bluuebunny/crossref_metadata_2025 huggingface dataset:
Rho/Rho kinase signaling mediates increased basal pulmonary vascular tone in chronically hypoxic rats
Authors: Nagaoka Tetsutaro , Morio Yoshiteru , Casanova Nina , Bauer Natalie , Gebb Sarah , McMurtry Ivan , Oka Masahiko
Published: September 2004

Recent evidence suggests that Rho/Rho kinase signaling plays an important role in the sustained vasoconstriction induced by many agonists and is involved in the pathogenesis of systemic vascular diseases. However, little is known about its role in increased vascular tone in hypoxic pulmonary hypertension (PH). The purpose of this study was to examine whether Rho/Rho kinase-mediated Ca2+sensitization contributed to sustained vasoconstriction and increased vasoreactivity in hypoxic PH in rats. Acute intravenous administration of Y-27632, a Rho kinase inhibitor, nearly normalized the high pulmonary arterial blood pressure and total pulmonary resistance in chronically hypoxic rats. In contrast to nifedipine, Y-27632 also markedly decreased elevated basal vascular tone in hypertensive blood-perfused lungs and isolated pulmonary arteries. Y-27632 and another Rho kinase inhibitor, HA-1077, completely reversed nitro-l-arginine-induced vasoconstriction in physiological salt solution-perfused hypertensive lungs, whereas inhibitors of myosin light chain kinase (ML-9), protein kinase C (GF-109203X), phosphatidylinositol 3-kinase (LY-294002), and tyrosine kinase (tyrphostin A23) caused only partial or no reversal of the vasoconstriction. Vasoconstrictor responses to KCl were augmented in hypertensive physiological salt solution-perfused lungs and pulmonary arteries, and the augmentation was eliminated by Y-27632. These results suggest that Rho/Rho kinase-mediated Ca2+sensitization plays a central role in mediating sustained vasoconstriction and increased vasoreactivity in hypoxic PH.
Fas/FasL-mediated apoptosis in perinatal murine lungs
Authors: De Paepe Monique E. , Mao Quanfu , Embree-Ku Michelle , Rubin Lewis P. , Luks Francois I.
Published: September 2004

Postcanalicular lung development is characterized by a time-specific increase in alveolar epithelial type II cell apoptosis. We have previously demonstrated that, in fetal rabbits, developmental type II cell apoptosis coincides with transient upregulation of the cell death regulator Fas ligand (FasL). The aims of this study were 1) to determine the spatiotemporal patterns of pulmonary apoptosis and Fas/ FasL gene expression in the murine model [embryonic day 17 (E17) through postnatal day 5 (P5)], and 2) to investigate the functional involvement of the Fas/FasL system by determining the effect of Fas activation and inhibition on perinatal pulmonary apoptosis. The apoptotic activity of alveolar epithelial type II cells, determined by combined TUNEL labeling and anti-surfactant protein B immunohistochemistry, showed a dramatic increase during the perinatal transition (type II cell apoptotic index <0.1% at E17, 1.5% at P1-P3, and 0.3% at P5). This timing of enhanced type II cell apoptosis coincided with a robust 14-fold increase in Fas mRNA and protein levels and a threefold increase in FasL protein levels; both Fas and FasL immunolocalized to type II and bronchial epithelial cells. In vitro and in vivo exposure of fetal and postnatal murine type II cells to anti-Fas antibody induced a fourfold increase in apoptotic activity that was prevented by administration of a broad-spectrum caspase inhibitor; the pulmonary apoptotic activity of Fas-deficient lpr mice remained unchanged. Conversely, administration of a caspase inhibitor to newborn mice (P1) resulted in marked diminution of pulmonary apoptotic activity. These combined findings strongly implicate the Fas/FasL system as a critical regulator of perinatal type II cell apoptosis. The developmental time dependence of apoptosis-related events in the murine model should facilitate investigations of the regulation of perinatal pulmonary apoptotic gene expression.
Susceptibility to neoplastic and non-neoplastic pulmonary diseases in mice: genetic similarities
Authors: Bauer Alison K. , Malkinson Alvin M. , Kleeberger Steven R.
Published: September 2004

Chronic inflammation predisposes toward many types of cancer. Chronic bronchitis and asthma, for example, heighten the risk of lung cancer. Exactly which inflammatory mediators (e.g., oxidant species and growth factors) and lung wound repair processes (e.g., proangiogenic factors) enhance pulmonary neoplastic development is not clear. One approach to uncover the most relevant biochemical and physiological pathways is to identify genes underlying susceptibilities to inflammation and to cancer development at the same anatomic site. Mice develop lung adenocarcinomas similar in histology, molecular characteristics, and histogenesis to this most common human lung cancer subtype. Over two dozen loci, called Pas or pulmonary adenoma susceptibility, Par or pulmonary adenoma resistance, and Sluc or susceptibility to lung cancer genes, regulate differential lung tumor susceptibility among inbred mouse strains as assigned by QTL (quantitative trait locus) mapping. Chromosomal sites that determine responsiveness to proinflammatory pneumotoxicants such as ozone (O3), particulates, and hyperoxia have also been mapped in mice. For example, susceptibility QTLs have been identified on chromosomes 17 and 11 for O3-induced inflammation ( Inf1, Inf2), O3-induced acute lung injury ( Aliq3, Aliq1), and sulfate-associated particulates. Sites within the human and mouse genomes for asthma and COPD phenotypes have also been delineated. It is of great interest that several susceptibility loci for mouse lung neoplasia also contain susceptibility genes for toxicant-induced lung injury and inflammation and are homologous to several human asthma loci. These QTLs are described herein, candidate genes are suggested within these sites, and experimental evidence that inflammation enhances lung tumor development is provided.
The human paracellin-1 gene (hPCLN-1): renal epithelial cell-specific expression and regulation
Authors: Efrati Edna , Arsentiev-Rozenfeld Julia , Zelikovic Israel
Published: September 2004

Tubular reabsorption of Mg2+is mediated by the tight junction protein paracellin-1, which is encoded by the gene PCLN-1 (CLDN16) and exclusively expressed in the kidney. Tubular Mg2+reclamation is modulated by many hormones and factors. The aim of this study was to define regulatory elements essential for renal tubular cell-specific expression of human PCLN-1 ( hPCLN-1) and to explore the effect of Mg2+transport modulators on the paracellin-1 gene promoter. Endogenous paracellin-1 mRNA and protein were detected in renal cell lines opossom kidney (OK), HEK293, and MDCT, but not in the fibroblast cell line NIH3T3. A 7.5-kb hPCLN-1 5′-flanking DNA sequence along with seven 5′-deletion products were cloned into luciferase reporter vectors and transiently transfected into the renal and nonrenal cells. The highest levels of luciferase activity resulted from transfection of a 5′-flanking 2.5-kb fragment (pJ2M). This activity was maximal in OK cells, was orientation dependent, and was absent in NIH3T3 cells. Mg2+deprivation significantly increased pJ2M-driven activity in transfected OK cells, whereas Mg2+load decreased it compared with conditions of normal Mg2+. Deletion analysis along with electrophoretic mobility-shift assay demonstrated that OK cells contain nuclear proteins, which bind a 70-bp region between −1633 and −1703 of major functional significance. Deleting this 70-bp segment, which contains a single peroxisome proliferator-response element (PPRE), or mutating the PPRE, caused a 60% reduction in luciferase activity. Stimulating the 70-bp sequence with 1,25(OH)2vitamin D decreased luciferase activity by 52%. This effect of 1,25(OH)2vitamin D was abolished in the absence of PPRE or in the presence of mutated PPRE. We conclude that the PPRE within this 70-bp DNA region may play a key role in the cell-specific and regulatory activity of the hPCLN-1 promoter. Ambient Mg2+concentration and 1,25(OH)2vitamin D may modulate paracellular, paracellin-1-mediated, Mg2+transport at the transcriptional level. 1,25(OH)2vitamin D exerts its activity on the hPCLN-1 promoter likely via the PPRE site.
Cyclosporin A produces distal renal tubular acidosis by blocking peptidyl prolyl cis-trans isomerase activity of cyclophilin
Authors: Watanabe Seiji , Tsuruoka Shuichi , Vijayakumar Soundarapandian , Fischer Gunter , Zhang Yixin , Fujimura Akio , Al-Awqati Qais , Schwartz George J.
Published: September 2004

Cyclosporin A (CsA), a widely used immunosuppressant, causes distal renal tubular acidosis (dRTA). It exerts its immunosuppressive effect by a calcineurin-inhibitory complex with its cytosolic receptor, cyclophilin A. However, CsA also inhibits the peptidyl prolyl cis-trans isomerase (PPIase) activity of cyclophilin A. We studied HCO3− transport and changes in β-intercalated cell pH on luminal Cl− removal in isolated, perfused rabbit cortical collecting tubules (CCDs) before and after exposure to media pH 6.8 for 3 h. Acid incubation causes adaptive changes in β-intercalated cells by extracellular deposition of hensin ( J Clin Invest 109: 89, 2002). Here, CsA prevented this adaptation. The unidirectional HCO3− secretory flux, estimated as the difference between net flux and that after Cl− removal from the lumen, was −6.7 ± 0.2 pmol·min−1·mm−1 and decreased to −1.3 ± 0.2 after acid incubation. CsA in the bath prevented the adaptive decreases in HCO3− secretion and apical Cl−:HCO3− exchange. To determine the mechanism, we incubated CCDs with FK-506, which inhibits calcineurin activity independently of the host cell cyclophilin. FK-506 did not prevent the acid-induced adaptive decrease in unidirectional HCO3− secretion. However, [AD-Ser]8 CsA, a CsA derivative, which does not inhibit calcineurin but inhibits PPIase activity of cyclophilin A, completely blocked the effect of acid incubation on apical Cl−:HCO3− exchange. Acid incubation resulted in prominent “clumpy” staining of extracellular hensin and diminished apical surface of β-intercalated cells [smaller peanut agglutinin (PNA) caps]. CsA and [AD-Ser]8 CsA prevented most hensin staining and the reduction of apical surface; PNA caps were more prominent. We suggest that hensin polymerization around adapting β-intercalated cells requires the PPIase activity of cyclophilins. Thus CsA is able to prevent this adaptation by inhibition of a peptidyl prolyl cis-trans isomerase activity. Such inhibition may cause dRTA during acid loading.
Interactions Between LTP- and LTD-Inducing Stimulation in the Sensorimotor Cortex of the Awake Freely Moving Rat
Authors: Froc David J. , Racine Ronald J.
Published: September 2004

Bidirectional modifications in synaptic efficacy are central components in models of cortical learning and memory. More recently, the regulation of synaptic plasticity according to the history of synaptic activation, termed “metaplasticity,” has become a focus of research on the physiology of memory. Here we explore such interactions between long-term potentiation (LTP) and long-term depression (LTD) in the chronically prepared rat. The effects of successive high- and low-frequency stimulation were examined in sensorimotor cortex in the adult, freely moving rat. High-frequency (300 Hz) stimulation (HFS) applied to the white matter was used to induce LTP, and prolonged, low-frequency (1 Hz) stimulation (LFS) was used to induce either depotentiation or LTD. Combined stimulation (HFS/LFS or LFS/HFS) during the induction phase attenuated potentiation effects only if the LFS followed the HFS. LTD induced by LFS alone was expressed as a reduction in the amplitude of both short- and long-latency field potential components, whereas depotentiation was primarily expressed as a decrease in the amplitude of the potentiated long-latency component. In other experiments, LTP (or LTD) was induced to asymptotic levels before applying LFS (or HFS). LFS caused depotentiation of the late component but had no measurable effect on the early component. HFS reversed previously induced LTD, but the potentiation decayed more rapidly than usual. LTP and LTD therefore modulate each other in the awake, behaving rat.
Contribution of Persistent Sodium Currents to Spike-Frequency Adaptation in Rat Hypoglossal Motoneurons
Authors: Zeng Jinsong , Powers Randall K. , Newkirk Gregory , Yonkers Marc , Binder Marc D.
Published: September 2004

In response to constant current inputs, the firing rates of motoneurons typically show a continuous decline over time. The biophysical mechanisms underlying this process, called spike-frequency adaptation, are not well understood. Spike-frequency adaptation normally exhibits a rapid initial phase, followed by a slow, later phase that continues throughout the duration of firing. One possible mechanism mediating the later phase might be a reduction in the persistent sodium current ( INaP) that has been shown to diminish the capacity of cortical pyramidal neurons and spinal motoneurons to sustain repetitive firing. In this study, we used the anticonvulsant phenytoin to reduce the INaP of juvenile rat hypoglossal motoneurons recorded in brain stem slices, and we examined the consequences of a reduction in INaP on the magnitude and time course of spike-frequency adaptation. Adding phenytoin to the bathing solution (≥50 μM) generally produced a marked reduction in the persistent inward currents (PICs) recorded at the soma in response to slow, voltage-clamp triangular ramp commands (−70 to 0 mV and back). However, the same concentrations of phenytoin appeared to have no significant effect on spike-frequency adaptation even though the phenytoin often augmented the reduction in action potential amplitude that occurs during repetitive firing. The surprising finding that the reduction of a source of sustained inward current had no appreciable effect on the pattern of spike generation suggests that several types of membrane channels must act cooperatively to insure that these motoneurons can generate the sustained repetitive firing required for long-lasting motor behaviors.
Adenosine Postsynaptically Modulates Supraoptic Neuronal Excitability
Authors: Ponzio Todd A. , Hatton Glenn I.
Published: September 2004

Effects of adenosine on the excitability of supraoptic nucleus neurons were investigated in whole cell patch-clamp experiments conducted in horizontal slices of rat hypothalamus. Adenosine (10–100 μM) inhibited all neurons tested by reducing or abolishing spontaneous or evoked discharge. Large hyperpolarizations were seen, averaging -6.08 ± 0.83 mV below resting membrane potential, and action potential durations were significantly reduced by 134 ± 41 μs in the presence of 100 μM adenosine. The A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 1 μM) blocked these effects, whereas the A1 agonists N6-cyclopentyladenosine (CPA) and N6-cyclohexyladenosine (CHA) mimicked the actions of adenosine. A2 receptor contributions to excitability were assessed by application of an A2 agonist, carboxamidoadenosine (CPCA). This resulted in membrane depolarizations (3.56 ± 0.65 mV) and maintenance of firing. The presence of endogenous adenosine in the slice was revealed by both the application of the adenosine uptake inhibitor dilazep (1–100 μM), which resulted in a strong inhibition of firing activity, and the application of DPCPX, which induced firing in cells silenced by negative current injection. We tested for postsynaptic actions of adenosine by blocking G protein activation via GDP-β-S infusion into recorded neurons. Under these conditions, the adenosinergic inhibition of firing and reduction of spike duration were blocked, suggesting the effects were mediated by postsynaptic adenosine receptors. That the effects on excitability could be due to direct activation of adenosine A1 receptors on supraoptic neurons was further explored immunocytochemically via the co-labeling of magnocellular neurons with polyclonal antibodies raised against the A1 receptors. It is concluded that adenosine, acting at postsynaptic A1 receptors, exhibits a powerful inhibitory influence on supraoptic magnocellular activity and is an important endogenous regulator of magnocellular neuroendocrine function.
Effect of Iron Deficiency Anemia on the Levels of Hemoglobin A1c in Nondiabetic Patients
Authors: Coban Erkan , Ozdogan Mustafa , Timuragaoglu Aysen
Published: September 2004

The major form of glycohemoglobin is hemoglobin A1c (HbA1c). The HbA1c fraction is abnormally elevated in chronic hyperglycemic diabetic patients and correlates positively with glycemic control. Previous studies suggest that iron deficiency anemia (IDA) affects the levels of HbA1c. The aim of this study was to determine the effect of IDA on HbA1c levels in nondiabetic patients. The population studied consisted of 50 patients (30 women, 20 men, mean age 35.7 ± 11.9 years) with IDA and 50 healthy subjects that were matched for age and sex. Patients who had glucose tolerance abnormalities (impaired glucose tolerance or diabetes mellitus), hemoglobinopathies, hemolytic anemia, chronic alcohol ingestion and chronic renal failure were excluded from the study. Hematologic investigations, fasting and postprandial glucose and HbA1c levels were measured in all subjects before iron therapy. All patients with IDA were treated with iron 100 mg/day for 3 months. We repeated the laboratory investigation after iron therapy. Before iron treatment, the mean HbA1c (7.4 ± 0.8%) level in patients with IDA was higher than in a healthy group (5.9% ± 0.5) (p < 0.001). In patients with IDA, HbA1c decreased significantly after iron treatment from a mean of 7.4% ± 0.8 to 6.2% ± 0.6 (p < 0.001). Iron deficiency must be corrected before any diagnostic or therapeutic decision is made based on HbA1c.
CD68 and MCP-1/CCR2 Expression of Initial Biopsies Reflect the Outcomes of Membranous Nephropathy
Authors: Yoshimoto Keiichi , Wada Takashi , Furuichi Kengo , Sakai Norihiko , Iwata Yasunori , Yokoyama Hitoshi
Published: September 2004

Background: A considerable diversity of prognosis is seen with idiopathic membranous nephropathy (IMN). The initial factors affecting long-term outcome remain unclear. Methods: We studied retrospectively 30 patients with IMN who had been followed up for at least 5 years, or until end-stage renal failure (ESRF). We analyzed the prognostic factors of ESRF in the first renal biopsies; these factors included presence of tubulointerstitial lesions and foam cells, as well as expression of CD68, monocyte chemoattractant protein-1 (MCP-1), its cognate receptor chemokine receptor 2 (CCR2) and α-smooth muscle actin. Results: The patients who developed ESRF showed higher percentages of glomerular segmental sclerosis, interstitial MCP-1 expression, CCR2- or CD68-positive monocyte/macrophages and foam cells in the interstitium, and these proved on multivariate analysis to be independent risk factors for ESRF. Finally, ESRF was characterized by the presence of ten interstitial CD68-positive cells per visual field at 200× magnification (hazard ratio 4.096, CI 1.271–15.029, p < 0.001). Conclusions: Our results suggested that an interstitial infiltration of CD68-positive cells accompanied by MCP-1/CCR2 expression is the most significant indicator of ESRF in IMN.
Hypoxia and Tubulointerstitial Injury: A Final Common Pathway to End-Stage Renal Failure
Authors: Nangaku Masaomi
Published: September 2004

Many clinical observations suggest common mediators in the progression of kidney disease leading to eventual kidney failure. Among them, accumulating evidence emphasizes the role of chronic hypoxia in the tubulointerstitium in this role. When advanced, tubulointerstitial damage is associated with the loss of peritubular capillaries, impairing blood delivery. Associated interstitial fibrosis further impairs oxygen diffusion and supply to tubular and interstitial cells. This in turn exacerbates chronic hypoxia in this compartment, resulting in a vicious cycle. Both singly or together, glomerular injury and vasoconstriction of efferent arterioles due to an imbalance in vasoactive substances decrease post-glomerular peritubular capillary blood flow and contribute to chronic hypoxia in the tubulointerstitium. Anemia in kidney disease also plays a significant role in hypoxia of the kidney. Moreover, increased metabolic demand in tubular cells, as observed in glomerular hyperfiltration for example, can cause relative hypoxia. Importantly, these factors can affect the kidney before the appearance of significant pathological changes in the vasculature and predispose it to tubulointerstitial injury. Therapeutic approaches targeting chronic hypoxia in the kidney should be effective against a broad range of renal diseases. Recent studies have elucidated the mechanisms of hypoxia-induced transcription, giving hope for the development of novel therapeutic approaches against this final common pathway.
Redistribution of Integrins in Tubular Epithelial Cells during Diabetic Glycogen Nephrosis
Authors: Londoño Irene , Bamri-Ezzine Saoussen , Gingras Diane , Bendayan Moise
Published: September 2004

Background/Aims: Even though many aspects of glycogen nephrosis in diabetes have already been studied, adhesion interactions between the glycogen-accumulating clear cells and the tubular basement membranes have not been addressed. As integrins play key roles in cell-to-matrix interactions, we investigated the expression and distribution of α3-, αV-, β1- and β3-integrin subunits in renal tissues from streptozotocin-induced hyperglycemic rats (3 months old) and their age-matched controls as well as from streptozotocin-injected normoglycemic animals. Methods: The levels and distribution of integrins were studied by immunocytochemistry and Western blot analysis. Results: Immunoblotting analysis of fractions enriched in glycogen-accumulating clear cells demonstrated enhanced expression of α3, αV and β1 subunits while expression of β3 did not differ from controls. The most striking cytochemical result was the redistribution of the α3-, αV-, and the β1-integrin subunits to the apical plasma membrane of these cells. This was found by light and electron microscopy. Conclusion: Our results suggest that the altered expression and distribution of integrins in clear cells of diabetic animals must have defined roles in the development of the renal tubulopathy.
Food Allergens Are Protected from Degradation during CD23-Mediated Transepithelial Transport
Authors: Bevilacqua Claudia , Montagnac Guillaume , Benmerah Alexandre , Candalh Céline , Brousse Nicole , Cerf-Bensussan Nadine , Perdue Mary H. , Heyman Martine
Published: September 2004

Background: CD23 (FcΕRII) is expressed by intestinal epithelial cells (IEC) following allergic stimulation and increases the uptake of IgE/allergen complexes. The aim of this study was to further analyze the role of CD23 in the intraepithelial processing of food allergens during transepithelial transport. Methods: Balb-C mice were sensitized intraperitoneally with horseradish peroxidase (HRP) or β-lactoglobulin (β-LG) in the presence of pertussis toxin. In control and sensitized mice, 3H-HRP, intact HRP, or 14C-β-LG fluxes were measured across jejunal segments mounted in Ussing chambers, in the presence or absence of mucosal anti-CD23 antibodies. HPLC analysis of serosal buffer was performed to detect HRP- or β-LG-derived radiolabelled metabolites generated during transepithelial transport. Results: In HRP-sensitized mice, 3H-HRP fluxes and intact HRP fluxes (3,836 ± 476 and 290 ± 86 ng/h ·cm2, respectively) were significantly increased compared to control mice (1,677 ± 297 ng/h · cm2, p < 0.01, and 106 ± 23 ng/h · cm2, p < 0.02, respectively). HPLC analysis indicated the presence of intact HRP in the serosal compartment already 10 min after addition of HRP to the mucosal compartment, a result not observed in the control mice. In the presence of anti-CD23 antibodies, intact HRP fluxes were significantly decreased (131 ± 27 ng/h · cm2) compared to control values in sensitized mice (290 ± 86 ng/h · cm2, p < 0.02), suggesting that CD23 is involved is this ‘protected’ transport pathway. A similar protection during intestinal transport was observed for β-LG in β-LG sensitized mice. Conclusions: These results confirm that CD23 is involved in the rapid transepithelial transport of intact allergens in sensitized animals, and indicate that CD23 opens a ‘protected’ transport pathway in IECs.
Comparison of the Effects in the Nose and Skin of a Single Dose of Desloratadine and Levocetirizine over 24 Hours
Authors: Passalacqua Giovanni , Guerra Laura , Compalati Enrico , Massacane Pierangela , Rogkakou Anthi , Zanella Cristian , Baena-Cagnani Rodrigo , Canonica Giorgio Walter
Published: September 2004

Background: Desloratadine (DL) and levocetirizine (LCZ) are the newest commercialized antihistamines. Pharmacokinetics, pharmacodynamics and clinical data are available for both drugs, but there is to date no direct comparison involving the nose and skin at the same time. We compared the effects of a single dose of the two drugs in the nose and skin over 24 h. Methods: Twenty-three patients with symptomatic allergic rhinitis were enrolled in a randomized double-blind crossover administration of DL and LCZ. The histamine-induced wheal and flare was measured at baseline and 2 and 24 h after dosing. A reflective total symptom score (rTSS) for the previous 24 h was assessed before and after each dose. An instant symptom score was also measured at various time points after each drug. Results: LCZ provided greater inhibition of the flare at 2 h (p = 0.05) and at 24 h (p = 0.007) and greater inhibition of the wheal only at 2 h (p = 0.02). The decrease in wheal and flare was significant versus baseline (p = 0.007) with both drugs. The rTSS of the previous 24 h decreased significantly with both LCZ (11.53 vs. 8.0; p < 0.05) and DL (11.3 vs. 7.9; p < 0.05). The instant TSS progressively decreased in parallel with both drugs, but a difference in favor of LCZ was seen 2 h after dosing. Conclusions: Single doses of DL and LCZ had a comparable effect on nasal symptoms, but LCZ was faster and displayed a greater effect on histamine wheal.
Cytogenetic Consequences of Vinblastine Treatment in Mouse Bone Marrow
Authors: Choudhury Ramesh C. , Palo Anil K. , Padhy Ananya
Published: September 2004

Background: Vinblastine (VBL), a vinca alkaloid, has very often been included in different cancer chemotherapeutic treatment regimens. Chemotherapy cures certain cancers and, at least, increases the life expectancy of cancer patients. However, in cancer survivors, a second malignancy frequently occurs after chemotherapy, which warrants detailed genotoxicity testing of the chemotherapeutic agents. The available genotoxicity test reports on VBL are self-contradictory and inconclusive. Thus, following a suitable experimental protocol, it is necessary to test the cytogenetic consequences of VBL treatment in mammals. Methods: Swiss mice received 1 of 3 different doses of VBL (0.5, 1.0 and 1.5 mg/kg body weight) as a single intraperitoneal injection. The cytogenetic toxicity of VBL was assessed from the induced aberrant metaphases, chromosomal aberrations (CAs) excluding gaps and the mitotic index (MI) 24 h after treatment, and micronuclei (MN) 30 h after treatment. Results: All 3 doses of VBL induced statistically significant (p ≤ 0.01) percentages of aberrant metaphases and CAs, but there was no significant change in the MI. The induced percentage of aberrant metaphases and CAs were decreased with the increase in the dose of VBL. On the other hand, there was a dose-dependent and significant (p ≤ 0.01) increase in MN induction. Conclusions: The results of this study indicate the clastogenic potential of VBL in the mouse bone marrow. In the present study, the induction of numerous relatively large-sized MN by VBL is in agreement with the reported aneugenic action of the drug. Although VBL is cytotoxic and is a spindle poison, the mechanism(s) involved in bringing about its clastogenic effects is yet to be elucidated.
Antimicrobial Resistance of Streptococcus pneumoniae Isolates of Outpatients in Germany, 1999–2000
Authors: Reinert Ralf René , Lütticken Rudolf , Reinert Susanne , Al-Lahham Adnan , Lemmen Sebastian
Published: September 2004

Background: The aim of the study was to determine the prevalence of antimicrobial resistance among clinical isolates of Streptococcus pneumoniae during the winter of 1999–2000 in Germany. Methods: Pneumococcal isolates were prospectively collected by 14 different clinical microbiology laboratories. Minimal inhibitory concentrations of penicillin G, erythromycin A, clarithromycin, roxithromycin, azithromycin, clindamycin, levofloxacin and telithromycin were determined by the broth microdilution method. Results: Among 328 strains 4.6% were nonsusceptible to penicillin G (intermediate and resistant strains) and 9.5% were resistant to erythromycin A. Analysis of erythromycin-resistant strains for the underlying resistance determinants revealed that 12 (38.7%) belonged to the erm(B) and 19 (61.3%) to the mef(E) type of resistance. Among the macrolide-resistant strains, serotypes 19F (n = 9) and 14 (n = 8) were the predominant types. Conclusions: Macrolide resistance in Germany is of growing concern and mainly due to the high prevalence of pneumococci expressing the mef(E) type of resistance.
Effects of Dexamethasone, All-Trans Retinoic Acid, Vitamin D3 and Interferon-α on FO Myeloma Cells
Authors: Ozdemir Feyyaz , Esen Nilgun , Ovali Ercument , Tekelioglu Yavuz , Yilmaz Mustafa , Aydin Fazil , Kavgaci Halil , Boruban Cem
Published: September 2004

Background: Since multiple myeloma responds poorly to conventional chemotherapy or radiotherapy, new therapeutic approaches are needed. This study investigated the effects of dexamethasone, all-trans retinoic acid (ATRA), the active metabolite of vitamin D3 [1,25(OH)2D3] and interferon-α on FO mouse myeloma cells (non-immunoglobulin-secreting myeloma cell line) in single drug or drug combination groups in vitro. Methods: Apoptosis ratio and change in cell counts in 4 single drug groups (dexamethasone, ATRA, vitamin D3 and interferon-α) and 6 combination drug groups (dexamethasone + vitamin D3, dexamethasone + ATRA, dexamethasone + interferon-α, vitamin D3 + ATRA, vitamin D3 + interferon-α, interferon-α + ATRA) were compared with the control group. Results: When treatment groups were compared with the control group, there was a significant increase in apoptosis in all, but this was most prominent in the group treated with dexamethasone alone. The apoptosis ratios were 0.10 and 6.82% in the control and dexamethasone-only groups, respectively. We also found that there was a significant decrease in cell count, particularly in the dexamethasone-only, ATRA-only, and ATRA-vitamin D3 combination groups. Conclusion: ATRA, interferon-α, vitaminD3 and particularly dexamethasone have significant effects on FO mouse myeloma cells resulting in a decreased cell count and an increased apoptosis ratio. This study should be repeated with human myeloma cell lines for further information.
Differentiation of Cognitive and Motor Aspects in a Digit Symbol Substitution Test in Anorexia nervosa Patients, before and after Weight Restoration
Authors: Pieters Guido , Maas Yvonne , Hulstijn Wouter , Vandereycken Walter , Probst Michel , Peuskens Joseph , Sabbe Bernard
Published: September 2004

Background: In a previous study, using computerized analysis of fine motor behaviour, seriously underweight anorexia nervosa patients in the early phase of treatment were found to have shorter reaction times, but not movement times, in experimental drawing and copying tasks. These differences persisted with weight restoration. Sampling and Methods: Using computerized analysis of writing and drawing behaviour during the performance of a Digit Symbol Substitution Test, 15 anorexia nervosa patients were compared with 15 normal controls, matched for age, sex and educational level. Patients were retested after weight restoration, as were controls after a similar interval. Results: Patients turned out to be superior in the cognitive, but not in the motor aspects of the Digit Symbol Substitution Test. These differences persisted after weight restoration. A practice effect, due to repeated testing, was found in both groups, which turned out to be cognitive in nature. Conclusions: The findings show that this new technique can add to the interpretation of classic neuropsychological tests. The results are compatible with previous findings of intact or even superior functioning in anorexia nervosa patients on neuropsychological tasks requiring considerable cognitive effort.
Attentional and Memory Bias in Persecutory Delusions and Depression
Authors: Taylor Jayne L. , John Carolyn H.
Published: September 2004

Background: Previous research has indicated that persecutory delusions and depression may share similar cognitive biases at implicit levels of processing, but differentiate at explicit levels, supporting the theory that paranoia may have a protective function against underlying negative schemata. The study aimed to investigate attentional bias and both implicit and explicit memory biases for personally salient and standardised emotional stimuli in persecutory delusions and depression. Sampling: 36 participants, with 12 in each group, were interviewed in order to generate personally salient stimuli to be employed within the cognitive tests. Standardised emotional stimuli were additionally employed as a control. Participants completed two probe detection tasks, one including personally salient stimuli and one including standard emotional stimuli. Memory for the stimuli presented in this task was assessed by a free recall task (explicit memory) followed by a word completion task (implicit memory). Results: On an implicit memory task, both the deluded and depressed groups displayed comparable retrieval of positive and negative words. However, on the explicit memory task, the depressed group demonstrated a bias for negative stimuli, whereas the deluded group demonstrated a bias for positive stimuli. The groups did not demonstrate an attentional bias for personally salient information. However, an attentional bias for standardised emotional stimuli was found in the depressed group, although this was not specific to either negative or positive stimuli. Conclusion: The results indicate that depression and persecutory delusions may share similar patterns of processing at an implicit level but differentiate at the explicit level, which may be indicative of cognitive avoidance of threatening stimuli in psychosis. However, this does not seem to be a feature of automatic attentional processes in people with persecutory delusions. Implications for further research are discussed.
Koro-Misidentification Syndrome in Schizophrenia? A Plea for Clinical Psychopathology
Authors: Rejón Altable Carlos , Rodríguez Urrutia Amanda
Published: September 2004

Although current diagnostic procedures favour the diagnosis of similar syndromes in different pathological processes, it cannot be overlooked that many psychiatric symptoms that share a similar ‘surface grammar’ differ in their ‘deep grammar’ or structure. In the case presented, we describe an acute psychosis where a Koro-misidentification syndrome might be diagnosed. In the discussion we point out how confusing this approach might be, as well as a feasible way to compensate for the shortcomings of contemporary descriptive psychopathology.
Predictors of Heart Failure Among Women With Coronary Disease
Authors: Bibbins-Domingo Kirsten , Lin Feng , Vittinghoff Eric , Barrett-Connor Elizabeth , Hulley Stephen B. , Grady Deborah , Shlipak Michael G.
Published: September 2004

Background—

Although heart failure is common among women with coronary disease, the risk factors for developing heart failure have not been well studied. We determined the risk factors for developing heart failure among postmenopausal women with established coronary disease.

Methods and Results—

This is a prospective cohort study using data from the Heart and Estrogen/progestin Replacement Study (HERS), a randomized, blinded, placebo-controlled trial of 4.1 years’ duration, and subsequent open-label observational follow-up for 2.7 years (HERS II), performed at 20 US clinical centers between 1993 and 2000. Of the 2763 postmenopausal women with established coronary disease in the HERS trial, we studied the 2391 women with no heart failure at baseline by self-report and physical examination. The primary outcome of this analysis was incident heart failure defined by hospital admission or death from heart failure. During the 6.3±1.4-year follow-up, 237 women (10%) developed heart failure. Nine predictors were identified: diabetes (defined as a self-reported history of diabetes on treatment), atrial fibrillation, myocardial infarction, creatinine clearance <40 mL/min, systolic blood pressure >120 mm Hg, current smoking, body mass index >35 kg/m
2
, left bundle-branch block, and left ventricular hypertrophy. Randomization to estrogen/progestin was not associated with heart failure (hazard ratio=1.0; 95% CI, 0.7 to 1.3). Diabetes was the strongest risk factor (adjusted hazard ratio=3.1; 95% CI, 2.3 to 4.2). Diabetic women with elevated body mass index or depressed creatinine clearance were at highest risk, with annual incidence rates of 7% and 13%, respectively. Among diabetic women, hyperglycemia was associated with heart failure risk (adjusted hazard ratio=3.0; 95% CI, 1.2 to 7.5 for fasting glucose >300 mg/dL compared with fasting glucose 80 to 150 mg/dL).

Conclusions—

We identified 9 predictors of heart failure in postmenopausal women with coronary disease. Diabetes was the strongest risk factor, particularly when poorly controlled or with concomitant renal insufficiency or obesity.
Effect of Ramipril in Reducing Sudden Deaths and Nonfatal Cardiac Arrests in High-Risk Individuals Without Heart Failure or Left Ventricular Dysfunction
Authors: Teo Koon K. , Mitchell L. Brent , Pogue Janice , Bosch Jackie , Dagenais Gilles , Yusuf Salim
Published: September 2004

Background—

ACE inhibitor therapy reduces the risk of cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure, and need for revascularization in high-risk patients with clinical heart failure, overt left ventricular systolic dysfunction, or vascular disease. In patients with clinical heart failure or overt left ventricular systolic dysfunction, ACE inhibitor therapy also reduces the risk of sudden or arrhythmia-related cardiac death. The objective of this study was to assess the effect of the ACE inhibitor ramipril on sudden unexpected death or resuscitated cardiac arrest among the 9297 individuals without clinical heart failure or overt left ventricular dysfunction enrolled in the Heart Outcomes Prevention Evaluation (HOPE) trial.

Methods and Results—

During the median follow-up of 4.5 years, the composite outcome of unexpected death, documented arrhythmic death, or resuscitated cardiac arrest was reduced by 21% in patients randomized to ramipril therapy compared with those randomized to placebo. There were 155 (3.3%) composite outcome events in patients randomized to ramipril therapy compared with 195 (4.2%) such events in patients randomized to placebo (RR 0.79, 95% CI 0.64 to 0.98,
P
=0.028). There were trends toward reductions in fatal primary outcome events (unexpected death or documented arrhythmic death; RR 0.81, 95% CI 0.64 to 1.02,
P
=0.072) and in nonfatal primary outcome events (resuscitated cardiac arrest; RR 0.65, 95% CI 0.38 to 1.13,
P
=0.127) in the ramipril treatment group.

Conclusions—

Ramipril reduces the risk of fatal and nonfatal serious arrhythmic events in high-risk patients without clinical heart failure or overt left ventricular systolic dysfunction.
Value of Delayed-Enhancement Cardiovascular Magnetic Resonance Imaging in Predicting Myocardial Viability After Surgical Revascularization
Authors: Selvanayagam Joseph B. , Kardos Attila , Francis Jane M. , Wiesmann Frank , Petersen Steffen E. , Taggart David P. , Neubauer Stefan
Published: September 2004

Background—

Despite the accepted utility of delayed-enhancement MRI in identifying irreversible myocardial injury, no study has yet assessed its role as a viability tool exclusively in the setting of coronary artery bypass surgery (CABG), and no study has repeated delayed-enhancement MRI late after revascularization. In a clinical trial in which patients underwent CABG by either the off-pump or on-pump surgical technique, we hypothesized that (1) preoperative delayed-enhancement MRI would have high diagnostic accuracy in predicting viability and (2) the occurrence of perioperative myocardial necrosis would affect late regional wall motion recovery.

Methods and Results—

Fifty-two patients undergoing multivessel CABG were studied by preoperative and early (day 6) and late (6 months) postoperative cine MRI for global and regional functional assessment and delayed-enhancement MRI for assessment of irreversible myocardial injury. Preoperatively, 611 segments (21%) had abnormal regional function, whereas 421 segments (14%) showed evidence of hyperenhancement. At 6 months after revascularization, 57% (343 of 611) of dysfunctional segments improved contraction by at least 1 grade. When all preoperative dysfunctional segments were analyzed, there was a strong correlation between the transmural extent of hyperenhancement and the recovery in regional function at 6 months (
P
<0.001). Of a total of 96 previously dysfunctional but nonenhancing or minimally hyperenhancing myocardial segments that did not improve regional function at 6 months, 35 (36%) demonstrated new perioperative hyperenhancement in the early postoperative MRI scan.

Conclusions—

Delayed-enhancement MRI is a powerful predictor of myocardial viability after surgery, suggesting an important role for this technique in clinical viability assessment.
Transplacental Fetal Treatment Improves the Outcome of Prenatally Diagnosed Complete Atrioventricular Block Without Structural Heart Disease
Authors: Jaeggi Edgar T. , Fouron Jean-Claude , Silverman Earl D. , Ryan Greg , Smallhorn Jeffrey , Hornberger Lisa K.
Published: September 2004

Background—

Untreated isolated fetal complete atrioventricular block (CAVB) has a significant mortality rate. A standardized treatment approach, including maternal dexamethasone at CAVB diagnosis and β-stimulation for fetal heart rates <55 bpm, has been used at our institutions since 1997. The study presents the impact of this approach.

Methods and Results—

Thirty-seven consecutive cases of fetal CAVB since 1990 were studied. Mean age at diagnosis was 25.6±5.2 gestational weeks. In 33 patients (92%), CAVB was associated with maternal anti-Ro/La autoantibodies. Patients were separated into those diagnosed between 1990 and 1996 (group 1; n=16) and those diagnosed between 1997 and 2003 (group 2; n=21). The 2 study groups were comparable in the clinical presentation at CAVB diagnosis but did differ in prenatal management (treated patients: group 1, 4/16; group 2, 18/21;
P
<0.0001). Overall, 22 fetuses were treated, 21 with dexamethasone and 9 with β-stimulation for a mean of 7.5±4.5 weeks. Live-birth and 1-year survival rates of group 1 were 80% and 47%, and these improved to 95% for group 2 patients (
P
<0.01). The 21 patients treated with dexamethasone had a 1-year survival rate of 90%, compared with 46% without glucocorticoid therapy (
P
<0.02). Immune-mediated conditions (myocarditis, hepatitis, cardiomyopathy) resulting in postnatal death or heart transplantation were significantly more common in untreated anti-Ro/La antibody–associated pregnancies compared with patients treated with steroids (0/18 versus 4/9 live births;
P
=0.007).

Conclusions—

A standardized treatment approach, including transplacental fetal administration of dexamethasone and β-stimulation at heart rates <55 bpm, reduced the morbidity and improved the outcome of isolated fetal CAVB.
Estrogen Modulates Inflammatory Mediator Expression and Neutrophil Chemotaxis in Injured Arteries
Authors: Miller Andrew P. , Feng Wenguang , Xing Dongqi , Weathington Nathaniel M. , Blalock J. Edwin , Chen Yiu-Fai , Oparil Suzanne
Published: September 2004

Background—

We have previously shown that estrogen (17β-estradiol; E2) inhibits neointima formation and migration of leukocytes, particularly neutrophils, into rat carotid arteries after acute endoluminal injury. This study tested the hypothesis that E2 inhibits expression of adhesion molecules, chemokines, and proinflammatory cytokines in rat carotid arteries in the early hours after balloon injury, thus attenuating the stimulus for leukocyte entry and negatively modulating the injury response.

Methods and Results—

Ovariectomized (OVX) rats were randomly assigned to treatment with E2 or vehicle (V) and subjected to balloon injury of the right carotid artery. After 2, 6, and 24 hours, rats were euthanized, and both carotid arteries were processed for real-time reverse transcription–polymerase chain reaction (2 and 24 hours), ELISA (6 hours), or neutrophil chemotaxis assay (24 hours). Expression of mRNA for adhesion molecules (P-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1), chemoattractants (cytokine-induced neutrophil chemoattractant [CINC]-2β and monocyte chemoattractant protein [MCP]-1), and proinflammatory cytokines (interleukin [IL]-1 and IL-6) was markedly increased (2 to 5000 times) in injured arteries of OVX+V rats at 2 hours and was reduced by 24 hours. E2 significantly attenuated expression of the proinflammatory mediators (by 60% to 80%) at 2 hours. ELISA confirmed injury-induced upregulation of neutrophil and monocyte/macrophage chemoattractants (CINC-2α, MCP-1) in OVX+V arteries and E2-induced inhibition of CINC-2α expression. E2 significantly (by 65%) inhibited neutrophil chemotactic activity of arterial homogenates.

Conclusions—

E2 attenuates the early vascular injury response, at least in part, by negatively modulating proinflammatory mediator expression and the resultant chemotactic activity of injured vessels for neutrophils.
Interleukin-1 Receptor Signaling Mediates Atherosclerosis Associated With Bacterial Exposure and/or a High-Fat Diet in a Murine Apolipoprotein E Heterozygote Model
Authors: Chi Hunghui , Messas Emmanuel , Levine Robert A. , Graves Dana T. , Amar Salomon
Published: September 2004

Background—

Current data demonstrate that progressive atherosclerosis is associated with activation of the inflammatory process, as evidenced by systemic elevations of molecules such as tumor necrosis factor, interleukin (IL)-6, and IL-1. It has been postulated that inflammatory events within an atherogenic lesion are induced by oxidized LDL. Recent evidence suggests that infectious agents, including those that cause periodontal disease, may also play an important role. Studies presented here tested the hypothesis that IL-1 receptor (IL-1R1) signaling plays a crucial role in bacteria- and/or high-fat diet (HFD)–enhanced atherogenesis.

Methods and Results—

Ten-week-old ApoE
+/−
mice lacking either 1 IL-1R1 allele (ApoE
+/−
/IL-1R1
+/−
) or 2 IL-1R1 alleles (ApoE
+/−
/IL-1R1
−/−
) fed either an HFD or regular chow were inoculated intravenously with live
Porphyromonas gingivalis
(
P gingivalis
) (10
7
CFU), an important periodontal pathogen, or vehicle once per week for 14 or 24 consecutive weeks. Histomorphometry of plaque cross-sectional area in the proximal aortas, en face measurement of plaque area over the aortic trees, and ELISA for systemic proinflammatory mediators were performed. Atherosclerotic lesions of proximal aortas and aortic tree were substantially reduced in ApoE
+/−
/IL-1R1
−/−
mice than in ApoE
+/−
/IL-1R1
+/−
mice challenged with
P gingivalis.
At 24 weeks after
P gingivalis
inoculation, proximal aortic lesion size quantified by histomorphometry was 5-fold–reduced in chow-fed ApoE
+/−
/IL-1R1
−/−
mice than in ApoE
+/−
/IL-1R1
+/−
mice (
P
<0.05). In the HFD group, ApoE
+/−
/IL-1R1
−/−
mice exhibited marked attenuation of the progression of atherosclerotic lesions (78% to 97%), with and without
P gingivalis
inoculation (
P
<0.05)

Conclusion—

Ablation of IL-1R1 under
P gingivalis
challenge and/or an HFD reduced the progression of atherosclerotic plaques. These results indicate that IL-1 plays a crucial role in bacteria- and/or HFD-enhanced atherogenesis.