bluuebunny/crossref_metadata_2025 huggingface dataset:
Contact Urticaria to Giraffe Hair
Authors: Herzinger Thomas , Scharrer Eva , Placzek Marianne , Przybilla Bernhard
Published: October 2005

Background: Immediate-type hypersensitivity to animal proteins is a common problem in people occupationally exposed to animals. Methods: A 19-year-old female working as a voluntary zookeeper in her off-time suffered from hives on her forearms following contact to the fur of a giraffe. For diagnostic evaluation, skin prick tests, assessment of specific serum IgE antibodies, and basophil activation tests were performed. Results: Skin prick tests with a standard series of common aeroallergens were positive for various pollens. Prick testing with native materials was positive for extracts of hair from two different giraffe subspecies in the patient, but not in control subjects. By CAP-FEIA, no specific serum IgE antibodies to dander of a large variety of animals were found in the patient. In the basophil activation test, expression of the activation marker CD63 was induced by extract of giraffe hair on the cells from the patient, but not on those from unaffected controls. Conclusions: This patient suffers from an ‘exotic’ immediate-type contact allergy to giraffe hair.
Hypersensitivity to Mycophenolate Mofetil in Systemic Lupus Erythematosus: Diagnostic Measures and Successful Desensitization
Authors: Szyper-Kravitz Martine , Sheinberg Pavel , Sidi Yechezkel , Schiffenbauer Yael , Trubniykov Ela , Shoenfeld Yehuda
Published: October 2005

Despite therapeutic advances in the treatment of systemic lupus erythematosus (SLE), several patients are still afflicted with severe and uncontrolled symptoms. Recently, mycophenolate mofetil (MMF) has been introduced in the treatment of SLE, with a significant therapeutic benefit, and minor side effects have been reported. Data on the adverse effects of MMF in SLE are lacking. We present an SLE patient who developed urticaria during MMF treatment. Rechallenge with MMF established the diagnosis of MMF-induced urticaria. As MMF was considered a necessary therapy, a desensitization protocol was devised, which successfully induced tolerance to MMF. This is the first published protocol for MMF desensitization, which induced tolerance in an SLE patient previously reacting with generalized urticaria.
Relationship between CTLA-4 and CD28 Molecule Expression on T Lymphocytes and Stimulating and Blocking Autoantibodies to the TSH-Receptor in Children with Graves’ Disease
Authors: Bossowski Artur , Stasiak-Barmuta Anna , Urban Mirosława
Published: October 2005

The present study was performed to elucidate the relationship between CTLA-4/CD28 molecules and stimulating (TSAb) and blocking (TBAb) antibodies to the TSH-receptor (TSH-R) in Graves’ disease. CD28 and CD152 (CTLA-4) are glycoprotein molecules which provide a potent costimulatory signal for T-cell activation and proliferation via interactions with their ligands, B7.1/B7.2 molecules, which are present on the surface of antigen-presenting cells. The aim of the study was to estimate the expression of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4, CD152), CD28, B7.1 (CD80), and B7.2 (CD86) molecules on peripheral blood cells in patients with Graves’ disease (GD) (n = 55, mean age 15.5 ± 5.1 years) and nontoxic nodular goiter (NTNG) (n = 55, mean age 15.2 ± 4.5 years), in comparison with sex and age-matched healthy control subjects (n = 55, mean age 15.2 ± 3.9 years). The expression of the costimulatory molecules on mononuclear cells was analyzed by three-color flow cytometry using a Coulter EPICS XL cytometer. Detection of TSAb and TBAb to the TSH-R using JPO9 CHO cells in unfractionated serum was measured by a highly sensitive commercial radioimmunoassay. When compared with healthy control subjects and euthyroid patients with GD, untreated patients with GD showed a significant increase of CD152+ (p < 0.001, p < 0.001) and CD28+ (p < 0.01, NS) T lymphocytes, respectively. After 6–12 months of methimazole therapy, the percentage of these cells in the peripheral blood of hyperthyroid patients returned to normal values. In addition, patients with GD showed an increase in the percentage of both B7.1 (3.8%) and B7.2 (18.4%) molecules on activated monocytes, compared to patients with NTNG (0.5% p < 0.05, 2.5% p < 0.01, respectively) and healthy control subjects (0.2% p < 0.05, 0.8% p < 0.003, respectively). In patients with untreated GD there was a statistically significant positive correlation between the expression of CTLA-4 on the surface of peripheral blood T cells and the index of TSAb antibodies (R = 0.54, p < 0.001) as well as a negative correlation with TBAb antibody titer (R = –0.58, p < 0.001). However, no such correlations were noted with regard to CD28 and anti-TPO, anti-TG, and TRAb antibodies. We conclude that changes in the expression of costimulatory molecules on the surface of peripheral blood T cells and their significant relationship with the level of antithyroid antibodies indicate an involvement of these molecules in the pathogenesis of GD.
Nutrition Rehabilitation of HIV-Infected and HIV-Negative Undernourished Children Utilizing Spirulina
Authors: Simpore Jacques , Zongo Frederic , Kabore Fatoumata , Dansou Deleli , Bere Augustin , Nikiema Jean-Baptiste , Pignatelli Salvatore , Biondi Daniela M. , Ruberto Giuseppe , Musumeci Salvatore
Published: October 2005

The objective of this study was to assess the impact of an alimentary integrator composed of spirulina (Spirulina platensis; SP), produced at the Centre Médical St Camille of Ouagadougou, Burkina Faso, on the nutritional status of undernourished HIV-infected and HIV-negative children. We compared two groups of children: 84 were HIV-infected and 86 were HIV-negative. The duration of the study was 8 weeks. Anthropometric and haematological parameters allowed us to appreciate both the nutritional and biological effect of SP supplement to traditional meals. Rehabilitation with SP shows on average a weight gain of 15 and 25 g/day in HIV-infected and HIV-negative children, respectively. The level of anaemia decreased during the study in all children, but recuperation was less efficient among HIV-infected children. In fact 81.8% of HIV-negative undernourished children recuperated as opposed to 63.6% of HIV-infected children (Z: 1.70 (95% CI –0.366, –0.002, p = 0.088)). Our results confirm that SP is a good food supplement for undernourished children. In particular, rehabilitation with SP also seems to correct anaemia and weight loss in HIV-infected children, and even more quickly in HIV-negative undernourished children.
Resting Energy Expenditure, Cardiovascular Risk Factors and Insulin Resistance in Obese Patients
Authors: de Luis D.A. , Aller R. , Izaola O. , Gonzalez Sagrado M. , Conde R.
Published: October 2005

Objective: The aim of our study was to determine whether energy expenditure modified by increasing body mass over the wide range of body mass index (BMI) was related to insulin resistance, cardiovascular risk factors and dietary intakes. Subjects and Methods: A population of 87 obese non-diabetic outpatients was analyzed prospectively. Indirect calorimetry, tetrapolar electrical bioimpedance, serial assessment of nutritional intake using written 3-day food records and biochemical analyses were performed. Results: The mean age was 45.1 ± 16.7 years and the mean BMI was 35.2 ± 5.2. Indirect calorimetry showed a resting metabolic rate (RMR) of 1,732.2 ± 406.6 kcal/day and oxygen consumption of 266.2 ± 63.3 ml/min. RMR corrected by fat-free mass was 36.8 ± 14.1 kcal/day/kg. Serial assessment of nutritional intake using written 3-day food records showed a calorie intake of 1,660 ± 551.7 cal/day, a carbohydrate intake of 168.63 ± 76.6 g/day, a fat intake of 72.1 ± 26.42 g/day and a protein intake of 81.1 ± 23.3 g/day. Insulin, HOMA, systolic blood pressure, diastolic blood pressure, waist circumference, fat mass, waist-to-hip ratio were higher in the third BMI tertile than in the first and second tertiles. No differences were detected in calorie intake, carbohydrate intake, fat intake, protein intake, drinking and alcoholic habit among BMI tertiles. RMR was similar in the different tertiles and the corrected RMR by fat-free mass was higher in first tertile than in the second and third tertiles (44.2 ± 20.7 vs. 34.5 ± 9.1 vs. 33.1 ± 8.5 kcal/kg/day; p < 0.05). In multivariate analysis with a dependent variable (RMR), the fat-free mass remained in the model (F = 7.8; p < 0.05), with an increase of 10.1 (95% CI 3.6–17.5) kcal/day with each 1 kg of fat-free mass adjusted by age and sex. Conclusion: Resting energy expenditure in obese patients is not related to the BMI, insulin resistance and dietary intake. RMR is related to fat-free mass in a multivariant model.
Evidence for a Major Gene Influence on Tumor Necrosis Factor-α Expression in Tuberculosis: Path and Segregation Analysis
Authors: Stein Catherine M. , Nshuti Lorna , Chiunda Allan B. , Boom W. Henry , Elston Robert C. , Mugerwa Roy D. , Iyengar Sudha K. , Whalen Christopher C.
Published: October 2005

Objective: Tuberculosis (TB) is a growing global public health problem. Several studies suggest a role for host genetics in disease susceptibility, but studies to date have been inconsistent and a comprehensive genetic model has not emerged. A limitation of previous genetic studies is that they only analyzed the binary trait TB, which does not reflect disease heterogeneity. Furthermore, these studies have not accounted for the influence of shared environment within households on TB risk, which may spuriously inflate estimates of heritability. Methods: We conducted a household contact study in a TB-endemic community in Uganda. Antigen-induced tumor necrosis factor-α (TNFα) expression, a key component of the underlying immune response to TB, was used as an endophenotype for TB. Results: Path analysis, conducted to assess the effect of shared environment, suggested that TNFα is heritable (narrow sense heritability = 34–66%); the effect of shared environment is minimal (1–14%), but gene-environment interaction may be involved. Segregation analysis of TNFα suggested a major gene model that explained one-third of the phenotypic variance, and provided putative evidence of natural selection acting on this phenotype. Conclusion: Our data further support TNFα as an endophenotype for TB, as it may increase power to detect disease-predisposing loci.
Psychopathology of Obsessive-Compulsive Disorder: A Phenomenological Approach
Authors: Bürgy M.
Published: October 2005

Until the beginning of the 20th century, the idea of obsession found in the literature was mostly a broad and unspecific one, and it has, to some extent, persisted in this form until the present day. At the same time, however, Esquirol and Westphal began to develop a concept of obsession in the strict sense, and Jaspers used the phenomenological method as a basis to give it its final form. The concept of obsession in the strict sense represents the formal and nosologically specific core symptom of obsessive-compulsive disorder. In conjunction with the distinction between primary and secondary obsessions, obsession in the strict sense is proving helpful in differential diagnosis, but it can also serve as a guideline in the further phenomenological investigation of obsessive-compulsive disorder. It is shown how the interaction between personality, affect and release situation develops the obsessive-compulsive disorder. The clarification of these aspects with the patient can at the same time be the starting point of psychotherapeutic treatment.
Reliability and Validity of the Hungarian Version of the European Addiction Severity Index
Authors: Gerevich József , Bácskai Erika , Kó József , Rózsa Sándor
Published: October 2005

We attempted a Hungarian adaptation of the European version (EuropASI) of the widely used Addiction Severity Index (ASI) within the frame of a multi-stage quality development programme. The ASI is characterised by good reliability and validity indicators. The empirical background for our research was the data obtained from ASI ratings for 266 alcohol- and drug-using patients presenting for treatment in addiction medicine clinics in different regions of the country. The reliability indicators for measurement tool rating (interrater) and time (test-retest) were high, with the exception of the correlation value for employment and support. The internal consistency of the test was good. The degree of correlation between the individual items did not exceed that found internationally. The psychometric results corresponded to the results obtained in foreign investigations. The Hungarian version of the ASI can be regarded as a useful and reliable measuring tool that can be used to identify the problems of addiction patients and to assess treatment efficacy.
PANSS Syndromes and Quality of Life in Schizophrenia
Authors: Karow A. , Moritz S. , Lambert M. , Schoder S. , Krausz M.
Published: October 2005

Background: Results from factor analysis studies have suggested that a five-dimensional structure appears to be a better representation of the psychopathological data of the PANSS. The purpose of this study was the detailed investigation of the association of schizophrenia syndromes and single symptoms with quality of life (QOL) in acute and remitted patients. The leading hypotheses were: (1) affective symptoms, especially depression and anxiety, are mostly associated with QOL longitudinally and (2) in the acute phase, QOL is also associated with positive schizophrenia symptoms. Methods: For the present study, schizophrenia and schizophreniform patients were studied on admission, at the end of the acute phase and 6 months after hospitalization. Psychopathology was measured using the PANSS syndromes, QOL was assessed using disease-specific (SWN) and generic (MLDL, EDLQ) scales. Results: Eighty-four patients entered the study and were assessed during the acute phase taking into account their history and actual treatment. Results revealed anxiety as the most important symptom and depression as the most important syndrome associated with different areas of QOL during and after hospitalization. Also cognitive and negative symptoms were associated with different QOL domains, but both positive symptom clusters showed no substantial association with QOL. Conclusions: Results of this longitudinal study investigating psychopathology and QOL in schizophrenia provide further support for the need to consider the psychopathological state and treatment setting when measuring QOL in schizophrenia and the need for a differential analysis of schizophrenia symptoms and QOL in the acute, mid-term and long-term phase. Anxiety reduction should be a critical goal of treatment in order to prevent further QOL impairment.
Interleukin-8 Is a Powerful Prognostic Predictor of All-Cause and Cardiovascular Mortality in Dialytic Patients
Authors: Panichi Vincenzo , Taccola Daniele , Rizza Giovanni Manca , Consani Cristina , Ghiadoni Lorenzo , Filippi Cristina , Cristofani Renza , Panicucci Erica , Migliori Massimiliano , Sidoti Antonino , Biagioli Marina , Boracelli Donella , Barsotti Giuliano , Tetta Ciro
Published: October 2005

Background: Cohort studies have demonstrated an association between C-reactive protein (CRP) and interleukin-6 (IL-6) and all-cause and cardiovascular mortality in end-stage renal disease (ESRD) patients. Interleukin-8 (IL-8) appears to be not only the plasma expression of the acute-phase response but also a direct pathogenetic mediator of the atherosclerotic process. Methods: To evaluate the role of IL-8 in predicting outcome, 76 chronic dialytic patients were prospectively followed for 18 months. At baseline, blood samples were taken for analysis of high-sensitivity CRP, IL-6, IL-8 and other standard laboratory analyses. Results: Median IL-8 was 5.2 mg/l, therefore near half of the patients had IL-8 values within the range of ‘normal limits’. IL-6 and CRP were significantly correlated (r = 0.45, p < 0.001) and a positive correlation was also found between IL-6 and IL-8 (r = 0.39, p < 0.001). The correlation coefficient between IL-6 and CRP was 0.43 (p < 0.001) and 0.50 (p < 0.001) in patients without and with history and/or clinical signs of cardiovascular disease, respectively. After a follow-up of 1.5 years, 8 patients had died from cardiovascular causes and another 7 patients for other reasons; furthermore 9 major nonfatal cardiovascular events were recorded. Stepwise regression analysis showed IL-8 as the strongest independent predictor of all-cause and cardiovascular events (p = 0.0025) even after adjustment for age and dialytic age, followed by IL-6 and CRP (p < 0.01). Conclusion: Despite a small population and a relatively short follow-up period, this study firstly demonstrated that IL-8 is a powerful independent predictive factor for cardiovascular and overall mortality cause in ESRD patients.
Tonsillectomy Using the Thermal Welding System
Authors: Karatzias George T. , Lachanas Vassilios A. , Papouliakos Sotirios M. , Sandris Vassilios G.
Published: October 2005

Objective: To evaluate and introduce a new method of tonsillectomy using the Thermal Welding System (TWS). Method: The TWS is a new surgical instrument which uses direct heat and pressure to seal and divide tissues. Fifty consecutive patients underwent tonsillectomy with the use of the TWS. Inclusion criteria were chronic tonsillitis, peritonsilar abscess history and obstructive sleep apnea syndrome. Patients undergoing adenoidectomy or any other procedure together with tonsillectomy and patients with bleeding disorders were excluded. Intraoperative bleeding, operative time, complication rates and return to normal diet were evaluated. Results: There was no measurable bleeding during surgery in any case. No postoperative hemorrhage or other complication occurred. Mean operative time was 23 min. Mean time for return to normal diet was 8.7 days. Conclusions: The TWS was found quite effective and safe, providing sufficient hemostasis and minimal intraoperative blood loss.
Do Predictive Mechanisms Improve the Angular Vestibulo-Ocular Reflex in Vestibular Neuritis?
Authors: Sprenger A. , Zils E. , Stritzke G. , Krüger A. , Rambold H. , Helmchen C.
Published: October 2005

Recovery from vestibular neuritis (VN) is often incomplete which leads to persistent vestibular imbalance during rapid head movements. Patients with unilateral vestibular lesions have a larger gain of the horizontal vestibulo-ocular reflex during active compared to passive head movements. To test whether this gain increase is related to predictive mechanisms we studied 15 patients with VN and 14 control subjects during predictable and unpredictable passive horizontal head impulses in the light and darkness. The vestibulo-ocular reflex showed a significantly shorter latency and higher gain in the light for predictable head impulses towards the ipsilesional side. However, this effect is small and might contribute but cannot exclusively account for the gain increase during active head movements.
Antiangiogenic Drugs for Chemotherapy of Bladder Tumours
Authors: Rocchetti Romina , Talevi Simona , Margiotta Chiara , Calza Roberta , Corallini Alfredo , Possati Laura
Published: October 2005

Background: Bladder cancers have different angiogenic pathways distinguishing not only papillary from solid tumours, but even papillary superficial from papillary invasive ones, thus representing selective targets for antiangiogenic drugs. Methods: The bacterial wall component tecogalan, inhibiting basic fibroblast growth factor (bFGF), the fumagillin derivative TNP-470, inhibiting vascular endothelial growth factor (VEGF), the distamycin A derivative PNU153429, and the tetracycline minocycline were administered to nude mice injected with the human bladder cancer cell lines 639V, causing bFGF-expressing papillary superficial tumours, or T24, causing VEGF-expressing papillary invasive tumours. Results: Tecogalan had no effect even on 639V tumour growth, where bFGF was unaffected. TNP-470 only had an effect on T24 tumours, delaying tumour appearance and growth and lowering VEGF; these effects were augmented by adding minocycline. PNU153429 had no effect on 639V tumours, and a slight effect on T24 tumours. Conclusion: TNP-470 may represent a selective drug for the treatment of VEGF-expressing invasive papillary bladder tumours.
Bioadhesive Drug Delivery System Using Glyceryl Monooleate for the Intravesical Administration of Paclitaxel
Authors: Lee Seung-Ju , Kim Sae Woong , Chung Hesson , Park Yeong Taek , Choi Young Wook , Cho Yong-Hyun , Yoon Moon Soo
Published: October 2005

Background: Many reports have shown that the efficacy of intravesical therapy for bladder cancer is in part limited by the poor penetration of drugs into the urothelium. The present study evaluated the effect of glyceryl monooleate (GMO) on the absorption of intravesically administered paclitaxel in a rabbit model of bladder cancer. Methods: Urine, plasma, and tissue pharmacokinetics were determined in rabbits treated for 120 min with paclitaxel (500 µg/20 ml) by intravesical instillation. Two formulations of GMO/paclitaxel were evaluated using different proportions of water, 15 and 30%, and Taxol® was used as a control. Animals were observed for clinical signs of toxicity and necropsy was performed. Results: 120 min after instillation, the bladder was emptied and excised. In the urine, paclitaxel concentration was decreased by 39.6 and 41.2% in the two experimental groups and by 25.2% in the control group. The paclitaxel concentrations in the urothelium were 53 and 56% of the urine concentration in both experimental groups, but 11% in the control group. The concentration then declined exponentially in the underlying capillary-perfused tissues, reaching equilibrium at a depth of 1,400–1,700 µm. The plasma concentrations were extremely low compared with concentrations in urine and bladder tissues and were not associated with clinical toxicity. Conclusions: We conclude that GMO has a significantly increased bioadhesiveness to bladder mucosa. Therefore, intravesical administration of GMO/paclitaxel/water provides a significant advantage for drugs targeting the bladder tissue, and paclitaxel represents a viable option for intravesical bladder cancer therapy.
Effect of the Farnesyl Transferase Inhibitor L-744,832 on the Colon Cancer Cell Line DLD-1 and Its Combined Use with Radiation and 5-FU
Authors: Kavgaci Halil , Özdemir Feyyaz , Ovali Ercüment , Yavuz Aydin , Yavuz Melek , Aydin Fazil
Published: October 2005

Background: Ras oncogenes are found in 25% of human tumors and they significantly affect prognosis. One of the major fields studied to improve anticancer drugs is blockade of the oncogenic ras protein function. One of the mechanisms to block the function of these proteins is to block farnesylation using a farnesyl transferase inhibitor (FTI) and thus to prevent the ras from anchoring to the cell membrane. Methods: In this study, we investigated the effects of FTI L-744,832 either alone or in combination with 5-fluorouracil (5-FU; 1 µM/l) and radiotherapy (2, 6, and 10 Gy) on the colon cancer cell line DLD-1 with mutations in K-, N- and H-ras, c-myb, c-myc, p53, fos, sis and DNA repair genes. Drugs were added 3 h after cultivation. Radiotherapy was performed on the 3rd day of the study. On the 3rd day, medium and drugs were changed. Evaluations were performed on the 6th day. Results: Administration of L-744,832, neither alone nor its combination with 5-FU and radiation, affected the number of DLD-1 cells and apoptosis rates. Regarding its effects on the cell cycle, L-744,832 was shown to lead to G₀/G1 and G2/M accumulation in a dose-dependent manner when administered alone. However, in combination with 5-FU, only a G₀/G1 accumulation was observed. Conclusion: Our study showed that FTI L-744,832 does not effect the cell number and apoptosis rate of DLD-1 cells and it cannot overcome 5-FU and radiation resistance, although it is able to modify some phases of the cell cycle.
Release of Exotoxin A, Peptidoglycan and Endotoxin after Exposure of Clinical Pseudomonas aeruginosa Isolates to Carbapenems in vitro
Authors: Horii Toshinobu , Muramatsu Hideaki , Monji Akio , Miyagishima Daisuke
Published: October 2005

Background: Production of several cell-associated components and extracellular enzymes can play important roles in the pathogenesis of Pseudomonas aeruginosa infections. Methods: We characterized the time course of morphological changes, production of exotoxin A (ETA) and release of peptidoglycan (PG) and endotoxin (ET) in clinical P. aeruginosa isolates after exposure to carbapenems including imipenem, panipenem, meropenem and biapenem at 0.5, 2, 8 and 32 µg/ml. Results: The amount of ETA in the supernatant of bacterial cultures exposed to carbapenems correlated with the number of viable cells, independently of morphological changes. Formation of ovoid cells and rapid cell lysis induced by carbapenems above the minimal inhibitory concentrations (MICs) decreased ETA production and ET release, while filamentation and prolonged cell lysis increased ETA production and/or ET release. Neither the number of viable cells nor bacterial morphology was related to the amount of PG released throughout the 6-hour observation period. Conclusion: Exposure to concentrations of carbapenems above the MIC resulted in rapid cell lysis of P. aeruginosa and decreased ETA levels and ET release, while filamentation and prolonged cell lysis induced by exposure to sub-MICs of carbapenems were associated with increased ETA production and/or greater ET release.
In vitro Antitumor Activity of Cyanidin-3-O-β-Glucopyranoside
Authors: Fimognari Carmela , Berti Fausto , Nüsse Michael , Cantelli Forti Giorgio , Hrelia Patrizia
Published: October 2005

Background: Little is currently known regarding the cancer-preventive potential of cyanidin-3-O-β-glucopyranoside (Cy-g) apart from its antioxidant activity. Methods: We tested Cy-g on Jurkat and HL-60 leukemia cell lines and, to help elucidate whether the effects of Cy-g are specific for cancer cells, also on normal T lymphocytes. Results: Cy-g induced apoptosis in all three cell systems, and this indicated that Cy-g was not selective towards leukemia cells. Moreover, Cy-g caused HL-60 differentiation. The induction of apoptosis and cytodifferentiation involved different proteins, thus suggesting that Cy-g-induced apoptosis and cytodifferentiation are two distinct events. Conclusions: Although obtained in vitro, our findings indicate that Cy-g possesses some interesting biological properties that should encourage further investigation as regards its chemotherapeutic potential.
Intestinal Permeability in the Assessment of Intestinal Toxicity of Cytotoxic Agents
Authors: Melichar Bohuslav , Dvořák Josef , Hyšpler Radomír , Zadák Zdeněk
Published: October 2005

The diagnosis and assessment of the severity of intestinal mucosal damage in cancer patients treated with cytotoxic drugs still rely on anamnestic data. There is cumulative evidence that measurement of intestinal permeability may represent a sensitive indicator of intestinal damage by cytotoxic agents. The intestinal permeability testing is based on differential permeability of tight junctions along the crypt-villus axis to nonmetabolized sugars. Cytotoxic drugs induce flattening of villi, leading to increased exposure of luminal contents to crypts and increased disaccharide absorption. An increased disaccharide/monosaccharide ratio and decreased xylose absorption have been described in patients treated with different cytotoxic drugs across a spectrum of malignant tumors that correlated with clinical manifestations, and were used to monitor the effect of therapeutic interventions.
T Cell Modulation of Intimal Thickening After Vascular Injury
Authors: Dimayuga Paul C. , Li Hongyan , Chyu Kuang-Yuh , Fredrikson Gunilla Nordin , Nilsson Jan , Fishbein Michael C. , Shah Prediman K. , Cercek Bojan
Published: October 2005

Background—

Immune deficiency results in exuberant intimal thickening after arterial injury. The mechanisms involved are not well defined. We investigated the role of T cells and IFN-γ in the response to injury in normal and immune-deficient Rag-1KO mice.

Methods and Results—

Carotid arterial injury was induced in wild-type (WT), Rag-1KO mice, and Rag-1KO mice reconstituted with T cell-enriched splenocytes. The exuberant intimal thickening in Rag-1KO mice compared with WT mice 21 days after injury was reduced by T cell transfer (
P
<0.01). Exogenous IFN-γ starting on the day of injury inhibited intimal thickening in Rag-1KO mice. However, antibody neutralization of endogenous IFN-γ in Rag-1KO mice starting 7 days after injury decreased intimal thickening, indicating that late presence of IFN-γ promoted intimal thickening in Rag-1KO mice. Results further suggest that the effect of late IFN-γ in Rag-1KO mice is mediated in part by increased IRF-1 and iNOS expression, coupled with low SOCS1 expression.

Conclusion—

T cells inhibit intimal thickening in the early stages of the response to injury through basal IFN-γ secretion. In the Rag-1KO mice, late IFN-γ expression promotes intimal thickening. These findings add novel insight to conditions of immune deficiency that affect intimal thickening.
Plasma Level of Endogenous Secretory RAGE Is Associated With Components of the Metabolic Syndrome and Atherosclerosis
Authors: Koyama Hidenori , Shoji Takuhito , Yokoyama Hisayo , Motoyama Kohka , Mori Katsuhito , Fukumoto Shinya , Emoto Masanori , Shoji Tetsuo , Tamei Hironori , Matsuki Hirokazu , Sakurai Shigeru , Yamamoto Yasuhiko , Yonekura Hideto , Watanabe Takuo , Yamamoto Hiroshi , Nishizawa Yoshiki
Published: October 2005

Objectives—

Advanced glycation endproducts, AGEs, and its specific receptor, RAGE, are involved in diabetic vascular complications. Endogenous secretory RAGE, esRAGE, has been identified as an alternatively spliced form of RAGE, and shown to act as a decoy receptor for AGE. Here, we measured plasma esRAGE level with a recently developed enzyme-linked immunosorbent assay (ELISA) and examined its association with atherosclerosis in age- and gender-matched 203 type 2 diabetic and 134 nondiabetic subjects.

Methods and Results—

Plasma esRAGE was inversely associated with carotid or femoral atherosclerosis, as quantitatively measured as intimal-medial thickness (IMT) by arterial ultrasound. Stepwise regression analyses revealed that plasma esRAGE was the third strongest and independent factor associated with carotid IMT, following age and systolic blood pressure. Plasma esRAGE was significantly lower in diabetic patients (0.176±0.092 ng/mL) than nondiabetic controls (0.253±0.111). Of note, in all, diabetic or nondiabetic group, plasma esRAGE was significantly and inversely correlated with components of the metabolic syndrome including body mass index, blood pressure, triglyceride, HbA1c, or an insulin resistance index. Stepwise regression analyses showed that body mass index or insulin resistance index was the major factor determining plasma esRAGE in all, nondiabetic or diabetic population.

Conclusions—

esRAGE is a novel and potential protective factor for the metabolic syndrome and atherosclerosis.
Vascular Neuronal NO Synthase Is Selectively Upregulated by Platelet-Derived Growth Factor
Authors: Nakata Sei , Tsutsui Masato , Shimokawa Hiroaki , Tamura Masahito , Tasaki Hiromi , Morishita Tsuyoshi , Suda Osamu , Ueno Susumu , Toyohira Yumiko , Nakashima Yasuhide , Yanagihara Nobuyuki
Published: October 2005

Objective—

We demonstrated recently that neuronal NO synthase (NOS) is expressed in arteriosclerotic lesions and exerts important vasculoprotective effects in vivo. In this study, we examined the molecular mechanism(s) for vascular neuronal NOS (nNOS) expression.

Methods and Results—

In cultured rat aortic smooth muscle cells, treatment with platelet-derived growth factor (PDGF) selectively upregulated nNOS expression but not inducible NOS (iNOS) or endothelial NOS (eNOS) expression. Treatment with PDGF also significantly caused activation of mitogen-activated protein kinase (MAPK) family, including extracellular signal-regulated kinase (ERK), p38MAPK, and c-Jun N-terminal kinase (JNK). ERK kinase (MAPK kinase [MEK]) inhibitors inhibited PDGF-induced nNOS expression, whereas a p38MAPK inhibitor or JNK inhibitor was without effects. Importantly, gene transfer of MEK per se elicited nNOS induction, and gene transfer of dominant-negative MEK abolished PDGF-induced nNOS expression. In isolated aortas of wild-type, eNOS
−/−
, and iNOS
−/−
mice, but not in those of nNOS
−/−
mice, treatment with PDGF significantly enhanced nNOS expression and nitrite plus nitrate production, both of which were again attenuated by a MEK inhibitor.

Conclusions—

These results provide the first evidence that vascular nNOS expression is upregulated selectively in response to PDGF through the MEK/ERK pathway. Upregulated nNOS may play an important compensatory role under arteriosclerotic/inflammatory conditions associated with eNOS dysfunction to maintain vascular homeostasis.
α-Lipoic Acid Prevents Endothelial Dysfunction in Obese Rats via Activation of AMP-Activated Protein Kinase
Authors: Lee Woo Je , Lee In Kyu , Kim Hyoun Sik , Kim Yun Mi , Koh Eun Hee , Won Jong Chul , Han Sung Min , Kim Min-Seon , Jo Inho , Oh Goo Taeg , Park In-Sun , Youn Jang Hyun , Park Seong-Wook , Lee Ki-Up , Park Joong-Yeol
Published: October 2005

Objective—

Lipid accumulation in vascular endothelial cells may play an important role in the pathogenesis of atherosclerosis in obese subjects. We showed previously that α-lipoic acid (ALA) activates AMP-activated protein kinase (AMPK) and reduces lipid accumulation in skeletal muscle of obese rats. Here, we investigated whether ALA improves endothelial dysfunction in obese rats by activating AMPK in endothelial cells.

Methods and Results—

Endothelium-dependent vascular relaxation was impaired, and the number of apoptotic endothelial cells was higher in the aorta of obese rats compared with control rats. In addition, triglyceride and lipid peroxide levels were higher, and NO synthesis was lower. Administration of ALA improved all of these abnormalities. AMPK activity was lower in aortic endothelium of obese rats, and ALA normalized it. Incubation of human aortic endothelial cells with ALA activated AMPK and protected cells from linoleic acid–induced apoptosis. Dominant-negative AMPK inhibited the antiapoptotic effects of ALA.

Conclusions—

Reduced AMPK activation may play an important role in the genesis of endothelial dysfunction in obese rats. ALA improves vascular dysfunction by normalizing lipid metabolism and activating AMPK in endothelial cells.
Severe Hypercholesterolemia in Four British Families With the D374Y Mutation in the PCSK9 Gene
Authors: Naoumova Rossi P. , Tosi Isabella , Patel Dilip , Neuwirth Clare , Horswell Stuart D. , Marais A. David , van Heyningen Charles , Soutar Anne K.
Published: October 2005

Objective—

Analysis of long-term (30 years) clinical history and response to treatment of 13 patients with the D374Y mutation of
PCSK9
(PCSK9 patients) from 4 unrelated white British families compared with 36 white British patients with heterozygous familial hypercholesterolemia attributable to 3 specific mutations in the low-density lipoprotein (LDL) receptor gene (
LDLR
) known to cause severe phenotype.

Methods and Results—

The PCSK9 patients, when compared with the LDLR patients, were younger at presentation (20.8±14.7 versus 30.2±15.7 years;
P
=0.003), had higher pretreatment serum cholesterol levels (13.6±2.9 versus 9.6±1.6 mmol/L;
P
=0.004) that remained higher during treatment with simvastatin (10.1±3.0 versus 6.5±0.9 mmol/L;
P
=0.006), atorvastatin (9.6±2.9 versus 6.4±1.0 mmol/L;
P
=0.006), or current lipid-lowering therapy, including LDL apheresis and partial ileal bypass in 2 PCSK9 patients (7.0±1.6 versus 5.4±1.0 mmol/L;
P
=0.001), and were affected >10 years earlier by premature coronary artery disease (35.2±4.8 versus 46.8±8.9 years;
P
=0.002). LDL from PCSK9 patients competed significantly less well for binding to fibroblast LDL receptors than LDL from either controls or LDLR patients.

Conclusions—

These British PCSK9 patients with the D374Y mutation have an unpredictably severe clinical phenotype, which may be a unique feature for this cohort, and requires early and aggressive lipid-lowering management to prevent cardiovascular complications.
Expression of Fractalkine (CX3CL1) and its Receptor, CX3CR1, Is Elevated in Coronary Artery Disease and Is Reduced During Statin Therapy
Authors: Damås Jan K. , Boullier Agnes , Wæhre Torgun , Smith Camilla , Sandberg Wiggo J. , Green Simone , Aukrust Pål , Quehenberger Oswald
Published: October 2005

Objective—Recent data derived primarily from studies in animal models suggest that fractalkine (CX3CL1) and its cognate receptor, CX3CR1, play a role in atherogenesis. We, therefore, hypothesized that enhanced CX3CL1/CX3CR1 expression may promote atherogenesis in patients with coronary artery disease (CAD).

Methods and Results—We examined the plasma levels of CX3CL1 and CX3CR1 expression in peripheral blood mononuclear cells (PBMC) in various CAD populations (30 patients with previous myocardial infarction, 40 patients with stable angina, 40 patients with unstable angina, and a total of 35 controls) and used various experimental approaches to characterize CX3CL1-mediated leukocyte responses. We found that the plasma levels of CX3CL1 are greatly increased in CAD, particularly in unstable disease. The parallel increase of CX3CR1 expression in PBMC was predominantly attributable to an expansion of the CX3CR1+CD3+CD8+T cell subset and was associated with enhanced chemotactic, adhesive, and inflammatory responses to CX3CL1. Statin therapy for 6 months reduced the expression of CX3CL1 and CX3CR1, reaching statistical significance for both parameters only during aggressive (atorvastatin, 80 mg qd) but not conventional (simvastatin, 20 mg qd) therapy. Consequently, the functional responses of the PBMC to CX3CL1 including migration, adhesion, and secretion of interleukin-8 were attenuated by the treatments.

Conclusion—Our results suggest that the CX3CL1/CX3CR1 dyad may contribute to atherogenesis and plaque destabilization in human CAD.
Mechanisms of Increased Vascular Superoxide Production in an Experimental Model of Idiopathic Dilated Cardiomyopathy
Authors: Mollnau Hanke , Oelze Matthias , August Michael , Wendt Maria , Daiber Andreas , Schulz Eberhard , Baldus Stephan , Kleschyov Andrei L. , Materne Anke , Wenzel Philip , Hink Ulrich , Nickenig Georg , Fleming Ingrid , Münzel Thomas
Published: October 2005

Objective—

In the present study, we sought to identify mechanisms underlying increased oxidative stress in vascular tissue in an experimental animal model of chronic congestive heart failure (CHF).

Methods and Results—

Superoxide and nitric oxide (NO) was measured in vessels from cardiomyopathic hamsters (CHF hamsters) and golden Syrian hamsters. We also determined expression of endothelial nitric oxide synthase (NOSIII), the soluble guanylyl cyclase, the cGMP-dependent kinase, and the NADPH oxidase. To analyze the contribution of the renin-angiotensin system to oxidative stress, CHF hamsters were treated with the angiotensin-converting enzyme inhibitor captopril for 200 days (120 mg · kg
−1
· d
−1
). CHF led to increased superoxide production by NOSIII and the NADPH oxidase. Decreased NO production in CHF was associated with a decrease in the expression of NOSIII and an inhibition of NO downstream signaling in the aorta. NOSIII expression was increased within the left ventricle. Captopril treatment normalized NOSIII expression in vessels and the myocardium, reduced superoxide levels, and prevented NOSIII uncoupling. Accordingly, endothelial function, NO production, and downstream signaling were improved in CHF vessels.

Conclusions—

Oxidative stress in CHF is mediated by NADPH oxidase and an uncoupled NOSIII secondary to an activation of the renin-angiotensin system leading to impaired NO downstream signaling.
Measures of Oxidized Low-Density Lipoprotein and Oxidative Stress Are Not Related and Not Elevated in Otherwise Healthy Men With the Metabolic Syndrome
Authors: Sjogren Per , Basu Samar , Rosell Magdalena , Silveira Angela , de Faire Ulf , Vessby Bengt , Hamsten Anders , Hellenius Mai-Lis , Fisher Rachel M.
Published: October 2005

Objective—

The metabolic syndrome predisposes to the development of cardiovascular diseases. Oxidative stress and elevated circulating oxidized low-density lipoprotein (LDL) concentrations are related to cardiovascular disease and proposed to be features of the metabolic syndrome. F
2
-isoprostanes are lipid peroxidation products and considered the most reliable biomarkers of oxidative stress.

Methods and Results—

Plasma oxidized LDL (oxLDL) and urinary 8-iso-prostaglandin F
2α
(8-iso-PGF
2α
; the major F
2
-isoprostane) were analyzed in a cross-sectional study of 289 healthy men (62 to 64 years of age). Individuals completed a 7-day dietary record, and fasting plasma insulin, lipid, and lipoprotein concentrations, LDL particle size, and inflammatory markers were determined. National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATPIII) criteria were used to define the metabolic syndrome and individuals were grouped according to the number of risk factors for the metabolic syndrome (0, [n=88; 30%]; ≥1, [n=179; 62%], metabolic syndrome [n=22; 8%]). Group comparisons revealed no differences for oxLDL, 8-iso-PGF
2α
, or reported intake of macronutrients, whereas C-reactive protein and interleukin-6 were increased in the metabolic syndrome. LDL cholesterol strongly determined oxLDL in univariate and multivariate analysis, but no relationship to 8-iso-PGF
2α
was found. In turn, 8-iso-PGF
2α
was related to reported intake of fat, fatty acids, and dietary antioxidants.

Conclusions—

There were no increases in plasma oxLDL or measures of oxidative stress (urinary 8-iso-PGF
2α
) in these otherwise healthy 63-year-old men with the metabolic syndrome. Furthermore, no relationship between oxLDL and 8-iso-PGF
2α
was found, but our results suggest a role for dietary factors in oxidative stress.
Transcriptional Repression of ATP-Binding Cassette Transporter A1 Gene in Macrophages
Authors: Takata Yasunori , Chu Van , Collins Alan R. , Lyon Christopher J. , Wang Wei , Blaschke Florian , Bruemmer Dennis , Caglayan Evren , Daley William , Higaki Jitsuo , Fishbein Michael C. , Tangirala Rajendra K. , Law Ronald E. , Hsueh Willa A.
Published: October 2005

Angiotensin II (Ang II) is a powerful accelerator of atherosclerosis. Herein, we describe a novel transcription mechanism through which Ang II inhibits macrophage expression of the ATP-binding cassette transporter A1 (ABCA1), a key regulator of reverse cholesterol transport. We demonstrate that chronic Ang II infusion substantially promotes macrophage infiltration, foam cell formation, and atherosclerosis in low-density lipoprotein receptor-deficient mice and significantly reduces ABCA1 expression in peripheral macrophages. Administration of the Ang II type 1 receptor blocker valsartan inhibited Ang II-induced ABCA1 mRNA repression, macrophage cholesterol accumulation, and atherosclerosis. Ang II treatment reduced ABCA1 promoter activity of in vitro cultured mouse peritoneal macrophages, inducing fos-related antigen 2 (Fra2) protein binding to an ABCA1 promoter E-box motif, a site known to negatively regulate macrophage ABCA1 transcription. Valsartan pretreatment blocked Fra2 binding to the ABCA1 promoter, and Fra2 small interfering RNA pretreatment attenuated Ang II-mediated ABCA1 transcriptional inhibition, confirming the role of Fra2 in this process. This new evidence suggests that Ang II, a well-known proinflammatory and pro-oxidative factor, alters macrophage cholesterol homeostasis by repressing ABCA1 to promote foam cell formation and atherosclerosis.
Discrepancies Between Nitroglycerin and NO-Releasing Drugs on Mitochondrial Oxygen Consumption, Vasoactivity, and the Release of NO
Authors: Núñez Cristina , Víctor Víctor M. , Tur Remedios , Alvarez-Barrientos Alberto , Moncada Salvador , Esplugues Juan V. , D’Ocón Pilar
Published: October 2005

It has been generally acknowledged that the actions of glyceryl trinitrate (GTN) are a result of its bioconversion into NO. However, recent observations have thrown this idea into doubt, with many studies demonstrating that NO is present only when there are high concentrations of GTN. We have explored this discrepancy by developing a new approach that uses confocal microscopy to directly detect NO. Intracellular levels of NO in the rat aortic vascular wall have been compared with those present after incubation with 3 different NO donors (DETA-NO, 3-morpholinosydnonimine, andS-nitroso-N-acetylpenicillamine), endothelial activation with acetylcholine, or administration of GTN. We have also evaluated the relaxant effects of these treatments on isolated rings of aorta following activation of the enzyme soluble guanylyl cyclase and their inhibitory action on mitochondrial respiration, which is an index of the interaction of NO with the enzyme of the electron transport chain cytochrome C oxidase. In the case of the various NO donors and acetylcholine, we detected a concentration-dependent relationship in the intensity of vascular relaxation and degree of NO fluorescence and an increase in the Michaelis constant (Km) for O2. GTN did not produce similar effects, and although clinically relevant concentrations of this compound caused clear, concentration-related relaxations, there was neither any increase in NO-related fluorescence nor an augmentedKmfor O2. The nature of these differences suggests that these concentrations of GTN do not release free NO but probably a different species that, although it interacts with soluble guanylyl cyclase in vascular smooth muscle, does not inhibit O2consumption by vascular mitochondria.
Dual Pathways for Nuclear Factor κB Activation by Angiotensin II in Vascular Smooth Muscle
Authors: Zhang Liping , Cheng Jizhong , Ma Yewei , Thomas Walter , Zhang Jiqiang , Du Jie
Published: October 2005

Activation of nuclear factor (NF)-κB by angiotensin II (Ang II) plays an essential role in stimulating expression of vascular adhesion molecules, which are essential for vascular inflammation. We report that Ang II activates NF-κB by phosphorylating its p65 subunit via a pathway mediated partially by ribosomal S6 kinase (RSK). In investigating other pathway(s) that may be involved, we found that the ability of Ang II to activate NF-κB in mouse embryonic fibroblast is suppressed (&70%) either by deletion of IκB Kinase (IKK) or by inhibiting or knocking down IKK in vascular smooth muscle cells using a dominant-negative IKK adenovirus or small interference RNA to IKKβ. Thus, Ang II also stimulates NF-κB via IKK. In vitro, we found that Ang II stimulates IKK to phosphorylate myelin basic protein and the p65 subunit of NF-κB. The mechanism by which Ang II activates IKK is to increase phosphorylation of IKKβ in its activation loop (Ser181) rather than IκB phosphorylation. Inhibiting both the RSK and IKK pathways completely blocks the Ang II–induced p65 phosphorylation and NF-κB activation. These 2 pathways are independent: inhibiting IKK does not block Ang II–induced phosphorylation of RSK, whereas inhibiting mitogen-activated protein kinase 1 does not affect phosphorylation of IKK. Finally, we found that Ang II can induce expression of vascular adhesion molecules by 2 pathways; both IKK and RSK lead to phosphorylation of the p65 subunit of NF-κB to increase vascular cell adhesion molecule-1 transcription. The 2 pathways are functionally important because inhibiting IKK and RSK in vascular smooth muscle cells blocks Ang II–induced expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 to limit vascular inflammation.