bluuebunny/crossref_metadata_2025 huggingface dataset:
KiSS-1 in the mammalian ovary: distribution of kisspeptin in human and marmoset and alterations in KiSS-1 mRNA levels in a rat model of ovulatory dysfunction
Authors: Gaytán F. , Gaytán M. , Castellano J. M. , Romero M. , Roa J. , Aparicio B. , Garrido N. , Sánchez-Criado J. E. , Millar R. P. , Pellicer A. , Fraser H. M. , Tena-Sempere M.
Published: January 2009

Kisspeptins, the products of the KiSS-1 gene acting via G protein-coupled receptor 54 (GPR54), have recently emerged as pivotal signals in the hypothalamic network triggering the preovulatory surge of gonadotropins and, hence, ovulation. Additional actions of kisspeptins at other levels of the hypothalamic-pituitary-ovarian axis have been suggested but remain to date scarcely studied. We report herein the pattern of expression of KiSS-1 and GPR54 in the human and nonhuman primate ovary and evaluate changes in ovarian KiSS-1 expression in a rat model of ovulatory dysfunction. KiSS-1 and GPR54 mRNAs were detected in human ovarian tissue and cultured granulosa-lutein cells. In good agreement, kisspeptin immunoreactivity was observed in cyclic human and marmoset ovaries, with prominent signals in the theca layer of growing follicles, corpora lutea, interstitial gland, and ovarian surface epithelium. GPR54 immunoreactivity was also found in human theca and luteal cells. Administration of indomethacin to cyclic female rats disturbed ovulation and resulted in a dramatic drop in ovarian KiSS-1, but not GPR54, cyclooxygenase-2 (COX-2), or progesterone receptor, mRNA levels at the time of ovulation; an effect mimicked by the selective COX-2 inhibitor NS398 and rescued by coadministration of PGE2. Likewise, the stimulatory effect of human choriogonadotropin on ovarian KiSS-1 expression was partially blunted by indomethacin. In contrast, KiSS-1 mRNA levels remained unaltered in another model of ovulatory failure, i.e., the RU486-treated rat. In summary, we document for the first time the expression of KiSS-1/kisspeptin and GPR54 in the human and nonhuman primate ovary. In addition, we provide evidence for the ability of inhibitors of COX-2, known to disturb follicular rupture and ovulation, to selectively alter the expression of KiSS-1 gene in rat ovary. Altogether, our results are suggestive of a conserved role of local KiSS-1 in the direct control of ovarian functions in mammals.
Anaphylatoxin C5a contributes to the pathogenesis of cisplatin-induced nephrotoxicity
Authors: Pan Hao , Shen Zhoujun , Mukhopadhyay Partha , Wang Hua , Pacher Pal , Qin Xuebin , Gao Bin
Published: January 2009

Nephrotoxicity is a common complication of cisplatin chemotherapy that limits its clinical use; however, the mechanisms underlying cisplatin-mediated nephrotoxicity are not fully understood. In this study, we investigated the role of anaphylatoxin C5a in the pathogenesis of cisplatin-mediated nephrotoxicity. Our data show that cisplatin-induced renal injury is significantly reduced in C5- or C5aR-deficient mice. However, pretreatment with C5 or C5a restores sensitivity to cisplatin-induced nephrotoxicity in C5-deficient mice. In wild-type mice, administration of cisplatin triggers the increased renal expression of multiple cytokines and caspases. This induction is diminished in C5-deficient mice, which is restored by pretreatment with C5 or C5a proteins. Interestingly, renal injury induced by cisplatin is similar between wild-type and CD59ab double knockout mice, and the formation of membrane attack complexes (MACs) by cisplatin in the kidney is diminished in C5-deficient mice, but not in C5aR-deficient mice. In conclusion, our findings suggest that C5a plays an important role in the pathogenesis of cisplatin nephrotoxicity. Likely, C5a binds to C5aR, leading to induction of proinflammatory cytokines and inflammation. The formation of MACs does not appear to contribute to the nephrotoxicity of cisplatin based on our study results.
Modulatory Effects of Serotonin on GABAergic Synaptic Transmission and Membrane Properties in the Deep Cerebellar Nuclei
Authors: Saitow Fumihito , Murano Mitsumasa , Suzuki Hidenori
Published: January 2009

Cerebellar outputs from the deep cerebellar nuclei (DCN) are critical for generating and controlling movement. DCN neuronal activity is primarily controlled by GABAergic inhibitory transmission by Purkinje cells in the cerebellar cortex and is also modulated by nerve inputs originating from other brain regions within and outside the cerebellum. In this study, we examined the modulatory effects of 5-HT on GABAergic synapses in the DCN. 5-HT decreased the amplitude of stimulation-evoked inhibitory postsynaptic currents (eIPSCs) in DCN neurons, and this effect was abolished by a 5-HT1B antagonist, SB 224289. The decrease in IPSC amplitude was associated with an increased paired-pulse ratio of the IPSC. 5-HT also decreased the frequency of miniature IPSCs without altering the amplitude. These data suggest that 5-HT presynaptically inhibited GABA release. Furthermore, 5-HT elicited a slow inward current in DCN neurons. Pharmacological studies showed that 5-HT activated the 5-HT5 receptor, which is positively coupled to G protein and elicited the slow inward current through enhancement of hyperpolarization-activated cation channel activation. Finally, we examined the effects of 5-HT on the spike generation that accompanies repetitive stimulation of inhibitory synapses. 5-HT increased the spontaneous firing rate in DCN neurons caused by depolarization. Increase in the 5-HT–induced tonic firing relatively decreased the contrast difference from the rebound depolarization-induced firing. However, the inhibitory transmission-induced silencing of DCN firing remained during the conditioning stimulus. These results suggest that 5-HT plays a regulatory role in spike generation and contributes to the gain control of inhibitory GABAergic synapses in DCN neurons.
Striatal Versus Hippocampal Representations During Win-Stay Maze Performance
Authors: Berke Joshua D. , Breck Jason T. , Eichenbaum Howard
Published: January 2009

The striatum and hippocampus are widely held to be components of distinct memory systems that can guide competing behavioral strategies. However, some electrophysiological studies have suggested that neurons in both structures encode spatial information and may therefore make similar contributions to behavior. In rats well trained to perform a win-stay radial maze task, we recorded simultaneously from dorsal hippocampus and from multiple striatal subregions, including both lateral areas implicated in motor responses to cues and medial areas that work cooperatively with hippocampus in cognitive operations. In each brain region, movement through the maze was accompanied by the continuous sequential activation of sets of projection neurons. Hippocampal neurons overwhelmingly were active at a single spatial location (place cells). Striatal projection neurons were active at discrete points within the progression of every trial—especially during choices or following reward delivery—regardless of spatial position. Place-cell–type firing was not observed even for medial striatal cells entrained to the hippocampal theta rhythm. We also examined neural coding in earlier training sessions, when rats made use of spatial working memory to guide choices, and again found that striatal cells did not show place-cell–type firing. Prospective or retrospective encoding of trajectory was not observed in either hippocampus or striatum, at either training stage. Our results indicate that, at least in this task, dorsal hippocampus uses a spatial foundation for information processing that is not substantially modulated by spatial working memory demands. By contrast, striatal cells do not use such a spatial foundation, even in medial subregions that cooperate with hippocampus in the selection of spatial strategies. The progressive dominance of a striatum-dependent strategy does not appear to be accompanied by large changes in striatal or hippocampal single-cell representations, suggesting that the conflict between strategies may be resolved elsewhere.
Intrathalamic Mechanisms of Visual Attention
Authors: Mayo J. Patrick
Published: January 2009

The classical model of visual processing emphasizes the lateral geniculate nucleus (LGN) as the major intermediary between the retina and visual cortex. Yet, anatomical findings inspired Francis Crick to suggest an alternative model in which the thalamic reticular nucleus, which envelops the LGN, acts as the “guardian” of visual cortex by modulating LGN activity. Recent work by McAlonan and colleagues supports Crick's hypothesis, thereby enhancing our understanding of the early stages of visual processing.
Clustering Objects Described by Juxtaposition of Binary Data Tables
Authors: Rebbouh Amar
Published: January 2009

This paper seeks to develop an allocation of 0/1 data matrices to physical systems upon a Kullback-Leibler distance between probability distributions. The distributions are estimated from the contents of the data matrices. We discuss an ascending hierarchical classification method, a numerical example and mention an application with survey data concerning the level of development of the departments of a given territory of a country.
Suppressive Effect of Hydroquinone, a Benzene Metabolite, on In Vitro Inflammatory Responses Mediated by Macrophages, Monocytes, and Lymphocytes
Authors: Cho Jae Youl
Published: January 2009

We investigated the inhibitory effects of hydroquinone on cytokine release, phagocytosis, NO production, ROS generation, cell‐cell/cell fibronectin adhesion, and lymphocyte proliferation. We found that hydroquinone suppressed the production of proinflammatory cytokines [tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β, and IL‐6], secretion of toxic molecules [nitric oxide (NO) and reactive oxygen species (ROS)], phagocytic uptake of FITC‐labeled dextran, upregulation of costimulatory molecules, U937 cell‐cell adhesion induced by CD18 and CD29, and the proliferation of lymphocytes from the bone marrow and spleen. Considering that (1) environmental chemical stressors reduce the immune response of chronic cigarette smokers and children against bacterial and viral infections and that (2) workers in petroleum factories are at higher risk for cancer, our data suggest that hydroquinone might pathologically inhibit inflammatory responses mediated by monocytes, macrophages, and lymphocytes.
Proteasome-Mediated Degradation and Functions of Hematopoietic Progenitor Kinase 1 in Pancreatic Cancer
Authors: Wang Hua , Song Xianzhou , Logsdon Craig , Zhou Guisheng , Evans Douglas B. , Abbruzzese James L. , Hamilton Stanley R. , Tan Tse-Hua , Wang Huamin
Published: January 2009

Hematopoietic progenitor kinase 1 (HPK1) regulates stress responses, proliferation, and apoptosis in hematopoietic cells. In this study, we examined the expression, regulation, and functions of HPK1 in pancreatic ductal adenocarcinomas (PDA). We found that loss of HPK1 protein expression correlated significantly with the progression of pancreatic intraepithelial neoplasias (P = 0.001) and development of invasive PDA. Similarly, HPK1 protein was not expressed in any of eight PDA cell lines examined but was expressed in immortalized human pancreatic duct epithelial (HPDE) cells. There was no difference in HPK1 mRNA levels in PDA cell lines or primary PDA compared with those in HPDE cells or ductal epithelium in chronic pancreatitis and normal pancreas, respectively. Treatment of Panc-1 cells with a proteasome inhibitor, MG132, increased the HPK1 protein levels in a dose-dependent manner, suggesting that alteration in proteasome activity contributes to the loss of HPK1 protein expression in pancreatic cancer. Like the endogenous HPK1, both wild-type HPK1 and its kinase-dead mutant, HPK1-M46, overexpressed in Panc-1 cells, were also targeted by proteasome-mediated degradation. After MG132 withdrawal, wild-type HPK1 protein expression was markedly decreased within 24 hours, but kinase-dead HPK1 mutant protein expression was sustained for up to 96 hours. Therefore, HPK1 kinase activities were required for the loss of HPK1 protein in PDAs. Furthermore, restoring wild-type HPK1 protein in PDA cells led to the increase in p21 and p27 protein expression and cell cycle arrest. Thus, HPK1 may function as a novel tumor suppressor and its loss plays a critical role in pancreatic cancer. [Cancer Res 2009;69(3):1063–70]
Role of Vitamin D Receptor in the Antiproliferative Effects of Calcitriol in Tumor-Derived Endothelial Cells and Tumor Angiogenesis In vivo
Authors: Chung Ivy , Han Guangzhou , Seshadri Mukund , Gillard Bryan M. , Yu Wei-dong , Foster Barbara A. , Trump Donald L. , Johnson Candace S.
Published: January 2009

Calcitriol (1,25-dihydroxycholecalciferol), the major active form of vitamin D, is antiproliferative in tumor cells and tumor-derived endothelial cells (TDEC). These actions of calcitriol are mediated at least in part by vitamin D receptor (VDR), which is expressed in many tissues including endothelial cells. To investigate the role of VDR in calcitriol effects on tumor vasculature, we established TRAMP-2 tumors subcutaneously into either VDR wild-type (WT) or knockout (KO) mice. Within 30 days post-inoculation, tumors in KO mice were larger than those in WT (P < 0.001). TDEC from WT expressed VDR and were able to transactivate a reporter gene whereas TDEC from KO mice were not. Treatment with calcitriol resulted in growth inhibition in TDEC expressing VDR. However, TDEC from KO mice were relatively resistant, suggesting that calcitriol-mediated growth inhibition on TDEC is VDR-dependent. Further analysis of the TRAMP-C2 tumor sections revealed that the vessels in KO mice were enlarged and had less pericyte coverage compared with WT (P < 0.001). Contrast-enhanced magnetic resonance imaging showed an increase in vascular volume of TRAMP tumors grown in VDR KO mice compared with WT mice (P < 0.001) and FITC-dextran permeability assay suggested a higher extent of vascular leakage in tumors from KO mice. Using ELISA and Western blot analysis, there was an increase of hypoxia-inducible factor-1α, vascular endothelial growth factor, angiopoietin 1, and platelet-derived growth factor-BB levels observed in tumors from KO mice. These results indicate that calcitriol-mediated antiproliferative effects on TDEC are VDR-dependent and loss of VDR can lead to abnormal tumor angiogenesis. [Cancer Res 2009;69(3):967–75]
MicroRNA Regulation of DNA Repair Gene Expression in Hypoxic Stress
Authors: Crosby Meredith E. , Kulshreshtha Ritu , Ivan Mircea , Glazer Peter M.
Published: January 2009

Genetic instability is a hallmark of cancer; the hypoxic tumor microenvironment has been implicated as a cause of this phenomenon. MicroRNAs (miR) are small nonprotein coding RNAs that can regulate various cellular pathways. We report here that two miRs, miR-210 and miR-373, are up-regulated in a hypoxia-inducible factor-1α–dependent manner in hypoxic cells. Bioinformatics analyses suggested that these miRs could regulate factors implicated in DNA repair pathways. Forced expression of miR-210 was found to suppress the levels of RAD52, which is a key factor in homology-dependent repair (HDR); the forced expression of miR-373 led to a reduction in the nucleotide excision repair (NER) protein, RAD23B, as well as in RAD52. Consistent with these results, both RAD52 and RAD23B were found to be down-regulated in hypoxia, but in both cases, the hypoxia-induced down-regulation could be partially reversed by antisense inhibition of miR-210 and miR-373. Importantly, luciferase reporter assays indicated that miR-210 is capable of interacting with the 3′ untranslated region (UTR) of RAD52 and that miR-373 can act on the 3′ UTR of RAD23B. These results indicate that hypoxia-inducible miR-210 and miR-373 play roles in modulating the expression levels of key proteins involved in the HDR and NER pathways, providing new mechanistic insight into the effect of hypoxia on DNA repair and genetic instability in cancer. [Cancer Res 2009;69(3):1221–9]
Transforming Growth Factor-β2 Is a Molecular Determinant for Site-Specific Melanoma Metastasis in the Brain
Authors: Zhang Chenyu , Zhang Fahao , Tsan Rachel , Fidler Isaiah J.
Published: January 2009

Murine melanomas produce site-specific experimental brain metastases that reflect clinical reality. When injected into the internal carotid artery of mice, K-1735 melanoma cells produce metastatic lesions only in the brain parenchyma, whereas B16 melanoma cells and the somatic hybrid cells of B16 × K-1735 melanoma cells produce metastatic lesions only in the leptomeninges and ventricles. In the present study, we identified transforming growth factor-β2 (TGF-β2), an isoform of the TGF-β family, as a molecular determinant of melanoma cell growth in the brain parenchyma. We found that the TGF-β2 mRNA was highly expressed by the K-1735 cells, whereas the B16 cells or any B16 × K-1735 somatic cell-cell fusion hybrids have low expression. Transfection of the TGF-β2 gene into B16 cells resulted in the production of microscopic metastatic lesions in the brain parenchyma, without a decrease in metastasis to the leptomeninges or ventricles. TGF-β2 knockdown in the K-1735 melanoma cells significantly reduced metastasis to the brain parenchyma but did not induce metastasis to the leptomeninges or ventricles. These data show that TGF-β2 expression by murine melanoma cells is necessary for the establishment and growth of metastases in the brain parenchyma. [Cancer Res 2009;69(3):828–35]
IFN-α–Induced Apoptosis in Hepatocellular Carcinoma Involves Promyelocytic Leukemia Protein and TRAIL Independently of p53
Authors: Herzer Kerstin , Hofmann Thomas G. , Teufel Andreas , Schimanski Christoph C. , Moehler Markus , Kanzler Stephan , Schulze-Bergkamen Henning , Galle Peter R.
Published: January 2009

IFNs are pleiotropic cytokines that have been shown to be important regulators of cell growth. IFN-α has recently been recognized to harbor therapeutic potential in prevention and treatment of hepatocellular carcinoma (HCC). However, HCC cells respond differentially to IFN treatment, the mechanism of which is largely unknown. To address this issue, we analyzed the effect of IFN-α on different liver tumor cell lines.

We found that growth inhibiting effects of IFN-α in hepatoma cells require PML-NB induction and, moreover, tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) expression on the mRNA and protein level. RNAi silencing of PML down-regulates TRAIL expression in hepatoma cells and correspondingly blocks IFN-α–induced apoptosis. In addition, PML-deficient primary hepatocytes fail to up-regulate TRAIL upon IFN-α-treatment in contrast to their wild-type counterparts. These data identify TRAIL as a novel downstream transcriptional target of PML-mediated apoptosis in hepatomas and suggest that PML and TRAIL play important roles in IFN-regulated apoptosis in HCC. Furthermore, the mechanism is independent of the p53 status of the tumor cells. In summary, our results identify central molecules mediating IFN-α induced apoptosis in liver tumors, shed light on the differential response of hepatoma cells to IFN exposure and, thus, may contribute to an efficient application of this substance in the treatment of liver cancer. [Cancer Res 2009;69(3):855–62]
Light Scattering Measurements of Subcellular Structure Provide Noninvasive Early Detection of Chemotherapy-Induced Apoptosis
Authors: Chalut Kevin J. , Ostrander Julie Hanson , Giacomelli Michael G. , Wax Adam
Published: January 2009

We present a light scattering study using angle-resolved low coherence interferometry (a/LCI) to assess nuclear morphology and subcellular structure within MCF-7 cells at several time points after treatment with chemotherapeutic agents. Although the nuclear diameter and eccentricity are not observed to change, the light scattering signal reveals a change in the organization of subcellular structures that we interpret using fractal dimension (FD). The FD of subcellular structures in cells treated with paclitaxel and doxorubicin is observed to increase significantly compared with that of control cells as early as 1.5 and 3 hours after application, respectively. The FD is then found to decrease slightly at 6 hours postapplication for both agents only to increase again from 12 to 24 hours posttreatment when the observations ceased. The changes in structure appear over two time scales, suggesting that multiple mechanisms are evident in these early apoptotic stages. Indeed, quantitative image analysis of fluorescence micrographs of cells undergoing apoptosis verifies that the FD of 4′,6-diamidino-2-phenylindole–stained nuclear structures does not change significantly in cells until 12 hours after treatment, whereas that of MitoTracker stained mitochondria is seen to modulate as early as 3 hours after treatment. In contrast, cells receiving an increased dose of paclitaxel that induced G2-M arrest, but not apoptosis, only exhibited the early change in subcellular structure but did not show the later change associated with changes in nuclear substructure. These results suggest that a/LCI may have utility in detecting early apoptotic events for both clinical and basic science applications. [Cancer Res 2009;69(3):1199–204]
El impacto de las vacunas en países con bajos ingresos y países con altos ingresos
Authors: Gothefors Leif
Published: January 2009

La vacunación ha llegado a ser la medida sanitaria más efectiva para el control de las enfermedades infecciosas después de la disponibilidad de agua potable limpia. La historia de la vacunación está marcada por grandes esperanzas y algunas decepciones. En particular, la segunda mitad del siglo XX ha sido testigo del desarrollo de notables proyectos de vacunación. Aunque existe la posibilidad de que la poliomielitis y el sarampión puedan ser erradicados en el curso de unos pocos años, casi tres millones de personas, habitualmente niños menores de 5 años, fallecen cada año por enfermedades que son evitables por medio de vacunas. Los países en vías de desarrollo se están esforzando para obtener las vacunas para niños que las necesitan desesperadamente. No obstante, en Europa y Norteamérica, la población llega a ser descuidada con respecto a las vacunas: ‘Estas enfermedades ya no constituyen una amenaza y la vacuna es más peligrosa que la enfermedad’. Estos conceptos erróneos han causado brotes de sarampión, difteria y tos ferina. La comunidad internacional debe seguir dedicando los recursos, fondos y potencial humano necesarios para aprovechar plenamente la promesa de que las vacunas sustentan el alivio de la miseria humana.
Investigación translacional para generar datos a favor de la introducción racional y eficiente de vacunas nuevas en países en vías de desarrollo: La experiencia del Instituto Internacional de Vacunas
Authors: Clemens John
Published: January 2009

En los últimos años, la introducción de vacunas nuevas en países opulentos ha tenido lugar a un ritmo asombroso. En comparación, se han introducido pocas vacunas de nueva generación en los programas de salud pública para los pobres de los países en vías de desarrollo, y para aquéllos que sí los tienen, la introducción ha sido penosamente lenta. Los recursos financieros limitados han retrasado la introducción. La lentitud también se debe a una escasez de datos necesarios para adoptar decisiones políticas racionales. El apoyo inadecuado para realizar estudios de fase 1 con candidatos vacunales orientados a enfermedades en países en vías de desarrollo es un obstáculo bien conocido. Además, se precisan otros tipos de investigación translacional para generar las pruebas necesarias para establecer una política. Se ha observado que numerosas vacunas actúan con menos eficacia en poblaciones empobrecidas del mundo en fase de desarrollo que en personas que residen en países más opulentos. En consecuencia, los ensayos de fase 2 y fase 3 constituyen un segundo tipo esencial de investigación translacional necesaria para la introducción de vacunas en países en vías de desarrollo. Por otra parte, incluso para las vacunas que obtienen la aprobación a través de ensayos clínicos en países en vías de desarrollo, pueden persistir dudas acerca de si la carga de patología justifica la introducción de la vacuna, si la administración de la vacuna en programas sanitarios será rentable, si la introducción de la vacuna será programáticamente factible y aceptable y si la introducción de la vacuna será financieramente sostenible. Para abordar estas dudas residuales es imprescindible un tercer tipo de investigación translacional. Desde sus comienzos, en 1987, el Instituto Internacional de Vacunas, una organización de investigación y desarrollo internacional sin afán de lucro, ubicada en Seúl, Corea, ha realizado investigación translacional con la introducción de nuevas vacunas para muy diversas enfermedades en 22 países de Asia, África, y América Latina. En este trabajo describimos los proyectos de investigación translacional emprendidos por el Instituto Internacional de Vacunas y las lecciones aprendidas sobre estrategias para incrementar el impacto de la investigación translacional sobre la política vacunal para el mundo en vías de desarrollo.
High Maternal Plasma Antioxidant Concentrations Associated with Preterm Delivery
Authors: Joshi Sadhana R. , Mehendale Savita S. , Dangat Kamini D. , Kilari Anitha S. , Yadav Hemlata R. , Taralekar Vaishali S.
Published: January 2009

Background/Aims: Our earlier study has shown that increased maternal oxidative stress and reduced antioxidants like vitamin E and C play an important role in fetal growth in preeclampsia. However, the role of antioxidants and their effects on gestation and birth outcome in normotensive pregnancies are not conclusive. The present study examined plasma malondialdehyde as a marker of oxidative stress and antioxidant concentrations (vitamins E and C) in maternal as well as in cord blood samples in normotensive women who delivered both preterm and at term. Methods: 140 normotensive pregnant women were recruited at Bharati Medical Hospital, Pune, India, during the year 2007. Maternal and cord samples were examined for oxidative stress levels and vitamin C and E concentrations in women who delivered preterm (n = 40) and at term (n = 100). Mean values were compared with those of women delivering at term using the t test. Results: Increased (p < 0.05) oxidative stress was seen in preterm mothers as well as in cord samples. Preterm mothers had higher vitamin C concentrations (p < 0.05), and these were positively associated with oxidative stress (p = 0.02). Vitamin E levels were comparable between groups. Conclusions: Increased maternal circulating vitamin C concentrations and increased oxidative stress are associated with preterm delivery.
Rapid Quantification of Aortic Lesions in ApoE–/– Mice
Authors: Beattie John H. , Duthie Susan J. , Kwun In-Sook , Ha Tae-Youl , Gordon Margaret-Jane
Published: January 2009

The quantification of aortic lesions is an important end-point analysis for evaluating atherogenesis in mouse models of atherosclerosis. Morphometric methods involving the staining of aorta with a Sudan lysochrome followed by image analysis of the stained lesion area are commonly used. We have developed a more rapid method involving solubilisation of the stain retained by aortic lesions. In 2 separate studies, 5-week-old male apoE–/– and C57BL/6 wild-type (apoE+/+) mice were given a high fat (21%), Western-type diet for 13, 15 or 25 weeks. At study termination, the descending thoracic aorta (DA) and/or aortic arch (AA) were stained with Oil Red O (ORO). The incorporated stain was extracted using chloroform/methanol (2:1) solvent and quantified by spectrophotometry at 520 nm. In study 1 (13 weeks), ORO stain in the AA and DA of apoE–/– mice was 1.9 and 1.4 times higher than background staining of apoE+/+ aorta tissue, respectively. At 15 and 25 weeks (study 2), ORO stain in the AA of apoE–/– mice was 1.9 and 2.5 times higher than the background, respectively. We conclude that the ORO solubilisation technique applied to AA samples is a very useful and rapid method for atherosclerotic lesion quantification.
Correlation between Retina Blood Flow Velocity Assessed by Retinal Function Imager and Retina Thickness Estimated by Scanning Laser Ophthalmoscopy/Optical Coherence Tomography
Authors: Landa Gennady , Garcia Patricia M.T. , Rosen Richard B.
Published: January 2009

Purpose: The purpose of this study was to evaluate the correlation between the retinal blood flow (RBF) assessed by the retinal functional imager (RFI) and central macular thickness/volume assessed by a spectral scanning laser ophthalmoscopy/optical coherence tomography (SLO-OCT) system. Methods: Seventeen eyes of 14 consecutive patients with various ocular diseases were examined. Retinal blood circulation characteristics were measured using the RFI. Retinal thickness/volume parameters were obtained by SLO-OCT. Analysis of correlation between RBF velocity and SLO-OCT findings was performed. Results: The analysis of the correlation between RBF and central retinal thickness/volume (5 × 5 mm grid pattern) showed a strong correlation between the average venous RBF velocity and central retinal volume. A linear relationship between the retinal blood velocity in veins and center, middle ring, outer ring and total central squares of macular volume [correlation coefficient 0.86 (p = 0.00001); 0.89 (p = 0.000001); 0.82 (p = 0.0004); 0.85 (p = 0.00001), respectively] has been observed. Arterial blood flow velocity did not correlate with thickness and with central retinal volume. Conclusions: Venous RBF, analyzed by the RFI, significantly correlated with the volume of the central retina, measured by SLO-OCT. Venous blood velocity increased linearly with the increase in the central retinal volume. In this small study, assessment using the RFI provides useful information and may contribute to the further understanding of hemodynamics in the retina blood vessels. The RFI shows promise of being able to analyze retinal hemodynamics noninvasively and may contribute to the further understanding of the relationship between retinal thickening and function.
Human Chorionic Gonadotropin in Cervicovaginal Secretions as a Predictor of Preterm Birth
Authors: Rengaraj Gayathri , Guleria Kiran , Suneja Amita , Gambhir Jasvinder K.
Published: January 2009

Objective: To compare the qualitative (QL) and quantitative (QN) levels of βhCG in cervicovaginal secretions as predictors of preterm birth. Methods: The study included 100 women. QL and QN assays were done with velocit kit and ELISA, respectively. Results: A positive QL assay had sensitivity of 78%, specificity 95%, positive predictive value (PPV) 90%, negative predictive value (NPV) 88% and odds ratio (OR) = 70.87 (95% CI = 18.50, 271.50). The likelihood ratios (LRs) for positive and negative tests were 15.6 and 0.06, respectively. Using a cutoff value of 34.5 mIU/ml, the QN assay had sensitivity of 86%, specificity 86%, PPV 78% and NPV 92%, OR = 36.90 (95% CI = 10.79, 126.15). The LRs for positive and negative tests were 6.14 and 0.16, respectively. Conclusion: The simple and cheaper QL βhCG test is a better predictor of preterm birth as compared to the QN test.
Association of Leptin with Hemodialysis-Related Muscle Cramps: A Cross-Sectional Study
Authors: Hung Chung-Ying , Chen Yung-Liang , Chen Chiou-Shya , Yang Chwei-Shiun , Peng Sheng-Jeng
Published: January 2009

Background/Aims: The mechanism of muscle cramp in hemodialysis patients is not well understood. Leptin, a middle molecule uremic toxin, is able to affect neuronal activity. This study aimed to determine the association between leptin and hemodialysis-related muscle cramps. Methods: A total of 79 hemodialysis patients were enrolled. The episodes of hemodialysis-related muscle cramps were recorded over a 28-day period. Serum levels of leptin were measured on the 15th day, a mid-week dialysis session. Results: Frequent hemodialysis-related cramps were associated with old age and elevated serum leptin levels. The risk of frequent hemodialysis-related cramps increased with increasing tertiles of leptin concentration. This relationship remained significant after adjustment for age, mean ultrafiltration ratio, gender, body mass index, insulin, resistin, c-reactive protein, albumin, peripheral arterial disease, electrolytes, and β2-microglobulin. Conclusion: Leptin levels are associated with frequent hemodialysis-related cramps. Further studies are necessary to elucidate the underlying mechanisms.
Dislocation of a Double-Lumen Tunneled Hemodialysis Catheter Causing Dysfunction and Bleeding
Authors: Haid B. , Zitt E. , Meusburger E. , Wöss E. , Lhotta K.
Published: January 2009

Dislocation of tunneled hemodialysis catheters is rare. This report describes displacement of a split catheter with the tip of the arterial limb outside and the venous limb inside the jugular vein. Use of the catheter with the limbs in inverse fashion caused severe hemorrhage along the catheter tunnel. To avoid this complication, a short subcutaneous catheter tunnel is recommended in adipose patients.
Renal Manifestations and Visceral Adiposity in Apparently Healthy Korean Women
Authors: Lee Ji-Won , Bae Urhee , Lee Duk-Chul , Lee Hye-Ree , Shim Jae-Yong , Linton John A.
Published: January 2009

Aims: It was the aim of this study to investigate the relationship between normal renal function – estimated glomerular filtration rate (GFR) – and visceral adiposity measured by CT in apparently healthy Korean women. Methods: A total of 425 apparently healthy women were recruited. We assessed body composition with CT and divided the study population into 2 groups based on fat distribution: the visceral fat dominant group and the subcutaneous fat dominant group. GFR was estimated using the abbreviated Modification of Diet in Renal Disease and quadratic equation. Results: After adjustment for age, mean blood pressure, body mass index, fasting glucose, homeostasis model assessment of the insulin resistance index, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, high-sensitivity C-reactive protein levels, and mean brachial-ankle pulse wave velocity, the visceral fat dominant group showed significantly lower GFR levels compared with the subcutaneous fat dominant group. The GFR level was negatively correlated with visceral fat areas after adjustment for age. By stepwise multiple regression analysis, age, triglyceride and visceral fat areas independently affected GFR levels. Conclusion: Our study shows that even in apparently healthy women, visceral fat seems to be an important contributor to renal impairment. Further studies on the causality between visceral adiposity and renal function are warranted.
A Mutation in the Mouse Chd2 Chromatin Remodeling Enzyme Results in a Complex Renal Phenotype
Authors: Marfella Concetta G.A. , Henninger Nils , LeBlanc Scott E. , Krishnan Namrata , Garlick David S. , Holzman Lawrence B. , Imbalzano Anthony N.
Published: January 2009

Background and Aims: Glomerular diseases are the third leading cause of kidney failure worldwide, behind only diabetes and hypertension. The molecular mechanisms underlying the cause of glomerular diseases are still largely unknown. The identification and characterization of new molecules associated with glomerular function should provide new insights into understanding the diverse group of glomerular diseases. The Chd2 protein belongs to a family of enzymes involved in ATP-dependent chromatin remodeling, suggesting that it likely functions as an epigenetic regulator of gene expression via the modification of chromatin structure. Methods: In this study, we present a detailed histomorphologic characterization of mice containing a mutation in the chromodomain helicase DNA-binding protein 2 (Chd2). Results: We show that Chd2-mutant mice present with glomerulopathy, proteinuria, and significantly impaired kidney function. Additionally, serum analysis revealed decreased hemoglobin and hematocrit levels in Chd2-mutant mice, suggesting that the glomerulopathy observed in these mice is associated with anemia. Conclusion: Collectively, the data suggest a role for the Chd2 protein in the maintenance of kidney function.
Vitamin E δ-Tocotrienol Levels in Tumor and Pancreatic Tissue of Mice after Oral Administration
Authors: Husain Kazim , Francois Rony A. , Hutchinson Sean Z. , Neuger Anthony M. , Lush Richard , Coppola Domenico , Sebti Said , Malafa Mokenge P.
Published: January 2009

Tocotrienols are natural vitamin E compounds that are known to have a neuroprotective effect at nanomolar concentration and anti-carcinogenic effect at micromolar concentration. In this report, we investigated the pharmacokinetics, tumor and pancreatic tissue levels, and toxicity of δ-tocotrienol in mice because of its anti-tumor activity against pancreatic cancer. Following a single oral administration of δ-tocotrienol at 100 mg/kg, the peak plasma concentration (Cmax) was 57 ± 5 μmol/l, the time required to reach peak plasma concentration (Tmax) was 2 h and plasma half-life (t1/2) was 3.5 h. The δ-tocotrienol was cleared from plasma and liver within 24 h, but delayed from the pancreas. When mice were fed δ-tocotrienol for 6 weeks, the concentration in tumor tissue was 41 ± 3.5 nmol/g. This concentration was observed with the oral dose (100 mg/kg) of δ-tocotrienol which inhibited tumor growth by 80% in our previous studies. Interestingly, δ-tocotrienol was 10-fold more concentrated in the pancreas than in the tumor. We observed no toxicity due to δ-tocotrienol as mice gained normal weight with no histopathological changes in tissues. Our data suggest that bioactive levels of δ-tocotrienol can be achieved in the pancreas following oral administration and supports its clinical investigation in pancreatic cancer.
Ziziphus jujuba Extract for the Treatment of Chronic Idiopathic Constipation: A Controlled Clinical Trial
Authors: Naftali Timna , Feingelernt Haya , Lesin Yevgeni , Rauchwarger Ariela , Konikoff Fred Meir
Published: January 2009

Purpose: To investigate the safety and efficacy of an extract of Ziziphus jujuba for chronic constipation.Constipated patients received liquid Z. jujuba or placebo for 12 weeks. Subjects completed questionnaires, a visual analog scale and transit time (TT) tests before and after treatment. Results: Of 37 patients with a prolonged TT, 18 received the study drug and 19 a placebo. Two (12%) of the study and 16 (84%) of the control group dropped out due to severe constipation. The TT decreased from 12.2 particles for the study group to 3 particles at week 11. Symptom severity ratings decreased from 6 and 6.2 to 2 and 5, and the quality of life score improved from 1.9 and 2.3 to 1.3 and 1.4 in the study and control groups, respectively. Conclusion:Z. jujuba extract is an effective and safe treatment for chronic constipation.
Signaling in Regulation of Podocyte Phenotypes
Authors: Chuang Peter Y. , He John C.
Published: January 2009

The kidney podocyte is a terminally differentiated and highly specialized cell. The function of the glomerular filtration barrier depends on the integrity of the podocyte. Podocyte injury and loss have been observed in human and experimental models of glomerular diseases. Three major podocyte phenotypes have been described in glomerular diseases: effacement, apoptosis, and proliferation. Here, we highlight the signaling cascades that are responsible for the manifestation of these pathologic phenotypes. The integrity of the podocyte foot process is determined by the interaction of nephrin with proteins in the slit diaphragm complex, the regulation of actin dynamics by the Rho family of GTPases, and the transduction of extracellular signals through focal adhesion complexes. Activation of the p38 mitogen-activated protein kinase and transforming growth factor-β1 causes podocyte apoptosis. Phosphoinositide 3-kinase and its downstream target AKT protect podocytes from apoptosis. In human immunodeficiency virus-associated nephropathy, Src-dependent activation of Stat3, mitogen-activated protein kinase 1,2, and hypoxia-inducible factor 2α is an important driver of podocyte proliferation. At the level of intracellular signaling, it appears that different extracellular signals can converge onto a few pathways to induce changes in the phenotype of podocytes.
Sexual Dimorphism in Mouse Metanephroi Exposed to 17β-Estradiol in vitro
Authors: Walker Kenneth A. , Caruana Georgina , Bertram John F. , McInnes Kerry J.
Published: January 2009

17β-Estradiol, the most potent circulating estrogen, has been shown to greatly impact on the development and formation of tissues of the urogenital tract. The adult kidney has previously been shown to be highly responsive to 17β-estradiol stimulation. However, the direct effect of 17β-estradiol on kidney development remains unclear. Aim: To investigate the direct effect of 17β-estradiol on male and female metanephric kidney development. Methods: Whole embryonic-day-12.5 (E12.5) C57Bl/6 male and female mouse metanephroi were cultured in the presence of varying concentrations of 17β-estradiol (0.1–5.0 nM) for 72 h. Metanephric development was assessed using immunofluorescence labeling techniques. The real-time polymerase chain reaction was used to investigate estrogen receptor-α (ERα), glial-cell-line-derived neurotrophic factor (GDNF) and its associated receptor cRET,  transforming growth factor-β (TGFβ1), TGFβ2 and TGFβ3 mRNA expression levels. Results:ERα was present in developing metanephroi at E12.5; however, ERβ was absent. No significant sex difference in ERα mRNA expression was observed. Significant increases in the number of ureteric branch points, terminal tips and developing glomeruli were observed in female metanephroi cultured in the presence of 1.0 and 5.0 nM 17β-estradiol. Conversely, no significant effect was observed in male metanephroi cultured with 17β-estradiol. GDNF and cRET mRNA expression was increased in both male and female metanephroi, whilst TGFβ1 and TGFβ2 mRNA expression was decreased following culture in the presence of 17β-estradiol. Conclusion: This study is the first to establish that the mouse metanephros displays a sexual dimorphism in response to specific concentrations of estrogens.
Long-Term Outcome after Total Parathyroidectomy for the Management of Secondary Hyperparathyroidism
Authors: Stracke Sylvia , Keller Frieder , Steinbach Gerald , Henne-Bruns Doris , Wuerl Peter
Published: January 2009

In patients with chronic renal failure, secondary hyperparathyroidism (sHPT) is a common problem requiring surgical parathyroidectomy (PTX) if medical treatment with active vitamin D and calcimimetics fails. To minimize the risk for recurrence, we perform total PTX (tPTX) without autotransplantation. From October 1997 to January 2004, 46 patients (31 men and 15 women) underwent tPTX without autotransplantation (median age 51 years; range 19–80 years; median dialysis time before PTX 5 years; range 0–25 years). Indications for PTX were hyperparathyroid bone disease in 41 cases and calciphylaxis in 5 cases. Postoperatively, all patients were supplemented with vitamin D analogues, both calcitriol and cholecalciferol. Patients were followed up for 4–107 months (median 63 months). Although tPTX was intended in all cases, we saw recurrent or persistent hyperparathyroidism in 26% and supernumerary glands in 15% of cases. In 7 patients (15%), five or more glands were documented and in another four suspected confirming the clinical relevance of intraoperative parathyroid hormone (PTH) measurement. In our study, the positive predictive value of a low intraoperative PTH (<20 pg/ml) for a successful tPTX was 92%. 15 patients received a renal transplant after tPTX without autotransplantation. Here, an uncomplicated hypocalcaemia was noted in 3 patients. Last available calcium levels were between 1.72 and 2.66 mmol/l (median 2.35 mmol/l). After follow-up, active vitamin D was given in a median daily dose of 0.5 μg calcitriol (range 0–2.5 μg/day). There was no evidence of clinical bone disease and no pathological fractures after tPTX after a median observation period of 63 months. tPTX still offers the highest percentage of cure for sHPT, it is safe and postoperatively easily manageable. It allows for adequate supplementation with active vitamin D, and it is the most cost-effective procedure. It should be reconsidered an option for the treatment of sHPT.
Arteriovenous Fistula Patency Associated with Angiotensin-Converting Enzyme I/D Polymorphism and ACE Inhibition or AT1 Receptor Blockade
Authors: Moon Ju-Young , Jeong Kyung-Hwan , Paik Seung-Sook , Han Jae-Joon , Lee Sang-Ho , Lee Tae-Won , Ihm Chun-Gyoo , Kim Myung-Jae , Chung Joo-Ho
Published: January 2009

Background: Compromise of arteriovenous fistula (AVF) patency is caused by venous intimal hyperplasia. Many studies indicated that the renin-angiotensin-aldosterone system plays an important role in the development of intimal hyperplasia. Here we determined whether angiotensin-converting enzyme (ACE) I/D polymorphism is an independent prognostic factor for AVF patency in hemodialysis (HD) patients. Methods: One hundred and fifty-five HD patients with native AVF were enrolled and genotyped, retrospectively. The primary end point was unassisted patency of the AVF, which was defined as the time from the first fistula surgery to the AVF failure. Results: The unassisted AVF patency at 58 months was 47.0% in the DD genotype group and 71.8/82.9% in ID/II groups (p < 0.01). ACE inhibitors (ACEI) or angiotensin II receptor blockers (ARB) intake had significant impact on AVF patency in the ACE DD group (p = 0.03). Using a Cox-adjusted model, we observed a significant correlation between the increase in the incidence of AVF failure and diabetic nephropathy, higher mean serum phosphorus level, and the ACE DD genotype. Conclusion: The ACE I/D polymorphism was associated with the development of AVF failure, and a preventive role of ACEI or ARB intake on AVF patency in ACE DD patients was observed.
Continuous Administration of Daily Low-Dose Temozolomide in Pretreated Patients with Advanced Non-Small Cell Lung Cancer: A Phase II Study
Authors: Kouroussis Charalambos , Vamvakas Lambros , Vardakis Nikolaos , Kotsakis Athanasios , Kalykaki Antonia , Kalbakis Kostas , Saridaki Zacharenia , Kentepozidis Nikolaos , Giassas Stelios , Georgoulias Vassilis
Published: January 2009

Purpose: Temozolomide, a novel triazene derivative, has shown activity in vitro against lung cancer as well as against brain metastases from a variety of solid tumors including non-small cell lung cancer (NSCLC). The aim of the study was to evaluate the efficacy and safety of temozolomide in pretreated patients with NSCLC. Patients and Methods: Thirty-one pretreated patients (median age 60 years) with histologically confirmed NSCLC were enrolled. Sixteen (52%) patients had a performance status (ECOG) of 0–1, 12 (39%) had pretreated brain metastases and 28 (90.3%) had received >2 lines of treatment. Temozolomide was administered at a dose of 75 mg/m2 daily for 21 days every 28 days. A total of 73 chemotherapy cycles were administered. Results: In an intention-to-treat analysis, 2 patients (6.5%; 95% CI: –2.2 to 15.1%) achieved a partial response and 3 (10%) stable disease. The median time to progression was 2.4 months, the median survival time 3.3 months and the 1-year survival rate 22.5%. There was a toxic death due to grade 4 neutropenia. Grade 3 and 4 lymphopenia occurred in 4 (13%) and 2 (6%) patients, respectively. Nonhematological toxicity was mild, consisting of grade 2–3 asthenia (n = 14 patients) and grade 3 diarrhea (n = 1 patient). Conclusion: Prolonged low daily doses of temozolomide demonstrate minimal activity as salvage therapy in patients with advanced NSCLC. The combination of low daily doses of temozolomide with other anticancer drugs probably merits further evaluation.