bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Gonadotropin-Releasing Hormone Agonist Treatment upon Angiogenesis in Uterine Leiomyoma
Authors: Abulafia Ovadia , Kleinhaus Karine , Levi Gabriel , Lee Yi-Chun , Sherer David M.
Published: April 2003

Objective: To assess the effect of gonadotropin-releasing hormone (GnRH) agonist treatment upon angiogenesis in uterine leiomyomata. Methods: Uterine leiomyomata specimens of 49 consecutive patients who underwent myomectomy or hysterectomy following presurgical treatment with (n = 23) and without (n = 26) GnRH agonist were stained immunohistochemically with antibody to factor VIII-related antigen. For each subject, age, parity, number of Lupron treatments, leiomyoma size (cm), and mean microvessel counts calculated from three fields (×400) were recorded. Differences in patient age, parity, microvessel counts and leiomyoma size between GnRH agonist treated and untreated patients were tested by unpaired Student’s t test. Differences among the various number of doses were tested by one-way ANOVA, with Bonferonni and Neuman-Keuls post hoc tests between specific dose-number groups. The relationship between microvessel counts and leiomyoma size was tested by Pearson correlation test. Multivariate stepwise regression tested the relationship between the number of Lupron doses and microvessel counts, correcting for age, parity, and leiomyoma size. p < 0.05 was considered significant. Results: Patient age and parity were similar in GnRH treated and untreated patients (mean 43.3 ± 6.6 versus 43.9 ± 7.5 years and median 2 (range 0–7) versus 1 (range 0–5), p = 0.78 and p = 0.45, respectively). Microvessel counts of leiomyomata specimens treated presurgically with GnRH agonist therapy (median 22.7, range 6.7–65.7) were not significantly different from microvessel counts of specimens without presurgical GnRH agonist treatment (median 19.8, range 6–53; p = 0.77). No correlation between leiomyoma size and microvessel counts was noted (r = 0.06, P = 0.7). Conclusion: Angiogenesis as assessed by microvessel counts in surgically removed leiomyomata is not affected by presurgical medical management with GnRH agonist therapy.
Treatment of Fetal Congenital Complete Heart Block with Maternal Administration of Beta-Sympathomimetics (Terbutaline)
Authors: Yoshida Hiroshi , Iwamoto Mari , Sakakibara Hideya , Shigeta Hiroyuki , Hirahara Fumiki , Sato Keiji
Published: April 2003

We report a case of fetal congenital heart block treated with maternal administration of beta-sympathomimetics. The case was diagnosed as fetal complete heart block associated with maternal anti-Ro/SS-A antibody at 22 weeks of gestation. By fetal sonography, the ventricular rate was revealed to be 60 beats/min and mild cardiomegaly was shown. We initiated maternal administration of a sympathomimetic, specifically terbutaline, to prevent fetal heart failure. An increase in the fetal ventricular rate and an improvement in cardiac function were both achieved during the treatment. A viable infant was delivered by an elective cesarean section without complications at term. Maternal administration of the beta-adrenergic agent terbutaline is suggested to be effective for improving fetal congenital heart block in order to prevent heart failure in utero.
Diagnostic Efficacy of Tumor Markers, Sonography, and Intraoperative Frozen Section for Ovarian Tumors
Authors: Wakahara Fumiyo , Kikkawa Fumitaka , Nawa Akihiro , Tamakoshi Koji , Ino Kazuhiko , Maeda Osamu , Kawai Michiyasu , Mizutani Shigehiko
Published: April 2003

Using sonography, we classified the adnexal masses of 292 patients into 4 patterns. Pattern A was benign cystic tumors; B was benign mixed tumors (cysts with a smooth solid component); C was malignant mixed tumors (cysts with an irregular solid component or thickened septum), and D was solid tumors. We diagnosed tumors showing patterns A and B as benign, while patterns C and D represented tumors with low malignant potential or actual malignancy. The sensitivity and specificity of sonography was 82.2 and 82.1%, respectively, and these values were superior to those for tumor markers (CA125, CA19-9, CA72-4). Both the sensitivity and specificity of intraoperative frozen sections were the highest, showing that this is the most reliable examination. However, 15 of 191 patients undergoing frozen section were upgraded by the final pathological diagnosis. If sonography is performed by an experienced gynecologic oncologist, this examination is more reliable than tumor markers. However, intraoperative frozen section should still be performed during surgery for patients with ovarian tumors.
Depot Medroxy Progesterone Acetate: A Poor Preparatory Agent for Endometrial Resection
Authors: Kriplani Alka , Manchanda Ranjit , Monga Dinesh , Takkar Deep
Published: April 2003

Objective: To evaluate the efficacy of depot medroxy progesterone acetate (DMPA) as a preparatory agent for endometrial resection. Study Design: Endometrial resection was performed on 50 women for excessive uterine bleeding. The patients were randomly divided into 2 equal groups, with the first group receiving DMPA and the second group not receiving any hormonal pre-medication. The resected tissue was sent for histopathology and all the patients were followed up regularly for a maximum period of 4 years. Results: DMPA was found to increase the thickness of the endometrium, making it more fluffy and oedematous. The procedure in these patients was associated with a significantly greater fluid consumption and deficit. A power analysis showed the overall power of the study to be >90%. Forty-four percent of group 1 and 64% of group 2 patients achieved amenorrhoea or spotting. Three patients in all underwent a repeat procedure, and 1 a hysterectomy, following a dissatisfactory result. However, no statistically significant difference was found in the outcomes of the 2 groups. Conclusion: As a preparatory agent, DMPA, seems to have no added benefit. Larger studies are required to bring out differences in outcomes, if any.
Implications of Differences in Coiling Indices at Different Segments of the Umbilical Cord
Authors: Blickstein Isaac , Varon Yael , Varon Einat
Published: April 2003

The purpose of this study was to find out if the coiling density is similar in all segments of term singleton umbilical cords. We compared the coiling index (coils/cm) at three different segments of 159 cords. There was no statistical difference between the coiling indices of the placental and middle segment, but significantly increased coiling was found at the fetal end compared with the placental and middle segments. Coiling indices were not significantly correlated with gestational age, cord length or birth weight. We diagnosed concordant hypo- and hypercoiling when the placental and fetal segments had the same density classification, and discordant hypo- and hypercoiling when these segments had different density classifications. Concordant hypocoiling and hypercoiling were found in 4.4 and 6.3% of the cords examined, respectively (total of 10.7%), concordant normal coiling in 95 (59.7%) and discordant density classifications in 29.6%. We concluded that the coiling index should be established in two distinct segments and that the spatial configuration of the coils, which protects the blood flow in the umbilical cord, might not be measured by coil density only.
Circulating Divalent Cations in Asymptomatic Ovarian Hyperstimulation and in vitro Fertilization Patients
Authors: O’Shaughnessy A. , Muneyyirci-Delale O. , Nacharaju V.L. , Dalloul M. , Altura B.M. , Altura B.T.
Published: April 2003

It is known that ovarian hyperstimulation and in vitro fertilization are accompanied by a steady increase in circulating estrogen and progesterone far beyond what is normal for young women. We have recently demonstrated that the biologically active fractions of calcium and magnesium in blood are altered depending on when in the menstrual phase a blood sample is drawn in normal cycling women. The serum ionized Ca/Mg ratio is also altered in accordance with the menstrual cycles. This suggests that the sex steroid hormones may modulate serum levels of ionized Mg and the ionized Ca/Mg ratio. We therefore studied the relationships between sex steroid hormones and the concentrations of ionized magnesium and calcium in the blood of hyperstimulated patients. We were able to demonstrate that with each increment in estrogen, a decrease in ionized Mg occurred, and as the progesterone rose in the blood, the ionized Ca/Mg ratio increased. Our results support the idea that serum estrogen and progesterone levels in women modulate the blood levels of circulating ionized Mg and the serum ionized Ca/Mg ratio.
Prevalence of Human Papillomavirus in Elderly Women with Cervical Cancer
Authors: Baay M.F.D. , Tjalma W.A.A. , Weyler J. , Pattyn G.G.O. , Lambrechts H.A.J. , Goovaerts G. , Baekelandt M. , Buytaert P. , van Marck E.A.E. , Lardon F. , Vermorken J.B.
Published: April 2003

To investigate the relation between the prevalence of human papillomavirus (HPV) and age in cervical cancer patients, material from 93 patients with Ia–IIb cervical carcinoma was analyzed for the presence of HPV by both type-specific and general primer polymerase chain reaction. Patients were divided into 2 groups: 64 years or younger, and 65 years and older. There was no statistically significant difference in either the prevalence of HPV DNA or distribution of genotypes amongst the 2 groups. Therefore, HPV detection can be equally well used in the management and follow-up of elderly cervical cancer patients.
Parathion, a Cholinesterase-Inhibiting Plaguicide Induces Changes in Tertiary Villi of Placenta of Women Exposed: A Scanning Electron Microscopy Study
Authors: Levario-Carrillo Margarita , Feria-Velasco Alfredo , De Celis Ruth , Ramos-Martínez Ernesto , Córdova-Fierro Lucina , Solís Francisco J.
Published: April 2003

The objective of this work was to describe the anatomy of placentas from women who were at risk of exposure to parathion during their pregnancy, when examined with the light and scanning electron microscopes. Twenty term placentas were analyzed; 10 from women living in an agricultural area, who were at risk of exposure to parathion during their pregnancy, and 10 from women living in an urban area, not expressly exposed to pesticides. Each sample was examined with both light and scanning electron microscopes. Cholinesterase activity was significantly reduced in blood from women of the exposed group. In some placentas of women exposed to parathion, recent microinfarctions, microcalcifications and increased deposition of fibrinoid material were seen, along with a larger proportion of atypical characteristics of villi, such as bullous and balloon-like formations with nonhomogeneous surface, and other areas devoid of microvilli. These observations suggest that in chronic exposure to pesticides, the rate of atypical characteristics of placental villi increases, which could be related to changes in the fetus biology. In this study, one newborn from the exposed group showed intrauterine growth retardation and another one, some signs of hypoxia.
Auswirkung der wiederholten antenatalen Kortikosteroidbehandlung auf das intrauterine Wachstum und auf die Grössenentwicklung im Kleinkindesalter
Authors: Hasbargen U. , Dadze A.K. , Reber D. , Strauss A. , Musäus J. , Hillemanns P. , Schulze A.
Published: April 2003

Fragestellung: Beeinflusst die wiederholte antepartale Gabe von Kortikosteroiden (KS) die Grösse des Kindes bei der Geburt und im Alter von 4 Jahren? Methode: Fall-Kontroll-Studie von Einlingsschwangerschaften mit 82 Indexpatientinnen, welche zwischen der 26. und der 28. Schwangerschaftswoche zur Induktion der fetalen Lungenreife KS erhielten, und 82 Kontrollpatientinnen ohne KS-Gabe mit Feten im gleichem Gestationsalter und mit dem gleichen Geschlecht. Ergebnisse: Bei der Geburt und im Alter von 4 Jahren bestanden zwischen den Kindern beider Kollektive keine Unterschiede bei den untersuchten Parametern Gewicht, Kopfumfang und Körperlänge. Schlussfolgerung: Die Studie konnte keinen negativen Einfluss der wiederholten antenatalen KS-Gabe nachweisen.
Nachweis von Epithelzellen im Knochenmark von Patientinnen mit Ovarialkarzinomenunter Anwendung von immunhistochemischen Methoden
Authors: Gabriel M. , Obrebowska A. , Spaczyński M.
Published: April 2003

In der vorliegenden Arbeit wurden mit immunhistochemischen Methoden unter Verwendung von monoklonalen Antikörpern atypische Epithelzellen im Knochenmark von Patientinnen mit Ovarialtumoren untersucht. Für die Analyse wurden Zytospinpräparate von gutartigen (n = 9) und malignen (n = 59) Tumoren der Eierstöcke verwendet. Es wurden zwei unterschiedliche monoklonale Antikörper (NCL-C11 and NCL-CA 125) eingesetzt. Mit beiden Antikörpern wurden keratinpositive bzw. CA-125-positive Zellen im Knochenmark von 9 (18,4%) Patientinnen mit Ovarialkarzinomen nachgewiesen. Beim Vergleich des immunchemischen Befundes mit anderen Prognoseparametern fiel auf, dass dieser mit dem Tumorstadium korreliert. Aufgrund der grossen Vielfalt der histologischen Formen der Ovarialkarzinome wäre an einer grösseren Anzahl Patientinnen zu klären, ob atypische Epithelzellen im Knochenmark prognostisch sowohl für die Überlebenszeit als auch für die Rezidivfreiheit bedeutsam sind.
Haplotype Analysis of BRCA2 8765delAG Mutation Carriers in French Canadian and Yemenite Jewish Hereditary Breast Cancer Families
Authors: Manning Andrew P. , Abelovich Dvorah , Ghadirian Parviz , Lambert Julie A. , Frappier Danielle , Provencher Diane , Robidoux André , Peretz Tamar , Narod Steven A. , Mes-Masson Anne-Marie , Foulkes William D. , Wang Teiling , Morgan Kenneth , Fujiwara T. Mary , Tonin Patricia N.
Published: April 2003

The BRCA2 8765delAG mutation was previously reported in hereditary breast cancer families of French Canadian and Yemenite Jewish descent. Haplotype analysis, using six microsatellite markers that span BRCA2 and two intragenic polymorphisms, was performed on 8765delAG mutation carriers to determine if there was evidence that the mutations were identical by descent. The alleles of the microsatellite markers most closely flanking BRCA2 (D13S1697 and D13S1701) were found to be identical in state in all the mutation carriers. However, the disease-associated allele of one of the intragenic markers differed between the Yemenite Jews and French Canadian families, indicating that the 8765delAG mutation has independent origins in these two geographically and ethnically distinct populations.
Evidence for mtDNA Admixture between the Finns and the Saami
Authors: Meinilä Maria , Finnilä Saara , Majamaa Kari
Published: April 2003

Objectives: The Finns, and to a more extreme extent the Saami, are genetic outliers in Europe. Despite the close geographical contact between these populations, no major contribution of Saami mtDNA haplotypes to the Finnish population has been detected. Methods:  To examine the extent of maternal gene flow from the Saami into Finnish populations, we determined the mtDNA variation in 403 persons living in four provinces in central and northern Finland. For all of these samples, we assessed the frequencies of mtDNA haplogroups and examined sequence variation in the hypervariable segment I (HVS-I). The resulting data were compared with published information for Saami populations. Results: The frequencies of the mtDNA haplogroups differed between the populations of the four provinces, suggesting a distinction between northern and central Finland. Analysis of molecular variance suggested that the Saami deviated less from the population of northern Finland than from that of central Finland. Five HVS-I haplotypes, including that harboring the Saami motif and the Asian-specific haplogroup Z, were shared between the Finns and the Saami and allowed comparisons between the populations. Their frequency was highest in the Saami and decreased towards central Finland. Conclusions: The high frequency of certain mtDNA haplotypes considered to be Saami specific in the Finnish population suggests a genetic admixture, which appears to be more pronounced in northern Finland. Furthermore, the presence of haplogroup Z in the Finns and the Saami indicates that traces of Asian mtDNA genotypes have survived in the contemporary populations.
Novel Nucleotide Substitutions within the Coding Region of DNMT2 Are in Strong Linkage Disequilibrium in Caucasians and Japanese
Authors: Franchina Maria , Kay Peter H.
Published: April 2003

Investigations into mechanims by which cytosine methylation may be genetically controlled have led to the identification of single nucleotide polymorphisms within the coding region of DNMT2 that are conserved in different ethnic groups. The DNMT2 I allele includes a G at nucleotide position 104 of exon 2 and a C at position 50 of exon 4. The alternative allele, DNMT2 II, includes an A and T, respectively, at these positions. G was never found in the absence of C and vice versa and A was never found in the absence of T and vice versa. The gene products of DNMT2 I and DNMT2 II differ by the inclusion of a histidine or tyrosine residue at the position specified by codon 101. This amino acid substitution alters the amino acid composition of a conserved methylating enzyme motif shown to be involved in S-adenosylmethionine binding in M.HhaI, a bacterial methyltransferase that is almost identical to DNMT2 in size and structure. Demonstration of strong linkage disequilibrium between the nucleotide substitutions associated with each DNMT2 allele provides valuable tools for the investigation of molecular genetic mechanisms of evolution and speciation.
Primary Role of CD4+ T Cells and Supplemental Role of Mast Cells in Allergic Pulmonary Eosinophilia
Authors: Ogawa Koji , Kaminuma Osamu , Kikkawa Hideo , Kameda Rieko , Ikezawa Katsuo , Suko Matsunobu , Okudaira Hirokazu , Akiyama Kazuo , Mori Akio
Published: April 2003

Background: We have recently demonstrated that allergic eosinophilic inflammation is transferred to unprimed mice by infusing IL-5-producing CD4+ T cells. The contribution of mast cells to the development of eosinophilic inflammation is controversial. Methods: To clarify the possible different roles of CD4+ T cells and mast cells in eosinophilic inflammation, we compared antigen-induced airway eosinophilia between mast-cell-deficient mice (WBB6F1-W/Wv) and their congenic normal littermates (WBB6F1-+/+). Results: The time course study indicated that equivalent numbers of eosinophils were recruited into the airway of both +/+ and W/Wv mice 6, 24, 96, and 216 h after antigen challenge, whereas the number of eosinophils 48 h after antigen challenge was significantly lower in W/Wv compared to +/+ mice. Administration of either anti-CD4 or anti-IL-5 monoclonal antibody almost completely inhibited antigen-induced eosinophil recruitment in W/Wv mice 48 h after antigen challenge. In contrast, the inhibitory effect of these antibodies in +/+ mice were partial (∼50% inhibition). Anti-CD4 and anti-IL-5 antibodies equally suppressed airway eosinophilia in both +/+ and W/Wv mice 96 h after antigen challenge. Conclusion: Our study indicates that CD4+ T cells are crucially involved in the development of allergic eosinophilic inflammation, while mast cells may play a supplemental role depending on the kinetics of the response.
Systemic T Helper 2 Cell Activation Is Not Sufficient for Antigen-Induced Eosinophil Recruitment into the Airways
Authors: Nakajima Hiroshi , Nakao Atsuhito , Kumano Kotaro , Yamamoto Hiroshi , Iwamoto Itsuo
Published: April 2003

Background: Airway eosinophilic inflammation is a characteristic feature of asthma. We have previously shown that antigen-induced eosinophil recruitment into the airways of sensitized BALB/c mice is mediated by CD4+ T cells and IL-5. However, the basis for the eosinophil recruitment into the airway are still largely unknown. Methods: To determine the regulatory mechanisms that control the magnitude of antigen-induced eosinophilic inflammation in the airways, we analyzed antigen-induced eosinophil and T cell infiltration into the trachea in several strains of mice, including BALB/c (H-2d), BALB/b (H-2b), C57BL/6 (H-2b), C57BL/10 (H-2b), and B10.D2 (H-2d) mice. In addition, cytokine production from antigen-stimulated splenocytes and the titer of antigen-specific IgE antibody in serum were assessed. Results: Antigen-induced eosinophil recruitment into the trachea in BALB/c mice was more than 20 times as abundant as that in C57BL/6 mice, the latter of which was also mediated by CD4+ T cells. In contrast, systemic Th2 responses, which were evaluated by the titers of antigen-specific IgE antibody in serum and antigen-induced IL-4 and IL-5 production from splenocytes, were similarly observed in BALB/c mice and C57BL/6 mice. In addition, the antigen-induced eosinophil recruitment into the trachea was high in BALB/b mice, like BALB/c mice, but low in B10.D2 mice. Conclusions: Systemic Th2 responses are not sufficient for causing antigen-induced eosinophil recruitment into the airways and an undefined determinant(s) that exists in the BALB background mice rather than the H-2 haplotype is vital for the regulation of antigen-induced eosinophil recruitment into the airways.
Stimulation of the β2 Integrin, αMβ2, Triggers Tyrosine Phosphorylation and Cellular Degranulation on Human Eosinophils
Authors: Kato Masahiko , Kita Hirohito , Kimura Hirokazu , Tachibana Atsushi , Motegi Youichi , Tokuyama Kenichi , Morikawa Akihiro
Published: April 2003

Activation of human eosinophils by specific extracellular stimuli triggers the cellular degranulation response. Because cellular adhesion is critical for this eosinophil degranulation, we have tested the hypothesis that ligation of the β2 integrin, αMβ2 (Mac-1, CD11b/CD18), leads to intracellular signaling events that contribute to the eosinophil activation response. Recently, we found that engagement of β2 integrin using two different approaches, such as cell adhesion induced by IL-5 or direct ligation of αMβ2, triggered tyrosine phosphorylation of Cbl, the product of the c-cbl proto-oncogene, paxillin, a cytoskeletal protein, an unidentified 115-kD protein, and subsequent cellular degranulation. The results of this study indicate that engagement of αMβ2 on eosinophils triggers an intracellular signaling cascade leading to cellular degranulation. Tyrosine phosphorylation of Cbl, paxillin, and a 115-kD protein may play important roles in adhesion-dependent cellular functions of eosinophils.
The Role of α-Galactosylceramide-Activated Vα14 Natural Killer T Cells in the Regulation of Th2 Cell Differentiation
Authors: Nakayama Toshinori , Yamashita Masakatsu , Kawano Tetsu , Shimizu Chiori , Shibata Youichi , Kamata Tohru , Kaneko Yoshikatsu , Kobayashi Seiichiro , Takeda Ushio , Motohashi Shinichiro , Cui Junqing , Taniguchi Masaru
Published: April 2003

Vα14 natural killer T (NKT) cells produce large amounts of both IL-4 and IFN-γ upon stimulation with a ligand, α-galactosylceramide (α-GalCer), and play a crucial role in various immune responses, including allergic diseases. Interestingly, Vα14 NKT cells are not essential for the induction of IgE responses but rather induce suppression of specific IgE production upon activation. The suppression in the IgE production is not detected either in Vα14 NKT cell-deficient mice or in IFN-γ-deficient mice. Thus, activated Vα14 NKT cells are likely to exert a potent suppressive activity on Th2 cell differentiation and subsequent IgE production by producing a large amount of IFN-γ. In marked contrast, little regulatory effect of IL-4 produced by Vα14 NKT cells on Th2 cell differentiation is suggested.
Immunochemical Characterization of Antigenic Fragments of Olea europaea and Phleum pratense
Authors: Fernández-Caldas Enrique , González Romano Leticia , Gallego Mayte , Casanovas Miguel , Guerra Francisco , Ferrer Angel , Berrens Lubertus
Published: April 2003

Background: The modulation of T cell responses by natural peptides is of potential use in the treatment of allergic diseases and reduces the risk of IgE-mediated reactions. The objectives of this study were to evaluate the allergenicity of depigmented, pepsin-digested fragments of Oela europaea and Phleum pratense extracts and their capacity to induce T cell proliferation. Methods: Lyophilized O. europaea and P. pratense extracts were depigmented following standardized methods, digested with pepsin and fractionated by ultrafiltration; a fraction containing components in the molecular weight range of 1–10 kD was selected. The blood of 20 allergic individuals was used to conduct T cell proliferation studies. Results: Pepsin-digested fragments of both pollen extracts lost more than 95% of their IgE-binding capacity by ELISA inhibition. Greater proliferation indexes than their respective native extracts were obtained in 55% of O. europaea and in 95% of P. pratense allergic patients. Conclusions: This study demonstrates that pepsin-digested allergenic fragments of depigmented extracts can be produced in a standardized, reproducible manner. These fragments are significantly less allergenic and retain, or even increase, their capacity to induce T cell proliferations.
Serum IgG and IgG4 Antibodies to Fel d 1 among Children Exposed to 20 μg Fel d 1 at Home: Relevance of a Nonallergic Modified Th2 Response
Authors: Platts-Mills Thomas A.E. , Vaughan John W. , Blumenthal Kevin , Pollart Squillace Susan , Sporik Richard B.
Published: April 2003

Exposure to foreign antigens is an essential element of all immune responses, including allergic sensitization. For some allergens (e.g. mite and cockroach), the prevalence of sensitization is directly correlated with exposure. However, for allergens derived from domestic animals, several studies have suggested that children with a cat in the home have a decreased risk of sensitization and asthma. We have now shown that many children exposed to greater than 20 µg of Fel d 1/g of dust at home made an IgG and IgG4 antibody response to Fel d 1 without IgE antibody. This modified Th2 response is not associated with symptoms and should be regarded as a form of immunological tolerance. The fact that the dose-response relationship between cat exposure and sensitization is bell shaped, while that for mite exposure and sensitization is linear, is highly relevant to understanding the role of allergens in the increase in allergic disease.
Histamine Upregulates Th1 and Downregulates Th2 Responses due to Different Patterns of Surface Histamine 1 and 2 Receptor Expression
Authors: Jutel M. , Klunker S. , Akdis M. , Małolepszy J. , Thomet Oliver A.R. , Żak-Nejmark T. , Blaser K. , Akdis C.A.
Published: April 2003

Histamine, which acts via G protein-coupled receptors, is an important mediator of immediate hypersensitivity and is also able to influence the nature of T cell responses. We demonstrated that TH1 and Th2 cells express distinct surface histamine receptor patterns and that Th1-type responses are enhanced by histamine, whereas Th2-type responses are negatively regulated, due to different intracellular signals generated by histamine stimulation. These findings account for negative feedback regulation in a wide variety of pathologies.
Immune Reactivity to Mite Allergens in Nonatopic Subjects: Immune Deviation or Immune Ignorance
Authors: Aalberse Rob C. , Vermeulen Ellen
Published: April 2003

Most subjects without IgE to Dermatophagoides pteronyssinus do not have IgG to Der p 1 or Der p 2 (as measured by RIA). However, by immunoblot or ELISA, IgG reactivity (mostly IgG1) to mite components is easily detectable. This discrepancy is caused largely by immune reactivity to mite components with a high molecular weight under native conditions (possibly mite gut flora cross-reactive with human gut flora) and partially by the presence of IgG with low affinity for fluid-phase antigen. We conclude that the pattern of IgG antibody in subjects without IgE to mites does not support the notion of immune deviation, but rather indicates a lack of a mite-induced high-affinity immune response.
Effect of the H1-Receptor Antagonist Cetirizine on the Stimulated Expression of Adhesion Molecules and the Activation of NFκB in Human Endothelial Cells
Authors: Ambrosch Andreas , Borgmann Stefan , Rihoux Jean-Pierre , König Wolfgang
Published: April 2003

Background: In the present work, we studied the effect of cetirizine on the cytokine-stimulated immune response of human umbilical vein endothelial cells (HUVECs). Methods: Our research was directed to analyze the effect of preincubation of HUVECs with cetirizine (1 µg/ml) on (1) the TNFα-, IL-4- and IFNγ-induced surface expression of ICAM-1 and VCAM-1, (2) the secretion of IL-6 and IL-8, (3) the recruitment of NFĸB and AP-1 and (4) the adhesion of histiocytic monocytes (U937) to activated endothelial monolayers. Results and Conclusion: Cetirizine exerts a stimulus-dependent pattern of regulatory action on various parameters of endothelial cell activation. In detail, cetirizine significantly reduces the expression of ICAM-1 and VCAM-1 paralleled by a reduced monocytic adhesion in particular to TNFα-activated HUVECs. With regard to the cytokine release, dual effects are obtained by cetirizine: IL-6 and IL-8 secretion is suppressed by cetirizine in TNFα and IL-4-activated cells, whereas the IFNγ-induced suppression of IL-8 is nearly abrogated. In this context, the TNFα-induced signal transduction with regard to NFĸB and AP-1 was also suppressed by cetirizine.
Baker’s Asthma due to Xylanase and Cellulase without Sensitization to Alpha-Amylase and Only Weak Sensitization to Flour
Authors: Merget Rolf , Sander Ingrid , Raulf-Heimsoth Monika , Baur Xaver
Published: April 2003

Background: The baking additives xylanase and cellulase were described as baking additives causing baker’s asthma. It is not known whether monosensitization to these enzymes may occur. Methods: We present a case report of a baker with work-related asthma evaluated by skin prick test (SPT), enzyme-linked immunosorbent assay (EAST), immunoblot, EAST and immunoblot inhibition, and specific bronchial challenge. Fungal xylanase and α-amylase were measured by two-site enzyme immunoassays in products used by the patient at work. Results: Allergy to xylanase and cellulase was demonstrated by SPT, EAST, immunoblot and specific bronchial challenge (for xylanase only). No sensitization to α-amylase could be demonstrated, but there was a weak flour allergy as documented by EAST and immunoblot and a positive occupational-type challenge with high concentrations of rye flour. Four baking additives contained measurable amounts of fungal α-amylase and xylanase, without a correlation between these enzymes. Conclusions: We conclude that occupational asthma due to the baking additives xylanase and cellulase may occur without concomitant sensitization to α-amylase and only weak sensitization to flour.
Human Cytomegalovirus Latency and Reactivation – A Delicate Balance between the Virus and Its Host’s Immune System
Authors: Söderberg-Nauclér Cecilia , Nelson Jay A.
Published: April 2003

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that still causes severe morbidity and mortality in immunocompromised individuals. During its evolution, the virus has developed sophisticated methods to evade immune recognition and to establish life-long persistence in its host. Today, we know that the virus establishes latency in myeloid lineage cells and that the virus is dependent on immune activation mechanisms to reactivate it from latency to produce a new viral progeny. During this process, a number of viral proteins are produced that interfere with different immune recognition pathways. The current knowledge of the delicate balance between the virus‘ continuous existence and its host’s immune system will be summarized in this chapter.
Cytomegalovirus-Induced Transendothelial Cell Migration
Authors: Scholz M. , Blaheta R.A. , Vogel J.-U. , Doerr H.W. , Cinatl Jr. J.
Published: April 2003

A variety of cells such as leukocytes and tumor cells may adhere to endothelial cells and subsequently transmigrate into the solid tissue by involving specific intercellular molecular pathways. One important prerequisite for transendothelial migration is the loosening of endothelial cell-to-cell contact sites, which can be triggered by extravasating cells. Cytomegalovirus (CMV) has obviously evolved the ability not only to influence host cells floating in the blood stream to adhere to endothelial cells, but also to induce the formation of intercellular gaps within the endothelium, resulting in transendothelial migration. These features allow the virus to disseminate and evade the immune system. In coculture experiments with human endothelial monolayers and human CMV (HCMV)-infected neuroblastoma cells or leukocytes, changes in the integrity of the monolayer were observed and further analyzed on the molecular level. For example, HCMV may activate the integrin β1α5 (VLA-5) that triggers adhesion to endothelial cells with subsequent focal disruption of endothelial cell-to-cell connections. It is hypothesized that a Ca2+-independent pathway following VLA-5 binding disconnects the cadherin-catenin-actin complex within the endothelial cells. The loss of cadherin function causes the loss of contact to the neighboring endothelial cells and thus could represent an important mechanism in HCMV-induced cellular transendothelial migration and disruption of the endothelial integrity.
Relative Potency of Cellular and Humoral Immune Responses Induced by DNA Vaccination
Authors: Otten Gillis R. , Doe Barbara , Schaefer Mary , Chen Minchao , Selby Mark J. , Goldbeck Cheryl , Hong Mei , Xu Fengfeng , Ulmer Jeffrey B.
Published: April 2003

DNA vaccines can prime broad-based immune responses in small animal models. In the present study, we sought to evaluate the relative ability of DNA vaccines to induce humoral and cellular immune responses. Using a DNA vaccine encoding HIV gag in mice, we observed that CD8+ T cell responses were primed more readily than were antibody responses, particularly at low doses of DNA. These CD8+ T cell responses were detected in spleen cells, as well as at local sites such as the lung and draining lymph nodes. The potency of the HIV gag DNA vaccine used was sufficient to prime strong CTL responses in macaques, but only low to undetectable antibody responses. Therefore, DNA vaccines appear able to prime strong, broad CTL but only modest antibody responses. These results may have implications on the development of vaccines against infectious diseases where both CTL and antibody responses are desired, such as HIV.
Heparins in Diabetic Microangiopathy: Rationale and Preliminary Clinical Results
Authors: van der Woude Fokko J.
Published: April 2003

It has been postulated, based upon epidemiological data, that genetic differences in the enzymes involved in the sulphation of glycosaminoglycan (GAG) side-chains of heparan sulphate (HS) proteoglycans are of crucial importance in the pathogenesis of diabetic nephropathy. An alteration in GAG metabolism is also believed to be responsible for the well-known co-occurrence of diabetic nephropathy and extrarenal micro- and macroangiopathy. In this article, recent in-vitro and in-vivo studies on the role of HS-GAG in the pathogenesis of diabetic nephropathy are discussed. Preliminary data suggest that HS-GAG treatment may be of benefit in patients with insulin-dependent diabetes mellitus, nephropathy and retinopathy. Results in patients with non-insulin-dependent diabetes mellitus are less convincing, although not completely negative.
Factor VIII Inhibitors in Two Families with Mild Haemophilia A: Structural Analysis of the Mutations
Authors: Knobe Karin E. , Villoutreix Bruno O. , Tengborn Lilian I. , Petrini Pia , Ljung Rolf C.R.
Published: April 2003

The development of inhibitory antibodies against coagulation factor VIII (FVIII) in patients with mild haemophilia A is uncommon. We describe here two families in which three or two members have developed inhibitors, suggesting a familial predisposition. The mutations found, in the A2 (Arg593Cys) and C1 domains (Tyr2105Cys), have been reported to give rise to inhibitor development in single individuals in addition to the family cluster we describe, strongly suggesting that these amino acid substitutions give rise to a more immunogenic protein. The analysis of structural models of activated factor VIII revealed that Arg593 is solvent-exposed and involved in a network of electrostatic interactions while Tyr2105 is partially buried and has hydrophobic interactions essentially with Ile2144. All these residues are strictly conserved in the FVIII amino acid sequence from man, pig and mouse, suggesting, at least, that they have structural roles. We propose that the two mutations in these families could cause mild haemophilia A because they induce local conformational changes (and possible secretion or intermolecular interaction problems, e.g., with von Willebrand factor) compatible with immunogenicity and production of inhibitors against the infused wild-type FVIII.
Cellular Consequences upon Factor VIIa Binding to Tissue Factor
Authors: Siegbahn Agneta
Published: April 2003

Tissue factor (TF) is a cell-surface-bound glycoprotein that binds the zymogen, factor (F) VII, and the active serine protease, FVIIa. The FVIIa/TF complex is the major activator of coagulation in vivo. Under normal physiological conditions, TF is expressed only on extravascular sites and perivascularly in the adventitial layer of blood vessels. Although not normally expressed by cells within the circulation, TF can be induced in monocytes and endothelial cells. Also, several malignant cells express high levels of TF. Recent reports have shown that FVIIa binding to TF can influence a number of biological functions, such as angiogenesis and cancer metastasis. TF also seems to play an important role in cell adhesion and migration. The intracellular signalling is independent of downstream activation of the blood coagulation cascade. FVIIa/TF seems to transduce signalling by two distinct mechanisms: one independent of the cytoplasmatic domain but dependent on the proteolytic activity of FVIIa, and one dependent on the cytoplasmatic domain of TF.
The Opossum Kidney Cell Type IIa Na/Pi Cotransporter Is a Phosphoprotein
Authors: Jankowski Maciej , Hilfiker Helene , Biber Jürg , Murer Heini
Published: April 2003

Background/Aim: Parathyroid hormone (PTH)-dependent inhibition of proximal tubular Pi reabsorption is mediated by protein kinase A and/or C and is associated with reduced border membrane expression of the type IIa Na/Pi cotransporter. The aim of this study was to analyze phosphorylation of the type IIa cotransporter protein. Methods: Opossum kidney cells were used as a ‘proximal tubular’ cell model. Protein phosphorylation was determined by immunoprecipitation of the type IIa Na/Pi cotransporter, followed by autoradiography. The transporter protein content was evaluated by Western blotting and transport activity by tracer Pi uptake. Results: Under control conditions (no PTH) the transporter was phosphorylated; upon treatment with PTH, a decrease in phosphorylation was observed. A protein phosphatase inhibitor (okadaic acid) was unable to prevent PTH-induced Na/Pi cotransporter inhibition but reduced transporter degradation. Conclusion: The type IIa Na/Pi cotransporter is a phosphoprotein, but alterations in its phosphorylation seem not to be involved in Pi transport inhibition.
High Glucose Stimulates Ca2+ Uptake via cAMP and PLC/PKC Pathways in Primary Cultured Renal Proximal Tubule Cells
Authors: Park Soo Hyun , Choi Hyun Ju , Lee Jang Hern , Yang Il Suk , Han Ho Jae
Published: April 2003

Alteration of [Ca2+]i by hyperglycemia is implicated in the pathogenesis of diabetic nephropathy. However, the effect of high glucose on Ca2+ regulation in proximal tubule cells is not known. Thus, we examined the mechanisms by which high glucose regulates Ca2+ uptake in primary cultured rabbit renal proximal tubule cells. Glucose increased the Ca2+ uptake in a time– and dose–dependent manner. A stimulatory effect of high glucose on Ca2+ uptake is predominantly observed using 25 mM glucose (high glucose) after 1 h, while 25 mM glucose did not affect cell viability and lactate dehydrogenase release. However, 25 mM mannitol and L–glucose did not affect Ca2+ uptake as compared with controls. Nifedipine and methoxyverapamil (L–type Ca2+ channel blockers) blocked high–glucose–induced stimulation of Ca2+ uptake. High–glucose–induced stimulation of Ca2+ uptake was blocked by pertussis toxin, SQ–22536 (adenylate cyclase inhibitor), myristoylated amide 14–22 (protein kinase A inhibitor), neomycin and U–73122 (phospholipase C inhibitors), and staurosporine and bisindolylmaleimide I (protein kinase C inhibitors). In addition, KN–62 (a Ca2+/calmodulin–dependent protein kinase II inhibitor) and W–7 (a Ca2+/calmodulin antagonist) blocked high–glucose–induced stimulation of Ca2+ uptake. In conclusion, high glucose stimulates the Ca2+ uptake through L–type Ca2+ channels via G–protein–coupled adenylate cyclase/cAMP and phospholipase C/protein kinase C pathways.
Differential Regulation of Cathepsin B and Prorenin Gene Expression in Renal Juxtaglomerular Cells
Authors: Todorov Vladimir , Müller Markus , Kurtz Armin
Published: April 2003

Cathepsin B (cathB) is a lysosome cysteine proteinase. It has been suggested to process prorenin to renin in the renin producing juxtaglomerular (JG) cells of the afferent arterioles (AA) of the kidney. Whether cathB expression is regulated similarly to prorenin production is yet unknown. We have measured prorenin and cathB mRNA levels as well as cathB protein levels in renal AA of Sprague-Dawley rats subjected to low (0.02% w/w) salt diet and ramipril treatment (10 mg/kg/day), or to normal (0.6%) or high (4%) salt diet. Prorenin and cathB expression were also analyzed in the JG cell line As4.1. Prorenin mRNA levels in animals on normal (plus ramipril), low or high salt diet correlated as 1:10:0.5, respectively, while cathB mRNA levels correlated as 1:1:0.6, respectively. Treatment of the As4.1 cells with 100 nM phorbol-12-myristate-13-acetate (PMA) for 16 h inhibited prorenin mRNA expression 3-fold relative to the control conditions. CathB mRNA abundance was not different between the PMA treated and the control As4.1 cells. Western analysis of the cathB protein abundance has shown no difference between the rats on normal and low salt diet, and decrease by 50% in the rats on high salt diet. The results of this study suggest that prorenin and cathB gene expression in renal JG cells are differentially regulated.
Influences of the N- and C-Termini of the Distal Nephron Inward Rectifier, ROMK
Authors: Bhandari Sunil , Hunter Malcolm
Published: April 2003

The inward rectifying potassium channels of the ROMK family are present in the distal nephron of the kidney. These channels have two membrane spanning portions, between which lies a hydrophobic domain thought to confer the majority of the conductive properties of the channel. The N- and C-termini are both intracellular. In this paper we have examined the contribution of the N- and C-termini to the pore by examining the interaction of Cs+ with the channels. ROMK1 has an additional 19 amino acids on its N-terminus in comparison to ROMK2. The C-terminus of ROMK2 was extended by addition of a streptavidin tag (sfROMK2). Currents were measured following expression in Xenopus oocytes using two-electrode voltage clamp. ROMK1, ROMK2 and sfROMK2 exhibited concentration- and voltage-dependent block of inward currents by extracellular Cs+. The Hill coefficients were not significantly different from one. The mean Kd values at 0 mV were 100.6 ± 10.6, 63.1 ± 3.9 and 40.6 ± 9.4, respectively (p < 0.05). The electric distances (δ) were 0.94 ± 0.06, 1.0 ± 0.05 and 1.37 ± 0.06 respectively. The δ of sfROMK2 was greater than either ROMK1 or ROMK2 (p < 0.001). ROMK1, ROMK2 and sfROMK2 are sensitive to extracellular Cs+. Block was both concentration- and voltage-dependent. sfROMK2 is most Cs+-sensitive. ROMK1 contains an additional N-terminal 19 amino acids. Thus the pore properties of these two isoforms are subtly different, and influenced by the N-terminus. The lower Kd in sfROMK2 suggests that the streptavidin tag, and perhaps the C-terminus, also affect the pore.
Hippurate Metabolism as a Hydroxyl Radical Trapping Mechanism in the Rat Kidney
Authors: Mályusz M. , Kähler W. , Gronow G.
Published: April 2003

Hippurate (Hip) is considered to be the end product of benzoate (BA) metabolism. However, the kidney is able to metabolize Hip. Although only Hip but no BA is present in the blood, rat urine contains under normal conditions less Hip (about 0.4 mM) than BA (about 4.5 mM) and of hydroxylated derivatives of BA (hydroxy-BAs = HB and dihydroxy-BAs = DHB). Generation of HBs and DHBs is the result of radical substitution by free OH radicals (·OH). Thus, rate of synthesis of HBs and DHBs may reflect the production rate of ·OH in the kidney. ·OH generation is elevated following ischemic stress. Therefore, production of HBs and DHBs can be expected to be elevated in postischemic injury. The validity of this assumption was tested in vitro on isolated tubular segments and in vivo in the rat. Metabolism of Hip at 0.1 mmol l–1 (0.1 mM) as well as of BA resulted in enlarged production of both HBs (especially 3-HB and 4-HB) and of DHBs (especially 2,6-DHB). Production of 2,3- and especially of 2,5-DHB was elevated in the presence of high concentration (1.0 mM) of salicylate (2-HB) only. In vivo both in acute (120 min) and in chronic (5 days) experiments ligation of one renal artery for 30 respectively 60 min resulted in enlarged excretion of HBs and DHBs, especially of 2,6- and 3,5-DHB. This finding is noteworthy since (a) formation of 2,6-DHB necessitates as precursor salicylate which could not be detected in our experiments and (b) the spontaneous attack of ·OH upon the benzol ring would prefer the positions 2,3- 2,5- and 3,4-. Therefore, the existence of regulating factor(s) guiding OH groups to definite positions is a distinct possibility. These results indicate that metabolism of Hip leading to hydroxylated BAs may be a renoprotective mechanism against attack of ·OH in reoxygenated renal tissue.
Effects of Sex Hormones on Na+/Glucose Cotransporter of Renal Proximal Tubular Cells following Oxidant Injury
Authors: Han Ho Jae , Park Soo Hyun , Park Hyung Joo , Lee Jang Hern , Lee Byung Cheon , Hwang Woo Suk
Published: April 2003

It was reported that reactive oxygen metabolites play an important role in the pathogenesis of several renal diseases including glomerulonephritis, ischemia and acute tubular necrosis. However, the effect of oxidants and protective effect of sex steroid hormones on Na+/glucose cotransporter of renal proximal tubular cells is not yet elucidated. In the present study, we examined the effect of sex steroid hormones against tert-butyl hydroperoxide (t-BHP)-induced alteration of Na+/glucose cotransporter activity in primary cultured rabbit renal proximal tubule cells (PTCs). t-BHP inhibited α-methyl-D-glucopyranoside (α-MG) uptake in a dose-dependent manner. t-BHP-induced inhibition of α-MG uptake was due not to Km but to the decrease of Vmax. 0.5 mM t-BHP-induced inhibition of α-MG uptake was significantly blocked by estradiol-17β, but not by progesterone and testosterone. This protective effect was not blocked by estrogen receptor antagonist or transcription and translation inhibitor. In addition, 0.5 mM t-BHP increased [3H]-arachidonic acid (AA) release and Ca2+ uptake. These effects of t-BHP were also significantly blocked by estradiol-17β, but not by progesterone and testosterone. Protective efficacy of estradiol-17β on t-BHP-induced inhibition of α-MG uptake is exhibited between antioxidants and iron chelators. In conclusion, estradiol-17β, but not progesterone and testosterone, partially prevented t-BHP-induced inhibition of α-MG uptake through its antioxidant activity dependent upon phenol structures and inhibition of AA release and Ca2+ influx.