bluuebunny/crossref_metadata_2025 huggingface dataset:
Macrophage TNF-α contributes to insulin resistance and hepatic steatosis in diet-induced obesity
Authors: De Taeye Bart M. , Novitskaya Tatiana , McGuinness Owen P. , Gleaves Linda , Medda Mousumi , Covington Joseph W. , Vaughan Douglas E.
Published: June 2007

Obesity is commonly associated with development of insulin resistance and systemic evidence of inflammation. Macrophages contribute to inflammatory amplification in obesity and may contribute directly to insulin resistance and the development of nonalcoholic fatty liver disease through the production of inflammatory cytokines, including tumor necrosis factor (TNF)-α. To test this hypothesis, we transplanted male wild-type (WT) and TNF-α deficient (KO) mice with either TNF-α-sufficient (TNF-α+/+) or TNF-α-deficient (TNF-α−/−) bone marrow. After consuming a high-fat diet for 26 wk, metabolic and morphometric characteristics of the animals were analyzed. While there were no differences in terms of relative weight gain, body composition analysis yielded a lower relative adipose and higher relative lean mass in mice lacking TNF-α, which was partially explained by reduced epididymal fat pad and liver weight. TNF-α−/−→KO mice exhibited enhanced insulin sensitivity compared with that observed in TNF-α+/+→KO mice; remarkably, no protection against insulin resistance was provided by transplanting TNF-α−/−bone marrow in WT mice compared with TNF-α+/+→WT. The preserved insulin sensitivity seen in TNF-α−/−→KO mice provided protection against the development of hepatic steatosis. Taken together, these data indicate that macrophage-derived TNF-α contributes to the pattern and extent of fat accumulation and insulin resistance in diet-induced obesity; however, this contribution is negligible in the presence of host-derived TNF-α.
Role of gap junctions in spontaneous activity of the rat bladder
Authors: Ikeda Y. , Fry C. , Hayashi F. , Stolz D. , Griffiths D. , Kanai A.
Published: June 2007

Increased gap junction expression in lamina propria myofibroblasts and urothelial cells may be involved in detrusor overactivity, leading to incontinence. Immunohistochemistry was used to compare connexin (Cx) 26, 43, and 45 expression in the bladders of neonatal, adult, and spinal cord-transected rats, while optical imaging was used to map the spread of spontaneous activity and the effects of gap junction blockade. Female adult Sprague-Dawley rats were deeply anesthetized, a laminectomy was performed, and the spinal cord was transected (T8/T9). After 14 days, their bladders and those of age-matched adults (4 mo old) and neonates (7–21 day old) were excised and studied immunohistochemically using frozen sections or optically using whole bladders stained with voltage- and Ca2+-sensitive dyes. The expression of Cx26 was localized to the urothelium, Cx43 to the lamina propria myofibroblasts, and Cx45 to the detrusor smooth muscle. While the expression of Cx45 was comparable in all bladders, the expression of Cx43 and Cx26 was increased in neonate and transected animals. In the bladders of adults, spontaneous activity was initiated at multiple sites, resulting in a lack of coordination. Alternatively, in neonate and transected animals spontaneous activity was initiated at a focal site near the dome and spread in a coordinated fashion throughout the bladder. Gap junction blockade (18β-glycyrrhetinic acid, 1 μM) abolished this coordinated activity but had no effect on the uncoordinated activity in adult bladders. These data suggest that coordinated spontaneous activity requires gap junction upregulation in urothelial cells and lamina propria myofibroblasts.
Heterogeneous nuclear ribonucleoprotein K contributes to angiotensin II stimulation of vascular endothelial growth factor mRNA translation
Authors: Feliers Denis , Lee Myung-Ja , Ghosh-Choudhury Goutam , Bomsztyk Karol , Kasinath B. S.
Published: June 2007

ANG II rapidly increases VEGF synthesis in proximal tubular epithelial cells through mRNA translation. The role of heterogeneous nuclear ribonucleoprotein K (hnRNP K) in ANG II regulation of VEGF mRNA translation initiation was examined. ANG II activated hnRNP K as judged by binding to poly(C)- and poly(U)-agarose. ANG II increased hnRNP K binding to VEGF mRNA at the same time as it stimulated its translation, suggesting that hnRNP K contributes to VEGF mRNA translation. Inhibition of hnRNP K expression by RNA interference significantly reduced ANG II stimulation of VEGF synthesis. ANG II increased hnRNP K phosphorylation on both tyrosine and serine residues with distinct time courses; only Ser302 phosphorylation paralleled binding to VEGF mRNA. Src inhibition using PP2 or RNA interference inhibited PKCδ activity and prevented hnRNP K phosphorylation on both tyrosine and serine residues and its binding to VEGF mRNA. Under these conditions, ANG II-induced VEGF synthesis was inhibited. ANG II treatment induced redistribution of both VEGF mRNA and hnRNP K protein from light to heavy polysomal fractions, suggesting increased binding of hnRNP K to VEGF mRNA that is targeted for increased translation. This study shows that hnRNP K augments efficiency of VEGF mRNA translation stimulated by ANG II.
Central versus Peripheral Cardiovascular Limitation to Exercise: the Role of Two-Modality Testing
Authors: Ben-Dov Issahar , Reuveny Ronen , Gaides Mark
Published: June 2007

Background: Uncertainty arises when physiological findings indicate a cardiovascular limitation but the limiting constituents within the cardiovascular system cannot be identified. Objectives: It was the aim of this study to investigate the value of two-modality exercise testing to assess effort intolerance when the cause remains obscure despite standard exercise testing. Methods: A second modality maximal exercise test to fatigue, using either upper extremity or supine exercise, was performed following a nonconclusive standard sitting ergometry. Six patients (4 males) with a mean age of 56 ± 22 years with severe exercise intolerance were enrolled in the study. Results: In 4 of the patients, arm exercise capacity exceeded leg capacity, indicating peripheral limitation. In 1 of these patients, hemoglobin saturation decreased markedly only during sitting exercise while it remained normal during arm exercise, indicating a unique, iatrogenic abnormality. In another patient, supine leg exercise capacity exceeded sitting capacity, indicating peripheral venous limitation, and in an additional patient, leg capacity exceeded arm capacity pointing towards a central abnormality. In all 6 patients, the second modality test highlighted the correct diagnosis. Conclusions: Arm exercise that is added to a standard leg exercise may distinguish between central circulatory and peripheral vascular lower extremity limitation. Supine posture augments venous return to the heart and is useful when preload may be limiting. These modes of exercise may be added to a standard sitting or upright test in order to differentiate between central cardiovascular versus peripheral vascular (arterial or venous) causes of exercise limitation.
Epithelial-Mesenchymal Transition and Colorectal Cancer: Gaining Insights into Tumor Progression Using LIM 1863 Cells
Authors: Bates Richard C. , Pursell Bryan M. , Mercurio Arthur M.
Published: June 2007

In addition to allowing epithelial cells to escape the structural constraints imposed by tissue architecture and adopt a phenotype more amenable to cell movement, it is now recognized that the epithelial-mesenchymal transition (EMT) may also represent a critical component permitting the progression of carcinomas towards invasive and metastatic disease. However, data supporting the actual occurrence of EMT in specific solid tumors and its relevance to the process of progression of these cancers has been scant. Despite an extensive knowledge of the genetic basis for colorectal cancer, the translation of this information into effective treatments has been limited. Clearly, there is a desperate need for new and improved therapies and since the switch to a metastatic phenotype is critical for outcome, it is of paramount importance to elucidate the biology that underlies the progression of this disease. Thus, the unique LIM 1863 model for studying the EMT of colorectal carcinoma has been used to both substantiate the importance of the transition for this cancer type and to identify molecular events that contribute to disease progression. Importantly, it has emerged that not only does EMT enhance migratory capacity, but also elicits additional selective advantages to colonic tumor cells. Specifically, the acquisition of autocrine growth factor signaling loops, mechanisms to evade apoptosis, and expression of specific integrins allowing invasive cells to interact with interstitial matrices and sustain activation of TGF-β combine to provide a compelling new biochemical framework for understanding how EMT contributes to tumor evolution.
Signal Transduction Pathways Involved in Epithelial-Mesenchymal Transition in Oral Cancer Compared with Other Cancers
Authors: Chang Julia Yu Fong , Wright John M. , Svoboda Kathy K.H.
Published: June 2007

Epithelial-mesenchymal transition (EMT) is a central mechanism governing destined cell movement in embryonic development. Emerging evidence reveals that EMT characterizing the progression of many carcinomas is linked to the acquisition of an invasive and metastatic phenotype. While it is established that EMT is controlled by well-conserved mechanisms, additional research is required for various tissue- or tumor-specific transitions. We review the literature related to the major components of EMT including adhesion molecules, cytoskeleton reorganization and signaling pathways in oral cancer.
β-Catenin/LEF-1 Signalling in Breast Cancer – Central Players Activated by a Plethora of Inputs
Authors: Gebeshuber Christoph A. , Sladecek Stefan , Grunert Stefan
Published: June 2007

Although the role of Wnt signalling in breast cancer is far from being fully understood, in the last years its importance has been reported frequently. Besides stimulation by canonical Wnt signalling, the downstream effectors β-catenin and the transcriptional modulators of the T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) family can also be activated by other inputs including the TGF-β pathway. Wnt and TGF-β signalling are both major signal transduction pathways, which provide important cues during development and tumor progression. However, particularly TGF-β has a complicated influence on oncogenesis, which ranges from suppressive to promoting activity. Signalling pathways activated in parallel with TGF-β might determine the oncogenic influence, and therefore place signals cooperating with TGF-β into the limelight. During early development Wnt and TGF-β signalling collaborate extensively. Here we provide an overview of the known interactions of Wnt with TGF-β signalling in development and metastasis, particularly in breast cancer. We want to focus on the Wnt-activated transcription factor complex β-catenin/LEF-1, its upstream activators, its downstream targets and consequences on the cellular level in response to β-catenin/LEF-1 activation.
β-Catenin and ZO-1: Shuttle Molecules Involved in Tumor Invasion-Associated Epithelial-Mesenchymal Transition Processes
Authors: Polette Myriam , Mestdagt Mélanie , Bindels Sandrine , Nawrocki-Raby Béatrice , Hunziker Walter , Foidart Jean-Michel , Birembaut Philippe , Gilles Christine
Published: June 2007

The cytoplasmic/nuclear relocalization of β-catenin and ZO-1 from the adherens and tight junctions are common processes of the epithelial-mesenchymal transition (EMT) associated with tumor invasion. Data are now accumulating to demonstrate that these molecules, which shuttle between the plasma membrane and the nucleus or the cytosol, are involved in signaling pathways, and contribute to the regulation of genes such as vimentin or matrix metalloproteinase-14 which are turned on during EMT.
Role of Glycogen Synthase Kinase-3 in Cell Fate and Epithelial-Mesenchymal Transitions
Authors: Doble Bradley W. , Woodgett James R.
Published: June 2007

Epithelial cells usually exist as sheets of immotile, tightly packed, well-coupled, polarized cells with distinct apical, basal and lateral surfaces. Remarkably, these cells can dramatically alter their morphology to become motile, fibroblast-like mesenchymal cells in a process of epithelial-mesenchymal transition (EMT). This process and the reverse, mesenchymal-epithelial transition, occur repeatedly during normal embryonic development. A phenomenon similar to physiological EMT occurs during the pathophysiological progression of some cancers. Tumours of epithelial origin, as they transform to malignancy, appear to exploit the innate plasticity of epithelial cells, with EMT conferring increased invasiveness and metastatic potential. Key to the maintenance of epithelial cell identity is the expression of E-cadherin, a protein that is required for tight intercellular adhesion along the lateral surfaces of adjacent epithelial cells. Loss of functional E-cadherin is a critical event in EMT. An important regulator of E-cadherin expression is the protein Snail, a zinc-finger transcriptional repressor. Snail contains several consensus sites for the kinase, glycogen synthase kinase-3 (GSK-3), and accumulating evidence indicates that it is a GSK-3 substrate. Phosphorylation of Snail by GSK-3 facilitates its proteasomal degradation. Conversely, inhibition of GSK-3 leads to Snail accumulation, E-cadherin downregulation, and development of EMT in cultured epithelial cells. Several signalling pathways implicated in the progression of EMT, including the Wnt and phosphoinositide 3-kinase pathways, use GSK-3 to mediate their responses. In these pathways, GSK-3’s regulation of other transcriptional effectors like β-catenin works in concert with changes in Snail to orchestrate the EMT process. This review focuses on the emerging role of GSK-3 as a modulator of cell fate and EMT in the contexts of development, in vitro cell culture and cancer.
Epithelial-Mesenchymal Transition in Ovarian Cancer Progression: A Crucial Role for the Endothelin Axis
Authors: Bagnato Anna , Rosanò Laura
Published: June 2007

In ovarian carcinoma, acquisition of invasiveness is accompanied by the loss of the epithelial features and the gain of a mesenchymal phenotype, a process known as epithelial-mesenchymal transition (EMT). The endothelin A receptor (ETAR)/endothelin-1 (ET-1) axis is overexpressed in primary and metastatic ovarian carcinoma. In this tumor type, the ET-1/ETAR axis has a critical role in ovarian carcinoma progression by inducing proliferation, survival, neoangiogenesis, loss of intercellular communication and invasion. Recently, we demonstrated that the ET-1/ETAR autocrine pathway drives EMT in ovarian tumor cells by inducing an invasive phenotype through downregulation of E-cadherin, increased levels of β-catenin, Snail and other mesenchymal markers, and suppression of E-cadherin promoter activity. Activation of ETAR by ET-1 triggers a phosphatidylinositol 3-kinase-dependent integrin-linked kinase (ILK)-mediated signaling pathway leading to glycogen synthase kinase-3β (GSK-3β) inhibition, Snail and β-catenin stabilization andtranscriptional programs that control EMT. Transfection of dominant negative ILK or exposure to an ILK inhibitor suppresses the ET-1-induced phosphorylation of GSK-3β as well as Snail and β-catenin protein stability, transcriptional activity and invasiveness, indicating that ET-1/ETAR-induced EMT depends on ILK activity. ETAR blockade by specific antagonists, or reduction by ETAR RNA interference, reverses EMT and cell invasion by inhibiting autocrine signaling pathways. In ovarian carcinoma xenografts, the specific ETAR antagonist ABT-627 suppresses EMT determinants and tumor growth. In human ovarian cancers, ETAR expression is associated with E-cadherin downregulation, N-cadherin expression and tumor grade. In conclusion, our findings demonstrate that ETAR activation by ET-1 is a key mechanism of the complex signaling network that promotes EMT as well as ovarian cancer cell invasion. The small molecule ETAR antagonist achieves concomitant suppression of tumor growth and EMT effectors, providing a new opportunity for therapeutic intervention in which targeting ILK pathway and the related Snail and β-catenin signaling cascade via ETAR blockade may be advantageous in the treatment of ovarian cancer.
CCN6 (WISP3) as a New Regulator of the Epithelial Phenotype in Breast Cancer
Authors: Kleer Celina G. , Zhang Yanhong , Merajver Sofia D.
Published: June 2007

CCN6 (WISP3) is a cysteine-rich secreted protein that belongs to the CCN (Cyr61, CTGF, Nov) family of genes. We found that CCN6 mRNA is reduced in 80% of cases of the most lethal form of locally advanced breast cancer, inflammatory breast cancer. CCN6 contains four highly conserved motifs with sequence similarities to insulin-like growth factor binding proteins, von Willebrand type C, thrombospondin 1, and a carboxyl-terminal domain putatively involved in dimerization. CCN6 has tumor growth-, proliferation-, and invasion-inhibitory functions in breast cancer. Recently, by using a small infering RNA to downregulate CCN6 in immortalized human mammary epithelial cells, CCN6 was found to be essential to induce the process of epithelial-mesenchymal transition (EMT) with repression of E-cadherin gene expression and induction of a protein expression program characteristic of EMT. This review will focus on the current knowledge regarding the function of CCN6 in breast cancer with special emphasis on the emerging role of CCN6 as a regulator of the epithelial phenotype and E-cadherin expression in the breast.
Regulation of Extracellular Matrix Remodeling following Transforming Growth Factor-β1/Epidermal Growth Factor-Stimulated Epithelial-Mesenchymal Transition in Human Premalignant Keratinocytes
Authors: Wilkins-Port Cynthia E. , Higgins Paul J.
Published: June 2007

During tumor progression, malignant cells exploit critical developmental and tissue remodeling programs, often promoting a plastic phenotype referred to as an epithelial-mesenchymal transition (EMT). Autocrine/paracrine signaling due to tumor microenvironment cytokines, such as members of the transforming growth factor-β (TGF-β) and epidermal growth factor (EGF) families, largely regulates the morphological and invasive phases of the EMT phenotype. Notably, epithelial cell initiation often coincides with a switch in the response of these cells to TGF-β and is concomitant with EGF receptor amplification. Modeling these events, we have observed that premalignant human keratinocytes, HaCaTs, acquire a highly motile and scattered phenotype indicative of EMT following stimulation with TGF-β1 and EGF. TGF-β1 and EGF have been shown to upregulate a number of matrix metalloproteinases (MMP) in epithelial cells, which may in turn play a role in developing metastatic potential in these cells. We have established that an increase in MMP-10 expression occurs following treatment of HaCaT cells with a combination of TGF-β1 and EGF. This increase in MMP-10 expression paralleled the development of a collagenolytic phenotype that was sensitive to components of the plasminogen activation system, including the plasminogen activator inhibitor type-1 (PAI-1). Significantly high levels of MMP-10 have been detected in squamous cell carcinomas of the head and neck, esophagus, oral cavity and skin. Importantly, TGF-β1 in addition to upregulating MMP-10 has been shown to upregulate PAI-1 expression in HaCaT cells. Taken together, these observations suggest that TGF-β1 and EGF play a complex role in modulating proteolytic and transitional events such as EMT that may facilitate the progression of human premalignant epithelial cells toward a more invasive phenotype.
Complexity in Interpretation of Embryonic Epithelial-Mesenchymal Transition in Response to Transforming Growth Factor-β Signaling
Authors: Ahmed Shaheen , Nawshad Ali
Published: June 2007

Epithelial-mesenchymal transition (EMT) is a highly conserved and fundamental process that governs morphogenesis in development and may also contribute to cancer metastasis. Transforming growth factor (TGF-β) is a potent inducer of EMT in various developmental and tumor systems. The analysis of TGF-β signal transduction pathways is now considered a critically important area of biology, since many defects occur in these pathways in embryonic development. The complexity of TGF-β signal transduction networks is overwhelming due to the large numbers of interacting constituents, complicated feedforward, feedback and crosstalk circuitry mechanisms that they involve in addition to the cellular kinetics and enzymatics that contribute to cell signaling. As a result of this complexity, apparently simple but highly important questions remain unanswered, that is, how do epithelial cells respond to such TGF-β signals? System biology and cellular kinetics play a crucial role in cellular function; omissions of such a critical contributor may lead to inaccurate understanding of embryonic EMT. In this review, we identify and explain why certain conditions need to be considered for a true representation of TGF-β signaling in vivo to better understand the controlled, yet delicate mechanism of embryonic EMT.
Multiple Transforming Growth Factor-β Isoforms and Receptors Function during Epithelial-Mesenchymal Cell Transformation in the Embryonic Heart
Authors: Mercado-Pimentel Melania E. , Runyan Raymond B.
Published: June 2007

Epithelial-mesenchymal cell transformation (EMT) is a critical process during development of the heart valves. Transition of endothelial cells into mesenchymal cells in the atrioventricular (AV) canal and the outflow tract regions of the heart form the cardiac cushions that eventually form the heart valves. Collagen gel invasion assay has aided in the identification of molecules that regulate EMT. Among those, transforming growth factor-β (TGF-β) ligands and receptors demonstrate a critical role during EMT. In the chick, TGF-β ligands and some receptors have specific functions during EMT. TGF-β2 mediates endothelial cell-cell activation and separation, and TGF-β3 mediates cell invasion into the extracellular matrix. Receptors involved in the EMT process include TGF-β receptor type II (TBRII), TBRIII, endoglin and the TBRI receptors, ALK2 and ALK5. In contrast, in the mouse model, TGF-β2 is the only ligand involved in EMT. The TGF-β2 null mouse has either increased EMT or a mesenchymal cell proliferation after EMT. However, functional studies of TGF-β1 in vivo and in vitro showed that TGF-β1 functions in the EMT of the mouse AV canal. Latent TGF-β-binding protein (LTBP-1) and endoglin have a role in the EMT process. Therefore, TGF-βs mediate cardiac EMT in both embryonic species. Further studies will reveal the identification of ligand and receptor-specific activities.
Liver Fibrosis: Possible Involvement of EMT
Authors: Ikegami Tadashi , Zhang Yining , Matsuzaki Yasushi
Published: June 2007

Hepatic fibrosis is a wound-healing process in the liver with acute and chronic injury and is characterized by an excess production and deposition of extracellular matrix components. Hepatic stellate cells as well as portal fibroblasts play a pivotal role in the liver fibrogenesis. Regarding the origin of these mesenchymal cells, two hypotheses emerge. One hypothesis argues in favor of BM-derived progenitor cells and a second hypothesis favors epithelial-mesenchymal transition (EMT) in the local formation of these mesenchymal cells from hepatic epithelium. In this short review, we describe (1) the principle mechanisms of hepatic fibrosis, (2) the cells which play a crucial role in hepatic fibrosis, and (3) the possible involvement of EMT in the process of hepatic fibrosis and carcinogenesis.
The Role of Tubular Epithelial-Mesenchymal Transition in Progressive Kidney Disease
Authors: Burns W.C. , Kantharidis P. , Thomas M.C.
Published: June 2007

The accumulation of interstitial matrix represents the final common pathway of most forms of kidney disease. Much of this matrix is synthesized by interstitial myofibroblasts, recruited from resident fibroblasts and circulating precursors. In addition, a significant proportion is derived from epithelial-mesenchymal transition (EMT) of tubuloepithelial cells. The importance of EMT has been demonstrated in experimental models, where blockade of EMT attenuates renal fibrosis. Although a number of factors may initiate EMT in the kidney, the most potent is transforming growth factor-β1 (TGF-β1). Moreover, many other prosclerotic factors have effects on EMT indirectly, via induction of TGF-β1. Signaling events in this pathway include activation of Smad/integrin-linked kinase (ILK) and connective tissue growth factor (CTGF). Basement membrane integrity is also a key regulator of EMT. In particular, overexpression of matrix metalloproteinase-2 has a key role in the initiation of EMT, membrane dissolution, and the interstitial transit of transformed mesenchymal cells. Endogenous inhibitors of EMT also play an important counterregulatory role both to prevent EMT and stimulate uncommitted cells to regain their tubular phenotype (mesenchymal-epithelial transition). Such inhibitors represent a potential therapeutic approach, offering a mechanism to slow or even redress established renal fibrosis.
A Protein-Permeable Scaffold of a Collagen Vitrigel Membrane Useful for Reconstructing Crosstalk Models between Two Different Cell Types
Authors: Takezawa Toshiaki , Nitani Aya , Shimo-Oka Tadashi , Takayama Yoshiharu
Published: June 2007

Soft and turbid collagen gel disks were previously converted into strong and transparent gel membranes utilizing a concept for the vitrification of heat-denatured of proteins. This novel stable and transparent gel has been termed ‘vitrigel’. By encompassing the collagen vitrigel membrane in a nylon frame, it can be easily handled with tweezers, and functions as an excellent scaffold for three-dimensional cell culture models, as cells can be cultured on both sides. Here, we investigated the molecular permeability of the collagen vitrigel membrane in a time course-dependent manner using glucose and serum proteins. Glucose penetrated through the collagen vitrigel membrane to the opposite side, and concentrations on each side were found to be equilibrated within 24 h. Serum proteins up to a molecular weight >100 kDa also gradually passed through the collagen vitrigel membrane. In addition, human microvascular endothelial cells (HMVECs) were cultured on one surface of the collagen vitrigel membrane with a nylon frame, and human dermal fibroblasts (HDFs) or HT-29 (a human colon carcinoma cell line) cells were cocultured on the opposite surface. Histomorphological observations revealed the formation of three-dimensional crosstalk models composed of HMVECs and HDFs or HMVECs and HT-29 cells. Resulting data suggest that the protein-permeable scaffold composed of the collagen vitrigel membrane is useful for the reconstruction and/or modeling of ‘crosstalk’ between two different cells types. Hereafter, such crosstalk models in vitro could be applied to research not only of paracrine factors, but also to epithelial- or endothelial-mesenchymal transitions.
Ocular Photodynamic Therapy – Standard Applications and New Indications (Part 1)
Authors: Mennel Stefan , Barbazetto Irene , Meyer Carsten H. , Peter Silvia , Stur Michael
Published: June 2007

Ocular photodynamic therapy (PDT) was introduced as a novel treatment for neovascular forms of age-related macular degeneration and choroidal neovascularization (CNV) secondary to pathologic myopia in the mid/end 1990s. The current treatment recommendations are based on the results of two large, prospective, multicenter, randomized clinical trials (Treatment of Age-Related Macular Degeneration with Photodynamic Therapy and Verteporfin in Photodynamic Therapy Studies) and thousands of patients have been treated worldwide over the last years. Meanwhile, PDT has been performed in several other ocular pathologies with some remarkable results, however, with most reports being case reports and small case series without statistical significance. These extended applications include CNV secondary to choroiditis and retinochoroiditis, angioid streaks, central serous chorioretinopathy, retinal angiomatous proliferation, parafoveal telangiectasia or CNV associated with macular dystrophy and idiopathic CNV, as well as diseases without CNV, such as choroidal hemangioma, retinal hamartoma, choroidal melanoma, chronic central serous chorioretinopathy, angiomatous lesions secondary to systemic diseases, rubeosis iridis or neovascular glaucoma. To date, with the introduction of anti-VEGF therapy, the role of PDT will certainly change. However, it is reasonable to believe that it will maintain an important role in combination therapy due to its unique properties of selective vascular targeting. Therefore, it is essential for the ophthalmologist to be familiar with the extended applications and their modifications of treatment parameters. This review will summarize the standard and experimental applications of PDT based on our own results and the literature.
Intraobserver Repeatability of Automated versus Adjusted Optical Coherence Tomography Measurements in Patients with Neovascular Age-Related Macular Degeneration
Authors: Tatlipinar Sinan , Shah Syed Mahmood , Campochiaro Peter A. , Nguyen Quan Dong
Published: June 2007

Aim: To assess the intraobserver repeatability of automated versusadjusted optical coherence tomography (OCT) measurements in patients with neovascular age-related macular degeneration (NVAMD). Methods: Ten eyes with NVAMD from 10 consecutive patients underwent two OCT measurements within 5 days by a single operator. Automated and adjusted central 1-mm foveal thickness and automated and adjusted total macular volume were measured in each study eye. The term ‘adjusted’ refers to manually corrected values, in which the interface landmarks for measurements are selected by the operator using Stratus® scan profiling and custom software. Bland-Altman method and bootstrap comparison of intraclass correlations (ICCs) were used for repeatability analysis. Results: Bland-Altman comparison did not reveal any statistically significant difference in any parameter, when results at first and second examination were compared (p > 0.05), indicating that the repeated measurements are similar. Further analysis was conducted using the bootstrap comparison of ICCs. The difference between adjusted and automated foveal thickness ICCs (r = 0.945 and 0.635, respectively) was significant (p = 0.031), indicating higher repeatability for adjusted foveal thickness. The ICCs for adjusted and automated total macular volume (r = 0.873 and 0.863, respectively) showed no statistically significant difference (p = 0.881). Conclusion: The repeatability of adjusted retinal thickness measurements, in which the errors of retinal boundary detection by OCT analysis software is corrected by the operator using scan profiling, is found to be higher than that of automated ones in this small group of NVAMD patients when performed by a single experienced operator.
Force and Geometry Determine Structure and Function of Glaucoma Filtration Capsules
Authors: Wilcox Michael , Kadri Omar A.
Published: June 2007

Background/Aims: Glaucoma shunts vent aqueous humor to orbital tissue across a fibrous capsule. The capsule consists of collagen and fibroblasts, and its formation was assumed to be a cicatricial process. Capsule fibrosis remains the leading cause of device failure. We tested the wound healing hypothesis using morphometry and polarization microscopy and found the capsule consists not of scar tissue but rather highly organized extracellular matrix. Methods: Polarization microscopy reveals collagen orientation within the extracellular matrix. Rotation of the specimen in the plane of polarized light reveals collagen bundle orientation with respect to capsule surface geometry. Capsule thickness was measured and correlated with device dimension. Results: Capsule collagen is highly organized and not scar tissue. Relative orientation is predictable from simple engineering principles and shows tissue deposits reinforcing collagen parallel to its principle stress axes along the capsule surface. Capsule thickness and collagen orientation correlate with device dimension and surface geometry. Conclusion: The corollary is true. Geometry can be used to manage the amount, distribution and orientation of collagen and thus control hydraulic conductivity and surface area of the filtration capsule.
Diurnal Variation of the Incidence of Symptomatic Branch Retinal Vein Occlusion
Authors: Oh Jaeryung , Oh In Kyung , Huh Kuhl
Published: June 2007

Aim: To investigate the diurnal variation that is related to the incidence of branch retinal vein occlusion (BRVO). Methods: This is a cross-sectional study. 72 consecutive patients who were newly diagnosed with BRVO were precisely questioned about the time of their symptom onset. The clinical history, systemic illnesses, ocular findings, and body mass index were obtained for each patient. Results: Analysis of the diurnal variation of symptom onset showed a distribution with the peak in the period from 6 a.m. to noon compared with all the other time periods (p < 0.001). Multivariate analysis showed that involvement of the superior retina was the only factor that influenced the onset time of BRVO. Conclusion: Patients with symptomatic BRVO frequently noted their visual deterioration in the morning, which is the same as the other types of ocular and systemic vascular disease. Our results may be helpful for understanding the pathophysiology of BRVO. Our findings require conformation and further studies on this subject are certainly warranted.
Clinical and Laboratory Examinations in the Subgroups of Chronic Urticaria
Authors: Irinyi Beatrix , Széles György , Gyimesi Edit , Tumpek Judit , Herédi Emese , Dimitrios Georgitsis , Ádány Róza , Hunyadi János , Szegedi Andrea
Published: June 2007

Background: The aetiology of chronic urticaria is heterogeneous. Physical urticaria (PU) is estimated at around 35%, autoimmune urticaria (AIU) at 25% and chronic idiopathic urticaria (CIU) at 35% of all chronic urticaria cases. Methods: Differences in clinical and laboratory parameters among AIU, PU and CIU groups were examined. AIU was diagnosed if the basophil CD63 assay was positive. Demographic data, severity of symptoms and association with allergic and autoimmune diseases were analysed by the aid of a questionnaire. Immunoassays were carried out and the effectiveness of therapy was also investigated. Results: Concerning the urticaria score, AIU patients had significantly higher total urticaria scores than patients with CIU (p = 0.013), dermatographic urticaria (p = 0.05) or cholinergic urticaria (p = 0.038). Between CIU and dermatographic urticaria and between CIU and cholinergic urticaria patients, we found insignificant differences in the urticaria score (p = 0.707 and p = 0.336, respectively). AIU was more frequently associated with autoimmune diseases in the personal history (p < 0.001) and with other types of urticaria in the family history (p < 0.001). Also, anti-thyroid antibodies were more frequently detected in the AIU group. Antihistamine therapy was less effective in the AIU group (12.8%) than in the PU (70.3%) and CIU groups (68.6%), but there were no significant differences between the CIU and PU groups regarding the effectiveness of antihistamine therapy. Conclusion: The autoimmune subgroup represents the most severe form of chronic urticaria. On the other hand, there were no significant differences between the CIU and PU groups neither in urticaria scores nor in response to antihistamine therapy.
Predictive Value of Autologous Plasma Skin Test for Multiple Nonsteroidal Anti-Inflammatory Drug Intolerance
Authors: Asero Riccardo
Published: June 2007

Background: Recent studies show that patients with multiple nonsteroidal anti-inflammatory drug (NSAID) intolerance are frequently characterized by autoreactivity; this can be detected by autologous serum skin test (ASST). Objective: To assess whether the autologous plasma skin test (APST), a test that was recently shown to be more sensitive than ASST, may be usefully employed as a predictive test for multiple NSAID intolerance in patients with a history of single NSAID intolerance. Methods: Thirty otherwise normal adults with a history of acute urticaria following the ingestion of one single NSAID underwent an APST before being challenged with a COX-1-inhibiting NSAID other than the offending drug. Results: Sixteen patients experienced urticaria following the ingestion of the alternative NSAID and were therefore classified as multiple NSAID reactors; all 16 (100%) scored positive on APST. In contrast only 3/14 patients finally classified as single NSAID reactors were positive on APST (p < 0.001). The positive and negative predictive value of APST for multiple NSAID intolerance were 86 and 100%, respectively. Conclusion: In patients with a history of acute urticaria induced by a single NSAID APST can be usefully employed to detect patients that are prone to react to NSAID other than the original offending one.
Occupational Sensitization to Fungal Enzymes Used in Animal Feed Industry
Authors: Caballero María Luisa , Gómez María , González-Muñoz Miguel , Reinoso Luis , Rodríguez-Pérez Rosa , Alday Enrique , Moneo Ignacio
Published: June 2007

Background: Industrial enzymes cause the increasing prevalence of occupational hypersensitivity. Our objective was to study workers occupationally exposed to fungal enzymes in 2 animal feed factories to determine if the sensitization originated in the enzymes or was caused by the microorganism used to produce the enzymes. Methods: Eighty-six consenting workers were studied by skin prick tests with extracts from the enzymatic products handled in their factories. Positive workers were then studied by IgE immunoblotting and basophil activation was measured by flow cytometry. Results: Eight of the 86 workers analysed (9%) tested positive and were more frequently sensitized to phytase from Trichoderma and Peniophora. Glucanase and α-amylase from Bacillus amyloliquefaciens did not cause sensitization in any worker. No cross-reactions were observed between Trichoderma and Peniophora sp. phytases. Workers were sensitized to the product that they handled. Conclusions: Fungal enzymes cause occupational hypersensitivity in animal feed industries. Immunoblotting and basophil activation are useful to evaluate the effects of handling enzymes as part of the medical surveillance of enzyme-exposed workers. We describe Peniophora sp. 6-phytase as a new allergen and enzymes from Trichoderma as strong sensitizers.
Detection and Quantification of Pharaoh Ant Antigens in Household Dust Samples as Newly Identified Aeroallergens
Authors: Kim Cheol-Woo , Song Jae-Seok , Choi Soo-Young , Park Jung-Won , Hong Chein-Soo
Published: June 2007

Background:The widespread house ant, Monomorium pharaonis (pharaoh ant, PA), was recently identified as a potential cause of respiratory allergies. However, there are no reports of the distribution of PA allergens in various environments. We developed specific ELISA inhibition assays and measured the distribution and amount of PA antigens in household dust samples. Methods:Floor dust was collected at 3-month intervals from 56 homes in Seoul over a 1-year period. PA antigens in fine dusts were quantified by ELISA inhibition assays using rabbit anti-PA sera, and specific IgE to PA antigens in residents’ serum was measured by ELISA. Results: In 18 of the 56 homes (32.1%), PA antigen was detected in at least 1 floor dust sample either from the living room or the kitchen. Levels of PA antigens showed seasonal variations with peaks in autumn and winter. The detection rate of PA antigens was significantly higher in homes with visual evidence of PA infestations (70%) than in homes without such infestations (23.9%; p < 0.05). However, a significant amount of PA antigens was still detected in uninfested homes. Thirteen of 113 (11.5%) residents were positive for PA-specific IgE. PA-specific IgE was detected more frequently in residents living in PA antigen-positive homes (19.6%) than in antigen-negative homes (4.8%; p < 0.05). Conclusion: A considerable level of PA antigens is distributed in the indoor environment. Therefore, inhalant exposure to PA antigens can occur during domestic activities. These results suggest that PAs might be a significant source of aeroallergens in households.
ICD-9 CM Code 333.1 as an Identifier of Patients with Essential Tremor: A Study of the Positive Predictive Value of This Code
Authors: Louis Elan D. , Applegate LaKeisha M. , Rios Eileen
Published: June 2007

Background/Aims: Health outcomes research often uses administrative databases. Patients with the diseases of interest are identified using International Classification of Diseases (ICD-9 CM) codes. The utility of the code for essential tremor (ET), 333.1, remains untested. We determined the positive predictive value (PPV) of the code 333.1. Methods: Patients with the ICD-9 CM code 333.1 were identified from billing records at the Neurological Institute of New York. Their medical records were reviewed to determine whether they met Consensus Criteria for ET. Results: Of 964 patients who carried the code 333.1, only 472 met diagnostic criteria for ET (i.e. PPV = 49.0%). The additional use of ICD 9-CM codes for parkinsonism and dystonia (as exclusionary criteria) only marginally improved this value (57.8%). Common diagnoses among the false positives were Parkinson’s disease, dystonia, enhanced physiological tremor, drug-induced tremor, orthostatic tremor, and psychogenic tremor. Patients seen by general neurologists (vs. movement disorder specialists) were half as likely to meet diagnostic criteria for ET (34.6 vs. 51.9%, OR 0.50, 95% CI 0.23–0.70, p < 0.001). Conclusion: The code 333.1 performed poorly when attempting to identify ET cases. Given the very high prevalence of ET, a unique diagnostic code would seem to be in order.
Lifestyle plus Exercise Intervention Improves Metabolic Syndrome Markers without Change in Adiponectin in Obese Girls
Authors: Park Tae-Gon , Hong Hae-Ryen , Lee Jiyoung , Kang Hyun-Sik
Published: June 2007

Background/Aims: Little is known about whether lifestyle plus exercise intervention improves obesity, metabolic syndrome markers, and circulating adiponectin concentrations in obese girls. The goal of this study was to investigate the effects of a 12-week lifestyle plus exercise intervention on adiponectin and metabolic syndrome markers in Korean obese adolescents. Methods: A total of 44 obese adolescent girls (13–15 years old), who were recruited from a local middle school via a flyer or a school newsletter, were randomized to a lifestyle plus exercise intervention group (LIFE+EX, n = 22) or control (CON, n = 22). The LIFE+EX group participated in 12 weeks of lifestyle plus exercise intervention, while the CON group maintained their lifestyle as usual. Body composition, metabolic syndrome markers, and adiponectin were measured prior to and after the intervention program. Results: Following the 12-week lifestyle plus exercise intervention, group analyses showed significant time × group interactions in changed scores in several of the metabolic syndrome markers such that the LIFE+EX group had significantly greater improvements in body composition including body weight, body mass index, percent body fat, waist circumference, and waist-to-hip ratio than the CON group. Similarly, the LIFE+EX group had significantly greater reductions in SBP, TC, LDLC, TG, TC/HDLC, glucose, insulin, HOMA-IR, CRP, and leptin than the CON group, while there were no significant time × group or time or group differences in DBP, HDLC, HbA1c, and adiponectin. Conclusion: The current findings suggest that lifestyle plus exercise intervention may be an effective means to improve several variables in the health hazards of obesity in Korean adolescent girls, with no change in circulating adiponectin.
A Comparative Study of Iron Bioavailability from Cocoa Supplemented with Ferric Pyrophosphate or Ferrous Fumarate in Rats
Authors: Navas-Carretero S. , Sarriá B. , Pérez-Granados A.M. , Schoppen S. , Izquierdo-Pulido M. , Vaquero M.P.
Published: June 2007

Background: Food iron fortification can be a good strategy to prevent iron deficiency. Iron bioavailability from cocoa powder enriched with ferric pyrophosphate encapsulated in liposomes or ferrous fumarate was assessed in rats. Methods: Three groups of rats consumed during 28 days either a control diet or two diets prepared with ferric pyrophosphate- or ferrous fumarate-enriched cocoa powder as the unique source of iron. Body weight and food intake were monitored and last-week feces were collected. On day 28, animals were sacrificed and livers and spleens were removed. Hemoglobin and total iron binding capacity (TIBC) were determined. Results: There were no significant differences in body weight and food intake. Apparent iron absorption and % absorption/intake were significantly lower in rats consuming enriched cocoa compared to the control group, without significant differences due to the iron form. Enriched cocoa groups showed significantly lower spleen iron content and concentration than the control. Liver iron was lower in the ferric pyrophosphate group compared to the other two groups. Hemoglobin and TIBC values showed a deficient iron status in ferric pyrophosphate rats. Conclusion: Cocoa powder is a good vehicle for iron fortification when enriched with ferrous fumarate compared to ferric pyrophosphate encapsulated in liposomes.
Factor Analysis of Cardiovascular Risk Clustering in Pediatric Metabolic Syndrome: CASPIAN Study
Authors: Kelishadi Roya , Ardalan Gelayol , Adeli Khosrow , Motaghian Molouk , Majdzadeh Reza , Mahmood-Arabi Minoo Sadat , Delavari Alireza , Riazi Mohammad Mehdi , Namazi Roshanak , Ramezani Mohammad Arash
Published: June 2007

Aims: To assess the results of factor analysis of coronary artery disease risk factors in a large national representative sample of children, and to compare its results on the variables measured between those with or without metabolic syndrome (MetS). Methods: This cross-sectional multicenter population survey was conducted on 4,811 nationally representative school students aged 6–18 years. MetS was defined based on criteria analogous to the Adult Treatment Panel III. Factor analysis by principle components analysis and Varimax rotation was carried out to cluster risk factors. Results: MetS was present in 14.1% of subjects (n = 678).From the nine variables assessed, factor analysis of the z scores of variables show that in all age groups, three similar factors were loaded: lipids, adiposity, and blood pressure, that accounted for 87.4–90.8% of the variance. Three factors were loaded in those with MetS (cholesterol/TG, metabolic/adiposity, and blood pressure) (65.9% of variance); and four factors (cholesterol, metabolic, adiposity, and blood pressure) were loaded among those without the MetS (75.6% of variance). We did not find a central feature that underlies all three factors among children with the MetS; however, waist circumference was the only variable that was loaded for two factors. Conclusion: These findings support a change in the concept of MetS from that of a single entity to one that represents several distinct but intercorrelated entities. An approach to assessing risk clustering from early life, and longitudinal studies that would elucidate how these various risk domains interact over time are needed.