bluuebunny/crossref_metadata_2025 huggingface dataset:
Pretherapy Gallium-67 Scanning in Paediatric Patients with Hodgkin’s Disease
Authors: Shah Syed G.M. , Younis M.N. , Usmani G.N. , Zafar N.
Published: February 2004

Objective: To investigate the correlation between gallium-67 (67Ga) uptake and histological subtypes of Hodgkin’s disease (HD) in paediatric patients. Subjects and Methods: Fifty-eight patients (45 males and 13 females aged 9.2 ± 4 years, range 1.5–17 years) with histologically diagnosed HD underwent pretherapy 67Ga scanning on days 2, 5, 12 or 14 days after intravenous administration of 25–50 MBq (0.7–1.4 mCi) of 67Ga citrate. The scans were evaluated both visually and quantitatively using the activity of 67Ga in the liver as a reference. Clinical outcome of 11 patients with high diffuse 67Ga skeletal uptake was compared with that of 17 patients showing normal distribution of 67Ga in the skeleton. Results: Of the 58 patients, the 67Ga scans were positive in 47 patients with 117 lesions. Visual analysis did not differentiate between the histological variants of HD. However, quantitative analysis of lesion-to-liver ratios showed significantly higher values of 67Ga uptake in the mixed cellularity type than in the nodular sclerosis type (t = –3.7, p < 0.001). Patients with high skeletal uptake had a higher relapse rate (6/11) than those with normal skeletal uptake (3/17). Conclusion: The findings show that quantitative analysis of 67Ga uptake can differentiate between the two main subtypes of HD (mixed cellularity and nodular sclerosis). Further diffuse skeletal uptake of 67Ga indicates a higher relapse rate.
Clinical Patterns of Diffuse Parenchymal Lung Disease in Kuwait: A Prospective Study
Authors: Abul A. , Onadeko B.O. , Khadadah M.E. , Behbehani N. , Cerna M. , Cherian J.M. , Maradni N. , Jayakrishnan B.
Published: February 2004

Objective: To report our experience of the clinicopathological patterns of diffuse parenchymal lung disease (DPLD). Subjects and Methods: Over a 4-year period, 75 patients (41 males, 34 females), aged 13–76 years, who were referred to Mubarak Al-Kabeer and the Chest Diseases Hospitals, Kuwait with a diagnosis of diffuse lung disease, were included in the study. After a comprehensive history and physical examination, further investigations were done, including hematological and immunological profiles, sputum and bronchoalveolar lavage fluid examination, chest radiograph, high resolution computed tomography (HRCT), pulmonary function test and lung biopsy. Results: Of the 75 patients 60 (80%) were over 40 years of age. The duration of symptoms in 34 patients (45%) was less than 6 months and longer than 1 year in 28 (37.7%) patients. Twenty-five of the patients were cigarette smokers. The mean forced lung capacity (FVC), total lung capacity and diffusing capacity for carbon monoxide were less than 60% of the predicted values in most patients. There was a significant difference in mean FVC value between smokers and nonsmokers (p < 0.05). The HRCT findings were at an advanced stage in 65 patients, with additional honeycombing in 21 of the 65 patients. Idiopathic pulmonary fibrosis was the most common cause of DPLD, occurring in 52 patients, followed by sarcoidosis and collagen vascular diseases. Conclusion: DPLD was observed predominantly in middle aged and elderly patients, due probably to increasing industrialization in the country. The role of cigarette smoking as a contributory factor remains unclear.
Oxidative Stress in Patients with Chronic Renal Failure: Effects of Hemodialysis
Authors: Durak İlker , Kaçmaz Murat , Elgün Serenay , Öztürk Hasan Serdar
Published: February 2004

Objective: To investigate blood oxidative status of patients with chronic renal failure (CRF) and possible effects of hemodialysis on the development of oxidative stress in blood. Materials and Methods: The levels of malondialdehyde (MDA) and oxidation resistance (OR) values were measured in blood plasma, erythrocyte hemolysate and erythrocyte membrane fractions of 33 patients with CRF and of 12 healthy controls. Of the 33 patients, 17 subjects were under hemodialysis treatment. Results: MDA levels were found to be increased in all blood fractions of the patients. OR values were unchanged in erythrocyte hemolysates but decreased in plasma and erythrocyte membrane fractions of the CRF patients. Moreover, erythrocyte MDA levels were determined to be higher in hemodialyzed patients compared with both controls and non-hemodialyzed patients. OR values were lower in all blood fractions of the hemodialyzed patients relative to controls and non-hemodialyzed patients. Conclusion: Results suggest that there is a significant oxidative stress (expressed as peroxidation) in blood samples from patients with CRF, which is further exacerbated by hemodialysis.
Monoclonal Gammopathy among Patients with Chronic Hepatitis C Infection
Authors: Al-Shemmari Salem H. , Siddique Iqbal , Hassan Fuad , Nkansa-Dwamena David , El-Naga Hisham Abu , Ameen Reem
Published: February 2004

Objective: To determine the prevalence of monoclonal gammopathies in Kuwait and its association with chronic hepatitis C virus (HCV) infection. Methodology: Serum protein electrophoresis and measurement of immunoglobulin levels were carried out prospectively in 100 consecutive patients with chronic HCV infection. Results: Among the 100 patients tested (82 males, 18 females; median age 45 years), 59 had polyclonal band in serum protein electrophoresis while the other 41 had a normal pattern. None of the patients had monoclonal gammopathy. The mean serum immunoglobulin levels were: IgG 18.4 g/l (range 4–39), IgA 2.9 g/l (range 0.09–8) and IgM 1.6 g/l (range 0.14–6.08). Conclusion: There was no evidence of monoclonal gammopathies in patients with chronic HCV infection in Kuwait.
Assessment of Chlamydia trachomatis Prevalence by Cell Culture and Transcription-Mediated Amplification in Symptomatic Women
Authors: Cicek Candan , Altuglu Imre , Ozacar Tijen , Kolday Kahraman , Demir Namik , Bilgic Altinay
Published: February 2004

Objective: The frequency of Chlamydia trachomatis in women with mucopurulent discharge was determined by a cell culture technique and a transcription-mediated amplification (TMA) assay in endocervical swab specimens. Subjects and Methods: Endocervical swab specimens were obtained from 116 symptomatic patients with genitourinary complaints or abdominal pain. All of the women were married, with an age range of between 19 and 44 (median 29) years. The cell culture assay was used in all specimens. For 75 specimens the TMA assay was also performed. Results: Positive cell culture test results were obtained in 6 (5.2%) patients. Among 75 specimens, 2 were positive by both TMA and culture assays, while 1 specimen was positive only by the culture assay. Of those positive for C. trachomatis, 5 were in the 19- to 25-year age group, and 1 was in the >25-year age group. All of the patients with positive results were of low socioeconomic status. Conclusions: This study revealed a relatively low rate of C. trachomatis infections in symptomatic married women in Turkey. A commercial TMA assay failed to identfy all positive patients, in contrast to a ‘gold standard’ culture assay used in patients having such infections.
Arginine Increases Growth Hormone Gene Expression in Rat Pituitary and GH3 Cells
Authors: Adrião Manoel , Chrisman Carolina J.S. , Bielavsky Monica , Olinto Silvia C.F. , Shiraishi Emilia M. , Nunes Maria Tereza
Published: February 2004

The effect of arginine (Arg) and Ornitargin® (OT) [a compound containing the aminoacids Arg, citrulline (Cit) and ornithine (Orn)] administration upon growth hormone (GH) gene expression was studied both in vivo and in vitro (hemipituitaries and GH3 cells) by Northern blot analysis. For in vivo studies, adult male Wistar rats were anesthetized, subjected to i.v. infusion of 200 µl of 150 mM NaCl (control group), Arg (15 or 150 mg) or OT (15 mg of Arg, 1 mg of Cit and 4 mg of Orn) at a rate of 20 µl/min, and killed 50 min thereafter. For the in vitro studies, hemipituitaries or GH3 cells were incubated in 1 ml of appropriate medium containing Arg (15 or 150 mg) or OT (15 mg of Arg, 1 mg of Cit and 4 mg of Orn) for 60 min. The pituitaries of the in vivo and in vitro studies and GH3 cells were subsequently processed for RNA extraction. Total RNA was subjected to electrophoresis in agarose (1%)/formaldehyde gel, transferred to a nylon membrane and subjected to hybridization with a rat GH 32P-cDNA, and 32P-18S rRNA probe to correct for the variability in RNA loading. After autoradiography of the membrane, the abundance of GH mRNA and 18S rRNA bands was quantified by densitometry. The in vivo study demonstrated that Arg and OT infusion induced a 2.3-fold increase in GH mRNA expression, which could result from the Arg-mediated inhibition of somatostatin release. In addition, in vitro Arg, but not OT, induced GH gene expression in hemipituitaries and GH3 cells, indicating that the aminoacid can act per se at the pituitary somatotrope level. In conclusion, our data show for the first time that arginine stimulates GH gene expression in parallel to its recognized GH-releasing activity.
Modulation of Neuroendocrine Response and Non-Verbal Behavior during Psychosocial Stress in Healthy Volunteers by the Glutamate Release-Inhibiting Drug Lamotrigine
Authors: Makatsori Aikaterini , Duncko Roman , Moncek Fedor , Loder Ingrid , Katina Stanislav , Jezova Daniela
Published: February 2004

The present work was aimed at verifying the following hypotheses: (a) lamotrigine, a drug used to treat mood disorders, affects regulation of stress hormone release in humans, and (b) non-verbal behavior during mental stress situations (public speech) is related to hormonal responses. To achieve these aims, we performed a controlled, double-blind study investigating hormonal responses and non-verbal behavior during public speech in healthy subjects with placebo or lamotrigine (300 mg per os) pretreatment. The stress procedure was performed in 19 young healthy males 5 h following drug or placebo administration. Data were obtained from cardiovascular monitoring, blood and saliva samples, as well as the video-recorded speech. Pre-stress hormone levels were not affected by lamotrigine treatment. Lamotrigine significantly inhibited diastolic blood pressure, growth hormone and cortisol increases during psychosocial stress. In contrast, it potentiated plasma renin activity and aldosterone responses. Non-verbal behavior analysis revealed a correlation between catecholamines and submissive or flight behavior in controls, while between catecholamines and displacement behavior following lamotrigine administration. In conclusion, effects of lamotrigine on hormone release might be of value for its mood-stabilizing action used in the treatment of bipolar disorder. The data are in support of a stimulatory role of glutamate in the control of cortisol and growth hormone release during psychosocial stress in humans; however, further studies using more selective drugs are needed to prove this suggestion. The effects on plasma renin activity and aldosterone release observed seem to be related to other actions of lamotrigine.
Health Care Resource Utilization and Costs of NSAID-Induced Gastrointestinal Toxicity
Authors: Delcò Fabiola , Michetti Pierre , Beglinger Christoph , Fried Michael , Szucs Thomas D.
Published: February 2004

Background and Aims: The well-recognized gastrointestinal toxicity of NSAIDs ranges from mild symptoms to severe complications requiring medical attention and leading to work loss. The present study evaluates the economic burden derived from health care resource utilization and work loss caused by NSAID-induced gastrointestinal toxicity in the Swiss population. The costs induced by conventional and COX2-selective NSAIDs were calculated separately, and the results were then extrapolated for the United States. Methods: A computer-generated random sampling of the Swiss population (n = 6,118) was administered a questionnaire by phone. Questions investigated NSAID intake, occurrence of adverse effects, consumption of gastroprotective drugs, health care resource utilization and work loss. Country-specific direct and indirect costs associated with NSAID-induced gastrointestinal toxicity were calculated according to current reimbursement costs in Switzerland and the United States. Medication expenses were used to compute separate iatrogenic cost factors for conventional and COX2-selective NSAIDs. The ability of demographic variables and symptoms to predict resource utilization was analyzed by univariate and multivariate analyses. Results: From among the 6,085 responders (99.5% response rate), 294 subjects had gastrointestinal adverse effects associated with NSAID intake. The annual amount spent on NSAID-related adverse effects was CHF 432.2 million for Switzerland and USD 7,425.7 million for the United States. This amount corresponded to CHF 581 and USD 272 per NSAID user, and was primarily due to costs derived from work loss. For Switzerland, 91.1% of total costs were associated with the use of conventional NSAIDs and could be saved by using COX2-NSAIDs instead. While additional 13% of the medication purchase costs are spent for gastrointestinal adverse effects among COX2-selective NSAID users, additional 315% are spent for the same reason among conventional NSAID users. Thus, given similar efficacy and purchase costs in the two drug groups, COX2-selective NSAIDs are 25.1 times more cost-effective than conventional NSAIDs. Language region, place of residence, nationality, marital status, epigastric pain, diarrhea, hematemesis and melena predicted resource utilization. Conclusions: Costs arising from NSAID-induced gastrointestinal toxicity are considerable and primarily associated with conventional NSAIDs. COX2-selective NSAIDs could decrease this economic burden.
Quantitative Assessment of Gastric Antrum Atrophy Shows Restitution to Normal Histology after Helicobacter pylori Eradication
Authors: van Grieken Nicole C.T. , Meijer Gerrit A. , Kale Ilse , Bloemena Elisabeth , Lindeman Jan , Offerhaus G. Johan A. , Meuwissen Stefan G.M. , Baak Jan P.A. , Kuipers Ernst J.
Published: February 2004

Background/Aims: Grading gastric mucosal atrophy in antrum biopsy specimens remains a controversial subject because of limitations in interobserver agreement. We previously described a reliable, quantitative method for grading atrophy of the corpus mucosa with excellent reproducibility and good correlation with the Sydney scores. The aims of the present study were to evaluate the applicability of this method for the grading of antral atrophy and to study the effect of Helicobacter pylori eradication on the antral mucosa. Methods: Antrum biopsy specimens were collected from 71 gastroesophageal reflux disease patients at baseline and after 3 and 12 months. After the first endoscopy, all subjects were treated with omeprazole 40 mg daily for 12 months. After randomization, 27 of the 48 H. pylori-positive patients additionally received eradication therapy. In 182 hematoxylin-eosin-stained specimens, which were of sufficient quality, the proportions (volume percentages) of glands (VPGL), stroma (VPS), infiltrate (VPI), and intestinal metaplasia in the glandular zone of the antrum mucosa were measured using a point-counting method. In these specimens, mucosal atrophy was assessed by two experienced gastrointestinal tract pathologists (E.B. and J.L.) according to the updated Sydney classification as either nonatrophic mucosa (n = 47) or as mild (n = 29), moderate (n = 50), or marked (n = 56) atrophy. In addition, a group of 23 cases with difficult-to-classify grades of atrophy were included. Results: The mean VPGL decreased with increasing Sydney grades of atrophy (p < 0.001), while the mean VPS and VPI increased (both p < 0.001). After H. pylori eradication, even the cases with the lowest VPGL regressed to normal levels. Conclusions: Overall, a low VPGL correlates with increasing grades of antrum mucosal atrophy. The present data indicate that gastric mucosal atrophy is reversible, since almost all cases showed regression of VPGL after H. pylori eradication. The cases with difficult-to-classify grades of atrophy showed significantly lower VPGLs and higher VPIs than the reference cases.
Role of Fibroblast Growth Factor-2 in the Expression of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Human Intestinal Myofibroblasts
Authors: Yasui Hirofumi , Andoh Akira , Bamba Shigeki , Inatomi Osamu , Ishida Hideaki , Fujiyama Yoshihide
Published: February 2004

Background and Aims: The coordinated expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) plays a crucial role in tissue remodeling. We investigated the effects of fibroblast growth factor (FGF)-2 on the secretion of MMPs and TIMPs in human intestinal subepithelial myofibroblasts (SEMFs). Methods: The secretion of MMP-s and TIMPs was determined by ELISA or Western blotting. The mRNA expression of MMPs and TIMPs was assessed by Northern blotting. The activating protein (AP)-1-DNA binding activity was evaluated by electrophoretic gel mobility shift assays (EMSA). Results: Unstimulated intestinal SEMFs constitutively secreted MMP-2 and TIMP-2. FGF-2 stimulated MMP-1, MMP-3 and TIMP-1 secretion, but did not affect MMP-2 or TIMP-2 secretion. FGF-2 induced AP-1-DNA binding activity, and the c-Jun/AP-1 inhibitor curcumin attenuated the FGF-2-induced MMP-1, -3 and TIMP-1 mRNA expression. Mitogen-activated protein (MAP) kinase inhibitors (U0126 and PD098059) also blocked the MMP-1, -3 and TIMP-1 secretion. Furthermore, FGF-2 dose-dependently induced FGF-2 mRNA expression in these cells. Conclusions: FGF-2 may be one of important regulatory factors for extracellular matrix turnover via a modulation of MMP and TIMP secretion from SEMFs.
Cronkhite-Canada Syndrome Containing Colon Cancer and Serrated Adenoma Lesions
Authors: Yashiro Masakazu , Kobayashi Hikaru , Kubo Naoshi , Nishiguchi Yukio , Wakasa Kenichi , Hirakawa Kosei
Published: February 2004

We describe a case of Cronkhite-Canada syndrome associated with sigmoid colon cancer, and provide a literature review. A 77-year-old man was diagnosed with sigmoid colon cancer after presenting with hypoproteinemia, nail atrophy, loss of scalp hair, hyperpigmentation, and gastrointestinal polyposis. The findings were consistent with Cronkhite-Canada syndrome. The colon polyps were histologically serrated adenomas, whose crypts showed a saw-toothed growth pattern with dysplasia, or tubular adenoma. Cronkhite-Canada syndrome associated with colon cancer has been reported in 31 cases. The availability of histologic material permitted reexamination of 25 of these cases. Serrated adenoma of the polypoid lesions was retrospectively found in 10 (40%) of the 25 cases. By comparison, the incidence of serrated adenomas has been estimated to occur in about 1% of all general polyps. Taken together, it is suggested that Cronkhite-Canada syndrome associated with colorectal cancer frequently has polyps containing serrated adenoma lesions. In the case described here, microsatellite instability and overexpression of the p53 protein were found in the cancer lesion and serrated adenoma lesions, and none of the lesions showed a loss of heterozygosity of various genes or K-ras mutations. Thus, genetic alterations between the serrated adenoma and the colorectal cancer was correlated in this case. These findings suggested the possibility of a serrated adenoma-carcinoma sequence in this case of Cronkhite-Canada syndrome.
Effects of Probucol on Renal Function and Urinary Protein Excretion in Spontaneously Hypercholesterolemic Rats Fed a Normal or High Cholesterol Diet
Authors: Nakao Akihide , Nosaka Kazuo , Imaki Hiromi , Noiri Eisei , Toda Akiko , Doi Kento , Suzuki Yoshifumi , Fujita Toshiro , Kimura Satoshi
Published: February 2004

Background/Aim: Spontaneously hypercholesterolemic (SHC) rats develop hypercholesterolemia and focal glomerular sclerosis, and have been thought to be a model of lipid-induced glomerular injury. However, recent studies suggest that the hypercholesterolemia might be due to secondary mechanisms by massive proteinuria. The purpose of the present study was to determine in SHC rats the effects of a high cholesterol diet on serum lipid profiles and renal function/histology, and to examine whether or not the model of lipid-induced renal injury could be developed in a short period of the time. The effects of probucol were also studied. Methods: SHC rats were fed a high cholesterol diet for 6 weeks (H) or with probucol (HP), while control SHC rats were fed normal rat chow (N) or with probucol (P). Lipid profile and renal function/histology were examined. Results: H and HP showed increased levels of urinary protein excretion and serum creatinine, as well as extremely high serum cholesterol levels, compared with N and P. HP tended to show reduced urinary protein excretion compared with H, but the difference was not statistically significant. H and HP presented histologically characteristic changes with numerous foam cells accumulated in the glomerular mesangial area, and showed glomerular sclerosis. Conclusion: The data demonstrate that SHC rats have an intrinsically abnormal lipid metabolism, and that probucol does not exert obviously beneficial effects on renal function or lipid-lowering action. A lipid-induced renal injury model of rats was produced in 6 weeks.
The Seasonal Variation in Allergic Rhinitis and Its Correlation with Outdoor Allergens in Kuwait
Authors: Behbehani N. , Arifhodzic N. , Al-Mousawi M. , Marafie S. , Ashkanani L. , Moussa M. , Al-Duwaisan A.
Published: February 2004

Background: Allergic rhinitis (AR) is the most common allergic problem in Kuwait. Most of the patients who have either AR or asthma are referred to the Al-Rashed Allergy Center. Objective: To determine if there is a seasonal variation in AR in Kuwait and to correlate it with the daily pollen count. Methods: Information about the new patients referred to the center over a 5-year study period (1996–2000) was extracted from the center’s records. The daily pollen count in Kuwait city was obtained from the Air Biology Laboratory. Results: There was a significant seasonal variation with a bimodal increase in the number of patients with AR referred to the center. The main peak in the number of patients occurred in September–October, and there was a smaller peak in April–May. The mean number ± SD of new patients per month over the 5-year period varied from 87 ± 32 for December to 367 ± 104 for September. Similarly, the average daily pollen count varied from 3.7 ± 1.0 pollens per mm3 in January to 124 ± 92 in October. There was high correlation between the number of new AR patients and the average total pollen count (Pearson correlation, r = 0.77, p < 0.001), as well as with Chenopodiaceae and Amaranthaceae (weed) pollens (r = 0.75, p < 0.001), while there was no correlation between the number of new patients and either tree or grass pollens. Conclusion: Seasonal AR occurs during two periods in Kuwait, i.e. September–October and April–May, with September–October being the main season. The rise in AR during late summer in Kuwait is mainly associated with the pollination of Chenopodiaceae species.
Wheat Allergy: Clinical and Laboratory Findings
Authors: Pourpak Zahra , Mansouri Mahboubeh , Mesdaghi Mehrnaz , Kazemnejad Anoushiravan , Farhoudi Abolhasan
Published: February 2004

Background: Food allergy affects 6–8% of infants and wheat allergy is one of the common food allergies among children. The clinical and laboratory manifestations of wheat allergy were evaluated in this study. Methods: Thirty-two children (≤12 years old) with suspected wheat allergy were evaluated for wheat allergy. The patients underwent wheat skin prick test (SPT), measurement of wheat-specific IgE and wheat challenge test. The patients with a convincing history of anaphylaxis following ingestion of wheat or with a positive challenge test, and those with a history of immediate hypersensitivity reaction following ingestion of wheat in addition to a positive wheat SPT and/or positive wheat-specific IgE were considered wheat allergic. Then, the laboratory and clinical manifestations of their disease were studied. Results: Among patients with suspected wheat allergy, 24 patients with definite wheat allergy were identified. Anaphylaxis was a dominant clinical feature, accounting for 54.1% of acute symptoms. Chronic allergy symptoms like asthma and eczema were noted in 50% of the patients. Wheat-specific IgE was higher in patients with anaphylaxis (p < 0.02) and the risk of anaphylaxis was 14.4 times more in patients with wheat-specific IgE equal to or more than 3+. Conclusions: Anaphylaxis had occurred in a remarkable number of patients repeatedly, which demonstrates the severity of the reactions, poor knowledge of the disease and probable existence of more patients with mild reactions. Regarding the higher level of wheat-specific IgE in patients with anaphylaxis, wheat-specific IgE could be used to predict the severity of symptoms.
Discovery and Immunologic Validation of New Antigens for Therapeutic Cancer Vaccines
Authors: Radvanyi Laszlo
Published: February 2004

Immunotherapy using both active and passive approaches is increasingly being used as a modality to treat human cancer. The last decade has seen a tremendous burst of activity in antigen discovery in cancer, and many new targets have now been identified for both monoclonal antibody therapy and active immunization. In addition, advances have been made in our understanding of the immune response against cancer and how new vaccine vectors, such as poxviruses, alphaviruses and bacterial vectors, can be used to overcome some of the traditional hurdles (e.g. self-tolerance and immune suppression in cancer patients) that have hindered the generation of effective antitumor immune responses. Improvements in genomics technology in the area of DNA microarrays and differential display and subtractive hybridization together with a new wave of mass spectrometry-based proteomics tools, as well as more sensitive assays to validate the immunoreactivity of new antigens, have all accelerated the rate of new antigen discovery in cancer. This rapid progress should initiate a major paradigm shift in how we treat cancer within the next 10 years, where, instead of being a novelty, the combination of targeted T cell-based vaccines and antiangiogenesis therapies will be routinely combined with traditional chemotherapy. The successful combination of these approaches will change the face of cancer from a relatively acute, life-threatening disease to a manageable chronic disorder with long survival times.
Renal Insufficiency and Heart Failure
Authors: McAlister Finlay A. , Ezekowitz Justin , Tonelli Marcello , Armstrong Paul W.
Published: February 2004

Background—

The prevalence, prognostic import, and impact of renal insufficiency on the benefits of ACE inhibitors and β-blockers in community-dwelling patients with heart failure are uncertain.

Methods and Results—

We analyzed data from a prospective cohort of 754 patients with heart failure who had ejection fraction, serum creatinine, and weight measured at baseline. Median age was 69 years, and 43% had an ejection fraction ≥35%. By the Cockcroft-Gault equation, 118 patients (16%) had creatinine clearances ≤30 mL/min and 301 (40%) had creatinine clearances between 30 and 59 mL/min. During follow-up (median 926 days), 385 patients (37%) died. Even after adjustment for all other prognostic factors, survival was significantly associated with renal function (
P
=0.002) in patients with either systolic or diastolic dysfunction; patients exhibited a 1% increase in mortality for each 1-mL/min decrease in creatinine clearance. The associations with 1-year mortality reductions were similar for ACE inhibitors (OR 0.46 [95% CI 0.26 to 0.82] versus OR 0.28 [95% CI 0.11 to 0.70]) and β-blockers (OR 0.40 [95% CI 0.23 to 0.70] versus OR 0.41 [95% CI 0.19 to 0.85]) in patients with creatinine clearances <60 mL/min versus ≥60 mL/min, although these drugs were used less frequently in patients with renal insufficiency.

Conclusions—

Renal insufficiency is more prevalent in patients with heart failure than previously reported and is an independent prognostic factor in diastolic and systolic dysfunction. ACE inhibitors and β-blockers were associated with similar reductions in mortality in patients with and without renal insufficiency.
Homeobox A9 Transcriptionally Regulates the EphB4 Receptor to Modulate Endothelial Cell Migration and Tube Formation
Authors: Bruhl Thomas , Urbich Carmen , Aicher Diana , Acker-Palmer Amparo , Zeiher Andreas M. , Dimmeler Stefanie
Published: February 2004

Homeobox genes (Hox) encode for transcription factors, which regulate cell proliferation and migration and play an important role in the development of the cardiovascular system during embryogenesis. In this study, we investigated the role of HoxA9 for endothelial cell migration and angiogenesis in vitro and identified a novel target gene, the EphB4 receptor. Inhibition of HoxA9 expression decreased endothelial cell tube formation and inhibited endothelial cell migration, suggesting that HoxA9 regulates angiogenesis. Because Eph receptor tyrosine kinases importantly contribute to angiogenesis, we examined whether HoxA9 may transcriptionally regulate the expression of EphB4. Downregulation of HoxA9 reduced the expression of EphB4. Chromatin-immunoprecipitation revealed that HoxA9 interacted with the EphB4 promoter, whereas a deletion construct of HoxA9 without DNA-binding motif (Δaa 206-272) did not bind. Consistently, HoxA9 wild-type overexpression activated the EphB4 promoter as determined by reporter gene expression. HoxA9 binds to the EphB4 promoter and stimulates its expression resulting in an increase of endothelial cell migration and tube forming activity. Thus, modulation of EphB4 expression may contribute to the proangiogenic effect of HoxA9 in endothelial cells.
LR11, an LDL Receptor Gene Family Member, Is a Novel Regulator of Smooth Muscle Cell Migration
Authors: Zhu Yanjuan , Bujo Hideaki , Yamazaki Hiroyuki , Ohwaki Kenji , Jiang Meizi , Hirayama Satoshi , Kanaki Tatsuro , Shibasaki Manabu , Takahashi Kazuo , Schneider Wolfgang J. , Saito Yasushi
Published: February 2004

LR11, a member of the LDL receptor family, is highly expressed in vascular smooth muscle cells (SMCs) of the hyperplastic intima, and induces enhanced migration of SMCs in vitro via its upregulation of urokinase-type plasminogen activator receptor (uPAR) expression. In this study, we have delineated the mechanism by which LR11 elevates the expression levels of uPAR in SMCs. Secretion of soluble LR11 is induced in SMCs during the rapidly proliferating phase, and the secreted LR11 induces the migration activities of SMCs. Both the cell-anchored and secreted forms of LR11 have the capacity to bind to and form complexes with uPAR. LR11-overexpressing cells show significantly enhanced uPAR binding, but decreased uPAR internalization. LR11 colocalizes with uPAR on the cell surface and inhibits the LDL receptor–related protein (LRP)-mediated binding and internalization of uPAR. Thus, LR11 mediates the uPAR localization to the plasma membrane. LR11 is highly expressed in the atheromatous plaque areas of apoE knockout mice, particularly in the intimal SMCs at the border between intima and media. The neutralization of LR11 function with anti-LR11 antibody reduced cuff-induced intimal thickness in mice. The novel mechanism of regulation of uPAR localization in SMCs accompanied with enhanced migration activity possibly constitutes an important factor in the process of atherosclerosis and arterial remodeling.
Prevention of Sympathetic and Cardiac Dysfunction After Myocardial Infarction in Transgenic Rats Deficient in Brain Angiotensinogen
Authors: Wang Hao , Huang Bing S. , Ganten Detlev , Leenen Frans H.H.
Published: February 2004

To provide evidence for the role of angiotensin II locally produced in the brain in the development of sympathetic hyperactivity and heart failure after myocardial infarction (MI), transgenic rats (TGR) were used, which express an antisense RNA against angiotensinogen. In TGR and control Sprague-Dawley (SD) rats, an MI was induced by acute coronary artery ligation. At 8 weeks after MI, MI sizes were similar in TGR and SD rats. In the groups with MI ≥25% of left ventricle (LV), LV peak systolic pressure decreased in SD rats but not in TGR. LV end-diastolic pressure increased substantially more in SD-MI than TGR-MI rats (from 2±1 to 15±2 mm Hg, and 2±1 to 8±1 mm Hg, respectively;
P
<0.05). LV dP/dt
max
decreased from ≈5400 to 3573±187 in SD-MI rats, but only to 4353±180 mm Hg/sec in TGR-MI (
P
<0.05). LV pressure volume curves in vitro showed a marked shift to the right in SD-MI rats. This shift was significantly attenuated by −70% in TGR versus SD rats with MI. Both RV weight and interstitial fibrosis in the LV increased clearly in the SD-MI rats, but not or significantly less in the TGR-MI rats. In SD-MI rats, arterial baroreflex control of heart rate and renal sympathetic nerve activity was markedly impaired but was not affected in the TGR-MI. Plasma angiotensin II levels tended to be higher in SD versus TGR rats, both in sham and MI-groups. This study provides the major new finding that in rats after MI, angiotensin II locally produced in the brain plays a dominant role in the development of LV dysfunction after MI, possibly through its effects on sympathetic function and on circulatory/cardiac renin-angiotensin system.
Mate Attentiveness, Seasonal Timing of Breeding and Long-term Pair Bonding in the House Finch (Carpodacus mexicanus)
Authors: Hill Geoffrey , McGraw Kevin
Published: February 2004

In seasonally breeding birds, natural selection favors individuals that begin breeding earlier in a year because they produce more or higher quality offspring than those that begin breeding later. Among the factors that influence the timing of breeding, which include the age, health, competitive ability, or mate quality of individuals, is the longevity of the pair bond, with birds that remain mated across years initiating breeding earlier in the season than newly formed pairs. The behavioural interactions between pair members that may facilitate long-term pair bonding and early breeding onset have infrequently been studied, however. Here we report the relationship between male-female affiliative behaviour, pair-bond duration, and breeding date in house finches (Carpodacus mexicanus), a short-lived, socially monogamous passerine species in which the duration of pair bonds is highly variable within and among seasons. Finches that initiated breeding earliest in the season were those that had bred with one another in previous years. Early breeding males from returning pairs maintained significantly closer contact with their mate during the first egg-laying period of the year than did males from late-breeding, newly formed pairs. Similarly, early-breeding females from returning pairs followed their mate more closely in nest-vicinity flights during the fertile period than females from late-breeding, newly formed pairs. These results suggest that attributes of and interactions between both pair members may help to maintain stable breeding pairs and influence the timing of breeding in seasonally nesting, short-lived songbirds. Rather than advertising for or seeking extra-pair fertilization opportunities, high-quality pairs of finches may invest heavily in their mate to secure the pair bond and ensure high intrapair reproductive success.
Starlings Have Difficulty in Detecting Dot Symmetry: Implications for Studying Fluctuating Asymmetry
Authors: Ruff Douglas , Swaddle John
Published: February 2004

Small differences between the left and right sides of otherwise symmetric traits are related to developmental instability and can indicate how well the genome is suited to current developmental conditions. As these small asymmetries (termed fluctuating asymmetry, or FA) can reveal how well the genome is suited to the environment, researchers have postulated that FA can indicate fitness and be used by other animals as a visual cue to fitness in sexual and social encounters. Despite these claims, we know little about how animals perceive subtle symmetry differences and whether such cues could be used in nature. Here we investigate the symmetry detection abilities of wild caught European starlings Sturnus vulgaris. We presented symmetric and asymmetric images, that resemble the complex dot patterns commonly observed on starling chest plumage, through a series of operant learning sessions. Asymmetric images were produced by introducing a 40% dot number asymmetry. Following extended learning sessions, the birds were not able to accurately discriminate symmetry from asymmetry. Although complex dot patterns (similar to those studies here) are common in nature, it appears unlikely that starlings (and perhaps other birds) could use number asymmetry in such traits as a direct cue to mediate behavioural interactions.
Male and Female White-crowned Sparrows Respond Differently to Geographic Variation in Song
Authors: Nelson Douglas , Soha Jill
Published: February 2004

Bird song varies both between species and across geographic areas, and there is abundant evidence from playback experiments that both male and female birds are sensitive to these differences in song structure. Comparisons between the sexes are complicated by differences in the behavioral assays used for each sex: males are often tested in the field, i.e. in a natural setting, and females usually in the laboratory with hormone treatment. We performed a field playback experiment to male and female white-crowned sparrows on their territories to see if they made similar distinctions between songs. After we temporarily removed the females' mates from their territories, females approached and called significantly more in response to playback of conspecific song than to heterospecific song. Females gave the same responses to the local dialect as they did to songs containing phrases from a foreign dialect. In contrast, males gave significantly weaker responses to songs containing a phrase from a foreign dialect than they did to the local dialect. We discuss reasons why our results conflict with previous studies that found that females are more selective in responding to song than are males.
On the Meaning of the 'Object and Purpose' Criterion, in the Context of the Vienna Convention on the Law of Treaties, Article 19
Authors: Linderfalk Ulf
Published: February 2004

According to the provisions laid down in Article 19 of the 1969 Vienna Convention on the Law of Treaties a state that consents to be bound by a treaty may not formulate such reservations to the agreement, which are incompatible with its object and purpose. This socalled 'object and purpose criterion' has long been puzzling actors of public international law. What does it mean for a reservation to be incompatible with 'the object and purpose' of a treaty? The answer suggested below is the following: a state may not formulate a reservation, if it means (i) that an application of the treaty as modified would run counter to a telos of the treaty; or (ii) that a remaining part of the treaty would be emptied of practical meaning.
Weather Modification—a Scenario for the Future
Authors: List Roland
Published: February 2004

The ever-increasing severe economic damage imposed on national and world wide economies by severe weather, the need for sufficient and safe water resources for an increasing world population, and the threat of adverse climate change led to this critical assessment of the state-of-the-art of weather modification (WM) and to a proposal of a road map for the future.

Special attention is given to rain enhancement because it is further developed than snowpack augmentation, hail suppression, tornado and hurricane modification, and other weather-related disaster control ideas. The question of what makes a rain enhancement experiment acceptable to the scientific community is answered by the World Meteorological Organization's (WMO) criteria, which address statistical evaluation, the measurement of rain, the understanding of nature's precipitation processes with the underlying physics and dynamics of clouds and cloud systems, and the transferability of experiment design. These criteria are no longer specific enough or satisfactory and will have to be reconsidered.

An actual WM experiment also involves a variety of techniques and technologies, aspects that need to be complemented by numerical modeling of clouds and cloud responses to seeding. Modeling also allows assessment of the extra-area effects, that is, detrimental effects of precipitation on adjacent areas. Assimilation models may be giving better estimates of the rain at the ground because they can integrate restricted information from radar and rain gauges with mesoscale meteorological and remote sensing, as well as hydrological, data. However, massive improvements in computer capacity are required to handle these problems.

Weather modification has been progressing very slowly in the past because of the enormity of the problem and the fact that the precipitation process is far from being understood. Considering that rain increases are attempted within a range of 10%–20%, the lack of knowledge at corresponding accuracy is particularly evident in the fields of cloud physics, cloud and cloud systems dynamics, weather forecasting, numerical modeling, and measuring technology.

Benefits of new intensive studies of precipitation processes will not be limited to WM; they are also vital to improving weather forecasting and climate change modeling. There is one additional aspect of WM; WM can also be used to test newly developed precipitation physics and models by studying if the clouds react to seeding in the predicted manner.

This article is a wake-up call to put more intellectual and financial resources into the exploration and modification of the precipitation processes in all their forms. All these points lead to the suggestion of an outline of a national precipitation research and weather modification program.
Estimating Land Surface Energy Budgets From Space: Review and Current Efforts at the University of Wisconsin—Madison and USDA–ARS
Authors: Diak George R. , Mecikalski John R. , Anderson Martha C. , Norman John M. , Kustas William P. , Torn Ryan D. , DeWolf Rebecca L.
Published: February 2004

Since the advent of the meteorological satellite, a large research effort within the community of earth scientists has been directed at assessing the components of the land surface energy balance from space. The development of these techniques from first efforts to the present time are reviewed, and the integrated system used to estimate the radiative and turbulent land surface fluxes is described. This system is now running in real time over the continental United States at a resolution of 10 km, producing daily and time-integrated flux components.
VEGF-mediated endothelial P-selectin translocation: role of VEGF receptors and endogenous PAF synthesis
Authors: Rollin Simon , Lemieux Caroline , Maliba Ricardo , Favier Judith , Villeneuve Louis R. , Allen Bruce G. , Soker Shay , Bazan Nicolas G. , Merhi Yahye , Sirois Martin G.
Published: February 2004

The acute increase in vascular permeability produced by vascular endothelial growth factor (VEGF-A165) requires activation of endothelial Flk-1 receptors (VEGFR-2) and stimulation of platelet-activating factor (PAF) synthesis. Like PAF, VEGF-A165 promotes translocation of P-selectin to the endothelial cell (EC) surface. However, the mechanisms involved remain unknown. By treating human umbilical vein endothelial cells (HUVECs) with VEGF analogs, we show that activation of VEGFR-1 or VEGFR-2 or both induced a rapid and transient translocation of endothelial P-selectin and neutrophil adhesion to activated ECs. The effects mediated by VEGF-A165 and VEGF-A121 (VEGFR-1/VEGFR-2 agonists) were blocked by a selective VEGFR-2 inhibitor, SU1498. VEGF-A165 was twice as potent as VEGF-A121, which can be explained by the binding capacity of VEGF-A165 to its coreceptor neuropilin-1 (NRP-1). Indeed, treatment with NRP-1 antagonist (GST-Ex7) reduced the effect of VEGF-A165 to the levels observed upon stimulation with VEGF-A121. Finally, the use of selective PAF receptor antagonists reduced VEGF-A165–mediated P-selectin translocation. Together, these data show that maximal P-selectin translocation and subsequent neutrophil adhesion was mediated by VEGF-A165 on the activation of VEGFR-2/NRP-1 complex and required PAF synthesis.
Combined deficiency in IκBα and IκBϵ reveals a critical window of NF-κB activity in natural killer cell differentiation
Authors: Samson Sandrine I. , Mémet Sylvie , Vosshenrich Christian A. J. , Colucci Francesco , Richard Odile , Ndiaye Delphine , Israël Alain , Di Santo James P.
Published: February 2004

Nuclear factor κB (NF-κB) transcription factors are key regulators of immune, inflammatory, and acute-phase responses and are also implicated in the control of cell proliferation and apoptosis. While perturbations in NF-κB activity impact strongly on B- and T-cell development, little is known about the role for NF-κB in natural killer (NK) cell differentiation. Inhibitors of NF-κB (IκBs) act to restrain NF-κB activation. We analyzed the cell-intrinsic effects of deficiencies in 2 IκB members (IκBα and IκBϵ) on NK cell differentiation. Neither IκBα nor IκBϵ deficiency had major effects on NK cell generation, while their combined absence led to NF-κB hyperactivation, resulting in reduced NK cell numbers, incomplete NK cell maturation, and defective interferon γ (IFN-γ) production. Complementary analysis of transgenic mice expressing an NF-κB-responsive reporter gene showed increased NF-κB activity at the stage of NK cell development corresponding to the partial block observed in IκBα × IκBϵ-deficient mice. These results define a critical window in NK cell development in which NF-κB levels may be tightly controlled. (Blood. 2004;103:4573-4580)
Survival of children with sickle cell disease
Authors: Quinn Charles T. , Rogers Zora R. , Buchanan George R.
Published: February 2004

Contemporary survival data are not available for children with sickle cell disease (SCD). The few previous childhood SCD cohort studies do not reflect the benefits of modern therapy. We defined an inception cohort of newborns with sickle cell anemia (SS), sickle-β°-thalassemia (S β°), sickle-hemoglobin C disease (SC), or sickle-β+-thalassemia (Sβ+) who were identified by newborn screening and followed for up to 18 years. The incidence of death and stroke were calculated. Overall survival, SCD-related survival (considering only SCD-related deaths), and strokefree survival were determined. The 711 subjects provided 5648 patient-years of observation. Twenty-five subjects died; mean age at death was 5.6 years. Five patients died from infection. Thirty had at least one stroke. Among SS and Sβ° subjects (n = 448), the overall rates of death and stroke were 0.59 and 0.85/100 patient-years. Survival analysis of SS and Sβ° subjects predicted the cumulative overall, SCD-related, and stroke-free survival to be 85.6%, 93.6%, and 88.5% by 18 years of age. No SCD-related deaths or strokes occurred in SC or Sβ+ subjects (n = 263). Childhood mortality from SCD is decreasing, the mean age at death is increasing, and a smaller proportion of deaths are from infection.