bluuebunny/crossref_metadata_2025 huggingface dataset:
The Importance of the Removal of the Intrauterine Device in Genital Colonization by Actinomyces
Authors: Bonacho Isolina , Pita Salvador , Gómez-Besteiro M. Inmaculada
Published: April 2003

Objective: To determine whether, in addition to treatment with antibiotics, it is necessary to remove the intrauterine device (IUD) to eliminate genital colonization by Actinomyces. Methods: A randomized clinical trial was carried out. Patients were divided into two groups. The intervention group did not have their IUDs removed, while the control group did. Both groups were treated with trimethoprim and sulfamethoxazole. A total of 43 patients were included. Results: The patients from the intervention group and the control group proved to be comparable. The post-intervention cytology smear tested negative for Actinomyces in 100% of the patients whose IUD had been removed and in 66.7% of those whose IUD had not been removed (p = 0.005). The probability that colonization by Actinomyces will continue if the IUD is not removed is greater the longer the patient has been exposed to the IUD. After 24 months, relative risk (RR) = 2, after 36 months RR = 2.16 and after 48 months RR = 2.66. Conclusions: The removal of the IUD has been effective in genital colonization by Actinomyces. The protective effect exerted by the removal of the IUD was found to be greater in proportion to the length of time the patient had used it.
Lack of an Association of a Single Nucleotide Polymorphism in the Promoter of the Matrix Metalloproteinase-1 Gene in Czech Women with Pregnancy-Induced Hypertension
Authors: Jurajda Michal , Kaňková Kateřina , Mužik Jan , Unzeitig Vít , Drábková Marie , Izakovičová-Hollá Lydie , Vácha Jiří
Published: April 2003

In preeclampsia the cytotrophoblast invasion of the decidual vessels is reduced. The endothelia in the decidual vessels may influence cytotrophoblast invasion and remodeling of decidual spiral arteries. The decidual endothelial cells from preeclamptic placentas produce less matrix metalloproteinase-1 (MMP1) than those from normal placentas. MMPs form a group of enzymes that are capable of degrading components of extracellular matrix. The present study investigated the prevalence and possible association of an insertion of guanine in the promoter of the MMP1 gene in pregnancy-induced hypertension, preeclampsia and eclampsia in the Czech population. This was a case-control study. No differences were observed in genotype frequencies between cases and controls. The insertion of the guanine in the promoter of the MMP1 gene does not appear to increase the risk of development of pregnancy-induced hypertension, preeclampsia and eclampsia.
Complete Response of a Stage IV Mucinous Cystadenocarcinoma of the Ovary to Systemic Chemotherapy Employing Paclitaxel and Carboplatin
Authors: Yokoyama Yuji , Kaji Hiroyuki , Kondoh Hajime , Takeuchi Eiji , Yamasaki Yoshikazu , Inui Yasunobu
Published: April 2003

Background: The survival rate of patients with advanced-stage mucinous cystadenocarcinoma of the ovary is dismal and no best treatment is known. We report a case of complete response of a stage IV mucinous cystadenocarcinoma of the ovary to systemic chemotherapy employing paclitaxel and carboplatin. Case: A 51-year-old nullipara diagnosed with International Federation of Gynecology and Obstetrics stage IV mucinous cystadenocarcinoma of the ovary underwent cytoreductive surgery followed by systemic chemotherapy employing paclitaxel and carboplatin every 4 weeks for 3 courses. The patient tolerated chemotherapy well, demonstrated a remarkable response showing no evidence of malignancy at a second-look laparotomy. As a consolidation chemotherapy after negative second-look laparotomy, she underwent another three courses of chemotherapy of the same regimen, and is showing no evidence of disease. Conclusion: Paclitaxel and carboplatin may be effective in treating mucinous cystadenocarcinoma of the ovary.
Risk and Prediction of Preterm Delivery in Pregnancies Complicated by Antepartum Hemorrhage of Unknown Origin before 34 Weeks
Authors: Leung Tak Yeung , Chan Lin Wai , Tam Wing Hung , Leung Tse Ngong , Lau Tze Kin
Published: April 2003

Objective: To assess the timing and risk factors of preterm delivery in pregnancies complicated by antepartum hemorrhage of unknown origin (APHUO) before 34 weeks of gestation, and to formulate a clinical management protocol. Methods: A retrospective study involving singleton pregnancies with APHUO occurring before the 34th week of gestation was performed over a 4-year period at a university teaching hospital. Results: Seventy-five cases were identified. Fifty-nine (78.7%) did not have any associated uterine contractions, 74.7 and 90.7% of the cases were classified as having mild bleeding according to history and physical examination, respectively. The number of cases delivering before 37 weeks of gestation and before 34 weeks were 28 (37.3%) and 22 (29.3%), respectively. Eighteen cases (24%) delivered within the first week of APHUO, and 4 (5.3%) within the first day. The number of cases delivering within the first week was significantly higher when there were uterine contractions (62.5 vs. 13.6%, p < 0.001). The severity of bleeding was not shown to be related to the time of delivery. Conclusion: APHUO that occurs before 34 weeks is associated with a high risk of preterm delivery before 34 weeks (29.3%). The chance of delivery within the first week is 62.5% when there are coexisting uterine contractions. Even if contractions are absent, the risk is still high (13.6%) and persists beyond the first week. We suggest that this group of patients should be managed with a course of steroid injection and hospitalization for 4 days.
Localization of Hyaluronan with a Hyaluronan-Specific Hyaluronic Acid Binding Protein in the Placenta in Pre-Eclampsia
Authors: Matejevic D. , Neudeck H. , Graf R. , Müller T. , Dietl J.
Published: April 2003

Hyaluronan (HA), a high molecular weight polysaccharide, is a major component of connective tissue and is thus present in the extracellular matrix of most tissues. Increased serum concentrations have been reported in association with pre-eclampsia and liver malfunction, amongst other disorders. We have performed histochemical investigations with a HA-specific hyaluronic acid binding protein in placentas from uncomplicated pregnancies and from patients with pre-eclampsia. Staining for HA was found in the stroma and blood vessel walls of stem villi in all the placentas investigated. The syncytiotrophoblast and cytotrophoblast cells usually remained unstained. In addition, reactivity for HA was found within and on the surface of intervillous and perivillous fibrinoid deposits. Since fibrinoid deposits are increased in pre-eclampsia, our findings suggest that the increased HA serum concentrations in cases of pre-eclampsia could result from the stroma of the infarcted villi and from the fibrinoid deposits. HA may reach the maternal blood through fibrinoid gaps.
The Lunar Cycle and the Number of Deliveries in Austria between 1970 and 1999
Authors: Waldhoer T. , Haidinger G. , Vutuc C.
Published: April 2003

The effect of the moon on the number of newborns has been investigated extensively with contradictory results but with few significant findings. In this paper, a possible lunar effect is analyzed by a nonlinear Poisson regression model similar to a Fourier analysis based on all children (n = 2,760,362) born in Austria between 1970 and 1999, i.e. 371 lunar cycles. We found no significant effect even when considering the influence of parity and gestation. Our study is in contrast to a French study using a similarly large data base which showed a weak but significant effect. Nevertheless, significant p values based on very large samples must be interpreted cautiously. Our study is in concordance with other studies which often use small and selected samples or rather inefficient statistical methods. We conclude that there is no significant effect of the lunar cycle on the number of deliveries in Austria.
Prediction of the Effect of Metformin Treatment in Patients with Polycystic Ovary Syndrome
Authors: Vrbíková J. , Hill M. , Stárka L. , Vondra K.
Published: April 2003

The objective of the study was to find predictors of a successful therapy with metformin in polycystic ovary syndrome. 24 women with polycystic ovary syndrome were examined (oral glucose tolerance test and gonadotropin-releasing hormone analogue test) before and after a 6-month course of metformin (1 g/day). In 58% of the women, a significant improvement in the menstrual cycle pattern was observed. After a treatment course, a significant reduction in gonadotropin-releasing hormone analogue stimulated levels of testosterone (p < 0.05), free testosterone index (p < 0.01), luteinizing hormone (p < 0.05), and estradiol (p < 0.01) was found. The best prediction of the improvement in menstrual cyclicity after metformin was achieved with a combination of basal values of 17-hydroxyprogesterone, testosterone, sex hormone binding globulin, and androstenedione. These variables correctly classified 86.7% of the responders. The best predictor of changes in the index of free testosterone after metformin treatment was the combination of estradiol and androstenedione in the gonadotropin-releasing hormone analogue test, with basal testosterone correctly classifying 91.7% of the subjects.
Unruptured Pelvic Abscesses in Pregnancy: Report of Two Cases
Authors: Yalcin O.T. , Tanir H.M. , Eskalen M.
Published: April 2003

Pelvic abscess is a rare entity in pregnancy. The true etiology is uncertain but a flare-up of an old pelvic inflammatory disease is most likely. Usually, these patients undergo laparotomy and these abscesses are discovered incidentally, as described in our series. Surgical drainage and conservative surgical procedures under antibiotics are recommended during pregnancy albeit there is no consensus on patient management. Through this report, we aim to discuss this clinical entity and to underline the importance of patient management in case of its diagnosis.
Chlamydienscreening: Ist das Nachweisproblem gelöst?
Authors: Niederhauser C. , Honegger C. , Kaempf L.
Published: April 2003

Fragestellung: Vor dem Hintergrund diskrepanter Nachweisraten von Chlamydia trachomatis bei Frauen mit Verdacht auf eine genitale Infektion wurden im Routinebetrieb drei verschiedene Testsysteme miteinander verglichen. Methode: Bei 594 Frauen wurden Zervixproben entnommen und jeweils eine Polymerasekettenreaktion (PCR) und zwei Immunofluoreszenztests (Chlamyset und Chlamydia direct IF) für den Nachweis von C. trachomatis durchgeführt. War einer dieser drei Tests positiv, wurde zusätzlich das auf die beiden Objektträger (IF-Tests) aufgetragene Material abgekratzt und davon eine PCR durchgeführt. Ergebnisse: Bei 15 von 594 Patientinnen liessen sich die Chlamydien im Zervixabstrich nachweisen. 14 dieser 15 «richtig»-positiven Proben waren mit der PCR positiv, 13 bzw. 8 mit den IFs der Firma Orion und der Firma Biomérieux. Mit dem IF-Test der Firma Orion waren zusätzlich 37 Proben falsch-positiv. Schlussfolgerungen: Der PCR-Test hat sowohl eine hohe Sensitivität als auch eine hohe Spezifität, wobei die Sensitivität durch eine bessere Probenvorbereitung noch optimiert werden kann. Der IF-Test der Firma Biomérieux hat eine gute Spezifität, leider aber eine geringe Sensitivität. Der IF-Test der Firma Orion hat eine sehr hohe Rate an falsch-positiven Resultaten. Zusammenfassend ist zu bemerken, dass die PCR das Potential hat, für den Nachweis von C. trachomatis zu einem neuen Goldstandard zu werden.
Rapid Production of Recombinant Allergens in Nicotiana benthamiana and Their Impact on Diagnosis and Therapy
Authors: Breiteneder H. , Krebitz M. , Wiedermann U. , Wagner B. , Essl D. , Steinkellner H. , Turpen T.H. , Ebner C. , Buck D. , Niggemann B. , Scheiner O.
Published: April 2003

Background: Type I allergies are immunological disorders that afflict a quarter of the world’s population. Recombinant allergens have improved the diagnosis of allergic diseases and allow the formulation of new therapeutic approaches. Over 50% of all allergens are of plant origin. Objective: We have applied a novel method of overexpressing plant allergens in the tobacco-related species Nicotiana benthamiana.Method: This method is based on the use of a chimeric tobacco mosaic virus that harbors a foreign gene sequence and directs its transcription after the infection of the host plant. Results: We have expressed the model allergen Bet v 1, the major birch pollen allergen, and two Hevea brasiliensis latex allergens, the spina-bifida-associated allergens Hev b 1 and Hev b 3, in N. benthamiana using such a viral vector. Bet v 1, Hev b 1 and Hev b 3 produced by this method were recognized by patients’ IgE suggesting that the plant-produced allergens were properly folded. Nonpurified Bet v 1 expressed in N.  benthamiana leaves had the same immunogenicity as purified Bet v 1 expressed in Escherichia coli or natural Bet v 1 when tested in a murine model of type I allergy. Conclusion: We conclude that this plant expression system offers a viable alternative to fermentation-based production of allergens in bacteria or yeasts.
Immune Responses to Birch during the First Seven Pollen Seasons of Life
Authors: Jenmalm M.C. , Björkstén B.
Published: April 2003

Background: Exposure to allergens early in life may have an impact on the incidence of allergy many years later, but the kinetics of the immune responses have still not been studied prospectively. Therefore, we wanted to study the development of immune responses of the Th1 and Th2 type to birch over the first pollen seasons. Material and Methods: Blood samples were obtained from 21 prospectively followed children during the second to the seventh pollen season of life. IgG subclass antibodies to rBet v 1 were analyzed by ELISA, IgE antibodies to birch with Magic LiteTM and birch-induced mononuclear cell proliferation by 3H-thymidine incorporation. Results: Proliferative responses and IgG1 antibodies were commonly seen both in children with and without allergic symptoms and sensitization to birch. Most nonsensitized children had a transient IgG4 antibody response, which was downregulated after the third pollen season, while the titers of this Th2-associated subclass increased with age in sensitized children with clinical symptoms to birch. Conclusions: Immune responses to birch can be demonstrated in children regardless of atopic status. A transient early Th2-like response is downregulated after the third pollen season in nonatopic but not atopic children.
Homing Receptor Expression on Cord Blood T Lymphocytes and the Development of Atopic Eczema in Infants
Authors: Kohno Yoichi , Shimojo Naoki , Kojima Hiroyuki , Katsuki Toshiyuki
Published: April 2003

Expression of the gut-homing receptor integrin αEβ7, but not cutaneous lymphocyte-associated antigen (CLA), on milk allergen-stimulated cord blood T lymphocytes precedes the development of milk-induced eczema in early infancy. The data indicate the involvement of integrin αEβ7 in the development of infantile allergic eczema and provide a clue to the avoidance of specific allergens and novel therapy targeting homing receptors in food allergy.
Purification of the Major Allergen of Red Soft Coral (Dendronephthya nipponica)
Authors: Onizuka Reiko , Kamiya Hisao , Muramoto Koji , Goto Rina , Inoue Kenjiro , Kumamoto Kenshi , Nakajima Yoshito , Iida Sakiko , Ishigami Fumitsugu
Published: April 2003

Red soft coral (RSC; Dendronephthya nipponica, a marine coelenterate) causes spiny lobster fishermen living along the Pacific coast of Miyazaki Prefecture in Japan to develop occupational allergies, such as conjunctivitis, rhinitis, dermatitis and bronchial asthma. The aim of this study was to purify and to characterize RSC allergen, which causes occupational asthma in spiny lobster fishermen. The allergic responsiveness of spiny lobster fishermen to RSC was examined. The examinations included specific IgE production, skin test responses, lymphocyte stimulation tests and specific IgG production. We found that RSC has a strong sensitizing activity in humans at a molecular weight of 10 kD or more, while it has no IgE-producing activity at a molecular weight of less than 10 kD. Neither the nonatopic controls nor the atopic non-coral-allergic controls exhibited any RAST-binding activity to any fraction. For the purification and the identification of this new allergen component, repeated gel filtration of the RSC extract was performed on a Sephacryl S-200 column, followed by gel filtration on a Superose-6 column. The purified major allergen component Den n 1, which is separated on a Mono-Q column, showed intradermal responses, lymphocyte stimulating activity and specific IgG-producing activity in RSC-induced bronchial asthma patients. The 53-kD component was electroblotted on a polyvinylidene difluoride membrane. The N-terminal amino acid sequence of this new allergen component (Den n 1) was determined as Asp-Asp-Ile-Asn-Arg-Tyr-Ala-Phe-Asp-Asn-Lys-Ile-Asn- Asp-Lys-Leu-Phe-Asp-His-Trp-Gln-Ser.
Total Serum IgE Levels in Chronic Hepatitis C: Influence of Interferon Alpha Therapy
Authors: González-Quintela A. , Alende M.R. , Lojo S. , Pérez L.F. , Padín E. , Tomé S. , Vidal C.
Published: April 2003

Background: Liver disease has been considered a prominent cause of IgE elevation. No data on serum IgE levels in chronic hepatitis C have been reported. Interferon-α is a standard therapy for chronic hepatitis C. Cytokine use is a promising type of immunomodulation in the treatment of IgE-mediated diseases. The effects of interferon-α therapy on serum IgE have not been fully evaluated. The aim of the study was to evaluate both serum IgE levels in patients with chronic hepatitis C and the course of these levels after interferon-α therapy. Patients and Methods: Serum IgE was determined in 100 adult patients with chronic hepatitis C (24 atopics according to positive skin prick tests and 76 nonatopics) and in 75 healthy controls (25 atopics and 50 nonatopics). Serum IgE measurements were repeated at 1 and 3 months of therapy with recombinant interferon-α (3 × 106 units s.c. 3 times weekly) in 34 of these patients. Results: Serum IgE levels were similar in chronic hepatitis C patients and in controls when adjusted for atopic status. Among patients with chronic hepatitis C, serum IgE levels were unrelated to liver necroinflammatory activity. A modest but statistically significant increase of IgE values was observed after interferon-α therapy, particularly in patients with no virological response. Conclusions: Chronic hepatitis C is not a significant cause of increased total serum IgE values. Serum IgE increase in some patients with liver disease may be related to the cause of liver injury and not to liver disease per se. Interferon-α therapy in patients with chronic hepatitis C is followed by no modification or even a moderate increase of serum IgE values.
Human Cytomegalovirus Escape from Immune Detection
Authors: Michelson Susan
Published: April 2003

Human cytomegalovirus (CMV) has devised numerous means of escaping immune surveillance. The CMV genome encodes at least 4 genes involved in downregulating surface expression of HLA class I molecules. In addition, it sequesters CC chemokines, induces Fc receptors, interferes with induction of HLA class II antigens, and can inhibit natural killer cell activity. CMV can efficiently block the presentation of immediate early antigens, the first viral proteins to be produced. Together, these mechanisms probably contribute to the ability of CMV to persist in its host and may play a role in the immunopathology of CMV disease.
Measurement of Anti-Human Cytomegalovirus T Cell Reactivity in Transplant Recipients and Its Potential Clinical Use: A Mini-Review
Authors: Kern Florian , Faulhaber Nicole , Khatamzas Elham , Frömmel Claudia , Ewert Ralf , Prösch Susanna , Volk Hans-Dieter , Reinke Petra
Published: April 2003

By allowing direct determination of the frequencies of antigen-specific memory T cells in peripheral blood, novel techniques based on flow cytometry provide new diagnostic opportunities in various clinical settings, including organ transplantation. While the importance of the T cell compartment for the anti-human cytomegalovirus (HCMV) immune response is undisputed, efficient monitoring of this response was previously impossible because the conventional methods for measuring CD4+ and CD8+ T cell responses are too time-consuming and cost-intensive. We analyzed how the rapid induction of anti-HCMV CD4+ and CD8+ memory T cells by HCMV viral lysate or HCMV-derived peptides, respectively, followed by a flow-cytometric detection step, may be used to monitor HCMV-specific CD4+ and CD8+ memory T cells in solid-organ recipients. We also discuss a number of preconditions for integrating such testing into the clinical routine.
Plasmid DNA Vaccines: Tissue Distribution and Effects of DNA Sequence, Adjuvants and Delivery Method on Integration into Host DNA
Authors: Manam Sujata , Ledwith Brian J. , Barnum Amy B. , Troilo Philip J. , Pauley Cindy J. , Harper Laural B. , Griffiths II Thomas G. , Niu Zhutian , Denisova Lyudmila , Follmer Thy T. , Pacchione Stephen J. , Wang Zhibin , Beare Carolann M. , Bagdon Walter J. , Nichols Warren W.
Published: April 2003

A variety of factors could affect the frequency of integration of plasmid DNA vaccines into host cellular DNA, including DNA sequences within the plasmid, the expressed gene product (antigen), the formulation, delivery method, route of administration, and the type of cells exposed to the plasmid. In this report, we examined the tissue distribution and potential integration of plasmid DNA vaccines following intramuscular administration in mice and guinea pigs. We compared needle versus Biojector (needleless jet) delivery, examined the effect of aluminum phosphate adjuvants, compared the results of different plasmid DNA vaccines, and tested a gene (the human papilloma virus E7 gene) whose protein product is known to increase integration frequency in vitro. Six weeks following intramuscular injection, the vast majority of the plasmid was detected in the muscle and skin near the injection site; lower levels of plasmid were also detected in the draining lymph nodes. At early time points (1–7 days) after injection, a low level of systemic exposure could be detected. Occasionally, plasmid was detected in gonads, but it dissipated rapidly and was extrachromosomal – indicating a low risk of germline transmission. Aluminum phosphate adjuvant had no effect on the tissue distribution and did not result in a detectable increase in integration frequency. Biojector delivery, compared with needle injection, greatly increased the uptake of plasmid (particularly in skin at the injection site), but did not result in a detectable increase in integration frequency. Finally, injection of a plasmid DNA vaccine containing the human papilloma virus type 16 E7 gene, known to increase integration in vitro, did not result in detectable integration in mice. These results suggest that the risk of integration following intramuscular injection of plasmid DNA is low under a variety of experimental conditions.
Human Natural Killer Cells in Asymptomatic Human Immunodeficiency Virus-1 Infection
Authors: Hultström A.L. , Hejdeman B. , Leandersson A.C. , Bratt G. , Carbone E. , Wahren B.
Published: April 2003

Objectives: We evaluated whether DNA immunization with HIV-1 regulatory genes change natural killer (NK) effector cell activity. NK cells are the most important cells for the immediate host defense against virus-infected and tumor cells. We analyzed the NK activities of HIV-1-infected individuals against K562 cells (the classical assay) as well as against a CD4+ cell line with and without HIV-1 infection. CD4+ T lymphocytes are the main target cells for HIV-1 infection in vivo. Various proportions of the CD4+ T lymphocyte population carry the HIV-1 genome, produce virus and contribute to the systemic spread of HIV-1. Methods: CD4+ cell lines were established through HTLV-1 transformation which made the cells susceptible to NK lysis. NK activity was then tested in a 51Cr release assay. Results: NK cells of asymptomatic HIV-infected individuals mediated considerable lytic activity against K562 cells as well as against the uninfected and HIV-1-infected CD4+ cell line, and so did the NK cells of HIV-1-infected patients on highly active antiretroviral treatment. Conclusion: DNA immunization with HIV-1-regulatory genes did not significantly change the NK effector cell activity.
DNA-Based Immunization against Lyssaviruses
Authors: Perrin P. , Jacob Y. , Tordo N.
Published: April 2003

Rabies is a fatal encephalomyelitis. Most cases occur in developing countries and are transmitted by dogs. Because of their high cost, cell culture vaccines have not totally replaced the unsafe brain-derived vaccines which are still used in many developing countries. Moreover, there will be a need for vaccines against rabies-related viruses against which classical vaccines are not always effective. DNA vaccines would, therefore, be a valuable alternative for the production of cheaper rabies vaccines against a larger spectrum of viruses. In this review we report published data on DNA-based immunization with sequences encoding rabies and rabies-related virus antigens.
DNA Vaccination against La Crosse Virus
Authors: Pavlovic J. , Schultz J. , Hefti H.P. , Schuh T. , Mölling K.
Published: April 2003

For the development of effective conventional vaccines or DNA vaccines against viruses, the availability of suitable animal models is an essential prerequisite. For many recently emerging zoonotic viruses, suitable animal models are still missing. We have established a novel small animal model for DNA vaccines using mice lacking a functional interferon-α/β receptor (IFNAR-1). IFNAR-1-deficient mice are highly susceptible to many different viruses despite their ability to mount a normal humoral and cellular immune response. Taking advantage of this animal model, we show that mice can be completely protected from lethal challenge with a single injection of plasmid DNA encoding the viral envelope proteins G1 and G2. By contrast, vaccination with a plasmid encoding the internal nucleocapsid protein N had little effect. In an effort to enhance the protective immune response to N we assessed the efficacy of vaccination with plasmid DNA encoding N in combination with a plasmid encoding the cytokine IL-12 as adjuvant. IL-12 enhanced the survival of mice following viral challenge, but the effect was independent of N indicating the involvement of components of the innate immune system such as NK cells.
What Else Can ‘Heparin’ Do?
Authors: Lindahl Ulf
Published: April 2003

This review article begins by discussing the molecular basis of the blood anticoagulant effect of heparin and some species of heparan sulphate (HS). A highly specific pentasaccharide sequence, containing a glucosamine 3-O-sulphate group, is a key structural element for this action. The biosynthesis of heparin and HS is outlined. Different types of HS proteoglycans exist. Analysis of HS preparations from different mammalian organs has indicated that the structural variability of the polysaccharide is due to regulated polymer modification. In addition to antithrombin, HS chains bind a very large number of other proteins in vivo. Such binding often appears to depend on the presence of specific sequences of different monosaccharide building-blocks and has diverse implications. Many physiological and pathological processes in the mammalian body appear to be influenced or regulated by HS proteoglycans. For example, the proper assembly of HS chains is believed to play an important role in normal embryonic and mammalian development. Diseases such as diabetes, amyloidosis and Alzheimer’s may be associated with changes in HS structure. Finally, the possibilities and strategies for developing drugs based on HS chemistry are discussed.
The Use of Heparin for Treating Human Malignancies
Authors: Ornstein Deborah L. , Zacharski Leo R.
Published: April 2003

There is a substantial amount of data implicating coagulation mechanisms in the pathogenesis of malignancy. Studies in some experimental animal models have shown that the anticoagulant heparin limits tumour growth and metastasis and prolongs survival. Experience with the effects of heparin on human malignancy is limited primarily to settings in which it was given either to prevent or to treat thrombosis in patients who also had cancer. However, these studies have shown noteworthy apparent improvement in cancer outcome with heparin, especially with low-molecular-weight heparin. There are several possible mechanisms by which heparin could potentially alter the natural history of cancer progression because of its ability to modify the cellular and molecular environment of tumour cells. This experience provides the rationale for definitive clinical trials of heparin in patients with cancer and also for further experimentation to define the mechanisms of antineoplastic activity by this familiar class of drugs.
Should Patients with Venous Thromboembolism and Cancer Be Treated Differently?
Authors: Smorenburg Susanne M. , Hutten Barbara A. , Prins Martin H.
Published: April 2003

Patients with malignant disease constitute a significant subgroup among patients with venous thromboembolism. Current results suggest that cancer patients are not only at an increased risk for thromboembolic events, particularly during chemotherapy treatment or after surgery, they also have an increased risk for bleeding complications while receiving oral anticoagulant treatment. The exact incidences of venous thromboembolic complications for the various types of cancer, however, are not well determined. Recent studies have indicated that subcutaneous low-molecular-weight heparin (LMWH) is as safe and effective as intravenous unfractionated heparin (UFH) in the initial treatment of venous thromboembolism. Moreover, a meta-analysis has provided preliminary evidence that, compared with UFH, LMWH treatment may prolong survival in cancer patients. Initiation of LMWH treatment in these patients is, therefore, recommended. Prospective randomized clinical trials to assess the optimum dose and duration of therapy are called for.
What Is the Optimal Management of Pregnant Women with Valvular Heart Disease in Pregnancy?
Authors: Chan Wee Shian
Published: April 2003

Women with mechanical heart valves require anticoagulation during pregnancy. Continued anticoagulation with coumadin throughout the first trimester can result in foetopathic effects in 6.4% (95% CI, 4.6–8.9%) of cases. Replacement of warfarin with heparin between 6 and 12 weeks’ gestation eliminates this risk. Although warfarin does cross the placenta, adverse central nervous system effects associated with its use are very few. Warfarin is effective in preventing maternal thromboembolic complications, while the effectiveness of heparin in preventing valve thrombosis is unproven. The optimal management (grade C2 recommendation) of women with mechanical heart valves may involve the use of warfarin throughout pregnancy except for two time periods – between 6 and 12 weeks’ gestation and after 36 weeks of gestation. During these times, adjusted-dose unfractionated heparin should be used to rigorously maintain a therapeutic mid-interval activated partial thromboplastin time of 2.0 to 2.5 times the control. The additional use of low-dose aspirin should be considered, particularly in women with high-risk valves, women with previous transient ischaemic attacks and/or strokes, and women with atrial fibrillation.
Intestinal Absorption of Low Molecular Weight Heparin in Animals and Human Subjects
Authors: Nissan Aviram , Ziv Ehud , Kidron Miriam , Bar-On Hanoch , Friedman Gideon , Hyam Esther , Eldor Amiram
Published: April 2003

Introduction: We had previously shown that the use of bile salts, which act as surfactants, facilitates the intestinal absorption of large molecules such as those of heparin and insulin. However, the bioavailability of unfractionated heparin (UFH) administered through the large intestine was low. The aim of the present study was to evaluate the absorption of low molecular weight heparin (LMWH) combined with bile salts through the gut mucosa in animals and human subjects. Materials and Methods: LMWH (Fragmin, Kabi-Pharmacia, Stockholm) or UFH with or without sodium cholate (Sch) was administrated rectally in rats and healthy volunteers via a microenema. Absorption was estimated by the activated partial thromboplastin time (aPTT), the plasma anti-factor Xa activity and the plasma lipoprotein lipase (LPL) activation. Results: In groups of 6 rats, LMWH at doses of 100–1,000 U with sodium cholate (10–20 mg/ml) was readily absorbed through the gut mucosa, as indicated by both, anti-factor Xa levels of up to 1 U/ml and a dose-dependent activation of LPL. The absorption was significantly superior to that of UFH with Sch or LMWH given without Sch (p < 0.001). The plasma anti-factor Xa levels in the 6 healthy volunteers who received a microenema containing 25,000 U of LMWH with 20 mg/ml of Sch were 0.38 U/ml at 15 min and 0.1 U/ml at 240 min. LPL activation and aPTT prolongation were also observed in these subjects. The plasma LMWH levels after rectal application were in the same range as those obtained after subcutaneous administration, however the elimination time (t½) was shorter. There were no adverse reactions. Conclusions: Intestinal absorption of LMWH facilitated by Sch is both feasible and safe. A slow release formulation will be needed to prolong the plasma half-life.
Mathematical Derivative Applied to International Normalised Ratio and Analytical Variations in Oral Anticoagulant Therapy Control
Authors: Introcaso G. , Cuboni A. , Ratto A. , Foieni F.
Published: April 2003

A reliable prothrombin time (PT) testing and a careful drug dosage can prevent thrombotic or bleeding complications of the oral anticoagulant therapy. The international normalised ratio (INR) as PT standardisation introduced an analytical variation that increases with higher PT measures and higher international sensitivity index (ISI) values. Our study was conducted to investigate the INR accuracy through the mathematical derivative application to reduce the analytical component of the INR uncertainty. The evaluation of accuracy among four different systems (prothrombin activity percent, PT seconds, PT ratio and INR) was determined by the simulation of a systematic error. Plasma samples were diluted 1:2; then they were compared observed with the expected values. We analysed the calculation system of the INR through the mathematical derivative in 87 PT ratio measurements. The analytical incidence of thromboplastin ISI was performed through an elaboration of INR mathematical derivative considering 10 different ISI values ranging from 1.1 to 2. The data expressed as PT ratios revealed a lower systematic error propagation suggesting that a linear system is more accurate. According to the calculation formula of INR, analytical variability increases with the PT measurements, then with the intensity of anticoagulation. Mathematical derivative suggests that the INR uncertainty due to the ISI can be reduced using a thromboplastin reagent with a low ISI or with ISI close to 1.
A New Approach to Antiplatelet Therapy: Inhibitor of GPIb/V/IX-vWF Interaction
Authors: Ikeda Yasuo , Handa Makoto , Murata Mitsuru , Goto Shinya
Published: April 2003

Evidence has been presented that the interaction between von Willebrand factor (vWF) and its platelet membrane receptor, the GPIb/V/IX complex, plays an important role in the pathogenesis of arterial thrombosis. A monoclonal antibody against the A1 domain of vWF has been shown to inhibit thrombus formation in the animal model of arterial thrombosis. Based upon these findings, a new approach to treating arterial thrombosis has been proposed by intervening in the interaction between vWF and platelet.
Differential Effects of Enalapril and Irbesartan in Experimental Papillary Necrosis
Authors: Garber Sandra L. , Mirochnik Yelena , Arruda Jose A.L. , Dunea George , Slobodskoy Leonid
Published: April 2003

This study was undertaken to determine whether angiotensin receptor blockers are as renoprotective as angiotensin-converting enzyme inhibitors in an experimental model of chronic interstitial renal disease. Groups of rats received one of the following treatments for 1 week: (1) enalapril, (2) diltiazem, (3) a cocktail of hydralazine, reserpine, and hydrochlorothiazide, or (4) irbesartan (an AT1 antagonist). The animals were injected with bromoethylamine (200 mg/kg), and antihypertensive treatment continued for 1 month. All drugs were effective in lowering the mean arterial pressure. The bromoethylamine-treated rats developed albuminuria and sustained a 40–50% decrease in creatinine clearance. Enalapril and irbesartan reduced albuminuria, but only enalapril partially prevented the decline in creatinine clearance and lowered the number of ED-1-positive cells. Diltiazem and cocktail had no effect on proteinuria, creatinine clearance, or ED-1 cells. In this experimental model, the effects of enalapril and irbesartan were not identical. Both drugs reduced proteinuria, but enalapril was more effective in protecting the renal function. The fact that the AT1 antagonist protected against albuminuria but did not affect the clearance of creatinine implies that the results seen with angiotensin-converting enzyme inhibition may be in part due to an effect on angiotensin II via AT2 receptor blockade or through an effect on bradykinin.
Solitary Nodular Goiter: Role of Ultrasonography in Fine-Needle Aspiration Cytology Diagnosis
Authors: Das Dilip K. , Pant Chandra S. , Chachra Krishan L. , Mandal Ashish K. , Kumar Rajan , Ganguly Saroj K. , Bhambhani Suresh , Tripathy Rajendra P.
Published: April 2003

Purpose: To assess the contribution of ultrasonography to the fine-needle aspiration cytology diagnosis of solitary nodular goiters (SNG). Methods: 759 cases of SNG detected by ultrasonography were subjected to fine-needle aspiration. The age of the patients ranged from 9 to 92 years with a median of 35 years. Male:female ratio was 135:624. May-Grünwald-Giemsa-stained smears were reviewed and the cytodiagnosis was correlated with clinical and ultrasonographic findings. Results: The right lobe of the thyroid was more frequently involved (52.3% cases) by solitary nodules compared to the left lobe (33.9% cases) and isthmus (13.8% cases). 27% of SNG cases missed at clinical examination could be detected because of ultrasonography. The frequency of solid echotexture in colloid goiter without cytologic evidence of cystic degeneration (60.3%) was significantly higher than that observed in colloid goiter with cystic degeneration (32.6%, p < 0.001). The difference of solid echotexture between hyperplastic nodules (55.4%) and colloid goiter (38.5%) was also statistically significant (p < 0.02). The frequency of solid echotexture and homogeneous hypoechoic pattern in neoplastic goiter (65.4 and 21.2%, respectively) was significantly higher than that in nonneoplastic lesions (43.3 and 8.6%, respectively, p < 0.01). Conclusion: Ultrasonography, besides its use in the detection of solitary nodules and selection of appropriate areas for aspiration, correlated with cytological interpretation in the majority of cases. However, ultrasonography cannot replace cytologic diagnosis as the specificity and positive predictive values are not sufficiently accurate.
Blockade of Nitric Oxide Formation Enhances Thermal and Behavioral Responses in Rats during Turpentine Abscess
Authors: Soszynski Dariusz
Published: April 2003

Objective: The purpose of this study was to investigate the role of nitric oxide (NO) during the development of fever and other symptoms of sickness behavior (i.e. anorexia, cachexia) in response to localized tissue inflammation caused by injection of turpentine in freely moving biotelemetered rats. Methods: To determine the role of NO in turpentine-induced fever, we injected the NO synthase (NOS) inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) intraperitoneally simultaneously or 5 h after turpentine injection. Results: Rats responded with fever to intramuscular injection of 20 µl of turpentine that commenced 6 h after injection and reached peak values 11 h after injection. Although turpentine did not significantly alter food and water intake, it caused a drop in body weight. Rats injected with turpentine and treated with L-NAME responded with a substantial rise in fever, independently of the time of L-NAME injection. The rise in body temperature (Tb) due to turpentine injection began slightly sooner and reached the maximal Tb value faster in rats treated with L-NAME than in the ones treated with saline (control for L-NAME). The enhanced decrease in food and water intake in rats treated with a combination of L-NAME and turpentine was also observed. As a result, L-NAME-injected rats responded with a profound drop in body mass due to turpentine, independently of the time of L-NAME injection. L-NAME alone did not affect food and water intake, but slightly suppressed the gain of body mass. Conclusion: These results indirectly indicate that NO is involved in pyrogenic and behavioral responses in rats during turpentine abscess.
Growth Hormone Prevents Fas-Induced Apoptosis in Lymphocytes through Modulation of Bcl-2 and Caspase-3
Authors: Mitsunaka Hiroki , Dobashi Hiroaki , Sato Makoto , Tanaka Terukazu , Kitanaka Akira , Yamaoka Genji , Tokuda Michiaki , Matoba Kenichiro , Hiraishi Takashi , Ishida Toshihiko
Published: April 2003

Objective: Growth hormone (GH) has been reported to have a potent effect on the immune system. However, the detailed mechanism of the effect of GH on the immune system has not yet been clarified. This study was designed to investigate the nature of this mechanism. Methods: In the present study, we investigated the effects of GH on the susceptibility of both human CEM/C7 lymphocytes and human IM-9 lymphocytes to Fas-induced apoptosis. Results: Both cell lines expressed GH receptor mRNA. GH rescued Fas-induced suppression of [3H]-thymidine incorporation into each cell line. GH prevented Fas-induced apoptosis in each cell line without changing Fas antigen expression. We next investigated the mechanisms of the prevention of Fas-induced apoptosis, by focusing on intracellular molecules related to the apoptotic signal. Bcl-2 expression was increased by GH treatment in both CEM/C7 and IM-9 lymphocytes. GH also downregulated caspase-3 expression and inhibited activation of caspase-3 in both cell lines. Conclusion: These findings suggest that GH regulates the human immune system through inhibition of Fas-induced apoptosis in activated T and B lymphocytes.
Does Gonadotropin-Releasing Hormone in the Cerebrospinal Fluid Modulate Luteinizing Hormone Release?
Authors: Skinner Donal C. , Caraty Alain , Evans Neil P.
Published: April 2003

The function of gonadotropin-releasing hormone (GnRH) in the cerebrospinal fluid (CSF) is unknown. This study on ovariectomized ewes investigated whether CSF-GnRH has a role in modulating luteinizing hormone (LH) secretion either through an ultrashort-loop feedback system to affect GnRH secretion or to directly act on the pituitary gland after entering the hypothalamo-hypophysial portal system. In the first experiment, a 3-hour continuous infusion of exogenous GnRH (700 or 7 pg/min; n = 8) was administered into the third ventricle through a permanent indwelling cannula. Jugular LH concentrations were measured as an estimate of the activity of the GnRH ‘pulse generator’. To assess the potential for a direct involvement of CSF-GnRH in pituitary stimulation of LH secretion, ewes were also implanted with a cannula to collect hypophysial portal blood. In a first investigation, radioactive (2 × 106 cpm 125I-GnRH; n = 3) GnRH was injected into the third ventricle, and the amount of radioactivity present in the portal and jugular blood after the injection measured. In a second investigation, cold GnRH was infused (400 pg/min; n = 3) into the third ventricle for 2 h, and portal and jugular blood collected for the determination of GnRH and LH concentrations, respectively. In the first experiment, neither rate of infusion of GnRH into the third ventricle had any effect on the mean interpulse interval, nadir, pulse amplitude or circulating level of systemic LH, suggesting that CSF-GnRH is not a component of an ultrashort-loop feedback system for GnRH. Furthermore, in the second experiment, despite extremely low levels of radioactivity (maximum: 120 cpm/ml) being detected in hypophysial portal blood (which may not have been intact decapeptide), in the second part of this experiment, no radioimmunoassayable GnRH associated with the period of infusion could be measured. These data demonstate in ewes that little, if any, CSF-GnRH reaches the hypophysial portal blood, and this compartment of GnRH does not, thus, directly affect the pituitary gland. The present study strongly suggests, therefore, that CSF-GnRH does not modulate LH secretion. Whether this compartment of GnRH is involved in sexual behavior remains to be established.
Role of Vasoactive Intestinal Peptide and 5-HT2 Receptor Subtype in Serotonin Stimulation of Basal and Thyrotropin-Releasing-Hormone- Induced Prolactin Release in vitro from Rat Pituitary Cells
Authors: Apfelbaum Marta E.
Published: April 2003

We have previously demonstrated that 5-HT stimulates not only basal but also thyrotropin-releasing-hormone (TRH)-induced prolactin (PRL) release by acting directly at the pituitary gland level. In the present report, the participation of an autoparacrine action of VIP in the stimulatory effects of 5-HT and the involvement of the 5-HT2 receptor type in mediating serotonin-induced PRL release have been examined. Cultured anterior pituitary cells from ovariectomized adult rats were incubated for 1 h in 1 ml of T3-supplemented medium with or without the test substances. The results obtained in the presence of T3 confirm our previous observations, since treatment of the cells with 5-HT caused dose-dependent increases in basal PRL release, with an approximate EC50 of 3.68 × 10–8 M, and led to a significant potentiation (1.3-fold) of the TRH-induced PRL release. In order to evaluate the possible participation of vasoactive intestinal peptide (VIP) as mediator of the effects of 5-HT on PRL release, cells were incubated in the presence of 5-HT alone (3–1,000 nM) or 100 nM 5-HT plus 30 nM TRH, with or without 200 nM VIP antagonist (VIP-At): [D,4-Cl-Ph6,Leu17]VIP. VIP-At partially inhibited the release of PRL induced by 5-HT, both basal and TRHstimulated release. The stimulatory effect of 5-HT, however, was not eliminated by VIP-At, since the PRL released in response to 5-HT was still over the respective control ones. These results further support the findings suggesting that 5-HT acts directly at pituitary level by stimulating PRL release. Addition of the 5-HT2 receptor antagonist, ketanserin (1 µM) into the incubation medium resulted in the loss of cellular responsiveness to 5-HT, preventing not only the stimulatory effect of 5-HT on the basal but also on the TRH-induced PRL release. In conclusion, the results further strengthen the possibility that 5-HT increases the basal PRL release and potentiates the stimulatory effect of TRH by acting directly at the level of the lactotropes. These effects are not simply a consequence of autoparacrine action of VIP. In addition, it was shown that ketanserin completely antagonizes PRL response to 5-HT, indicating the involvement of the 5-HT2 receptor type in mediating PRL release.