bluuebunny/crossref_metadata_2025 huggingface dataset:
Stiffness- and relaxation-based quantitation of radial left ventricular oscillations: elucidation of regional diastolic function mechanisms
Authors: Riordan Matt M. , Kovács Sándor J.
Published: January 2007

Traditionally, global and longitudinal (i.e., regional) left ventricular (LV) diastolic function (DF) assessment has utilized features of transmitral Doppler E and A waves or Doppler tissue imaging (DTI)-derived mitral annular E′ and A′ waves, respectively. Quantitation of regional DF has included M-mode echocardiography-based approaches and strain and strain rate imaging (in selected imaging planes), while analysis of mitral annular “oscillations” has recently provided a new window into longitudinal (long-axis) function. The remaining major spatial degree of kinematic freedom during diastole, radial (short-axis) motion, has not been fully characterized, nor has it been exploited for its potential to provide radial LV stiffness ( krad) and relaxation/damping ( crad) indexes. Prior characterization of regional (longitudinal) DF used only annular E′- and A′-wave peak velocities or, alternatively, myocardial strain and strain rate. By kinematically modeling short-axis tissue motion as damped radial oscillation, we present a novel method of estimating krad and crad during early filling. As required by the (near) constant-volume property of the heart and tissue/blood incompressibility, in subjects ( n = 10) with normal DF, we show that oscillation duration-determined longitudinal ( klong and clong) and radial ( klong and crad) parameters are highly correlated ( R = 0.69 and 0.92, respectively). Selected examples of diabetic and LV hypertrophic subjects yield radial ( klong and crad) parameters that differ substantially from controls. Results underscore the utility of the incompressibility-based causal relation between DTI-determined mitral annular long-axis (longitudinal mode) and short-axis (radial mode) oscillations in healthy subjects. Selected pathological examples provide mechanistic insight and illustrate the value and potential role of regional (longitudinal and radial) DF indexes in fully characterizing normal vs. impaired DF states.
Targeting Bladder Tumor CellsIn vivoand in the Urine with a Peptide Identified by Phage Display
Authors: Lee Seung-Min , Lee Eun-Ju , Hong Hai-Yan , Kwon Mi-Kyung , Kwon Tae-Hwan , Choi Je-Yong , Park Rang-Woon , Kwon Tae-Gyun , Yoo Eun-Sang , Yoon Gil-Suk , Kim In-San , Ruoslahti Erkki , Lee Byung-Heon
Published: January 2007

Bladder cancer is one of the most common tumors of the genitourinary tract. Here, we use phage display to identify a peptide that targets bladder tumor cells. A phage library containing random peptides was screened for binding to cells from human bladder tumor xenografts. Phage clones were further selected for binding to a bladder tumor cell line in culture. Six clones displaying the consensus sequence CXNXDXRX/RC showed selective binding to cells from primary human bladder cancer tissue. Of these, the CSNRDARRC sequence was selected for further study as a synthetic peptide. Fluorescein-conjugated CSNRDARRC peptide selectively bound to frozen sections of human bladder tumor tissue, whereas only negligible binding to normal bladder tissue was observed. When the fluorescent peptide was introduced into the bladder lumen, in a carcinogen-induced rat tumor model, it selectively bound to tumor epithelium. Moreover, when the peptide was intravenously injected into the tail vein, it homed to the bladder tumor but was not detectable in normal bladder and control organs. Next, we examined whether the peptide can detect tumor cells in urine. The fluorescent peptide bound to cultured bladder tumor cells but not to other types of tumor cell lines. Moreover, it bound to urinary cells of patients with bladder cancer, while showing little binding to urinary cells of patients with inflammation or healthy individuals. The CSNRDARRC peptide may be useful as a targeting moiety for selective delivery of therapeutics and as a diagnostic probe for the detection of bladder cancer. (Mol Cancer Res 2007;5(1):11–19)
Stromal Cell–Derived Factor-1/Chemokine (C-X-C Motif) Ligand 12 Stimulates Human Hepatoma Cell Growth, Migration, and Invasion
Authors: Sutton Angela , Friand Veronique , Brulé-Donneger Severine , Chaigneau Thomas , Ziol Marianne , Sainte-Catherine Odile , Poiré Aurelie , Saffar Line , Kraemer Michel , Vassy Jany , Nahon Pierre , Salzmann Jean-Loup , Gattegno Liliane , Charnaux Nathalie
Published: January 2007

In addition to their physiologic effects in inflammation and angiogenesis, chemokines are involved in cancer pathology. The aim of this study was to determine whether the chemokine stromal cell–derived factor 1 (SDF-1) induces the growth, migration, and invasion of human hepatoma cells. We show that SDF-1 G protein–coupled receptor, chemokine (C-X-C motif) receptor 4 (CXCR4), and SDF-1 mRNA are expressed in human hepatoma Huh7 cells, which secrete and bind SDF-1. This binding depends on CXCR4 and glycosaminoglycans. SDF-1 associates with CXCR4, and syndecan-4 (SDC-4), a heparan sulfate proteoglycan at the plasma membrane of Huh7 cells, induces the growth of Huh7 cells by promoting their entry into the cell cycle, and inhibits the tumor necrosis factor-α–mediated apoptosis of the cells. SDF-1 also reorganizes Huh7 cytoskeleton and induces tyrosine phosphorylation of focal adhesion kinase. Finally, SDF-1 activates matrix metalloproteinase-9, resulting in increased migration and invasion of Huh7 cells. These biological effects of SDF-1 were strongly inhibited by the CXCR4 antagonist AMD3100, by a glycosaminoglycan, heparin, as well as by β-d-xyloside treatment of the cells, or by c-jun NH2-terminal kinase/stress-activated protein kinase inhibitor. Therefore, the CXCR4, glycosaminoglycans, and the mitogen-activated protein kinase signaling pathways are involved in these events. The fact that reducing SDC-4 expression by RNA interference decreased SDF-1–induced Huh7 hepatoma cell migration and invasion strongly indicates that SDC-4 may be an auxiliary receptor for SDF-1. Finally, the fact that CXCR4 is expressed in hepatocellular carcinoma cells from liver biopsies indicates that the in vitro results reported here could be extended to in vivo conditions. (Mol Cancer Res 2007;5(1):21–33)
A Dominant-Negative Form of the Major Human Abasic Endonuclease Enhances Cellular Sensitivity to Laboratory and Clinical DNA-Damaging Agents
Authors: McNeill Daniel R. , Wilson David M.
Published: January 2007

Apurinic/apyrimidinic (AP) endonuclease 1 (APE1) is the primary enzyme in mammals for the repair of abasic sites in DNA, as well as a variety of 3′ damages that arise upon oxidation or as products of enzymatic processing. If left unrepaired, APE1 substrates can promote mutagenic and cytotoxic outcomes. We describe herein a dominant-negative form of APE1 that lacks detectable nuclease activity and binds substrate DNA with a 13-fold higher affinity than the wild-type protein. This mutant form of APE1, termed ED, possesses two amino acid substitutions at active site residues Glu96 (changed to Gln) and Asp210 (changed to Asn). In vitro biochemical assays reveal that ED impedes wild-type APE1 AP site incision function, presumably by binding AP-DNA and blocking normal lesion processing. Moreover, tetracycline-regulated (tet-on) expression of ED in Chinese hamster ovary cells enhances the cytotoxic effects of the laboratory DNA-damaging agents, methyl methanesulfonate (MMS; 5.4-fold) and hydrogen peroxide (1.5-fold). This MMS-induced, ED-dependent cell killing coincides with a hyperaccumulation of AP sites, implying that excessive DNA damage is the cause of cell death. Because an objective of the study was to identify a protein reagent that could be used in targeted gene therapy protocols, the effects of ED on cellular sensitivity to a number of chemotherapeutic compounds was tested. We show herein that ED expression sensitizes Chinese hamster ovary cells to the killing effects of the alkylating agent 1,3-bis(2-chloroethyl)-1-nitrosourea (also known as carmustine) and the chain terminating nucleoside analogue dideoxycytidine (also known as zalcitabine), but not to the radiomimetic bleomycin, the nucleoside analogue β-d-arabinofuranosylcytosine (also known as cytarabine), the topoisomerase inhibitors camptothecin and etoposide, or the cross-linking agents mitomycin C and cisplatin. Transient expression of ED in the human cancer cell line NCI-H1299 enhanced cellular sensitivity to MMS, 1,3-bis(2-chloroethyl)-1-nitrosourea, and dideoxycytidine, demonstrating the potential usefulness of this strategy in the treatment of human tumors. (Mol Cancer Res 2007;5(1):61–70)
Enoxaparin Reduces H2O2-Induced Activation of Human Endothelial Cells by a Mechanism Involving Cell Adhesion Molecules and Nuclear Transcription Factors
Authors: Manduteanu Ileana , Dragomir Elena , Voinea Manuela , Capraru Monica , Simionescu Maya
Published: January 2007

There are data that document the anti-inflammatory effect of enoxaparin (EP) and its possible antioxidant potential. This study was designed to search for the antioxidant mechanism(s) of EP directly on endothelial cells exposed to an oxidant stimulus. For this purpose cultured human endothelial cells were exposed to nontoxic concentrations of hydrogen peroxide in the presence or absence of EP, and the adhesion of monocytes, the expression of cell adhesion molecules and transcription factors possibly involved in the process were tested. Adhesion assays, ELISA and Western blot analysis revealed that EP reduced monocyte adhesion, ICAM-1 and P-selectin expression, decreased the nuclear levels of c-Jun and p65 proteins, and diminished the phosphorylation of c-Jun protein, MAPK p38 and JNK. Together, the data demonstrate the antioxidant effect of EP and the involvement of ICAM-1, P-selectin, MAPK p38, JNK and the transcription factors NF-ĸB and AP-1 in the mechanism of action of this drug.
The Antinatriuretic Effect of Insulin: An Unappreciated Mechanism for Hypertension Associated with Insulin Resistance?
Authors: Sarafidis Pantelis A. , Bakris George L.
Published: January 2007

Insulin resistance is proposed to be causally related to the metabolic syndrome disorders, but a direct cause-and-effect relationship between insulin resistance and hypertension was not originally obvious. Previous data suggested that insulin promotes sodium retention from the kidney, and thus research efforts focused on this action among several other possible pathways connecting insulin resistance and hyperinsulinemia with hypertension. A review of numerous studies provides evidence that this antinatriuretic effect of insulin is preserved in states of metabolic insulin resistance, representing a major mechanism for blood pressure elevation. More recent experimental and clinical studies have added data about the exact tubular sites of this insulin action, its relation with the respective insulin action on potassium handling, its possible role in the development of salt sensitivity in essential hypertension, as well as the involvement of oxidant stress in these associations. This review summarizes the current state of knowledge in this area and attempts to highlight an important but rather overlooked pathway for hypertension development in the metabolic syndrome, the influence of high insulin levels leading to volume expansion.
Morphological and Morphometric Analysis of the Adrenal Cortex of Androgenized Female Rats
Authors: da Silva Benedito Borges , Lopes-Costa Pedro Vitor , Rosal Marta Alves , Pires Cleicilene Gomes , dos Santos Lina Gomes , Gontijo José Antônio , Alencar Airlane Pereira , de Jesus Simões Manuel
Published: January 2007

Aim: We evaluated the thickness of the adrenal cortex zones of female rats androgenized to mimic polycystic ovary syndrome. Methods: Forty-four female virgin Wistar-Hannover rats were divided into two groups: controls (n = 17) and animals which received testosterone propionate on the 2nd day of life (n = 27). At 90 days of life, after confirmation of persistent estrus, the animals were sacrificed, and the adrenal cortex zones were evaluated. Student’s t test and Levene’s test were used in the statistical analysis (p < 0.05 considered significant). Results: The adrenal glands of the androgenized rats were more voluminous and had a more intensely vascularized zona reticularis than the control animals. The mean thicknesses of zona glomerulosa and zona reticularis in the androgenized rats were 58.4 and 730.7 µm, respectively, significantly thicker than the values in the control group (45.0 and 328.3 µm, respectively). Conclusion: Zona reticularis and zona glomerulosa of the androgenized female rats were significantly thicker than those of the control animals.
Prevalence and Implications of Isolated Microscopic Hematuria in Asymptomatic Chinese Pregnant Women
Authors: Szeto Cheuk-Chun , To Ka-Fai , Lai Fernand Mac-Moune , Chow Kai-Ming , Tam Wing-Hung , Chung Kwok-Yi , Leung Chi-Bon , Lui Siu-Fai , Li Philip Kam-Tao , Lau Tze-Kin
Published: January 2007

Background: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. However, the actual prevalence of microscopic hematuria and IgAN is unknown in the Chinese population. Methods: We screened 7,828 consecutive pregnant women for microscopic hematuria in the antenatal clinic of a tertiary referral center. Persistent microscopic hematuria was defined as urine Hemastix® (Bayer Diagnostics, Hong Kong) of 1+ for red cells in two clinic visits. Subjects were referred to the renal clinic for specialist evaluation, including measurement of blood pressure, serum creatinine, urine bacterial culture, and quantification of proteinuria. Result: There were 207 women (2.64%) with microscopic hematuria. Mean age was 31.8 ± 5.0 years. In 101 patients (48.8%), there was proteinuria >0.1 g/day by quanti- tative assay. Hematuria was found to resolve before or shortly after delivery in 126 (60.9%) and 68 women (32.9%), respectively. Five patients (2.4%) had urinary tract infection proved by repeated urine culture, 1 had papillary necrosis, and 1 had duplex collecting system. Three patients were confirmed to have IgAN by renal biopsy; all had normal blood pressure and serum creatinine, but dysmorphic red cells in urine microscopy, and proteinuria of over 0.5 g/day that persisted after delivery. Renal biopsy on another woman showed no specific pathology. Two women were lost to follow-up, both with normal renal function and no detectable proteinuria. The overall prevalence of IgAN was 38 cases per 100,000 population (95% confidence interval: 8–112 cases). Conclusion: Microscopic hematuria is not uncommon in pregnant women, and IgAN is present in a small proportion of these patients. Further study is needed to determine whether screening for microscopic hematuria would allow early diagnosis and improve the prognosis of these patients.
Osteoprotegerin and RANKL Serum Levels and Their Relationship with Serum Ghrelin in Children with Chronic Renal Failure and on Dialysis
Authors: Ozkaya Ozan , Buyan Necla , Bideci Aysun , Gonen Sevim , Ortac Erol , Fidan Kibriya , Cinaz Peyami , Söylemezoğlu O.
Published: January 2007

Background: Osteoprotegerin (OPG) and receptor activator of the nuclear factor ĸB ligand (RANKL) constitute a complex system of mediators involved in the regulation of bone resorption process. Ghrelin, a growth hormone secretagogue, has been shown to modulate proliferation and differentiation of osteoblasts. The present study was carried out to evaluate the serum concentrations of OPG and sRANKL in children with chronic renal impairment (CRI) and on dialysis, and to establish a possible relationship between their serum levels and that of ghrelin. Methods: 33 patients including 10 patients with CRI, 12 peritoneal dialysis (PD) and 11 hemodialysis (HD) patients and 22 healthy controls were enrolled into the study. OPG, sRANKL and ghrelin levels were studied with radioimmunoassay. Results: Serum OPG levels in CRI, PD and HD groups were significantly higher than the healthy controls (p = 0.002, p < 0.001, p < 0.001, respectively) whereas sRANKL levels were significantly lower than the healthy controls (p = 0.03, p = 0.01, p = 0.001, respectively). Ghrelin levels were significantly higher in CRI, PD and HD groups compared to healthy controls (p = 0.001, p < 0.001, p < 0.001, respectively). We observed a negative correlation between the sRANKL and OPG levels (r = –0.27, p = 0.04) as well as between sRANKL and ghrelin levels (r = –0.31, p = 0.02). OPG levels showed a positive correlation with ghrelin levels (r = 0.63, p < 0.001). Conclusion: We found a lower RANKL bioactivity index in children with CRI and on dialysis. The mechanism and the role of elevated OPG and low sRANKL in uremia are unclear, but they might partly represent a compensatory mechanism to the negative balance of bone remodeling in renal bone disease in children. Additionally, we demonstrated for the first time that ghrelin and the RANKL/OPG system have a close relationship in CRF. Therefore, ghrelin may be of importance in mediating the effects of the RANKL/OPG system in renal bone disease.
Secondary Hyperparathyroidism Is Associated with Higher Cost of Care among Chronic Kidney Disease Patients with Cardiovascular Comorbidities
Authors: Khan Samina
Published: January 2007

Background: Chronic kidney disease (CKD) is associated with high morbidity and mortality, and incurs a substantial cost. Secondary hyperparathyroidism (SHPT) is a major complication associated with CKD and has been linked with cardiovascular disease, leading to poor outcomes. Methods: We analyzed retrospective studies for the prevalence of congestive heart failure (CHF) and acute myocardial infarction/ischemic heart disease (AMI/IHD) in pre-dialysis CKD patients to estimate the additional hospitalization cost incurred secondary to high parathyroid hormone (PTH) levels. Two models were developed to estimate the contribution of elevated PTH levels towards hospitalization costs in CKD patients with CHF and AMI/IHD. Results: Cost contributions were estimated for the time intervals relative to initiation of dialysis, with the largest contributions estimated for the 3- to 1-month period prior to initiation of dialysis, USD 205.24 per patient-month at risk for CHF and USD 69.44–111.75 per patient-month at risk for AMI/IHD, without and with major complications, respectively. Conclusion: Higher PTH levels are associated with a high prevalence of CHF and AMI/IHD. Our cost analyses show that elevated PTH levels contribute significantly toward the overall cost of care among CKD patients with CHF and AMI/IHD. The contribution of elevated PTH levels toward hospitalization cost is highest during the months directly leading up to initiation of dialysis. Further studies are required to evaluate the relationship between hyperparathyroidism and cardiovascular disease, and its impact on economic outcomes.
Plasma Levels of Leptin Are Associated with the Plasma Levels of LDL Conjugated Dienes in Children
Authors: Shin Min-Jeong , Park Eunju
Published: January 2007

Background: Plasma leptin has been suggested to be involved in the proatherogenic process by increasing oxidative stress. We investigated the relationship between leptin and plasma conjugated diene formation, a measure of LDL oxidation in vivo in schoolchildren. Methods: We measured blood lipid profiles, plasma antioxidant vitamins, leptin and diene conjugation in LDL of 118 Korean children (35 overweight-obese vs. 83 normal weight children). Results: The overweight-obese children showed significantly higher levels of leptin (p < 0.0001), conjugated dienes (p = 0.02), total cholesterol (p < 0.05), triglyceride (p < 0.005) and LDL cholesterol (p < 0.01) and a significantly lower level of plasma lycopene (p < 0.0001) compared with the normal weight children. When all the subjects were classified into the three groups by tertiles of leptin levels, significant differences in circulating conjugated dienes (p < 0.05), lipid-corrected lycopene (p < 0.05), total cholesterol (p < 0.05), triglyceride (p < 0.05) and LDL cholesterol (p < 0.05) were found among the three groups. Conclusion: Our results showed that leptin was positively associated with the LDL conjugated diene formation, which might be related to the proatherogenic process in schoolchildren.
Mechanism and Rate of Middle Ear Fluid Absorption
Authors: Petrova Petia , Freeman Sharon , Sohmer Haim
Published: January 2007

Several mechanisms have been suggested to explain the clearance of fluids from the middle ear. These include a pumping action through the eustachian tube, mucociliary beating through the tube, outflow of water to the blood due to osmotic gradients and an active Na+ transport driving water absorption. In order to assess these mechanisms, the middle ear cavity of paralyzed, ventilated (eustachian tube occluded) guinea pigs was filled with fluids varying in osmotic pressure (hypotonic, isotonic, hypertonic) to which a vertical tube was attached. The change in height of fluid in the tube was taken as a measure of changes in middle ear fluid volume. A greater fluid volume reduction was seen with the hypotonic (1/5 saline) solution. A small volume increase was observed with the hypertonic solution. These results provide evidence that in these experimental conditions, water absorption due to osmotic gradients can contribute to middle ear fluid clearance.
Ganglioneuroma of the Internal Auditory Canal: A Case Report
Authors: Ozluoglu Levent Naci , Yilmaz Ismail , Cagici Can Alper , Bal Nebil , Erdogan Bulent
Published: January 2007

Ganglioneuroma is a rare, benign, slow-growing tumor thought to develop from cells of neural crest origin, even though hypotheses on the pathogenesis of that lesion differ. Ganglioneuromas, which do not release excessive catecholamine or steroid hormones, develop primarily in the posterior mediastinum and retroperitoneum. Because of their slow growth, many ganglioneuromas are large when they are diagnosed. In this case report, a 50-year-old woman with hearing loss is described. Magnetic resonance imaging revealed a mass (3 × 4 mm) in the internal auditory canal (IAC). The encapsulated tumor was entirely excised via the middle fossa approach. The results of histopathological examination indicated that the excised lesion was a ganglioneuroma. To our knowledge, this is the first report of a ganglioneuroma of the IAC. We suggest that ganglioneuroma be considered in the differential diagnosis of all tumors of the IAC.
Residual Hearing Thresholds in Cochlear Implantation and Reimplantation
Authors: Di Nardo Walter , Cantore Italo , Cianfrone Francesca , Melillo Pietro , Rigante Mario , Paludetti Gaetano
Published: January 2007

Implant and reimplantation surgery should be carried out with preservation of residual hearing. The aim of this study is to evaluate the effects of such a surgery on hearing threshold. We report the results on 40 patients, 20 males and 20 females, aged between 5 and 70 (mean 29) years, 16 pre-verbal and 24 post-verbal, with measurable pre-operative auditory thresholds. We used the following implants: Advanced Bionics, Med-El, Cochlear, and MXM Digisonic. Four of the patients underwent cochlear reimplantation owing to device failure. A complete insertion was obtained in all patients. Responses to pure-tone stimuli were evaluated in each ear in pre-implant conditions and 3 months after cochlear implant or reimplantation. The explantation was performed with minimal cochlear trauma and preservation of the explanted electrode integrity. 35% showed no change of the hearing threshold, 45% showed a slight worsening of the hearing threshold level in the implanted ear, and 20% had a total loss of residual hearing. Median increases of threshold levels were 10, 5, 10 and 3 dB HL respectively for 125, 250, 500 and 1 kHz. In the group of 4 patients who underwent cochlear reimplantation, 2 showed no variation of the hearing threshold, 1 preserved an appreciable hearing threshold, and 1 had a total loss of residual hearing. The data seem to suggest that hearing function is rather resistant to mechanical trauma during implant and reimplant surgery; the authors hypothesize a role for direct spiral ganglion activation under intense mechanical stimulation.
Identification of Mutations in Members of the Connexin Gene Family as a Cause of Nonsyndromic Deafness in Taiwan
Authors: Yang Jiann-Jou , Huang Shih-Hsin , Chou Kvei-Hsiu , Liao Pei-Ju , Su Ching-Chyuan , Li Shuan-Yow
Published: January 2007

Connexins (Cx), a large family of membrane proteins, are key components of gap junction channels. These channels are critical intercellular pathways through which ions or small molecules are passed, regulating a variety ofphysiological and developmental processes. One of these processes is hearing. In the current study, a genetic survey was made on 380 Taiwanese individuals, 260 with nonsyndromic deafness and 120 with normal hearing. All the 380 Taiwanese were screened for the presence of mutations in 8 genes of the Cx gene family. These genes included Cx26 (GJB2), Cx29 (GJE1), Cx30 (GJB6), Cx30.3 (GJB4), Cx31 (GJB3), Cx32 (GJB1), Cx43 (GJA1) and pseudogene [ρ] of Cx43 (ρ GJA1). Mutations were identified in 7 out of the 8 screened genes of the Cx family from 62 of the 260 deaf subjects (23.85%). Of the 17 mutations observed in the Cx gene family, 11 were novel mutations. Fourteen polymorphisms that were not associated with hearing loss were identified in the Cx gene family. The first 2 most frequently occurring mutations were found in the Cx26 (28/62; 45.16%) and the ρ Cx43 (17/62; 27.42%), respectively. Nine cases of mutations were found in the Cx30.3 (9/62; 14.52%). In the Cx30, 1 novel mutation was identified in 1 case (1/62; 1.61%). Two patients with mutations of each of Cx29 and Cx43 were found (2/62; 3.23%). One novel mutation of Cx31 was identified in 3 patients with nonsyndromic deafness (3/62; 4.84%). The Cx32 was the only gene without detecting any mutation or polymorphism.Our study provides information for understanding the importance of genetic factors in nonsyndromic deafness of the Taiwanese and may be of use in the improvement of genetic diagnosis of hearing loss in Taiwan.
Susceptibility to Tinnitus Revealed at 2 kHz Range by Bilateral Lower DPOAEs in Normal Hearing Subjects with Noise Exposure
Authors: Job Agnès , Raynal Marc , Kossowski Michel
Published: January 2007

We investigated potential markers of susceptibility to tinnitus in a group of normal hearing young pilots aged 25–35 years and with 8 ± 5 years of aircraft noise exposure. 316 pilots were interviewed about their tinnitus status and were tested for hearing thresholds (audiograms) and distortion products otoacoustic emissions (DPOAE-grams). There was no subject with permanent tinnitus. 23% reported having occasionally perceived tinnitus after flight missions and 77% reported never having experienced tinnitus after flight missions. General discomfort in the ears to noise was higher in the occasional tinnitus group (15 vs. 6%). The major finding was that difference of susceptibility to tinnitus in normal hearing subjects exposed to noise on a daily basis seemed to be clearly related to lower DPOAEs, bilaterally, in the 1500- to 2800-kHz range. However, no difference could be observed between groups on audiograms at the 2-kHz frequency range. This study provided evidence of outer hair cell dysfunctions in normal hearing subjects exposed to noise and susceptible to tinnitus. Hypersensitivity to noise and decreased DPOAEs in a non-noise-specific frequency range support the idea of another alteration mechanism than noise itself. This point was discussed in the light of recent publications.
Effects of Dietary Salt Load and Salt Depletion on the Course of Hypertension and Angiotensin II Levels in Male and Female Heterozygous Ren-2 Transgenic Rats
Authors: Husková Zuzana , Kramer Herbert J. , Vaňourková Zdenka , Thumová Monika , Malý Jan , Opočenský Martin , Škaroupková Petra , Kolský Alexander , Vernerová Zdena , Červenka Luděk
Published: January 2007

Background: In the present study we evaluated plasma and kidney angiotensin II (ANG II) levels in female and male Ren-2 transgenic rats (TGR) in comparison to age-matched female and male normotensive Hannover Sprague-Dawley rats. Methods: The rats were maintained on a normal sodium (NS) diet (0.6% NaCl) or fed a high sodium (HS) diet (2% NaCl) for 4 days or were sodium depleted by administration of 40 mg furosemide per liter drinking water overnight followed by 3 days of low sodium diet (0.01% NaCl) (LS + F). ANG II levels were determined by radioimmunoassay. Results: Female TGR at the age of 38 days were already hypertensive and had developed cardiac hypertrophy, whereas male TGR at this age still exhibited a normotensive phenotype. HS diet increased the blood pressure (BP) but did not alter the ANG II levels in TGR at any age. LS + F decreased the BP without significant change in ANG II concentrations in TGR. Female TGR responded to salt loading and salt depletion by more pronounced changes in BP than male TGR. Conclusions: Female TGR develop hypertension more rapidly and the salt-sensitive component of hypertension is more pronounced in female than in male TGR.
Optimizing Intracranial Metastasis Detection for Stereotactic Radiosurgery
Authors: Engh Johnathan A. , Flickinger John C. , Niranjan Ajay , Amin Devin V. , Kondziolka Douglas S. , Lunsford L. Dade
Published: January 2007

Background and Purpose: The authors characterize the detection of additional intracranial metastases in cancer patients at the time of stereotactic radiosurgery (SRS) using a specialized high-resolution magnetic resonance imaging (MRI) protocol. Methods: A retrospective review of 150 consecutive radiosurgical procedures for patients with ≤5 known metastatic intracranial tumors diagnosed using MRI was undertaken at a single center. On the day of SRS, all patients underwent rigid head fixation in a stereotactic frame followed by a specialized MRI using a 3-dimensional fast spoiled-gradient sequence on a 1.5-tesla magnet with double-dose gadolinium. Axial imaging was performed using 2-mm cuts and no gap. Results: Additional metastases were detected in 29.3% of patients. The number of known tumors before SRS was predictive of additional metastases being found (p = 0.014). In multivariate analysis, we more frequently found additional metastases at radiosurgery in patients with 3–5 previously known metastases (p = 0.005), in patients with non-small cell lung cancer (p = 0.012) and in patients with a longer time interval between their diagnostic MRI and their stereotactic MRI (p = 0.030). Age, sex and prior fractionated radiation therapy were not predictive factors. Conclusion:Our specialized protocol of high-resolution, double-dose contrast-enhanced MRI is a reliable method to evaluate the extent of intracranial disease in patients with known brain metastasis. Treatment planning for radiosurgery, radiation therapy and open surgical therapy are all impacted by improved metastasis detection.
Differential Effects of Organic Nitrates on Endothelial Progenitor Cells Are Determined by Oxidative Stress
Authors: Thum Thomas , Fraccarollo Daniela , Thum Sabrina , Schultheiss Maximilian , Daiber Andreas , Wenzel Philip , Munzel Thomas , Ertl Georg , Bauersachs Johann
Published: January 2007

Objective—Reduced levels and impaired function of endothelial progenitor cells (EPCs) foster development and progression of atherosclerotic lesions. Endothelial nitric oxide synthase (eNOS)–derived NO regulates EPC mobilization and function. Organic nitrates release NO, and therefore may favorably affect EPC biology.

Methods and Results—We compared the effects of 2 different nitrates on circulating EPC numbers and function. Treatment of rats with pentaerythritol-trinitrate (PETriN) or isosorbide dinitrate (ISDN) increased circulating EPC levels. EPC from ISDN- but not PETriN-treated animals displayed impaired migratory capacity and increased reactive oxygen species formation in EPCs. In vitro treatment with ISDN reduced migration and incorporation of human EPCs into vascular structures on matrigel, whereas PETriN improved EPC function. ISDN, but not PETriN, increased NADPH oxidase–mediated oxidative stress in cultured human EPCs. Addition of polyethylene-glycolated superoxide dismutase or diphenyliodonium normalized both ISDN-induced superoxide anion production and impaired migratory capacity of EPCs.

Conclusions—Long-acting nitrates increase levels of circulating EPCs, but differ in their effects on EPC function dependent on the induction of intracellular oxidative stress. Organic nitrates that improve EPC function may confer long-term cardiovascular protection based on their beneficial effects on EPC biology.
Vascular Dysfunction and Reduced Circulating Endothelial Progenitor Cells in Young Healthy UK South Asian Men
Authors: Murphy Cliona , Kanaganayagam Gajen S. , Jiang Benyu , Chowienczyk Philip J. , Zbinden Rainer , Saha Mrinal , Rahman Salman , Shah Ajay M. , Marber Michael S. , Kearney Mark T.
Published: January 2007

Objectives—

The objective of this study was to examine determinants of excess coronary artery disease risk in UK South Asians, more prevalent in this population than UK Caucasians, by examining differences in risk factors, vascular function, and endothelial progenitor cells (EPCs).

Methods and Results—

24 South Asian and 25 Caucasian healthy age-matched nonsmoking men were studied. Vascular function was assessed by flow-mediated and GTN brachial artery dilatation and blood flow responses to infusion of ACh, SNP, and L-NMMA. EPC number and function were measured by flow cytometry (CD34, CD133, and KDR positive cells), and CFU/migration assays. Traditional risk factors and anthropometric measurements were similar in the groups. South Asians had higher fasting insulin levels (6.01 versus 3.62 μU/mL;
P
=0.02). South Asians had lower FMD (6.9 versus 8.5%;
P
=0.003), L-NMMA response (0.8 versus 1.3 mL/min/100 mL;
P
=0.03), mean SNP response (9.5±0.6 versus 11.6±0.6;
P
=0.02), EPC number (0.046±0.005% versus 0.085±0.009%;
P
=< 0.001), and CFU ability (CFU 4.29±1.57 versus 18.86±4.00;
P
=0.005). EPC number was the strongest predictor of FMD. Ethnicity was the strongest predictor of EPC number.

Conclusions—

Healthy South Asian men are more insulin resistant, and demonstrate endothelial dysfunction and reduced EPC number and function compared with Caucasians. These abnormalities may contribute to their increased CAD risk.
Cholesterol Enhances Thrombin-Induced Release of Fibroblast Growth Factor-2 in Human Vascular Smooth Muscle Cells
Authors: Rauch Bernhard H. , Scholz Godehard A. , Baumgärtel-Allekotte Dana , Censarek Petra , Fischer Jens W. , Weber Artur-Aron , Schrör Karsten
Published: January 2007

Objective—

The mitogenic response to the G protein–coupled receptor agonist thrombin in human vascular smooth muscle cells (SMCs) depends on release of fibroblast growth factor-2 (FGF-2). Yet, intracellular mechanisms triggering FGF-2 release are unknown. The present study investigates possible effects of cholesterol enrichment and depletion, which have been shown to influence FGF-2–dependent signaling and SMC mitogenesis, on thrombin-induced FGF-2 release.

Methods and Results—

Cultured human aortic and saphenous vein SMCs were enriched with cholesterol by using a cyclodextrin-cholesterol complex. Cholesterol accumulation was determined by a fluorometric assay. ELISA, Western blotting, and RT-PCR were used for quantification of FGF-2 levels. DNA synthesis was determined by [
3
H]-thymidine incorporation, proliferation by cell counting. Stimulation of SMCs with thrombin (30 nmol/L) resulted in release of FGF-2 into the pericellular space within 10 minutes. Preincubation with cyclodextrin-cholesterol caused accumulation of cellular cholesterol, increased thrombin-induced FGF-2 release, and stimulated FGF-2 de novo synthesis. Thrombin-induced DNA synthesis and proliferation were enhanced in cholesterol-rich SMCs. This effect was inhibited by FGF-2-neutralizing antibodies.

Conclusions—

Enhanced cellular cholesterol stimulates thrombin-induced release of FGF-2 and increases the mitogenic response toward thrombin in human SMCs. This mechanism might also be relevant for thrombin-induced mitogenesis in hypercholesterolemia in vivo.
Carbamylated Low-Density Lipoprotein Induces Monocyte Adhesion to Endothelial Cells Through Intercellular Adhesion Molecule-1 and Vascular Cell Adhesion Molecule-1
Authors: Apostolov Eugene O. , Shah Sudhir V. , Ok Ercan , Basnakian Alexei G.
Published: January 2007

Objective—Carbamylated low-density lipoprotein (LDL), the most abundant modified LDL isoform in human blood, has been recently implicated in causing the atherosclerosis-prone injuries to endothelial cells in vitro and atherosclerosis in humans. This study was aimed at testing the hypothesis that carbamylated LDL acts via inducing monocyte adhesion to endothelial cells and determining the adhesion molecules responsible for the recruitment of monocytes.

Methods and Results—Exposure of human coronary artery endothelial cells with carbamylated LDL but not native LDL caused U937 monocyte adhesion and the induction of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 adhesion molecules as measured by cell enzyme-linked immunosorbent assay. Silencing of intercellular adhesion molecule-1 by siRNA or its inhibition using neutralizing antibody resulted in decreased monocyte adhesion to the endothelial cells. Similar silencing or neutralizing of vascular cell adhesion molecule-1 alone did not have an effect but was shown to contribute to intercellular adhesion molecule-1 when tested simultaneously.

Conclusions—Taken together, these data provide evidence that intercellular adhesion molecule-1 in cooperation with vascular cell adhesion molecule-1 are essential for monocyte adhesion by carbamylated low-density lipoprotein-activated human vascular endothelial cells in vitro.
Deficiency of Glutathione Peroxidase-1 Accelerates the Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice
Authors: Torzewski Michael , Ochsenhirt Viola , Kleschyov Andrei L. , Oelze Matthias , Daiber Andreas , Li Huige , Rossmann Heidi , Tsimikas Sotirios , Reifenberg Kurt , Cheng Fei , Lehr Hans-Anton , Blankenberg Stefan , Förstermann Ulrich , Münzel Thomas , Lackner Karl J.
Published: January 2007

Background—

We have recently demonstrated that activity of red blood cell glutathione peroxidase-1 is inversely associated with the risk of cardiovascular events in patients with coronary artery disease. The present study analyzed the effect of glutathione peroxidase-1 deficiency on atherogenesis in the apolipoprotein E-deficient mouse.

Methods and Results—

Female apolipoprotein E-deficient mice with and without glutathione peroxidase-1 deficiency were placed on a Western-type diet for another 6, 12, or 24 weeks. After 24 weeks on Western-type diet, double-knockout mice (GPx-1
−/−
ApoE
−/−
) developed significantly more atherosclerosis than control apolipoprotein E-deficient mice. Moreover, glutathione peroxidase-1 deficiency led to modified atherosclerotic lesions with increased cellularity. Functional experiments revealed that glutathione peroxidase-1 deficiency leads to increased reactive oxygen species concentration in the aortic wall as well as increased overall oxidative stress. Peritoneal macrophages from double-knockout mice showed increased in vitro proliferation in response to macrophage-colony-stimulating factor. Also, we found lower levels of bioactive nitric oxide as well as increased tyrosine nitration as a marker of peroxynitrite production.

Conclusions—

Deficiency of an antioxidative enzyme accelerates and modifies atherosclerotic lesion progression in apolipoprotein E-deficient mice.
Membrane-Type Serine Protease-1/Matriptase Induces Interleukin-6 and -8 in Endothelial Cells by Activation of Protease-Activated Receptor-2
Authors: Seitz Isabell , Hess Sibylle , Schulz Henk , Eckl Robert , Busch Gabriele , Montens Hans Peter , Brandl Richard , Seidl Stefan , Schömig Albert , Ott Ilka
Published: January 2007

Objective—

The serine protease MT-SP1/matriptase plays an important role in cell migration and matrix degradation. Hepatocyte growth factor (HGF), urokinase-type plasminogen activator (uPA), and protease-activated receptor 2 (PAR-2) have been identified as in vitro substrates of MT-SP1/matriptase. Because PAR-2 is expressed in endothelial cells and contributes to inflammatory processes, we sought to investigate the effects of MT-SP1/matriptase on endothelial cytokine expression and analyzed MT-SP1/matriptase expression in vascular cells and atherosclerotic lesions.

Methods and Results—

In endothelial cells, recombinant MT-SP1/matriptase dose-dependently induced interleukin (IL)-8 and IL-6 mRNA and protein expression dependent on its proteolytic activity. MT-SP1/matriptase time-dependently induced phosphorylation of p38 MAPK and p42/44 MAPK. Inhibitor experiments revealed that p38 MAPK and PKCα were necessary for IL-8 induction. PAR-2 downregulation abolished and PAR-2 overexpression augmented MT-SP1/matriptase-induced IL-8 expression as evidence for PAR-2 signaling. In human atherectomies, MT-SP1/matriptase was expressed in blood cells adherent to the endothelium. Concordantly, basal MT-SP1/matriptase expression was detected in isolated monocytes. Coincubation of monocytes and endothelial cells resulted in an increased IL-8 release, which was reduced after downregulation of endothelial PAR-2 and monocytic MT-SP1/matriptase.

Conclusion—

MT-SP1/matriptase induces release of proinflammatory cytokines in endothelial cells through activation of PAR-2. MT-SP1/matriptase is expressed in monocytes, thus, interaction of monocytic MT-SP1/matriptase with endothelial PAR-2 may contribute to atherosclerosis.
Nrf2 Gene Transfer Induces Antioxidant Enzymes and Suppresses Smooth Muscle Cell Growth In Vitro and Reduces Oxidative Stress in Rabbit Aorta In Vivo
Authors: Levonen Anna-Liisa , Inkala Matias , Heikura Tommi , Jauhiainen Suvi , Jyrkkänen Henna-Kaisa , Kansanen Emilia , Määttä Kirsi , Romppanen Elina , Turunen Päivi , Rutanen Juha , Ylä-Herttuala Seppo
Published: January 2007

Background—

Reactive oxygen species (ROS) play a major role in vascular inflammation and pathophysiology of many vascular diseases such as atherosclerosis and injury-induced neointima formation after balloon angioplasty. Nuclear factor E2–related factor-2 (Nrf2) is a transcription factor orchestrating antioxidant and cytoprotective responses on oxidative and electrophilic stress, and it has been shown to have antiinflammatory effects in vascular cells in vitro. We therefore postulated that Nrf2 gene transfer would have salutary effects on vascular inflammation after angioplasty.

Methods and Results—

Transduction of vascular smooth muscle cells (VSMCs) with Nrf2-expressing adenovirus increased the expression of several antioxidant enzymes including heme oxygenase-1 (HO-1) compared with β-galactosidase (AdLacZ)-transduced controls. Moreover, Nrf2 gene transfer also inhibited vascular smooth muscle cell (VSMC) proliferation, and the effect was partially reversed by the HO inhibitor Sn(IV) protoporphyrin. In vivo, adenoviral gene transfer effectively reduced oxidative stress determined by antibody staining against oxidized epitopes of LDL, as well as inhibited vascular inflammation assessed by the macrophage cell count and monocyte chemoattractant protein-1 (MCP-1) staining. However, the antiproliferative effects of Nrf2 in vivo were counterbalanced with diminished apoptosis in neointimal VSMCs, resulting in no change in neointimal hyperplasia.

Conclusions—

Nrf2 gene transfer or Nrf2-inducing drugs may have therapeutic applications in vascular diseases in which inflammation and oxidative stress play a role. However, the contrasting growth inhibitory and antiapoptotic effects of Nrf2 need to be considered in pathological conditions in which SMC proliferation plays a critical role.
Epigenetic Modification of the Renin-Angiotensin System in the Fetal Programming of Hypertension
Authors: Bogdarina Irina , Welham Simon , King Peter J. , Burns Shamus P. , Clark Adrian J.L.
Published: January 2007

Hypertension is a major risk factor for cardiovascular and cerebrovascular disease. Lifelong environmental factors (eg, salt intake, obesity, alcohol) and genetic factors clearly contribute to the development of hypertension, but it has also been established that stress in utero may program the later development of the disease. This phenomenon, known as fetal programming can be modeled in a range of experimental animal models. In maternal low protein diet rat models of programming, administration of angiotensin converting enzyme inhibitors or angiotensin receptor antagonists in early life can prevent development of hypertension, thus implicating the renin-angiotensin system in this process. Here we show that in this model, expression of the AT
1b
angiotensin receptor gene in the adrenal gland is upregulated by the first week of life resulting in increased receptor protein expression consistent with the increased adrenal angiotensin responsiveness observed by others. Furthermore, we show that the proximal promoter of the AT
1b
gene in the adrenal is significantly undermethylated, and that in vitro, AT
1b
gene expression is highly dependent on promoter methylation. These data suggest a link between fetal insults to epigenetic modification of genes and the resultant alteration of gene expression in adult life leading ultimately to the development of hypertension. It seems highly probable that similar influences may be involved in the development of human hypertension.
Suboptimal Control of Atherosclerotic Disease Risk Factors After Cardiac and Cerebrovascular Procedures
Authors: Cheng Eric M. , Asch Steve M. , Brook Robert H. , Vassar Stefanie D. , Jacob Erin L. , Lee Martin L. , Chang Donald S. , Sacco Ralph L. , Hsiao An-Fu , Vickrey Barbara G.
Published: January 2007

Background and Purpose—

Undergoing a carotid endarterectomy, a coronary artery bypass graft, or a percutaneous coronary intervention provides an opportunity to optimize control of blood pressure and low-density lipoprotein.

Methods—

Using Veterans Administration databases, we determined whether patients who underwent a carotid endarterectomy (n=252), coronary artery bypass graft (n=486), or percutaneous coronary intervention (n=720) in 2002 to 2003 at 5 Veterans Administration Healthcare Systems had guideline-recommended control of blood pressure and low-density lipoprotein in 12-month periods before and after a vascular procedure. Postprocedure control of risk factors across procedure groups was compared using χ
2
tests and multivariate logistic regression.

Results—

The proportion of patients undergoing carotid endarterectomy who had optimal control of both blood pressure and low-density lipoprotein increased from 23% before the procedure to 33% after the procedure (
P
=0.05) compared with increases from 32% to 43% for coronary artery bypass graft (
P
=0.001) and from 29% to 45% for percutaneous coronary intervention (
P
=0.002). Compared with the carotid endarterectomy group, the percutaneous coronary intervention group was more likely to achieve optimal control of blood pressure (OR: 1.92, 95% CI: 1.42 to 2.59) or low-density lipoprotein (OR: 1.51, 95% CI: 1.01 to 2.26) and the coronary artery bypass graft group was more likely to achieve optimal control of blood pressure (OR: 1.53, 95% CI: 1.42 to 2.59). Postprocedure cardiology visits, increase in medication intensity, and greater frequency of outpatient visits were also associated with optimal postprocedure risk factor control.

Conclusions—

Although modest improvements in risk factor control were detected, a majority of patients in each vascular procedure group did not achieve optimal risk factor control. More effective risk factor control programs are needed among most vascular procedure patients.