bluuebunny/crossref_metadata_2025 huggingface dataset:
LOCALIZATION OF GRAVITY IN BRANE WORLD COSMOLOGIES
Authors: SINGH PARAMPREET , DADHICH NARESH
Published: May 2003

The most remarkable and interesting feature of brane world scenario is the use of bulk's curvature to localize gravity on the brane, albeit with fine tuning of the brane and bulk parameters. For FRW expanding universe on the brane, it is a moving hypersurface in Schwarzschild anti de Sitter bulk spacetime. We show that zero mass gravitons have bound state on the brane for suitable values of brane and bulk parameters. There occur various cases giving rise to different cosmological models, in particular we discuss a model with positive cosmological constant on the brane.
ON THE RELAXATION OF SUPERSTRING AXION MINI-CLUSTERS
Authors: POLLOCK M. D.
Published: May 2003

The cosmological axion theory leads to the prediction of axionic mini-clusters of mass M ~ 10-9M⊙, which form at the time t e of equipartition of matter and radiation. By applying the two-body relaxation formula of Spitzer and Hart, we show, for the heterotic superstring theory of Gross et al., that these mini-clusters, considered as point masses, themselves cluster into axion mini-stars of mass [Formula: see text] within the age of the Universe t0 only if they are located within a distance R ~ 0.1 pc of the Galactic Center. Here, λ ≡ fB/fA is the ratio of the second to model-independent axion decay constants, assuming the QCD decay constant to be in the range [Formula: see text], and [Formula: see text] is the strong-interaction coupling parameter. Thus, if axion mini-stars are to explain the microlensing observations by the EROS and MACHO groups towards the Galactic Bulge and the Large and Small Magellanic Clouds, then a collisionless relaxation mechanism is required, as proposed by Seidel and Suen (essentially the violent relaxation of Lynden–Bell), or the four-axion self-interaction effect considered by Tkachev.
Phospholipid-Based Signaling in Plants
Authors: Meijer Harold J.G. , Munnik Teun
Published: May 2003

Phospholipids are emerging as novel second messengers in plant cells. They are rapidly formed in response to a variety of stimuli via the activation of lipid kinases or phospholipases. These lipid signals can activate enzymes or recruit proteins to membranes via distinct lipid-binding domains, where the local increase in concentration promotes interactions and downstream signaling. Here, the latest developments in phospholipid-based signaling are discussed, including the lipid kinases and phospholipases that are activated, the signals they produce, the domains that bind them, the downstream targets that contain them and the processes they control.
Nitric Oxide: The Versatility of an Extensive Signal Molecule
Authors: Lamattina Lorenzo , García-Mata Carlos , Graziano Magdalena , Pagnussat Gabriela
Published: May 2003

Nitric oxide (NO) is a small highly diffusible gas and a ubiquitous bioactive molecule. Its chemical properties make NO a versatile signal molecule that functions through interactions with cellular targets via either redox or additive chemistry. In plants, NO plays a role in a broad spectrum of pathophysiological and developmental processes. Although nitric oxide synthase (NOS)-dependent NO production has been reported in plants, no gene, cDNA, or protein has been isolated to date. In parallel, precise and regulated NO production can be measured from the activity of the ubiquitous enzyme nitrate reductase (NR). In addition to endogenous NO formation, high NO emissions are observed from fertilized soils, but their effects on the physiology of plants are largely unknown. Many environmental and hormonal stimuli are transmitted either directly or indirectly by NO signaling cascades. The ability of NO to act simultaneously on several unrelated biochemical nodes and its redox homeostatic properties suggest that it might be a synchronizing molecule in plants.
Perception and Signal Transduction of Cytokinins
Authors: Kakimoto Tatsuo
Published: May 2003

Cytokinins are plant hormones implicated in diverse and essential processes in plant growth and development, and key genes for the metabolism and actions of cytokinins have recently been identified. Cytokinins are perceived by three histidine kinases—CRE1/WOL/AHK4, AHK2, and AHK3—which initiate intracellular phosphotransfer. The final destination of the transferred phosphoryl groups is response regulators. The type-B Arabidopsis response regulators (ARRs) are DNA-binding transcriptional activators that are required for cytokinin responses. On the other hand, the type-A ARRs act as repressors of cytokinin-activated transcription. How phosphorelay regulate response regulators and how response regulators control downstream events are open questions and discussed in this review.
Transfer Cells: Cells Specialized for a Special Purpose
Authors: Offler Christina E. , McCurdy David W. , Patrick John W. , Talbot Mark J.
Published: May 2003

Transfer cells are plant cells with secondary wall ingrowths. These cells are ubiquitous, occurring in all plant taxonomic groups and in algae and fungi. Transfer cells form from differentiated cells across developmental windows and in response to stress. They are considered to play a central role in nutrient distribution by facilitating high rates of transport at bottlenecks for apo-/symplasmic solute exchange. These properties are conferred by their unique structural features—an invaginated secondary wall ensheathed by an amplified area of plasma membrane enriched in a suite of solute transporters. Recent development of transfer cell experimental systems, combined with technologies to image the three-dimensional structure of wall ingrowths, is allowing identification of inductive and regulatory signals, discovery of sequential processes involved in their differentiation, and a search for transfer cell identity genes. A model of key events in differentiation of a transfer cell is presented to highlight areas for future investigation.
Remodeling the Cytoskeleton for Growth and Form: An Overview with Some New Views
Authors: Wasteneys Geoffrey O. , Galway Moira E.
Published: May 2003

The cytoskeleton coordinates all aspects of growth in plant cells, including exocytosis of membrane and wall components during cell expansion. This review seeks to integrate current information about cytoskeletal components in plants and the role they play in generating cell form. Advances in genome analysis have fundamentally changed the nature of research strategies and generated an explosion of new information on the cytoskeleton-associated proteins, their regulation, and their role in signaling to the cytoskeleton. Some of these proteins appear novel to plants, but many have close homologues in other eukaryotic systems. It is becoming clear that the mechanisms behind cell growth are essentially similar across the growth continuum, which ranges from tip growth to diffuse expansion. Remodeling of the actin cytoskeleton at sites of exocytosis is an especially critical feature of polarized and may also contribute to axial growth. We evaluate the most recent work on the signaling mechanisms that continually remodel the actin cytoskeleton via the activation of actin-binding proteins (ABPs) and consider the role the microtubule cytoskeleton plays in this process.
Iron Transport and Signaling in Plants
Authors: Curie Catherine , Briat Jean-François
Published: May 2003

Cellular and whole organism iron homeostasis must be balanced to supply enough iron for metabolism and to avoid excessive, toxic levels. To perform iron uptake from the environment, iron distribution to various organs and tissues, and iron intracellular compartmentalization, various membranes must be crossed by this metal. The uptake and transport of iron under physiological conditions require particular processes such as chelation or reduction because ferric iron has a very low solubility. The molecular actors involved in iron acquisition from the soil have recently been characterized. A few candidates belonging to various gene families are hypothesized to play major roles in iron distribution throughout the plant. All these transport activities are tightly regulated at transcriptional and posttranslational levels, according to the iron status of the plant. These coordinated regulations result from an integration of local and long-distance transduction pathways.
Gibberellins and Flowering of Grasses and Cereals: Prizing Open the Lid of the “Florigen” Black Box
Authors: King Rod W. , Evans Lloyd T.
Published: May 2003

Comprehensive studies in grasses show that gibberellins (GAs) play a role as a florigen. For Lolium temulentum, which flowers in response to a single long day (LD), GAs are a transmitted signal, their content increasing in the leaf early in the LD and then, hours later, at the shoot apex. There is a continuous trail of evidence of hormonal action of these GAs for L. temulentum and support for a similar role in the flowering of other LD-responsive temperate grasses and cereals. A characteristic of the initial flowering responses of grasses and cereals is their limited stem elongation. Interestingly, it is GAs with low effectiveness for stem elongation, GA5 and GA6, that reach the shoot apex and, structurally, are probably not degraded by 2-oxidase enzymes. By contrast, GA1 and GA4 cause stem elongation, may be inactive for floral evocation, and do not reach the vegetative shoot apex apparently because of susceptibility to degradation. However, GA4 can be florally active if protected against 2-oxidases either structurally or by using a 2-oxidase inhibitor. Later in inflorescence development, GA1 and GA4 can be detected at the shoot apex and are florally active if applied. The 2-oxidase restricting accessibility to the apex has probably declined at this time so there is a second florigenic, LD-regulated GA action. A growing body of molecular evidence supporting these actions of GA may provide a future basis for manipulating flowering of grasses and cereals.
Incidence and Predicting Factors of Hypozincemia in Very-Low-Birth-Weight Infants at Near-Term Postmenstrual Age
Authors: Itabashi K. , Saito T. , Ogawa Y. , Uetani Y.
Published: May 2003

We prospectively investigated serum zinc (Zn) concentrations and clinical factors in 118 very-low-birth-weight infants with a gestational age of 29.5 ± (SD) 2.5 weeks and a birth weight of 1,194 ± 254 g at near-term postmenstrual age. The 25th percentile of the serum Zn concentration was 7.0 µmol/l. The infants whose serum Zn concentrations were less than 7.0 µmol/l (defined as hypozincemia) did not have apparent symptoms of Zn deficiency. Multivariate logistic regression analyses demonstrated that hypozincemia was associated with factors such as weight gain (1-g/kg/day increase of weight; OR 1.1762, 95% CI 1.0414–1.3286) and serum albumin concentration (1-g/dl increase of serum albumin; OR 0.0816, 95% CI 0.0152–0.4372). The types of milk feeding did not affect the serum Zn concentrations in the study subjects. This study suggests that hypozincemia in very-low-birth-weight infants at near-term postmenstrual age is associated with greater weight gain and lower serum albumin concentration. Nutritional supply of Zn by human milk fortifier and preterm formula does not appear to meet the demands of rapidly growing very-low-birth-weight infants.
Changes in Fluid Compartments and Body Composition in Obese Women after Weight Loss Induced by Gastric Banding
Authors: Sergi Giuseppe , Lupoli Lucia , Busetto Luca , Volpato Stefania , Coin Alessandra , Bertani Roberta , Calliari Irene , Berton Adriano , Enzi Giuliano
Published: May 2003

Background/Aims: Surgical gastric banding procedures induce considerable and rapid weight losses in obese subjects. Nevertheless changes in lean mass and body fluids following these surgical treatments are not well known. Methods: We studied 6 obese women aged 38–42 years, before, and 8 and 24 weeks after laparoscopic adjustable silicone gastric banding (LAP-BANDTM). Fat-free mass (FFM) and fat mass (FM) were investigated using dual energy X-ray absorptiometry (DEXA), while total body water (TBW) and extracellular water (ECW) were assessed by dilution methods. Results: The subjects showed a total weight loss of 16% of initial weight; the weight reduction was greater during the first 8 weeks. FFM decrease after 24 weeks was very limited and represented only 14% of the weight loss. The mean FFM changes per week were similar in the two periods of observation (0–8 and 8–24 weeks after LAP-BAND). TBW showed a global reduction of 2.2 ± 1.8 litres mainly due to a decline in intracellular water (ICW), while ECW remained constant during weight loss. As a consequence, the ECW/ICW ratio increased after LAP-BAND. Conclusion: LAP-BAND seems to achieve satisfactory weight losses while sparing FFM and causing only mild body fluid alterations.
Determination of D- and L-Pipecolic Acid in Food Samples Including Processed Foods
Authors: Fujita Toru , Fujita Manabu , Kodama Taku , Hada Toshikazu , Higashino Kazuya
Published: May 2003

Background: Pipecolic acid, a metabolite of lysine, is found in human physiological fluids and is thought to play an important role in the central inhibitory γ-aminobutyric acid system. However, it is unclear whether plasma D- and L-pipecolic acid originate from oral food intake or intestinal bacterial metabolites. Methods: We analyzed the contents of D- and L-pipecolic acid in several processed foods including dairy products (cow’s milk, cheese and yogurt), fermented beverages (beer and wine) and heated samples (beef, bovine liver, bread and tofu) to clarify the relationship between plasma D- and L-pipecolic acid and dietary foods. Results: Our study revealed that some of the samples contained high concentrations of total pipecolic acid, and a higher proportion of L- than D-isomers. The other samples also showed high proportions of L-pipecolic acid. It was also shown that there is no significant change in the ratio of the D-isomer before and after heat treatment. The heat treatments could not cause the racemization of pipecolic acid in this study. Conclusion: These findings suggest that plasma pipecolic acid, particularly the D-isomer, does not originate from direct food intake and that D- and L-pipecolic acid can possibly be derived from intestinal bacterial metabolites.
Enhancement of Antiradiation Potential of Some Aminothiols by Beta-Carotene
Authors: Al-Wandawi Hussain K.
Published: May 2003

In the present study, protection of mice, BALB/c inbred as measured by survival at 30 days against whole-body gamma exposure at two dose levels, namely, 7.60 and 10.12 Gy by prior irradiation treatment with combination of β-carotene, N-(2-mercapto-propionyl)-glycine (MPG) and S-(2-aminoethyl) isothiouroniumbromide hydrobromide (AET), is reported. It was found that administration of β-carotene (1 mg per 20 g body mass) and 24 h before whole-body irradiation (7.60 Gy) had significantly improved the post-irradiation survival. It was also found that administration of a combination of AET (260 mg per kg body mass) and MPG (60 mg per kg body mass) 20 min before exposure to 7.60 Gy gamma irradiation to mice which have been treated with β-carotene (1 mg per 20 g body mass) 24 h before exposure had resulted in 80% survival in comparison to 10% survival recorded for control animals. On the other hand, when the animals were exposed to a higher dose (10.12 Gy) under similar experimental conditions as above, a significant improvement in survival was observed during the first 10 days following the exposure but only a slight effect afterward. On the other hand, the response of male and female mice 10 days after exposure to the above radiation dose indicated that the females were more radioresistant than the males.
Increased Vitronectin and Endothelin-1 in the Breath Condensate of Patients with Fibrosing Lung Disease
Authors: Carpagnano G.E. , Kharitonov S.A. , Wells A.U. , Pantelidis P. , du Bois R.M. , Barnes P.J.
Published: May 2003

Background: Non-specific interstitial pneumonia (NSIP) and fibrosing alveolitis associated with systemic sclerosis (FASSc) are diseases of unknown aetiology that are characterised by the accumulation of mononuclear cells, followed by the progressive deposition of collagen within the interstitium and subsequent destruction of lung airspace. Better understanding of mediators involved in fibrosis may be useful for early diagnosis and in clinical monitoring of disease progression. Objective: The aim of this study was to investigate the presence of two profibrotic markers, the vitronectin and the endothelin-1 (ET-1) in the airways of NSIP and FASSc patients. Methods: Ten NSIP (6 males, age 57 ± 2 years) and 15 FASSc (8 males, age 55 ± 4 years) patients were recruited along with 10 normal subjects (4 male, age 52 ± 2 years). Vitronectin and ET-1 concentrations were measured in their breath condensate, using a specific enzyme immunoassay. Results: Higher levels of vitronectin and ET-1 were observed in NSIP and FASSc patients [median 92.8 (91.7–93.9) µg/ml; median 8.3 (7.9–9.3) pg/ml] than in control subjects [median 80.3 (89.3–91.4) µg/ml; p < 0.01; median 5.3 (4.9–5.9) pg/ml, p < 0.0001]. We also found increased concentrations of vitronectin in patients with clinical deterioration compared to those remaining stable and in ex-smokers compared to non-smokers and, increased vitronectin and ET-1 in patients treated with steroids compared to untreated patients. Conclusion: These findings justify further studies of vitronectin and ET-1 levels in exhaled breath condensate, as a means of monitoring activity and predicting progression of pulmonary fibrosis.
Endobronchial Ultrasound
Authors: Falcone Franco , Fois Flavio , Grosso Daniele
Published: May 2003

Complex technical problems interfered with the application of thoracic ultrasound (US) for studies and clinical research. Moreover, in contrast to radiologists, cardiologists, gastroenterologists, internists, obstetricians, gynecologists and others, pulmonologists were not trained in the basics of US images. However, endoscopic US methods were developed in the last 20 years and these methods also provided important results for pulmonologists. As soon as the technical problems interfering with US application in air-containing spaces were solved, endobronchial US (EBUS) became a valuable technique as well. With EBUS, the delicate multilayer structure of the tracheobronchial wall can be analyzed. This knowledge became decisive for the management of early cancer in the central airways. These lesions can undergo local treatment instead of surgical intervention if the bronchial cartilage is intact and if the adjacent lymph nodes are not involved. EBUS proved valuable as well for the staging of more advanced lung cancer, especially with regard to endoluminal, intramural and extraluminal tumor spread. Endobronchial endosonographers are able to diagnose mediastinal lymph nodes similar to the experience of gastrointestinal endosonographers. EBUS-guided transbronchial needle aspiration (TBNA) improved the results of N-staging of lung cancer, especially in difficult lymph node levels without any clear endoscopic landmarks. The possibility of identifying N2 and N3 stages by means of a nonsurgical procedure can modify the management of lung cancer and decrease the number of unnecessary surgical interventions. EBUS can reduce the need for more invasive procedures such as thoracoscopy or mediastinoscopy. It is also useful for biopsying peripheral lesions or solitary pulmonary nodules instead of fluoroscopic guidance and also plays an important role in the strategy of interventional endoscopy.
Retinoic Acid Does Not Affect Alveolar Septation in Adult FVB Mice with Elastase-Induced Emphysema
Authors: Lucey Edgar C. , Goldstein Ronald H. , Breuer Raphael , Rexer Brent N. , Ong David E. , Snider Gordon L.
Published: May 2003

Background: Administration of all-trans retinoic acid (ATRA) to adult Sprague-Dawley rats with emphysema induced by porcine pancreatic elastase (PPE) reversed the emphysema perhaps by inducing new alveolar formation. Objective: A study was conducted to determine whether ATRA can induce new alveolar septa and reverse the airspace enlargement caused in adult mice by PPE treatment. Methods: 48 FVB mice were divided into 6 groups. Three groups received 15 µg of PPE in 0.1 ml of 0.9% saline and 3 groups received 0.1 ml of saline, intratracheally. Starting at day 22, the mice received 12 daily intraperitoneal injections of cottonseed oil, with or without ATRA (12.5 µg or 50 µg). The mice were killed for study 1 day after the last injection. Results: Measurements of plasma and lung tissue ATRA levels showed statistically significant elevated levels after the 50-µg but not after the 12.5-µg doses of ATRA. In situ hybridization studies of elastin and α1(I) collagen mRNA expression in pulmonary parenchyma as well as in airways and blood vessels showed no effect of ATRA. Airspace size was determined by the mean linear intercept (Lm) method. The Lm of the groups receiving PPE and ATRA (46.2 ± 4.1 µm, mean ± SD) was not significantly different from the group receiving PPE and oil (47.8 ± 6.0 µm). The Lm for groups receiving saline and ATRA (40.6 ± 2.5 µm) were not significantly different from the group receiving saline and oil (41.0 ± 2.7 µm). Comparison of the fixed lung volume data and calculated internal surface area also showed no differences between the control and ATRA-treated groups. Conclusion: ATRA treatment does not affect airspace size or expression of elastin or α1(I) collagen mRNA in adult FVB mice with PPE-induced emphysema.
Gardening in Greenhouses as a Risk Factor for Silicosis
Authors: Rottoli Paola , Bargagli Elena , Perari Maria G. , Cintorino Marcella , Romeo Riccardo
Published: May 2003

Silicosis is a typical occupational disease, although some cases caused by non-industrial exposure have also been reported. We saw a 53-year-old male gardener with recurrent non-productive cough. A routine radiograph of the chest showed bilateral pulmonary nodules and subsequent computed tomography suggested that the infiltrates could be metastases. Open lung biopsy revealed nodules consisting of fibrotic tissue while the presence of birefringent silica particles was observed by polarised light microscopy. Mineralogical analysis of the substrata from the patient’s workplace revealed an SiO2 concentration of 31%. This case indicates that the inhalation of siliceous particles in a closed environment such as a greenhouse is a risk factor for silicosis.
Metabolic Risk Factors in Pediatric and Adult Calcium Oxalate Urinary Stone Formers: Is There Any Difference?
Authors: Tefekli Ahmet , Esen Tarık , Ziylan Orhan , Erol Bülent , Armagan Abdullah , Ander Haluk , Akinci Mustafa
Published: May 2003

Objectives: Urolithiasis in children is recognized with an increasing frequency, while exact etiological factors remain to be determined. The aim of this study is to compare the metabolic risk factors and saturation of urine in pediatric and adult calcium oxalate (Ca-Ox) stone formers. Methods: A total of 33 pediatric (mean age: 6.8 ± 3.1 years) and 120 adult patients (mean age: 39.7 ± 5.7 years), with documented Ca-Ox urinary stone disease, underwent a comprehensive metabolic evaluation at our institution. Beside a broad serum analysis, concentrations of calcium, oxalate, magnesium, uric acid and citrate were measured in 24-hour collected urine. Saturation of urine was calculated by Marshall-Robertson’s nomograms. Results: Hypocitraturia, observed in 60.6%, and hypomagnesuria, detected in 39.4%, but not hypercalciuria, were the most common metabolic risk factors in the pediatric group. In adults, hypercalciuria still represented one of the major metabolic risk factors, detected in 44.1%, although hypocitraturia, observed in 45.8%, was the most prevalent metabolic risk factor, as it was in the pediatric group. Pediatric cases had significantly (p < 0.05) higher prevalence of hypocitraturia, hypomagnesuria and supersaturated urine when compared to adults. Metabolic abnormalities could be detected in a high percentage (82%) of primary and recurrent pediatric Ca-Ox stone formers, but not in primary adult stone formers. Conclusions: Metabolic risk factors significantly differ in pediatric and adult Ca-Ox stone formers. Hypocitraturia and hypomagnesuria seem to play a major role in stone formation, and metabolic abnormalities can be detected in a significant percentage of both primary and recurrent pediatric stone formers. Thus, a comprehensive metabolic evaluation is of utmost importance for all children with Ca-Ox stones.
Prucalopride Is Effective in Patients with Severe Chronic Constipation in Whom Laxatives Fail to Provide Adequate Relief
Authors: Coremans Georges , Kerstens René , de Pauw Martine , Stevens Marita
Published: May 2003

Background: Chronic constipation (CC) is common and there is a need for more effective and better-tolerated agents that normalize bowel function without affecting secretion. Prucalopride is a novel, selective serotonin4 receptor agonist with enterokinetic properties. Aims: Pilot study to compare the efficacy and tolerability of prucalopride and placebo in patients with severe CC referred to a tertiary centre. Methods: After 4-weeks’ run in, patients were randomized to 4 weeks’ once daily, double-blind treatment with either prucalopride 4 mg (n = 27) or placebo (n = 26). A 50% dose reduction after 2 weeks’ treatment was possible for patients with an excessive gastrointestinal response to the study medication (severe cramps, abdominal pain, and diarrhea). Patients assessed efficacy using a visual analogue scale (VAS) and recorded bowel function in daily diaries. The investigator assessed efficacy and total gut transit time (marker study). Results: Patient VAS assessment demonstrated that prucalopride was significantly more effective than placebo in softening stools, and decreasing straining and time to first stool. Prucalopride also had a positive effect on stool frequency, feeling of complete evacuation and total gut transit time, although these differences were not statistically significant compared with placebo. The most common adverse events were gastrointestinal symptoms and headache; most were mild to moderate. There were no clinically relevant effects on cardiovascular or laboratory parameters. Conclusions: Once-daily prucalopride 4 mg for 4 weeks is effective and well tolerated in patients with severe CC. It improves whole gut transit, reducing straining, softening stools and reducing time to first bowel movement.
Incidence, Risk Factors and Prognosis of Stroke and TIA: The Need for High-Quality, Large-Scale Epidemiological Studies and Meta-Analyses
Authors: Rothwell Peter M.
Published: May 2003

Stroke is a considerable clinical, social and economic burden. In recent clinical trials, a number of strategies have been shown to reduce the risk of stroke and transient ischaemic attack (TIA) in both primary and secondary prevention settings. Whether these treatments are leading to a significant reduction in the incidence of first and recurrent stroke in the clinic, however, remains unclear due to a paucity of high-quality epidemiological data. A similar lack of reliable epidemiological studies has undermined our understanding of the relationship between many potentially important vascular risk factors and stroke risk. Improvement in our knowledge of stroke epidemiology is a prerequisite for the planning of stroke services, the effective application of current stroke prevention strategies, the development of new strategies, and our understanding of the mechanisms of stroke. Future studies must take into account the clinical and pathological heterogeneity of TIA and stroke, and must be powered to allow subtype differences in risk factor relationships and prognosis to be determined reliably. In many cases, this will require meta-analysis of detailed individual patient data from multiple independent studies.
Copper Supplementation Has No Effect on Markers of DNA Damage and Liver Function in Healthy Adults (FOODCUE Project)
Authors: O’Connor J.M. , Bonham M.P. , Turley E. , McKeown A. , McKelvey-Martin V.J. , Gilmore W.S. , Strain J.J.
Published: May 2003

Background/Aims: Copper is routinely used in the laboratory to promote oxidation in vitro. However, copper concentrations are million-fold higher than physiological concentrations and, in contrast, accumulating evidence suggests that copper may have an antioxidant role in vivo. The aim of this study was to provide data on how increased intake of copper affected mononuclear leukocyte DNA damage and liver function in healthy young free-living men and women. Methods: The study design was a double-blind repeated crossover trial with treatment and intervening placebo periods, each of 6 weeks’ duration. The following supplementations were given orally in sequence: CuSO4 at a dose of 3 mg copper/day and copper amino acid chelates at doses of 3 and 6 mg copper/day. Oxidative DNA damage was assessed using a modification of the alkaline Comet assay incorporating an endonuclease III digestion step. The assessment of liver function was by measurement of the liver enzymes, alanine aminotransferase and L-γ-glutamyltransferase. Results: There was no significant alteration in mononuclear leukocyte DNA damage or on liver function after 6 weeks of copper supplementation at two doses (3 and 6 mg/day). Conclusions: Copper supplementation (giving total copper intake at the highest level of 7 mg/day) did not induce DNA damage or adversely affect liver function in healthy adults.
Blood Pressure and Vitamin C and Fruit and Vegetable Intake
Authors: Beitz Roma , Mensink Gert B.M. , Fischer Beate
Published: May 2003

Background: A high vitamin C intake was recently associated with lower blood pressure levels. We examined this association and compared it with that between blood pressure and fruit and vegetable intake among German adults. Methods: Complete data were available for 1,628 women and 1,340 men, aged 18–79 years, who participated in the German Nutrition Survey, a subsample of the National Health Survey 1998. The participants completed a health and lifestyle questionnaire and underwent a medical examination and a comprehensive dietary interview. Multiple regression models were used to analyze the association between blood pressure and vitamin C and fruit and vegetable intakes. The associations were adjusted for age and body mass index and in addition for smoking among women and alcohol intake and sport activity among men. Results: Systolic blood pressure showed a significant inverse association with fruit and vegetable but not with vitamin C intake among women. If information about vitamin C and fruit and vegetable intakes was considered simultaneously, a high fruit and vegetable intake was stronger associated with lower systolic blood pressure levels as compared with a high vitamin C intake among women. Among men, we did not observe significant associations between blood pressure and vitamin C and fruit and vegetable intakes. Conclusion: The total vitamin C intake seems to be less associated with blood pressure levels as compared with the intake of fruit and vegetables among women.
Functional Analysis of the Fibrinogen Aα Thr312Ala Polymorphism
Authors: Standeven Kristina F. , Grant Peter J. , Carter Angela M. , Scheiner Thomas , Weisel John W. , Ariëns Robert A.S.
Published: May 2003

Background—

The fibrinogen Aα Thr312Ala polymorphism occurs within the αC domain of fibrinogen, which is important for lateral aggregation and factor XIII-induced cross-linking of fibrin fibers. We have previously shown an association of Ala312 fibrinogen with poststroke mortality in subjects with atrial fibrillation and with pulmonary embolism in subjects with venous thrombosis.

Methods and Results—

We studied the properties of clots formed from purified Ala312 and Thr312 fibrinogen and found that Ala312 fibrinogen produces stiffer clots, associated with increased α chain cross-linking, as demonstrated by SDS-Page. On electron microscopy analysis, we found larger fiber diameters in the Ala312 clots and observed a lower number of fibers per square micrometer. The number of branch points per square micrometer was similar between genotypes.

Conclusions—

Our study shows that Ala312 influences clot structure and properties by increased factor XIII cross-linking and formation of thicker fibrin fibers. These findings may provide a mechanism by which Ala312 fibrinogen could predispose to clot embolization.
Stenting of Culprit Lesions in Unstable Angina Leads to a Marked Reduction in Plaque Burden: A Major Role of Plaque Embolization?
Authors: Prati Francesco , Pawłowski Tomasz , Gil Robert , Labellarte Antonella , Gziut Aneta , Caradonna Eugenio , Manzoli Alessandro , Pappalardo Alessandro , Burzotta Francesco , Boccanelli Alessandro
Published: May 2003

Background—

Intravascular ultrasound (IVUS) studies have shown that a mechanism of plaque compression/embolization contributes toward the poststenting increase in lumen area. The aim of this IVUS study was to compare the mechanisms of lumen enlargement after coronary stenting in 54 consecutive patients with unstable angina (UA) (group 1) and 56 with stable angina (group 2) to verify whether plaque embolization plays a major role in the former.

Methods and Results—

Both groups underwent the IVUS assessment (speed, 0.5 mm/sec) before the intervention and after stent implantation. The lumen area, the external elastic membrane area, and the plaque+media area (PA) were measured at 0.5-mm intervals. PA reduction in the lesion site was significantly greater in group 1 (−2.50±1.97 versus −0.53±1.43 mm
2
,
P
<0.001). After stenting, 47% of the lumen area increase in group 1 was obtained by means of PA reduction, and 53% was attributable to external elastic membrane area increase; the corresponding figures in group 2 were 13% and 87% (
P
<0.05). Decrease in PA after stenting was the only significant predictor of the MB fraction of creatinine kinase (CK-MB) release in a multiple regression model (
P
=0.047).

Conclusions—

Serial volumetric IVUS assessment revealed in UA lesions a marked poststenting reduction in plaque volume, which is significantly greater than in stable angina and is associated with postprocedural CK-MB release. The decrease in PA during the procedure predicts CK-MB release in a multiple regression model. These findings suggest that stent deployment is often associated with plaque embolization in patients with UA.
Histamine Upregulates Gene Expression of Endothelial Nitric Oxide Synthase in Human Vascular Endothelial Cells
Authors: Li Huige , Burkhardt Christian , Heinrich Ulf-Rüdiger , Brausch Isolde , Xia Ning , Förstermann Ulrich
Published: May 2003

Background—

Histamine has a short-term, transient, stimulating effect on endothelial nitric oxide synthase (eNOS) activity; however, long-term effects on eNOS have not been described yet. In addition, the vascular effect of histamine seems to depend critically on eNOS functionality. Therefore, we studied the effects of histamine on eNOS gene expression and function.

Methods and Results—

In human umbilical vein endothelial cells (HUVECs) and HUVEC-derived EA.hy 926 cells, histamine upregulated eNOS mRNA (RNase protection assay) and protein (electron microscopic immunocytochemistry) expression. The upregulation of eNOS could be prevented by mepyramine, a selective antagonist at the H
1
receptor, but not by H
2
and H
3
receptor antagonists. Incubation of EA.hy 926 cells with histamine led to the activation of calcium/calmodulin-dependent protein kinase II (CaMK II; in vitro phosphorylation assay). The histamine-induced eNOS expression was completely prevented by KN-93, an inhibitor of CaMK II. Histamine increased the activity of a 1.6-kb human eNOS promoter fragment (luciferase reporter gene assay), an effect that was also blocked by mepyramine. Under normal conditions, eNOS upregulation by histamine resulted in increased nitric oxide production (measured by nitric oxide chemiluminescence and RFL-6 reporter cell assay). Under conditions of oxidative stress, however, the eNOS upregulated by histamine produced reactive oxygen species (CM-H
2
DCFDA oxidation-based fluorescence assay).

Conclusions—

Stimulation of the H
1
receptor increases eNOS transcription in endothelial cells by a signaling pathway involving CaMK II. This eNOS upregulation may be protective under normal conditions, but it may become harmful under conditions of oxidative stress when eNOS produces reactive oxygen species at the expense of nitric oxide.
Quality of Life in a Randomized Trial of Group Psychosocial Support in Metastatic Breast Cancer: Overall Effects of the Intervention and an Exploration of Missing Data
Authors: Bordeleau Louise , Szalai John Paul , Ennis Marguerite , Leszcz Molyn , Speca Michael , Sela Rami , Doll Richard , Chochinov Harvey M. , Navarro Margaret , Arnold Andrew , Pritchard Kathleen I. , Bezjak Andrea , Llewellyn-Thomas Hilary A. , Sawka Carol A. , Goodwin Pamela J.
Published: May 2003

Purpose: To evaluate the effect of a standardized group psychosocial intervention on health-related quality of life (HrQOL) in women with metastatic breast cancer and to explore the effect of missing data in HrQOL analyses.

Patients and Methods: Between 1993 and 1998, seven Canadian centers randomly assigned 235 eligible women to participate in a weekly, 90-minute, therapist-led support group that adhered to principles of supportive-expressive (SE) therapy or to a control arm (no SE). All women received educational material and any type of medical or psychosocial care deemed necessary. HrQOL data were prospectively collected using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) at baseline, 4, 8, and 12 months. The primary HrQOL analyses compared scores in the two study arms. Analyses were limited to women with appropriate baseline HrQOL information (n = 215).

Results: Baseline EORTC QLQ-C30 scores were not different between the two study arms (all P > .05). Primary analysis of all subscales failed to show a significant influence of the intervention on HrQOL (all P > .05). There was a significant deterioration over time in several functional scales of the EORTC QLQ-C30: global (P = .03), physical (P = .0002), role (P = .01), and cognitive functioning (P = .04); and in symptom scales: dyspnea (P = .007), appetite loss (P = .04), and fatigue (P = .003); these changes were independent of randomization allocation. Results were similar in additional analyses of overall HrQOL using a variety of approaches to handling missing data.

Conclusion: Supportive-expressive group therapy in patients with metastatic breast cancer does not appear to influence HrQOL, as measured by the EORTC QLQ-C30.
Phase III Trial Comparing Whole-Pelvic Versus Prostate-Only Radiotherapy and Neoadjuvant Versus Adjuvant Combined Androgen Suppression: Radiation Therapy Oncology Group 9413
Authors: Roach M. , DeSilvio M. , Lawton C. , Uhl V. , Machtay M. , Seider M.J. , Rotman M. , Jones C. , Asbell S.O. , Valicenti R.K. , Han S. , Thomas C.R. , Shipley W.S.
Published: May 2003

Purpose: This trial tested the hypothesis that combined androgen suppression (CAS) and whole-pelvic (WP) radiotherapy (RT) followed by a boost to the prostate improves progression-free survival (PFS) by 10% compared with CAS and prostate-only (PO) RT. This trial also tested the hypothesis that neoadjuvant and concurrent hormonal therapy (NCHT) improves PFS compared with adjuvant hormonal therapy (AHT) by 10%.

Materials and Methods: Eligibility included localized prostate cancer with an elevated prostate-specific antigen (PSA) ≤ 100 ng/mL and an estimated risk of lymph node (LN) involvement of 15%. Between April 1, 1995, and June 1, 1999, 1,323 patients were accrued. Patients were randomly assigned to WP + NCHT, PO + NCHT, WP + AHT, or PO + AHT. Failure for PFS was defined as the first occurrence of local, regional, or distant disease; PSA failure; or death for any cause.

Results: With a median follow-up of 59.5 months, WP RT was associated with a 4-year PFS of 54% compared with 47% in patients treated with PO RT (P = .022). Patients treated with NCHT experienced a 4-year PFS of 52% versus 49% for AHT (P = .56). When comparing all four arms, there was a progression-free difference among WP RT + NCHT, PO RT + NCHT, WP RT + AHT, and PO RT + AHT (60% v 44% v 49% v 50%, respectively; P = .008). No survival advantage has yet been seen.

Conclusion: WP RT + NCHT improves PFS compared with PO RT and NCHT or PO RT and AHT, and compared with WP RT + AHT in patients with a risk of LN involvement of 15%.
Primary Metastatic Osteosarcoma: Presentation and Outcome of Patients Treated on Neoadjuvant Cooperative Osteosarcoma Study Group Protocols
Authors: Kager Leo , Zoubek Andreas , Pötschger Ulrike , Kastner Ulrike , Flege Silke , Kempf-Bielack Beate , Branscheid Detlev , Kotz Rainer , Salzer-Kuntschik Mechthild , Winkelmann Winfried , Jundt Gernot , Kabisch Hartmut , Reichardt Peter , Jürgens Heribert , Gadner Helmut , Bielack Stefan S.
Published: May 2003

Purpose: To determine demographic data and define prognostic factors for long-term outcome in patients presenting with high-grade osteosarcoma of bone with clinically detectable metastases at initial presentation.

Patients and Methods: Of 1,765 patients with newly diagnosed, previously untreated high-grade osteosarcomas of bone registered in the neoadjuvant Cooperative Osteosarcoma Study Group studies before 1999, 202 patients (11.4%) had proven metastases at diagnosis and therefore were enrolled onto an analysis of demographic-, tumor-, and treatment-related variables, response, and survival. The intended therapeutic strategy included pre- and postoperative multiagent chemotherapy as well as aggressive surgery of all resectable lesions.

Results: With a median follow-up of 1.9 years (5.5 years for survivors), 60 patients were alive, 37 of whom were in continuously complete surgical remission. Actuarial overall survival rates at 5 and 10 (same value for 15) years were 29% (SE = 3%) and 24% (SE = 4%), respectively. In univariate analysis, survival was significantly correlated with patient age, site of the primary tumor, number and location of metastases, number of involved organ systems, histologic response of the primary tumor to preoperative chemotherapy, and completeness and time point of surgical resection of all tumor sites. However, after multivariate Cox regression analysis, only multiple metastases at diagnosis (relative hazard rate [RHR] = 2.3) and macroscopically incomplete surgical resection (RHR = 2.4) remained significantly associated with inferior outcomes.

Conclusion: The number of metastases at diagnosis and the completeness of surgical resection of all clinically detected tumor sites are of independent prognostic value in patients with proven primary metastatic osteosarcoma.
Serum HER-2/neu and Response to the Aromatase Inhibitor Letrozole Versus Tamoxifen
Authors: Lipton A. , Ali S.M. , Leitzel K. , Demers L. , Harvey H.A. , Chaudri-Ross H.A. , Brady C. , Wyld P. , Carney W.
Published: May 2003

Purpose: To determine the effect of elevated serum HER-2/neu on the response of metastatic breast cancer patients to an aromatase inhibitor versus an antiestrogen.

Patients and Methods: Five hundred sixty-two estrogen receptor–positive metastatic breast cancer patients were randomized to first-line hormone therapy with either letrozole or tamoxifen. An automated enzyme-linked immunosorbent assay was used to detect serum HER-2/neu.

Results: For patients with normal serum HER-2/neu (70.5%), objective response rate (ORR; 39% in letrozole-treated patients v 26% in tamoxifen-treated patients; P = .008), clinical benefit (CB; 57% v 45%; P = .016), time to progression (TTP; median, 12.2 v 8.5 months; P = .0019), and time to treatment failure (TTF; median, 11.6 v 6.2 months; P = .0066) were significantly better in patients treated with letrozole. In the elevated HER-2/neu group (29.5%), there was no significant difference in ORR (17% in letrozole-treated patients v 13% in tamoxifen-treated patients; P = .45) or CB (33% v 26%; P = .31), but there was a strong trend in favor of a longer TTP with letrozole (median, 6.1 v 3.3 months; P = .0596) and a significantly longer TTF with letrozole (median, 6.0 v 3.2 months; P = .0418). Multivariate analysis revealed that elevated serum HER-2/neu was a negative predictor for ORR and TTP.

Conclusion: Patients with normal serum HER-2/neu receiving letrozole demonstrated a significantly greater ORR and CB and longer TTP and TTF than patients receiving tamoxifen. Although in patients with elevated serum HER-2/neu there was no significant difference between letrozole and tamoxifen in ORR or CB, there was a strong trend favoring longer TTP and significantly longer TTF with letrozole.
Progesterone Receptor Status Significantly Improves Outcome Prediction Over Estrogen Receptor Status Alone for Adjuvant Endocrine Therapy in Two Large Breast Cancer Databases
Authors: Bardou Valerie-Jeanne , Arpino Grazia , Elledge Richard M. , Osborne C. Kent , Clark Gary M.
Published: May 2003

Purpose: To determine whether progesterone receptor (PgR) status provides additional value to estrogen receptor (ER) status and improves prediction of benefit from endocrine treatment among patients with primary breast cancer.

Patients and Methods: Clinical outcomes of patients in two large databases were analyzed as a function of steroid receptor status. The first database (PP), contained 3,739 patients who did not receive any systemic adjuvant therapy and 1,688 patients who received adjuvant endocrine therapy but no chemotherapy. The second database (SPORE), contained 10,444 patients who received adjuvant endocrine therapy but no chemotherapy. Biochemical ER and PgR assays were identically performed in two different central laboratories.

Results: In univariate and multivariate analyses, the prognostic significance of PgR status among systemically untreated patients is modest. Among endocrine-treated patients, however, multivariate analyses, including lymph-node involvement, tumor size, and age, demonstrate that PgR status is independently associated with disease-free and overall survival. For recurrence, the reduction in relative risk (RR) was 25% for ER-positive/PgR-negative patients and 53% for ER-positive/PgR-positive patients, compared with ER-negative/PgR-negative patients (P < .0001, PP patients). Patients with ER-positive/PgR-negative tumors have a reduction in RR of death of 30% (SPORE patients) and 38% (PP patients), compared with patients with ER-negative/PgR-negative tumors (P < .0001). For ER-positive/PgR-positive tumors, the reduction of the risk of death was greater than 46% in SPORE patients and 58% in PP patients, indicating that ER-positive/PgR-positive patients derive more benefit from endocrine therapy (P < .0001).

Conclusion: When accurately measured, PgR status is an independent predictive factor for benefit from adjuvant endocrine therapy. Therefore, PgR status should be taken into account when discussing RR reductions expected from endocrine treatment with individual patients.