bluuebunny/crossref_metadata_2025 huggingface dataset:
Tuberculin Skin Test Conversion and Reactivity Rates among Adults with and without Human Immunodeficiency Virus in Urban Settings in Ethiopia
Authors: Tegbaru Belete , Wolday Dawit , Messele Tsehaynesh , Legesse Mengistu , Mekonnen Yared , Miedema Frank , van Baarle Debbie
Published: July 2006

To investigate whether low CD4
+
T-cell counts in healthy and human immunodeficiency virus (HIV)-infected Ethiopians influence tuberculosis (TB) immunological memory, tuberculin skin test (TST) conversion and reactivity rates were investigated among adults with and without HIV infection in urban settings in Ethiopia. Reaction to the TST was analyzed with purified protein derivative by the Mantoux technique. A total of 1,286 individuals with TST results of ≥5-mm (
n
= 851) and ≤4-mm (
n
= 435) induration diameters were included. Individuals with ≤4-mm induration sizes were followed up for 21.4 ± 9.5 months (mean ± standard deviation) to observe skin test conversion. The overall TST reactivity (≥5-mm induration diameter) was 66.2% (
n
= 851). Reactivity was significantly lower among HIV-positive persons (40.5%) than among HIV-negative persons (68.7%) (
P
< 0.001). Of the above persons, 32 incident TB patients were checked for their TST status 13.05 ± 11.1 months before diagnosis and reactivity was found among 22 (68.7%) of them. Of the TST-negative persons with 0- to 4-mm indurations who were followed up for 3 years, the conversion rate to positivity was 17.9/100 person-years of observation (PYO) (14.4/100 PYO and 18.3/100 PYO in HIV-positive and -negative persons, respectively). Despite lower absolute CD4
+
T-cell numbers in Ethiopians, higher TST conversion and reactivity rates show the presence of a higher rate of latent TB infection and/or transmission. The lower TST positivity rate before a diagnosis of TB disease showed the lower sensitivity of the test. This indicates the need for other sensitive and specific diagnostic and screening methods to detect TB infection, particularly among HIV-positive persons, so that they can be given prophylactic isoniazid therapy.
Antibody Response to
Cryptococcus neoformans
Capsular Polysaccharide Glucuronoxylomannan in Patients after Solid-Organ Transplantation
Authors: Jalali Ziba , Ng Lucky , Singh Nina , Pirofski Liise-anne
Published: July 2006

Cryptococcosis is an important complication of solid-organ transplantation, but the risk factors for disease are poorly understood. The goal of this study was to investigate whether specific or nonspecific serum immunoglobulin levels determined in samples obtained before and after solid-organ transplantation differed in patients who did or did not develop cryptococcosis after transplantation. We analyzed pretransplantation sera from 25 subjects, 15 who subsequently developed cryptococcosis and 10 who did not, and posttransplantation sera from 24 subjects, 13 who developed cryptococcosis and 11 who did not. All subjects received a tacrolimus-based immunosuppressive regimen. Total immunoglobulin levels were measured by immunodiffusion, and
Cryptococcus neoformans
capsular polysaccharide glucuronoxylomannan (GXM)-specific serum antibody levels were determined by enzyme-linked immunosorbent assays. The results showed that solid-organ transplantation had a significant effect on total immunoglobulin and GXM-reactive antibody levels. GXM-reactive antibody levels differed in subjects who did and did not develop cryptococcosis. In pretransplant serum samples, the levels of GXM-reactive immunoglobulin M (IgM) were significantly lower in subjects who developed cryptococcosis after transplantation than in those who did not. For posttransplant serum samples, the levels of GXM-reactive IgM and IgG were significantly higher among the subjects who developed cryptococcosis than among those who did not. These findings suggest that perturbations in the preexisting antibody or B-cell repertoire and/or related to treatment of rejection, transplantation, or immunosuppressive therapy could translate into an increased risk for transplant-associated cryptococcosis.
Macrorestriction Analysis of Clinical and Environmental Isolates of
Sporothrix schenckii
Authors: O'Reilly L. C. , Altman S. A.
Published: July 2006

Sporothrix schenckii
causes sporotrichosis, a disease that most commonly presents as a subacute or chronic skin infection. An unusually high incidence of clinical cases of sporotrichosis occurred in the southwest of Western Australia over the last 5 years. Anecdotal accounts from patients implicated contact with hay prior to infection. Isolates of
S. schenckii
from hay and clinical cases were investigated by traditional phenotypic methods and pulsed-field gel electrophoresis (PFGE). The phenotypic evaluation separated
S. schenckii
from
Ophiostoma
spp. A DNA macrorestriction method using SfiI and NotI macrorestriction digestion by PFGE was developed to investigate the epidemiological connections. BioNumerics software was used to analyze the results. DNA macrorestriction digestion patterns for the recent Western Australian clinical isolates and four hay isolates were indistinguishable. Eastern state clinical isolates, national Quality Assurance Program isolates, and other environmental isolates gave different macrorestriction patterns. Clinical isolates from the southwest of Western Australia collected in the 1980s and 1990s were also characterized using PFGE. The patterns generated were indistinguishable from those of the recent clinical isolates. PFGE showed that the dominant strain of
S. schenckii
causing sporotrichosis in Western Australia is present in hay, has caused sporotrichosis for at least 15 years, and is a different strain from the strains found in other parts of Australia.
Sternal Wound Infection byTrichosporon inkinfollowing Cardiac Surgery
Authors: Davies Frances , Logan Sarah , Johnson Elizabeth , Klein John L.
Published: July 2006

Wound infection following cardiac surgery is well described but is rarely due to fungal infection. We describe a case of sternal wound infection caused byTrichosporon inkinwith a fatal outcome, in an immunocompetent patient following aortic root surgery.
Toxin Gene Content of the Lyon Methicillin-Resistant
Staphylococcus aureus
Clone Compared with That of Other Pandemic Clones
Authors: Ferry Tristan , Bes Michèle , Dauwalder Olivier , Meugnier Hélène , Lina Gerard , Forey Françoise , Vandenesch François , Etienne Jerome
Published: July 2006

The methicillin-resistant
Staphylococcus aureus
(MRSA) Lyon clone, detected throughout France, contains the enterotoxin A gene (
sea
), like other pandemic clones of clonal complex 8 (CC8). The
egc
locus was detected in MRSA pandemic clones of CC5, CC22, and CC45, occasionally with the toxic shock syndrome toxin 1 gene. The representative strain of the EMRSA-16 clone (CC30) harbored both
sea
and the
egc
locus.
Culture-Independent Molecular Subtyping of
Mycoplasma pneumoniae
in Clinical Samples
Authors: Dumke Roger , Lück Paul Christian , Noppen Christoph , Schaefer Christoph , von Baum Heike , Marre Reinhard , Jacobs Enno
Published: July 2006

A new molecular subtyping approach was developed which is based on the amplification and sequencing of a repetitive region of the P1 gene of
Mycoplasma pneumoniae
. It allows the differentiation of all known subtypes and variants of
M. pneumoniae
as well as the identification of new subtypes directly in clinical samples to characterize endemic and epidemic
M. pneumoniae
infections.
Sequence Analysis of
Enterococcus faecium
Strain 10/96A (VanD4), the Original Vancomycin-Resistant
E. faecium
Strain in Brazil
Authors: Camargo Ilana L. B. C. , Dalla Costa Libera M. , Woodford Neil , Gilmore Michael S. , Darini Ana L. C.
Published: July 2006

Enterococcus faecium
strain 10/96A (VanD4) was the first vancomycin-resistant enterococcus (VRE) isolated in Brazil. Subsequent Brazilian VRE strains have all had the VanA phenotype. Multilocus sequence typing showed that strain 10/96A was isolated sporadically, has a unique sequence type (ST 281), and was not the progenitor of the VRE strains isolated from hospital outbreaks in Brazil.
Hospital-Acquired
Bordetella bronchiseptica
Infection following Hematopoietic Stem Cell Transplantation
Authors: Huebner Elizabeth S. , Christman Brian , Dummer Stephen , Tang Yi-Wei , Goodman Stacey
Published: July 2006

Two patients who had undergone nonmyeloablative allogeneic stem cell transplantation 53 and 112 days earlier and were being monitored at the same transplant center developed severe
Bordetella bronchiseptica
infections within 3 days of each other. Pulsed-field gel electrophoresis analysis indicated that the isolates from the two cases were identical. Neither patient had had direct contact with animals since transplantation. These findings strongly support nosocomial transmission of
B. bronchiseptica.
Prevalence of In Vitro Resistance to Eleven Standard or New Antimalarial Drugs among
Plasmodium falciparum
Isolates from Pointe-Noire, Republic of the Congo
Authors: Pradines Bruno , Hovette Philippe , Fusai Thierry , Atanda Henri Léonard , Baret Eric , Cheval Philippe , Mosnier Joel , Callec Alain , Cren Julien , Amalvict Rémy , Gardair Jean Pierre , Rogier Christophe
Published: July 2006

We determined the level of in vitro resistance of
Plasmodium falciparum
parasites to standard antimalarial drugs, such as chloroquine, quinine, amodiaquine, halofantrine, mefloquine, cycloguanil, and pyrimethamine, and to new compounds, such as dihydroartemisinin, doxycycline, atovaquone, and lumefantrine. The in vitro resistance to chloroquine reached 75.5%. Twenty-eight percent of the isolates were intermediate or had reduced susceptibility to quinine. Seventy-six percent and 96% of the tested isolates showed in vitro resistance or intermediate susceptibilities to cycloguanil and pyrimethamine, respectively. Only 2% of the parasites demonstrated in vitro resistance to monodesethylamodiaquine. No resistance was shown with halofantrine, lumefantrine, dihydroartemisinin, or atovaquone. Halofantrine, mefloquine, and lumefantrine demonstrated high correlation. No cross-resistance was identified between responses to monodesethyl-amodiaquine, dihydroartemisinin, atovaquone, and cycloguanil. Since the level of chloroquine resistance in vitro exceed an unacceptable upper limit, high rates of in vitro resistance to pyrimethamine and cycloguanil and diminution of the susceptibility to quinine, antimalarial drugs used in combination, such as amodiaquine, artemisinin derivatives, mefloquine, lumefantrine, or atovaquone, seem to be appropriate alternatives for the first line of treatment of acute, uncomplicated
P. falciparum
malaria.
Genetic Differentiation of Chinese Isolates of
Rickettsia sibirica
by Partial
ompA
Gene Sequencing and Multispacer Typing
Authors: Zhang LiJuan , Jin JianLing , Fu XiuPing , Raoult Didier , Fournier Pierre-Edouard
Published: July 2006

Current data on rickettsiae and rickettsial diseases in China remain limited. Using partial
ompA
gene sequencing and multispacer typing, we identified 15 rickettsial isolates from China. All isolates were found to belong to
Rickettsia sibirica
subsp.
sibirica
. Four isolates from
Dermacentor sinicus
collected in Beijing, China, were fully identical to strain BJ-90, previously demonstrated to belong to
R. sibirica
subsp.
sibirica
despite antigenic and genotypic specificities. All 11 remaining isolates were similar to the
R. sibirica
subsp.
sibirica
type strain, 246. These were widely distributed in China in humans and different tick species. We emphasize the importance of surveying the distribution of
R. sibirica
in China.
Evaluation of the Quidel QuickVue Test for Detection of Influenza A and B Viruses in the Pediatric Emergency Medicine Setting by Use of Three Specimen Collection Methods
Authors: Agoritsas Konstantinos , Mack Kathy , Bonsu Bema K. , Goodman Debbie , Salamon Douglas , Marcon Mario J.
Published: July 2006

The Quidel QuickVue influenza test was compared to viral culture and reverse transcriptase PCR by the use of three different respiratory specimen types. Of 122 pediatric subjects enrolled, 59 had influenza virus infections: 44 were infected with influenza A virus and 15 were infected with influenza B virus. The sensitivity of the QuickVue test was 85% with nasopharyngeal swabs, 78% with nasal swabs, and 69% with nasopharyngeal washes. Specificities were equivalent (97% to 98%) for all three collection methods.
Optical Properties of InAsSb Single Crystals with Cutoff Wavelengths of 8–12 µm Grown by Melt-Epitaxy
Authors: Gao Yu Zhu , Gong Xiu Ying , Yamaguchi Tomuo
Published: July 2006

The transmittance spectra of melt epitaxiy (ME)-grown InAsSb single crystals with cutoff wavelengths of 8–12 µm were measured and calculated under the assumption of a microscopic composition distribution function. A good agreement between the experimental and theoretical transmittance spectra was obtained. The results indicate that a microscopic composition distribution inhomogeneity exists in long-wavelength InAsSb epilayers with different compositions, which may be related to the energy band gap narrowing of this InAsSb.
Reentrant Effect on the Transport Properties of La0.7Sr0.3MnO3 Films
Authors: Yang S. Y. , Kuang W. L. , Liou Yung , Tse W. S. , Lee S. F. , Yao Y. D.
Published: July 2006

In this work, the transport properties of polycrystalline manganite La0.7Sr0.3MnO3 (LSMO) films were investigated. The LSMO was grown on MgO(001) and SiO2/Si(001) substrates by using a magnetron dc sputtering technique to obtain polycrystalline films. It was found that the variation in the resistance with the temperature was dominated by the spin fluctuation around the magnetic domain walls. In addition, the reentrant spin glass gave rise to the upturn resistance of the polycrystalline LSMO films at low temperatures. The spin fluctuation and the reentrant effect also led to the significant magnetoresistance occurring in the LSMO films, which is larger than the colossal magnetoresistance of the LSMO film by one order of magnitude.
Differential Phase Shift Quantum Key Distribution Using 1.3-µm Up-Conversion Detectors
Authors: Takesue Hiroki , Honjo Toshimori , Kamada Hidehiko
Published: July 2006

We report a differential phase shift quantum key distribution (DPS-QKD) experiment in the 1.3-µm band that uses single photon detectors based on a frequency up-conversion technique. By combining a fast-clock DPS-QKD and up-conversion detectors operated in a non-gated mode, we have achieved a sifted key rate of 180 kbit/s over 10 km of fiber, which is one order of magnitude larger than a previously reported 1.3-µm band result.
Ablation and Amorphization of Crystalline Si by Femtosecond and Picosecond Laser Irradiation
Authors: Izawa Yusaku , Setuhara Yuichi , Hashida Masaki , Fujita Masayuki , Izawa Yasukazu
Published: July 2006

The ablation and amorphization of crystalline Si by femtosecond and picosecond laser irradiations are reported in this paper. Laser pulse width was varied in the range of 100 fs–200 ps. We obtained the dependences of ablation rate and fluence for amorphization on laser pulse width. At a lower fluence than a single-shot ablation threshold, femtosecond laser irradiation induced the amorphization of crystalline Si. We confirmed the thickness of an amorphous Si layer by transmission electron microscopy. The thickness of an amorphized layer, which was about 50 nm and almost uniform, did not depend on the number of irradiated laser pulses and fluence. The fluence range for amorphization decreased with increasing laser pulse width.
Development of Small Form Factor Optical Disk for Mobile Device Application
Authors: Ryu Hojun , Yoo Yonggoo , Jung Woosug , Kim Eun Kyung , Paek Mun Cheol , Kang Kwangyong
Published: July 2006

The small form factor disk which is satisfied the blu-ray specification especially 320 nm track pitch has been implemented. The data area of the fabricated disk is located 7.2 mm from the disk center to 13.5 mm from the same position. The cover layer on the disk is formed by spin coating method and the specially designed metal chucking hub has been adopted for preventing vibration during high speed rotation. The static recording measurement for power transition effect has been carried out. The optimum condition for writing the bit is obtained at the 10 mW input laser and 45 ns pulse width for this disk. The disk has 1 GB capacity with single layer and shows very low deflection and good tilt margin.
Exciton Binding Energy under Electric Field in ZnTe1-xSx/ZnS Strained-Layer Superlattices
Authors: Onodera Chikara , Shoji Tadayoshi , Hiratate Yukio , Taguchi Tsunemasa
Published: July 2006

Conduction and valence band offsets in ZnTe1-x
S
x
/ZnS strained-layer superlattices (SLSs) are calculated as a function of sulfur (S) concentration (x). The valence band offsets markedly decreases with increasing x because the energy difference between the band gaps ZnS and ZnTe1-x
S
x
decreases with increasing x. Exciton binding energy in the ZnTe1-x
S
x
/ZnS SLSs decreases with increasing ZnTe1-x
S
x
and ZnS layer thickness. This system has two exciton systems under an applied electric field. The energy splitting of the exciton systems increases with increasing electric field strength.
Electrical Properties of Low-Fire Ferroelectric+Ferrimagnetic Ceramic Composite
Authors: Hsu Rung-Tsung , Peng Te-Ming , Jean Jau-Ho
Published: July 2006

A low-fire, densified ferroelectric+ferrimagnetic ceramic composite consisting of Pb(Ni1/3Nb2/3)O3–PbZrO3–PbTiO3 (PNZT) and Ni–Cu–Zn ferrite powders is prepared at temperatures below 900 °C. The low-fire densification behavior is attributed to the migration of PbO from PNZT into Ni–Cu–Zn ferrite, enhancing the sintering compatibility between PNZT and ferrite. This in turn promotes the densification of the binary composite taking place at temperatures close to those of pure PNZT and Ni–Cu–Zn ferrite. For all compositions investigated, no new phases except the initial ferroelectric PNZT and ferrimagnetic Ni–Cu–Zn ferrite were detected in the ceramic composites. Both the saturation polarization in the polarization-electric field hysteresis curves and the dielectric constant of the binary PNZT+ferrite composite increase with increasing ferroelectric PNZT content. With increasing ferrimagnetic Ni–Cu–Zn ferrite content in the composite, the coercive magnetic field decreases but the saturation magnetization and initial permeability increase.
Effect of Inner Electrode on Reliability of (Zn,Mg)TiO3-Based Multilayer Ceramic Capacitor
Authors: Lee Wen-His , Su Chi-Yi , Lee Ying Chieh , Yang Jackey , Yang Tong , PinLin Shih
Published: July 2006

In this study, different proportions of silver-palladium alloy acting as the inner electrode were adopted to a (Zn,Mg)TiO3-based multilayer ceramic capacitor (MLCC) sintered at 925 °C for 2 h to evaluate the effect of the inner electrode on reliability. The main results show that the lifetime is inversely proportional to Ag content in the Pd/Ag inner electrode. Ag+1 diffusion into the (Zn,Mg)TiO3-based MLCC during cofiring at 925 °C for 2 h and Ag+1 migration at 140 °C against 200 V are both responsible for the short lifetime of the (Zn,Mg)TiO3-based MLCC, particularly the latter factor. A (Zn,Mg)TiO3-based MLCC with high Ag content in the inner electrode Ag/Pd=99/01 exhibits the shortest lifetime (13 h), and the effect of Ag+1 migration is markedly enhanced when the activation energy of the (Zn,Mg)TiO3 dielectric is greatly lowered due to the excessive formation of oxygen vacancies and the semiconducting Zn2TiO4 phase when Ag+ substitutes for Zn+2 during co-firing.
Electrooptic Response of Thermotropic Liquid Crystal Underwater to Alternating Applied Voltage
Authors: Okuda Shinichi , Uto Sadahito
Published: July 2006

A thermotropic liquid crystal membrane was fabricated in distilled water successfully and an alternating square voltage was applied to it. The electrooptic response of the membrane was measured using an optical system with crossed-polarizers, and it was found that there are two types of the membrane. One has a dominant second harmonic component of the applied frequency in its response to the field and the other has a dominant fundamental component.
Surface Acoustic Wave Based Pressure Sensor with Ground Shielding over Cavity on 41° YX LiNbO3
Authors: Lee Keekeun , Wang Wen , Kim Geunyoung , Yang Sangsik
Published: July 2006

A surface acoustic wave (SAW)-based pressure sensor was fabricated for stable mechanical compression force measurement. A single phase unidirectional transducer (SPUDT) and two acoustic tracks were employed to minimize inherent insertion loss and improve reflectivity from the reflectors. The coupling of modes (COM) theory and finite element methods (FEMs) were used to determine optimal design parameters. A LiNbO3 diaphragm was bonded to a heavily doped silicon substrate with a cavity of ∼250 µm deep, in which gold was lined all over the inner cavity to reduce the coupling loss of SAW energy to the surrounding atmosphere. As a mechanical compression force was applied to the diaphragm, the diaphragm bent, resulting in phase shifts of the reflected peaks. The phase shifts were modulated depending on the amount of mechanical compression applied. The measured reflection coefficient S11 showed good agreement with simulated results.
Microwave-Induced Combustion Synthesis and Ion Conductivity of Ce1-xLaxO2-1/2x Ceramics
Authors: Fu Yen-Pei
Published: July 2006

Ce1-x
La
x
O2-1/2x
nanopowders were successfully synthesized by a microwave-induced combustion process. The phase identification, ionic conductivity and thermal expansion coefficient of Ce1-x
La
x
O2-1/2x
ceramics were investigated in the current study. The results revealed that the bulk densities of Ce1-x
La
x
O2-1/2x
ceramics sintered at 1450 °C for 3 h were all greater than 94% of the in theoretical densities, the maximum ionic conductivity of the sintered specimens was 0.047 S/cm at 850 °C for Ce0.84La0.16O1.92. Moreover, the minimum activity energy E
a determined from 500 to 850 °C for Ce0.84La0.16O1.92 was 0.759 eV. It is found that the ionic conductivity increased with decreasing thermal expansion coefficient. For Ce1-x
La
x
O2-1/2x
ceramics, the ionic conductivity increased with La doping concentration until x=0.16, and then decreased.
Characteristics of the Linear Ultrasonic Motor using an Elliptical Shape Stator
Authors: Ho Shine-Tzong
Published: July 2006

A prototype linear ultrasonic motor using normal vibration and tangential vibration modes of an elliptical shape stator was fabricated and studied in this research. The composite structure of the stator is formed by two multilayer piezoelectric actuators clamped in an elliptical elastic body. The geometry of the stator has been computed with the help of the finite element analysis. The dimensions of the stator's structure were determined by making the two resonance frequencies close to each other. Two modes of normal and tangential vibration degenerate at the dimensional ratio of major axis and minor axis diameter equal to about 1.6 for coincidence of two resonance frequencies when the thickness is 6 mm and the width is 3 mm. The construction and some operational characteristics of the linear motor are presented. The maximum moving speed of the prototype was about 180 mm/s when applying 11 Vp driving voltage by using two signal driving method.
Tracking Single Molecular Diffusion on Glass Substrate Modified with Periodic Ag Nano-architecture
Authors: Takimoto Baku , Nabika Hideki , Murakoshi Kei
Published: July 2006

Diffusion of individual dye-labeled molecules in self-spreading lipid bilayer on glass substrate in aqueous solution was observed directly using total internal reflection fluorescence microscopy (TIRFM). The molecular diffusion was evaluated quantitatively by the mean square displacement (MSD) analysis for the trajectories of individual molecules. The mode of normal Brownian diffusion in lipid bilayer was changed in the presence of the periodic triangular Ag nanoparticles on the surface of the substrate. Suppressed diffusivity observed at the system with the triangular Ag nanoparticles was attributed to the confinement of the molecular motion in the micro-compartment surrounded by the Ag triangles.
Formation of Metastable Silver Nanowires of Hexagonal Structure and Their Structural Transformation under Electron Beam Irradiation
Authors: Liang Changhao , Terabe Kazuya , Hasegawa Tsuyoshi , Aono Masakazu
Published: July 2006

We fabricated Ag nanowires (AgNWs) of 4H hexagonal structure with a diameter of ca. 20 nm using dc electrodeposition inside an anodic alumina oxide (AAO) membrane at low current density. 4H-AgNWs were formed in scale inside an AAO membrane with a pore diameter of ca. 20 nm. We propose that a small-pore-size AAO membrane and appropriate growth conditions favor the growth of 4H-Ag. Transmission electron microscopy (TEM) revealed the coexistence of single-crystalline 4H-AgNWs and fcc-AgNWs. The 4H-AgNWs tended to transform into fcc Ag particles under intense electron beam (EB) irradiation, which may be attributed to the knock-on displacement of Ag atoms by electrons generating defects.
Intrinsic Regulators of Pancreatic β-Cell Proliferation
Authors: Heit Jeremy J. , Karnik Satyajit K. , Kim Seung K.
Published: July 2006

Once thought incapable of significant proliferation, the pancreatic β-cell has recently been shown to harbor immense powers of self-renewal. Pancreatic β-cells, the sole source of insulin in vertebrate animals, can grow facultatively to a degree unmatched by other organs in experimental animals. β-cell growth matches changes in systemic insulin demand, which increase during common physiologic states such as aging, obesity, and pregnancy. Compensatory changes in β-cell mass are controlled by β-cell proliferation. Here we review recent advances in our understanding of the intrinsic factors and mechanisms that control β-cell cycle progression. Dysregulation of β-cell proliferation is emerging as a fundamental feature in the pathogenesis of human disease states such as cancer and diabetes mellitus. New experimental observations and studies of these diseases suggest that β-cell fate and expansion are coordinately regulated. We speculate on how these advances may accelerate the discovery of new strategies for the treatment of diseases characterized by a deficiency or excess of β-cells.
Pharmacogenetics and Pharmacogenomics: Development, Science, and Translation
Authors: Weinshilboum Richard M. , Wang Liewei
Published: July 2006

Pharmacogenetics and pharmacogenomics involve the study of the role of inheritance in individual variation in drug response, a phenotype that varies from potentially life-threatening adverse drug reactions to equally serious lack of therapeutic efficacy. This discipline evolved from the convergence of rapid advances in molecular pharmacology and genomics. Originally, pharmacogenetic studies focused on monogenic traits, often involving genetic variation in drug metabolism. However, contemporary studies increasingly involve entire “pathways” encoding proteins that influence both pharmacokinetics—factors that influence the concentration of a drug reaching its target(s)—and pharmacodynamics, the drug target itself, as well as genome-wide approaches. Pharmacogenomics is also increasingly moving across the “translational interface” into the clinic and is being incorporated into the drug development process and the governmental regulation of that process. However, significant challenges remain to be overcome if pharmacogenetics-pharmacogenomics is to achieve its full potential as a major medical application of genomic science.
Structural and Functional Dynamics of Human Centromeric Chromatin
Authors: Schueler Mary G. , Sullivan Beth A.
Published: July 2006

Centromeres are the elements of chromosomes that assemble the proteinaceous kinetochore, maintain sister chromatid cohesion, regulate chromosome attachment to the spindle, and direct chromosome movement during cell division. Although the functions of centromeres and the proteins that contribute to their complex structure and function are conserved in eukaryotes, centromeric DNA diverges rapidly. Human centromeres are particularly complicated. Here, we review studies on the organization of homogeneous arrays of chromosome-specific α-satellite repeats and evolutionary links among eukaryotic centromeric sequences. We also discuss epigenetic mechanisms of centromere identity that confer structural and functional features of the centromere through DNA-protein interactions and post-translational modifications, producing centromere-specific chromatin signatures. The assembly and organization of human centromeres, the contributions of satellite DNA to centromere identity and diversity, and the mechanism whereby centromeres are distinguished from the rest of the genome reflect ongoing puzzles in chromosome biology.
The Laminopathies: The Functional Architecture of the Nucleus and Its Contribution to Disease
Authors: Burke Brian , Stewart Colin L.
Published: July 2006

Most inherited diseases are associated with mutations in a specific gene. Often, mutations in two or more different genes result in diseases with a similar phenotype. Rarely do different mutations in the same gene result in a multitude of seemingly different and unrelated diseases. Mutations in the Lamin A gene (LMNA), which encodes largely ubiquitously expressed nuclear proteins (A-type lamins), are associated with at least eight different diseases, collectively called the laminopathies. Studies examining how different tissue-specific diseases arise from unique LMNA mutations are providing unanticipated insights into the structural organization of the nucleus, and how disruption of this organization relates to novel mechanisms of disease.
Mouse Chromosome Engineering for Modeling Human Disease
Authors: van der Weyden Louise , Bradley Allan
Published: July 2006

Chromosomal rearrangements occur frequently in humans and can be disease-associated or phenotypically neutral. Recent technological advances have led to the discovery of copy-number changes previously undetected by cytogenetic techniques. To understand the genetic consequences of such genomic changes, these mutations need to be modeled in experimentally tractable systems. The mouse is an excellent organism for this analysis because of its biological and genetic similarity to humans, and the ease with which its genome can be manipulated. Through chromosome engineering, defined rearrangements can be introduced into the mouse genome. The resulting mouse models are leading to a better understanding of the molecular and cellular basis of dosage alterations in human disease phenotypes, in turn opening new diagnostic and therapeutic opportunities.
Prediction of Genomic Functional Elements
Authors: Jones Steven J.M.
Published: July 2006

As the number of sequenced genomes increases, the ability to deduce genome function becomes increasingly salient. For many genome sequences, the only annotation that will be available for the foreseeable future will be based on computational predictions and comparisons with functional elements in related species. Here we discuss computational approaches for automated genome-wide annotation of functional elements in mammalian genomes. These include methods for ab initio and comparative gene-structure predictions. Gene features such as intron splice sites, 3′ untranslated regions, promoters, and cis-regulatory elements are discussed, as is a novel method for predicting DNaseI hypersensitive sites. Recent methodologies for predicting noncoding RNA genes, including microRNA genes and their targets, are also reviewed.
Therapeutic hypercapnia prevents chronic hypoxia-induced pulmonary hypertension in the newborn rat
Authors: Kantores Crystal , McNamara Patrick J. , Teixeira Lilian , Engelberts Doreen , Murthy Prashanth , Kavanagh Brian P. , Jankov Robert P.
Published: July 2006

Induction of hypercapnia by breathing high concentrations of carbon dioxide (CO2) may have beneficial effects on the pulmonary circulation. We tested the hypothesis that exposure to CO2 would protect against chronic pulmonary hypertension in newborn rats. Atmospheric CO2 was maintained at <0.5% (normocapnia), 5.5%, or 10% during exposure from birth for 14 days to normoxia (21% O2) or moderate hypoxia (13% O2). Pulmonary vascular and hemodynamic abnormalities in animals exposed to chronic hypoxia included increased pulmonary arterial resistance, right ventricular hypertrophy and dysfunction, medial thickening of pulmonary resistance arteries, and distal arterial muscularization. Exposure to 10% CO2 (but not to 5.5% CO2) significantly attenuated pulmonary vascular remodeling and increased pulmonary arterial resistance in hypoxia-exposed animals ( P < 0.05), whereas both concentrations of CO2 normalized right ventricular performance. Exposure to 10% CO2 attenuated increased oxidant stress induced by hypoxia, as quantified by 8-isoprostane content in the lung, and prevented upregulation of endothelin-1, a critical mediator of pulmonary vascular remodeling. We conclude that hypercapnic acidosis has beneficial effects on pulmonary hypertension and vascular remodeling induced by chronic hypoxia, which we speculate derives from antioxidant properties of CO2 on the lung and consequent modulating effects on the endothelin pathway.
Relationship between local perfusion and FFA uptake in human skeletal muscle—no effect of increased physical activity and aerobic fitness
Authors: Hannukainen Jarna C. , Nuutila Pirjo , Kaprio Jaakko , Heinonen Olli J , Kujala Urho M. , Janatuinen Tuula , Rönnemaa Tapani , Kapanen Jukka , Haaparanta-Solin Merja , Viljanen Tapio , Knuuti Juhani , Kalliokoski Kari K.
Published: July 2006

We investigated heredity-independent effects of increased physical activity and aerobic fitness on skeletal muscle free fatty acid (FFA) uptake, perfusion, and their heterogeneity at rest and during exercise. Also, the relationship between local skeletal muscle FFA uptake and perfusion was studied. Nine young adult male monozygotic twin pairs with significant difference in physical activity [229 min (SD 156) average time spent for conditioning exercise per week in more and 98 min (SD 71) in less active twins, P = 0.013] and aerobic fitness [18% (SD 10) difference in maximum O2 uptake] between brothers were studied using positron emission tomography. Submaximal knee-extension exercise increased perfusion, FFA uptake, and oxygen uptake in quadriceps femoris muscles 6–10 times compared with resting values ( P < 0.001). More active twins tended to utilize more oxygen, while no differences were found in muscle perfusion or FFA uptake between groups. Mean perfusion and FFA uptake correlated strongly at a whole muscle level, both at rest ( r = 0.97, P = 0.03 in more and r = 0.98, P = 0.02 in less active twins) and during exercise ( r = 0.99, P = 0.01 and r = 0.94, P = 0.06), but at the voxel level (87 mm3) correlation was only moderate during exercise [ r = 0.73 (SD 0.08) vs. r = 0.74 (SD 0.10), P = 0.92] and weak at rest [ r = 0.28 (SD 0.13) vs. r = 0.33 (SD 0.21), P = 0.58]. Exercise decreased both perfusion and FFA uptake heterogeneity within the muscles ( P < 0.001) similarly in both groups. In conclusion, long-term history of moderately increased physical activity tends to enhance muscle oxidative metabolism, but it does not have any significant influence on the FFA uptake or perfusion rates or their heterogeneity in skeletal muscle. Submaximal knee-extension exercise decreases heterogeneity of muscle FFA uptake and perfusion and improves matching between local muscle perfusion and FFA uptake. Thus it seems that the genetic influence is more important to determine the heterogeneity of perfusion and FFA uptake in skeletal muscle than exercise training.
Immunolesions of Glucoresponsive Projections to the Arcuate Nucleus Alter Glucoprivic-Induced Alterations in Food Intake, Luteinizing Hormone Secretion, and GALP mRNA, but Not Sex Behavior in Adult Male Rats
Authors: Fraley Gregory S.
Published: July 2006

Metabolic signals such as insulin, leptin and glucose are known to alter hypothalamic function. Although insulin and leptin are known to directly alter hypothalamic areas that regulate reproduction, the mechanisms by which glucose alters reproductive function are not as clear. Catecholaminergic neurons in the A1/C1 region in the hindbrain are glucose-responsive and project to the arcuate nucleus. To determine if this pathway is involved in the regulation of sex behavior and luteinizing hormone (LH) secretion, this catecholaminergic pathway was lesioned with injections of saporin conjugated with anti-dopamine-β-hydroxylase (DSAP) or unconjugated saporin (SAP) in adult male rats. Rats were given glucoprivic challenges and feeding and sex behavior was observed. As was expected, the DSAP-treated rats showed decreased feeding during glucoprivation (250 mg/kg 2-deoxy-D-glucose, 2DG) compared to SAP controls. Glucoprivation caused a significant reduction in sex behavior in both SAP and DSAP animals equally, compared to saline treatments (p < 0.05). At the end of the experiment, animals were given a final challenge with 2DG or saline, euthanized by decapitation and trunk blood was assayed for plasma LH levels. In situ hybridization analysis revealed that 2DG treatment caused a significant reduction in GALP mRNA in SAP controls compared to saline treatment. This reduction in GALP mRNA was prevented with DSAP treatment. In SAP animals, 2DG elicited a significant decrease in plasma LH levels (p < 0.05); this reduction in plasma LH was absent in the DSAP-treated male rats. These data indicate that the A1/C1 efferents to the ventromedial hypothalamus are involved in the glucostatic regulation of GALP mRNA, feeding behavior and LH secretion, but not sex behavior in the adult male rat.
Diverting Ileostomy Set Removable without Laparotomy – Feasibility Study
Authors: Motyčka Petr , Ferko Alexander , Šubrt Zdeněk , Hadži Nikolov Dimitar
Published: July 2006

We constructed an ileostomy set that creates a diverting ileostomy not requiring surgery for closure. The set has two primary components: a double-balloon drainage catheter and a plastic holder. The plastic holder has a rotary component that is used to tighten a percutaneosly placed lasso-loop stitch and purse the enterotomy after the drainage catheter is removed. We tested the ileostomy set in 10 experimental pigs. The drainage catheter was introduced transcecally into the terminal ileum behind Bauhin’s valve, and the balloon was inflated. Three to seven days later the drainage catheter was removed, and the cecotomy was closed by percutaneous tightening of the lasso-loop stitch. One week later each animal underwent relaparotomy, and we examined the abdominal cavity for peritonitis. An ileocecal resection was performed, and specimens were collected and evaluated microscopically to ensure that the catheter had not damaged the intestinal wall. The only change noted in the terminal ileum was submucosa lymphatic tissue hyperplasia. No intestinal leaks occurred, and percutaneous enterotomy closure was successful.
Correction of Anemia in Uremic Rats by Intramuscular Injection of Lentivirus Carrying an Erythropoietin Gene
Authors: Oh Tae Keun , Quan Gui Hong , Kim Hae Young , Park Frank , Kim Seung Taik
Published: July 2006

Background: Anemia is an inevitable consequence of chronic renal failure. Gene therapy using lentiviral vector (LV) would be an effective tool to treat anemia associated with renal failure. Methods: A LV carrying the erythropoietin (EPO) cDNA was administered to skeletal muscle of partially nephrectomized rats, which is a model of uremia. The red blood cell production and serum EPO levels were temporally monitored in these rats. Polymerase chain reaction assays were done to validate the presence of the LV in the experimental rats. Results: After a single intramuscular injection of LV at a dose of 55 µg p24 Gag antigen (∼5 × 107 transducing units), blood hematocrit (Hct) levels increased and peaked at 3 weeks (47.8 ± 4.2%, p < 0.01, n = 8) with the levels being maintained for at least 20 weeks (duration of study; 44.9 ± 3.3%, p < 0.01, n = 3). The control rats receiving LV expressing lacZ had Hct levels of 36.9 ± 4.1% (n = 8) at 3 weeks and 33.1 ± 3.7% (n = 4) at 20 weeks, respectively. The serum EPO levels in the rats injected with the LV expression EPO significantly increased (p < 0.01) to 156.3 ± 3.0 mU/ml compared to the control rats (63.9 ± 1.7 mU/ml). Polymerase chain reaction analysis of the isolated genomic DNA from the LV-injected rats showed specific positive detection of the LV in only the skeletal muscle tissue at the site of injection, whereas the other tissues, including the liver, spleen, and kidney, were negative. Conclusions: This study demonstrates that intramuscular injection of LV can produce highly efficient and sustained EPO secretion in uremic rats, and suggests that this approach could be an effective tool to deliver secretable proteins at therapeutic levels in various animal disease models.
Endothelial α
ν
β
3
Integrin–Targeted Fumagillin Nanoparticles Inhibit Angiogenesis in Atherosclerosis
Authors: Winter Patrick M. , Neubauer Anne M. , Caruthers Shelton D. , Harris Thomas D. , Robertson J. David , Williams Todd A. , Schmieder Anne H. , Hu Grace , Allen John S. , Lacy Elizabeth K. , Zhang Huiying , Wickline Samuel A. , Lanza Gregory M.
Published: July 2006

Objective—

Angiogenic expansion of the vasa vasorum is a well-known feature of progressive atherosclerosis, suggesting that antiangiogenic therapies may stabilize or regress plaques. α
ν
β
3
Integrin–targeted paramagnetic nanoparticles were prepared for noninvasive assessment of angiogenesis in early atherosclerosis, for site-specific delivery of antiangiogenic drug, and for quantitative follow-up of response.

Methods and Results—

Expression of α
ν
β
3
integrin by vasa vasorum was imaged at 1.5 T in cholesterol-fed rabbit aortas using integrin-targeted paramagnetic nanoparticles that incorporated fumagillin at 0 μg/kg or 30 μg/kg. Both formulations produced similar MRI signal enhancement (16.7%±1.1%) when integrated across all aortic slices from the renal arteries to the diaphragm. Seven days after this single treatment, integrin-targeted paramagnetic nanoparticles were readministered and showed decreased MRI enhancement among fumagillin-treated rabbits (2.9%±1.6%) but not in untreated rabbits (18.1%±2.1%). In a third group of rabbits, nontargeted fumagillin nanoparticles did not alter vascular α
ν
β
3
-integrin expression (12.4%±0.9%;
P
>0.05) versus the no-drug control. In a second study focused on microscopic changes, fewer microvessels in the fumagillin-treated rabbit aorta were counted compared with control rabbits.

Conclusions—

This study illustrates the potential of combined molecular imaging and drug delivery with targeted nanoparticles to noninvasively define atherosclerotic burden, to deliver effective targeted drug at a fraction of previous levels, and to quantify local response to treatment.
Polymorphisms of the Phosphodiesterase 4D, cAMP-Specific (
PDE4D
) Gene and Risk of Ischemic Stroke
Authors: Zee Robert Y.L. , Brophy Victoria H. , Cheng Suzanne , Hegener Hillary H , Erlich Henry A. , Ridker Paul M
Published: July 2006

Background and Purpose—

In an Icelandic population, gene variants of the phosphodiesterase 4D, cAMP-specific (
PDE4D
) gene were reported to be risk predictors for ischemic stroke. Case–control studies in other populations have yielded mixed evidence for association. A recent analysis in a prospective, non-Icelandic study found an association with stroke after stratification by hypertension.

Methods—

We evaluated nine
PDE4D
single nucleotide polymorphisms (SNPs) among 259 incident ischemic stroke cases and 259 controls were matched on age and smoking status and length of follow up since randomization, all drawn from initially healthy white males within the Physicians’ Health Study cohort who were prospectively followed for first-ever stroke events.

Results—

Genotype and allele distributions were similar between cases and controls. Results from single-marker conditional logistic regression analysis adjusting for traditional stroke risk factors showed significant association of SNP56 with risk of ischemic stroke (recessive odds ratio [OR], 2.26; 95% confidence interval [CI], 1.11 to 4.61;
P
=0.03). Among the participants without baseline hypertension, SNP42 (additive OR, 1.68; 95% CI, 0.99 to 2.86,
P
=0.06), SNP45 (dominant odds ratio, 2.24; 95% CI, 1.00 to 5.00,
P
=0.05), and SNP56 (additive odds ratio, 1.77; 95% CI, 1.02 to 3.10,
P
=0.04) showed modest association with increased risk of ischemic stroke.

Conclusions—

We found modest associations between several
PDE4D
gene polymorphisms and risk of incident ischemic stroke in men without baseline hypertension in this prospective, non-Icelandic study. Although of borderline statistical significance, the direction and magnitude of the effect for SNP42 parallels that observed in a recent study evaluating women from an independent, nested case–control study.
Embolic Lesion Pattern in Stroke Patients With Patent Foramen Ovale Compared With Patients Lacking an Embolic Source
Authors: Jauss Marek , Wessels Tiemo , Trittmacher Susan , Allendörfer Jens , Kaps Manfred
Published: July 2006

Background and Purpose—

Multiple acute ischemic lesions on diffusion-weighted magnetic resonance imaging (DWI-MRI) are thought to be of embolic origin. However, in several patients with multiple ischemic lesions on DWI-MRI, no embolic source was detected, despite a thorough clinical work-up. Stroke etiology in such cases is then classified as cryptogenic. In other patients, a potential embolic source is limited to a patent foramen ovale (PFO) that may act as an embolic source of unsure relevance. We therefore examined the prevalence of the multiple-lesion pattern in patients with cryptogenic stroke compared with patients with PFO.

Methods—

We screened 650 stroke patients by DWI-MRI. For the subsequent evaluation, we excluded patients with a cardiac embolic source other than PFO, symptomatic carotid artery disease, and other apparent stroke causes, such as dissection or vasculitis, and patients whose diagnostic work-up was incomplete. For the remaining 106 patients, we found DWI lesions in 73, who were subjected to further evaluation.

Results—

There were no differences in the occurrence of the multiple-lesion pattern in patients with cryptogenic stroke compared with patients with PFO, either for the entire group or for the subgroup of young stroke patients who were <50 years old. Patients with PFO showed a significantly higher incidence of multiple lesions in the posterior circulation.

Conclusions—

The multiple-lesion pattern on DWI-MRI is not uncommon, even when extensive testing does not reveal any embolic source. Therefore, it is not possible to discriminate between cryptogenic stroke and stroke from an assumed paradoxical embolism.