now even more valuable, additional locality from new matrix representations will be important to keep multiple processors busy. The default storage representations of both C and Fortran, row- and column-major respectively, have fundamental deficiencies with many matrix computations. By switching the storage representation from cartesian to block indices, one is able to take better advantage of cache locality at all levels from L1 to paging. This paper only changes storage representation from row-major to Morton-hybrid, and applies it to matrix multiplication. Its purpose is to show that, even with only traditional iterative algorithms, simply changing storage representation offers significant speedups.
The Brain, Appetite, and Obesity
Authors: Berthoud Hans-Rudolf , Morrison Christopher
Published: December 2007

Food intake and energy expenditure are controlled by complex, redundant, and distributed neural systems that reflect the fundamental biological importance of adequate nutrient supply and energy balance. Much progress has been made in identifying the various hormonal and neural mechanisms by which the brain informs itself about availability of ingested and stored nutrients and, in turn, generates behavioral, autonomic, and endocrine output. While hypothalamus and caudal brainstem play crucial roles in this homeostatic function, areas in the cortex and limbic system are important for processing information regarding prior experience with food, reward, and emotion, as well as social and environmental context. Most vertebrates can store a considerable amount of energy as fat for later use, and this ability has now become one of the major health risks for many human populations. The predisposition to develop obesity can theoretically result from any pathological malfunction or lack of adaptation to changing environments of this highly complex system.
The Evolution of a Cognitive Psychologist: A Journey from Simple Behaviors to Complex Mental Acts
Authors: Bower Gordon H.
Published: December 2007

The author summarizes his evolving interests from conditioning studies within a behaviorist orientation, thence to human memory, knowledge representation, and narrative understanding and memory. Arguing that the study of skilled reading provides a microcosm for revealing cognitive processes, he illustrates this by reviewing his research on the use of spatial priming to investigate readers’ on-line updating of their situational models of texts. Conceptual entities close to the reader's focus of attention within the model are readily retrieved. Retrieval speed from memory declines with the probed object's distance from the current focus and decays with time elapsed in the narrative since the item was last in focus. The focus effect varies with the character's perspective, his status in the story, his active goals, and other factors. The results are accommodated within an associative network model distinguishing just-read sentences in short-term memory from activated portions of long-term memory structures to which they refer.
Integrated DNA-Nanoparticle Complexes: Synthesis, Electrical and Optical Properties
Authors: Vasudev Milana , Yamanaka Takayuki , Yang Jianyong , Li Yang , Stroscio Michael A. , Dutta Mitra
Published: December 2007

We have studied the optoelectronic properties of nanostructure-DNA complexes chemically assembled on transparent, semi-rigid substrates such as poly-methyl methacrylate (PMMA). DNA can be immobilized on these substrates by chemically modifying the PMMA substrates and using suitable cross-linking agents. Additionally, DNA strands end-terminated with TiO2 nanoparticles are used in this study to observe DNA cleavage through photo-induced charge carriers from the TiO2 trapped in guanine (G-) rich sites; polaron transport in such a DNA molecule is analyzed theoretically (3) to provide an understanding of charge injection into DNA as well as the formation, transport of polarons in DNA. Subsequent AFM measurements are used to study the structural characteristics of DNA on the PMMA substrates. Raman spectral lines observed in the 750-850 cm-1 region may be attributed to the phosphodiester backbone in the DNA. The fabrication of these nanostructure-DNA ensembles wil l be discussed and their Raman and AFM characterization will be presented.
Electrical Contacts to Molecular Devices by Electroless Deposition of Cu on Carboxylic Acid Terminated Self-Assembled Monolayers on GaAs
Authors: Wu Lingling , Camacho-Alanis Fernanda , Williams Keith , Zangari Giovanni , Swami Nathan
Published: December 2007

Copper electroless deposition (ELD) for fabrication of electrical contacts to molecular devices and diffusion barriers for nanoelectronics was carried out using Cu2+ complexation through the replacement reaction of the hydroxyl group in carboxylic acid terminated monolayers to generate the seed layer, followed by electroless reduction on the seed to form additional Cu layers. Whereas copper deposition on monolayers on gold was higher at defect sites, deposition on monolayers on GaAs was uniform across the substrate as observed by Scanning Electron Microscopy of Cu overlayers on the underlying monolayer. Cu deposition morphology was closely correlated to the crystallinity of the underlying monolayer. Cyclic voltammetry of the hydrogen evolution reaction on Cu ELD layers deposited on the monolayer on GaAs showed a 0.3 V overvoltage in comparison to Cu deposited on bare GaAs, and this significant difference is strong evidence that the copper overlayer did not penetrate the underlying monolayer.
Chemical-Mechanical Planarization Compatible for Both Copper/Low k Level in a 90 nm Technology and Thick Copper Level in an RF Technology
Authors: Loquet Yannick , Perrot Cedric , Bouillon Pierre , Iteprat Blaise
Published: December 2007

The emergence of wireless communication technologies has increased the need for high performance radio frequency (RF) circuits as transceivers or filters (1). These functions imply high quality factor (Q) inductors. One way to reach such high Q value is to increase the ultimate copper thickness (above 3µm). Whereas Cu CMP has been widely reported as one of the leading techniques to integrate copper interconnects, many issues are still encountered for thick copper applications, where uniformity, topology and process time are major concerns. In this study, we develop a copper bulk CMP process compatible for both thick copper/low k interconnects and RF application. Starting from conventional sub-0.18µm slurry, an additive solution is added to enhance its removal rate. Results obtained on a 4 µm thick level are presented. It is shown that electrical performances are preserved, notably sheet resistance uniformity. Other usual CMP param eters, like planarization and consumables aging are also presented.
Effect of Slurry Characteristics on the Surface Tribology During Copper CMP Process
Authors: Mudhivarthi Subrahmanya R. , Kakireddy Veera Raghava , Kumar Ashok , Obeng Y.
Published: December 2007

Tribological properties at the polishing interface during chemical mechanical polishing (CMP) in different slurry chemical environments need to be studied in greater detail, to understand the mechanism and science of CMP. The chemical reactions in different environments significantly affect the actual tribological behavior at the interface. In the present research, slurry temperature, oxidizer percentage and complexing agent concentrations in the slurry are varied and their effect on the tribology at the interface on polyurethane pads has been studied. Specifically, the main goal of this research is to develop fundamental understanding about the role of coefficient of friction in CMP and the effect of slurry characteristics on the tribology at the interface. From the results the effect of slurry temperature was found to be very weak when compared to the other process parameters such as pressure and velocity.
Integrating a CMP Robust ILD Module
Authors: Naughton John J. , Towner Janet M. , Aytes S. , Nelson M. M.
Published: December 2007

CMP (chemical mechanical planarization) micro-scratches are yield and reliability limiting defects in semiconductor manufacturing. Silicon oxide films doped with boron and phosphorus have been standard in pre-metal dielectric stacks but are prone to CMP micro-scratching. A novel film stack was integrated utilizing a thick,undoped PECVD cap layer to mitigate device failure and reliability problems. The sequence of depositing the integral film layers in conjunction with the densification proved critical in maintaining device performance.
Retinal Nerve Fiber Layer Images Captured by GDx-VCC in Early Diagnosis of Glaucoma
Authors: Zheng Wang , Baohua Cui , Qun Cao , Zhi Qiao , Hong Dai
Published: December 2007

Objectives: To compare differences in retinal nerve fiber layer (RNFL) parameters between normal subjects and patients with various degrees of glaucoma, evaluate the sensitivity and specificity of GDx-VCC parameters, and determine the capability of GDx-VCC parameters and the most valuable indicators for the diagnosis of early glaucoma. Methods: GDx-VCC was used to measure RNFL in 80 patients with early glaucoma (130 eyes), 70 patients with advanced glaucoma (90 eyes) and 40 normal controls (80 eyes). All glaucoma patients were divided into an early glaucoma group and an advanced glaucoma group, according to the mean defect of the visual field. RNFL parameters were compared between normal subjects and patients with various degrees of glaucoma. Receiver operating characteristic (ROC) curves of GDx parameters were drawn to determine the most valuable GDx parameters for the diagnosis of early glaucoma. Results: The RNFLs were significantly thinner in patients with early glaucoma than those in normal subjects; they were also significantly thinner in patients with advanced glaucoma than those in patients with early glaucoma. The differences in all parameters reached statistical significance (p < 0.001). The mean defect of the visual field was significantly correlated with all RNFL parameters (p < 0.001). The areas under the ROC curves were >0.7 for all parameters, which could effectively differentiate early glaucoma from normal subjects. The areas under the ROC curves were 0.81 for nerve fiber indicator and inferior average with better differentiation capability. Conclusions: GDx-VCC can provide quantitative measurements of RNFL thickness for clinical use, which can effectively differentiate patients with early glaucoma from normal subjects, and will be clinically very helpful for the early diagnosis of glaucoma. Nerve fiber indicator and inferior average are the most effective indicators for the early diagnosis of glaucoma.
Effects of Generated trans-Arachidonic Acids on Retinal Capillary during Nitrative Stress in Diabetic Rats
Authors: Xu Lin , Xun Guoliang , Yao Zhujun , Liu Yumin , Qiu Yunping , Liu Kun , Zhu Dongqing , Gu Qing , Xu Xun , Ho Patrick C.P.
Published: December 2007

Purpose: To investigate whether the trans-arachidonic acids (TAAs) change in diabetic conditions and the effect on capillary cells and its possible mechanism. Methods: Diabetes was induced by intraperitoneal injection of streptozotocin at 60 mg kg–1 body weight. The amount of TAAs and arachidonic acid (AA) in serum of diabetic rats was measured by the gas chromatography and mass spectrometry method and the ratio of the peak area of TAAs to AA with a selected ion of 79 was estimated by group t test. The expression level of thrombospondin-1 (TSP-1) in the retina was examined by Western blot. The pericyte apoptotic index was investigated by flow cytometry. Result: The ratio of TAAs to AA significantly increased in serum at the time points of 8, 12 and 16 weeks after streptozotocin induction (p < 0.05). The expression of TSP-1 in the retina of diabetic rats elevated with longer duration of diabetes (checking the time points of 2-, 4-, 8-, 12- and 16-week diabetic rats). The expression of TSP-1 tended to be physiologically elevated in relation to age but less significantly than in the diabetic group. TAAs could not induce the apoptosis of retinal pericytes (p > 0.05). Conclusion: TAAs were generated associated with nitrative stress in diabetic rats and a possible mechanism of microvascular injury exits in diabetic conditions.
Rat Model for Anterior Segment Intraocular Surgery Induced Blood-Retinal Barrier Breakdown
Authors: Xie Mao-Song , Xu Guo-Xing , Huang Yan
Published: December 2007

Purpose: To develop a practical rat model of blood-retinal barrier (BRB) breakdown induced by anterior segment intraocular surgery. Methods: A 27-gauge needle attached to infusion tubing running to a bottle of balanced salt solution was inserted through the limbus into the rat anterior chamber. The pressure of the balanced salt solution was oscillated from 0 to 12 mm Hg above the atmospheric pressure for 30 times. The needle was removed and the anterior chamber was formed. Then the eye was exposed vertically to the light of the operating microscope. The contralateral eye was left untreated. The eyes were applied with ofloxacin ophthalmic solution after surgery. At several time points after surgery, the integrity of the BRB was assessed by fluorescence fundus angiography, optical coherence tomography, immunohistochemical staining for serum albumin and quantitative measurement using Evans blue as a tracer. Results: The extravasation of fluorescein, the increased central retinal thickness, strong staining for albumin in the retina and substantially elevated retinal Evans blue leakage demonstrated BRB breakdown after anterior segment intraocular surgery. On the 1st day after surgery, the model group showed a statistically significant elevation in the retinal Evans blue leakage as compared to the contralateral control group and the normal control group. These increased and reached the peak on the 2nd day after surgery and decreased to the point that there was no significant difference as compared to the contralateral control group and the normal control group on the 7th day after surgery. Conclusions: This study establishes a practical rat model of BRB breakdown induced by anterior segment intraocular surgery.
Nerve Growth Factor Helps Protect Retina in Experimental Retinal Detachment
Authors: Sun Xiaodong , Xu Xun , Wang Fenghua , Zhang Xi , Ho Patrick C.P. , Liu Haiyang , Qian Jin , Yu Zhang , Lu Hongfen , Xu Weiqi
Published: December 2007

Purpose: To investigate the expression of nerve growth factor (NGF) and its receptor TrkA on the retina at different time points after retinal detachment (RD) and the protection effect of NGF in experimental RD. Methods: Sprague-Dawley rats were used as an RD animal model by injection of 0.1% sodium hyaluronate under the neurosensory retina. The expression of endogenous NGF and its receptor TrkA in the rat retina was detected using immunohistochemistry. The NGF (5 µg/eye) or phosphate-buffered saline were injected separately into vitreous every 4 days after the RD. The rat eyes were then observed at various time points. Morphologic changes were investigated by light microscopy. Retinal gliosis was detected by glial fibrillary acidic protein labeling. Results: The expression of endogenous NGF and TrkA was upregulated during RD procedure. Most of the NGF-treated retina had a well-organized structure. In NGF-treated RD eyes, the cells were still significantly more numerous than in phosphate-buffered-saline-treated retina. Glial fibrillary acidic protein labeling increased quickly after RD; the NGF-treated retina had less reactive gliosis than the control groups. Conclusions: Intravitreal injection of exogenous NGF can protect retinal cells from degeneration in experimental RD. It may exert its protective action by preventing the apoptosis of retinal cells after RD.
Manometric Evaluation of the Esophagus in Patients with Behçet’s Disease
Authors: Bektas Mehmet , Altan Mehmet , Alkan Murat , Ormeci Necati , Soykan Irfan
Published: December 2007

Introduction: Gastrointestinal (GI) involvement in Behçet’s disease (BD) mainly appears in mucosa and affects 5–40% of patients, however the effects of the disease on lower esophageal sphincter (LES) pressure and esophageal contractions are not well known. The aims of this study were to evaluate esophageal motor function and to identify whether there was any specific motility pattern for patients with BD who had upper GI symptoms without endoscopic abnormality. Materials and Methods: 25 patients with BD, with a mean age of 43.1 (range 20–66) years, were admitted to our clinic whose main complaints were dyspeptic such as reflux, epigastric pain, vomiting and bloating. 25 healthy and age-matched individuals were also included in the study as controls. After one night fasting, LES pressure and esophageal contractions were measured. Results: Esophageal motor abnormalities were detected in 16% (4/25) of these patients with manometric studies (non-specific esophageal motor disorder in 1, esophageal hypomotility in 2, and LES hypotension in 1 patient); 16% (4/25) of these patients had endoscopic findings and overall 32% (8/25) of the cases showed esophageal pathology. All cases with esophageal motor abnormalities were suffering from reflux and endoscopy showed grade B esophagitis in 2 of these cases. Median LES pressure and LES relaxation were significantly lower in patients with BD compared to the control group (16.8 ± 10.5 vs. 20.4 ± 6.1, p = 0.02, and 92.1 ± 10.1 vs. 96.4 ± 4.5, p = 0.03 respectively). Conclusion: Esophageal involvement in BD is significantly high. We propose manometric studies are necessary to evaluate esophageal manifestations in BD patients with esophageal symptoms even without endoscopic findings.
Empirical Therapy for Symptomatic Gastroesophageal Reflux Disease in Primary Care: Determinants of Efficacy
Authors: Arts J. , Eisendrath P. , Devière J. , Tack J.
Published: December 2007

Aim: We conducted a prospective survey of the use, relationship to existing guidelines and outcome of empirical treatment by general practitioners (GPs) in gastroesophageal reflux disease (GERD) patients. Methods: In total 815 GPs completed a questionnaire on consecutive GERD patients in whom they started empirical therapy without additional investigation. Results: The study population included 4,177 patients (50.3% men, mean age 39.3 ± 11.0 years) without previous endoscopy presenting with typical GERD symptoms (96%). According to Belgian-French guidelines, endoscopic examination was recommended in 2,083 patients, but all received empirical therapy. Data were collected for 3,955 patients (94.7%) at 1-month follow-up; 3,360 patients (85.0%) were responders to empirical therapy (no symptoms during the last 7 days), which was not significantly influenced by the type of treatment. Presence of alarm symptoms (15.5%), alcohol consumption, failure of previous treatment or recurrence after previous treatment were significant predictors of nonresponsiveness to empirical therapy. Follow-up endoscopy in 521 patients showed reflux esophagitis in 70.6%, peptic ulcer in 5.9% and Barrett’s in 0.2%. Conclusions: Empirical treatment of typical symptomatic GERD by GPs is highly successful. Predictors of nonresponsiveness to empirical therapy are the presence of alarm symptoms, alcohol consumption and failure of or recurrence after a previous treatment.
A New Eradication Resistance Index as a Predictor of Metronidazole-Containing Second-Line Treatment of Helicobacter pylori
Authors: Nishizawa Toshihiro , Suzuki Hidekazu , Masaoka Tatsuhiro , Iwasaki Eisuke , Hibi Toshifumi
Published: December 2007

Background: It is helpful in clinical practice to predict the effects of eradication therapy on Helicobacter pylori. Aim: To develop a useful predictor of the response to metronidazole (MNZ)-containing second-line regimens by combining minimal inhibitory concentrations (MICs) of both amoxicillin (AMX) and MNZ, and the results of urea breath test (UBT) before the treatment. Methods: We enrolled 107 patients who showed eradication failure following first-line triple therapy with a proton pump inhibitor, AMX and clarithromycin. The eradication resistance index was defined as: [pre-treatment UBT result (‰)] × [AMX MIC (µg/ml)] × [MNZ MIC (µg/ml)]. Second-line eradication therapy with lansoprazole, AMX and MNZ was administered for 1 week. Eradication was confirmed by the UBT. Results: The eradication resistance index in subjects showing eradication failure and those showing successful eradication was 9.72 ± 6.63 and 1.25 ± 2.31, respectively (p < 0.001). When a cutoff value of 3 was used, the eradication resistance index predicted the response to therapy with a specificity of 93.8%, sensitivity of 81.8%, and accuracy of 92.5%. Conclusions: The eradication resistance index is a more useful predictor of response to MNZ-containing regimens for second-line treatment than only pretreatment UBT results or MNZ resistance.
Adminstration of PEG-Interferon to a Patient with Ulcerative Colitis and Chronic Hepatitis C Correlated with Reduced Colonic Inflammation and Reversal of Peripheral Th1/Th2 Ratios
Authors: Kasahara Katsuhiro , Nakase Hiroshi , Uza Norimitsu , Ueno Satoru , Matsuura Minoru , Mikami Sakae , Inoue Satoko , Chiba Tsutomu
Published: December 2007

A 42-year-old man with chronic hepatitis C and ulcerative colitis (UC) was referred to our hospital in August 2004 because of bloody diarrhea. He was clinically and endoscopically diagnosed with flare of UC. After informed consent had been obtained, he was treated with PEG-IFN-α-2a. Four weeks after initiation of PEG-IFN therapy, his abdominal symptoms gradually subsided. Intracellular cytokine assay revealed that the ratio of T-helper (Th) 1 (IFN-γ)/Th 2 (IL-4) increased after IFN therapy. Three months after starting IFN therapy, colonoscopy revealed a normal mucosal pattern. He was uneventfully treated with PEG-IFN-α-2a for one year. When last seen in November 2006, he was still in remission of UC. Our intracellular cytokine data suggested that alteration of Th1/Th2 cytokine balance by IFN is one possible mechanisms of reducing intestinal inflammation in patients with UC. In this regard, IFN therapy could be useful for some patients with UC refractory to other conventional therapies.
Combined pH-Metry/Impedance Monitoring Increases the Diagnostic Yield in Patients with Atypical Gastroesophageal Reflux Symptoms
Authors: Bajbouj Monther , Becker Valentin , Neuber Martin , Schmid Roland M. , Meining Alexander
Published: December 2007

Background: Globus sensations, hoarseness and chronic cough are suggested to be atypical manifestations of Gastroesophageal Reflux Disease (GERD). The aim of the study was to investigate whether combined pH-metry and multichannel intraluminal impedance monitoring increases the diagnostic yield. Methods: 41 patients with atypical GERD symptoms were included in the study. Globus sensation was the dominant symptom in 23 patients (56.1%). The remaining 18 patients (43.9%) complained mainly about hoarseness or chronic cough. All patients were examined by endoscopy, dual-channel pH-metry and impedance monitoring off-therapy with proton pump inhibitors (PPI). Diagnostic yield of the respective method was determined. Results: A total of 26 patients (63.4%) had pathological findings in any method. The highest diagnostic yield was achieved by combined 24-h pH-metry/impedance measurement (61.0%), followed by solely impedance measurement (48.8%), distal pH-metry (29.3%), endoscopy (22.8%) and proximal pH-metry (17.1%). All patients with a positive PPI-test and 25% of patients (5/20) with a negative PPI-test had a pathological result in pH-metry/impedance. Conclusion: Multichannel intraluminal impedance monitoring increases the diagnostic yield for objective detection of atypical manifestation of GERD. Combined 24-h pH-metry/impedance measurement has the best diagnostic yield for detection of gastroesophageal reflux and has therefore the potential to represent a new diagnostic gold standard.
Wireless Capsule pH Monitoring: Does It Fulfil All Expectations?
Authors: Maerten Philippe , Ortner Marianne , Michetti Pierre , Dorta Gian
Published: December 2007

pH monitoring has been used as a diagnostic tool in gastro-oesophageal reflux disease (GERD) for many years. Recent studies have shown that wireless capsule pH monitoring is better tolerated and interferes less with daily activities as compared to traditional catheter-based pH monitoring. Moreover, prolonged recording time (48 h instead of 24 h) is possible with wireless pH monitoring. The main secondary effect of wireless capsule pH monitoring is induction of thoracic discomfort in 10–65% of the patients, which can vary from mild foreign body sensation to severe chest pain. Sensitivity and specificity of wireless capsule monitoring is comparable to that of traditional pH monitoring. It has not been proven yet that better tolerability and a longer recording time increases the diagnostic yield of wireless capsule monitoring in GERD.
Pulmonary Hypertension Associated with Myeloproliferative Disorders: A Retrospective Study of Ten Cases
Authors: Guilpain P. , Montani D. , Damaj G. , Achouh L. , Lefrère F. , Le Pavec J. , Marfaing-Koka A. , Dartevelle P. , Simonneau G. , Humbert M. , Hermine O.
Published: December 2007

Background: Pulmonary hypertension (PH) is a severe hemodynamic disorder in which the pulmonary artery pressure is persistently elevated, leading to right-sided heart failure. Some studies have suggested an association between PH and myeloproliferative diseases (MPD). Objectives: This study describes clinical, hematological and hemodynamic characteristics of PH associated with MPD. Methods: We retrospectively reviewed 10 cases of PH associated with MPD: polycythemia vera (8 patients) and essential thrombocythemia (2 patients), followed between 1993 and 2002. The baseline evaluation was established by right-sided heart catheterization, ventilation/perfusion lung scan and pulmonary angiography if required. Results: Six patients had confirmed chronic thromboembolic pulmonary hypertension (CTEPH) and 4 had pulmonary arterial hypertension (PAH) associated with MPD without other risk factors for PAH. The hemodynamic characteristics of CTEPH and PAH associated with MPD were similar. The diagnosis of CTEPH was concomitant to that of MPD in all cases (5 polycythemia vera and 1 essential thrombocythemia). The PAH associated with MPD occurred later in the evolution of the MPD (3 polycythemia vera and 1 essential thrombocythemia) with a median of 162 months after the diagnosis of MPD, and it was associated with myeloid metaplasia (p < 0.01). Conclusion: We describe 2 distinct forms of PH in the context of MPD: CTEPH, which is diagnosed at an early stage of the MPD, and PAH, which occurs later in the course of the MPD and is associated with myeloid metaplasia. Progressively increasing dyspnea in a patient with an MPD warrants further investigation to rule out PAH and CTEPH, while a diagnosis of CTEPH warrants ruling out MPD.
α-Klotho: A Regulator That Integrates Calcium Homeostasis
Authors: Nabeshima Yo-ichi , Imura Hiroaki
Published: December 2007

Intensive study on calcium homeostasis regulation over the past several decades has established a systematized construal of its role in living phenomena, leaving us with the impression that this field is fairly defined and understood. However, the unveiling of the molecular function of α-Klotho has recently given new insight into this field. α-Klotho is a unique molecule that plays pivotal roles in: (i) the rapid tuning of extracellular Ca2+ concentration through transepithelial Ca2+ transport; (ii) parathyroid hormone secretion and subsequent Ca2+ increase in the serum, and (iii) the signal transduction of FGF23 that adjusts the calcium concentration by downregulating the production of 1,25(OH)2D3. Through these pathways, α-Klotho participates in the regulation of calcium homeostasis of the CSF and blood/body fluids by its actions in the choroid plexus, parathyroid glands and DCT nephrons. In this regard, α-Klotho is a key player that integrates ‘a multi-step regulatory system of calcium homeostasis’ that rapidly adjusts the extracellular calcium concentration and continuously maintains its concentration within a narrow physiological range.
Testicular Mixed Germ Cell Tumor in an Adolescent with Cowden Disease
Authors: Devi Minati , Leonard Norma , Silverman Svetlana , Al-Qahtani Mohamed , Girgis Rose
Published: December 2007

Cowden disease (also known as Cowden syndrome) is characterized by multiple organ hamartomatous tumors and an increased risk of malignancy, in particular of the breast, thyroid and endometrium. Testicular tumors including seminoma have previously been reported in adult patients. We are reporting, for the first time, a case of testicular mixed germ cell tumor in an adolescent with Cowden disease. An association of testicular malignancy in Cowden disease could be explained by the previous observation of strong PTEN gene expression in the basal cell layer around seminiferous tubules and increased frequency of PTEN mutations in cultured testicular cancer cell lines. Surveillance for breast, thyroid, endometrial and renal cancer has been recommended for individuals with Cowden disease. The association of Cowden disease and testicular malignancy in our case suggests the need for additional screening of testes.
Femoral Atherosclerosis In Heterozygous Familial Hypercholesterolemia
Authors: Junyent Mireia , Gilabert Rosa , Zambón Daniel , Pocoví Miguel , Mallén Miguel , Cofán Montserrat , Núñez Isabel , Civeira Fernando , Tejedor Diego , Ros Emilio
Published: December 2007

Objective—

The purpose of this study was to assess femoral atherosclerosis by ultrasound in patients with molecularly defined heterozygous familial hypercholesterolemia (FH) in comparison with matched control subjects and in relation to mutational class in the LDL receptor and apolipoprotein B (APOB) genes.

Methods and Results—

Femoral intima-media thickness (IMT) and plaque were evaluated in 146 FH patients carrying null alleles (n=48), defective-receptor alleles (n=62), undetermined-function alleles (n=25), or APOB defects (n=11) and in 193 healthy subjects. Twenty-three patients had coronary heart disease (CHD). The frequency of both tendon xanthomas and CHD was ≈2-fold higher and average LDL cholesterol was 30 mg/dL higher in null-allele genotype compared with receptor-defective mutations. All femoral measurements were increased in FH patients versus controls (
P
<0.001), and null-allele mutations showed higher age-, sex-, and LDL cholesterol-adjusted maximum IMT than receptor-defective or APOB defects (
P
for trend, 0.001). By multivariate analysis, independent associations of mean IMT, a measure of early atherosclerosis, were age, LDL cholesterol, sex, and systolic blood pressure. Age, null-allele genotype, sex, and smoking explained 42% of the variability of maximum IMT, a measure of advanced atherosclerosis.

Conclusions—

FH patients have increased femoral IMT in relation to mutational class. The findings support the usefulness of genetic testing in FH beyond securing the diagnosis.
Iliac Venous Stenting
Authors: McBane Robert D. , Leadley Robert J. , Baxi Sangita M. , Karnicki Krzysztof , Wysokinski Waldemar
Published: December 2007

Objective—

The clinical use of venous stents is increasing dramatically. Although antiplatelet agents are required for arterial stent patency, optimal thrombo-prophylaxis after venous stenting remains undefined. To address this issue, PD0348292, a direct Factor Xa inhibitor, was compared with antiplatelet therapy in a porcine venous stent model.

Methods and Results—

Four hours before stent deployment, pigs (n=5 to 6 per group) received oral PD0348292 at 0.4, 0.9, 4.3 mg/kg, or 0.4 mg/kg plus aspirin (325 mg). Aspirin, clopidogrel (75 mg), aspirin plus clopidogrel, or vehicle (n=10) were administered daily for 2 days before the procedure. Two hours after stent placement, thrombi were quantified by autologous
111
In-platelet content and weights. Thrombus weight and platelet deposition were significantly reduced by PD0348292 at 0.4 (49±79 mg and 110±145×10
6
/cm
2
), 0.9 (5±6 mg and 107±128×10
6
/cm
2
), 4.3 mg/kg (0±0 mg and 87±125×10
6
/cm
2
), and PD348292 plus aspirin (20±40 mg and 157±70×10
6
/cm
2
) compared with vehicle (402±226 mg; 584±454×10
6
/cm
2
). Despite prolonging bleeding times and inhibiting platelet aggregation, neither aspirin (567±683 mg and 533±622×10
6
/cm
2
), clopidogrel (404±349 mg and 178±101×10
6
/cm
2
), nor aspirin plus clopidogrel (247±261 mg and 231±266×10
6
/cm
2
) significantly decreased stent thrombosis.

Conclusions—

PD0348292 completely inhibited thrombosis after venous stenting. Platelet accretion in these venous thrombi appear to involve pathways distinct from arachidonate metabolism or ADP P
2
Y
12
receptor activation.
Molecular Mechanisms of Angiotensin II–Mediated Mitochondrial Dysfunction
Authors: Doughan Abdulrahman K. , Harrison David G. , Dikalov Sergey I.
Published: December 2007

Mitochondrial dysfunction is a prominent feature of most cardiovascular diseases. Angiotensin (Ang) II is an important stimulus for atherogenesis and hypertension; however, its effects on mitochondrial function remain unknown. We hypothesized that Ang II could induce mitochondrial oxidative damage that in turn might decrease endothelial nitric oxide (NO
·
) bioavailability and promote vascular oxidative stress. The effect of Ang II on mitochondrial ROS, mitochondrial respiration, membrane potential, glutathione, and endothelial NO
·
was studied in isolated mitochondria and intact bovine aortic endothelial cells using electron spin resonance, dihydroethidium high-performance liquid chromatography –based assay, Amplex Red and cationic dye fluorescence. Ang II significantly increased mitochondrial H
2
O
2
production. This increase was blocked by preincubation of intact cells with apocynin (NADPH oxidase inhibitor), uric acid (scavenger of peroxynitrite), chelerythrine (protein kinase C inhibitor),
N
G
-nitro-
l
-arginine methyl ester (nitric oxide synthase inhibitor), 5-hydroxydecanoate (mitochondrial ATP-sensitive potassium channels inhibitor), or glibenclamide. Depletion of p22

phox

subunit of NADPH oxidase with small interfering RNA also inhibited Ang II–mediated mitochondrial ROS production. Ang II depleted mitochondrial glutathione, increased state 4 and decreased state 3 respirations, and diminished mitochondrial respiratory control ratio. These responses were attenuated by apocynin, 5-hydroxydecanoate, and glibenclamide. In addition, 5-hydroxydecanoate prevented the Ang II–induced decrease in endothelial NO
·
and mitochondrial membrane potential. Therefore, Ang II induces mitochondrial dysfunction via a protein kinase C–dependent pathway by activating the endothelial cell NADPH oxidase and formation of peroxynitrite. Furthermore, mitochondrial dysfunction in response to Ang II modulates endothelial NO
·
and

generation, which in turn has ramifications for development of endothelial dysfunction.
Agonist-Stimulated Endothelial Nitric Oxide Synthase Activation and Vascular Relaxation
Authors: Fulton David , Ruan Ling , Sood Sarika G. , Li Chunying , Zhang Qian , Venema Richard C.
Published: December 2007

Tyr83 in endothelial nitric oxide synthase (eNOS) has been identified previously as a site of Src kinase–mediated phosphorylation of eNOS in bovine aortic endothelial cells (BAECs) that is phosphorylated in response to oxidant stress. In the present study, we have used a phospho-specific antibody to show that Tyr83 in eNOS is also phosphorylated in both BAECs and intact blood vessel segments in response to treatment with a variety of different eNOS-activating agonists, including thapsigargin, vascular endothelial growth factor, bradykinin, ATP, sphingosine-1-phosphate, estrogen, angiopoietin, and acetylcholine. Agonist stimulation of eNOS Tyr83 phosphorylation as well as agonist stimulation of endothelial NO release in BAECs is blocked by Src kinase inhibition by either 4-amino-5-(4-chlorophenyl)-7-(
t
-butyl) pyrazolo [3,4-d] pyrimidine (PP2) or by dominant negative Src. Mutation of Tyr83 to a nonphosphorylatable Phe blocks agonist stimulation of NO release from eNOS-reconstituted eNOS knockdown endothelial cells. Mutation of Tyr83 also attenuates agonist-induced relaxation of eNOS-reconstituted aortic rings from eNOS knockout mice. Phosphorylation of eNOS at Tyr83 thus appears to be a common covalent modification that is induced, not only by oxidant stress but also by other physiologically relevant extracellular signals known to be important in regulation of eNOS activity in vivo. Moreover, our results demonstrate an important role for Src-mediated phosphorylation of eNOS at Tyr83 in agonist stimulation of eNOS activation and vascular relaxation.
Edaravone Attenuates Brain Edema and Neurologic Deficits in a Rat Model of Acute Intracerebral Hemorrhage
Authors: Nakamura Takehiro , Kuroda Yasuhiro , Yamashita Susumu , Zhang Xia , Miyamoto Osamu , Tamiya Takashi , Nagao Seigo , Xi Guohua , Keep Richard F. , Itano Toshifumi
Published: December 2007

Background and Purpose—

Our previous studies have demonstrated that oxidative DNA injury occurs in the brain after intracerebral hemorrhage (ICH). We therefore examined whether edaravone, a free-radical scavenger, could reduce ICH-induced brain injury.

Methods—

These experiments used pentobarbital-anesthetized, male Sprague-Dawley rats that received an infusion of either 100 μL autologous whole blood (ICH), FeCl
2
, or thrombin into the right basal ganglia. The rats were humanely killed 24 hours later. There were 4 sets of experiments. In the first, the dose-dependent effects of edaravone on ICH-induced brain injury were examined by measuring brain edema and neurologic deficits. In the second set, apurinic/apyrimidinic abasic sites and 8-hydroxyl-2′-deoxyguanosine, which are hallmarks of DNA oxidation, were investigated after treatment for ICH. In the third, the effect of delayed treatment with edaravone on ICH-induced injury was determined, whereas the fourth examined the effects of edaravone on iron- and thrombin-induced brain injury.

Results—

Systemic administration of edaravone immediately or 2 hours after ICH reduced brain water content 24 hours after ICH compared with vehicle (
P
<0.05). Edaravone treatment immediately or 2 hours after ICH also ameliorated neurologic deficits (
P
<0.05). Edaravone also attenuated ICH-induced changes in apurinic/apyrimidinic abasic sites and 8-hydroxyl-2′-deoxyguanosine and reduced iron- and thrombin-induced brain injury.

Conclusions—

Edaravone attenuates ICH-induced brain edema, neurologic deficits, and oxidative injury. It also reduces iron- and thrombin-induced brain injury. These results suggest that edaravone is a potential therapeutic agent for ICH.
Cerebrovascular Responses to Hypoxia and Hypocapnia in Ethiopian High Altitude Dwellers
Authors: Claydon Victoria E. , Gulli Giosué , Slessarev Marat , Appenzeller Otto , Zenebe Guta , Gebremedhin Amha , Hainsworth Roger
Published: December 2007

Background and Purpose—

Cerebrovascular responses to hypoxia and hypocapnia in Peruvian altitude dwellers are impaired. This could contribute to the high incidence of altitude-related illness in Andeans. Ethiopian high altitude dwellers may show a different pattern of adaptation to high altitude. We aimed to examine cerebral reactivity to hypoxia and hypocapnia in healthy Ethiopian high altitude dwellers. Responses were compared with our previous data from Peruvians.

Methods—

We studied 9 Ethiopian men at their permanent residence of 3622 m, and one day after descent to 794 m. We continuously recorded cerebral blood flow velocity (CBFV; transcranial Doppler). End-tidal oxygen (P
ET
o
2
) was decreased from 100 mm Hg to 50 mm Hg with end-tidal carbon dioxide (P
ET
co
2
) clamped at the subject’s resting level. P
ET
co
2
was then manipulated by voluntary hyper- and hypoventilation, with P
ET
o
2
clamped at 100 mm Hg (normoxia) and 50 mm Hg (hypoxia).

Results—

During spontaneous breathing, P
ET
co
2
increased after descent, from 38.2±1.0 mm Hg to 49.8±0.6 mm Hg (
P
<0.001). There was no significant response of CBFV to hypoxia at either high (−0.19±3.1%) or low (1.1±2.9%) altitudes. Cerebrovascular reactivity to normoxic hypocapnia at high and low altitudes was 3.92±0.5%.mm Hg
−1
and 3.09±0.4%.mm Hg
−1
; reactivity to hypoxic hypocapnia was 4.83±0.7%.mm Hg
−1
and 2.82±0.5%.mm Hg
−1
. Responses to hypoxic hypocapnia were significantly smaller at low altitude.

Conclusions—

The cerebral circulation of Ethiopian high altitude dwellers is insensitive to hypoxia, unlike Peruvian high altitude dwellers. Cerebrovascular responses to P
ET
co
2
were greater in Ethiopians than Peruvians, particularly at high altitude. This, coupled with their high P
ET
co
2
levels, would lead to high cerebral blood flows, and may be advantageous for altitude living.