bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of lung parenchyma as a parametric porous medium
Authors: Lande Boris , Mitzner Wayne
Published: June 2006

The dynamic behavior of the lung in health and disease depends on its viscoelastic properties. To better understand these properties, several mathematical models have been utilized by many investigators. In the present work, we present a new approach that characterizes the dynamics of gas flow into a viscoelastic porous medium that models the lung structure. This problem is considered in terms of the lung input impedance on a macro level and parenchymal tissue impedance on the level of an alveolar wall. We start from a basic theoretical analysis in which macroscopic tissue deformations are represented in accordance with the linearized Navier-Stokes equations. This approach has strong theoretical underpinnings in other situations but has not been applied to analyze the impedance of the inflated lung. Our analysis provides a theoretical basis for analyzing the interaction between flow into the lungs as a biophysical diffusion process and parenchymal viscoelasticity described phenomenologically, within the frameworks of standard viscoelasticity and structural damping. This lung impedance incorporates parameters of porosity, permeability, and viscoelasticity on micro and macro levels of parenchymal tissue. The analysis shows the theoretical basis of the transformation from the impedance of alveolar walls or isolated tissue strips to that of the intact parenchyma. We also show how the loading impedance at the lung boundary may have a significant impact on the dynamic behavior of whole lung viscoelasticity. Our analysis may be useful in directing specific tests of different models and for analyzing experimental measurements of viscoelastic parameters of lung material under normal and pathological conditions.
16th Annual Meeting of the Société Francophone de Primatologie
Authors: Folia Primatologica Editors
Published: June 2006

Introduction: An apparent re-emergence of kernicterus has been recently reported, with some cases occurring in otherwise healthy breastfed newborn. Methods: We describe a case of kernicterus in a term Caucasian newborn. Results: An exceptional polymorphism of UGT1A 1 gene promoter co-existed with asymptomatic inherited spherocytosis, due to erythroid anion exchange (band-3) deficiency. Both concurred to the development of severe neonatal hyperbilirubinaemia. Conclusion: As some cases of kernikterus remain unresolved, haemolytic diseases and bilirubin metabolism disorders should be carefully investigated in unexplained severe neonatal hyperbilirubinaemia.
Social, Political, and Epistemological Aspects of Genetics and Genomics
Authors: Lock Margaret , Cox Susan , d’Agincourt-Canning Lori
Published: June 2006

The papers in this special issue were first given at a conference in Toronto, Canada, in April 2004 entitled ‘Genomics, Genetics, and Society: Bridging the Disciplinary Divides’. The papers fall into four intersecting themes. (1) The introduction of genetic and genomic technologies into communities. (2) Governance, the morals of scientific discourse and policy making. (3) What is a gene? (4) Public knowledge, public trust and improved dialogue between the public and scientists.
Community Genetics and Dignity in Diversity in the Quebec Network of Genetic Medicine
Authors: Scriver Charles R.
Published: June 2006

The Quebec Network of Genetic Medicine (QNGM), implemented in 1971, has been an integrated program of community genetics serving the population (approximately 7.5 million) of Quebec province in Canada. QNGM reported to the Minister of Social Affairs and operated under an umbrella of universal health insurance in the province. The Network’s programs have been run by members of the four university medical schools of the province under the direction of a central committee. A global annual budget was awarded to QNGM from its inception. Among its many programs, QNGM supported: (1) two newborn screening programs (using blood and urine samples) for early diagnosis, treatment and research in phenylketonuria, hereditary tyrosinemia, congenital hypothyroidism, and in a large number of other hereditary metabolic diseases; (2) follow-up of confirmatory diagnostic tests at regional centers, followed by supervision of ambulatory treatment modalities; (3) carrier screening and reproductive counseling for Tay-Sachs and β-thalassemia diseases; (4) a spectrum of feasibility (research) studies (e.g., screening for biotinidase deficiency, neuroblastoma, hemoglobinopathies, and cystic fibrosis) to inform policy decisions. QNGM performed economic analyses of its major programs and followed prevailing ethical guidelines. Its global budget and integrated structure terminated in 1994, although some of its programs continue independently.
From Hype to Mothballs in Four Years: Troubles in the Development of Large-Scale DNA Biobanks in Europe
Authors: Rose Hilary
Published: June 2006

This paper analyses the difficulties experienced by three large European DNA biobanks. The first, Icelandic-based deCode, generated immense commercial interest and intense ethical controversy. As a biotechnology company, deCode succeeded, but the Icelandic Health Sector Data Base failed. The second firm, Swedish UmanGenomics, marketed itself as the ‘ethical’ biotech company. Management problems including the inadequate recognition of intellectual property issues led to the company failing to secure adequate investment. The third and largest, UK Biobank, has, as a non-profit organization, not experienced these problems. But when the product – bio information – is marketed, the issue of ethically acceptable purchasers could well become contentious.
Tracking the Shift to ‘Postgenomics’
Authors: Stotz Karola C. , Bostanci Adam , Griffiths Paul E.
Published: June 2006

Current knowledge about the variety and complexity of the processes that allow regulated gene expression in living organisms calls for a new understanding of genes. A ‘postgenomic’ understanding of genes as entities constituted during genome expression is outlined and illustrated with specific examples that formed part of a survey research instrument developed by two of the authors for an ongoing empirical study of conceptual change in contemporary biology.
How to Foster Citizens’ Statistical Reasoning: Implications for Genetic Counseling
Authors: Kurzenhäuser Stephanie , Hertwig Ralph
Published: June 2006

Objectives: Our aim is to provide an overview of key research findings from cognitive psychology regarding effective ways of communicating statistical information, and to point out the implications of these findings for genetic testing. Method: We review the literature on the presentation of statistical information in diagnostic test results, discuss various representations that invite misunderstandings, and propose alternative representations that foster understanding. Results: Single-event probabilities, conditional probabilities and relative risks are easily misunderstood. Specifying the class of events to which a probability refers and using natural frequency statements improve understanding. Conclusions: Cognitive psychology has identified simple and effective tools for improving statistical reasoning. They can help to improve the public’s understanding of diagnostic test results.
Microhardness as a Predictor of Sound and Carious Dentine Removal Using Alumina Air Abrasion
Authors: Paolinelis G. , Watson T.F. , Banerjee A.
Published: June 2006

Clinical air abrasion is known to remove dental hard tissues effectively. The aim of this study was to quantify and compare the efficiency of alumina air abrasion in the removal of sound and carious dentine. Twelve non-cavitated carious lesions in freshly extracted molars were bisected mesiodistally. The Knoop hardness number (KHN) was measured on the cut sample surface at 250-µm intervals along a line running axially through the centre of the lesion, from the enamel-dentine junction to the pulp including both sound and carious tissue. The cut surface was then abraded over the same path using alumina particles (27 µm). Powder flow rates, pressure, distance and the angle of the nozzle to the tooth were kept constant throughout the experiment. Non-contact surface profilometry and surface analysis software were used to calculate the rate of dentine removal at the site of each KHN measurement. The results showed that dentine Knoop hardness can be used as a predictor of the rate of dentine removal, with a Somers’ D value of 0.826. Carious dentine with a low KHN was removed less efficiently than the hard sound dentine with a higher KHN. Thus, dentists should be aware that air abrasion systems using alumina particles remove healthy dentine more efficiently than carious dentine, with the associated implications for clinical caries excavation and cavity preparation.
Plasma Adiponectin, T94G Gene Polymorphism and PAI-1 in Patients with and without Hypertension
Authors: Jeng Jing-Ren
Published: June 2006

Background: Reduced adiponectin level has been associated with metabolic syndrome, type 2 diabetes, coronary artery disease and gene polymorphisms, but the interrelationships of T94G genotype, plasma adiponectin and plasminogen activator inhibitor-1 (PAI-1) are less understood. Patients and Methods: The T94G genotypes and plasma levels of adiponectin, and PAI-1 were determined in 568 Chinese patients, 212 with and 356 without hypertension, to study the possible associations of T94G genotype, plasma adiponectin, PAI-1 and blood pressure. Results: Hypertensive patients showed significantly lower plasma adiponectin (9.7 ± 11.1 vs. 11.5 ± 10.0 µg/ml, p = 0.04) and higher PAI-1 (p < 0.001) levels but not significantly greater adiponectin TT genotype percentage (38.7 vs. 33.5%) and T allele frequency (0.620 vs. 0.585) than normotensive subjects. Plasma adiponectin was inversely related to PAI-1 activity (r = –0.09, p = 0.03) and antigen (r = –0.202, p < 0.001). Furthermore, the TT genotypic group showed significantly lower plasma adiponectin level (10.4 ± 10.5 vs. 13.4 ± 10.8 µg/ml, p = 0.03) and higher plasma PAI-1 activity (17.0 ± 9.7 vs. 13.5 ± 7.6 IU/ml, p = 0.003) and antigen (32.3 ± 22.7 vs. 25.9 ± 14.7 ng/ml, p = 0.01) than the GG genotypic group. Multiple linear regression analysis in all study subjects, in men and in normotensives documented an impact of adiponectin T94G genotype on plasma levels of adiponectin (p = 0.007, 0.003 and 0.03) and PAI-1 activity (p = 0.02, 0.03 and 0.04) and antigen (p = 0.03, 0.007 and 0.04) after adjustment for potential confounding factors. Conclusions: The present study demonstrated a significant correlation of the TT genotype with lower plasma adiponectin and higher plasma PAI-1 levels in a Chinese population. The contribution of this genotype seemed greater in men and normotensives. It suggested the adiponectin gene T94G polymorphism might affect the regulation of circulating adiponectin and PAI-1.
Impact of Early Initiation of Intravenous Therapy for Acute Decompensated Heart Failure on Outcomes in ADHERE
Authors: Peacock IV W. Frank , Fonarow Gregg C. , Emerman Charles L. , Mills Roger M. , Wynne Janet
Published: June 2006

Background: Since most acute decompensated heart failure (ADHF) patients present for hospital care via the emergency department (ED), we sought to determine the impact of early ED initiation of ADHF-specific therapy, as indicated by nesiritide use, on subsequent outcomes. Methods: We queried the Acute Decompensated Heart Failure National Registry (ADHERE®) to identify patients with initial systolic blood pressure >90 mm Hg and negative cardiac biomarkers, hospitalized after presentation to the ED, who received nesiritide but no other intravenous vasoactive drugs. Intensive care unit use and total hospital length of stay were compared based on the hospital unit where nesiritide therapy was initiated after multivariate adjustment for baseline differences in study populations. Results: Nesiritide was started in the ED in 1,613 patients (EDN group) and after admission to an inpatient unit in 2,687 patients (INN group). EDN patients had higher baseline systolic and diastolic blood pressure (both p < 0.001); while INN patients were more likely to be male and have baseline renal dysfunction (both p < 0.001). Nesiritide was initiated a median of 2.8 and 15.5 h after presentation in EDN and INN patients, respectively (p < 0.001). Compared to INN, EDN patients had a shorter adjusted mean total hospital length of stay (5.4 vs. 6.9 days; p < 0.001), were less likely to require transfer to the intensive care unit from another inpatient unit (odds ratio [OR]: 0.301; 95% confidence interval [CI]: 0.206–0.440), and were more likely to be discharged home (OR: 1.154; 95% CI: 1.005–1.325). Conclusions: Initiation of ADHF-specific therapy early, while the patient is in the ED, is associated with improved clinical outcomes.
Periodontitis Is an Important and Occult Source of Inflammation in Hemodialysis Patients
Authors: Kadiroglu Ali Kemal , Kadiroglu Ela Tules , Sit Dede , Dag Ahmet , Yilmaz M. Emin
Published: June 2006

Aim: To evaluate the association between C-reactive protein (CRP) levels and the periodontal status of hemodialysis (HD) patients. Methods: 41 HD patients on rHuEPO therapy were enrolled in the study. Hematologic and biochemical parameters and CRP levels were recorded. The plaque index, gingival index, probing pocket depth and periodontal disease index were used to identify periodontal disease. The patients were divided into 2 groups: group 1 (n = 21), high CRP, and group 2 (n = 20), normal CRP. Results: After periodontal therapy, while the mean CRP level and erythrocyte sedimentation rate declined from 30.46 to 10.36 (p = 0.001) and from 93.4 to 35.8 mg/l (p = 0.001), respectively, the hemoglobin level increased from 9.4 to 10.6 g/dl (p = 0.009) and hematocrit level from 28.2 to 32.0% (p = 0.008) in group 1. Conclusion: Periodontitis is an important and occult source of chronic inflammation and increases the CRP levels in HD patients. Periodontitis can cause hyporesponsiveness to rHuEPO treatment and decrease the hemoglobin levels.
Production and Proteomic Characterization of Pharmaceutical-Grade Dermatophagoides pteronyssinus and Dermatophagoides farinae Extracts for Allergy Vaccines
Authors: Batard Thierry , Hrabina Alexandre , Bi Xue Zhi , Chabre Henri , Lemoine Pierrick , Couret Marie-Noëlle , Faccenda Dominique , Villet Bertrand , Harzic Philippe , André Françoise , Goh Sock Yong , André Claude , Chew Fook Tim , Moingeon Philippe
Published: June 2006

Background: House dust mites (HDM) such as Dermatophagoides pteronyssinus and Dermatophagoides farinae represent a major cause of type 1 allergies worldwide. Hence large quantities of well-characterized HDM extracts are needed to prepare pharmaceutical-grade allergy vaccines. To this aim, the present study was undertaken to define optimal conditions for large-scale cultures. Methods:D. pteronyssinus and D. farinae were grown on different media combining various proportions of wheat germ, yeast and synthetic amino acids (the latter resembling the composition of the human stratum corneum). Extracts thus obtained were analyzed for their total allergenic activity, as well as major allergen and protein contents, using immunosorbent assays, HPLC, immunoblotting, two-dimensional electrophoresis and peptide mass fingerprinting. Results: An optimal culture medium (Stalmite APF®) based on wheat germ, yeast and amino acids in defined proportion (42, 42 and 15% w/w, respectively) was selected to grow various HDM species with high yields. A detailed proteomic analysis revealed that D. pteronyssinus extracts generated under such conditions did not contain allergens originating from culture medium components and that major prevalent HDM allergens (i.e. groups 1, 2, 7, 10, 13 and 20) are found among the most abundant proteins in the D. pteronyssinus extract. Semiquantitative dot-blot assays confirmed the presence of Der p 3–10 as well as Der p 13 and 14 allergens within the extracts. Conclusions: We developed a well-defined medium allowing to grow various HDM species at an industrial scale in a highly reproducible manner. Extracts from mites produced under such pharmaceutical conditions contain all the relevant allergens for desensitization purposes and in vivodiagnosis.
Oral Administration of IL-12 Abrogates the Induction but Not the Maintenance of Oral Tolerance
Authors: Yoshida Tadashi , Uno Tsukasa , Hirano Aki , Wada Hanae , Takahashi Koji , Hattori Makoto
Published: June 2006

Background: IL-12 is a Th1-inducing cytokine and known to be induced by some food factors. This function of such foods is expected to be applied for antiallergic materials. However, the influence of IL-12 on the immune responses has not been fully investigated. Oral tolerance is an immunologically unresponsive state induced by orally administered food antigens. Although a failure in the induction of oral tolerance would result in food allergy, the mechanisms for the induction and abrogation of oral tolerance have not been clarified. IL-12 induced by food factors may also affect the induction of oral tolerance. In this study we examined the effect of the oral administration of IL-12 on the induction and maintenance of oral tolerance. Methods: BALB/c mice were fed β-lactoglobulin with or without IL-12. After immunizing them with the antigen, the serum antibody titer of these mice was measured to evaluate the induction of oral tolerance. Results: The induction of oral tolerance was prevented in the mice that had been simultaneously fed the antigen and IL-12. On the other hand IL-12 did not abrogate the already established oral tolerance when it was administered after feeding the antigen. We also found that oral tolerance could be induced normally in mice that had failed to induce such tolerance by simultaneous feeding of IL-12 and the antigen. Conclusions: The results indicate that IL-12 induced in the intestine by some food factors is involved in the regulation of oral tolerance.
Impact of Desloratadine and Loratadine on the Crosstalk between Human Keratinocytes and Leukocytes: Implications for Anti-Inflammatory Activity of Antihistamines
Authors: Traidl-Hoffmann C. , Münster I. , Ring J. , Behrendt H.
Published: June 2006

Background: Desloratadine is an H1-histamine antagonist which possesses additional anti-inflammatory properties through inhibition of leukocyte activation and reduction of ICAM-1 expression on mucosal epithelial cells. So far no studies have addressed the potential anti-inflammatory activities of desloratadine and loratadine on skin keratinocytes. Objective: In this study the capacity of desloratadine and loratadine to counteract human keratinocyte activation by interferon-γ (IFN-γ) was analyzed. In particular, the chemokine release of kerationcytes and the crosstalk between keratinocytes and lymphocytes were examined. Method: Keratinocyte cultures established from normal skin of healthy donors were activated by IFN-γ in the absence or presence of desloratadine and loratadine, and tested for the release of CCL5/RANTES, CXCL8/IL-8, CCL17/TARC and CXCL10/IP-10. Furthermore the supernatants of differentially stimulated keratinocytes were used for migration studies of human neutrophils, eosinophils and polarized Th1/Th2 clones. Results: Desloratadine and loratadine inhibited the constitutive and IFN-γ-induced release of CCL5, CXCL8 and CXCL10 from keratinocytes, while the low release of CCL17 remained unchanged. Furthermore the crosstalk between lymphocytes and keratinocytes was blocked as shown by a reduced capacity of desloratadine/loratadine-stimulated keratinocytes to attract human neutrophils, eosinophils and T cells. Conclusions: The results indicate that desloratadine has the capacity to block the IFN-γ-induced activation of keratinocytes, and that it can thus exert important regulatory effects on cell-mediated immune responses in the skin. The rather high doses required for these effects argue for a topical application when trying to use desloratadine in epidermal inflammatory conditions.
Once Daily Sublingual Immunotherapy without Updosing – A New Treatment Schedule
Authors: Rodriguez F. , Boquete M. , Ibáñez M.D. , de la Torre-Martínez F. , Tabar A.I.
Published: June 2006

Background: Treatment regimens with specific immunotherapy include updosing. Due to excellent tolerance of sublingual immunotherapy (SLIT), it was hypothesized that administration of once-daily SLIT could be initiated safely without updosing. The objective was to evaluate tolerability of SLIT administered once daily without updosing. Methods: 135 patients suffering from allergic rhinitis with/without asthma were included in a double-blind, placebo-controlled, parallel-group study. Patients were randomized into two groups. Group 1 (n = 69) received active treatment throughout the study, including 10 days updosing (T1), 20 days maintenance treatment (T2), and 2 consecutive months on maintenance treatment (T3 and T4). Group 2 (n = 66) obtained placebo updosing (T1), placebo maintenance (T2), initiated active treatment (maintenance) at T3, and continued active treatment until the end of the study (T4). Adverse events (AEs) were assessed at T1–T4. 66 grass- and 69 mite-allergic patients were evenly distributed between groups. Results: 229 AEs were reported, 157 AEs were related to treatment. The most frequently reported AEs (>5% of patients in any group) related to treatment were oral itching, ocular itching, rhinitis, and sublingual edema. For group 1 at T2, the rate of all AEs related to treatment per dose administered was 1.79%, and for group 2 at T3 the rate was 1.33% (p = 0.37). For the most frequently reported AE, oral itching, the rate per dose administered was 1.01% for group 1 at T2, and 0.74% for group 2 at T3 (p = 0.53). Conclusions: Once daily SLIT was well tolerated and can be safely initiated without updosing.
Measurements of Eosinophil Activation before and after Food Challenges in Adults with Food Hypersensitivity
Authors: van Odijk J. , Peterson C.G.B. , Ahlstedt S. , Bengtsson U. , Borres M.P. , Hulthén L. , Magnusson J. , Hansson T.
Published: June 2006

Background: Objective assessment of inflammatory reactions in the gastrointestinal tract could be useful in the diagnosis of food hypersensitivity. The aim of the present study was to investigate the involvement of eosinophils and mast cells in the inflammatory response of patients with food hypersensitivity before and after food challenges. Methods: Eleven patients (4 with IgE-mediated allergy and 7 without) with food hypersensitivity and positive double-blind, placebo-controlled food challenge were subjected to food challenge in a single-blinded fashion. Four subjects with no known food hypersensitivity were recruited as controls. Placebo was given after a 1-week washout period followed by an active dose. Stool, urinary and serum samples were collected and symptoms were recorded in a diary. Fecal samples were analyzed for eosinophil protein X (F-EPX) and tryptase; urinary samples for EPX (U-EPX) and leukotriene E4 (U-LTE4) and serum samples were analyzed for eotaxin and food-specific IgE antibodies. Results: Patients with IgE-mediated food allergy had increased levels of F-EPX compared to controls and tended to have lower serum levels of eotaxin compared to non-allergic patients and controls. U-LTE4 was significantly higher in allergic patients compared to non-allergic patients after challenge. Moreover, F-EPX correlated to U-LTE4 (p = 0.011). Reported symptoms, abdominal pain, distension, flatulence and nausea were similar in the allergic and non-allergic patients. Conclusion: The results strongly indicate that eosinophils are activated in the gastrointestinal tract of food-allergic patients but not in patients with non-allergic food hypersensitivity. Due to the inconsistent pattern of symptoms after placebo and active food challenge, it was not possible to relate the levels of inflammation markers to the recorded symptoms.
Rapid Whole Blood Flow Cytometric Test to Detect ICOS Deficiency in Patients with Common Variable Immunodeficiency
Authors: Bunk Robert , Dittrich Anna-Maria , Schulze Ilka , Horn Julia , Schmolke Kathrin , Volk Hans-Dieter , Wahn Volker , Höflich Conny
Published: June 2006

Background/Aims: Common variable immunodeficiency (CVID) is the most common primary immunodeficiency. With respect to underlying defects it comprises a heterogeneous group of deficiencies. For some patients, distinct phenotypical abnormalities have been described, e.g. partial CD40L deficiency or complete ICOS deficiency. For the diagnosis of CD40L deficiency, a rapid whole blood flow cytometric method has been described several years ago. We aimed to determine if the same method can be used to diagnose ICOS deficiency. Methods: Whole blood from 8 healthy volunteers was stimulated for 4 and 20 h with phorbol 12-myristate 13-acetate (PMA) and ionomycin. Induction of ICOS expression was analyzed on CD8–CD3+ lymphocytes using three-color flow cytometry. Blood from a patient with diagnosed ICOS deficiency was also analyzed. Results: Whole-blood stimulation with PMA and ionomycin for 20 h resulted in a significant induction of ICOS expression on CD8–CD3+ lymphocytes in healthy volunteers. Four-hour incubation also demonstrated ICOS upregulation but to a much lower extent. In CD8–CD3+ lymphocytes from an ICOS-deficient patient, no ICOS expression could be induced following 20 h of stimulation. Conclusion: ICOS expression can be analyzed using a rapid whole blood flow cytometric test.
Characteristics and Risk Factors of Cisplatin-Induced Ototoxicity in Testicular Cancer Patients Detected by Distorsion Product Otoacoustic Emission
Authors: Biro K. , Noszek L. , Prekopp P. , Nagyiványi K. , Géczi L. , Gaudi I. , Bodrogi I.
Published: June 2006

Objective: The characteristics and risk factors of the long-term ototoxic effect of cisplatin in testicular cancer patients was studied by measuring distortion product otoacoustic emissions (DPOAEs), which is a highly sensitive, new method for detecting high-frequency hearing loss. Methods: 223 patients with a median follow-up time of 4.27 years (range 0.5–20 years) and a median age of 37 years (range 18–55 years) were assessed by DPOAE. 100 mg/m2 cisplatin were administered per cycle, in EP, BEP, VeIP, VIP or VPB regimens. The control group consisted of 40 testicular cancer patients without chemotherapy (median age 35 years, range 16–54 years). A detailed medical history evaluated audiological risk factors and hearing complaints. DPOAE was measured in eight frequencies from 750 to 8,000 Hz. Paired t test and Mann-Whitney test were used for statistical evaluation. Results: Symptomatic ototoxicity was observed in 20% of the patients. In patients receiving ≤300 mg/m2 cisplatin, no amplitude changes were detected. Beyond this dose, hearing impairment proved to be dose dependent. Contrary to the literature, not only high frequencies were affected. In patients receiving ≧400 mg/m2, our method could detect significant hearing impairment at lower frequencies that are important for speech perception. At 400 mg/m2, significant amplitude change was detected at 3,000 Hz (p = 0.01); at 500–600 mg/m2, significant amplitude change was detected at 1,500, 2,000 and 3,000 Hz (p = 0.004, 0.0001 and 0.0002, respectively), and at 700 mg/m2 significant amplitude change was detected at 3,000 Hz (p = 0.01). We detected the lowest amplitudes in those 44 patients who had symptomatic ototoxicity. The only statistically significant risk factor was the cumulative dose of cisplatin; neither smoking nor noise exposure were independent risk factors. Conclusion: DPOAE is a fast, noninvasive and reliable method in detecting late ototoxicity in testicular cancer patients. Contrary to the literature, not only high frequencies are affected. In patients receiving at least 400 mg/m2, using DPOAE we were able to detect significant hearing impairment at lower frequencies that are important for speech perception.
Genetic Risk for Ischemic and Hemorrhagic Stroke
Authors: Yamada Yoshiji , Metoki Norifumi , Yoshida Hidemi , Satoh Kei , Ichihara Sahoko , Kato Kimihiko , Kameyama Takashi , Yokoi Kiyoshi , Matsuo Hitoshi , Segawa Tomonori , Watanabe Sachiro , Nozawa Yoshinori
Published: June 2006

Objective—We performed an association study to identify gene polymorphisms for assessing the genetic risk of ischemic or hemorrhagic stroke.

Methods and Results—The study population comprised 3151 unrelated Japanese individuals: 1141 stroke patients (636 with atherothrombotic cerebral infarction, 282 with intracerebral hemorrhage, and 223 with subarachnoid hemorrhage) and 2010 controls. The genotypes for 202 polymorphisms of 152 genes were determined by suspension array technology. Multivariable logistic regression analysis with adjustment for conventional risk factors revealed that the –572G→C polymorphism of the interleukin-6 (IL-6) gene (IL6) was significantly (P<0.001) associated with both atherothrombotic cerebral infarction and intracerebral hemorrhage and that the –55C→T polymorphism of the uncoupling protein 3 gene (UCP3), the –863C→A polymorphism of the tumor necrosis factor (TNF) gene (TNF), and the G→A (Gly243Asp) polymorphism of the polycystic kidney disease 1–like gene (PKD1-like) were significantly associated with subarachnoid hemorrhage.

Conclusions—IL6genotype may be useful in assessing the genetic risk for atherothrombotic cerebral infarction and intracerebral hemorrhage, and genotypes forUCP3,TNF, andPKD1-likemay be similarly beneficial in assessment of the risk for subarachnoid hemorrhage. Validation of our findings will require additional studies with independent subject panels.
Tumor Necrosis Factor-α Induces Endothelial Dysfunction in the Prediabetic Metabolic Syndrome
Authors: Picchi Andrea , Gao Xue , Belmadani Souad , Potter Barry J. , Focardi Marta , Chilian William M. , Zhang Cuihua
Published: June 2006

Inflammation is a condition that underscores many cardiovascular pathologies including endothelial dysfunction, but no link is yet established between the vascular pathology of the metabolic syndrome with a particular inflammatory cytokine. We hypothesized that impairments in coronary endothelial function in the obese condition the prediabetic metabolic syndrome is caused by TNF-α overexpression. To test this, we measured endothelium-dependent (acetylcholine) and -independent vasodilation (sodium nitroprusside) of isolated, pressurized coronary small arteries from lean control and Zucker obese fatty (ZOF, a model of prediabetic metabolic syndrome) rats. In ZOF rats, dilation to ACh was blunted compared with lean rats, but sodium nitroprusside–induced dilation was comparable. Superoxide (O
2
·
−
) generation was elevated in vessels from ZOF rats compared with lean rats, and administration of the O
2
·
−
scavenger TEMPOL, NAD(P)H oxidase inhibitor (apocynin), or anti–TNF-α restored endothelium-dependent dilation in the ZOF rats. Real-time PCR and Western blotting revealed that mRNA and protein of TNF-α were higher in ZOF rats than that in lean rats, whereas eNOS protein levels were reduced in the ZOF versus lean rats. Immunostaining showed that TNF-α in ZOF rat heart is localized in endothelial cells and vascular smooth muscle cells. Expression of NAD(P)H subunits p22 and p40-phox were elevated in ZOF compared with lean animals. Administration of TNF-α more than 3 days also induced expression of these NAD(P)H subunits and abrogated endothelium-dependent dilation. In conclusion, the results demonstrate the endothelial dysfunction occurring in the metabolic syndrome is the result of effects of the inflammatory cytokine TNF-α and subsequent production of O
2
·
−
.
Novel Genomic Loci Influencing Plasma Homocysteine Levels
Authors: Kullo Iftikhar J. , Ding Keyue , Boerwinkle Eric , Turner Stephen T. , Mosley Thomas H. , Kardia Sharon L.R. , de Andrade Mariza
Published: June 2006

Background and Purpose—

Genetic factors that influence interindividual variation in levels of plasma homocysteine, a risk factor for vascular disease, are not fully understood. We performed linkage analyses to identify genomic regions that influence homocysteine levels in blacks and non-Hispanic whites.

Methods—

Subjects (n=2283) belonged to hypertensive sibships and included 1319 blacks (63±10 years, 70% women) and 964 non-Hispanic whites (61±7 years, 57% women). Fasting plasma homocysteine was measured by high-pressure liquid chromatography. Genotypes were measured at 366 microsatellite marker loci distributed across the 22 autosomes. Plasma homocysteine adjusted for age, sex, body mass index, serum creatinine, and estrogen use (in women) was used in the genetic analyses. Heritability and linkage analyses were performed using a variance components approach.

Results—

Mean (±SD) homocysteine levels were 10.4±5.27 μmol/L in blacks and 10.0±2.84 μmol/L in non-Hispanic whites (
P
=0.58 for difference). Homocysteine levels were significantly (
P
<0.0001) heritable in blacks (
h
2
=0.70) and in non-Hispanic whites (
h
2
=0.49). Linkage analyses demonstrated significant evidence of linkage (multipoint logarithm of odds≥3.0) for homocysteine on chromosomes 1q42, 14q32, and 19p13 in blacks and on chromosomes 9q34 and 12q24 in non-Hispanic whites. Tentative evidence of linkage (logarithm of odds 1.3 to 2.0) was present on chromosomes 2q32, 7p15, 8q24, 18q21, and 20p12 in blacks and chromosomes 6q26 and 18q21 in non-Hispanic whites. Four genes in the homocysteine metabolism pathway (
MTR
,
DNMT1
,
GAMT
, and
CARM1
) were present under 2 of the significant linkage signals in blacks (chromosomes 1q42 and 19p13).

Conclusions—

Plasma homocysteine is a significantly heritable trait. Linkage analyses reveal several unique genomic loci that may influence circulating levels of homocysteine and therefore susceptibility to vascular diseases including stroke.
Cytokine Polymorphisms Associated With Carotid Intima-Media Thickness in Stroke Patients
Authors: Brenner David , Labreuche Julien , Touboul Pierre-Jean , Schmidt-Petersen Klaus , Poirier Odette , Perret Claire , Schönfelder Jacqueline , Combadière Christophe , Lathrop Mark , Cambien François , Brand-Herrmann Stefan-Martin , Amarenco Pierre
Published: June 2006

Background and Purpose—

Carotid intima-media thickness (IMT) reflects generalized atherosclerosis and is predictive of future vascular events. Evidence exists that carotid IMT is heritable, and genetic studies can provide clues in the pathogenesis of atherosclerosis.

Methods—

We recruited 470 white ischemic stroke patients, measured common carotid artery (CCA) IMT, and analyzed 54 polymorphisms with suspected roles in atherosclerosis.

Results—

Among the polymorphisms tested, the angiotensin-converting enzyme insertion/deletion, osteopontin (OPN) T-443C, monocyte chemoattractant protein-1 (MCP-1) G-927C, and MCP-1 A-2578G polymorphisms were associated with CCA–IMT in age-gender–adjusted analysis. In multivariate analysis, the association between the OPN and MCP-1 polymorphisms remained significant. The OPN-443C allele was associated with increased IMT in the dominant model (0.053 mm for the TC and CC genotypes;
P
=0.001). The MCP-1-927C allele was associated with increased IMT in the additive model (0.040 mm for each C allele;
P
=0.001), and the MCP-1-2578 G allele was associated with decreased IMT in the recessive model (0.088 mm for the GG genotype;
P
=0.002).

Conclusions—

The OPN and MCP-1 genes, coding for 2 cytokines with known roles in atherosclerosis, may contribute to increased carotid IMT and warrant further study.
Brain Temperature During 340-kHz Pulsed Ultrasound Insonation
Authors: Fatar Marc , Stroick Mark , Griebe Martin , Alonso Angelika , Hennerici Michael G. , Daffertshofer Michael
Published: June 2006

Background and Purpose—

Because ultrasound is used for improving thrombolysis of cerebral infarction but continuous ultrasound insonation also has significant thermal effects, we evaluated brain temperature increase and tissue destruction during pulsed ultrasound emission.

Methods—

We examined 340-kHz pulsed ultrasound effects in male Wistar rats. Ultrasound was applied transcranially for 30 minutes on different power levels (1 to 7 W/cm
2
). Temperature was measured at different locations (brain, in the focus of ultrasound beam, inner ear, temporalis muscle, and rectum). The cooling time after 30-minute insonation for every power level was recorded, and animals were examined by postmortem brain histology (TUNEL and hematoxylin/eosin).

Results—

Brain temperature increased within 2 to 5 minutes of insonation. Brain temperature increase and cooling time were in proportion to power level, and even with the highest intensity of 7 W/cm
2
for 30 minutes, the maximum elevation of mean brain temperature was 0.9°C, with the highest cooling time of 40 minutes. No deleterious side effects of this treatment could be found in histological examination.

Conclusions—

Using a pulsed ultrasound design, only a moderate temperature increase could be observed with no histopathological abnormalities. Deleterious side effects of mid-kilohertz ultrasound (eg, intracerebral hemorrhage) are therefore not a consequence of local brain temperature increase.
Retinal Arteriolar Emboli and Long-Term Mortality
Authors: Wang Jie Jin , Cugati Sudha , Knudtson Michael D. , Rochtchina Elena , Klein Ronald , Klein Barbara E.K. , Wong Tien Yin , Mitchell Paul
Published: June 2006

Background and Purpose—

To assess the relationship between retinal arteriolar emboli and mortality in older people.

Methods—

Pooled data from 2 population-based cohort studies. At baseline, the Beaver Dam Eye Study (BDES) examined 4926 persons 43 to 86 years of age (1988 to 1990), and the Blue Mountains Eye Study (BMES) examined 3654 persons 49 to 97 years of age (1992 to 1994). Retinal arteriolar emboli were assessed by grading retinal photographs using standardized methods. Deaths and causes of death were determined from death certificates or Australian National Death Index. Cox regression models were used to estimate mortality hazard ratios (HRs) associated with emboli, adjusting for age, gender, body mass index, hypertension, diabetes, smoking, serum total cholesterol, high-density lipoprotein cholesterol, study site, and past histories of stroke, angina, and acute myocardial infarct.

Results—

Of 8580 baseline participants, 8384 (98%) had retinal photographs available, and 111 showed retinal arteriolar emboli (BDES n=61; BMES n=50). Over 10 to 12 years, 2506 participants (30%) died, including 344 (4%) from stroke-related and 1315 (16%) from cardiovascular causes. The cumulative mortality rates were higher in participants with than without emboli (all-cause 56% versus 30%; stroke-related 12% versus 4.0%; cardiovascular 30% versus 16%). The increased mortality risk associated with emboli was independent of age, gender, other vascular risk factors, and past histories of stroke or heart disease for all-cause (multivariate-adjusted HR, 1.3; CI, 1.0 to 1.8) and stroke-related mortality (HR, 2.0; CI, 1.1 to 3.8) but not for cardiovascular mortality (HR, 1.2; CI, 0.8 to 1.7).

Conclusions—

Our pooled data from 2 older populations suggest that retinal emboli predict a modest increase in all-cause and stroke-related mortality independent of cardiovascular risk factors.
Vasospasm and p53-Induced Apoptosis in an Experimental Model of Subarachnoid Hemorrhage
Authors: Cahill Julian , Calvert John W. , Solaroglu Ihsan , Zhang John H.
Published: June 2006

Background and Purpose—

Despite intensive research efforts, the etiology of vasospasm (sustained constriction of the cerebral vessels) remains unknown. In this study, we investigated the role of p53-induced apoptosis in the vasculature at 24 and 72 hours. To completely examine the apoptotic cascades, key proteins of the caspase-dependent, -independent and mitochondrial pathways were examined.

Methods—

In this study, adult rats were divided into 3 groups: sham (n=21), nontreatment (subarachnoid hemorrhage [SAH]+dimethyl sulfoxide; n=42), and treatment (SAH+pifithrin-α) (n=42) groups. Each animal in the SAH group underwent a surgical procedure to induce SAH, and the basilar artery was harvested at 24 and 72 hours for analysis.

Results—

We found severe vasospasm at the 24-hour time point, which persisted to 72 hours. Furthermore, we found that the markers of the apoptotic cascades rose significantly at the 24-hour time point but had dissipated by 72 hours. However, the neurological outcome and mortality scores improved at the 72-hour time point.

Conclusions—

Apoptosis, and in particular p53, may play an important role in the etiology of vasospasm with relation to SAH, and in this model, vasospasm persisted to 72 hours, despite the fact that apoptosis does not.
Familial Risk of Ischemic and Hemorrhagic Stroke
Authors: Sundquist Kristina , Li Xinjun , Hemminki Kari
Published: June 2006

Background and Purpose—

Previous studies of familial risks have often combined ischemic and hemorrhagic stroke even though it seems unlikely that these 2 very different pathological conditions are under the same genetic influence. This study is the first to investigate the concordant (same subtype) and disconcordant (different subtype) association between ischemic and hemorrhagic stroke.

Methods—

Data of first hospitalization for stroke were obtained from the Hospital Discharge Register during the study period 1987 to 2001. All individuals born in Sweden from 1932 onwards were included and linked to their siblings. Risks were calculated as standardized incidence ratios and compared with individuals without affected siblings. Results were standardized for age, gender, geographical region and socioeconomic status.

Results—

Ischemic stroke (n=25 630) was associated only with ischemic stroke (n=7961), which was also the case for hemorrhagic stroke. The statistically significant standardized incidence ratios were 2.14 (95% CI, 1.21 to 3.74) and 1.82 (95% CI, 1.21 to 2.75), respectively. For discordant subtypes of stroke no significant associations were found.

Conclusions—

The results suggest that ischemic and hemorrhagic stroke are not under the same genetic influence. However, further studies of the human genome are needed in order to identify the specific genes that play roles in the pathogenesis of common subtypes of stroke.
Gender Differences in Out-of-Pocket Prescription Drug Expenditures Among the Elderly
Authors: Wei Wenhui , Akincigil Ayse , Crystal Stephen , Sambamoorthi Usha
Published: June 2006

Many elderly in the United States face high out-of-pocket prescription drug (OOP-PD) expenditures, with elderly women being disproportionably affected. Using Medicare Current Beneficiary Survey data for 1992 to 2000, the authors examined the gender differences in OOP-PD expenditures and burden among community-dwelling elderly Medicare beneficiaries. Oaxaca-Blinder decomposition techniques were used to evaluate the contribution of observed demographic, socioeconomic, and utilization factors on the gender gap in OOP-PD expenditures and burden. Among observed characteristics, differences in utilization and supplemental insurance coverage were the major drivers of the gender gap in OOP-PD expenditures and burden. Unobservable factors contributed to the majority of the gender gap in OOP-PD expenditures.
Validity of Criteria Used to Evaluate Fingerstick Devices That Assess International Normalized Ratio
Authors: Shermock Kenneth M. , Connor Jason T. , Smith Nicole T. , Fink Jodie M. , Bragg Lee
Published: June 2006

Background . Investigators commonly rely on unvalidated, mainly arithmetic criteria to predict if point-of-care fingerstick devices that assess International Normalized Ratio (INR) lead to the same warfarin dosing decisions as a standard measure. Methods . Criteria that predict warfarin dosing agreement between 2 INR measurements were evaluated using clinicians’ actual dosing decisions as the standard. Bayesian hierarchical modeling was used to rank the criteria by the proportion of correct dosing predictions and the magnitude of difference between actual and predicted dosing agreement. Results . The prediction criteria misclassified dosing agreement for between 19% and 38% of paired INR values (x̄x: 27%). The magnitude of misclassification varied inconsistently throughout the INR scale. Conclusion . The unvalidated criteria used to predict warfarin dosing agreement between 2 INR measurements are associated with large error. Warfarin dosing decisions should be measured directly in such assessments.
Increased hematopoietic stem cell mobilization in aged mice
Authors: Xing Zhenlan , Ryan Marnie A. , Daria Deidre , Nattamai Kalpana J. , Van Zant Gary , Wang Lei , Zheng Yi , Geiger Hartmut
Published: June 2006

Hematopoietic stem and progenitor cells (HSPCs) are located in the bone marrow in close association with a highly organized 3-dimensional structure formed by stroma cells, referred to as the niche. Mobilization of HSPCs from bone marrow to peripheral blood in response to granulocyte colony-stimulating factor (G-CSF) requires de-adhesion of HSPCs from the niche. The influence of aging of HSPCs on cell-stroma interactions has not been determined in detail. Using a mouse model of G-CSF–induced mobilization, we demonstrated that the ability to mobilize hematopoietic stem cells is approximately 5-fold greater in aged mice. Competitive mobilization experiments confirmed that enhanced mobilization ability was intrinsic to the stem cell. Enhanced mobilization efficiency of primitive hematopoietic cells from aged mice correlated with reduced adhesion of hematopoietic progenitor cells to stroma and with elevated levels of GTP-bound Cdc42. These results might indicate that stroma–stem cell interactions are dynamic over a lifetime and result in physiologically relevant changes in the biology of primitive hematopoietic cells with age.
Reversible inhibition of the platelet procoagulant response through manipulation of the Gardos channel
Authors: Wolfs Jef L. , Wielders Simone J. , Comfurius Paul , Lindhout Theo , Giddings John C. , Zwaal Robert F. , Bevers Edouard M.
Published: June 2006

The platelet procoagulant response requires a sustained elevation of the intracellular Ca2+ concentration, [Ca2+]i, causing exposure of phosphatidylserine (PS) at the outer surface of the plasma membrane. An increased [Ca2+]i also activates Ca2+-dependent K+ channels. Here, we investigated the contribution of the efflux of K+ ions on the platelet procoagulant response in collagen-thrombin–activated platelets using selective K+ channel blockers. The Gardos channel blockers clotrimazol, charybdotoxin, and quinine caused a similar decrease in prothrombinase activity as well as in the number of PS-exposing platelets detected by fluorescence-conjugated annexin A5. Apamin and iberiotoxin, inhibitors of other K+ channels, were without effect. Only clotrimazol showed a significant inhibition of the collagen-plus-thrombin–induced intracellular calcium response. Clotrimazol and charybdotoxin did not inhibit aggregation and release under the conditions used. Inhibition by Gardos channel blockers was reversed by valinomycin, a selective K+ ionophore. The impaired procoagulant response of platelets from a patient with Scott syndrome was partially restored by pretreatment with valinomycin, suggesting a possible defect of the Gardos channel in this syndrome. Collectively, these results provide evidence for the involvement of efflux of K+ ions through Ca2+-activated K+ channels in the procoagulant response of platelets, opening potential strategies for therapeutic interventions.