September-October 2007 l Vol 13 l No 9-10

Association of STAT4 with Rheumatoid Arthritis in the Korean Population
Hye-Soon Lee, Elaine F Remmers, Julie M Le, Daniel L Kastner, Sang–Cheol Bae, and Peter K Gregersen
Risk genes for rheumatoid arthritis (RA) have been identified in both White and Asian populations. A recent study in the North American White population has documented the association of a common STAT4 haplotype with risk for (RA) and systemic lupus erythematosus.  To examine this finding in the Korean population, Lee et al. (455-460) performed a case-control association study.  Sixty-seven single nucleotide polymorphisms (SNPs) were genotyped within the STAT1 and STAT4 regions in 1123 Korean patients with RA and 1008 ethnicity-matched controls.  The most significant four risk SNPs are identical with those in the North American study.  All four SNPs have modest risk for RA susceptibility and a common haplotype defined by these markers carries significant risk for RA in Koreans.  Unlike several other risk genes for RA, a haplotype of the STAT4 gene shows consistent association with RA susceptibility across Whites and Asians, suggesting that this risk haplotype predated the divergence of the major racial groups.
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Transcription Factors in Muscle Atrophy Caused by Blocked Neuromuscular Transmission and Muscle Unloading in Rats
Jenny Nordquist, Anna-Stina Höglund, Holly Norman, Xiaorui Tang, Barry Dworkin, and Lars Larsson
Muscle wasting associated with long-term intensive care unit treatment has a negative effect on muscle function resulting in prolonged periods of rehabilitation and a decreased quality of life.  Skeletal muscle atrophy is mediated by a shift in the normal balance between protein synthesis and protein breakdown.  While potential molecular switches controlling this balance have been identified, knowledge regarding these signaling pathways is limited.  Here, Nordquist et al. (461-470) investigate the mechanisms involved in muscle wasting using a rat model to mimic conditions in an intensive care unit. While results show that ubiquitin ligases are up-regulated, differences exist between fast- and slow-twitch muscles, suggesting these muscles respond differently to muscle unloading signals. Future work using this model may allow for more detailed studies of muscle wasting, which may advance intensive care intervention for patients kept on a mechanical ventilator.
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Induction of Tolerance to Human Arylsulfatase A in a Mouse Model of Metachromatic Leukodystrophy
Ulrich Matzner, Frank Matthes, Eva Herbst, Renate Lüllmann-Rauch, Zsuzsanna Callaerts-Vegh, Rudi D’Hooge, Cecilia Weigelt, Carl Eistrup, Jens Fogh, and Volkmar Gieselmann
Metachromatic Leukodystrophy (MLD) is a member of a family of genetic diseases known as leukodystrophies, which affect the growth, development and maintenance of myelin.  MLD is a lysosomal storage disease caused by a deficiency of arylsulfatase A (ASA), which leads to the accumulation and deposition of sulfatide in oligodendrocytes and Schwann cells.  The result is demyelination of the peripheral and central nervous system, which leads to neurological symptoms and premature death.  Enzyme replacement therapy is a putative treatment for MLD, however, repeated injection of human ASA (hASA) in ASA knock out mice elicits an immune response leading to treatment resistance, anaphylactic reactions and high mortality.  In contrast to ASA knockout mice, the majority of MLD patients is not completely ASA deficient, but expresses a low or normal ASA level with reduced specific activity or stability.  Therefore, knockout ASA animal models, currently the only available model for MLD, may not be truly representative of the patient population.  In this work, Matzner et al. (471-479) transgenically expressed an active site mutant of hASA in the knockout animals, which allowed tolerance to hASA and maintained the MLD-like phenotype.  This novel transgenic strain may be advantageous to assess the benefit and risk of long-term enzyme replacement therapy.
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Fibrin Gel-Immobilized VEGF and bFGF Efficiently Stimulate Angiogenesis in the AV Loop Model
Andreas Arkudas, Jimmy Tjiawi, Oliver Bleiziffer, Lucia Grabinger, Elias Polykandriotis, Justus P Beier, Michael Stürzl, Raymund E Horch, and Ulrich Kneser
Cells transplanted in the body require sufficient supplies of oxygen and nutrients for survival.  Suboptimal initial vascularization limits the survival of cells in the center of large cellularized implants, but angigogenic factors may be used to shorten the time period between implantation and vascularization of matrices.  Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) are two of the most extensively tested angioinductive growth factors in animal models.  Here, Arkudas et al. (480-487) evaluated the angiogenic effects of VEGF and bFGF immobilized in a fibrin-based drug delivery system in the arteriovenous loop (AVL) model.  VEGF and bFGF both induced absolute and relative vascular density as well as blood vessel sprouting.  Implanting vascular carriers into growth factor-loaded matrix volumes may allow efficient generation of axially vascularized, tissue-engineered composites.
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Adrenomedullin and Adrenomedullin Binding Protein-1 Protect Endothelium-Dependent Vascular Relaxation in Sepsis
Mian Zhou, Subir R Maitra, and Ping Wang
Sepsis, septic shock and multiple organ failure continue to be the most common causes of death in noncardiac intensive care units. Despite advances in the management of trauma victims, the incidence of sepsis and septic shock has increased significantly over the past two decades.  Downregulation of vascular endothelial constitutive nitric oxide synthase (ecNOS) contributes to the vascular hyporesponsiveness in sepsis.  Circulating levels of adrenomedullin (AM) increase significantly in patients with septic shock, systemic inflammation response syndrome and after major surgery, but AM binding protein (AMBP-1) was significantly reduced in sepsis.  While co-administration of AM and the AMBP-1 maintains cardiovascular stability and reduces mortality in sepsis, it is unknown whether AM/AMBP-1 prevents endothelial cell dysfunction.  Zhou et al. (488-494) investigated this possibility in an animal model of sepsis.  Their results indicate that that AM/AMBP-1 preserves ecNOS and this mechanism may be responsible for the beneficial effect of AM/AMBP-1 in sepsis.
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Genome-Level Longitudinal Expression of Signaling Pathways and Gene Networks in Pediatric Septic Shock
Thomas P Shanley, Natalie Cvijanovich, Richard Lin, Geoffrey L Allen, Neal J Thomas, Allen Doctor, Meena Kalyanaraman, Nancy M Tofil, Scott Penfil, Marie Monaco, Kelli Odoms, Michael Barnes, Bhuvaneswari Sakthivel, Bruce J Aronow, and Hector R Wong
Septic shock affects a large number of children worldwide.  Morbidity and mortality associated with pediatric septic shock remain high and current therapy is limited to prevention and supportive care.  Translational research at the genomic level may represent a powerful approach to more comprehensively understand the biological complexity of pediatric septic shock.  In this work, Shanley et al. (495-508) generated genome-level expression profiles from children with septic shock. Gene expression and functional analyses demonstrated time-dependent, differential regulation of genes involved in multiple signaling pathways and gene networks, primarily related to immunity and inflammation.  The data represent the largest reported cohort of patients with septic shock subjected to longitudinal genome-level expression profiling.  The data further advance our genome-level understanding of pediatric septic shock and support novel hypotheses.
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Erythropoietin Protects the Intestine Against Ischemia/Reperfusion Injury in Rats
Ensari Guneli, Zahide Cavdar, Huray Islekel, Sulen Sarioglu, Serhat Erbayraktar, Muge Kiray, Selman Sokmen, Osman Yilmaz, and Necati Gokmen
Ischemia reperfusion (I/R) injury occurs in a variety of clinical conditions and is associated with high morbidity and mortality.  Reperfusion injury occurs as a result of blood flow restoration to an ischemic, or blood-restricted, region.  The resulting tissue injury may be more damaging than the original ischemic injury.  While the exact mechanisms have not been elucidated, oxidative stress mediators are believed to play an important role.  Erythropoietin (EPO) produced by the kidney in the regulation of red blood cells also acts as a tissue-protecting factor.  Though the favorable effects of EPO are not fully understood, Guneli et al. (509-517) examined the effect of recombinant human EPO on I/R intestinal injury.  Their results indicate that EPO protects against intestinal I/R injury in rats by reducing oxidative stress and apoptosis, which the authors attribute to the antioxidative properties of EPO.  Knowledge regarding EPO signaling pathways in the intestine may lead to its use in clinical practice in the future.
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Selective Suppression of NF-kBp65 in Hepatitis Virus-Infected Pregnant Women Manifesting Severe Liver Damage and High Mortality
Bhupesh K Prusty, Suresh Hedau, Ajay Singh, Premashis Kar, and Bhudev C Das
Viral hepatitis constitutes a major public health problem in developing countries. In addition to parentally transmitted hepatitis B and C viruses, enterically transmitted hepatitis E virus (HEV) infection is mainly responsible for epidemics related to poor hygiene and sanitation. In several countries, fulminant hepatic failure (FHF) leads to high mortality rates in HEV-infected pregnant women.  While decreased cell-mediated immunity is a major cause of death, the exact mechanisms remain unknown.  Here, Prusty et al. (518-526) investigated the role of NF-kB in hepatitis virus-infected pregnant women manifesting severe liver damage.  Results indicate that suppression of p65 expression may be associated with the breakdown of immunity and severe liver degeneration leading to patient death.  These findings provide a molecular basis for developing therapeutic approaches to target HEV-infected pregnant women.
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DNA Microarrays: a Powerful Genomic Tool for Biomedical and Clinical Research   
Victor Trevino, Francesco Falciani, and Hugo A Barrera-Saldaña
Among the many benefits of the Human Genome Project are new and powerful tools such as the genome-wide hybridization devices referred to as microarrays.  Initially designed to measure gene transcriptional levels, microarray technologies are now used for comparing other genome features among individuals and their tissues and cells.  Results provide valuable information on disease subcategories, disease prognosis and treatment outcome.  This review by Trevino et al. (527-541) describes the technology and applications that reveal our genetic inheritance. 
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Differences in Extracellular Matrix Production and Basic Fibroblast Growth Factor Response in Skin Fibroblasts from Sporadic and Familial Alzheimer’s Disease
Catia Bellucci, Cinzia Lilli, Tiziano Baroni, Lucilla Parnetti, Sandro Sorbi, Carla Emiliani, Eleonora Lumare, Paolo Calabresi, Stefania Balloni, and Maria Bodo
Alzheimer’s disease (AD) accounts for over 50 percent of dementia disorders and extracellular matrix (ECM) molecules and growth factors, such as fibroblast growth factor (FGF), play a crucial role in this disease.  While AD is characterized by amyloid deposits, it has been suggested that amyloid accumulation is only partly responsible for the neurodegeneration observed in this disease.  Here, Bellucci et al. (542-550) examined skin fibroblasts from familial and sporadic AD patients to determine if phenotypic alterations in ECM production were present in non-neuronal AD cells associated with the expression and response of FGF.  Their results show different ECM synthesis and mRNA levels in the two populations of AD patients.  These data suggests that in addition to being characterized by the known pathologies affecting the nervous system, AD may also be associated with abnormalities in somatic peripheral cells.
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