bluuebunny/crossref_metadata_2025 huggingface dataset:
Nitrogen Oxide Sensors For Automotive Applications
Authors: Mukundan R. , Brosha Eric L. , Garzon Fernando , Novak Robert , Soltis Rick
Published: November 2006

Mixed potential sensors for the detection of hydrocarbons and carbon monoxide have been studied at Los Alamos National Laboratory (LANL) over the past decade. The LANL sensors have a unique design incorporating dense ceramic-pellet/metal- wire electrodes and porous zirconia-based electrolytes. When these sensors are exposed to various gases, in addition to their mixed-potential response, their resistance also changes. This change in resistance is associated with the electrode/ electrolyte interface and can be used to yield a total NOx response. The NOx sensors are operated in a current bias mode where the voltage response can be related to the total NOx concentration in the atmosphere.
Microscale Chloride Sensor
Authors: Cao Feifei , Greve David , Oppenheim Irving , VanBriesen Jeanne
Published: November 2006

Measurements of chloride concentration are important in a range of applications. We report here on our progress toward the fabrication and testing of small, inexpensive chloride sensors integrated with sensing electronics on a CMOS chip. We describe and demonstrate a process for formation of gold and silver chloride/ silver electrodes on a CMOS chip. Cyclic voltammetry is performed on chip-scale electrodes and the test results are discussed.
Electrical Characterization of Semiconducting Nanowire and Its Application to a Chemical Sensor
Authors: Park Jonghyurk , Moon Seungeon , Kim Eunkyoung , Lee Hong-Yeol , Park Kang-Ho , Kim Gyu-Tae
Published: November 2006

Semiconducting oxide nanowire devices were fabricated using more convenient way to combine photolithography and e-beam lithography, and their electrical properties were studied. To realize the reliable device operation which is a key factor for a chemical sensor, the contact resistance should be optimized. Here, we studied the contact resistance problem under post-deposition annealing or etching process using scanning probe microscopic tool to analyze IV spectroscopic and surface potential behaviors. And, its performance as a chemical sensor was also studied for several gas specie
Voltammetric Determination of Catechol in the Presence of an Interferent Ascorbic Acid at a Sonogel-Carbon Electrode Modified with Titanium Oxide (TiO2)
Authors: Stinson Jelynn A. , Lunsford Suzanne K. , Dionysiou Dionysios , Choi Hyeok
Published: November 2006

Abstract: A newly developed sonogel-carbon electrode was prepared by coating it with a TiO2 sol-gel and heated at 500 ºC. The electrochemical response of the newly developed sonogel-carbon electrode modified with TiO2 was compared to that of an unmodified sonogel- carbon electrode. The modified electrode showed marked enhanced detection of catechol in the prescence of ascorbic acid. Also the sonogel-carbon electrode modified with TiO2 stability was compared to an electrochemically prepared conducting poly(3-methylthiophene) electrode in the detection of catechol over 25 scans. The sonogel-carbon electrode modified with TiO2 was more stable over repetitive scans. This new modified titanium oxide electrode surface could be used in several chemical sensor applications of environmental and biological interest.
Silicon Carbide Thin Films using 1,3-Disilabutane Single Precursor for MEMS Applications - A Review
Authors: Maboudian Roya , Roper Christopher S. , Carraro Carlo , Howe Roger T.
Published: November 2006

Significant progress has been made over the past several years in the development of silicon carbide (SiC) films grown via low pressure chemical vapor deposition (LPCVD) from the single precursor, 1,3-disilabutane (DSB) for microelectromechanical systems (MEMS) applications. Polycrystalline 3C-SiC (poly- SiC) deposition capabilities have been scaled up from depositions on a single 1cm x 1cm piece of Si to forty-five 150 mm Si wafers. In-situ doping with gaseous ammonia and post- deposition annealing have been developed, resulting in a lowest resistivity of ~0.02 Ω·cm to date. Plasma etch chemistries for SiC with good selectivity to silicon dioxide and silicon nitride masking layers have been discovered and characterized. Extensive mechanical, electrical, and tribological characterization of the SiC films have been performed. These SiC films have been applied as both MEMS structural layers for high-frequency resonators and thin film coating layers to improve anti-stiction properties and harsh environment performance.
High-Rate Anisotropic Silicon Etching with the Expanding Thermal Plasma Technique
Authors: Blauw Michiel A. , Van Lankvelt Peter , Roozeboom F. , Kessels Erwin , van de Sanden Richard
Published: November 2006

Deep anisotropic silicon etching with the expanding thermal plasma (ETP) technique using fluorine-based chemistries was demonstrated for the first time. The ETP technique has a remote high-density plasma source and a good control of the downstream plasma chemistry. High etch rates between 4 and 12 µm per min were obtained while feature profiles were competitive to those obtained with the widely used inductively coupled plasma (ICP) reactors. Therefore, this novel deep anisotropic silicon etching process is an attractive, alternative fabrication technology for micromechanical devices, trench capacitors, and 3D-interconnects.
Exposure of Thick Polymethylglutarimide Films for Structural MEMS
Authors: Foulds Ian G. , Johnstone Robert W. , Tsang See-Ho H. , Parameswaran M (Ash)
Published: November 2006

Polymethylglutarimide (PMGI) based resists are commercially available resists intended for use in bilayer lift-off applications. Literature on exposure and development of PMGI films is restricted to films less than 2.5um in thickness, and limited to using TMAH based developers. This paper investigates the exposure and development of PMGI thick films greater than 6um in thickness using both TMAH and TEAH based developers. At this thickness, the absorption of the PMGI leads to non-uniform doses through the film, and so creates large gradients in the dissolution properties. Etch rates as a function of surface dose and development time are reported in this paper.
Novel Electrochemical Patterning Method of Silicon Carbide
Authors: D'Arrigo Giuseppe A. , Raineri Vito , Di Franco Salvatore , Spinella Corrado , Rimini Emanuele
Published: November 2006

Silicon Carbide (SiC) is the most promising material for the fabrication of a new category of sensors and devices, to be used in very hostile environments (height temperature, corrosive ambient, presence of radiation ...). The fabrication of Silicon Carbide sensors requires new processes able to realize microstructures on bulk material or on the silicon carbide surface. A very promising method to create microstructures in SiC is the electrochemical etch in aqueous solution of hydrofluoric acid. In this paper the bulk micromachining of SiC substrate and the structural and electrical characterization of porous silicon carbide formation are reported. These results were used to create a novel method for the bidimensional pattering of SiC substrate. In particular a novel Si-based hard mask to transfer the design onto the SiC substrate was used. The hard mask is formed by a sandwich structures made by subsequent deposition of VAPOX, POLY Si, SiO2.
Monitoring of Instant-Mask Plating for Fabrication of Patterned Copper Microstructures
Authors: Zhang Gang
Published: November 2006

EFAB is a multilayer electrochemical microfabrication technology for the manufacture of truly 3-demensional (3-D) metal micro-devices. It includes a unique process, instant-mask (IM) plating, for the electrodeposition of patterned metal microstructures. As IM plating occurs in a completely closed micro plating cell and cannot be observed visually, this paper presents a method for monitoring the plating process for deposit quality control. In this method, the cell voltage of IM plating is recorded and presented in real-time after a plating current is applied. The recorded cell voltage reveals the real- time information of IM plating, including 1) if the plating process is normal; 2) if the anode and the cathode of a micro plating cell are shorted; and/or 3) if the plating process produces flash deposits.
MEMS Capacitive Switch Fabrication using Photodefinable Metal Oxide Dielectrics
Authors: Henderson Clifford , Romeo Michael , Wang Guoan , Papapolymerou John
Published: November 2006

In this paper, design, fabrication and measurement of reliable low cost capacitive RF MEMS switches with a novel fabrication approach using direct photo-definable high-k metal oxides are presented. In this approach, a radiation sensitive metal- organic precursor is deposited via spin coating and converted to a high-k metal oxide via ultraviolet exposure. Measurements of the bridge-type switches have been done up to 40 GHz. These switches are reliable (> 340 million cycles) and exhibited low insertion loss (around 0.3 dB at 20 GHz) and better isolation (around 24 dB at 20 GHz) at frequencies below resonant frequency as compared to switches fabricated using a simple silicon nitride dielectric.
Photodefinable Thermally Sacrificial Polycarbonate Materials & Methods for MEMS & Microfluidic Device Fabrication
Authors: Henderson Clifford , Hua Yueming
Published: November 2006

In this work, a cross-linkable polycarbonate sacrificial polymer and examples of microfabrication processes utilizing it are presented. The cross-linkable polycarbonate was made by end-capping a hydroxyl terminated polycarbonate oligomer with methacryloyl chloride, thus allowing direct polymer patterning using both positive and negative tone lithographic processes. Cross-linking the polymer significantly increases its resistance to thermal deformation and flow even at low cross- link densities. Thermogravimetric analysis of low cross-link density polycarbonates shows that decomposition of the cross- linked polymer exhibits the same behavior as the pure polycarbonate oligomer except for a low weight fraction tail that requires slightly higher temperatures to fully decompose. As a result of the increased resistance to thermal deformation and flow in the cross-linked polycarbonate, this new photodefinable sacrificial polymer has been shown to be compatible with a variety of microfabrication processes including metal evaporation, sputtering, and electroplating which are typically incompatible with non-crosslinked polycarbonate sacrificial materials.
Pushing Capillary Electrophoresis in Chip Format into the Low Cost Region
Authors: Hoffmann Werner E. , Mühlberger Holger , Demattio Horst , Gas Bohuslav , Guber Andreas E. , Saile Volker
Published: November 2006

Scaling down of capillary electrophoresis into the microfluidic chip format needs further effort to bring this powerful but still cost-intensive separation technique to broader application at reasonable budget charging. Here, two key components of the measurement system are addressed: Chip substrate material and analyte detector. Based on polymer chips, including the favored polyether ether keton (PEEK) material for chemical analysis and introducing electrically contactless conductivity detection (CCD) well compatible to electrophoretic separation a low cost, simple to handle and flexible measurement system was developed. As demonstrated, this Miniaturized Capillary Electrophoresis (MinCE) device is well suitable for small ion analysis. It is designed for budget-conscious application of lab-on-a-chip technology ranging from food analysis, environment monitoring and medical diagnostics to basic research or even for education in electromigration separation analytical techniques.
Easy Fabrication of Microfluidic Device Using Photosensitive Sheet
Authors: Ito Takeshi , Maruyama Kenichi , Ohya Seishiro , Suzuki Koji
Published: November 2006

We proposed a novel technique to fabricate a microfluidic device by using a photosensitive sheet intercalated between substrates. Basic properties of photosensitive sheet were evaluated, which were the chemical resistance, electrical resistance, and dissolution of ions dependent on process. Considering the results, the microfluidic device was suitable to a disposable device. For such a device, we fabricated a micro bio-reactor integrated with an electrochemical detector. As the result of measuring the concentration of glucose by using the device, analytical curve of that was liner in range from 0.1 to 10 mM.
Metal-Catalyzed Carbon Nanotube Piezoresistors with Very Large Longitudinal Piezoresistivity
Authors: Tabib-Azar Massood , Xie Yan , Wang Run
Published: November 2006

Multi-walled carbon nanotube (MWCNT) bridges, grown using low- pressure metal-catalyzed chemical vapor deposition technique between silicon posts, were used as tiny piezoresistors to monitor vibration and bending/deformation of silicon cantilever beams. The weld strength of CNTs measured using atomic force microscope was larger than 100 nN/CNT and their full-scale resistance change was larger than 1e5 Ohm.The effective longitudinal piezoresistivity of these CNTs was larger than 4x1e-8 1/Pa which is larger than that of Pi44 in silicon.
CMOS-Based Microsensors
Authors: Brand Oliver , Seo Jae Hyeong
Published: November 2006

Fabrication technologies for CMOS-based microsensors are highlighted, dividing them into pre-CMOS, intra-CMOS and post-CMOS approaches, depending on whether the MEMS module precedes, interrupts or succeeds the CMOS fabrication process. As an example, CMOS-based resonant microsensors for chemical and biochemical sensing applications are detailed.
MEMS Arrayed Scanning Probes for Soft Nanolithography
Authors: Liu Chang , Li Shifeng
Published: November 2006

In the past several years, much progress have been made in the area of scanning probe based, parallel soft nano lithography for patterning biomolecules directly with nano-meter resolution and high degree of registration accuracy. We report the development and demonstrations of arrayed soft nanolithography probes for dip pen nanolithography (DPN), scanning probe contact printing (SPCP), and multi-functional scanning nanolithography. The probes have been used for high throughput direct write of thoil molecules.
Low-Noise Chemical Detection with a Piezoresistive Microcantilever Array
Authors: Hesketh P. J. , Choudhury Arnab , Hu Zhiyu , Thundat Thomas , Newcomb Steven R.
Published: November 2006

Piezoresistive microcantilever systems are well suited for chemical sensing with low detection limits. A major hurdle in the realization of such systems is measurement noise associated with DC piezoresistance measurements. A piezoresistive microcantilever array has been fabricated and phase sensitive detection methods are used for realization of a low detection limit piezoresistive cantilever array. Reference cantilevers in the array can act as thermomechanical or chemical references to aid in lowering the detection limits.
Influence of Interface Recombination in Light Emission from Lateral Si-Based Light Emitting Devices
Authors: Hoang Tu , LeMinh Phuong , Holleman Jisk , Schmitz Jurriaan
Published: November 2006

The influence of interface recombination on the electroluminescence profile of a lateral p+/p/n+ light emitting diode fabricated on Silicon On Insulator (SOI) materials has been experimentally investigated. Our device resembles a MOSFET fabricated on SOI (1), except that the source region has opposite doping to the drain. By controlling the voltage bias at the poly gate on top of active emitting region in association with a bias on the silicon substrate under the active region we were able to diminish the non- radiative recombination component at Si/SiO2 interface and therefore enhance the radiative recombination in the thin film SOI. When the diode is working under constant current condition, we observe an increased light output of ~ 20 % as the gate and/or the substrate are biased negatively. The intensity profile across the device is also strongly influenced. To understand the device thoroughly, the structure has also been simulated showing agreement with experimental results.
Ultra-Fast All-Optical Wavelength Conversion in Silicon Waveguides using Femtosecond Pulses
Authors: Dekker Ronald , Niehusmann Jan , Först Michael , Driessen Alfred
Published: November 2006

The propagation of 300 femtosecond optical pulses in Silicon- on Insulator waveguides has been studied by means of a pump- probe set-up. Large Cross Phase Modulation (XPM) induced red and blue shifts (9nm and 15nm, respectively) of the probe signal have been observed depending on the delay between pump (1554nm) and probe (1683nm) pulses. A numerical model taking into account Two Photon Absorption (TPA) and Free Carrier Absorption (FCA) in the semiconductor waveguide is presented and provides good agreement with the experimental data. Our model reveals that the wavelength conversion is dominated by the instantaneous optical Kerr effect, enabling ultra-fast all- optical functionalities. Furthermore, the importance of waveguide dispersion on the wavelength conversion efficiency will be treated in the case of femtosecond pulses.
Organising Light on the Nano-Scale: Surface Plasmon Engineering for Repeatable SERS Sensing and Applications for Trace Analyte Detection
Authors: Charlton Martin D. , Netti Caterena Maria , Zoorob Majd , Perney Nicholas , Baumberg Jeremy
Published: November 2006

In this paper we review the physical connections between surface plasmons and Surface Enhanced Raman Scattering (SERS) enhancement factors relating to SERS substrates based on gold metalised inverted pyramidal pits. We investigate the effect of the introduction of liquids into the holes and finally present real world applications in trace level detection of illicit drugs and drug metabolite detection at physiological levels.
Thin Film III-V Devices Integrated on Silicon-on-Insulator Waveguide Circuits
Authors: Roelkens Gunther , Brouckaert Joost , Van Thourhout Dries , Baets Roel
Published: November 2006

Thin film InP/InGaAsP active opto-electronic devices were fabricated on top of Silicon-on-Insulator waveguide circuits. Device integration was done using adhesive die to wafer bonding. Both photodetectors and laser diodes were fabricated on and coupled to Silicon-on-Insulator waveguide circuits. Integration of laser diodes and photodetectors was done simultaneously using identical processing steps.
Reactive Ion Etching of Y2O3 Films Applying F-, Cl- and Cl/Br-Based Inductively Coupled Plasmas
Authors: Worhoff K. , Bradley Jonathan , Ay Feridun , Pollnau Markus
Published: November 2006

Reactive ion etching of yttrium oxide thin films was investigated using CF4/O2, BCl3, HBr and Cl2 inductively coupled plasmas. For all gas combinations, with the exception of Cl2, the etch rate was found to be similar, indicating a primarily physical etch process, enhanced in Cl2 by an additional chemical-etching component. The highest observed etch rate was 53 nm/min in Cl2, suitable for controlled etching of optical ridge waveguide structures several hundred nm in height. Overall, the surface quality of the etched Y2O3 films was the highest after etching in CF4/O2 plasmas, indicating a trade-off in etch rate and film quality between the various process gases. Preliminary selectivity measurements show that Ni is a suitable material for etch-masking of high resolution structures in Y2O3.
Structure and Electrical Properties of Reactively rf-Sputtered nc-TiO2-Delta (-0.04 < or Equal to Delta < or Equal to 0.2) Thin Films
Authors: Comedi David M. , Villafuerte Manuel , Juárez Gabriel , Heluani Silvia
Published: November 2006

The structure and DC transport in rf-sputtered nc-TiO2-d thin films are studied. Possible transport mechanisms and correlations between structure and electrical properties are discussed.
Sensitized Solar Cells based on Hexagonal Dyes of Terpyridine-Ruthenium(II): Effect of the Electropolymerization of Dyes during their Performance in Solar Cells
Authors: Manríquez Juan , Hwang Seok-Ho , Cho Tae Joo , Moorefield Charles N. , Newkome George R. , Godínez Luis A.
Published: November 2006

A study of the photovoltaic properties and performance for dye- sensitized solar cells, using three hexagonal macrocycles based on terpyridine-ruthenium (II) is reported. Photo- and electrochemical results suggest that the global conversion efficiencies for these devices were strongly dependent of the electropolymerization of dyes during the cells performance.
Electrodes Modified with Nanocomposites of PAMAM Dendrimers and Inorganic Electrocatalysts: Sensing Molecules with Biological Importance
Authors: Bustos Erika , García Maria G. , Chapman Thomas W. , Juaristi Eusebio , Godinez L. A.
Published: November 2006

Dendrimers resemble covalent micelles that provide well defined cavities and can enhance the hydrophobic nature of an electrode- solution interface. Dendrimers attached to an electrode can stabilize and concentrate mediators such as catalytic nanoparticles by forming nanocomposites. Such nanocomposites can improve the kinetics of specific electrochemical reactions. In this work we describe the preparation and testing of electrodes modified with nanocomposites of inorganic electrocatalysts, namely, Prussian Blue (PB) and platinum-group metals (Ir, Os, Pd, Pt, Rh and Ru), within tethered PAMAM dendrimers for use as amperometric sensors. These electrodes offer good sensitivity in the detection of molecules with biological importance, such as H2O2 and dopamine, in neutral aqueous media.
Competitive Complexing of Supramolecular Additives with Anions and Neutral Solvent Species Verified by Spectrosopic Techniques
Authors: Siekierski Maciej , Kalita Michał , Plewa Anna , Zukowska Zofia , Sołgała Agnieszka
Published: November 2006

This article presents spectroscopic studies of interaction between the solvent and the anion receptor using FTIR and 1HNMR. It is shown that the anion receptor can interact also with solvent particles and receptor-solvent complex formation constants are calculated. The results also show that the interactions of liquid solvent (1,2-dimethoxyethane and 1,4-dioxane) differs from that for solid poly(ethylene oxide) and liquid poly(ethylene glycol) dimethyl ether having similar dielectric constant and coordinating properties (donor and acceptor numbers). These results are compared with electrochemical results presented in previous articles.
Neutropenia due to Parvovirus B19 Infections in Patients with Paroxysmal Nocturnal Hemoglobinuria
Authors: Abe Rokuo , Shichishima Tsutomu , Ogawa Kazuei , Saitoh Yurie , Maruyama Yukio
Published: November 2006

Two patients with paroxysmal nocturnal hemoglobinuria (PNH) and parvovirus B19 (PVB19) infection are reported. One was infected by PVB19-contaminated blood transfusion, whereas the other had become infected naturally. Both patients completely recovered after transient pancytopenia, but showed severe and intermediate neutropenia (0.216 and 0.768 × 109/l, respectively) at the nadirs of aplastic crises. In the literature, PNH cases also showed neutropenia (0 and 0.54 × 109/l) at aplastic crises. When patients with PNH are infected by PVB19, they may show severe neutropenia and mild thrombocytopenia in addition to severe reticulocytopenia. Therefore, these patients might have to be treated with granulocyte colony-stimulating factor to be able to recover from severe neutropenia.
Soluble Transferrin Receptor-1 Levels in Mice Do Not Affect Iron Absorption
Authors: Flanagan Jonathan M. , Peng Hongfan , Wang Lei , Gelbart Terri , Lee Pauline , Johnson Sasu Barbra , Beutler Ernest
Published: November 2006

Soluble transferrin receptor-1 (sTfR1) concentrations are increased in the plasma under two conditions that are associated with increased iron absorption, i.e. iron deficiency and increased erythropoiesis. To determine the possible role of sTfR1 as a signaling mechanism for iron absorption, a hydrodynamic gene transfer technique was established to express transfected plasmid constructs of human sTfR1 (hsTfR1) and murine sTfR1 (msTfR1) from the livers of C57BL/6 mice. Iron absorption, serum iron levels and hepcidin expression were then measured. The hydrodynamic gene transfer technique proved to be an effective approach to achieving sustained expression of sTfR1 in mice. Although expression of high levels of sTfR1 significantly increased serum iron levels, repeated experiments showed that neither hsTfR1 nor msTfR1 had any effect on iron absorption or hepcidin mRNA expression levels. Thus, despite its attractiveness as a potential modifier of iron absorption, sTfR1 levels do not exert a regulatory effect on iron absorption.
Bortezomib and Dexamethasone in Previously Untreated Multiple Myeloma Associated with Renal Failure and Reversal of Renal Failure
Authors: Malani Ashok Kumar , Gupta Vicram , Rangineni Raj
Published: November 2006

Multiple myeloma (MM) associated with renal failure carries a worse prognosis when compared with MM without renal failure. Bortezomib, a reversible proteosome inhibitor, is a new drug indicated for the treatment of refractory or relapsed myeloma. Published data on the use of bortezomib in patients with myeloma and renal failure are few. We report our experience with bortezomib and dexamethasone in 3 previously untreated and 1 relapsed patient with MM and renal failure. All patients achieved rapid improvement in their renal function as measured by serum creatinine levels with only 1–2 cycles of bortezomib (± dexamethasone), 3 of 4 patients had a near complete response and 1 patient had a partial response. The rapid reversal of renal dysfunction with bortezomib (± dexamethasone) treatment may be an effective strategy to prevent end stage renal failure in MM, thereby improving the morbidity and mortality in this otherwise poor prognosis subset of patients with myeloma.
Conséquences des restrictions pondérales imposées par le sport chez l’enfant et l’adolescent
Authors: Boisseau Nathalie
Published: November 2006

De nos jours, de jeunes sportifs de compétition entreprennent des programmes d’entraînement comportant un haut degré d’activité physique dès un âge précoce. Cet entraînement intensif (volume et intensité) augmente les dépenses énergétiques, qui doivent être compensées par une augmentation des apports nutritionnels. Les danseurs de corps de ballet, les patineurs artistiques, les gymnastes ou les compétiteurs de gymnastique rythmique commencent leur entraînement dès l’âge de 5–6 ans et, pour la plupart d’entre eux, consacrent plus de 20 à 30 heures par semaine à leur discipline. Dans ces activités, ainsi que dans celles où le poids joue un rôle (lutteurs, jockeys, judokas ou boxeurs), les jeunes sportifs de haut niveau décident délibérément de réduire leur consommation alimentaire afin de maintenir leur minceur physique prépubertaire ou de «faire le poids». Des apports adéquats en calories et en micronutriments sont essentiels chez l’enfant en croissance, et des restrictions caloriques et liquidiennes au cours de l’entraînement physique pendant l’enfance ou l’adolescence pourraient perturber les régulations métaboliques et hormonales intervenant dans la croissance, la maturité, la composition corporelle, les cycles menstruels et l’aptitude à la reproduction, et pourraient augmenter le risque de lésions telles que des fractures de contrainte. De plus, ces stratégies peuvent entraîner l’apparition de troubles alimentaires (anorexie mentale et/ou boulimie nerveuse), particulièrement chez les adolescentes, affectant l’image corporelle et l’estime de soi et favorisant des inadaptations sociales et affectives.
Historical development of analysing large-scale changes in the human genome
Authors: Pearson P.L.
Published: November 2006

A widely held belief today is that genomics really only started with the DNA sequence information emanating from the genome programs for various organisms, with the human genome playing the leading role. In fact there is a discernable trail stretching for more than a 100 years from the observations of Boveri on tissue instability involving polyploidy in sea urchin embryos and human tumours to the present day. This historical review follows that trail and shows that many theoretical and technical advantages taken for granted in today’s genomics era rely heavily on earlier cytogenetic and gene mapping discoveries. Three specific examples of technical developmental paths involving in situ hybridisation, flow-sorting and DNA reassociation kinetics will be explored. In the mid-1980s the two former approaches merged to give rise to several applications of which chromosome painting and chromosome CGH are arguably the most important. The latter developed into array CGH which has now become the pre-eminent method for detecting micro-imbalances in a large number of targets. A competing emerging technology is that of genome-wide SNP typing, which itself is a product of the much earlier RFLP approach linked to DNA sequence information. Do such approaches spell the final demise of the microscope? Perhaps for narrowly defined activities this may occur, but for addressing general questions, microscopic examination will remain pre-eminent.
Development of bioinformatics resources for display and analysis of copy number and other structural variants in the human genome
Authors: Zhang J. , Feuk L. , Duggan G.E. , Khaja R. , Scherer S.W.
Published: November 2006

The discovery of an abundance of copy number variants (CNVs; gains and losses of DNA sequences >1 kb) and other structural variants in the human genome is influencing the way research and diagnostic analyses are being designed and interpreted. As such, comprehensive databases with the most relevant information will be critical to fully understand the results and have impact in a diverse range of disciplines ranging from molecular biology to clinical genetics. Here, we describe the development of bioinformatics resources to facilitate these studies. The Database of Genomic Variants (http://projects.tcag.ca/variation/) is a comprehensive catalogue of structural variation in the human genome. The database currently contains 1,267 regions reported to contain copy number variation or inversions in apparently healthy human cases. We describe the current contents of the database and how it can serve as a resource for interpretation of array comparative genomic hybridization (array CGH) and other DNA copy imbalance data. We also present the structure of the database, which was built using a new data modeling methodology termed Cross-Referenced Tables (XRT). This is a generic and easy-to-use platform, which is strong in handling textual data and complex relationships. Web-based presentation tools have been built allowing publication of XRT data to the web immediately along with rapid sharing of files with other databases and genome browsers. We also describe a novel tool named eFISH (electronic fluorescence in situ hybridization) (http://projects.tcag.ca/efish/), a BLAST-based program that was developed to facilitate the choice of appropriate clones for FISH and CGH experiments, as well as interpretation of results in which genomic DNA probes are used in hybridization-based experiments.
Idiopathic learning disability and genome imbalance
Authors: Knight S.J.L. , Regan R.
Published: November 2006

Learning disability (LD) is a very common, lifelong and disabling condition, affecting about 3% of the population. Despite this, it is only over the past 10–15 years that major progress has been made towards understanding the origins of LD. In particular, genetics driven advances in technology have led to the unequivocal demonstration of the importance of genome imbalance in the aetiology of idiopathic LD (ILD). In this review we provide an overview of these advances, discussing technologies such as multi-telomere FISH and array CGH that have already emerged as well as new approaches that show diagnostic potential for the future. The advances to date have highlighted new considerations such as copy number polymorphisms (CNPs) that can complicate the interpretation of genome imbalance and its relevance to ILD. More importantly though, they have provided a remarkable ∼15–20% improvement in diagnostic capability as well as facilitating genotype/phenotype correlations and providing new avenues for the identification and understanding of genes involved in neurocognitive function.
Molecular karyotyping of patients with MCA/MR: the blurred boundary between normal and pathogenic variation
Authors: de Ravel T.J.L. , Balikova I. , Thienpont B. , Hannes F. , Maas N. , Fryns J.-P. , Devriendt K. , Vermeesch J.R.
Published: November 2006

Molecular karyotyping has revealed that microdeletions/duplications in the human genome are a major cause of multiple congenital anomalies associated with mental retardation (MCA/MR). The identification of a de novo chromosomal imbalance in a patient with MCA/MR is usually considered causal for the phenotype while a chromosomal imbalance inherited from a phenotypically normal parent is considered as a benign variation and not related to the disorder. Around 40% of imbalances in patients with MCA/MR in this series is inherited from a healthy parent and the majority of these appear to be (extremely) rare variants. As some of these contain known disease-causing genes and have also been found to be de novo in MCA/MR patients, this challenges the general view that such familial variants are innocent and of no major phenotypic consequence. Rather, we argue, that human genomes can be tolerant of genomic copy number variations depending on the genetic and environmental background and that different mechanisms play a role in determining whether these chromosomal imbalances manifest themselves.
Impact of low copy repeats on the generation of balanced and unbalanced chromosomal aberrations in mental retardation
Authors: Erdogan F. , Chen W. , Kirchhoff M. , Kalscheuer V.M. , Hultschig C. , Müller I. , Schulz R. , Menzel C. , Bryndorf T. , Ropers H.-H. , Ullmann R.
Published: November 2006

Low copy repeats (LCRs) are stretches of duplicated DNA that are more than 1 kb in size and share a sequence similarity that exceeds 90%. Non-allelic homologous recombination (NAHR) between highly similar LCRs has been implicated in numerous genomic disorders. This study aimed at defining the impact of LCRs on the generation of balanced and unbalanced chromosomal rearrangements in mentally retarded patients. A cohort of 22 patients, preselected for the presence of submicroscopic imbalances, was analysed using submegabase resolution tiling path array CGH and the results were compared with a set of 41 patients with balanced translocations and breakpoints that were mapped to the BAC level by FISH. Our data indicate an accumulation of LCRs at breakpoints of both balanced and unbalanced rearrangements. LCRs with high sequence similarity in both breakpoint regions, suggesting NAHR as the most likely cause of rearrangement, were observed in 6/22 patients with chromosomal imbalances, but not in any of the balanced translocation cases studied. In case of chromosomal imbalances, the likelihood of NAHR seems to be inversely related to the size of the aberration. Our data also suggest the presence of additional mechanisms coinciding with or dependent on the presence of LCRs that may induce an increased instability at these chromosomal sites.
Whole-genome array-CGH screening in undiagnosed syndromic patients: old syndromes revisited and new alterations
Authors: Krepischi-Santos A.C.V. , Vianna-Morgante A.M. , Jehee F.S. , Passos-Bueno M.R. , Knijnenburg J. , Szuhai K. , Sloos W. , Mazzeu J.F. , Kok F. , Cheroki C. , Otto P.A. , Mingroni-Netto R.C. , Varela M. , Koiffmann C. , Kim C.A. , Bertola D.R. , Pearson P.L. , Rosenberg C.
Published: November 2006

We report array-CGH screening of 95 syndromic patients with normal G-banded karyotypes and at least one of the following features: mental retardation, heart defects, deafness, obesity, craniofacial dysmorphisms or urogenital tract malformations. Chromosome imbalances not previously detected in normal controls were found in 30 patients (31%) and at least 16 of them (17%) seem to be causally related to the abnormal phenotypes. Eight of the causative imbalances had not been described previously and pointed to new chromosome regions and candidate genes for specific phenotypes, including a connective tissue disease locus on 2p16.3, another for obesity on 7q22.1→q22.3, and a candidate gene for the 3q29 deletion syndrome manifestations. The other causative alterations had already been associated with well-defined phenotypes including Sotos syndrome, and the 1p36 and 22q11.21 microdeletion syndromes. However, the clinical features of these latter patients were either not typical or specific enough to allow diagnosis before detection of chromosome imbalances. For instance, three patients with overlapping deletions in 22q11.21 were ascertained through entirely different clinical features, i.e., heart defect, utero-vaginal aplasia, and mental retardation associated with psychotic disease. Our results demonstrate that ascertainment through whole-genome screening of syndromic patients by array-CGH leads not only to the description of new syndromes, but also to the recognition of a broader spectrum of features for already described syndromes. Furthermore, on the technical side, we have significantly reduced the amount of reagents used and costs involved in the array-CGH protocol, without evident reduction in efficiency, bringing the method more within reach of centers with limited budgets.
Gene copy number changes in dermatofibrosarcoma protuberans – a fine-resolution study using array comparative genomic hybridization
Authors: Kaur S. , Vauhkonen H. , Böhling T. , Mertens F. , Mandahl N. , Knuutila S.
Published: November 2006

Dermatofibrosarcoma protuberans (DFSP) is a rare, slow-growing, low-grade dermal tumor. Cytogenetic and FISH studies have revealed that the chromosomal rearrangements characteristic of DFSP tumors involve both translocations and the formation of a supernumerary ring derived from chromosomes 17 and 22. The t(17;22) (q22;q13.1) translocation generates a gene fusion between COL1A1 and PDGFB, which serves as a diagnostic marker of DFSP. In the present study we performed array-CGH (aCGH) analysis on ten DFSP tumors. The COL1A1 region at 17q was gained in 71% (5/7) of the samples and the PDGFB region at 22q was gained in 43% (3/7) of the individual samples. In addition to the 17q and 22q gains, altogether 17 minimal common regions of gain and one region of loss were detected.
Pathophysiology of Acute Ischaemic Stroke: An Analysis of Common Signalling Mechanisms and Identification of New Molecular Targets
Authors: Mitsios N. , Gaffney J. , Kumar P. , Krupinski J. , Kumar S. , Slevin M.
Published: November 2006

Stroke continues to be a major cause of death and disability. The currently available therapies have proven to be highly unsatisfactory (except thrombolysis) and attempts are being made to identify and characterize signalling proteins which could be exploited to design novel therapeutic modalities. The pathophysiology of stroke is a complex process. Delaying interventions from the first hours to days or even weeks following blood vessel occlusion may lead to worsening or impairment of recovery in later stages. The objective of this review is to critically evaluate the major mechanisms underlying stroke pathophysiology, especially the role of cell signalling in excitotoxicity, inflammation, apoptosis, neuroprotection and angiogenesis, and highlight potential novel targets for drug discovery.
P16-Immunostaining Pattern as a Predictive Marker of Lymph Node Metastasis and Recurrence in Early Uterine Cervical Cancer
Authors: Yamazaki Tatsuo , Tomita Shigeki , Ichikawa Kazuhito , Ono Yuko , Inaba Fujiyuki , Fukasawa Ichio , Imai Yasuo , Imura Johji , Fukui Hirokazu , Fujimori Takahiro , Inaba Noriyuki
Published: November 2006

Objectives: We investigated the relationship between P16-immunostaining patterns and clinicopathological factors in early uterine cervix cancers and assessed whether P16-immunostaining patterns predict the prognosis of the patients with early uterine cervix cancers. Methods: Twenty-nine early squamous cell carcinoma (SCC) specimens of the uterus were examined using immunohistochemistry for P16 expression. The P16-immunostaining pattern was classified into two groups: the homogeneous type and the heterogeneous type. P16-immunostaining patterns were evaluated in different parts of the carcinoma in situ (CIS): the center of the tumor and the front interface of the infiltrating tumor. Results: All specimens were of the homogeneous type in CIS. The P16-immunostaining pattern was significantly of the heterogeneous type in the front interface of the infiltrating tumor with lymphatic invasion, vascular invasion, lymph node metastasis, and recurrence. Regarding the P16-immunostaining patterns in the front interface of the infiltrating tumor, the patients with the heterogeneous type showed a significantly worse prognosis than the patients with the homogeneous type. Conclusions: The prognosis of patients with early uterine cervical SCC may be predicted by evaluating the P16-immunostaining pattern in the front interface of the infiltrating tumor.
Combination Analysis of a Whole Lymph Node by One-Step Nucleic Acid Amplification and Histology for Intraoperative Detection of Micrometastasis
Authors: Taniyama Kiyomi , Motoshita Junichi , Sakane Junichi , Makita Kyoko , Akai Yasumasa , Daito Motonari , Otomo Yasuhiro , Ono Hiroshi , Mizunoe Tomoya , Takeuchi Yukiyasu , Tominaga Harumi , Koseki Masato
Published: November 2006

Objective: The aim was to develop a more efficient molecular detection system than histological examination (HE) for lymph node (LN) metastasis. Methods: Cytokeratin (CK) 19 mRNA copy numbers of 5 colon carcinoma cell lines (Lovo, DLD1, WiDr, Colo201 and Colo320) were calculated and compared by one-step nucleic acid amplification (OSNA) and conventional real-time reverse-transcription polymerase chain reaction (RT-PCR). Then, 91 LN submitted for HE from 6 patients with advanced colorectal adenocarcinoma and 64 LN submitted for frozen diagnosis from 47 patients with different malignancies were examined by OSNA and HE. Results: CK19 mRNA copy numbers of all but Colo320 cells detected by OSNA were within double of those detected by RT-PCR. The least cell count of Lovo cells detected at one reaction (2 µl) by OSNA was calculated as 0.8 cells. Carcinoma metastasis showing either HE+ or OSNA+ was detected in 7.9% of the LN from advanced colorectal adenocarcinomas and in 30.0% of the LN for frozen diagnosis from different malignancies; HE–/OSNA+ metastasis was detected in 4.8 and 4.0%, respectively. OSNA analysis of 1 LN could be completed within 40 min. Conclusion: A combined analysis of LN by HE and OSNA could increase the sensitivity for detecting micrometastasis during surgery.
A Comparative Study of Neovascularisation in Atherosclerotic Plaques Using CD31, CD105 and TGFβ1
Authors: Li Chenggang , Mollahan Pamela , Baguneid Mohamed S. , McMahon Ray F. , Kumar Pat , Walker Michael G. , Freemont Anthony J. , Kumar Shant
Published: November 2006

Objectives: This study aims to identify plaque neovascularisation using antibodies to CD31, CD105 and TGFβ1, and to compare their patterns of expression. Methods: Tissue expression of CD31, CD105 and TGFβ1 was examined immunohistologically in atherosclerotic plaques from 53 patients who had undergone carotid endarterectomy and in 10 controls. Results: CD31 was observed in a proportion of the microvessels within atheroma. The expression of CD105 was barely visible in normal arteries, but was markedly enhanced in atherosclerotic plaques. The vast majority of the microvessels in atheroma were positive for CD105 with pronounced expression around the periphery of the lipid core. In consecutive sections, microvessels showing negative staining for CD31 were positive for CD105. Although TGFβ1 was seen in the thickened intima, it was more strongly expressed in well-formed fibrous plaques. Consecutive sections showed that some microvessels were stained by both CD105 and TGFβ1, but in certain areas microvessels were exclusively CD105 positive. Conclusions: These observations highlight the distinctive expression patterns of CD31, CD105 and TGFβ1, suggesting their specific roles in the development of atherosclerotic plaques. CD105 is almost universally expressed in microvessels within the atheroma and is therefore a better vascular marker than CD31 and TGFβ1 for assessing neovascularisation in atherosclerotic plaques.
Imbalance of Matrix Metalloproteinase-1 and Tissue Inhibitor of Metalloproteinases: A Novel Approach for Explaining the Parenchymal Liquefaction of the Septic Spleen?
Authors: Gunia S. , Albrecht K. , May M. , Stosiek P.
Published: November 2006

Objective: The causal pathophysiological mechanisms involved in the parenchymal liquefaction of the septic spleen are still far from clear. The balance between matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), is largely responsible for the remodelling of tissues. Deregulation of this balance is a characteristic of extensive tissue degradation in certain chronic inflammatory diseases. Methods: This study focuses on a search for alterations in the balance between MMP-1 (interstitial collagenase) and TIMP-1 by means of immunostaining, by immunoblotting, and by gel zymography. Results: We found a deregulation of the balance between MMP-1 and TIMP-1 in the septic spleen in favor of the active form of MMP-1. Conclusion: Our findings suggest that active MMP-1 is involved in collagenolytic extracellular matrix breakdown in the septic spleen.
Cardiovascular Effects of Sildenafil in Neonates and Infants with Congenital Diaphragmatic Hernia and Pulmonary Hypertension
Authors: Noori Shahab , Friedlich Philippe , Wong Pierre , Garingo Arlene , Seri Istvan
Published: November 2006

Background: Pulmonary hypertension is a common problem in patients with congenital diaphragmatic hernia (CDH). In a subset of these patients, pulmonary hypertension persists despite optimized ventilatory management and supportive care. Sildenafil, a phosphodiestrase V inhibitor, has been used in the treatment of pulmonary hypertension in adults and children. Cardiovascular effects of sildenafil in patients with CDH and pulmonary hypertension are not known. Objective: To describe the changes in cardiovascular and respiratory parameters in newborn infants with CDH and persistent pulmonary hypertension refractory to inhaled nitric oxide (iNO) during the first 2 weeks of sildenafil administration. Methods: Retrospective data analysis of seven patients with CDH (birth weight = 2,573 ± 1,019 g; gestational age = 35.6 ± 4.3 weeks) receiving oral sildenafil for pulmonary hypertension refractory to iNO. Findings of serial echocardiograms and data on cardiovascular and respiratory status were assessed. Results: Right cardiac output increased and left cardiac output tended to increase 1.5–4 h after initiation of sildenafil and the increase was sustained throughout the study. Echocardiographic indices of pulmonary hypertension showed an apparent reduction in abnormally high pulmonary vascular resistance. Systemic blood pressure tended to decrease. Shortening fraction did not change. Ventilatory index and the need for iNO tended to decrease in the five surviving infants. Conclusions: These preliminary findings suggest that sildenafil may improve cardiac output by reducing pulmonary hypertension refractory to iNO in patients with CDH.