bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Circumcision Status on Periurethral and Glanular Bacterial Flora
Authors: Günşar Cüneyt , Kurutepe Semra , Alparslan Oğuz , Yilmaz Ömer , Dağlar Zafer , Şencan Aydin , Genç Abdülkadir , Taneli Can , Mir Erol
Published: April 2004

Introduction: Circumcision is a historical operation which is still performed for different purposes. The aim of this study is to investigate the changes in periurethral and glanular sulcus flora due to circumcision to determine the role of circumcision on urinary tract infections (UTIs). Patients and Methods: Fifty patients who were circumcised for social-religious reasons between January 2000 and January 2001 were evaluated in this prospective study. Two swabs were taken from the periurethral and glanular sulcus regions both just before circumcision and 4 weeks after, and the bacteria cultured were recorded. Results: We isolated pathogenic bacteria in the periurethral region of 32 (64%) patients (enterococci in 14 cases; Escherichia coli in 12 cases) before circumcision, and this number decreased to 5 (10%) after circumcision. Similarly, pathogenic bacteria were cultured from the glanular sulcus swabs of 33 (68%) patients (enterococci in 14 cases; E. coli in 10 cases), as well as coagulase-negative staphylococci in another 15 patients before circumcision. Following circumcision, we detected pathogenic bacteria in the glanular cultures of only 4 cases, whereas 40 children had non-pathogenic skin flora. Only 1 of 5 children with history of UTIs (n = 1) and retractable phimosis (n = 4) had periurethral pathogenic bacteria (Proteus spp.) in the post-circumcision period. The differences between pre- and post-circumcision values of the pathogenic bacterial colonizations were statistically significant in both groups sampled (p < 0.05). Conclusion: Non-circumcised patients have similar pathogenic bacterial colonizations in the periurethral and the inner preputial regions, although they have no phimosis. The origin of periurethral flora should be the deeper preputial regions. The flora greatly changed with skin commensals after circumcision. Circumcision might be beneficial from this point of view.
Role of Urinary Zinc and Copper on Calcium Oxalate Stone Formation
Authors: Ozgurtas Taner , Yakut Gurer , Gulec Mahir , Serdar Muhittin , Kutluay Turker
Published: April 2004

Introduction: It is considered that many factors may play a role in urolithiasis. Experimental and clinical studies have shown that zinc has an inhibitory effect on urolithiasis. Materials and Methods: In this study, urinary zinc and copper were measured in 27 healthy controls and 30 calcium oxalate stone formers. Results: Urinary zinc excretion was significantly higher (p < 0.001) in stone formers than healthy controls (2,575 ± 274 and 960 ± 80 mg/day, respectively). There was no significant difference in urinary copper excretion between healthy controls and stone formers (32.3 ± 3.5 and 33.3 ± 3.2 µg/day, respectively). Conclusions: According to our results, the potent inhibitory effect of urinary zinc excretion on urolithiasis could be reviewed.
Renal Tubular Alteration by Crystalluria in Stone Disease – An Experimental Study by Means of MDCK Cells
Authors: Lahme S. , Feil G. , Strohmaier W.L. , Bichler K.-H. , Stenzl A.
Published: April 2004

Objectives: Physicochemical properties of urine do not explain the formation of urinary stones. Clinical findings and results of animal experiments suggest that alteration to the renal tubular cell plays a key role in the initiation of urinary stone formation. It is not clear whether this is a primarily intracellular alteration of metabolic origin which, after lysis of the renal tubular cell in the lumen, presents a nucleus for the formation of concretions, or whether in the lumen it is tubular cell damage induced by crystalluria that triggers the formation of urinary stones. Materials and Method: Using Madin-Darby canine kidney cells, the influence of crystalluria on the renal tubular cell was tested in cell cultures. The influence of parathyroid hormone, vitamin D3, oxalate and calcium concentrations and the extent to which these processes can be inhibited by allopurinol and selenium were investigated. Results: Calcium oxalate monohydrate crystals produced reproducible damage to the renal tubular cell which was independent of parathyroid hormone and vitamin D3. The crystalluria-induced effects were unrelated to the oxalate and calcium concentration or the pH. Allopurinol and selenium were able to inhibit the processes. Conclusion: The results indicate secondary involvement of the renal tubular cell in lithogenesis as a result of luminal alteration caused by calcium oxalate crystals. Mechanical damage and interaction between crystal and tubular cell lead to the apposition of crystals. The nephroprotective effect of allopurinol and selenium as antioxidants might explain the benefit of allopurinol found clinically in terms of stone metaphylaxis.
Urological and Surgical Complications in 362 Consecutive Living Related Donor Kidney Transplantations
Authors: Koçak Taner , Nane Ismet , Ander Haluk , Ziylan Orhan , Oktar Tayfun , Ozsoy Cavit
Published: April 2004

Objective: The aim of this study is to review retrospectively the surgical and urological complications encountered in 362 cases of living related donor kidney transplantations (LRDTs). Material and Methods: Between 1983 and 2002, 362 consecutive LRDTs were performed at our institution. The urological and surgical complications were determined in these cases. Results: Overall, urological and surgical complications were encountered in 57 (15.7%) of the renal transplants. Of the 362 patients, urological complications were detected in 29 of them (8.01%), including 5 urinary fistula (with 1 distal ureteral necrosis), 2 ureteric stenosis, 1 renal calculi, 8 symptomatic vesicoureteral reflux and 13 lymphocele requiring intervention. Vascular complications were developed in 5 patients such as renal vein thrombus in 1 and renal arterial stenosis in 4 cases. Wound infection was detected in 6 patients. Fourteen patients underwent surgical explorations due to perinephric hematoma during the early postoperative period. Renal allograft rupture due to accelerated rejection was developed in 2 cases. A lower segmental arterial injury occurred in 1 patient during the operation. Conclusion: LRDT is an important treatment alternative for patients with end-stage renal disease. Many complications may occur after renal transplantations. Our rate of complications is within the range of the current literature. After a modification of our surgical technique, as not dissecting the external iliac artery, the number of lymphoceles has decreased dramatically and with using ureteric stents, we detected a significant decrease in urinary complication rates.
Isolated Late Penile Metastasis of an Adenocarcinoma of the Rectum
Authors: Yilmaz Erdal , Batislam Ertan , Altınok Gülçin , Altınok Deniz , Kara Simay , Başar Murat
Published: April 2004

Penile metastatic tumors are relatively infrequent and very rare compared to extraurogenital tumor metastasis. We present an interesting rare occurrence of a late penile metastasis on an adenocarcinoma of the rectum.
A Retroperitoneal Bronchogenic Cyst: Laparoscopic Treatment
Authors: Ishizuka O. , Misawa K. , Nakazawa M. , Nishizawa O.
Published: April 2004

Subdiaphragmatic bronchogenic cysts are rare, and those located retroperitoneally are exceptional. We describe a retroperitoneal cyst presenting as an asymptomatic adrenal mass which was treated with laparoscopic surgery with three trocars.,
Solitary Neurofibroma of theSpermatic Cord
Authors: Milathianakis Konstantinos N. , Karamanolakis Dimitrios K. , Mpogdanos Ioannis M. , Trihia-Spyrou Eleni I.
Published: April 2004

Neurofibromas, which arise from perineural and Schwann cells, commonly occur throughout the body, but they rarely have been reported to originate from the spermatic cord. The solitary neurofibroma is a localized tumour that, by definition, occurs in patients who do not have von Recklinghausen’s disease. Its exact incidence is unknown because of the difficulty in excluding von Recklinghausen’s disease in some cases. Leiomyomas, lipomas, fibromas, haemangiomas, and epidermoid cysts have been described as benign tumours of the scrotum, but rarely has an extratesticular solitary neurofibroma of the spermatic cord been reported. We report a case of a solitary neurofibroma arising from the left spermatic cord. No signs of von Recklinghausen’s disease were identified.
The Return of Ehrlich’s ‘Therapia magna sterilisans’ and Other Ehrlich Concepts?
Authors: Sörgel F.
Published: April 2004

On March 14th of this year, the birthday of Paul Ehrlich, the great German researcher and ‘founder of chemotherapy’, returned for the 150th time. Interestingly, his later colleague Emil von Behring was born one day later in 1854. Both were coworkers in Robert Koch’s laboratory and became Nobel Prize laureates (for their work in immunology), making great contributions to antiinfectious treatments. Emil von Behring’s approach was through the use of immunological agents, while Ehrlich favored an approach of antiinfectious treatment by chemical agents. Through an ingenious concept that was a clear continuation of his early days in research with dyes, he found the first chemotherapeutic agents. From his dye work, he had concluded the following: if there are dyes that one can use to stain cells, why not develop pharmacological agents that, like stains, also attach to a structure in the living pathogen and kill them. He gave these agents the emotionally charged name ‘magic bullets’. This introductory review will initiate a series of papers on the occasion of Ehrlich’s 150th birthday and the ‘World Conference on Dosing of Antiinfectives: Dosing the Magic Bullets’, which is going to be held in Nürnberg, Germany, from September 9 to 11, 2004 (see www.ehrlich2004.org). Apart from the conference topic, this conference will also commemorate a real science giant of the last century and yet a modest human being whom, as Robert Koch put it, ‘one had to like’. This article recalls Ehrlich’s ingenious concepts, including modern syphilis treatment, one-dose treatment (‘therapia magna sterilisans’) of Helicobacter pylori infections and introduction of an arsenic compound, arsenic trioxide, as well as experiments and new exciting data on Congo red, a well-known ‘non-Ehrlich dye’.
Determination of the Pharmacodynamic Profile of Daptomycin against Streptococcus pneumoniae Isolates with Varying Susceptibility to Penicillin in a Murine Thigh Infection Model
Authors: Dandekar Prachi K. , Tessier Pamela R. , Williams Peter , Zhang Cuilian , Nightingale Charlie H. , Nicolau David P.
Published: April 2004

Background: Daptomycin has demonstrated in vitro activity against gram-positive organisms, including Streptococcus pneumoniae. However, the pharmacodynamic (PD) profile of daptomycin is needed to relate the activity of the drug to biologically achievable concentrations. Methods: The PD profile of daptomycin against four S. pneumoniae isolates was determined using the immunocompromised murine thigh model. Due to the high protein binding of this agent, PD parameters were calculated based on free drug exposures. Efficacy was assessed by the change in log colony-forming units (CFU) in thighs after 24 h of drug treatment. Results: Daptomycin produced a 7.1 (95% confidence interval 7.0–7.2) log10 CFU kill. The ratio between overall drug exposure and the minimum inhibitory concentration (MIC) (AUC/MIC) was the most predictive of the PD parameters. The S. pneumoniae AUC/MIC required for static effects was 12 (95% confidence interval 10–14). Eighty percent and 99% of maximal kill was achieved at ratios of 35 (95% confidence interval 32–39) and 184 (95% confidence interval 160–208), respectively. Conclusion: Clinically achievable serum drug exposures produced by the lowest dose of daptomycin currently studied in humans (4 mg/kg/day) should result in a potent in vivo bactericidal effect against infections due to S. pneumoniae such as bacteremia, where serum drug concentrations adequately reflect the concentration at the site of infection.
Pharmacokinetics of Cationic Liposome-Encapsulated Doxycycline in Mice Challenged with Genital Infection by Chlamydia trachomatis
Authors: Selliah S. , Ravaoarinoro M.
Published: April 2004

Our previous studies demonstrated the efficacy of cationic liposome-encapsulated doxycycline (CaL-DOX) on the course of infection with Chlamydia trachomatis in vitro and in vivo. In this investigation, the pharmacokinetics of CaL-DOX are reported. Female mice inoculated intravaginally with 4.84 × 105 inclusion-forming units were treated intramuscularly, 3 days postinfection, as determined by a preliminary study, with 0.1 ml of unencapsulated doxycycline (DOX) or CaL-DOX, at 10 µg/ml body weight for 3 consecutive days. Sampling was performed at 12, 24, 48, 72 and 96 h after treatment. The microbiological test was used to measure the DOX concentration in sera, liver, kidneys and genital organs. The maximum concentration in kidneys, liver and genital organs was higher in mice treated with DOX than in those treated with CaL-DOX. However, in sera, the amount was similar to that in mice treated with DOX. The DOX concentration found in mice treated with CaL-DOX was much less than in those treated with unencapsulated DOX. This may have a direct impact on the secondary effects caused by the medication. Decreased secondary effects should have a positive outcome on patient physical and mental health. Even if this study is the only one of its kind so far, CaL-DOX could be an alternative solution for the treatment of chlamydial infections.
Serum Bactericidal Activity of Piperacillin/Tazobactam against Staphylococcus aureus, Piperacillin-Susceptible and Piperacillin-Resistant Escherichia coli and Pseudomonas aeruginosa
Authors: Lemmen S.W. , Zolldann D. , Klik S. , Lütticken R. , Kümmerer K. , Häfner H.
Published: April 2004

Background: The serum bactericidal test measures the highest level of an antibiotic-containing serum dilution at which 99.9% of bacteria are killed. In this study the serum bactericidal activity of piperacillin/tazobactam was determined for bacteria often involved in severe infections. In earlier studies titres ≧1:8 in the serum bactericidal tests correlated well with clinical success in the treatment of endocarditis and osteomyelitis as well as bacterial eradication. Methods: Blood samples of 6 healthy volunteers were taken before and 1 and 4 h after piperacillin/tazobactam (4.5 g) administration. Serum concentrations and serum bactericidal activity were determined for 10 strains each of Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli, both piperacillin-resistant and piperacillin-susceptible according to NCCLS guidelines. Results: 100% of S. aureus and piperacillin-susceptible E. coli, 90% of piperacillin-resistant E. coli and 80% of P. aeruginosa were killed 1 h after drug administration. 4 h after drug administration serum bactericidal activity decreased to 60% for S. aureus, 90% for piperacillin-susceptible E. coli, 80% for piperacillin-resistant E. coli and 30% for P. aeruginosa. Conclusions: Excellent serum bactericidal activity of piperacillin/tazobactam was recorded 1 h after drug administration for S. aureus, E. coli and P. aeruginosa. After 4 h limited killing rates for P. aeruginosa could be detected, which supports the idea of a combination therapy.
Interference by Anti-Cancer Chemotherapeutic Agents in the MTT-Tumor Chemosensitivity Assay
Authors: Ulukaya Engin , Colakogullari Mukaddes , Wood Edward J.
Published: April 2004

Background: One of the major goals of oncology is to predict the response of patients with cancer to chemotherapeutic agents by employing laboratory methods variously called ‘tumor chemosensitivity assays’, ‘drug response assays’, or ‘drug sensitivity assays’, in vitro. The MTT assay is one of the methods used to predict the drug response in malignancies. However, it may suffer from interference by the anticancer drugs with the MTT assay. Methods: The MTT assay, a colorimetric viability assay, was checked in a cell-free system in terms of its possible chemical interactions with 22 different anticancer drugs. Results: It was found that epirubicine, paclitaxel, doxetaxel, and cisplatin caused a relatively significant increase in absorbance values, resulting in the MTT assay giving rise to false results (untrue increase in viability) although most of the drugs tested did not seem to cause any significant change. Conclusion: It was concluded that before employing the MTT assay, drugs (or any kind of substances) to be included in the assay should be checked first in terms of possible chemical interactions with MTT, otherwise it may be impossible to evaluate the MTT viability assay results correctly.
Virulence and Cord Blood Mononuclear Cells Cytokine Production Induced by Perinatal Listeria monocytogenes Strains from Different Phylogenetic Lineages
Authors: Mereghetti Laurent , Roche Sylvie M. , Lanotte Philippe , Watt Stéphane , van der Mee-Marquet Nathalie , Velge Philippe , Quentin Roland
Published: April 2004

Some of the phylogenetic lineages of Listeria monocytogenes are more likely to cause invasive disease in humans than are strains from other phylogenetic lineages. This suggests that strains belonging to these lineages display different levels of pathogenicity. To investigate this, we carried out a plaque-forming assay with HT-29 cells to evaluate the virulence of six perinatal strains from the three lineages that compose the species. All of the strains were largely over the 3.34 cutoff (between 4.29 and 5.97 mean log) with the HT-29 model and can therefore be considered to be equally virulent. We also explored part of the immune response of cord blood mononuclear cells by measuring cytokine production. All strains induced the production of similar amounts of TNF-α and IL-1β. High concentrations of IL-6 and IL-8 were produced (between 6,000 and 17,000 pg/ml), whereas little or no IFN-γ or IL-12 was produced. Thus, there is no difference between the strains from the three genetic lineages in terms of virulence or cytokine response. Given the epidemiological distribution of the serotypes responsible for human listeriosis and the genetic structure of the L. monocytogenes species, our results suggest: (i) that all strains from lineage I (serotypes 1/2b and 4b), a genetically homogeneous subpopulation, have a similar level of pathogenicity, and (ii) that lineage II (serotypes 1/2a and 1/2c), which is genetically more heterogeneous, is composed of strains with different levels of pathogenicity. The ones responsible for invasive diseases, particularly perinatal infections, display a similar level of pathogenicity to lineage-I strains and are not virulence-attenuated strains that can only infect the most immunocompromised hosts, whereas the other lineage-II strains are probably less pathogenic for humans.
No Evidence for a Genetic Relationship between Alzheimer’s Disease and Longevity
Authors: Heun Reinhard , Bonsignore Marzia
Published: April 2004

Objective: Late onset Alzheimer’s disease (AD) is frequent in subjects who have reached an age above the average life expectancy. AD and life expectancy are both influenced by genetic factors. Consequently, a possible genetic relationship between AD and longevity was investigated using family study data. Methods: First-degree relatives of patients with AD (n = 645) and of non-demented controls (n = 1,106) were examined by direct interview or by family history in the case of already deceased or unavailable subjects. Survival of subjects with an assumed familial load for AD (i.e. first-degree relatives of AD patients) and of controls was compared using the Kaplan-Meier analysis and log-rank statistics. Results: Relatives with AD reached higher ages than other family members. However, there was no significant co-aggregation of AD and longevity in first-degree relatives of AD patients in comparison with those of controls. This applied to all diseased as well as non-demented relatives. Conclusions: Longevity is an independent prerequisite for the development of the disease, but is not genetically related to AD. The apparent longevity in relatives with AD is likely to result from the selection of subjects fulfilling this prerequisite.
Temporal Lobe Hypoperfusion in Isolated Amnesia with Slow Onset: A Single Photon Emission Computer Tomography Study
Authors: Høgh Peter , Madsen Sjö Nina , Gade Anders , Waldemar Gunhild
Published: April 2004

Single photon emission computer tomography (SPECT) applied early in the course of Alzheimer’s disease (AD) may identify regions with impaired brain function. Moreover, it may be relevant to characterize SPECT perfusion patterns in patients with mild cognitive impairment (MCI), in particular the subgroup of MCI patients with isolated amnesia, as these patients have been demonstrated to convert to AD in more than half of the cases within 3 years. The primary aim of the present study was to characterize the regional cerebral blood flow (CBF) in patients with neuropsychologically verified isolated amnesia. We examined 32 patients (11 men/21 women) with isolated amnesia according to strict neuropsychological criteria and 15 healthy volunteers (11 men/4 women). All subjects had an SPECT-99mTc-d,l-HMPAO perfusion study and neuropsychological assessments. Cranial MRI or CT was performed in all subjects. Semiquantitative (cerebellar relative) flow values were calculated and statistically compared. Patients with isolated amnesia had significant hypoperfusion in several cortical regions of interest compared to control subjects, most prominently in the left temporal cortex. Additionally, there was a trend towards globally reduced CBF in the patients, although this was not significant. These findings may indicate the presence of a progressive degenerative illness affecting multiple brain regions at its early or preclinical stage.
Does the Pattern of Atrophy of the Corpus callosum Differ between Patients with Frontotemporal Dementia and Patients with Alzheimer’s Disease?
Authors: Hensel A. , Ibach B. , Muller U. , Kruggel F. , Kiefer M. , Gertz H.J.
Published: April 2004

The pattern of callosal atrophy might be useful for the differentiation between frontotemporal dementia (FTD) and Alzheimer’s disease (AD) in advanced cases. However, it is unclear whether the pattern of callosal atrophy differs between patients with FTD and patients with AD in mild to moderate stages. Volumetric MR images were recorded from 48 probands (12 with FTD, 12 with late-onset AD, and 24 controls). All patients were in a mild or in a moderate stage. The corpus callosum was divided into five segments. A repeated-measures analysis of variance showed that there was no difference in the pattern of callosal atrophy between the groups. We provide evidence that patients with FTD and patients with late-onset AD do not differ in the pattern of callosal atrophy on condition that: (1) FTD patients and AD patients are in a mild to moderate stage and (2) FTD patients and AD patients differ in age.
CT Brain Findings in Clinical Dementia Investigation – Underestimation of Mixed Dementia
Authors: Nägga Katarina , Rådberg Claes , Marcusson Jan
Published: April 2004

Dementia has been found to display a more heterogeneous clinical picture than previously recognized. We investigated brain changes on computed tomography (CT) in a clinical dementia population consisting of 67 cases with Alzheimer’s disease (AD), 13 with mixed dementia (AD and vascular dementia, VaD), 71 with VaD, and 12 cases that were not demented. Temporal cortical atrophy and atrophy around the temporal horns were more common in patients with mixed dementia compared to patients with VaD and the non-demented, respectively. Frontal white matter changes were present in 64% of AD, in 85% of mixed dementia and in 79% of VaD cases, but there were no differences between the dementia groups. Lacunes were present in almost 40% of AD cases and in 80 and 85% of VaD and mixed dementia cases, respectively. Only 14% of the VaD cases had large infarcts on the CT. We conclude that large infarcts were rare, even in VaD cases. The increased incidence of white matter changes and lacunes in AD patients strongly indicates an underestimation of the mixed dementia diagnosis. More distinct criteria for this diagnostic category are warranted.
Critical Role of Platelet P-Selectin in the Response to Arterial Injury in Apolipoprotein-E–Deficient Mice
Authors: Manka David , Forlow S. Bradley , Sanders John M. , Hurwitz Debra , Bennett Daniel K. , Green Samuel A. , Ley Klaus , Sarembock Ian J.
Published: April 2004

Objective—Mice deficient in apolipoprotein-E (apoE−/−) experience severe hypercholesterolemia that is exacerbated by a high-fat Western-type diet and atherosclerotic lesions spontaneously develop. In addition, we have reported that deficiency of P-selectin dramatically protects against neointimal lesion formation after arterial injury in apoE−/−mice. To define the mechanism, bone marrow transplantation (BMT) after lethal irradiation was used to generate apoE−/−chimeric mice deficient in platelet, but not endothelial, P-selectin.

Methods and Results—Mice underwent vascular injury and were euthanized 4 weeks later. Absence of platelet P-selectin (pPS) expression in apoE−/−mice after BMT was confirmed by flow cytometry and Western blot analysis. Lack of pPS in apoE−/−mice resulted in a 62% reduction in neointimal area (45 000±27 000 versus 17 000±13 000 μm2,P<0.000001) and a 30% reduction (P<0.02) in macrophage infiltration, compared with control apoE−/−BMT. Absence of pPS was also associated with a reduction in plaque neovascularization as compared with pPS-competent controls (0/8 versus 3/8,P<0.05).

Conclusions—Lack of pPS significantly attenuates macrophage recruitment and neointimal lesion formation, indicating that pPS on platelets lining the vessel wall plays a critical role in inflammation after wire-withdrawal injury of the carotid artery in apoE−/−mice.
Ascorbate Supplement Reduces Oxidative Stress in Dyslipidemic Patients Undergoing Apheresis
Authors: Chien Chiang-Ting , Chang Wei-Tien , Chen Heui-Wen , Wang Tzung-Dau , Liou Shaw-Yih , Chen Tzay-Jinn , Chang Yen-Lin , Lee Yuan-Teh , Hsu Su-Ming
Published: April 2004

Objective—

The effect of ascorbate treatment on apheresis-induced oxidative stress in uremic and dyslipidemic patients was evaluated.

Methods and Results—

We developed a chemiluminescence-emission spectrum and high-performance liquid chromatography analysis to assess the effect of ascorbate supplement on plasma reactive oxygen species (ROS) scavenging activity and oxidized lipid/protein production in hyperlipidemic and uremic patients undergoing apheresis. Apheresis was efficient in reduction of atherogenic lipoproteins, complement, fibrinogen, soluble intercellular adhesion molecule-1, and oxidative parameters including phosphatidylcholine hydroperoxide (PCOOH), malonaldehyde, methylguanidine, and diotyrosine. Apheresis itself, however, activated leukocytes to increase ROS activity and reduced the plasma ROS scavenging activity. Ascorbate administration selectively diminished apheresis-enhanced H
2
O
2
and inflammatory mediators such as tumor necrosis factor alpha (TNF-α) and monocyte chemoattractant protein-1. Chronically dyslipidemic and uremic patients undergoing biweekly apheresis plus ascorbate treatment had lower levels of C-reactive protein and PCOOH than did those without ascorbate treatment during a 6-month follow-up study period.

Conclusions—

We demonstrate that apheresis with ascorbate treatment provides a therapeutic potential in reducing atherosclerotic risk via inhibition of H
2
O
2
-induced oxidative stress in patients with uremia or dyslipidemia.
Caspase-3 and Tissue Factor Expression in Lipid-Rich Plaque Macrophages
Authors: Hutter Randolph , Valdiviezo Carolina , Sauter Bernhard V. , Savontaus Mikko , Chereshnev Igor , Carrick Francine E. , Bauriedel Gerhard , Lüderitz Berndt , Fallon John T. , Fuster Valentin , Badimon Juan J.
Published: April 2004

Background—

Macrophages associated with arterial wall lipid deposition contribute to inflammatory processes. Tissue factor (TF) has been implicated in the thrombogenicity of atherosclerotic plaques. Intimal cells undergoing apoptosis have been postulated as a source for TF. However, there is only limited knowledge of cell type, plaque component, and conditions associated with TF expression and apoptosis. We examined the hypothesis that macrophages exposed to conditions of lipid-rich plaque undergo apoptosis and express TF.

Methods and Results—

In human carotid (n=15) and coronary (n=6) atherosclerotic plaques, TF and caspase-3 mRNA and protein expression (evaluated by in situ hybridization and immunohistochemistry) were increased significantly in lipid-rich compared with fibrous plaque components (
P
<0.01) and correlated with high macrophage content (
P
<0.05). Double-labeling studies demonstrated colocalization of TF and active caspase-3. In hyperlipidemic mice, expression of TF and active caspase-3 was observed simultaneously and colocalized in neointimal macrophages after arterial injury. In neointima of normolipidemic animals, TF and active caspase-3 were absent after arterial injury. In monocytes cultured in the presence of oxidized LDL, strong induction and colocalization of TF and active caspase-3 were found compared with baseline (
P
<0.05). Both antigens were significantly decreased after cotreatment with a caspase inhibitor (
P
<0.05) and were absent in untreated control cells.

Conclusions—

The expression of TF as the primary cell-associated activator of the coagulation pathway proves to be closely related to macrophages undergoing apoptosis in conditions of lipid-rich plaque, pointing to a key role of lipid content and inflammatory cell viability in determining plaque thrombogenicity.
Upregulation of the CD40/CD40 Ligand Dyad and Platelet-Monocyte Aggregation in Cigarette Smokers
Authors: Harding S.A. , Sarma J. , Josephs D.H. , Cruden N.L. , Din J.N. , Twomey P.J. , Fox K.A.A. , Newby D.E.
Published: April 2004

Background—

Smoking is a potent cardiovascular risk factor and is associated with proinflammatory and prothrombotic responses. The CD40/CD40 ligand (CD40L) dyad and platelet-monocyte aggregation mediate a range of proinflammatory and prothrombotic processes thought to be important in atherothrombosis. We investigated whether expression of the CD40/CD40L dyad and platelet-monocyte aggregation are altered in cigarette smokers.

Methods and Results—

C-reactive protein (CRP), soluble (s) CD40L, and surface expression of CD40L on platelets and T cells and of CD40 on monocytes and platelet-monocyte aggregates were compared in 25 cigarette smokers and 25 age- and gender-matched nonsmokers. Cigarette smokers had increased serum CRP (2.47±2.60 versus 0.94±0.96 mg/L,
P
=0.008) and appeared to have elevated plasma sCD40L (0.8±1.09 versus 0.37±0.21 ng/mL,
P
=0.07) concentrations. Smokers also had increased surface expression of CD40 on monocytes (45.9±7.7% versus 39.9±6.5%,
P
=0.006), of CD40L on platelets (2.9±1.0% versus 2.3±0.6%,
P
=0.03), and of platelet-monocyte aggregates (26.6±10.9% versus 19.7±8.6%,
P
=0.02). Plasma cotinine concentrations correlated with monocyte CD40 expression, platelet CD40L expression, and platelet-monocyte aggregates.

Conclusions—

Cigarette smokers have upregulation of the CD40/CD40L dyad and platelet-monocyte aggregation that may account for the atherothrombotic consequences of this major cardiovascular risk factor.
Overexpression of the 5-Hydroxytryptamine Transporter Gene
Authors: MacLean Margaret R. , Deuchar Graeme A. , Hicks Martin N. , Morecroft Ian , Shen Sanbing , Sheward John , Colston Janet , Loughlin Lynn , Nilsen Margaret , Dempsie Yvonne , Harmar Anthony
Published: April 2004

Background—

Increased serotonin (5-hydroxytryptamine, 5-HT) transporter activity has been observed in human familial pulmonary hypertension.

Methods and Results—

We investigated pulmonary hemodynamics and the development of hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling in mice overexpressing the gene for the 5-HT transporter (5-HTT+ mice). Right ventricular pressure was elevated 3-fold in normoxic 5-HTT+ mice compared with their wild-type controls. Hypoxia-induced increases in right ventricular hypertrophy and pulmonary vascular remodeling were also potentiated in the 5-HTT+ mice. 5-HTT–like immunoreactivity, protein, and binding sites were markedly increased in the lungs from the 5-HTT+ mice. Hypoxia, however, decreased 5-HT transporter immunoreactivity, mRNA transcription, protein, and binding sites in both wild-type and 5-HTT+ mice.

Conclusions—

Increased 5-HT transporter expression causes elevated right ventricular pressures, and this occurs before the onset of right ventricular hypertrophy or pulmonary arterial remodeling. Hypoxia-induced remodeling is, however, increased in 5-HTT+ mice, whereas hypoxia inhibits 5-HTT expression. This provides a unique model that demonstrates differential mechanisms for familial pulmonary arterial hypertension and pulmonary arterial hypertension with hypoxemia.
Cardiac Uptake-1 Inhibition by High Circulating Norepinephrine Levels in Patients with Pheochromocytoma
Authors: Eldadah Basil A. , Pacak Karel , Eisenhofer Graeme , Holmes Courtney , Kopin Irwin J. , Goldstein David S.
Published: April 2004

Neuronal reuptake (uptake-1) constitutes the main route of inactivation of the sympathetic neurotransmitter norepinephrine in the heart and therefore contributes importantly to cardiac sympathetic neuroeffector function. In laboratory animals and in vitro preparations, half saturation of the transporter occurs at norepinephrine concentrations of 0.1 to 1 μmol/L. This study addressed whether endogenous norepinephrine can attain high enough plasma concentrations in humans to inhibit cardiac uptake-1. Patients with increased plasma norepinephrine levels due to pheochromocytoma were assessed by 6-[
18
F]fluorodopamine positron emission tomography. Above an antecubital venous plasma concentration of 3 nmol/L (≈500 pg/mL), left ventricular myocardial 6-[
18
F]fluorodopamine-derived radioactivity varied inversely with the logarithm of the plasma norepinephrine concentration (
r
=−0.77,
P
<0.0001). Reduction of plasma norepinephrine levels by treatment of the pheochromocytoma increased myocardial 6-[
18
F]fluorodopamine-derived radioactivity. At sufficiently high plasma concentrations, endogenous norepinephrine can compete with sympathetic imaging agents for uptake-1. The results call for caution in drawing quantitative conclusions about uptake-1 in the setting of high circulating concentrations of endogenous norepinephrine.
Store-Operated Ca
2+
Entry Activates the CREB Transcription Factor in Vascular Smooth Muscle
Authors: Pulver Renee A. , Rose-Curtis Patricia , Roe Michael W. , Wellman George C. , Lounsbury Karen M.
Published: April 2004

Ca
2+
-regulated gene transcription is a critical component of arterial responses to injury, hypertension, and tumor-stimulated angiogenesis. The Ca
2+
/cAMP response element binding protein (CREB), a transcription factor that regulates expression of many genes, is activated by Ca
2+
-induced phosphorylation. Multiple Ca
2+
entry pathways may contribute to CREB activation in vascular smooth muscle including voltage-dependent Ca
2+
channels and store-operated Ca
2+
entry (SOCE). To investigate a role for SOCE in CREB activation, we measured CREB phosphorylation using immunofluorescence, intracellular Ca
2+
levels using a fluorescence resonance energy transfer (FRET)–based Cameleon indicator, and
c-fos
transcription using RT-PCR. In this study, we report that SOCE activates CREB in both cultured smooth muscle cells and intact arteries. Depletion of intracellular Ca
2+
stores with thapsigargin increased nuclear phospho-CREB levels, intracellular Ca
2+
concentration, and transcription of
c-fos
. These effects were abolished by inhibiting SOCE through lowering extracellular Ca
2+
concentration or by application of 2-aminoethoxydiphenylborate and Ni
2+
. Inhibition of Ca
2+
influx through voltage-dependent Ca
2+
channels using nimodipine partially blocked intact artery responses, but was without effect in cultured smooth muscle cells. Our findings indicate that Ca
2+
entry through store-operated Ca
2+
channels leads to CREB activation, suggesting that SOCE contributes to the regulation of gene expression in vascular smooth muscle.
Localization of Pacemaker Channels in Lipid Rafts Regulates Channel Kinetics
Authors: Barbuti Andrea , Gravante Biagio , Riolfo Monica , Milanesi Raffaella , Terragni Benedetta , DiFrancesco Dario
Published: April 2004

Lipid rafts are discrete membrane subdomains rich in sphingolipids and cholesterol. In ventricular myocytes a function of caveolae, a type of lipid rafts, is to concentrate in close proximity several proteins of the β-adrenergic transduction pathway. We have investigated the subcellular localization of HCN4 channels expressed in HEK cells and studied the effects of such localization on the properties of pacemaker channels in HEK and rabbit sinoatrial (SAN) cells. We used a discontinuous sucrose gradient and Western blot analysis to detect HCN4 proteins in HEK and in SAN cells, and found that HCN4 proteins localize to low-density membrane fractions together with flotillin (HEK) or caveolin-3 (SAN), structural proteins of caveolae. Lipid raft disruption by cell incubation with methyl-β-cyclodextrin (MβCD) impaired specific HCN4 localization. It also shifted the midpoint of activation of the HCN4 current in HEK cells and of
I
f
in SAN cells to the positive direction by 11.9 and 10.4 mV, respectively. These latter effects were not due to elevation of basal cyclic nucleotide levels because the cholesterol-depletion treatment did not alter the current response to cyclic nucleotides. In accordance with an increased
I
f
, MβCD-treated SAN cells showed large increases of diastolic depolarization slope (87%) and rate (58%). We also found that the kinetics of HCN4- and native f-channel deactivation were slower after lipid raft disorganization. In conclusion, our work indicates that pacemaker channels localize to lipid rafts and that disruption of lipid rafts causes channels to redistribute within the membrane and modifies their kinetic properties.
Role of Fibroblast Growth Factor-2 Isoforms in the Effect of Estradiol on Endothelial Cell Migration and Proliferation
Authors: Garmy-Susini B. , Delmas E. , Gourdy P. , Zhou M. , Bossard C. , Bugler B. , Bayard F. , Krust A. , Prats A.C. , Doetschman T. , Prats H. , Arnal J.F.
Published: April 2004

Both 17β-estradiol (E
2
) and fibroblast growth factor-2 (FGF2) stimulate angiogenesis and endothelial cell migration and proliferation. The first goal of this study was to explore the potential link between this hormone and this growth factor. E
2
-stimulated angiogenesis in SC Matrigel plugs in
Fgf2
+/+
mice, but not in
Fgf2
−/−
mice. Cell cultures from subcutaneous Matrigel plugs demonstrated that E
2
increased both migration and proliferation in endothelial cells from
Fgf2
+/+
mice, but not from in
Fgf2
−/−
mice. Several isoforms of fibroblast growth factor-2 (FGF2) are expressed: the low molecular weight 18-kDa protein (FGF2
lmw
) is secreted and activates tyrosine kinase receptors (FGFRs), whereas the high molecular weight (21 and 22 kDa) isoforms (FGF2
hmw
) remains intranuclear, but their role is mainly unknown. The second goal of this study was to explore the respective roles of FGF2 isoforms in the effects of E
2
. We thus generated mice deficient only in the FGF2
lmw
(
Fgf2
lmw−/−
). E
2
stimulated in vivo angiogenesis and in vitro migration in endothelial cells from
Fgf2
lmw−/−
as it did in
Fgf2
+/+
mice. E
2
increased FGF2
hmw
protein abundance in endothelial cell cultures from
Fgf2
+/+
and
Fgf2
lmw−/−
mice. As shown using siRNA transfection, these effects were FGFR independent but involved FGF2-Interacting Factor, an intracellular FGF2
hmw
partner. This is the first report for a physiological role for the intracellular FGF2
hmw
found to mediate the effect of E
2
on endothelial cell migration via an intracrine action.
Neuroprotective Action of Halogenated Derivatives of L-Phenylalanine
Authors: Kagiyama Tomoko , Glushakov Alexander V. , Sumners Colin , Roose Brandy , Dennis Donn M. , Phillips M. Ian , Ozcan Mehmet S. , Seubert Christoph N. , Martynyuk Anatoly E.
Published: April 2004

Background and Purpose—

The aromatic amino acid L-Phenylalanine (L-Phe) significantly and reversibly depresses excitatory glutamatergic synaptic transmission (GST) via a unique set of presynaptic and postsynaptic mechanisms. Therefore, we hypothesized that endogenous derivatives of L-Phe, which display potent antiglutamatergic activity, may safely and efficaciously protect the brain during conditions characterized by overactivation of glutamate receptors.

Methods—

We tested this hypothesis in vitro with a combination of patch-clamp and lactate dehydrogenase (LDH) analyses in rat cultured neurons exposed to simulated ischemia, and in vivo using a rat model of experimental stroke caused by transient middle cerebral artery occlusion (MCAO).

Results—

3,5-diiodo-
l
-tyrosine (DIT) and 3,5-dibromo-
l
-tyrosine (DBrT), endogenous halogenated derivatives of L-Phe, attenuated GST by similar mechanisms as L-Phe, but with greater potency. For example, the IC
50
s for DIT and DBrT to depress the frequency of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptor-mediated mEPSCs were 104.6±14.1 μmol/L and 127.5±13.3 μmol/L, respectively. Depression of GST by DIT and DBrT persisted during energy deprivation. Furthermore, DBrT significantly reduced LDH release in neuronal cultures exposed to oxygen glucose deprivation. In rats subjected to transient MCAO, DBrT decreased the brain infarct volume and neurological deficit score to 52.7±14.1% and 57.1±12.0% of control values, respectively. DBrT neither altered atrioventricular nodal and intraventricular conduction in isolated heart, nor heart rate and blood pressure in vivo.

Conclusions—

DBrT, an endogenous halogenated derivative of L-Phe, shows promise as a representative of a novel class of neuroprotective agents by exerting significant neuroprotection in both in vitro and in vivo models of brain ischemia.
International Comparison of Stroke Cost Studies
Authors: Evers Silvia M.A.A. , Struijs Jeroen N. , Ament André J.H.A. , van Genugten Marianne L.L. , Jager J. (Hans) C. , van den Bos Geertrudis A.M.
Published: April 2004

Purpose—With the rapid international spread of interventions, there is a need to understand the economic implications of these changes and to interpret these economic implications on the international level. The purpose of this study is to systematically compare total health care expenditures on stroke, the costs of stroke per capita, and the distribution of stroke costs within different countries, with special attention to the allocation of resources among different health care facilities.

Methods—Studies for this literature review were selected by conducting a literature search from January 1966 to July 2003. Key methodological, country-related, and monetary issues of the selected stroke cost studies were evaluated using a checklist.

Results—After selection, 25 stroke cost studies were reviewed. Although the selected cost of illness studies used different methodologies, the estimated expenditures for stroke are approximately similar. The proportion of national health care in the 8 countries studied is unequivocal for the more recent studies, ie, ≈3% of total health care expenditures. A shift is observed from the inpatient treatment costs (in the first year) toward outpatient treatment and long-term care costs (in the latter years). Furthermore, it is remarkable that in the studies, little attention is paid to costs borne by the patient and family or to the costs of comorbidity.

Conclusions—This study highlights the importance of studying the economic consequences of stroke and of interpreting the results on the international level. The results of stroke cost studies provide insight into the distribution of the costs of stroke and the impact of stroke on the national expenditure on health care.
Favorable Outcome of Ischemic Stroke in Patients Pretreated with Statins
Authors: Martí-Fàbregas Joan , Gomis Meritxell , Arboix Adrià , Aleu Aitziber , Pagonabarraga Javier , Belvís Robert , Cocho Dolores , Roquer Jaume , Rodríguez Ana , García María Dolores , Molina-Porcel Laura , Díaz-Manera Jordi , Martí-Vilalta Josep-Lluis
Published: April 2004

Background and Purpose—

Statins may be beneficial for patients with acute ischemic stroke. We tested the hypothesis that patients pretreated with statins at the onset of stroke have less severe neurological effects and a better outcome.

Methods—

We prospectively included consecutive patients with ischemic stroke of <24-hour duration. We recorded demographic data, vascular risk factors, Oxfordshire Classification, National Institutes of Health Stroke Scale (NIHSS) score, admission blood glucose and body temperature, cause (Trial of Org 10172 in Acute Treatment [TOAST] criteria), neurological progression at day 3, previous statin treatment, and outcome at 3 months. We analyzed the data using univariate methods and a logistic regression with the dependent variable of good outcome (modified Rankin Scale [mRS] 0 to 1, Barthel Index [BI] 95 to 100).

Results—

We included 167 patients (mean age 70.7±12 years, 94 men). Thirty patients (18%) were using statins when admitted. In the statin group, the median NIHSS score was not significantly lower and the risk of progression was not significantly reduced. Favorable outcomes at 3 months were more frequent in the statin group (80% versus 61.3%,
P
=0.059 with the mRS; 76.7% versus 51.8%,
P
=0.015 with the BI). Predictors of favorable outcome with the BI were: NIHSS score at admission (OR: 0.72; CI: 0.65 to 0.80;
P
<0.0001), age (OR: 0.96; CI: 0.92 to 0.99;
P
=0.017), and statin group (OR: 5.55; CI: 1.42 to 17.8;
P
=0.012).

Conclusions—

Statins may provide benefits for the long-term functional outcome when administered before the onset of cerebral ischemia. However, randomized controlled trials will be required to evaluate the validity of our results.
Increasing Stroke Incidence in Sweden Between 1989 and 2000 Among Persons Aged 30 to 65 Years: Evidence From the Swedish Hospital Discharge Register
Authors: Medin J. , Nordlund A. , Ekberg K.
Published: April 2004

Background and Purpose—

Stroke mortality is decreasing in Sweden, as is the case in other Western European countries. However, both decreases and increases have been reported in Sweden for persons younger than age 65 years. The aim of this study was to compare the incidence of stroke in Sweden between the periods 1989 and 1991 and 1998 and 2000 in persons aged 30 to 65 years.

Methods—

All first-ever stroke patients aged 30 to 65 years in the Swedish Hospital Discharge Register between 1989 and 2000 were included.

Results—

The age-standardized, 3-year average incidence increased by 19%, from 98.9 to 118.0 per 100 000 among men, and by 33%, from 48.4 to 64.4 among women, between 1989 and 1991 and 1998 and 2000. The largest increase was seen among those younger than 60 years. On a county level, the change in age-standardized stroke incidence varied from small decreases (−3%) to large increases (82%).

Conclusion—

Stroke incidence increased in Sweden for both men and women between 1989 and 2000. The increase was larger among women. This calls for action when it comes to studying risk factors and planning for prevention and health promotion and indicates the need for gender-specific studies.