bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel Treatments for Drug-Induced Toxic Epidermal Necrolysis (Lyell’s Syndrome)
Authors: Paquet Philippe , Piérard Gérald E. , Quatresooz Pascale
Published: February 2005

Drug-induced toxic epidermal necrolysis (TEN) is a life-threatening disease characterized by extensive destruction of the epidermis. It apparently results from the formation of specific toxic drug metabolites by the keratinocytes. The mortality rate which averages 25–30% is mainly due to secondary septicemia, and to ionic and metabolic disturbances following loss of epidermal integrity. Apoptosis is the likely mechanism leading to massive keratinocyte death in TEN. Dysregulations in the tumor necrosis factor-α (TNF-α) pathway, CD95 system (Fas ligand, CD95L; Fas receptor, CD95R) and calcium homeostasis in the epidermis are involved in this apoptotic process. An active role has also been ascribed to T lymphocytes, macrophages and factor XIIIa-positive dermal dendrocytes. Despite progress, treatment of TEN remains controversial. In the past, systemic glucocorticoids were used in order to target the inflammatory reaction in TEN. However, there was no evidence for improvement of the healing process, while corticosteroids worsened the prognosis by increasing the risk of septicemia. Only a few cases have been treated with other drugs including cyclophosphamide, pentoxyfilline, thalidomide, anti-TNF-α antibodies and cyclosporin A. In the recent past, some TEN patients were treated with intravenous human immunoglobulins (IVIG). The rationale for such a treatment was to block the CD95 system on keratinocytes. The early promising clinical results of IVIG treatment in TEN were subsequently challenged. This review compares the effectiveness and drawbacks of the major drugs presently used in TEN treatment. Some future prospects in TEN management are also discussed.
In vitro Analysis of Birch-Pollen-Associated Food Allergy by Use of Recombinant Allergens in the Basophil Activation Test
Authors: Erdmann S.M. , Sachs B. , Schmidt A. , Merk H.F. , Scheiner O. , Moll-Slodowy S. , Sauer I. , Kwiecien R. , Maderegger B. , Hoffmann-Sommergruber K.
Published: February 2005

Background: Basophil activation is associated with the expression of CD63. In birch-pollen-associated food allergy to celery, carrot and apple, Bet v 1, Api g 1, Dau c 1 and Mal d 1 are major allergens. Recombinant allergens have not yet been used in the CD63-based basophil activation test (BAT). Objective: To evaluate the feasibility of using recombinant allergens in the BAT in the diagnosis of allergy to apple, carrot and celery and to compare results with routine tests, i.e. skin prick tests (SPTs) and specific IgE. Methods: Thirty-two patients with an oral allergy syndrome induced by apple, carrot or celery and 22 controls were studied. SPTs were performed with native foods. Specific IgE was determined by the CAP method and basophil activation by flowcytometry upon double staining with anti-IgE/anti-CD63 monoclonal antibodies after incubating with purified recombinant Bet v 1, Bet v 2, Api g 1, Dau c 1 and Mal d 1. Results: By the combined use of the BAT and the CAP method, sensitization to Bet v 1 and Bet v 2 was detected in 100 and 25% of all subjects, respectively. Sensitivity of specific IgE for apple, carrot and celery was 60, 70 and 75% with corresponding specificities of 64, 86 and 82%. Sensitivity of the BAT for Mal d 1, Dau c 1 and Api g 1 was 75, 65 and 75% with corresponding specificities of 68, 100 and 77%. Conclusions: The BAT using recombinant allergens provides a valuable new in vitro method for the detection of sensitization to foods. Although double-blind placebo-controlled food challenges remain the gold standard to confirm food allergy, the CD63-based BAT with recombinant allergens may supplement routine tests for allergy diagnosis.
Nasal Eosinophils Display the Best Correlation with Symptoms, Pulmonary Function and Inflammation in Allergic Rhinitis
Authors: Ciprandi Giorgio , Vizzaccaro Andrea , Cirillo Ignazio , Tosca Mariangela , Massolo Alessandro , Passalacqua Giovanni
Published: February 2005

Background: The pathogenesis of allergic rhinitis and its link with asthma are well known. Nevertheless, a complete cross-sectional evaluation of the usually available clinical, functional and immunological parameters has never been made. We assessed nasal symptoms and flow, cytology, cytokines, pulmonary function and methacholine positivity in a large number of patients with pure pollinosis. Methods: Young men presenting at a military hospital for routine follow-up were recruited for the study. They had to suffer from rhinitis alone (without asthma) for at least 2 years and had to have a positive skin prick test to pollens only. During the pollen season, they underwent symptom evaluation, measurement of nasal flow, nasal scraping and lavage (cell count and assay for IL-4, IL-5, IL-8 and IFNγ), pulmonary function tests and methacholine challenge. Results: Fifty subjects (23.7 ± 4.9 years old) were enrolled. All patients had high clinical scores (9.5 ± 1.6) and inflammatory cells (eosinophils: 10.5 ± 4 and neutrophils 21.3 ± 6) and low nasal flow (482 ± 111 ml/s). We found that the number of eosinophils in nasal scrapings highly correlated with all the above-mentioned parameters, including nasal flow, cytokines and spirometric values. A significant positive correlation was found between all inflammatory cells and all cytokines. IL-8, IL-4 and neutrophils displayed only a partial correlation with pulmonary parameters (FEV1, FVC and FEF25–75%), at variance wit IL-5 and eosinophils. Methacholine test positivity significantly correlated with the number of eosinophils in the nasal smear. Conclusion: Eosinophils in the nasal smear display the best correlation with all the clinical and immunological parameters in allergic rhinitis and also correlate well with methacholine response.
Indolent Systemic Mastocytosis with Elevated Serum Tryptase, Absence of Skin Lesions, and Recurrent Severe Anaphylactoid Episodes
Authors: Florian Stefan , Krauth Maria-Theresa , Simonitsch-Klupp Ingrid , Sperr Wolfgang R. , Fritsche-Polanz Robert , Sonneck Karoline , Födinger Manuela , Agis Hermine , Böhm Alexandra , Wimazal Friedrich , Horny Hans-Peter , Valent Peter
Published: February 2005

Background: In contrast to aggressive mastocytosis, patients with indolent systemic mastocytosis (ISM) usually present with urticaria pigmentosa-like skin lesions. In those who lack skin lesions, mastocytosis is often overlooked or confused with endocrinologic, allergic, or other internal disorders. Case Report and Results: We report on a 33-year-old male patient in whom severe hypotensive episodes occurred after contact with ants or yellow jackets. Since no specific IgE was detected, the serum tryptase concentration was measured and found to be clearly elevated (70 ng/ml). Consecutive staging and examination of the bone marrow revealed ISM. The patient was advised to circumvent insect contact, to take antihistamines on demand, and to carry an epinephrine self-injector for emergency events. In a retrospective analysis of 40 patients seen between 1988 and 2003, only 2 had a life-threatening mediator-related episode before ISM was diagnosed. Conclusions: Our report confirms the diagnostic value of tryptase in patients with suspected mastocytosis. In addition, the report suggests that the lack of typical skin lesions does not exclude an indolent form of mastocytosis even if the serum tryptase is clearly elevated. Finally, our case further shows that mastocytosis can be an important differential diagnosis to be considered in patients with unexplained anaphylactoid or other mediator-related symptoms.
Interferon-γ Inhibits in vitro Mobilization of Eosinophils by Interleukin-5
Authors: Park Choon-Sik , Choi Eun Nam , Kim Jung Sun , Choi Yun Sung , Rhim Tai Youn , Chang Hun Soo , Chung Il Yup
Published: February 2005

Background: Th2 cytokines play pivotal roles in allergic inflammation, including eosinophilia, and their actions are antagonized by Th1 cytokines, conferring them therapeutic potential. Methods: In this study, we examined the ability of a number of cytokines to suppress the activation of eosinophils that function as effector cells for allergic airway diseases. Results: Interleukin (IL)-5, IL-6, and tumor necrosis factor (TNF) induced an eosinophil shape change, whereas interferon (IFN)-γ significantly inhibited the shape change. Other cytokines, including IL-1β, IL-4, IL-10 and IL-13, had little or only slightly enhancing or reducing effects on the shape change. We further analyzed the IFN-γ effect, showing that pretreatment with IFN-γ strongly suppressed IL-5-induced eosinophil shape change, and cycloheximide (CHX) abrogated the suppression by IFN-γ, suggesting that new protein synthesis is required for the inhibitory effect by this cytokine. In agreement with these results, IFN-γ blocked the eosinophil migration and ERK phophorylation induced by IL-5, and the addition of CHX restored eosinophil chemotaxis. Conclusions: Collectively, IFN-γ may attenuate eosinophilic inflammation by directly negating eosinophil mobilization.
Functional, Structural, and Neuronal Alterations in Urinary Bladder during Diabetes: Investigations of a Mouse Model
Authors: Poladia Deepali Pitre , Bauer John Anthony
Published: February 2005

Urinary bladder dysfunction is a common complication in diabetes, but the mechanisms involved are undefined and treatment options are limited. Murine models provide opportunities to utilize transgenic technologies for bladder research and here we investigate the functional, structural and neuronal aspects of the bladder in a mouse model of type-1 diabetes. Mice were injected with streptozotocin (150 mg/kg) or vehicle and studied at 5 weeks. Increases in blood glucose and total urine output were observed. In vitro cystometry showed a 2-fold increase in bladder capacity and compliance and decreased intravesical plateau pressure in diabetics versus controls. Bladder structure and composition were evaluated by digital imaging; region-specific changes included increased smooth muscle and urothelium and no change in collagen content. Alterations in cholinergic, adrenergic and nitric oxide-related functional responsiveness were also observed. The prevalence of cholinergic and adrenergic neuronal tracts was determined by immunohistochemistry: decreased vesicular acetylcholine transferase was observed in smooth muscle, whereas tyrosine hydroxylase was increased in the lamina propria, demonstrating a ‘neuronal remodeling’ shift toward pro-relaxant neuronal pathways. These studies demonstrate that this mouse model of diabetes exhibits important features of urinary bladder remodeling that are similar to the findings in humans and other animal models and will therefore be useful for further mechanistic investigations.
Group 13 Allergens as Environmental and Immunological Markers for Grass Pollen Allergy: Studies by Immunogold Field Emission Scanning and Transmission Electron Microscopy
Authors: Grote Monika , Swoboda Ines , Valenta Rudolf , Reichelt Rudolf
Published: February 2005

Background: Polygalacturonases were recently identified as important grass pollen allergens and designated group 13 allergens. The objective of the present study was to investigate the presence of group 13 grass pollen allergens in different grass species, their release and ultrastructural location in dry and hydrated grass pollen. Methods: Nitrocellulose-blotted allergen extracts from 12 wild and cultivated grass genera were probed with a rabbit antiserum raised against purified recombinant timothy grass pollen allergen, Phl p 13. The release kinetics of Phl p 13 from timothy grass pollen hydrated for 0.5 min to 3 h were analyzed by immunoblotting. Phl p 13 was localized in dry and hydrated grass pollen grains by immunogold field emission scanning and transmission electron microscopy. Results: Group 13 allergens were detected in all 12 wild and cultivated grass genera representing the major subfamilies of the Poaceae. Ultrastructurally, the allergen was located in the wall and in the cytoplasm of timothy grass pollen grains. In the cytoplasm, Phl p 13 was associated with polysaccharide particles and as yet undescribed stacks of microtubule-like structures. After hydration in rain water, pollen grains expel cytoplasmic particles of respirable size containing Phl p 13, which becomes detectable in aqueous supernatants already after 0.5 min. Conclusions: Group 13 allergens represent one set of marker allergens which specifically occur in pollen of the major grass subfamilies and are rapidly released in association with respirable particles after pollen hydration. They may be considered as environmental markers for grass pollen exposure and group 13-specific IgE antibodies as immunological markers for genuine grass pollen sensitization.
Characterization of Modified Allergen Extracts by in vitro β-Hexosaminidase Release from Rat Basophils
Authors: Gehlhar Kirsten , Peters Marcus , Brockmann Kirsten , van Schijndel Hans , Bufe Albrecht
Published: February 2005

Background: To date, there is no well-established test available that can be used to measure functional properties of modified allergens (allergoids). Due to the cross-linking process, the IgE-binding capacity of the allergens, normally necessary for their characterization, is lost. The aim of this study was to test whether the rat basophilic leukaemia (RBL) cell assay (β-hexosaminidase release by rat basophils upon allergen stimulation) can be adopted to characterize allergoids and to evaluate the assay for testing allergoids and native allergens as well. Methods: Mice were immunized with native and modified Phleumpratense extracts in the presence of alum. Their sera were used to sensitize RBL-2H3 cells and measure basophil stimulation induced by different allergen extracts in the presence or absence of various additives. Results: Sera containing specific IgE against both extract formulations were obtained. Native as well as modified extracts induced dose-dependent β-hexosaminidase release from RBL cells. Both extracts were used to evaluate the characteristics of the assay, which showed high precision. Storage conditions were chosen to enhance extract degradation, which could be read directly from the altered stimulatory capacity of the extracts. Additives turned out to have diverse effects on the assay, whereas phenol had no measurable effect, alum had an inhibitory effect and glycerol elevated basophil activation. Conclusions: For the first time, a reliable, precise in vitro assay is available that is able to directly measure the properties of modified allergen extracts after their production process. The test is well evaluated and its advantages and limitations are discussed in this report.
Multi-Glycoside of Tripterygium wilfordii Hook f. Ameliorates Proteinuria and Acute Mesangial Injury Induced by Anti-Thy1.1 Monoclonal Antibody
Authors: Wan Yigang , Gu Liubao , Suzuki Koichi , Karasawa Tamaki , Fujioka Yumiko , Han Gi Dong , Koike Hiroko , Kawachi Hiroshi , Shimizu Fujio
Published: February 2005

Background/Aims: Multi-glycoside from Tripterygium wilfordii Hook f. (GTW) is used for various immune and inflammatory diseases including renal diseases represented by mesangial proliferative glomerulonephritis (MsPGN) in China. However, there have been no fundamental studies on the operating mechanism of GTW on MsPGN. The aim of this study is to examine as the first step the effects of GTW on acute injurious process such as mesangial injury and proteinuria in an acute and reversible Thy.1.1 glomerulonephritis (Thy1.1GN) model and then to clarify the action mechanism of GTW at molecular level by examining its effects on various injurious factors in this model. Methods: Thy1.1 GN was induced in rats by a single intravenous injection with 500 µg of anti-Thy1.1 mAb 1-22-3. Daily oral administration of GTW and vehicle as a control was started from 3 days before injection of mAb to the day of sacrifice in each experiment. Fourteen rats were randomly divided into 2 groups, GTW-treated and vehicle-treated groups, and sacrificed on day 14 in experiment 1 or on day 7 in experiment 2 after induction of Thy1.1 GN. Proteinuria was determined on days 1, 3, 5, 7, 10 and 14 in experiment 1 or on 1, 3, 5 and 7 in experiment 2. From blood and kidneys taken at sacrifice, blood biochemical parameters, mesangial morphological changes, glomerular macrophage infiltration, and glomerular mRNA expression of cytokines were examined. Results: In experiment 1, proteinuria and mesangial matrix expansion were significantly attenuated by GTW treatment. In experiment 2, GTW treatment significantly ameliorated proteinuria, mesangial lesions and macrophage accumulation in glomerulus. In addition, it significantly reduced the glomerular expression of mRNA for PDGF, MCP-1 and IL-2. Conclusion: GTW ameliorated not only proteinuria but also mesangial alterations in Thy1.1 GN most likely by reducing expression of injurious cytokines, indicating that GTW has suppressive effects on acute inflammatory changes in glomeruli.
Effect of Heavy Metals on, and Handling by, the Kidney
Authors: Barbier Olivier , Jacquillet Grégory , Tauc Michel , Cougnon Marc , Poujeol Philippe
Published: February 2005

Heavy metals such as cadmium (Cd), mercury (Hg), lead (Pb), chromium (Cr) and platinum (Pt) are a major environmental and occupational hazard. Unfortunately, these non-essential elements are toxic at very low doses and non-biodegradable with a very long biological half-life. Thus, exposure to heavy metals is potentially harmful. Because of its ability to reabsorb and accumulate divalent metals, the kidney is the first target organ of heavy metal toxicity. The extent of renal damage by heavy metals depends on the nature, the dose, route and duration of exposure. Both acute and chronic intoxication have been demonstrated to cause nephropathies, with various levels of severity ranging from tubular dysfunctions like acquired Fanconi syndrome to severe renal failure leading occasionally to death. Very varied pathways are involved in uptake of heavy metals by the epithelium, depending on the form (free or bound) of the metal and the segment of the nephron where reabsorption occurs (proximal tubule, loop of Henle, distal tubule and terminal segments). In this review, we address the putative uptake pathways involved along the nephron, the mechanisms of intracellular sequestration and detoxification and the nephropathies caused by heavy metals. We also tackle the question of the possible therapeutic means of decreasing the toxic effect of heavy metals by increasing their urinary excretion without affecting the renal uptake of essential trace elements. We have chosen to focus mainly on Cd, Hg and Pb and on in vivo studies.
[3H]BQ-123 Binding to Native Endothelin ETA Receptors in Human Astrocytoma 1321N1 Cells and Screening of Potential Ligands
Authors: Griessmeier Kerstin J. , Müller Christa E.
Published: February 2005

Endothelin ETA receptors on the human astrocytoma 1321N1 cell line were characterized in radioligand binding studies using the ETA-selective antagonist radioligand [3H]BQ-123. A membrane preparation of the cell line showed a high expression level of ETA receptors (Bmax = 128 fmol/mg protein). The KD value for [3H]BQ-123 (KD = 2.29 nmol/l) was comparable to that previously determined at the human neuroblastoma cell line SK-N-MC. The specific labeling of ETA receptors on astrocytoma 1321N1 cells by [3H]BQ-123 was confirmed by determining the rank order of potency of a series of agonists and antagonists. A competition assay for the screening of potential ETA ligands was established and a series of new disubstituted imidazo[1,2-c]pyrimidine and pyrimido[1,6-a]pyrimidine derivatives was investigated. Moderate ETA affinity was detected for several derivatives [30–40% inhibition of [3H]BQ-123 binding (3 nmol/l) at a concentration of 10 µmol/l]. Astrocytoma 1321N1 cells natively express relatively high levels of ETA receptors. They are useful for the screening of potential ETA ligands in radioligand binding assays with [3H]BQ-123.
Antimicrobial Resistance and β-Lactamase Production of Clinical Isolates of Prevotella and Porphyromonas Species
Authors: Bahar Hrisi , Torun Müzeyyen Mamal , Demirci Mehmet , Kocazeybek Bekir
Published: February 2005

Background: This study determined the β-lactamase production and the antimicrobial resistance of 72 Prevotella species and 48 Porphyromonas species isolated from different clinical specimens. Methods: All strains were identified using API 32 ID. The β-lactamase production was determined by nitrocefin disks. E test strips of benzylpenicillin, ampicillin + sulbactam, cefoxitin, clindamycin, metronidazole and imipenem were tested for each strain. Results: Nineteen Prevotella melaninogenica, 18 Prevotella intermedia, 16 Prevotella denticola, 11 Prevotella loescheii and 8 Prevotella bivia strains were identified. Four wereclindamycin resistant. The highest β-lactamase production was found at a rate of 68.4% in P. melaninogenica species. Additionally, 33 Porphyromonas asaccharolytica and 15 Porphyromonas gingivalis strains were identified. None of them produced β-lactamase. Conclusion: In view of the emerging antibiotic resistance among anaerobes, the current local susceptibility profile of our Prevotella and Porphyromonas species will establish the basis for additional surveys tracing significant changes in the antimicrobial resistance of our clinical isolates.
Laparoscopic-Assisted Intraperitoneal Chemotherapy for Patients with Scirrhous Gastric Cancer
Authors: Ikeguchi Masahide , Matsumoto Sachiko , Yoshioka Shizue , Murakami Daiki , Kanaji Shingo , Ohro Shotaro , Yamaguchi Ken-ichi , Saito Hiroaki , Tatebe Shigeru , Kondo Akira , Tsujitani Shun-ichi , Kaibara Nobuaki
Published: February 2005

Background: The prognosis for patients with scirrhous gastric cancer (SGC) is extremely poor. To improve the patients’ prognosis, laparoscopic-assisted intraperitoneal chemotherapy (IPC) was introduced for SGC. In this study, we analyzed whether IPC reduced the number of cancer cells in the peritoneal cavity of patients or changed the gene expression levels of cytokines in the peritoneal cavity. We also investigated whether IPC improved the prognosis of patients with SGC. Methods: Total RNA was extracted from 50 ml of peritoneal wash from 11 SGC patients before and after cisplatin-based IPC. The gene expression levels of survivin, c-myc, transforming growth factor-β (TGF-β), interleukin-2 (IL-2), IL-6, and IL-12 were analyzed using real-time reverse transcription-polymerase chain reaction (RT-PCR) assays. Also, carcinoembrionic antigen (CEA) messenger RNA (mRNA) was used to identify the number of gastric cancer cells in peritoneal washes by the real-time RT-PCR method. The gene expression levels of cytokines and the number of cancer cells in the peritoneal cavity were compared before and after cisplatin-based IPC treatment. Results: Before IPC, the gene expression of IL-2 from peritoneal washes of patients was significantly suppressed compared to the controls (p = 0.029); however, other gene expression levels did not differ. In 7 cases, more than 90% of the cancer cells were removed from the peritoneal cavity after cisplatin-based IPC. These 7 cases were named the IPC effective group, and the remaining 4 cases were named the IPC ineffective group. In the IPC effective group, elevated IL-2 and IL-6 genes were detected in 5 (71%) and in 6 (86%) after IPC. The correlation between IPC effectiveness and elevated gene expression after IPC (IL-2: p = 0.137, and IL-6: p = 0.044) was observed. However, the 50% survival period of the IPC effective group (9 months) was not different from that of that of the IPC ineffective group (6 months, p = 0.267). Conclusion: IPC effectiveness may correlate with elevation of gene expression of inflammatory cytokines, such as IL-2 and IL-6 in the peritoneal cavity after IPC. However, the prognostic benefits of IPC for SGC patients remain unclear.
Trichophyton rubrum Isolated from AIDS and Human Immunodeficiency Virus-Infected Patients in São Paulo, Brazil: Antifungal Susceptibility and Extracellular Enzyme Production
Authors: Da Silva B.C.M. , Auler M.E. , Ruiz L.S. , Gandra R.F. , Dos Santos J.I. , Paula C.R. , Yoshioka M.C.N. , Castro L.G.M. , Nunes R.S. , Bouchara J.P. , Larcher G. , Chabasse D. , Gambale W.
Published: February 2005

Background: In order to identify intraspecific variations in Trichophyton rubrum and to correlate them to the immunological status of the host, sixty strains isolated from AIDS, HIV-positive and HIV-negative patients were compared for the production of extracellular enzymes and for their susceptibility to several antifungal drugs. Methods: The isolates were tested for their ability to secrete keratinases, proteinases, phospholipases, lipases and DNases. Likewise, we investigated their susceptibility to amphotericin B, ketoconazole, ciclopiroxolamine, griseofulvin, miconazole and tolnaftate. Results: Variations in the Minimal Inhibitory Concentration (MIC80) values were observed for all antifungals tested, but they were similarly distributed among the three clinical groups. Griseofulvin showed the most prominent differences among the three groups of isolates. Regarding enzyme secretion, all samples secreted keratinases and DNases, while none secreted phospholipases. Proteinases and lipases were secreted by some of them. Conclusions: The differences among isolates of the three groups were not statistically significant and therefore could not be ascribed to a given clinical status. Intraspecific variations similarly occurred in each group, irrespective of the immunological status of the patients.
Combined Electric and Acoustic Stimulation of the Auditory System: Results of a Clinical Study
Authors: Kiefer Jan , Pok Marcel , Adunka Oliver , Stürzebecher Ekkehard , Baumgartner Wolfgang , Schmidt Marcus , Tillein Jochen , Ye Qing , Gstoettner Wolfgang
Published: February 2005

Combined electric and acoustic stimulation (EAS) of the auditory system is a new therapy for patients with severe to profound high- and mid-frequency hearing loss but remaining low-frequency hearing. In a prospective study, 13 patients with low-frequency hearing of better than 60 dB below 1 kHz were implanted with a MED-EL COMBI 40+ cochlear implant. Pure tone thresholds as well as monosyllabic word scores and Hochmair-Schulz-Moser sentences in quiet and in noise were measured with hearing aids, cochlear implant alone and in the combined stimulation mode (EAS) in the same ear. Hearing could be partially preserved in 11 out of the 13 patients. All patients scored significantly higher with cochlear implant alone than with hearing aids. Seven patients scored higher in the EAS mode than with cochlear implant alone for sentences in noise, 4 remained unchanged, and 2 could not use EAS. Synergistic effects of EAS were most prominent for hearing in noise with increases of up to 72% as compared to cochlear implant alone.
Effects of Stimulation Rate on Speech Recognition with Cochlear Implants
Authors: Friesen Lendra M. , Shannon Robert V. , Cruz Rachel J.
Published: February 2005

Phoneme and speech recognition were measured as a function of stimulation pulse rate in 12 listeners with three types of cochlear implants. Identification of consonants and vowels and recognition of words and sentences were measured in 5 Clarion C1 subjects fit with continuous interleaved sampling (CIS) processors having 4 or 8 electrodes, 4 Nucleus 24 subjects fit with CIS processors having 4, 8, 12 or 16 electrodes and 3 Clarion C2 subjects fit with CIS processors with 4, 8, 12 and 16 electrodes. Stimulation rates ranged from 200 to more than 5000 Hz per electrode, depending on the device, number of electrodes used and stimulation strategy. Listeners were also tested on the same materials with their original processor prior to receiving the experimental processors. All testing was done in quiet listening conditions with essentially no practice with the experimental processor prior to data collection. Listeners scored the highest with their original processor. Little difference in speech understanding was observed for listener scores with processors using different stimulation rates. Speech recognition was significantly poorer only at the lowest stimulation rate and at high rates that used noninterleaved pulses. Speech recognition was similar for processors using 8, 12 or 16 electrodes. Only 4-electrode processors produced a significantly poorer performance. These results suggest that patients with present commercial implants are not able to make full use of the number of channels of spectral information delivered by the present speech processors. In addition, the results show no significant change in performance as a function of stimulation rate, suggesting that high stimulation rates do not result in improved access to temporal cues in speech, at least under quiet listening conditions.
Uric Acid, Microalbuminuria and Cardiovascular Events in High-Risk Patients
Authors: Short Robert A. , Johnson Richard J. , Tuttle Katherine R.
Published: February 2005

Background: Elevated levels of serum uric acid and albuminuria are associated with cardiovascular disease, but the relationships have not consistently been demonstrated to be independent of hypertension, other risk factors, or each other. The purpose of this study was to evaluate people at high risk for cardiovascular disease for the influence of uric acid and microalbuminuria on cardiovascular events. Methods: Consecutive consenting patients undergoing elective angiography (n = 316) had coronary artery disease, risk factors, renal function and diuretic use assessed at baseline. Cardiovascular mortality and major clinical events (myocardial infarction, stroke, amputation, and kidney failure) were ascertained over 5 years. Results: Cardiovascular events occurred in 10% of the patients. Significant correlates (p < 0.05) of cardiovascular events with baseline measures included uric acid ≧5.2 mg/dl, total cholesterol ≧200 mg/dl, severe angiographic coronary artery disease, loop diuretic therapy, and diagnosis of hypertension. A stepwise Cox modeling procedure identified uric acid (p = 0.040), the interaction of hypertension and uric acid (p = 0.029), the interaction of total cholesterol and severe coronary artery disease (p = 0.001) and loop diuretic therapy (p = 0.009) as significant independent predictors of events. Although microalbuminuria was not retained in the final multivariate model, it was associated with poorer cardiovascular disease outcomes. The mean event-free survival for albumin-to-creatinine >30 mg/g was 51 months and for albumin-to-creatinine <30 mg/g the mean was 57 months (p = 0.021). Conclusions: Uric acid ≧5.2 mg/dl independently imparted a 3.5-fold increased risk (OR 3.5, 95% CI 1.0–11.9) for cardiovascular death and major clinical events over a 5-year period. Uric acid may be a contributing factor to the progression of atherosclerosis and its complications.
Activation of Hypoxia-Inducible Factor-1 in Bacillary Angiomatosis
Authors: Kempf Volkhard A.J. , Lebiedziejewski Maria , Alitalo Kari , Wälzlein Joo-Hee , Ehehalt Urs , Fiebig Jeannette , Huber Stephan , Schütt Burkhardt , Sander Christian A. , Müller Steffen , Grassl Guntram , Yazdi Amir S. , Brehm Bernhard , Autenrieth Ingo B.
Published: February 2005

Background—

Bartonella
species are the only known bacterial pathogens causing vasculoproliferative disorders in humans (bacillary angiomatosis [BA]). Cellular and bacterial pathogenetic mechanisms underlying the induction of BA are largely unknown.

Methods and Results—

Activation of hypoxia-inducible factor-1 (HIF-1), the key transcription factor involved in angiogenesis, was detected in
Bartonella henselae
–infected host cells in vitro by immunofluorescence, Western blotting, electrophoretic mobility shift, and reporter gene assays and by immunohistochemistry in BA tissue lesions in vivo. Gene microarray analysis revealed that a
B henselae
infection resulted in the activation of genes typical for the cellular response to hypoxia. HIF-1 was essential for
B henselae
–induced expression of vascular endothelial growth factor as shown by inhibition with the use of HIF-1–specific short-interfering RNA. Moreover, infection with
B henselae
resulted in increased oxygen consumption, cellular hypoxia, and decreased ATP levels in host cells. Infection with a pilus-negative variant of
B henselae
did not lead to cellular hypoxia or activation of HIF-1 or vascular endothelial growth factor secretion, suggesting a crucial role of this bacterial surface protein in the angiogenic reprogramming of the host cells.

Conclusions—

B henselae
induces a proangiogenic host cell response via HIF-1. Our data provide for the first time evidence that HIF-1 may play a role in bacterial infections.
Maintenance of Long-Term Clinical Benefit With Sirolimus-Eluting Coronary Stents
Authors: Fajadet Jean , Morice Marie-Claude , Bode Christoph , Barragan Paul , Serruys Patrick W. , Wijns William , Constantini Constantino R. , Guermonprez Jean-Léon , Eltchaninoff Hélène , Blanchard Didier , Bartorelli Antonio , Laarman Gert-Jan , Perin MarcoAntonio , Sousa J. Eduardo , Schuler Gerhard , Molnar Ferenc , Guagliumi Giulio , Colombo Antonio , Ban Hayashi Ernesto , Wülfert Egon
Published: February 2005

Background—

The use of sirolimus-eluting coronary stents has been associated with a nearly complete elimination of restenosis at 6 months and with a very low 1-year incidence of major adverse cardiac events (MACE). This analysis examined whether these beneficial effects persist over the longer term.

Methods and Results—

This multicenter trial randomly assigned 238 patients to revascularization of single, de novo, native coronary artery lesions with sirolimus-eluting versus conventional bare-metal stents. Survival free from target lesion revascularization (TLR), target vessel failure (TVF), and MACE up to 3 years of follow-up was compared between the 2 treatment groups. Complete data sets were available in 94.2% of patients treated with sirolimus-eluting stents and in 94.1% of patients randomized to the control group. The cumulative 1-, 2-, and 3-year event-free survival rates were 99.2%, 96.5%, and 93.7% for TLR and 95.8%, 92.3%, and 87.9% for TVF, respectively, in the sirolimus-eluting stent group, versus 75.9%, 75.9%, and 75.0% for TLR and 71.2%, 69.4%, and 67.3% for TVF in the control group (
P
<0.001 for both comparisons at 3 years). Rates of MACE at 3 years were 15.8% in patients randomly assigned to sirolimus-eluting stents versus 33.1% in patients assigned to bare-metal stents (
P
=0.002). One patient treated with a sirolimus-eluting stent died of a cardiac cause between 12 and 36 months.

Conclusions—

Treatment of de novo coronary stenosis with sirolimus-eluting stents was associated with a sustained clinical benefit and very low rates of TLR and of other MACE up to 3 years after device implantation.
Plaque Instability Frequently Occurs Days or Weeks Before Occlusive Coronary Thrombosis
Authors: Rittersma Saskia Z.H. , van der Wal Allard C. , Koch Karel T. , Piek Jan J. , Henriques José P.S. , Mulder Karla J. , Ploegmakers Johanna P.H.M. , Meesterman Martin , de Winter Robbert J.
Published: February 2005

Background—

Acute ST-elevation myocardial infarction (STEMI) is caused by sudden occlusive coronary thrombosis, after plaque disruption; however, a considerable time interval between plaque disturbance and the onset of symptoms has been suggested. We therefore studied the age of intracoronary thrombi, aspirated during angioplasty in patients with acute STEMI.

Methods and Results—

Percutaneous intracoronary thrombectomy during angioplasty was performed in 211 consecutive STEMI patients within 6 hours after onset of anginal symptoms. The aspirated material was histologically screened on thrombus and plaque components, and thrombus age was classified as fresh (<1 day), lytic thrombus (1 to 5 days), and organized thrombus (>5 days). In all patients, intracoronary-derived material was retrieved in the filter of the collection bottle. Thrombus was identified in 199 (95%) of 211 patients. In 12 patients (5%), only plaque components were identified, and in 85 patients (41%), both thrombus and plaque material were aspirated. In 18 (9%) of 199 patients, the thrombus was organized, and in 70 patients (35%), the thrombus showed lytic changes, whereas in 98 (49%), a completely fresh thrombus was found. In 14 (7%) of 199 patients, the thrombus showed combined features of both fresh thrombus and organized thrombus.

Conclusions—

In at least 50% of patients with acute STEMI, coronary thrombi were days or weeks old. This indicates that sudden coronary occlusion is often preceded by a variable period of plaque instability and thrombus formation, initiated days or weeks before onset of symptoms.
Endothelial Progenitor Cells Are Rapidly Recruited to Myocardium and Mediate Protective Effect of Ischemic Preconditioning via “Imported” Nitric Oxide Synthase Activity
Authors: Ii Masaaki , Nishimura Hiromi , Iwakura Atsushi , Wecker Andrea , Eaton Elizabeth , Asahara Takayuki , Losordo Douglas W.
Published: February 2005

Background—

The function of bone marrow–derived endothelial progenitor cells (EPCs) in repair of ischemic tissue has been the subject of intense scrutiny, and the capacity of these cells to contribute significantly to new blood vessels remains controversial. The possibility that EPCs could act as reservoirs of cytokines has been implied by several observations; however, a specific role for cytokine delivery has not been identified.

Methods and Results—

We performed a series of experiments that revealed the rapid recruitment of EPCs to the myocardium by very short periods of ischemia, so-called ischemic preconditioning. The recruited EPCs express an array of potentially cardioprotective cytokines including nitric oxide synthase isoforms. Bone marrow transplantation studies, using donor marrow null for nitric oxide synthase isoforms, revealed that both endothelial and inducible nitric oxide synthase derived from bone marrow cells play essential roles in the cardioprotective effect that normally occurs after ischemic preconditioning.

Conclusions—

These findings provide novel insights about the role of bone marrow–derived cells in ischemic preconditioning and also reveal that distinct mechanisms regulate recovery after ischemia-reperfusion and chronic ischemic injury.
α-Adrenergic Receptor–Stimulated Hypertrophy in Adult Rat Ventricular Myocytes Is Mediated via Thioredoxin-1–Sensitive Oxidative Modification of Thiols on Ras
Authors: Kuster Gabriela M. , Pimentel David R. , Adachi Takeshi , Ido Yasuo , Brenner Daniel A. , Cohen Richard A. , Liao Ronglih , Siwik Deborah A. , Colucci Wilson S.
Published: February 2005

Background—

α-Adrenergic receptor (αAR)–stimulated hypertrophy in adult rat ventricular myocytes is mediated by reactive oxygen species–dependent activation of the Ras-Raf-MEK1/2-ERK1/2 signaling pathway. Because Ras is known to have redox-sensitive cysteine residues, we tested the hypothesis that αAR-stimulated hypertrophic signaling is mediated via oxidative modification of Ras thiols.

Methods and Results—

The effect of αAR stimulation on the number of free thiols on Ras was measured with biotinylated iodoacetamide labeling. αAR stimulation caused a 48% decrease in biotinylated iodoacetamide–labeled Ras that was reversed by dithiothreitol (10 mmol/L), indicating a decrease in the availability of free thiols on Ras as a result of an oxidative posttranslational modification. This effect was abolished by adenoviral overexpression of thioredoxin-1 (TRX1) and potentiated by the TRX reductase inhibitor azelaic acid. Likewise, αAR-stimulated Ras activation was abolished by TRX1 overexpression and potentiated by azelaic acid. TRX1 overexpression inhibited the αAR-stimulated phosphorylation of MEK1/2, ERK1/2, and p90RSK and prevented cellular hypertrophy, sarcomere reorganization, and protein synthesis (versus β-galactosidase). Azelaic acid potentiated αAR-stimulated protein synthesis. Although TRX1 can directly reduce thiols, it also can scavenge ROS by increasing peroxidase activity. To examine this possibility, peroxidase activity was increased by transfection with catalase, and intracellular reactive oxygen species were measured with dichlorofluorescein diacetate fluorescence. Although catalase increased peroxidase activity ≈20-fold, TRX1 had no effect. Likewise, the αAR-stimulated increase in dichlorofluorescein diacetate fluorescence was abolished with catalase but retained with TRX1.

Conclusions—

αAR-stimulated hypertrophic signaling in adult rat ventricular myocytes is mediated via a TRX1-sensitive posttranslational oxidative modification of thiols on Ras.
Worldwide Survey on the Methods, Efficacy, and Safety of Catheter Ablation for Human Atrial Fibrillation
Authors: Cappato Riccardo , Calkins Hugh , Chen Shih-Ann , Davies Wyn , Iesaka Yoshito , Kalman Jonathan , Kim You-Ho , Klein George , Packer Douglas , Skanes Allan
Published: February 2005

Background—

The purpose of this study was to conduct a worldwide survey investigating the methods, efficacy, and safety of catheter ablation (CA) of atrial fibrillation (AF).

Methods and Results—

A detailed questionnaire was sent to 777 centers worldwide. Data relevant to the study purpose were collected from 181 centers, of which 100 had ongoing programs on CA of AF between 1995 and 2002. The number of patients undergoing this procedure increased from 18 in 1995 to 5050 in 2002. The median number of procedures per center was 37.5 (range, 1 to 600). Paroxysmal AF, persistent AF, and permanent AF were the indicated arrhythmias in 100.0%, 53.0%, and 20.0% of responding centers, respectively. The most commonly used techniques were right atrial compartmentalization between 1995 and 1997, ablation of the triggering focus in 1998 and 1999, and electrical disconnection of multiple pulmonary veins between 2000 and 2002. Of 8745 patients completing the CA protocol in 90 centers, of whom 2389 (27.3%) required >1 procedure, 4550 (52.0%; range among centers, 14.5% to 76.5%) became asymptomatic without drugs and another 2094 (23.9%; range among centers, 8.8% to 50.3%) became asymptomatic in the presence of formerly ineffective antiarrhythmic drugs over an 11.6±7.7-month follow-up period. At least 1 major complication was reported in 524 patients (6.0%).

Conclusions—

The findings of this survey provide a picture of the variable and evolving methods, efficacy, and safety of CA for AF as practiced in a large number of centers worldwide and may serve as a guide to clinicians considering therapeutic options in patients suffering from this arrhythmia.
Predictors of New-Onset Diastolic and Systolic Hypertension
Authors: Franklin Stanley S. , Pio Jose R. , Wong Nathan D. , Larson Martin G. , Leip Eric P. , Vasan Ramachandran S. , Levy Daniel
Published: February 2005

Background—

Factors leading differentially to the development of isolated diastolic (IDH), systolic-diastolic (SDH), and isolated systolic (ISH) hypertension are poorly understood. We examined the relations of blood pressure (BP) and clinical risk factors to the new onset of the 3 forms of hypertension.

Methods and Results—

Participants in the Framingham Heart Study were included if they had undergone 2 biennial examinations between 1953 and 1957 and were free of antihypertensive therapy and cardiovascular disease. Compared with optimal BP (SBP <120 and DBP <80 mm Hg), the adjusted hazard ratios (HRs) for developing new-onset IDH over the ensuing 10 years were 2.75 for normal BP, 3.29 for high-normal BP (both
P
<0.0001), 1.31 (
P
=0.40) for SDH, and 0.61 (
P
=0.36) for ISH. The HRs of developing new-onset SDH were 3.32, 7.96, 7.10, and 23.12 for the normal BP, high-normal BP, ISH, and IDH groups, respectively (all
P
<0.0001). The HRs of developing ISH were 3.26 for normal and 4.82 for high-normal BP (both
P
<0.0001), 1.39 (
P
=0.24) for IDH, and 1.69 (
P
<0.01) for SDH. Increased body mass index (BMI) during follow-up predicted new-onset IDH and SDH. Other predictors of IDH were younger age, male sex, and BMI at baseline. Predictors of ISH included older age, female sex, and increased BMI during follow-up.

Conclusion—

Given the propensity for increased baseline BMI and weight gain to predict new-onset IDH and the high probability of IDH to transition to SDH, it is likely that IDH is not a benign condition. ISH arises more commonly from normal and high-normal BP than from “burned-out” diastolic hypertension.
Impact of Obesity on 24-Hour Ambulatory Blood Pressure and Hypertension
Authors: Kotsis Vasilios , Stabouli Stella , Bouldin Marshall , Low Annette , Toumanidis Savvas , Zakopoulos Nikos
Published: February 2005

The purpose of the present study was to determine the relationship between body mass index (BMI) and parameters derived from 24-hour ambulatory blood pressure monitoring including mean 24-hour daytime and nighttime systolic and diastolic blood pressures, 24-hour daytime and nighttime pulse pressure, mean 24-hour daytime and nighttime heart rate, dipping and nondipping status. 3216 outpatient subjects who visited our hypertension center and were never treated with antihypertensive medication underwent 24-hour blood pressure monitoring. BMI was significantly correlated with clinic systolic and diastolic blood pressures. Significant correlations were also found between BMI and mean 24-hour daytime and nighttime systolic blood pressure, 24-hour daytime and nighttime pulse pressure, and mean 24-hour daytime and nighttime heart rate. In multivariate regression analysis, clinic systolic, diastolic blood pressure, mean 24-hour systolic blood pressure, 24-hour pulse pressure, and high-density lipoprotein were independently correlated with BMI. The incidence of white coat hypertension was higher in overweight and obese patients than in normal weight subjects. Confirmed ambulatory blood pressure hypertension was also found to be higher in overweight and obese individuals compared with normal weight subjects. Our data also highlight the higher incidence of nondipping status in obesity. These findings suggest that obese patients had increased ambulatory blood pressure parameters and altered circadian blood pressure rhythm with increased prevalence of nondipping status.
Cilostazol Inhibits Vascular Smooth Muscle Cell Growth by Downregulation of the Transcription Factor E2F
Authors: Kim Mi-Jung , Park Keun-Gyu , Lee Kyeong-Min , Kim Hye-Soon , Kim So-Yeon , Kim Chun-Soo , Lee Sang-Lak , Chang Young-Chae , Park Joong-Yeol , Lee Ki-Up , Lee In-Kyu
Published: February 2005

Neointimal formation, the leading cause of restenosis, is caused by proliferation of vascular smooth muscle cells (VSMCs). Patients with diabetes mellitus have higher restenosis rates after coronary angioplasty than nondiabetic patients. Cilostazol, a selective type 3 phosphodiesterase inhibitor, is currently used to treat patients with diabetic vascular complications. Cilostazol is a potent antiplatelet agent that inhibits VSMC proliferation. In the present study, we examine whether the antiproliferative effect of cilostazol on VSMCs is mediated by inhibition of an important cell cycle transcription factor, E2F. Cilostazol inhibited the proliferation of human VSMCs in response to high glucose in vitro and virtually abolished neointimal formation in rats subjected to carotid artery injury in vivo. Moreover, the compound suppressed high-glucose–induced E2F–DNA binding activity, and the expression of E2F1, E2F2, cyclin A, and PCNA proteins. These data suggest that the beneficial effects of cilostazol on high-glucose–stimulated proliferation of VSMCs are mediated by the downregulation of E2F activity and expression of its downstream target genes, including E2F1, E2F2, cyclin A, and PCNA.