bluuebunny/crossref_metadata_2025 huggingface dataset:
Intra-Arterial Bone Marrow Cell Transplantation Induces Angiogenesis in Rat Hindlimb Ischemia
Authors: Yoshida M. , Horimoto H. , Mieno S. , Nomura Y. , Okawa H. , Nakahara K. , Sasaki S.
Published: April 2003

Background: Bone marrow (BM) cells have been shown to augment local angiogenesis by differentiating vessels themselves and/or secreting paracrinally angiogenic growth factors. Herein, the angiogenic effects of intra-arterial BM mononuclear cell (BM-MNC) transplantation were evaluated in a rat ischemic hindlimb model. Methods: Unilateral hindlimb ischemia was created by excising the femoral artery and its branch in Lewis rats. BM-MNCs were isolated by centrifugation through a Histopaque density gradient. One week after excision of the unilateral femoral artery, BM-MNCs (5 × 106 cells, Group A, n = 6) or PBS (Group B, n = 7) were injected into the ischemic thigh skeletal muscles at the six points with a gauge needle. Another injection of BM-MNCs (3 × 107 cells, Group C, n = 6) or PBS (Group D, n = 7) was administered via the indwelling catheter in the right common iliac artery. Results: Four weeks after the BM-MNC transplantation, angiographic examination revealed the development of collateral vessels in both BM-MNC-transplanted groups. The difference in skin temperature between right and left hindlimbs was significantly reduced in both BM-MNC-transplanted groups (0.93 ± 0.15 vs. 2.84 ± 0.35 vs. 1.20 ± 0.26 vs. 2.61 ± 0.37°C, Group A vs. Group B vs. Group C vs. Group D, p < 0.05). Moreover, immunohistochemical analysis demonstrated that capillary endothelial cells were increased in both BM-MNC-transplanted groups. Conclusion: BM-MNC implantation was able to induce functional neovascularization in rat ischemic hindlimb. The intra-arterial administration offered similar levels of angiogenic activity as intramuscular injection.
Effect of a Recombinant Lectin, Viscum album Agglutinin on the Secretion of Interleukin-12 in Cultured Human Peripheral Blood Mononuclear Cells and on NK-Cell-Mediated Cytotoxicity of Rat Splenocytes in vitro and in vivo
Authors: Hajto Tibor , Hostanska Katarina , Weber Klaus , Zinke Holger , Fischer Janos , Mengs Ulrich , Lentzen Hans , Saller Reinhard
Published: April 2003

A plant lectin, Viscum album agglutinin-I (VAA-I) has been shown to increase the number and cytotoxic activity of natural killer (NK) cells in animal models, but the mechanisms underlying these effects are poorly understood. We investigated the effects of the recombinant form of this lectin (rVAA) on secretion of interleukin (IL)-12 and on NK-mediated cytotoxicity against K562 target cells in cultures of human peripheral blood mononuclear cells (PBMC) as well as against YAC-1 target cells in cultured rat spleen cells. In 24-hour cultures of PBMC, 10 ng/ml plant VAA-I and 50 ng/ml rVAA induced significant increases in the secretion of total IL-12. Its biologically active heterodimeric form, p70, was also significantly induced by rVAA. Preincubation of PBMC or splenocytes for 48 h with rVAA in concentrations ranging between 10 pg/ml and 100 pg/ml resulted in moderate enhancements of NK-mediated cytotoxicity. However, coincubation of a low dose of rVAA (100 pg/ml) together with IL-2 and IL-12 (60 U/ml and 2 U/ml, respectively) led to additive stimulation of NK activity. In in vivo experiments, rVAA showed an enhancing effect on NK activity with a bell-shaped curve of efficacy. Forty-eight hours after a single intravenous injection of its most effective doses, 0.5 and 1 ng/kg, into Wistar rats, the NK cytotoxicity of splenocytes against YAC-1 targets doubled, and the frequency of large granular lymphocytes in peripheral blood showed 2.1- and 3-fold increases as compared to control animals. Twenty-four hours following these low lectin doses, the number of large granular lymphocytes was also significantly elevated. After 48 h, 0.5 ng/kg rVAA induced a significant augmentation in the percentage of peripheral Mac-1+ mononuclear cells, including activated monocytes and NK cells. The present results suggest that rVAA augments the secretion of an active form of IL-12 and potentiates the cytokine-induced NK activation. These effects of rVAA may be related to its stimulatory effects on MHC-unrestricted cytotoxicity in vivo.
Natural Anti-Immunoglobulin Autoantibodies: Irrelevant By-Products or Immunoregulatory Molecules?
Authors: Terness P. , Opelz G.
Published: April 2003

Anti-immunoglobulin autoantibodies (anti-Ig auto-Abs), particularly IgM-anti-IgG (classical rheumatoid factor), have been studied mainly in the context of rheumatoid arthritis. In this article we focus on other members of the anti-Ig family, including the natural IgG-anti-F(ab′)2 auto-Ab, and look for clinical and experimental findings supporting a role of these antibodies in the regulation of the immune response. We discuss the evidence for suppression of auto- and alloreactive B cells by IgG-anti-F(ab′)2 auto-Ab and the role of this Ab in the pathogenesis of certain diseases, such as autoimmune hemolytic anemia. The structure of the antibody’s antigen-binding site was clarified by isolating the VL and VH gene segments from the cDNA of B cells. Sequence analyses revealed germline gene identity of VL chains and 88% homology with the closest germline gene of VH chains. Finally, we discuss hypothetical models concerning the immunoregulatory role of natural anti-Ig auto-Abs.
Lactobacillus casei Inhibits Antigen-Induced IgE Secretion through Regulation of Cytokine Production in Murine Splenocyte Cultures
Authors: Shida Kan , Makino Kumiko , Morishita Aki , Takamizawa Kotaro , Hachimura Satoshi , Ametani Akio , Sato Takehito , Kumagai Yoshihiro , Habu Sonoko , Kaminogawa Shuichi
Published: April 2003

Background:Lactobacillus casei is a nonpathogenic gram-positive bacterium widely used in dairy products and has been shown to enhance the cellular immunity of the host. Methods: To examine the inhibitory effect of L. casei on IgE production, splenocytes obtained from ovalbumin (OVA)-primed BALB/c mice were restimulated in vitro with the same antigen in the presence of heat-killed L. casei. The effect of this bacterium on T helper (Th) phenotype development was also examined with naive T cells from OVA-specific T cell receptor-transgenic mice. Results:L. casei induced IFN-γ, but inhibited IL-4 and IL-5 secretion, and markedly suppressed total and antigen-specific IgE secretion by OVA-stimulated splenocytes. The inhibitory effect of L. casei on IgE, IL-4, and IL-5 production was partially abrogated by addition of neutralizing antibody to IFN-γ. Augmented IL-12 production was also observed in the cell cultures containing L. casei, and anti-IL-12 monoclonal antibody completely restored the IgE, IL-4, and IL-5 production to the control levels. The IL-12 augmentation by L. casei was macrophage-dependent. The Th cell development assay showed the ability of L. casei to induce Th1 development preferentially. This effect was also completely blocked by anti-IL-12 antibody. Conclusions: This is the first demonstration that a nonpathogenic microorganism, L. casei, can inhibit antigen-induced IgE production through induction of IL-12 secretion by macrophages. The findings suggest a potential use of this organism in preventing IgE-mediated allergy.
Histamine-Stimulated Cytokine Secretion from Human Conjunctival Epithelial Cells: Inhibition by the Histamine H1 Antagonist Emedastine
Authors: Weimer L.K. , Gamache D.A. , Yanni J.M.
Published: April 2003

The present studies demonstrate that histamine induces the secretion of IL-6, IL-8 and GM-CSF from human conjunctival epithelial cells in a dose- and time-dependent manner. The histamine antagonists emedastine (H1), ranitidine (H2) and thioperamide (H3) were evaluated for their ability to inhibit secretion of these cytokines. Emedastine potently inhibited histamine-induced IL-6, IL-8 and GM-CSF secretion with mean IC50 values of 2.23, 3.42 and 1.50 nM, respectively. Ranitidine and thioperamide failed to inhibit cytokine secretion over a wide dose range. These data suggest that mast cell derived histamine may stimulate inflammatory cytokine production in allergic conjunctivitis via activation of epithelial cell H1 receptors. The histamine H1 antagonist emedastine potently inhibits this response.
Ultraviolet A Radiation (320–400 nm) Protects Hairless Mice from Immunosuppression Induced by Ultraviolet B Radiation (280–320 nm) or Cis-Urocanic Acid
Authors: Reeve V.E. , Bosnic M. , Boehm-Wilcox C. , Nishimura N. , Ley R.D.
Published: April 2003

T cell-mediated immune function, here measured as the contact hypersensitivity reaction, is readily suppressed by moderate exposure of mice to ultraviolet B (UVB) or solar-simulated radiation (SSUV), or by topical application of cis-urocanic acid. The effect of ultraviolet A (UVA) radiation on immune function has been unclear. Here we have demonstrated that when UVA radiation from a fluorescent tube source was rigorously filtered to remove contaminating UVB radiation, it was immunologically innocuous at physiologically relevant doses. Furthermore, we have found that mice exposed to UVA radiation, either immediately after, or up to 24 h before, immunosuppressive treatment with either UVB radiation, SSUV or cis-urocanic acid, became refractory to the immunosuppression and retained more normal contact hypersensitivity. A greater UVA exposure reversed the immunosuppression more effectively. The results suggest that there are immunologically significant interactions between UV wavebands, and that UVA exposure may induce a relatively long-lived immunoprotective photoproduct, as yet unidentified, that can inhibit the activity of epidermal cis-urocanic acid and thus provide protection from photoimmunosuppression.
The Hemodynamic Effects of Internal Carotid Artery Stenting: A Study with Color-Coded Duplex Sonography
Authors: Lu Chien-Jung , Kao Hsien-Li , Sun Yu , Liu Hon-Man , Jeng Jiann-Shing , Yip Ping-Keung , Lee Yuan-Teh
Published: April 2003

Background: Stenting has been used as an alternative treatment for patients with internal carotid artery (ICA) stenosis. Color-coded duplex sonography (CDS) is able to measure not only the prestenting stenosis but also the poststenting hemodynamic changes. The purpose of this study was to quantify, using CDS, the hemodynamic changes after ICA stenting. Methods: Both symptomatic and asymptomatic patients were included in this study. The degree of ICA stenosis before stenting was required to be more than 50%. Thirty-two treated ICAs were included to compare the prestenting and poststenting CDS findings, including the diameter and cross-sectional area of the lumen, the flow peak systolic and end-diastolic velocities, the resistivity index and the amount of flow in bilateral extracranial carotid and vertebral arteries. Results: After stenting, the turbulent flow pattern in the stenotic ICA recovered to laminar flow, and the reversed ophthalmic flow direction normalized. Of the CDS parameters applied to evaluate the effect of stenting on ICA stenosis, the diameter, residual area, peak systolic velocity, diastolic velocity and the ration of systolic flow velocity ratio in the ICA to that in the common carotid artery (CCA) were altered significantly. The mean area and residual area of these stenotic ICAs showed increases of 24% (p = 0.005) and 84% (p = 0.001) after ICA stenting, respectively. The mean peak systolic flow velocity significantly decreased by 71%. The mean diastolic flow velocity also significantly decreased (by 77%). Both the systolic and diastolic velocities of the ipsilateral CCA significantly increased after stenting. The amount of flow in the contralateral ICA decreased significantly after stenting. The change in the amount of flow in the vertebral arteries after ICA stenting was insignificant. Conclusions: The results of this CDS study clearly demonstrated the hemodynamic changes after ICA stenting. The carotid stenting significantly changed the ICA flow pattern, diameter, residual area, peak systolic velocity and ICA to CCA velocity ratio.
Local Intra-Arterial Fibrinolysis in Acute Hemispheric Stroke: Effect of Occlusion Type and Fibrinolytic Agent on Recanalization Success and Neurological Outcome
Authors: Eckert Bernd , Kucinski Thomas , Neumaier-Probst Eva , Fiehler Jens , Röther Joachim , Zeumer Hermann
Published: April 2003

Background: To evaluate the effect of occlusion type and fibrinolytic agent on recanalization success and clinical outcome in patients undergoing local intra-arterial fibrinolysis (LIF) in acute hemispheric stroke. Methods: LIF was performed in 137 patients with angiographically established occlusion in the carotid circulation within 6 h of stroke onset. Retrospective analysis included recanalization success, recanalization time, type of occlusion and fibrinolytic treatment mode. Five types of occlusion were categorized: intracranial bifurcation (carotid ‘T’) of the internal carotid artery (ICA; n = 35); proximal segment of the middle cerebral artery (MCA; n = 66); distal segment of the MCA (n = 20); extracranial ICA with MCA embolism (n = 8); multiple peripheral branches of the anterior cerebral artery and the MCA (n = 8). Neurologic outcome was evaluated after 3 months by Barthel Index (BI) as good (BI >90), moderate (BI 50–90), poor (BI <50) or death. Results: Recanalization was achieved in 74 patients (54%). Mean recanalization time in recanalized patients was 91 min. Neurologic outcome was good in 48 patients (35%), moderate in 34 (25%), poor in 30 (22%) and 25 died (18%). Outcome was significantly better in recanalized than in nonrecanalized patients (p < 0.001). Treatment results were significantly better in proximal and distal MCA occlusion than in carotid ‘T’ occlusions (p < 0.001). Recanalization success hardly differed between urokinase and rt-PA. Combined treatment with rt-PA and lys-plasminogen tended toward a faster recanalization. Parenchymal hemorrhage occurred in 13 patients (9%). Conclusion: The type of occlusion is of high prognostic value for successful fibrinolysis in the anterior circulation. However, recanalization is a time-consuming process even with an intra-arterial approach. Recanalization did not differ between type or dosage of plasminogen activators. Further innovative attempts are warranted towards hastening recanalization time in endovascular acute stroke treatment.
Stereotactic Radiosurgery for Well-Circumscribed Fibrillary Grade II Astrocytomas: An Initial Experience
Authors: Hadjipanayis Constantinos G. , Niranjan Ajay , Tyler-Kabara Elizabeth , Kondziolka Douglas , Flickinger John C. , Lunsford L. Dade
Published: April 2003

Objective: To examine the role of stereotactic radiosurgery in the management of patients with progressive, well-circumscribed grade II fibrillary astrocytomas. Methods: During a 13-year interval, 12 patients (median age: 25 years) required multimodality management for recurrent or unresectable World Health Organization (WHO) grade II fibrillary astrocytomas. Tumors involved the brainstem (n = 4), thalamus (n = 1), cerebellum (n = 1), frontal lobe (n = 4), temporal lobe (n = 1), and parietal lobe (n = 1). Diagnosis was confirmed by stereotactic biopsy (n = 5), partial resection (n = 5), and near total resection (n = 2). Multimodality management of patients prior to radiosurgery included fractionated radiation therapy (n = 4), stereotactic cyst drainage (n = 1), and ventriculoperitoneal shunt placement (n = 2). Tumor volumes varied from 1.2 to 45.1 cm3. The median radiosurgical dose to the tumor margin was 16 Gy. Results: After radiosurgery, serial imaging showed complete tumor resolution in 1 patient, reduced tumor volume in 4, stable tumor volume in 3, and delayed tumor progression in 4 (3 patients with increase in cyst size only). Therapy after radiosurgery included additional cytoreductive surgery (n = 1) for recurrence of a higher grade tumor, stereotactic cyst aspiration (n = 1), and stereotactic intracavitary irradiation (n = 1). All patients were alive at a median follow-up of 52 months after radiosurgery and 103 months after diagnosis. In 8 patients, follow-up lasted more than 60 months. Conclusion: Stereotactic radiosurgery is a potential alternative or adjunctive strategy in the management of selected patients with WHO grade II fibrillary astrocytomas.
Stereotactic Management of Craniopharyngiomas
Authors: Pollock Bruce E. , Natt Neena , Schomberg Paula J.
Published: April 2003

Eleven patients with craniopharyngiomas underwent 13 stereotactic procedures (intracavitary irradiation, n = 7; radiosurgery, n = 6). Nine patients (82%) had recurrent tumors after prior surgery (median, 2 operations). The median patient age was 50 years (range, 6–63 years). At a median follow-up of 38 months (range, 24–102 months), no patient had progression of the treated tumor component. Two patients developed new cysts, so the actuarial 2- and 4-year progression-free survival rates were 91 and 73%, respectively. Visual function improved in 3 patients, remained stable in 6 patients, and worsened in 1 patient. Two patients (both without prior surgery) not having diabetes insipidus pre-operatively continued to have normal posterior pituitary function. Stereotactic techniques should be considered for patients with craniopharyngiomas, especially those who have failed prior surgical resection.
Nasal Cytology and Genotoxic Damage in Nasal Epithelium and Leukocytes: Asthmatics versus Nonasthmatics
Authors: Fortoul Teresa Imelda , Valverde Mahara , López Maria del Carmen , López Irma , Sánchez Ivonne , Avila-Costa Maria Rosa , Avila-Casado Maria del Carmen , Mussali-Galante Patricia , Soria Elizabeth , Rojas Emilio
Published: April 2003

Background: The best example of a chronic inflammatory respiratory disease is asthma, a disease which has an increasing prevalence worldwide. This chronic inflammation is also related to the generation of oxidative stress since the cells involved in the allergic reaction are capable of producing reactive oxygen species (ROS), and this might predispose asthmatics to increased genotoxic damage. Methods: A respiratory symptomatology questionnaire was self-applied by asthmatic and nonasthmatic students. A single cell gel electrophoresis assay in two different cell types (nasal epithelial cells and leukocytes) was performed, and the cytology of the nasal smears stained with HE was evaluated. Results: Both groups reported having a runny nose. Asthmatics had greater DNA damage in the nasal epithelial cells in contrast to nonasthmatics. In leukocytes no statistical significance in DNA damage was identified. Metaplasia was evident in asthmatics that also showed eosinophils and neutrophils as well as goblet cells and mucus at a higher frequency compared with nonasthmatics. Conclusions: Nasal symptoms did not correlate with genotoxic damage, since they were reported in both groups. Nasal epithelial cells of asthmatics are more sensitive to genotoxic damage, and chronic inflammatory response. Also the activity of eosinophils might mediate the DNA damage through the generation of ROS.
Mast Cells in Basal Cell Carcinoma Express VEGF, IL-8 and RANTES
Authors: Aoki Mikako , Pawankar Ruby , Niimi Yayoi , Kawana Seiji
Published: April 2003

Background: Basal cell carcinoma (BCC) is the most common malignant tumor of the skin. Although an increase in mast cell infiltration was observed in BCC lesions, definite evidence of an active role of mast cells in the pathogenesis of BCC is still lacking. BCC is accompanied by cellular infiltrates. Moreover, the stroma in the BCC lesions is characterized by an increased number of mast cells and increased vascularity. The aim of this study was to elucidate the probable role of mast cells in BCC, especially focusing on the relationship between mast cells and lymphocytic infiltration as well as angiogenesis. Methods: We examined the expression and distribution of VEGF, IL-8 and RANTES in 16 nodular BCC lesions by immunohistochemistry. We also examined the lymphocyte subset, and the correlation between VEGF expression and microvessel density in the BCC lesion. mRNA expression of IL-8 and RANTES was examined by the reverse transcriptase-polymerase chain reaction. Results: T cells, especially CD4+/CD45RO+ memory T cells were the predominant infiltrating lymphocyte population in BCC lesions. An increased number of tryptase+ cells (mast cells) was found in the stroma. VEGF+/IL-8+/RANTES+ cells were also found abundantly in the stroma of all BCC lesions. The number of VEGF+, IL-8+ and RANTES+ cells was significantly higher than that in controls. By immunohistochemistry of serial sections, tryptase+ cells were found to express VEGF, IL-8 or RANTES. Messenger RNA expression of IL-8 and RANTES was also observed in the BCC lesions. Conclusion: This study suggests that mast cells may play an active role in the angiogenesis of BCC through the production of VEGF and IL-8. Furthermore, mast cells may also regulate lymphocytic infiltration through the production of IL-8 and RANTES.
1,25-Dihydroxyvitamin D3 Stimulates Osteopontin Expression in Rat Kidney
Authors: Han Ki-Hwan , Jung Ju-Young , Cha Jung-Ho , Kim Hyang , Madsen Kirsten M. , Kim Jin
Published: April 2003

Osteopontin (OPN) is a secreted phosphoprotein expressed constitutively in the descending thin limb (DTL) and papillary surface epithelium (PSE) of the kidney. Although its function is not fully established, a role for OPN in the regulation of calcium-mediated or calcium-dependent processes has been proposed. The aim of this study was to examine the effects of 1,25-dihydroxyvitamin D3 (vitD), a hormone involved in the regulation of calcium homeostasis, on renal OPN expression. Four groups of rats were studied: acute vehicle (single intraperitoneal [i.p.] injection of 0.1 ml 10% ethanol-90% propylene glycol, 12 h before being killed); acute vitD (single injection of vitD, 2 ng/g i.p., 12 h before being killed); chronic vehicle (daily subcutaneous [s.c.] injection of 0.1 ml 10% ethanol-90% propylene glycol for 7 days); and chronic vitD (daily s.c. injection of vitD, 0.5 ng/g, for 7 days). Kidneys were processed for light and electron microscope immunocytochemistry, in situ hybridization, and Western blot analysis. In vehicle-treated animals, OPN mRNA and protein were expressed primarily in the DTL and PSE. In the acute vitD group, OPN mRNA and immunoreactivity appeared in the thick ascending limb (TAL) of the inner stripe of the outer medulla, and increased slightly in the DTL and PSE. The proximal tubules exhibited strong OPN immunoreactivity, but no hybridization signal. In the chronic vitD group, there was a marked increase in OPN mRNA and immunoreactivity in the distal tubule, including the TAL, as well as in the DTL and PSE. A weak hybridization signal and immunostaining were also observed in some proximal tubules. Administration of vitD causes a marked increase in OPN mRNA and protein in the rat kidney, mainly in the distal nephron, but also in the DTL, PSE, and proximal tubules. These results indicate that vitD is involved in the regulation of OPN expression in the kidney.
Simulated in vitro Quinolone Pharmacodynamics at Clinically Achievable AUC/MIC Ratios: Advantage of IE over Other Integral Parameters
Authors: Firsov A.A. , Zinner S.H. , Lubenko I.Y. , Portnoy Y.A. , Vostrov S.N.
Published: April 2003

To compare the antimicrobial effects of clinically achievable ratios of area under the curve (AUC) to MIC, a clinical isolate of Moraxella catarrhalis was selected with MICs corresponding to the MIC50s of four quinolones. Monoexponentially declining concentrations observed in human plasma after oral administration of 1,000 mg of ciprofloxacin (as two 500-mg doses at a 12-hour interval), 320 mg gemifloxacin, 500 mg levofloxacin or 400 mg moxifloxacin (each as a single dose) and were simulated in an in vitro dynamic model. The respective half-lives were 4, 7.4, 6.8 and 12.1 h, and the AUC/MICs were 730, 1,130, 920 and 690 h. The time-kill/regrowth curves yielded similar patterns with the four quinolones: a rapid reduction in bacterial numbers followed by bacterial regrowth that occurred later with moxifloxacin than with ciprofloxacin, gemifloxacin, and levofloxacin. The total antimicrobial effect of moxifloxacin as expressed by the IE parameter (area between the control growth and time- kill curves from time zero to the time when bacterial counts on the regrowth curve achieve the same maximal numbers as in the absence of antimicrobial) was 30, 55, and 120% greater than gemifloxacin, levofloxacin and ciprofloxacin, respectively. Unlike IE, the other integral indices determined over a fixed time (24 h) – the area between the control growth and time-kill curves, area above the time-kill curve and area under the time-kill curve were similar for the four fluoroquinolones, thus precluding their differentiation.
Negative Growth Effects of Ciglitazone on Kidney Interstitial Fibroblasts: Role of PPAR-γ
Authors: Parameswaran Narayanan , Hall Carolyn S. , Bomberger Jennifer M. , Sparks Harvey V. , Jump Donald B. , Spielman William S.
Published: April 2003

Background/Aims: Ciglitazone and other thiazolidinedione compounds are peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands and improve renal function in diabetic nephropathy independent of blood glucose control. Because interstitial fibroblasts and glomerular mesangial cells are important cell types affected in diabetic nephropathy, the major aim of the present study was to examine the effect of ciglitazone on apoptosis and growth of renal interstitial fibroblasts (NRKs) and glomerular mesangial cells (MMCs). Methods: The effect of ciglitazone on apoptosis and cell growth of cultured NRKs and MMCs was done using DNA fragmentation and MTS cell-growth assays, respectively. The potential role of PPAR-γ in these two cell types was examined by reporter gene analysis. Results: Ciglitazone induced caspase-dependent apoptosis of both NRKs and MMCs and caused a significant decrease in cell growth. Other PPAR-γ ligands also mimicked this effect. Interestingly, ciglitazone did not activate the PPRE-TK-CAT (peroxisome proliferator regulatory element, a thymidine kinase promoter and a chloramphenicol acetyltransferase gene) when transfected into NRKs, suggesting that ciglitazone does not activate the endogenous PPAR-γ system in NRKs. On the other hand, ciglitazone activated the endogenous PPAR-γ in MMCs. Conclusions: Apoptotic and negative growth effects of ciglitazone, in NRKs, are not mediated through PPAR-γ. The thiazolidinediones have important cellular effects on renal interstitial fibroblasts and glomerular mesangial cells that may be therapeutically useful in non-diabetic renal disease.
The AN69 Hemofiltration Membrane Has a Decreasing Effect on the Intracellular Diadenosine Pentaphosphate Concentration of Platelets
Authors: Jankowski Joachim , Schlüter Hartmut , Henning Lars , van der Giet Markus , Jankowski Vera , Zidek Walter , Tepel Martin
Published: April 2003

Background/Aim: The biocompatibility of hemodialysis membranes has a substantial impact on the mortality of patients with end-stage renal failure. In the present study, the effects of hemodialysis on the intracellular amount of diadenosine pentaphosphate (Ap5A), a hydrophilic, anionic substance with a low molecular weight, was investigated. Methods: The intracellular Ap5A concentrations were measured before and after hemodialysis using either polyacrylonitrile (AN69; n = 10) or polysulfone (n = 23) membranes. Ap5A was isolated from platelets using affinity chromatography and reversed-phase chromatography methods. Results: The Ap5A concentrations were quantified by ultraviolet absorption at 254 nm. The Ap5A concentrations were significantly higher in platelets from the patients with end-stage renal failure as compared with the 21 healthy control subjects (136 ± 50 vs. 9 ± 6 fg/platelet; mean ± SEM, p < 0.01). Before hemodialysis, the intracellular Ap5A concentrations in platelets from 10 patients with end-stage renal failure using an AN69 membrane were not significantly different from those in platelets from 23 patients using a polysulfone membrane (93 ± 39 vs. 155 ± 70 fg/platelet). However, after a hemodialysis session, the intracellular Ap5A concentrations in platelets from patients with end-stage renal failure using an AN69 membrane were significantly lower as compared with those in platelets before hemodialysis (51 ± 18 vs. 93 ± 39 fg/platelet, p < 0.05) as well as compared with those in platelets from patients using a polysulfone membrane (51 ± 18 vs. 250 ± 59 fg/platelet, p < 0.05). Conclusions: It was found that hemofiltration by using an AN69 membrane has a direct effect on the intracellular amount of Ap5A and that changes of intracellular hydrophilic substances are dependent on the hemodialysis membrane used.
The KOX zinc finger genes: Genome wide mapping of 368 ZNF PAC clones with zinc finger gene clusters predominantly in 23 chromosomal loci are confirmed by human sequences annotated in EnsEMBL
Authors: Rousseau-Merck M.F. , Koczan D. , Legrand I. , Möller S. , Autran S. , Thiesen H-J.
Published: April 2003

The chromosome locations of 368 human Kruppel-type zinc finger (ZNF) PAC clones were physically mapped by FISH to human chromosomes in support of recent efforts of assigning KOX cDNAs (KOX1–KOX32) to zinc finger gene clusters. Recent mapping results were validated and confirmed by sequence comparisons to zinc finger gene sequences automatically annotated in EnsEMBL. In toto, 799 Kruppel-type zinc finger genes have been annotated in EnsEMBL of which 290 genes are found to encode KRAB domains. Sequence homologies of the zinc finger domains were used to establish phylogenic trees of KOX zinc finger genes as well as of all KRAB containing human zinc finger and KOX genes documenting the evolution of KRAB zinc finger genes late in primate evolution. A list of 368 assigned ZNF PAC clones is available under http://www.pzr.uni-rostock.de/supplements.
Tectal Gliomas in Children: The Implications for Natural History and Management Strategy
Authors: Dağlıoğlu Ergün , Çataltepe Oğuz , Akalan Nejat
Published: April 2003

Tumors involving the tectal region constitute a distinct subgroup of brain stem gliomas with an indolent clinical course. Here, we present the clinical and neuroradiologic features of 9 children with tectal tumors. All patients presented with signs and symptoms of hydrocephalus and were managed with ventriculoperitoneal shunt insertion. MRI studies revealed focal hyperintense lesions on T2-weighted images without any contrast enhancement, and no evidence of progression was demonstrated in any patient. We also reviewed the published series of tectal gliomas in the literature to compare with our results. Based on these and other published series, it was concluded that intrinsic tectal gliomas of childhood with sizes less than 2 cm in diameter and without any tumor extension or contrast enhancement constitute a specific subgroup of tectal masses which rarely display invasive clinical behavior and should be managed conservatively. CSF diversion procedures and long-term yearly follow-up examinations with MRI scans are sufficient in these patients.
Down-Regulation of Connexin 32 Gene Expression through DNA Methylation in a Human Renal Cell Carcinoma Cell
Authors: Hirai Ayako , Yano Tomohiro , Nishikawa Kazuhiro , Suzuki Kazuyuki , Asano Ryuji , Satoh Haruna , Hagiwara Kiyokazu , Yamasaki Hiroshi
Published: April 2003

Background: We have recently reported that connexin (Cx) 32 is down-regulated in a human renal cell carcinoma (RCC) cell (Caki-2 cell). Hypothesis: We postulated that the down-regulation of Cx32 gene in the RCC cell is due to hypermethylation of its promoter region. Methods: We estimated methylation status in the promoter region of Cx32 gene in the RCC cell by DNA digestion with methylation-sensitive restriction enzyme and PCR, and methylation-specific PCR (MSP). We also checked the recovery of Cx32 gene expression in the RCC cell treated with a DNA methyltranferase inhibitor, 5-Aza-2’-deoxycytidine (5-Aza-CdR). Results: Treatment with 5-Aza-CdR resulted in induction of Cx32 expression in the RCC cell. Hypermethylation of the Cx32 promoter region in the RCC cell was confirmed by DNA digestion with methylation-sensitive restriction enzyme and PCR, and MSP. Conclusion: We suggest that hypermethylation in the promoter region is a mechanism for the Cx32 gene repression in the RCC cell.
Resveratrol blocks interleukin-1β–induced activation of the nuclear transcription factor NF-κB, inhibits proliferation, causes S-phase arrest, and induces apoptosis of acute myeloid leukemia cells
Authors: Estrov Zeev , Shishodia Shishir , Faderl Stefan , Harris David , Van Quin , Kantarjian Hagop M. , Talpaz Moshe , Aggarwal Bharat B.
Published: April 2003

Resveratrol, an edible polyphenolic stilbene, has been reported to possess substantial antileukemic activities in different leukemia cell lines. We investigated whether resveratrol is active against fresh acute myeloid leukemia (AML) cells and its mechanism of action. Because interleukin 1β(IL-1β) plays a key role in proliferation of AML cells, we first tested the effect of resveratrol on the AML cell lines OCIM2 and OCI/AML3, both of which produce IL-1β and proliferate in response to it. Resveratrol inhibited proliferation of both cell lines in a dose-dependent fashion (5-75 μM) by arresting the cells at S phase, thus preventing their progression through the cell cycle; IL-1β partially reversed this inhibitory effect. Resveratrol significantly reduced production of IL-1β in OCIM2 cells. It also suppressed the IL-1β–induced activation of transcription factor nuclear factor κB (NF-κB), which modulates an array of signals controlling cellular survival, proliferation, and cytokine production. Indeed, incubation of OCIM2 cells with resveratrol resulted in apoptotic cell death. Because caspase inhibitors Ac-DEVD-CHO or z-DEVD-FMK partially reversed the antiproliferative effect of resveratrol, we tested its effect on the caspase pathway and found that resveratrol induced the activation of the cysteine protease caspase 3 and subsequent cleavage of the DNA repair enzyme poly (adenosine diphosphate [ADP]–ribose) polymerase. Finally, resveratrol suppressed colony-forming cell proliferation of fresh AML marrow cells from 5 patients with newly diagnosed AML in a dose-dependent fashion. Taken together, our data showing that resveratrol is an effective in vitro inhibitor of AML cells suggest that this compound may have a role in future therapies for AML.
The role of autocrine FGF-2 in the distinctive bone marrow fibrosis of hairy-cell leukemia (HCL)
Authors: Aziz Khalil A. , Till Kathleen J. , Chen Haijuan , Slupsky Joseph R. , Campbell Fiona , Cawley John C. , Zuzel Mirko
Published: April 2003

Bone marrow (BM) fibrosis is a central diagnostic and pathogenetic feature of hairy-cell leukemia (HCL). It is known that fibronectin (FN) produced and assembled by the malignant hairy cells (HCs) themselves is a major component of this fibrosis. It is also known that FN production is greatly enhanced by adhesion of HCs to hyaluronan (HA) via CD44. The aim of the present study was to establish the roles of fibrogenic autocrine cytokines (fibroblast growth factor-2 [FGF-2] and transforming growth factor β [TGFβ]) and of different isoforms of CD44 in this FN production. We show that HC adhesion to HA stimulates FGF-2, but not TGFβ, production and that HCs possess FGF-2 receptor. In a range of experiments, FN production was greatly reduced by blocking FGF-2 but not TGFβ. Moreover FN, but not FGF-2, secretion was blocked by down-regulation of the v3 isoform of CD44 and by addition of heparitinase. These results show that autocrine FGF-2 secreted by HCs is the principal cytokine responsible for FN production by these cells when cultured on HA. The central role of FGF-2 in the pathogenesis of the BM fibrosis of HCL was supported by our immunohistochemical demonstration of large amounts of this cytokine in fibrotic BM but not in HCL spleen where there is no fibrosis. As regards CD44 isoforms, the present work demonstrates that CD44v3 is essential for providing the heparan sulfate necessary for HC stimulation by FGF-2, whereas the signal for production of the cytokine was provided by HA binding to CD44H, the standard hematopoietic form of the molecule.
Consensus statement on crush injury and crush syndrome
Authors: Greaves Ian , Porter Keith , Smith Jason
Published: April 2003

Crush syndrome remains rare in European practice. It is however common in areas of civil disorder and where the normal structures of society have given way to civil war or natural disaster. Western doctors are becoming increasingly involved in such situations and there is no reason to believe that instances due to more conventional causes, such as collapse in the elderly or road traffic accidents, will cease. For all these reasons it is important that clinicians who deal infrequently with crush syndrome have access to appropriate guidelines. This consensus report seeks to provide such advice. It reports the findings of a consensus meeting on crush injury and crush syndrome held in Birmingham on 31 May 2001, and coordinated by the Faculty of Pre-Hospital Care of the Royal College of Surgeons of Edinburgh.
Results of a Randomized Study of Preradiation Chemotherapy Versus Radiotherapy Alone for Nonmetastatic Medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Children’s Cancer Study Group PNET-3 Study
Authors: Taylor Roger E. , Bailey Clifford C. , Robinson Kath , Weston Claire L. , Ellison David , Ironside James , Lucraft Helen , Gilbertson Richard , Tait Diana M. , Walker David A. , Pizer Barry L. , Imeson John , Lashford Linda S.
Published: April 2003

Purpose: To determine whether preradiotherapy (RT) chemotherapy would improve outcome for Chang stage M0–1 medulloblastoma when compared with RT alone. Chemotherapy comprised vincristine 1.5 mg/m2 weekly for 10 weeks and four cycles of etoposide 100 mg/m2 daily for 3 days, and carboplatin 500 mg/m2 daily for 2 days alternating with cyclophosphamide 1.5 g/m2.

Patients and Methods: Patients aged 3 to 16 years inclusive were randomly assigned to receive 35 Gy craniospinal RT with a 20 Gy posterior fossa boost, or chemotherapy followed by RT.

Results: Of 217 patients randomly assigned to treatment, 179 were eligible for analysis (chemotherapy + RT, 90 patients; RT alone, 89 patients). Median age was 7.67 years, and median follow-up was 5.40 years. Overall survival (OS) at 3 and 5 years was 79.5% and 70.7%, respectively. Event-free survival (EFS) at 3 and 5 years was 71.6% and 67.0%, respectively. EFS was significantly better for chemotherapy and RT (P = .0366), with EFS of 78.5% at 3 years and 74.2% at 5 years compared with 64.8% at 3 years and 59.8% at 5 years for RT alone. There was no statistically significant difference in 3-year and 5-year OS between the two arms (P = .0928). Multivariate analysis identified use of chemotherapy (P = .0248) and time to complete RT (P = .0100) as having significant effect on EFS.

Conclusion: This is the first large multicenter randomized study to demonstrate improved EFS for chemotherapy compared with RT alone. It is anticipated that this regimen could reduce ototoxicity and nephrotoxicity compared with cisplatin-containing schedules. The importance of avoiding interruptions to RT has been confirmed.
Presurgical Chemotherapy Compared With Immediate Surgery and Adjuvant Chemotherapy for Nonmetastatic Osteosarcoma: Pediatric Oncology Group Study POG-8651
Authors: Goorin Allen M. , Schwartzentruber Douglas J. , Devidas Meenakshi , Gebhardt Mark C. , Ayala Alberto G. , Harris Michael B. , Helman Lee J. , Grier Holcombe E. , Link Michael P.
Published: April 2003

Purpose: Successful therapeutic interventions to prevent disease progression in patients with nonmetastatic osteosarcoma have included surgery with adjuvant chemotherapy. Presurgical chemotherapy has been advocated for these patients because of putative improvement in event-free survival (EFS). The advantages of presurgical chemotherapy include early administration of systemic chemotherapy, shrinkage of primary tumor, and pathologic identification of risk groups. The theoretic disadvantage is that it exposes a large tumor burden to marginally effective chemotherapy. The contribution of chemotherapy and surgery timing has not been tested rigorously.

Patients and Methods: Between 1986 and 1993, we conducted a prospective trial in patients with nonmetastatic osteosarcoma who were assigned randomly to immediate surgery or presurgical chemotherapy. Except for the timing of surgery (week 0 or 10), patients received 44 weeks of identical combination chemotherapy that included high-dose methotrexate with leucovorin rescue, doxorubicin, cisplatin, bleomycin, cyclophosphamide, and dactinomycin.

Results: One hundred six patients were enrolled onto this study. Six were excluded from analysis. Of the remaining 100 patients, 45 were randomly assigned to immediate chemotherapy, and 55 were randomly assigned to immediate surgery. Sixty-seven patients remain disease-free. At 5 years, the projected EFS ± SE is 65% ± 6% (69% ± 8% for immediate surgery and 61% ± 8% for presurgical chemotherapy; P = .8). The treatment arms had similar incidence of limb salvage (55% for immediate surgery and 50% for presurgical chemotherapy).

Conclusion: Chemotherapy was effective in both treatment groups. There was no advantage in EFS for patients given presurgical chemotherapy.
Cancer Patients Seeking a Second Surgical Opinion: Results of a Study on Motives, Needs, and Expectations
Authors: Mellink W.A.M. , Dulmen A.M.V. , Wiggers Th. , Spreeuwenberg P.M.M. , Eggermont A.M.M. , Bensing J.M.
Published: April 2003

Purpose: To explore the sociodemographic and clinical characteristics of cancer patients seeking a second-opinion consultation and to analyze their second opinion–related motives, needs, and expectations.

Patients and Methods: In 212 consecutive patients seeking a second opinion at the Surgical Oncology Outpatient Clinic, satisfaction with the first specialist, motivation for the second opinion, need for information, preference for decision participation, and hope for and expectation of a different second opinion were assessed with a questionnaire.

Results: The mean age was 53 years. Most patients were women (82%), of whom 76% were diagnosed with breast cancer. Half of the patients (51%) had a low educational level. The majority of patients (62%) only had internal motives for second-opinion seeking associated with the need for reassurance and more certainty, whereas a substantial minority of patients (38%) also had external motives related to negative experiences or unfulfilled needs. The externally motivated patients had a higher anxiety disposition, were less satisfied with their first specialist, preferred a more active role in medical decision making, and more often hoped for and expected a different second opinion.

Conclusion: Motives for second-opinion consultations differ greatly. Understanding the difference between internal and external motivation is necessary to develop strategies to prevent unnecessary second-opinion seeking. Additional studies are warranted to evaluate the objective and subjective outcomes of second-opinion consultations.
Differential Binding and Neutralization of Activins A and B by Follistatin and Follistatin Like-3 (FSTL-3/FSRP/FLRG)
Authors: Schneyer Alan , Schoen Amy , Quigg Alicia , Sidis Yisrael
Published: April 2003

Modulation of activin and other TGFβ superfamily signaling is the primary mechanism of action for both follistatin (FS) and FS-like 3 (FSTL-3). However, most studies of these ligands use activin A due to its wide availability. We have now tested the ability of FS288 and FSTL-3 to bind and neutralize activin B relative to activin A. Activin B bound to both FS and FSTL-3 at a potency approximately 10-fold lower than that of activin A. Moreover, whereas both activins had similar biological activity in 293 cell reporter assays, FS and FSTL-3 were approximately 3-fold more effective in neutralizing activin A relative to activin B. These results suggest that neutralization of activins A and B by FS and FSTL-3 are not identical, so that the relative activity of each activin in tissues where both are produced, such as in the ovary, could be quite different. In addition, biological systems that use primarily activin B, but which have been examined in vitro using activin A, may need to be reevaluated to determine the actual physiologic roles of FS or FSTL-3.
Development of test procedures and performance criteria to improve compatibility in car frontal collisions
Authors: Edwards M J , Davies H , Thompson A , Hobbs A
Published: April 2003

Compatibility is now generally recognized as the next big step forwards for car occupant secondary safety. The work performed to date has focused on the structural performance of vehicles, with the aim of providing a safe environment for the protection of the occupants in which intelligent restraint systems of the future could operate. This paper outlines the present understanding of compatibility for frontal impact collisions and reports the current state of development of three possible test procedures to address the fundamental issues, namely structural interaction, frontal stiffness matching and passenger compartment strength. Recent advances in the development of a deformable barrier face for the full-width test to assess structural interaction, using high-resolution load cell wall measurements, are described. Analysis of the load cell wall data collected in EuroNCAP tests, to address the frontal stiffness problem, is reported together with initial work to investigate the repeatability of the passenger compartment strength test. In addition, for some of these tests, possible performance criteria are suggested. This research is being carried out in co-operation with the European Enhanced Vehicle-safety Committee and the International Harmonization of Research Activities Working Groups and is funded by the Department for Transport.
Theoretical investigation of a linear planar model of a passenger car with seated people
Authors: Stein G J , Múčka P
Published: April 2003

This paper deals with simulation results of a planar passenger car model, supposed to simulate a ‘standard European saloon car’, with simple linear cushioned seats and a seated human model, which accounts for variation in the body weight. As excitation a short harmonic undulation (so called ‘rollete’) is used, sometimes encountered ahead of traffic-light-controlled road crossings. The simulation results indicate some dependence of the respective frequency response characteristics on the stipulated driver's and passenger's weights. Further large vertical acceleration values at axle hop frequencies are observed, which may under circumstances even exceed the standard gravity acceleration. These decrease with increased traversing velocity, say, above 50 km/h to bearable values. Further it is illustrated that the visibility of lights or signs may be momentarily impaired when accelerating from standstill at a road crossing with a large ‘rollete’ directly before the crossing.
Limiting stationary motions of a body on a string
Authors: Mirer S A , Sarychev V A
Published: April 2003

A string suspension is suggested as an experimental arrangement for examining new samples of air flight and space flight vehicles or their components. The dynamics of a rigid body on a string suspension is considered. Stationary motions of an axisymmetric body on a string are studied at high angular velocities of the system rotation. In the case where the suspension point is on the axis of symmetry, all limiting permanent rotations and regular precessions are determined, the domains of their existence are obtained and also the system' equilibria evolution when its parameters are changed is examined. In the case of the displaced suspension point the exact upper bound of the number of possible permanent rotations of the system is given and all types of limiting equilibrium configurations are determined as well as the domains of their existence. The domain in the space of dimensionless parameters of the system is found where the maximal number of different permanent rotations exist at sufficiently high angular velocity.