bluuebunny/crossref_metadata_2025 huggingface dataset:
Thymus and Aging: Potential of Gene Therapy for Restoration of Endocrine Thymic Function in Thymus-Deficient Animal Models
Authors: Goya Rodolfo G. , Cónsole Gloria M. , Hereñú Claudia B. , Brown Oscar A. , Rimoldi Omar J.
Published: April 2003

Objective and Background: The aim of the present article is to discuss the potential of gene therapy for thymic hormones as a novel therapeutic strategy to treat dyshomeostatic states associated with athymia, as Di George syndrome, or hypothymic conditions like those associated with AIDS, chronic stress or aging. First we review the advantages of the athymic (nude) mouse as an animal model to implement experimental thymic hormone gene therapy strategies to restore endocrine thymic function. The aging rat, known to be markedly hypothymic, is also considered as an alternative model. Methods and Expected Results: The possibility of constructing adenoviral vectors harboring a synthetic gene for the thymic hormone thymulin is discussed. The adenoviral vector so constructed would then be injected intramuscularly in nude mice or senile rats. Transduced myocytes should then begin to act as an ectopic source of thymulin thus restoring circulating thymulin levels to normal youthful levels. Conclusion: We conclude that the implementation of thymulin gene therapy should provide novel biotechnological tools that will boost basic studies on the molecular biology of thymulin and would also allow an assessment of the potential of gene therapy to restore circulating thymulin levels in thymodeficient animal models.
Bactericidal Activity of Renal Tubular Cells: The Putative Role of Human β-Defensins
Authors: Nitschke Martin , Wiehl Sandra , Baer Patrick C. , Kreft Burkhard
Published: April 2003

Renal tubular epithelial cells (RTC) form a barrier between the host and ascending microbes in upper urinary tract infection. Previous studies have shown the ability of the kidney to produce defensins – antimicrobial peptides that play a pivotal role in unspecific host defense. To further clarify the role of renal epithelium for direct antibacterial activity we investigated the expression, regulation and production of antimicrobial peptides by cultured human RTC. Cell culture supernatants of RTC exert strong bactericidal activity against Escherichia coli and Klebsiella pneumoniae, two of the most important pathogens in urinary tract infections. The antimicrobial effect depends on salt concentration, a typical feature of human defensins. RT-PCR of RNA from cultured proximal and distal RTC showed constitutive expression of human β-defensin 1 (hbd-1) and human β-defensin 2 (hbd-2) whereas only hbd-1 expression could be detected in RNA preparation from renal biopsy material. Hbd-2 expression of RTC was induced by inflammatory processes as shown by semiquantitative competitive RT-PCR. Coincubation of the cultured cells with IL-1α or E. coli promote the strongest hbd-2 induction whereas TNF-α and LPS lead to a weaker or no (IL-6) hbd-2 induction. This is the first evidence that human RTC are able to produce antibacterial substances in a biologically relevant amount and that β-defensins are candidate proteins responsible for this effect.
Involvement of Endothelial Cell Adhesion Molecules in the Development of Anti-Thy-1 Nephritis
Authors: Isome Masato , Fujinaka Hidehiko , Yaoita Eishin , Feng Lili , Adhikary Laxman P. , Abe Akira , Tsuchida Satoko , Kawasaki Katsutoshi , Suzuki Hitoshi , Kihara Itaru , Wilson Curtis B. , Yamamoto Tadashi
Published: April 2003

To study an involvement of glomerular endothelial cells in the development of anti-Thy-1 nephritis, we examined the expression of endothelial cell adhesion molecules during the course of this model. Ribonuclease protection assay elucidated that expression of mRNA for intercellular adhesion molecule-1 (ICAM-1) was markedly enhanced in the glomeruli with a peak at 2 h (6.5-fold, p < 0.05) after the anti-Thy-1 antibody injection when mesangial cell lysis was recognized and IL-1β mRNA expression was induced in the glomeruli. The glomerular ICAM-1 was predominantly localized in the endothelial cells and was intensely immunostained at day 1 in the glomerular endothelial cells. In contrast, platelet endothelial cell adhesion molecule-1 (PECAM-1) and vascular endothelial-cadherin mRNA expression increased gradually with a peak at day 6 (2.6-fold (p < 0.05) and 4.2-fold (p < 0.05), respectively) in the glomeruli with mesangial proliferative lesion. PECAM-1 was also immunolocalized in the glomerular endothelial cells and the immunoreactivity was greatly enhanced at day 6. Glomerular expression of vascular cell adhesion molecule-1 and endothelial leukocyte adhesion molecule-1 (E-selectin) was unchanged at a low level during the course of anti-Thy-1 nephritis. Blocking of ICAM-1 by administration of anti-ICAM-1 antibody showed significant decrease in the number of polymorphonuclear leukocytes accumulating in the glomeruli by 45.7% (9.4 ± 0.2 vs. 5.1 ± 0.1 per glomerular cross section, p < 0.01) at 2 h. These results suggest a significant involvement of glomerular endothelial cells in the development and repair of anti-Thy-1 nephritis via direct or indirect intercellular interactions between mesangial cells and glomerular endothelial cells.
Estradiol-17β Stimulates Phosphate Uptake and Is Mitogenic for Primary Rabbit Renal Proximal Tubule Cells
Authors: Han Ho Jae , Lee Yeune Hee , Park Kwon Moo , Taub Mary
Published: April 2003

The direct effects of estradiol-17β (E2) on phosphate (Pi) uptake and on DNA synthesis in the primary rabbit kidney proximal tubule cells (PTCs) have been investigated. In the present study, E2 (>10–9M, over 9 days) causes an increase both in [3H]thymidine incorporation and the number of PTCs. The anti-estrogen tamoxifen completely prevented the E2-induced increase in [3H]thymidine incorporation, and ameliorated the stimulatory effect of E2 on growth. E2 (>10–9 M, over 5 days) also stimulated the Pi uptake and its effect was due to the Vmax values but not to the Km value for Pi uptake. Estriol and estrone also exerted significant stimulatory effects on Pi uptake. Progesterone, tamoxifen, actinomycin D and cycloheximide prevented the E2-induced stimulation of Pi uptake. In conclusion, estrogens at physiological concentrations stimulate Pi uptake and DNA synthesis in the renal proximal tubule cells, and these effects are estrogen receptor mediated.
Coagulation, Fibrinolysis and Angiogenesis: New Insights from Knockout Mice
Authors: Brodsky Sergey V.
Published: April 2003

Angiogenesis plays a key role in a broad array of physiologic and pathologic processes. Two major systems – coagulation and fibrinolysis – maintaining hemostasis, have recently been implicated in angiogenesis. Generation of mice deficient in components of coagulation and plasminogen systems has provided an extraordinary opportunity to define the role of each of these systems in vivo and to elucidate molecular mechanisms involved in angiogenesis. It appears that several factors of the coagulation system, such as the tissue factor, the factor V and the thrombin receptor, play an important role in embryonic vessel formation, most probably in the formation of the primitive vascular wall. In addition, the plasminogen system appears to play a significant role in angiogenesis in adulthood, regulating the migration of endothelial and smooth muscle cells, the degradation of the extracellular matrix and activity of the metalloproteinase system. These new revelations open a possibility for future therapeutic strategies to specifically control angiogenesis in different pathological processes where abnormalities of tissue vascularization are pathogenetically prominent.
Characterization of Adenosine Receptors in Human Kidney Proximal Tubule (HK-2) Cells
Authors: Lee H. Thomas , Emala Charles W.
Published: April 2003

Renal proximal tubule cells are particularly vulnerable to injury following ischemia and reperfusion due to their marginal blood supply and high metabolic demand. Renal adenosine receptor (AR) modulations preserve renal function following ischemic-reperfusion injury in vivo. Numerous intracellular proteins have been shown to be pivotal in the signal transduction of adenosine-mediated protection in vivo. However, characterization of the expression and function of ARs and intracellular proteins mediating protection in human proximal tubular cells is lacking. Therefore, we studied the ARs in an immortalized human renal proximal tubular cell (HK-2) line to determine if this cell line could function as an in vitro model of AR coupling. Immunoblotting with AR subtype specific antibodies detected all 4 subtypes of ARs (A1, A2a, A2b and A3), several isoforms of protein kinase C (α, δ, and Ε and several heterotrimeric G-protein isoforms (Giα, Gsα and Gqα). The A1 and A3 ARs inhibited forskolin- stimulated adenylyl cyclase activity. The A1 ARs also activated 42/44-kD ERK mitogen-activated protein kinases via Gi- and tyrosine kinase-dependent pathways. The A2a ARs stimulated adenylyl cyclase activity and activated the protein kinase A→CREB pathway. Chronic (48 h) treatment with a nonselective AR antagonist (8-phenyltheophylline) upregulated A1, A2a ARs and Giα. Conversely, chronic stimulation of HK-2 ARs with a nonselective AR agonist (N-ethylcarbamoyladenosine) downregulated all 4 subtypes of ARs and Gsα. Based on these findings, HK-2 cells are a useful in vitro model to study the signaling cascades of AR-mediated renal protection.
Role of the PDZ Scaffolding Protein in Tubule Cells in Maintenance of Polarised Function
Authors: Glynne Paul A. , Evans Thomas J.
Published: April 2003

Polarized tubule epithelial cell functions are dependent on correct delivery of effector proteins to the target apical or basolateral plasma membrane and associated cortical cytoskeleton. PDZ (Postsynaptic density protein 95/Drosophila Disks large/Zona occludens-1) domain-containing proteins have been identified as playing a critical role in membrane trafficking and sorting of ion transporters, receptors and other signalling proteins. These scaffolding proteins coordinate the assembly of functional plasma membrane multiprotein complexes, through PDZ domain binding to a consensus amino acid motif within the carboxyl-terminus of target proteins. The organization of these proteins into submembranous complexes may facilitate downstream signalling. Although several epithelial PDZ proteins that bind to a number of important mammalian proteins have been isolated, in many cases the significance of these interactions is unclear. However, the epithelial PDZ domain-containing Na+/H+ exchanger regulatory factor tethers the Na+/H+ exchanger and cystic fibrosis transmembrane regulator Cl– channel within an apical plasma membrane signalling complex, and has been shown to regulate the activity of these proteins. This article reviews the current evidence that supports a central role for the PDZ protein in the regulation of polarized tubule cell functions, such as vectorial solute transport.
The Mechanisms of Peroxynitrite-Induced Relaxations in Isolated Rat Anococcygeus Muscle
Authors: Ademoğlu Feyza , Başgut Bilgen , Abacioğlu Nurettin , Çakıcı Iclal
Published: April 2003

We have previously reported that peroxynitrite (ONOO–) caused relaxations on isolated rat anococcygeus muscle and in the present study the possible mechanisms of the relaxant effect were investigated. ONOO– (0.03– 1.0 mmol/l)-induced relaxations were reduced significantly by the presence of an ATP-sensitive potassium channel (K+ATP channel) blocker, glibenclamide (0.3 µmol/l), or 1H-(1,2,4)oxadiazolo(4,3-α)quinoxalin-1-one (ODQ) (30.0 µmol/l), a guanylyl cyclase inhibitor. However, 3-aminobenzamide (3.0 mmol/l), an inhibitor of poly(ADP- ribose)synthase, did not influence the relaxant effect of ONOO– (1.0 mmol/l). Results of the present study implicate that activation of K+ATP channels and/or cGMP/K+ATP channel interaction might play a role in the relaxant responses to ONOO– in isolated rat anococcygeus muscle.
Therapeutic Approach to Hypokalemia
Authors: Kim Gheun-Ho , Han Jin Suk
Published: April 2003

For successful potassium replacement, one should consider the optimal potassium preparation, route of administration, and the appropriate speed of administration. In the absence of an independent factor causing transcellular potassium shifts, the plasma potassium concentration can be used as a rough index to estimate body potassium stores. Oral KCl replacement therapy is preferable if there are bowel sounds, except in the setting of life-threatening abnormalities such as ventricular arrhythmias, digitalis intoxication, or paralysis. In patients with impaired renal function or those treated with intravenous potassium, the risk of hyperkalemia should be monitored. Since potassium depletion rarely occurs as an isolated phenomenon, associated fluid and electrolyte disorders should be corrected, and the causes of potassium loss should be sought and eliminated to complete the treatment of hypokalemia.
Intermittent ‘Double Bubble’ Sign in a Case of Congenital Pyloric Atresia
Authors: Yoshizato Toshiyuki , Satoh Shoji , Taguchi Tomoaki , Suita Sachiyo , Nakano Hitoo
Published: April 2003

We report a case of congenital pyloric atresia in which two cystic masses in the fetal upper abdomen and polyhydramnios were observed from 24 weeks’ gestation to term. The two cystic masses were thought to indicate the ‘double bubble’ sign in utero, leading to a misdiagnosis of congenital duodenal obstruction. At 33 weeks’ gestation, continuous ultrasound observation of the two cystic masses was made for 60 min. During the periods when gastric peristalsis was absent, the ‘double bubble’ sign was observed. However, during the periods when gastric peristalsis was present, the ‘double bubble’ sign disappeared. In retrospect, both cystic masses were stomach and the ‘double bubble’ sign disappeared with peristalsis of the antrum. In order to differentiate from congenital duodenal obstruction, whole stomach configuration should be delineated by continuous observation covering periods when gastric peristalsis is active as well as quiet.
Prenatal Diagnosis of a Fetus with Unbalanced Translocation (4;13)(p16;q32) with Overlapping Features of Patau and Wolf-Hirschhorn Syndromes
Authors: Tapper Jill K. , Zhang Shuliu , Harirah Hassan M. , Panova Neli I. , Merryman Linda S. , Hawkins Judy C. , Lockhart Lillian H. , Gei Alfredo B. , Velagaleti Gopalrao V.N.
Published: April 2003

Wolf-Hirschhorn syndrome (WHS) and Patau syndrome are two of the most severe conditions resulting from chromosome abnormalities. WHS is caused by a deletion of 4p16, while Patau syndrome is caused by trisomy for some or all regions of chromosome 13. Though the etiologies of these syndromes differ, they share several features including pre- and postnatal growth retardation, microcephaly, cleft lip and palate, and cardiac anomalies. We present here a female fetus with deletion of 4p16 → pter and duplication of 13q32 → qter due to unbalanced segregation of t(4;13)(p16;q32) in the father. She displayed overlapping features of both of these syndromes on ultrasound. To the best of our knowledge, this is the first report of a fetus with both partial trisomy 13 and deletion of 4p16, the critical region for WHS.
First Trimester Maternal Serum Free Human Chorionic Gonadotropin as a Predictor of Adverse Pregnancy Outcome
Authors: Yaron Yuval , Ochshorn Yifat , Heifetz Sigal , Lehavi Ofer , Sapir Yaron , Orr-Urtreger Avi
Published: April 2003

Objective: The purpose of this study was to evaluate whether abnormal levels of first trimester maternal serum free human chorionic gonadotropin (β-hCG) are predictive of adverse pregnancy outcomes. Methods: The study included 1,622 consecutive patients with singleton pregnancies who underwent first trimester Down syndrome screening using nuchal translucency, and maternal serum free β-hCG and pregnancy-associated plasma protein-A. Patients with fetal anomalies or chromosome aberrations were excluded from the study. The incidences of various adverse pregnancy outcomes were evaluated according to maternal serum free β-hCG levels. Outcome variables included spontaneous miscarriage, proteinuric and non-proteinuric pregnancy-induced hypertension, fetal growth restriction, intrauterine fetal demise, spontaneous preterm delivery, oligohydramnios and placental abruption. Results: No significant differences were noted between groups for any of the demographic variables. The only statistically significant result was an increase in the relative risk for spontaneous miscarriage (RR = 6.33) at free β-hCG <0.2 multiples of the medians. No other statistically significant result was noted for the other adverse outcomes or for the overall complication rate. Conclusion: Low free β-hCG is associated with a higher incidence of spontaneous miscarriage but is a poor predictor of other pregnancy complications.
Vertebral Artery Dissection in Children: A Comprehensive Review
Authors: Hasan Izhar , Wapnick Simon , Tenner Michael S. , Couldwell William T.
Published: April 2003

Vertebral artery dissection (VAD) has been infrequently recognized in children. The authors have reviewed 68 reported cases of VAD in children in the existing literature. An association between routine types of neck movement in sports and the evolution of VAD was recognized in half of the reported cases. Boys outnumbered girls by a ratio of 6.6 to 1, in contrast to adults, for whom the male to female ratio is approximately equal (1.3 to 1). Neck pain, one of the hallmark symptoms of VAD in adults, was infrequently noted in this young population (12%). Most children presented with various combinations of symptoms and signs, including ataxia (53%), headache (38%) and vomiting (34%). Eye signs or symptoms were noted in 72% of patients, and paresis/paralysis of one or more extremity occurred in 54%. Angiography was the method most frequently used to diagnose VAD (63/68; 93%). Magnetic resonance angiography (MRA) revealed pathognomonic signs of VAD in only 3 out of 13 patients evaluated (23%). In this series of 68 patients, 48 reports failed to indicate whether or not a cervical X-ray was performed, but in the 20 patients for whom such information was recorded, half had skeletal abnormalities in the occipital/atlas/axis region. The most common treatments were antiplatelet therapy (n = 15) and anticoagulation with (n = 8) or without (n = 7) supplemental antiplatelet therapy. Asymptomatic recovery occurred in 12 of the 15 patients (80%) who received antiplatelet therapy compared with 4 of the 15 patients (27%) who received anticoagulation therapy with or without antiplatelet therapy. There is a very high incidence of associated cervical anomalies in children with VAD. Further studies are required to determine if noninvasive examinations such as magnetic resonance imaging, ultrasonography, computed tomography angiography and MRA could replace angiography as the modality of choice in establishing the diagnosis of VAD in children. The role of different therapies for children presenting with symptoms related to VAD is unclear.
Timing of Shunt Surgery in Childhood Tuberculous Meningitis with Hydrocephalus
Authors: Kemaloglu Serdar , Özkan Ümit , Bukte Yaşar , Ceviz Adnan , Özates Mustafa
Published: April 2003

Hydrocephalus is a common complication of tuberculous meningitis (TBM) in children. The aims of this study are to review our experience of hydrocephalus in childhood TBM and to evaluate the effect of the timing of ventriculoperitoneal shunting (VPS) on the final outcome. In this study, 156 patients with TBM and hydrocephalus were reviewed retrospectively between 1990 and 2000. Patients’ ages ranged from 6 months to 15 years, with a mean age of 4.1 years. There were 85 boys, and the male-to-female ratio was 1.19:1.0. Sixty-two percent of the children were younger than 6 years old. VPS was performed 2 days after the diagnosis in 100 patients, and in the remaining 56 patients, 3 weeks after the diagnosis. The average follow-up period was 8.5 months. Good recovery or minor sequelae was seen in 82 patients (52.6%), and 51 died (12.3%). The timing of the VPS procedure and cerebral complications had an effect on the final outcome. Early VPS gave a better outcome in mild and moderate hydrocephalus (p = 0.040). This study has shown that early surgical procedure for mild/moderate hydrocephalus has a positive effect on the morbidity and mortality of hydrocephalus in childhood TBM (p = 0.014, p = 0.040, respectively). In severe hydrocephalus, there was a tendency for early shunting to have a positive effect on morbidity, although this did not reach statistical significance.
Trans Fatty Acids in Maternal Diet May Impair Lipid Biosynthesis in Mammary Gland of Lactating Rats
Authors: Assumpção R.P. , Santos F.D. , Setta C.L. , Barreto G.F. , Matta I.E.A. , Estadella D. , Azeredo V.B. , Tavares do Carmo M.G.
Published: April 2003

Although trans fatty acids are known to influence essential fatty acid (EFA) metabolism and serum levels of lipids and lipoproteins, little is known about their effects on the metabolism of mammary glands (MGs) during lactation. In this study, 5 groups of lactating Wistar rats were fed semisynthetic diets containing 7% soy oil (control); 7% partially hydrogenated vegetable oil (7% PHVO); 13% PHVO +7% soy oil (13% PHVO); 5% PHVO +2% soy oil (5% PHVO), and 3.5% PHVO +3.5% soy oil (3.5% PHVO). Dams were killed on the 12th day of lactation. Weight, lipid content (LC), in vivo lipogenesis rate (LR) and activity of the lipogenic (ATP-citrate lyase and malic) enzymes were evaluated in the MGs. Maternal food intake, weight gain, and total MG weight were not found to be significantly different between the groups. The groups with 13, 7 and 5% PHVO presented a lower (p < 0.05) LR in MGs when compared to controls, whereas MG LC was higher in the 7 and 13% groups than in controls. The observed decrease in MG lipogenesis was accompanied by a diminution (p < 0.05) in the activities of ATP-citrate lyase and malic enzymes. These data indicate a potential impairment of lipid metabolism in the MG by trans isomers in lactating rats.
Modulation of Absorption of Beta-Carotene and Tissue Accumulation of Beta-Carotene and Vitamin A by Different Surfactants in Rats
Authors: Schweigert Florian J. , Trüpschuch Annett , Hantschel Claudia
Published: April 2003

Background/Aims: The absorption of β-carotene is closely associated with the absorption of dietary fats in the duodenum. Aim of the study was to evaluate two different surfactants, taurocholate and Pluronic L-81, which are known to stimulate or inhibit the absorption of dietary fats, respectively with regard to the absorption of β-carotene and tissue accumulation of β-carotene and vitamin A. Methods: Rats were kept on a vitamin-A- deficient diet for 4 weeks and then either kept on this diet or fed this diet enriched with β-carotene (200 mg/kg feed) alone or in combination with taurocholate (10 g/kg) or Pluronic L-81 (5 ml/kg) for another two weeks. Results: β-carotene was not detectable in liver or plasma of rats fed the deficient diet. The supplementation of β-carotene alone led to an increase of β-carotene in plasma and organs (p < 0.05) and resulted in an increase of vitamin A in the liver (p < 0.01), indicating its conversion. The addition of taurocholate enhanced the absorption of β-carotene (p < 0.01), but had little affect on the levels of total vitamin A in the liver. In contrast, Pluronic L-81 caused a reduced uptake of β-carotene as indicated by lower concentrations in plasma and liver (p < 0.01) as well as reduced total vitamin A levels in the liver (p < 0.01) either caused by the reduced availability of β-carotene or a reduced conversion into vitamin A. Conclusions: The study shows that surfactants can modulate β-carotene absorption differently. The results for taurocholate confirm known observations concerning an enhanced absorption of β-carotene. Pluronic L-81 might diminish the uptake of β-carotene into the enterocyte, which would be in disagreement with regard to its function in the absorption of total lipids in general, or might effect the excretion into the blood by modulation chylomicron secretion.
Single Preoperative Oral Application of Ascorbic Acid Does Not Affect Postoperative Plasma Levels of Ascorbic Acid
Authors: Rümelin A. , Dörr S. , Fauth U.
Published: April 2003

Background and Aims: A decrease in ascorbic acid (AA) plasma concentration is well known during the postoperative period and postulated to be caused by increased radical scavenging activity in response to surgical trauma. This often affects postoperative patients and is associated with multiple organ failure. Therefore, substitution of AA could potentially decrease the risk of postoperative complications. This study examines the effect of preoperative oral administration of 1,000 mg AA on the postoperative AA plasma concentration. Methods: 54 patients were randomly split into two groups; patients in group 1 received no AA preoperatively while group 2 received oral AA (1,000 mg). Plasma samples were obtained preoperatively and on the first postoperative day for AA analysis (HPLC). Results: In both groups the AA concentration was normal preoperatively and reduced postoperatively. Conclusion: A preoperative substitution of 1,000 mg AA is not sufficient to prevent postoperative lowered plasma concentration.
Comparison of the Effects of Dietary Saturated, Mono-, and n–6 Polyunsaturated Fatty Acids on Blood Lipid Profile, Oxidant Stress, Prostanoid Synthesis and Aortic Histology in Rabbits
Authors: Bayindir Oya , Özmen Dilek , Mutaf Işil , Turgan Nevbahar , Habif Sara , Gülter Ceyda , Parildar Zuhal , Uysal Ayşegül
Published: April 2003

Background/Aims: To compare the effects of saturated, monounsaturated and polyunsaturated n–6 fatty acid-enriched diets on the development of atherosclerosis and thrombosis in New Zealand white male rabbits, 3- to 6-month-old animals were supplemented daily (10 g/100 g diet) with butter (n = 8), olive oil (n = 8) or corn oil (n = 8) by oral administration for 7 weeks. Methods: Total cholesterol (TC), HDL- (HDL-C) and LDL-cholesterol (LDL-C), triglycerides (TG), apolipoprotein A-1 (ApoA-1), apolipoprotein B (ApoB), lipid peroxides as thiobarbituric acid-reactive substances (TBARS), thromboxane B2 (TXB2) and 6-ketoprostaglandin F1α (6-ketoPGF1α) concentrations were determined in blood samples drawn before and after each group was fed the different dietary regimens. Histological examination was performed on the aortic tissues. Results: After 7 weeks, TC, ApoB and TXB2 increased significantly (p < 0.05) in the butter-fed animals compared to pre-experimental concentrations. Olive oil administration lead to a significant (p < 0.05) decrease in TC and ApoB levels. The corn oil-enriched diet decreased TC, LDL-C concentrations, TC/HDL-C ratios and 6-ketoPGF1α (stable metabolite of prostacyclin-PGI2; p < 0.05 for all) but increased TBARS levels and TXB2/6-ketoPGF1α ratios. Light microscopic findings were in accordance with these biochemical alterations. Conclusion: Although effective in lipid lowering, corn oil increased oxidant stress as evidenced by increased TBARS and induced endothelial damage which lead to a reduction in PGI2 synthesis and consequently to an increase in the TXB2/6-ketoPGF1α ratio. Olive oil administration did not induce oxidant stress and it had no affect on PGI2 and TXB2 levels which are implicated in platelet aggregation. These findings suggest that oleic acid is more effective than linoleic acid in the protection of endothelial integrity.
Differential Expression of Mcp-1 and Its Receptor CCR2 in Glucose Primed Human Mesangial Cells
Authors: Janssen Ulf , Sowa Eveline , Marchand Petra , Floege Jürgen , Phillips Aled O. , Radeke Heinfried H.
Published: April 2003

Background: Glomerular mononuclear cell infiltration is associated with the development of a diffuse glomerulosclerosis in patients with diabetic nephropathy. Monocyte chemoattractant protein-1 (MCP-1) plays an important role in the recruitment and accumulation of monocytes and lymphocytes within the glomerulus. In the present study, we examined whether the ambient glucose concentration alters the expression of MCP-1 and its receptor CCR2 in primary human mesangial cells (HMC). Methods: MCP-1 mRNA expression was assessed by Northern blot and CCR2 mRNA expression by RT-PCR analysis. MCP-1 protein production was determined by ELISA. Migration studies were performed to assess functional MCP-1 receptor expression. Results: Exposure of HMC to 30 mMD-glucose led to a 30% increase in MCP-1 mRNA expression as compared to 5 mMD-glucose and osmotic controls while there was no difference in MCP-1 protein production. Simultaneously, CCR2 mRNA expression was down-regulated in HMC exposed to 30 mMD-glucose. 5 mMD-glucose primed HMC showed a dose-dependent migration towards MCP-1 that was dose-dependently inhibited by pertussis toxin, the broad-spectrum chemokine antagonist vMIP-II as well as the CCR2 receptor antagonist (1–8del)MCP-1 – demonstrating functional activity of MCP-1 receptor expression in primary HMC. In accordance with the downregulatory effects of 30 mMD-glucose on CCR2 mRNA expression no migratory response towards MCP-1 was observed under these conditions. The additional proinflammatory stimulus TNFα increased MCP-1 protein production in 30 as compared to 5 mMD-glucose primed HMC (2,194 ± 568 vs. 1,422 ± 379 pg MCP-1/104 cells × ml in 30 vs. 5 mMD-glucose primed HMC +24 h TNFα 500 U/ml, p = 0.002). However, this was not associated with an increased MCP-1 mRNA transcription. The 30 mMD-glucose induced downregulation of CCR2 mRNA expression was prevented in the presence of TNFα. Conclusion: High ambient glucose does not affect mesangial MCP-1 release and decreases its CCR2 receptor expression. However, in the presence of an inflammatory stimulus these effects of high glucose are reversed and an autocrine pathway of MCP-1 develops in mesangial cells.
Recurrent Lupus nephritis in the Second Allograft of a Patient with Systemic Lupus erythematosus
Authors: Isaac Jorge , Shihab Fuad S.
Published: April 2003

Lupus glomerulonephritis is a common and serious complication of systemic lupus erythematosus (SLE) affecting up to 50% of lupus patients. Recurrent lupus nephritis is rare, complicating as low as 1% of the lupus transplant population according to some authors. However, it may be underreported with more realistic recurrent rates oscillating from 2.8 to 8.7%. We report the case of a patient with SLE who lost her first allograft 4 years after transplantation with a diagnosis of de novo fibrillary glomerulopathy. She underwent a second renal transplantation and her renal function was stable for the past 5 years. She now presented with skin rash, arthralgias and positive lupus serologies. Her creatinine was slightly elevated and proteinuria was also noted. A renal biopsy performed revealed a recurrent focal proliferative lupus nephritis (WHO III). Retrospectively, we believe that her first allograft was also lost to recurrent lupus nephritis. This is a unique case of recurrent lupus nephritis in the second allograft of a patient with SLE.
Cellular Component of Vascular Calcification
Authors: Watanabe Y. , Suzuki M. , Oyama Y. , Kusano E. , Tamba K. , Iimura O. , Ito C. , Imai M. , Asano Y.
Published: April 2003

It has been reported that calcium deposition and calcium content in cultured human aortic smooth muscle cells (SMC) increased when the cells are incubated in a medium with a high phosphate concentration (2 mM). To determine the cellular components or soluble factors contributing to the deposition, we cultured commercially available SMC, fibroblasts (Fb) and endothelial cells (Ed). These cells and their mixtures were incubated for 10 days in normal or high-phosphate media. Calcium crystals were stained by the von-Kossa staining and counted in the defined area. Calcium content was measured by a colorimetric assay. SMC were incubated in high-phosphate media (up to 2 mM) or β-glycerophosphate (β-GP) media, resulting in no obvious deposition of calcium crystals, irrespective of the coating of type I collagen on the dish. Next, various combinations of cells were cultured, and a significant number of depositions were observed only when Fb were included in the combination. The calcium content was significantly higher in cultures of SMC and Fb. The calcium deposition on single or mixture of the cells did not increase compared with control when cells were incubated in a high concentration of phosphate, cultured in the existence of β-GP or uremic serum. We therefore conclude that Fb, rather than SMC or Ed, are essential for calcium deposition and calcium accumulation in culture. Phosphate concentration in the medium and uremic serum did not influence the deposition of calcium.
Concurrent Chemoradiotherapy with Low-Dose Cisplatin plus 5-Fluorouracil for the Treatment of Patients with Unresectable Head and Neck Cancer
Authors: Kohno Naoyuki , Kitahara Satoshi , Tamura Etsuyo , Tanabe Tetsuya
Published: April 2003

Objective: The purpose of this study was to determine the efficacy of concurrent chemoradiotherapy using conventional radiotherapy combined with low-dose daily 5-fluorouracil (5FU) and cisplatin (CDDP) for the locally unresectable head and neck cancer patients. Patients and Methods: From September 1996 through December 2000, we carried out a phase II study of concurrent chemoradiotherapy with low-dose CDDP plus 5FU for the treatment of patients with unresectable squamous cell carcinoma of the head and neck. Chemoradiotherapy consisted of irradiation with 1.6–2.0 Gy/day for 5 days per week up to a total dose 68 Gy and CDDP 3 mg/m2 by intravenous infusion over 1 h plus 5FU 150 mg/m2 by intravenous infusion over 24 h per day for 5 days per week. Results: Ninety percent of the patients had stage IV disease, including 65% of patients with T4 disease. Thirty-three patients (83%) received the full treatment as planned; 39 (98%) received full-dose radiotherapy and 33 (83%) full-dose chemotherapy. Of the 40 patients evaluable for response, 20 (50%) achieved complete response (CR) and 12 (30%) partial response with an overall response rate of 80%. Among the 20 CR patients, 15 underwent endoscopic blind biopsies and 4 had positive lesions. The most frequently observed toxicity was mucositis. Ten patients developed grade III mucositis, and 3 patients required enteral nutritional support through a feeding tube. Grade III leukopenia, anemia and thrombocytopenia were observed in 28, 25 and 20% of the patients, respectively. The median duration of follow-up at the time of analysis was 18 months. The median survival time was 23 months. The responders survived longer (34 months) than the nonresponders (4 months; p < 0.05). Conclusion: This regimen is safe and efficacious in the treatment of patients with advanced unresectable head and neck cancer.
Early Tandem High-Dose Ifosfamide, Carboplatin, Etoposide Therapy with Stem Cell Rescue for Small-Cell Lung Cancer: Brief Report on the Results of a Phase-I/II Trial
Authors: Oelmann E. , Thomas M. , Serve H. , Kienast J. , Zühlsdorf M. , Mohr M. , Klinke F. , Dölken G. , Macha H. , Schmidt E.W. , Berdel W.E.
Published: April 2003

Objective: High-dose therapy (HDT) for small-cell lung cancer is experimental. Late intensification HDT for chemosensitive disease can increase the number and quality of remissions and prolong relapse-free survival, but has not yet shown impact on overall survival. This is possibly due to resistant residual disease. To overcome the development of resistance, we have tested early intensification tandem HDT. Methods: We performed a phase-I/II trial using 1 conventional cycle of ifosfamide, carboplatin, etoposide (ICE) plus granulocyte colony-stimulating factor for stem cell recruitment followed by 2 cycles of high-dose ICE with rescue by CD34+ cell-enriched peripheral blood mononuclear cells. Dose escalation was performed for the 2 high-dose ICE cycles. Radiotherapy for limited disease was according to standard protocols. Results: 17 patients were entered: 2 female patients; 15 male patients; median age 53 (range 36–65) years; 2 patients with limited disease, and 15 patients with extensive disease. We treated 4 patients at dose level 1, 11 patients at level 2, and 2 patients at level 3. The maximum tolerable dose was at level 2 with neuropathy being dose-limiting. Overall, toxicity was ≤grade 2 for all patients up to dose level 2 with hematotoxicity being grade 4 for all patients. There were 15 partial remissions (88%), 1 no change (6%), and 1 progressive disease (6%). Median time to progression was 7.9 months. Overall survival was 12.9 months (median). Conclusions: Early intensification with this protocol is feasible. Although a comparatively good response rate and median time to progression have been observed in this group dominated by patients with extensive disease, overall survival is short and no substantial long-term survival was found.
Long-Term Mortality of Women with a Diagnosis of Breast Cancer
Authors: Levi Fabio , Randimbison Lalao , Te Van-Cong , La Vecchia Carlo
Published: April 2003

Survival from breast cancer has improved over the last few years, but scanty information is available on the long-term follow-up. We therefore considered data on 1,095 women with breast cancer diagnosed between 1974 and 1984 in the Swiss Cancer Registry of Vaud (population 616,000 inhabitants) who had survived for at least 10 years. Overall, 129 deaths from breast cancer were observed 10–19 years after the original diagnosis, corresponding to a standardized mortality ratio (SMR) of 20.3 (95% confidence interval (CI) 17.0–24.2). An excess mortality from breast cancer was observed 10–14 (SMR = 22.6) and 15–19 (SMR = 13.4) years after the original diagnosis. The SMR was 25.2 for women diagnosed with breast cancer at age <60 years. Consequently, total mortality was also elevated (SMR = 2.0, based on 294 deaths). None of the other causes of death was significantly elevated, but mortality from cardiovascular disease was 1.4 (95% CI 0.9–2.0) 15–19 years after breast cancer diagnosis. A second primary breast cancer was observed in 89 women. Of these, 19 (21%) died of breast cancer. Therefore in women diagnosed with breast cancer, there remains a substantial excess of breast cancer mortality up to 20 years after the original diagnosis.
c-Met Expression in Gastric Cancer with Liver Metastasis
Authors: Amemiya Hideki , Kono Koji , Itakura Jun , Feng Tang Rui , Takahashi Akihiro , An Feng-Qi , Kamei Shigeo , Iizuka Hidehiko , Fujii Hideki , Matsumoto Yoshiro
Published: April 2003

Liver metastasis is one of the poor prognostic factors for gastric cancer. Hepatocyte growth factor (HGF) and its receptor, c-Met, have been reported to be related to the proliferation of carcinoma cells. We examined c-Met and HGF expression in stage IV gastric cancers (n = 121) and compared the results in groups with liver metastasis (n = 47, LM group) and without liver metastasis (n = 74, no-LM group). The survival rate for the LM group was significantly poorer than for the no-LM group (p < 0.01). We found a high frequency of c-Met expression in the LM group compared with the no-LM group at protein level detected by immunohistochemistry (p = 0.0005) and at mRNA level detected by semiquantitative reverse transcriptase-polymerase chain reaction (p = 0.0386) in primary gastric tumors. Furthermore, we evaluated HGF expression in both carcinoma cells and stromal cells in gastric cancers. There was no significant difference in the HGF expression between the LM and no-LM groups. The labeling index of proliferating cell nuclear antigen for the carcinomas in the LM group was higher than that in the no-LM group (47.1 ± 24.5 vs. 26.2 ± 24.5%, p < 0.0001). Thus, the high frequency of c-Met overexpression in carcinoma cells may be involved in the mechanism of liver metastasis in gastric cancers. Moreover, the evaluation of c-Met expression might be a useful indicator of liver metastasis in patients with gastric cancer.
Increased Ratio of Serum Cortisol to Cortisone in Acute-Phase Response
Authors: Vogeser M. , Zachoval R. , Felbinger T.W. , Jacob K.
Published: April 2003

Background/Objectives: 11β-Hydroxysteroid dehydrogenase (11β-HSD) enzymes convert cortisol into inactive cortisone and vice versa. While 11β-HSD type 2 (mainly localized in the kidney) unidirectionally inactivates cortisol to cortisone, type I isoform (mainly localized in the liver) acts bidirectionally and can thus potentially restore cortisone to active cortisol. The aim of this pilot study was to investigate whether the serum cortisol:cortisone ratio is altered during the acute-phase response, possibly due to altered modulation of 11β-hydroxysteroid dehydrogenase isoforms. Methods: Using liquid chromatography electrospray tandem mass spectrometry, cortisol and cortisone were measured in the serum of hospitalized patients with normal and abnormal CRP concentrations, the latter indicating acute-phase response. Fifteen unselected samples were analyzed, all with a CRP concentration within one of the following ranges to cover a wide range of CRP concentrations evenly: <5, 5–20, 21–50, 51–100, 101–200, and >200 mg/l. Results: In the heterogeneous study population, increased CRP concentrations significantly correlated with an increased cortisol:cortisone ratio (p < 0.001; r = 0.65, Spearman correlation coefficient). This correlation was independent of increased serum cortisol concentrations found by multivariate regression analysis. The median ratio was 6.4 (interquartile range 5.5–7.4; n = 30) in patients with a CRP concentration ≤20 mg/l, and 11.2 (interquartile range 8.8–13.9; n = 60) in patients with CRP >20 mg/l (p < 0.01). Conclusion: The balance between serum cortisol and cortisone is altered during acute-phase response with a shift towards active cortisol, suggesting that 11β-HSD isoenzymes play a role in the modulation of systemically available cortisol during acute illness.
The 20-kD Human Growth Hormone Reduces Body Fat by Increasing Lipolysis and Decreasing Lipoprotein Lipase Activity
Authors: Takahashi Shunichi , Satozawa Noboru
Published: April 2003

Aim: The aim of this study was to estimate the lipolytic activity of the human growth hormone variant, 20-kD human growth hormone (20K-hGH). Methods: Obese KV-Ay mice were given daily subcutaneous injections of 20K-hGH (0.25, 0.5, 1.0 mg/kg), 22K-hGH (0.25 mg/kg) or saline as a control for 2 weeks. Body composition (fat, water and protein), lipolysis and lipoprotein lipase (LPL) activity were measured 24 h after the final injection. Results: Both growth hormone isoforms significantly reduced relative fat pad and whole body lipids. In addition, 20K-hGH produced an inhibition of LPL activity in adipose tissue and stimulated lipolysis in adipocytes. Conclusion: These data strongly suggest that inhibition of LPL activity in adipose tissue and stimulation of lipolysis in adipocytes by 20K-hGH treatment reduce adipose tissue mass, resulting in body fat reduction.
Does Graves’ Disease during Puberty Influence Adult Bone Mineral Density?
Authors: Radetti G. , Bona G. , Corrias A. , Cappa M. , DeSanctis V. , Lauriola S. , Paganini C. , Rigon F.
Published: April 2003

Aim: To evaluate the bone mineral density at lumbar spine and at femoral neck in a group of young adults in whom Graves’ disease developed during childhood and adolescence. Patients and Methods: We examined 28 patients (5 male, 23 female, age 20.9 ± 3.3 years) who were 11.8 ± 2.9 years old at the onset of Graves’ disease. They were treated either with methimazole (14 patients) or with methimazole plus l-thyroxine (14 patients). At the time of the investigation, 13 patients were considered cured following antithyroid treatment, 2 were still on antithyroid drugs, 3 were on replacement therapy with l-thyroxine because of hypothyroidism, and 10, treated either surgically or with 131I, were on replacement therapy. The bone mineral density was measured at the lumbar spine (L2–L4) and at the femoral neck, using dual-energy X-ray absorptiometry. Results: The spinal bone mineral density SD score was –0.28 ± 1.02, the femoral neck bone mineral density SD score was 0.36 ± 1.02, and both were not different from zero (NS). We did not find any correlation between the bone mineral density of the femoral neck and that of the lumbar spine and the clinical parameters. Conclusion: Graves’ disease, beginning in childhood and adolescence, when appropriately treated, does not affect attainment of peak bone mass.
Increased Expression of the S25 Ribosomal Protein Gene Occurs during Ageing of the Rat Liver
Authors: Lavery W. Lindsay , Goyns Malcolm H.
Published: April 2003

Background: It appears that consistent changes in the levels of activity of a small cohort of genes (probably <1% of all active genes) occur in all mammalian cells during ageing. Identification of such genes could provide valuable insights into the ageing process. Objective: We have studied age-related changes in gene expression profiles in the rat liver. One of the genes which exhibited clear and consistent increases in expression is characterised. Methods: Analysis of the gene expression profile was carried out using a combination of an optimised form of differential display and single-strand conformational polymorphism (SSCP) gel analysis. Gene expression levels were quantified by Northern blot analysis. The gene’s identity was determined by comparing its nucleotide sequence to DNA databases. Results: During this investigation we observed one gene which exhibited an increase in expression in livers from young adult (6 months) to old adult (24 months) rats. The differential expression of this gene was confirmed by SSCP gel analysis and Northern blotting. Densitometry of the latter indicated that expression increased by 165% with age. Characterisation of the isolated polymerase chain reaction fragment demonstrated it to code for the ribosomal protein S25 (RPS25). Conclusion: This increase in RPS25 expression is further evidence that the composition of ribosomes may alter with age and as a result could have significant effects on protein synthesis.