bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms of Paclitaxel-Induced Apoptosis in an Ovarian Cancer Cell Line and Its Paclitaxel-Resistant Clone
Authors: Sugimura Masaki , Sagae Satoru , Ishioka Shin-ichi , Nishioka Yoshihiro , Tsukada Kuniko , Kudo Ryuichi
Published: March 2004

Background: To understand the complicated network of paclitaxel (PTX)-induced apoptosis pathways and to elucidate mechanisms of drug resistance in ovarian cancer, we looked at PTX-induced apoptosis by using cDNA microarray. We also quantitated the changes in apoptosis-related proteins in the process of apoptosis. Methods: An ovarian cancer cell line KF, and its PTX-resistant clone KFTX, were treated with PTX or carboplatin (CBDCA). After exposure to PTX or CBDCA, the induction of apoptosis was examined by internucleosomal DNA fragmentation. Changes in mRNA expression after 12 h of exposure to PTX were studied using cDNA microarray and RT-PCR. Changes in P53 and Bcl-2 levels were also measured over 24 h by ELISA. Results: With increased doses of PTX or CBDCA, an increase in apoptosis was noted in both cell lines. cDNA microarray revealed that PTX treatment upregulated expression of caspase 1, 2, 3, 4, 6, 9, 10, their activator apaf-1, and stress reaction-related genes, gadd34, gadd153 in KF, although most of them were unchanged or downregulated in KFTX. bag-1 and hsc70 were markedly upregulated in KFTX. p53 and bcl-2 were not upregulated in either cell line. Results from protein studies also supported the cDNA microarray data. Conclusion:p53-independent mitochondrial pathways and stress-reaction-induced pathways play critical roles in PTX-induced apoptosis in ovarian cancer cells. Suppression of those pathways and upregulation of bag-1 and hsp-70 played an important role in acquiring resistance to PTX.
Pharmacokinetics of 1α,25-Dihydroxyvitamin D3 in Normal Mice after Systemic Exposure to Effective and Safe Antitumor Doses
Authors: Muindi Josephia R. , Modzelewski Ruth A. , Peng Yibing , Trump Donald L. , Johnson Candace S.
Published: March 2004

Objective: Calcitriol, 1α,25-dihydroxyvitamin D3 (1,25-D3) has potent antiproliferative effects and potentiates the antitumor activity of many other cytotoxic drugs. 1,25-D3 plasma pharmacokinetic (PK) parameters associated with antitumor activity in experimental animal models are unknown. The objective of this study was to determine plasma calcitriol PK in normal mice at doses of calcitriol which are active in suppressing tumor growth. Methods: Plasma 1,25-D3 PK were examined in normal C3H/HeJ mice after a single intraperitoneal dose of 0.125 or 0.5 µg 1,25-D3/mouse. PK blood samples were collected from groups of 5–9 mice at each time point up to 24 h after 1,25-D3 administration. Plasma 1,25-D3 concentrations were measured by radioimmunoassy. Plasma 1,25-D3 concentration diurnal variation was determined in blood samples from untreated animals collected in the morning (9:00–11:00 a.m.) and in the evening (4:00–9:00 p.m.). Results: Median baseline plasma 1,25-D3 concentration measured in the morning and in the evening were 0.082 ng/ml (CI 95%, 0.076–0.099) and 0.067 ng/ml (CI 95%, 0.058–0.075), respectively (p = 0.004). After 0.125 and 0.5 µg dosing, peak plasma 1,25-D3 concentrations (Cpmax) were 12.0 ng/ml (CI 95%, 10.8–12.6) and 41.6 ng/ml (CI 95%, 40.8–53.6), respectively. The corresponding areas under the curve (AUC0–>24 h) were 47.0 (CI 95%, 43.2–51.1) and 128.0 (CI 95%, 127.0–130.0) ng·h/ml. No dose-related changes in time to Cpmax and apparent total plasma clearance were observed. Conclusions: These results demonstrate diurnal variation in baseline plasma 1,25-D3 concentrations in mice. Plasma 1,25-D3 PK in mice receiving doses that are effective in slowing tumor growth, inducing cell cycle arrest and apoptosis, and potentiating taxanes and platinum analogue antitumor activity are at least 5–10 times higher than those easily achieved and nontoxic in patients receiving high-dose intermittent oral therapy.
β-Hydroxyisovalerylshikonin and Cisplatin Act Synergistically to Inhibit Growth and to Induce Apoptosis of Human Lung Cancer DMS114 Cells via a Tyrosine Kinase-Dependent Pathway
Authors: Xu Ying , Kajimoto Sachiko , Nakajo Shigeo , Nakaya Kazuyasu
Published: March 2004

β-Hydroxyisovalerylshikonin (β-HIVS) and cisplatin (CDDP) had a synergistic growth-inhibitory effect on cultured human small-cell lung carcinoma DMS114 cells, as well as on human leukemia U937 and epidermoid carcinoma A431 cells, while β-HIVS and CDDP alone at the same respective concentrations had little effect. Growth inhibition was accompanied by induction of apoptosis, as determined by an ELISA for the detection of cell death and the TUNEL assay. Using phosphotyrosine-specific antibodies (PY20), we observed that tyrosine kinase activity in DMS114 cells was inhibited by treatment with β-HIVS and CDDP together. The tyrosine kinase activity of isolated Src and that of isolated receptors for epidermal growth factor were also inhibited by the two agents together. The synergistic effects of the growth of DMS114 cells of β-HIVS and CDDP were not due simply to the intracellular accumulation of CDDP or to levels of DNA adducts. Our data suggest that the synergistic effect on the growth of DMS114 cells of β-HIVS and CDDP might be a result of the inhibition of a tyrosine kinase-dependent pathway.
Robust Indices of Hardy-Weinberg Disequilibrium for QTL Fine Mapping
Authors: Deng Hong-Wen , Li Yu-Mei , Li Miao-Xin , Liu Peng-Yuan
Published: March 2004

Hardy-Weinberg disequilibrium (HWD) measures have been proposed using dense markers to fine map a quantitative trait locus (QTL) to regions < ∼ 1 cM. Earlier HWD measures may introduce bias in the fine mapping because they are dependent on marker allele frequencies across loci. Hence, HWD indices that do not depend on marker allele frequencies are desired for fine mapping. Based on our earlier work, here we present four new HWD indices that do not depend on marker allele frequencies. Two are for use when marker allele frequencies in a study population are known, and two are for use when marker allele frequencies in a study population are not known and are only known in the extreme samples. The new measures are a function of the genetic distance between the marker locus and a QTL. Through simulations, we investigated and compared the fine mapping performance of the new HWD measures with that of the earlier ones. Our results show that when marker allele frequencies vary across loci, the new measures presented here are more robust and powerful.
High-Resolution Joint Linkage Disequilibrium and Linkage Mapping of Quantitative Trait Loci Based on Sibship Data
Authors: Fan Ruzong , Jung Jeesun
Published: March 2004

This paper proposes variance component models for high resolution joint linkage disequilibrium (LD) and linkage mapping of quantitative trait loci (QTL) based on sibship data; this can include population data if independent individuals are treated as single sibships. One application of these models is late onset complex disease gene mapping, when parental data are not available. The models simultaneously incorporate both LD and linkage information. The LD information is contained in mean coefficients of sibship data. The linkage information is contained in the variance-covariance matrices of trait values for sibships with at least two siblings. We derive formulas for calculating the probability of sharing two trait alleles identical by descent (IBD) for sibpairs in interval mapping of QTL; this is the coefficient of dominant variance of the trait covariance of sibpairs on major QTL. To investigate the performance of the formulas, we calculate the numerical values via the formulas and get satisfactory approximations. We compare the power and sample sizes for both LD and linkage mapping. By simulation and theoretical analysis, we compare the results with those of Fulker and Abecasis ‘AbAw’ approach. It is well known that the resolution of linkage analysis can be low for complex disease gene mapping. LD mapping, on the other hand, can increase mapping precision and is useful in high resolution mapping. Linkage analysis is less sensitive to population subdivisions and admixtures. The level of LD is sensitive to population stratification which may easily lead to spurious association. Performing a joint analysis of LD and linkage mapping can help to overcome the limits of both approaches. Moreover, the advantages of the two complementary strategies can be utilized maximally. In practice, linkage analysis may be performed using pedigree data to identify suggestive linkage between markers and trait loci based on a sparse marker map. In the presence of linkage, joint LD and linkage mapping can be carried out to do fine gene mapping based on a dense genetic map using both pedigree and population data. Population and pedigree data of any type can be combined to perform a joint analysis of high resolution LD and linkage mapping of QTL by generalizing the method.
A Framework for Controlling False Discovery Rates and Minimizing the Amount of Genotyping in the Search for Disease Mutations
Authors: van den Oord Edwin J.C.G. , Sullivan Patrick F.
Published: March 2004

Objectives: To develop a method for designing studies to find disease mutations that can achieve a set of goals with respect to proportions of false and true discoveries with the minimum amount of genotyping. Methods: Derivation of an analytical framework supplemented with simulation techniques. The approach is illustrated for a fine mapping study and a whole-genome linkage disequilibrium scan. Results: The use of multiple stages where earlier stages are characterized by very high false discovery rates (FDR) followed by an abrupt change to the required FDR in the final stage results in a 50–75% reduction in genotyping. The proportion of true discoveries is a much more important determinant of the genotyping burden than the FDR. Neither sample size nor controlling the false discoveries will present major problems in whole-genome LD scans but the amount of genotyping will be extremely large even if the study is completely designed to minimize genotyping. Conclusions: The proposed statistical framework presents a simple and flexible approach to determine the design parameters (e.g. sample size, p values at which tests need to be performed at each stage) that minimize the genotyping burden given a set of goals for the percentage of true and false discoveries.
How to Model a Complex Trait
Authors: Strauch Konstantin , Fimmers Rolf , Baur Max P. , Wienker Thomas F.
Published: March 2004

Complex traits are often governed by more than one trait locus. The first step towards an adequate model for such diseases is a linkage analysis with two trait loci. Such an analysis can be expected to have higher power to detect linkage than a standard single-trait-locus linkage analysis. However, it is crucial to accurately specify the parameters of the two-locus model. Here, we recapitulate the general two-locus model with and without genomic imprinting. We relate heterogeneity, multiplicative, and additive two-locus models to biological or pathophysiological mechanisms, and give the corresponding averaged (‘best-fitting’) single-trait-locus models for each of the two loci. Furthermore, we derive the two-locus penetrances from the averaged single-locus models, under the assumption of one of the three model classes mentioned above. Using these formulae, if the best-fitting single-locus models are available, investigators may perform a two-trait-locus linkage analysis under a realistic model. This procedure will maximize the power to detect linkage for traits which are governed by two or more loci, and lead to more accurate estimates of the disease-locus positions.
Psychometric Theory Is an Obstacle to the Progress of Clinical Research
Authors: Fava Giovanni A. , Ruini Chiara , Rafanelli Chiara
Published: March 2004

Psychometric theory is the basis for the development of assessment instruments in psychiatric research. However, the psychometric model appears to be largely inadequate in the clinical setting because of its lack of sensitivity to change and its quest for homogeneous components. Clinimetrics offers a viable alternative to psychometrics, both from a conceptual and a methodological viewpoint. Current diagnostic entities (DSM) are based on clinimetric principles, but their use is still influenced by psychometric models. Suggestions for switching gears in assessment research are offered.
Telomere Length Variation and Telomerase Activity Expression in Patients with Congenital and Acquired Aplastic Anemia
Authors: Polychronopoulou Sophia , Koutroumba Paraskevi
Published: March 2004

Telomeres represent the nucleoprotein tails of chromosomes that get shortened with each cell division. When the telomere length reaches a critical point, cell senescence and death occur. Telomerase is a reverse transcriptase that counteracts telomere loss by adding telomeric sequences. In patients with acquired aplastic anemia, the mean telomere length (TRF) of peripheral blood leukocytes is generally short when compared to normal controls, without it being clear whether a relationship between TRF and disease severity exists. Additionally, increased telomerase activity (TA) is found in the bone marrow mononuclear cell population (MNCs) of aplastic anemia patients, especially in the chronic form of the disease. Fanconi anemia (FA) patients generally demonstrate increased TA and short telomeres in peripheral blood MNCs, a fact attributed to the high turnover of hematopoietic progenitor cells in combination with direct breakages at telomeric sequences. Furthermore, a strong correlation has been shown between TRF and the severity of aplastic anemia, but not with FA evolution towards myelodysplastic syndrome or acute myeloblastic leukemia. In respect of dyskeratosis congenita (DC), a disease of either X-linked or autosomal dominant/recessive inheritance which is characterized by premature ageing of highly regenerative tissues, studies have been carried out in order to elucidate whether the X-linked DC is caused by a defect in ribosomal RNA processing and/or telomere maintenance. Finally, the direct genetic link established between DC pathogenesis and short telomeres may lead to the development of new therapeutic protocols for diseases characterized by short telomere length and subsequent genomic instability.
Age-Dependent Changes in the Incidence and Etiology of Childhood Thrombocytosis
Authors: Matsubara Kousaku , Fukaya Takashi , Nigami Hiroyuki , Harigaya Hidekazu , Hirata Takuya , Nozaki Hideo , Baba Kunizo
Published: March 2004

To determine the incidence and etiology of childhood thrombocytosis, over 15,000 platelet counts in 7,539 patients performed at a single regional hospital were reviewed. When thrombocytosis was defined as ≧500 × 109/l of platelet counts, the condition could be diagnosed in 6.0% (456 cases) of the patients. All patients were classified as having secondary thrombocytosis. The incidence of thrombocytosis dramatically changed throughout child development; it was 12.5% in neonates, peaked to 35.8% in 1-month-old infants and then returned to 12.9% in 6- to 11-month-old infants. Thereafter, it gradually decreased with age to only 0.6% in 11- to 15-year-old children. Frequent causes of thrombocytosis included infection (67.5%), Kawasaki disease (9.4%), prematurity (7.7%) and iron deficiency anemia (6.4%). Thrombocytosis was an incidental finding in a substantial population of early infants. Thrombocytosis as a reaction to several types of infection and Kawasaki disease was more common in children under 7 years old, while autoimmune disease and tissue damage were major causes in children aged 11–15 years. No child had thromboembolic complications. These findings indicate that childhood thrombocytosis is a benign condition and its incidence and etiology seem to depend on age.
Improvement of Cardiac Function in Thalassemia major Treated with L-Carnitine
Authors: El-Beshlawy Amal , Ragab Lamis , Fattah Alia Abdel , Ibrahim Ilham Youssry , Hamdy Mona , Makhlouf Ali , Aoun Elie , Hoffbrand Victor , Taher Ali
Published: March 2004

Introduction: Heart disease secondary to chronic anemia and hemosiderosis remains the major cause of morbidity and mortality in thalassemic patients. Chronic anemia and the tissue hypoxia it induces impair free fatty acid oxidation and ATP production in myocardial cells. The use of L-carnitine, a butyric acid derivative, may help overcome some of these defects. Objective: To investigate the effect of L-carnitine therapy on cardiac function in thalassemia major patients. Materials and Methods: Cardiac function was evaluated in 30 patients attending our clinic. The mean (±SD) age was 15.87 ± 3.19 years. The studies we performed included echocardiography, Doppler and multigated equilibrium radionuclide angiography (MUGA). Systolic and diastolic function was evaluated before starting L-carnitine treatment and after 6 months of oral L-carnitine (50 mg/kg/day). Results: Echocardiography studies revealed no significant changes in systolic and diastolic function after L-carnitine therapy (p > 0.05). Analysis of the data taken by MUGA performed in 20 of the patients, however, showed a significant improvement of diastolic function after 6 months of L-carnitine therapy. The mean peak filling rate (end-diastolic volume/s) increased from 3.15 ± 1.06 to 3.61 ± 1.68 (p < 0.03). The time to peak (during filling) decreased significantly from 143.45 ± 42.04 to 117.70 ± 24.40 s (p < 0.02). Systolic function showed a significant increase in the left ventricular ejection fraction from 58.25 ± 9.92 to 63.95 ± 10.11% (p = 0.0001). Conclusion:L-Carnitine may be an effective drug for improving the cardiac status of thalassemic patients. MUGA is the most accurate technique of those used here for assessing left ventricular function in these patients.
The Diverse Molecular Basis and Hematological Features of Hb H and AEBart’s Diseases in Northeast Thailand
Authors: Boonsa Supap , Sanchaisuriya Kanokwan , Fucharoen Goonnapa , Wiangnon Surapon , Jetsrisuparb Arunee , Fucharoen Supan
Published: March 2004

We defined the molecular basis and correlated the hematological phenotypes with the globin genotypes in 52 patients with Hb H disease and 29 patients with AEBart’s disease of northeast Thailand. Among the former group, the most prevalent molecular defect was found to be the interaction of α-thalassemia 1 (SEA type) with the Hb Constant Spring (Hb CS; 35 of 52 patients), followed by the deletion of three α-globin genes with the SEA type α-thalassemia 1 and the 3.7- or 4.2-kb deletion of α-thalassemia 2 (14 of 52 patients) and the interaction of the SEA α-thalassemia 1 with the Hb Paksé which was found in the remaining 3 patients. Among the 29 patients of the latter group, in 18 disease was caused by interactions of Hb E heterozygotes with the SEA α-thalassemia 1 and Hb CS. Interaction of Hb E heterozygotes with a deletional form of Hb H disease was detected in 7 patients and the Hb Paksé AEBart’s disease was found in another 3 patients. A remaining patient with an unusually severe form of AEBart’s disease with a lower Hb E level and observable Hb H was associated with a hitherto undescribed condition, the interaction of Hb E heterozygote with α-thalassemia 1 and an α2 codon 30 (GAG) deletion. Hematological characterization of the patients demonstrated that although disease in most of them was associated with thalassemia intermedia phenotypes, it was apparent that association with the nondeletional form of α-thalassemia 2 produced a more severe phenotype than that of the deletional one. Therefore, α-globin gene analysis of Hb H and AEBart’s disease patients would be useful for predicting the clinical outcome and improving genetic counseling.
Diagnostic Invasive Procedures in Diffuse Infiltrative Lung Diseases
Authors: Poletti Venerino , Chilosi Marco , Olivieri Dario
Published: March 2004

The diagnosis of infiltrative diffuse lung disease may require invasive procedures after all noninvasive tools have failed. The clinical context in which these diseases develop and the radiological patterns are crucial for defining the timing and the methods to be used. Immunocompromised hosts are usually acutely ill with fever, cough, shortness of breath, and often with progressive hypoxemia. In this context a prompt diagnosis is necessary to decrease mortality. Bronchoalveolar lavage [especially in cases that show ground-glass attenuation or alveolar opacification in high-resolution CT scan (HRCT)] is the most important invasive procedure allowing the identification of infectious agents, neoplastic elements and characteristic cytological and phenotypical profiles (for drug injury) in the majority of cases. Less frequently transbronchial lung biopsy, transbronchial needle aspiration and biopsy or surgical lung biopsy are necessary. In immunocompetent patients the clinical spectrum of diffuse lung disease is quite broad. Furthermore, in the last two decades HRCT, used in conjunction with clinical and other noninvasive investigative modalities, has increased the accuracy of diagnosis for some diseases without the need of surgical biopsy. Also in these patients bronchoalveolar lavage, frequently in combination with transbronchial lung biopsy, is sufficient to achieve a definitive diagnosis in the majority of cases. Surgical lung biopsy is, however, still relevant in cases with idiopathic interstitial pneumonias. In this article invasive diagnostic procedures in patients with diffuse lung infiltrates are discussed from the perspective of their clinical context and their imaging characteristics.
Chlamydia pneumoniae Infection and Inflammation in Adults with Asthma
Authors: Sävykoski T. , Harju T. , Paldanius M. , Kuitunen H. , Bloigu A. , Wahlström E. , Rytilä P. , Kinnula V. , Saikku P. , Leinonen M.
Published: March 2004

Background:Chlamydia pneumoniae infection and immune response to the C. pneumoniae heat shock protein 60 (CpHsp60) have been suggested to be associated with asthma. Objectives: To study whether a slightly elevated C-reactive protein (CRP) level as a marker of low-grade systemic inflammation has a role in this association, we collected serum and sputum samples from 103 asthma patients with disease severity ranging from mild to moderate and from 30 healthy volunteers. Methods: IgA and IgG antibodies to C. pneumoniae elementary bodies (CpEB) and CpHsp60 were measured by enzyme immunoassay. Serum CRP levels were measured with a rapid two-site ultra-sensitive assay based on time-resolved immunofluorometry. Results: The asthma patients, especially those with moderate asthma, had higher serum IgA antibody levels to CpHsp60 than the healthy controls (test for trend, p = 0.05), whereas antibody levels to CpEB antigen did not differ between the study groups. CRP levels were higher in both asthma groups compared to the control group and moreover, the patients with moderate asthma had higher CRP levels than those with mild asthma (test for trend, p < 0.01). The subjects with a slightly elevated CRP level, defined as ≧1.8 mg/l, had higher CpEB IgA (p = 0.001), CpEB IgG (p = 0.008) and CpHsp60 IgA (p = 0.023) antibody levels in serum compared to the subjects with lower CRP levels. Conclusions: Slightly elevated CRP levels as a marker of low-grade systemic inflammation may be associated with C. pneumoniae infection in asthma patients.
Visits to the Emergency Room for Asthma Attacks and Short-Term Variations in Air Pollution
Authors: Boutin-Forzano S. , Adel N. , Gratecos L. , Jullian H. , Garnier J.M. , Ramadour M. , Lanteaume A. , Hamon M. , Lafay V. , Charpin D.
Published: March 2004

Background: The ‘case-crossover’ design is a strategy fitted to studying transient effects of intermittent exposure on acute-onset disease occurring shortly after exposure. It has the important advantage of eliminating most confounding variables, allowing a stronger causality inference. Objectives: The objective of the study was to evaluate the relationships between emergency room (ER) visits for asthma attacks and gaseous air pollution changes. Methods: The study included 549 individuals, 3–49 years old, visiting the ER during 1 year. Exposure to gaseous air pollutants (SO2, NO2, O3) on the same day and up to 4 days before was computed according to the patient’s address. The statistical analysis included meteorological data as potential confounding variables. Results: No association could be shown between ER visits and SO2 or NO2 levels. In contrast, there was a statistically significant association between ER visits and mean O3 levels, on the day of admission and also on D –2 and D –3. For an increase of 10 µg/m3, the risk of requiring an ER admission increased by 6–10%. Conclusions: Using this new strategy, we confirmed that ozone changes lead to a moderate increase in risk of requiring an ER admission in asthmatic subjects.
Acute Antiarrhythmic Effects of Bi-Level Positive Airway Pressure Ventilation in Patients with Acute Respiratory Failure Caused by Chronic Obstructive Pulmonary Disease: A Randomized Clinical Trial
Authors: Marvisi Maurizio , Brianti Marco , Marani Giuseppe , Turrini Gabriele , Zambrelli Paolo , Ajolfi Corrado , Delsignore Roberto
Published: March 2004

Background: Cardiac arrhythmias are common in patients with chronic obstructive pulmonary disease (COPD) and acute respiratory failure (ARF) and may be life threatening. Recently, non-invasive positive pressure ventilation has been advanced as a useful tool in COPD patients with ARF. This method can affect global cardiac performance through its effects on many determinants of cardiac function and may be helpful in reducing arrhythmias. Objective: To assess the role of bi-level positive pressure ventilation (BiPAP) in the management of cardiac arrhythmias in patients with ARF caused by COPD. Methods: We studied 30 consecutive patients with ARF related to COPD diagnosed according to American Thoracic Society criteria. All subjects were smokers; the mean age was 68 ± 7 years. They were randomly assigned to receive BiPAP plus standard therapy (group 1) or standard therapy alone (group 2). Patients randomized to receive BiPAP were first fitted with a nasal mask, and BiPAP was administered after 12 h of standard therapy. All subjects were studied using a computerized 24-hour Holter ECG. Blood gases, plasma electrolytes, respiratory rate and blood pressure were measured at study entry, at 30, 60 and 120 min and then every 3 h. Results: Heart rate decreased from 86.08 ± 7.86 to 74.92 ± 5.39 in group 1 (p < 0.001) versus 82.77 ± 8.78 to 75.82 ± 6.76 in group 2 (p = 0.033). Ventricular premature complexes decreased from 564.38 ± 737.36 to 166.15 ± 266.26 in group 1 (p < 0.001) versus 523.38 ± 685.75 to 353.54 ± 469.93 in group 2 (p = 0.021). Atrial premature complexes decreased from 570.00 ± 630.36 to 152.31 ± 168.88 in group 1 (p < 0.001) versus 513.77 ± 553.81 to 328.62 ± 400.81 in group 2 (p = 0.021). Conclusions: Cardiac arrhythmias decreased significantly in both groups after the start of both treatments, although data obtained from group 1 revealed a more important statistical significance. Our data seem to support the hypothesis that BiPAP may be a useful tool in managing COPD patients with ARF and mild arrhythmias.
Thrombocytosis as a Useful Prognostic Indicator in Patients with Lung Cancer
Authors: Aoe Keisuke , Hiraki Akio , Ueoka Hiroshi , Kiura Katsuyuki , Tabata Masahiro , Tanaka Motoyuki , Tanimoto Mitsune
Published: March 2004

Background: Thrombocytosis can accompany various cancers including lung cancer. This finding has recently been suggested to indicate poor prognosis. Objectives and Methods: We retrospectively examined the clinical records of 611 patients with lung cancer to investigate whether there is a correlation between thrombocytosis, other clinicopathologic factors, and survival Results: Ninety-eight of the patients (16%) manifested thrombocytosis at the time of their first evaluation at our hospital. Thrombocytosis and age (p = 0.0006) and thrombocytosis and performance status (p = 0.0002) are significantly correlated, but thrombocytosis is not related to gender, tumor histology, clinical stage, or serum lactate dehydrogenase concentrations. Survival is significantly shorter in patients with thrombocytosis: [median survival time (MST) 7.5 months; n = 98] than without thrombocytosis (MST 10.1 months; n = 513; p = 0.0029). Multivariate analysis of prognostic factors using the Cox proportional hazards model indicated that thrombocytosis had independent prognostic significance. Conclusion: Thrombocytosis at the first patient evaluation is an independent prognostic factor in lung cancer.
Vascular Stenting for Palliation of Superior Vena cava Obstruction in Non-Small-Cell Lung Cancer Patients: A Future ‘Standard’ Procedure?
Authors: Greillier Laurent , Barlési Fabrice , Doddoli Christophe , Durieux Olivier , Torre Jean-Philippe , Gimenez Céline , Kleisbauer Jean-Pierre
Published: March 2004

Background: Stenting is a relatively new option in the management of superior vena cava obstruction (SVCO), but available data often concern non-malignant and/or various malignant diseases. Objective: The aim of this study was to assess the efficacy of vascular stenting as a first-choice treatment in SVCO in the exclusive setting of NSCLC. Patients and Methods: Retrospective study of NSCLC patients with SVCO treated in the past year. Demographic data, disease characteristics, etiologic and palliative treatment (use of vascular stenting) were recorded as well as treatment outcome and survival. Results: 17 patients were recruited. Eight had vascular stenting while 9 did not. Except for stenting, there was no difference between the two groups (median age 54 years; 80% men; 53% stage IIIB and 47% stage IV). Stenting (median length 60 mm) achieved complete resolution of SVCO more frequently (75 vs. 25%, p = 0.05) and faster (2 vs. 21 days, p = 0.002) without immediate or delayed complication. All patients with stents received anticoagulation therapy. Relapse rate after complete response (33 g, 50%, p = 0.6) was lower and time to relapse (6.5 g, 2 months) was longer for patients undergoing stenting, without reaching statistical significance. Median overall survival was not statistically different (8 and 5 months, p = 0.06). Conclusions: This study demonstrated the effectiveness of vascular stenting for SVCO in NSCLC patients. The high response rate, quick effect and safety of vascular stenting make this palliative treatment a candidate as a potential standard procedure. The results, however, must be confirmed in a prospective randomized trial including quality of life assessment.
Treatment of Primary Pulmonary Hypertension with Oral Sildenafil
Authors: Karatza Ageliki A. , Narang Indra , Rosenthal Mark , Bush Andrew , Magee Alan G.
Published: March 2004

Sildenafil, a selective phosphodiesterase-5 inhibitor, was administered orally to a 14-year-old girl with primary pulmonary hypertension (PPH) at a dose of 0.5 mg/kg/4 h on a daily basis, increased to doses of 1 and 2 mg/kg at monthly intervals. Following therapy, oxygen saturation increased and exercise capacity improved significantly, but with no change in pulmonary haemodynamics. No side-effects were noted. Sildenafil may be beneficial in children with PPH, but the mechanism of benefit is unclear.
Regional Glucose Metabolism within Cortical Brodmann Areas in Healthy Individuals and Autistic Patients
Authors: Hazlett Erin A. , Buchsbaum Monte S. , Hsieh Pauline , Haznedar M. Mehmet , Platholi Jimcy , LiCalzi Elizabeth M. , Cartwright Charles , Hollander Eric
Published: March 2004

A new Brodmann area (BA) delineation approach was applied to FDG-PET scans of autistic patients and healthy volunteers (n = 17 in each group) to examine relative glucose metabolism (rGMR) during performance of a verbal memory task. In the frontal lobe, patients had lower rGMR in medial/cingulate regions (BA 32, 24, 25) but not in lateral regions (BA 8–10) compared with healthy controls. Patients had higher rGMR in occipital (BA 19) and parietal regions (BA 39) compared with controls, but there were no group differences in temporal lobe regions. Among controls, better recall and use of the semantic-clustering strategy was associated with greater lateral and medial frontal rGMR, while decreased rGMR in medial-frontal regions was associated with greater perseverative/intrusion errors. Patients failed to show these patterns. Autism patients have dysfunction in some but not all of the key brain regions subserving verbal memory performance, and other regions may be recruited for task performance.
Tianeptine as a Slightly Effective Therapeutic Option for Attention-Deficit Hyperactivity Disorder
Authors: Niederhofer Helmut
Published: March 2004

Objective: Because of the hypotonic side effect of clonidine, the use of tianeptine was studied as an alternative because of its longer excretion half-life, decreased sedative side effects and more selective binding profile. Method: We rated sixty-eight psychiatric outpatients diagnosed with attention-deficit hyperactivity disorder (ADHD) at baseline and while taking tianeptine to determine its efficacy as a treatment for ADHD and used comparisons of Conners’ parent ratings within each subject to measure behavioral changes in the subjects. Results: During tianeptine treatment, patients’ mean scores improved significantly overall, and also for Conners’ Hyperactivity, Inattention and Immaturity factors. Conclusions: This preliminary study indicates that tianeptine might be a slightly effective beneficial and useful treatment for ADHD, reducing hyperactive behaviors and enabling greater attentional ability with minimal side effects.
Brain Regions Activated during an Auditory Discrimination Task in Insomniac Postmenopausal Patients before and after Hormone Replacement Therapy: Low-Resolution Brain Electromagnetic Tomography Applied to Event-Related Potentials
Authors: Anderer Peter , Saletu Bernd , Saletu-Zyhlarz Gerda , Gruber Doris , Metka Markus , Huber Johannes , Pascual-Marqui Roberto D.
Published: March 2004

Electrical sources of auditory event-related potentials (ERPs) determined by means of low-resolution brain electromagnetic tomography (LORETA) in 48 unmedicated insomniac postmenopausal patients aged between 46 and 67 years were compared with those obtained in 48 age-matched normal female controls. Subsequently, the patients were included in a double-blind, placebo-controlled, comparative, randomized 3-arm trial phase – Climodien 2/3 [estradiol valerate (EV) 2 mg + the progestin dienogest 3 mg] was compared with EV 2 mg and placebo – followed by an open-label phase in which all of them received Climodien 2/2 (EV 2 mg + dienogest 2 mg). The double-blind and the open-label phase lasted 2 months. ERPs were recorded from 19 EEG leads in a two-tone oddball paradigm and electrical sources of standard N1 and P2 as well as target N2 and P300 components were estimated. In both patients and controls, LORETA revealed an activation of the superior temporal gyrus [auditory cortex, Brodmann areas (BA) 41, 42, 22] for all four components. For standard P2, an additional activation was observed medially parietally in the precuneus (BA 7, 5). For target N2, also a medial frontal source (BA 9, 10, 32) was identified. Finally, for the target P300 component – in addition to the aforementioned sources – activations in the prefrontal cortex (BA 9, 10, 46, 47), the inferior parietal cortex (supramarginal gyrus, BA 40, 39) and the posterior cingulum (BA 31) were found. Thus, patients and controls did not differ in the structural processes engaged in these fundamental aspects of information processing. However, patients demonstrated significantly reduced source strength – for standard ERP components predominantly in the temporal lobe and for target components predominantly in the frontal lobe, indicating reduced energetic resources available for perceptual and cognitive demands of the discrimination task. While, as compared with placebo, estrogen alone had only minor effects on ERP source strength, Climodien generally increased the impressed current density at the ERP peak latencies, predominantly in the temporal lobe, indicating an increased stimulus-induced cortical arousal in the primary and higher-order auditory cortex. Specifically, Climodien enhanced P300 source strength in the left middle temporal gyrus and in the left superior frontal gyrus, brain regions that on the one hand have been shown to be affected by hormone therapy in positron emission tomography and functional magnetic resonance neuroimaging studies and that on the other hand are among those critical for encoding and memory processes.
Effects of Zolpidem and Zaleplon on Sleep, Respiratory Patterns and Performance at a Simulated Altitude of 4,000 m
Authors: Beaumont Maurice , Batéjat Denise , Coste Olivier , van Beers Pascal , Colas Anthony , Clère Jean-Michel , Piérard Christophe
Published: March 2004

The effects of zolpidem or zaleplon on sleep architecture, respiratory patterns and performance were assessed at a simulated altitude of 4,000 m. Twelve male healthy subjects spent 4 nights in a decompression chamber, 1 at sea level (baseline), 3 at 4,000 m to test zolpidem (10 mg), zaleplon (10 mg) and placebo, given 15 min before switching the lights off. Sleep and respiratory patterns were analysed using polysomnography. Cognitive and physical performance was examined the next morning at sea level conditions. The study demonstrates that both zolpidem and zaleplon improved slow wave sleep at altitude, with zolpidem showing more marked effects than zaleplon. Both agents did not adversely affect respiration at altitude during the night, or cognitive or physical performance the next morning at the dosages used in this study. Thus, climbers may safely use both hypnotic agents.
Global Approach to Multichannel Electroencephalogram Analysis for Diagnosis and Clinical Evaluation in Mild Alzheimer’s Disease
Authors: Yoshimura Masafumi , Isotani Toshiaki , Yagyu Takami , Irisawa Satoshi , Yoshida Tsunetaka , Sugiyama Masao , Minami Tomohisa , Sugimoto Tatsuya , Nobuhara Kenji , Okugawa Gaku , Kinoshita Toshihiko
Published: March 2004

To establish an early diagnosis of Alzheimer’s disease (AD), we evaluated brain spatial dynamics and cognitive function in mild AD. Seventeen patients with the diagnosis of mild AD and 17 age-matched controls were examined for Ω (global complexity), Σ (total power) and Φ (generalized frequency) by 19-channel electroencephalography (EEG). As a result, the mild AD group showed significantly higher Ω values than the control group. The Φ values were highly correlated with the Mini-Mental State Examination scores and the full IQ and performance IQ scores of the Japanese Wechsler Adult Intelligence Scale Revised. These results indicate an increase in spatial complexity of the brain electric field in mild AD, as well as a close relationship between slowing of the global frequency of field changes and the cognitive decline in mild AD.
Autoclavable Two-Piece Noncased Wide-Angle Contact Lens System for Vitrectomy
Authors: Shah Vinay A. , Chalam K.V.
Published: March 2004

Purpose: To describe an autoclavable wide-angle two-piece noncased contact lens system (two lenses: equatorial and wider-angle lens) for vitrectomy. Design: The inferior lens is made of an autoclavable plastic with a concave contact surface of 7.7 mm and the superior lens is a convex glass lens. The superior lens is mounted on the inferior one to make the lens assembly. Result: The equatorial lens has a power of +81 D and a field of view of 80–96°, while the wider-angle lens power is +151 D and the field 110–120°. The lens is kept on the cornea upon a drop of viscoelastic substance. An assistant holds it with a conventional lens holder. The lens is easy to sterilize by autoclaving and does not require expensive gas sterilization or potentially injurious chemical sterilization. Conclusion: This lens system provides a panoramic wide-angle view of the retina during vitreous surgery. The autoclaving makes this lens system cost-effective and fast to reuse.
Suppression of N-Methyl-N-Nitrosourea-Induced Photoreceptor Apoptosis in Rats by Docosahexaenoic Acid
Authors: Moriguchi Kaei , Yoshizawa Katsuhiko , Shikata Nobuaki , Yuri Takashi , Takada Hideho , Hada Takahiko , Tsubura Airo
Published: March 2004

We evaluated the effects of dietary intake of docosahexaenoic acid (DHA) on photoreceptor cell apoptosis caused by N-methyl-N-nitrosourea (MNU). Five-week-old female Sprague-Dawley rats were fed basal diet (AIN-76A) or DHA diet (modified AIN-76A containing 9.5% DHA) for 2 weeks, and then received a single intraperitoneal injection of 60 mg/kg body weight MNU at 50 days of age. Then, rats continued to receive the same diet or were switched to the opposite diet: group 1, basal diet before and after MNU injection; group 2, DHA diet before MNU injection and basal diet after MNU injection; group 3, basal diet before MNU injection and DHA diet after MNU injection; group 4, DHA diet before and after MNU injection (10 rats in each group). Rats were starved for 24 h, then sacrificed 3 or 7 days after MNU. Morphologically, at 3 days after MNU injection, photoreceptor cell apoptosis was advanced in group 1 compared with group 4. At this time point, as evaluated by retinal damage ratio [(length of retina less than 4 photoreceptor cells thick/whole retinal length) ×100], retinal damage was highest in group 1 (82.4 ± 5.1%), followed by group 2 (41.1 ± 7.3%), group 3 (24.7 ± 11.5%), and group 4 (6.6 ± 6.6%); severity tended to be inversely correlated with serum DHA composition. At 7 days after MNU injection, active signs of photoreceptor cell apoptosis ended in all MNU-treated groups, and retinal damage ratio was high in group 1 (88.4 ± 2.8%), whereas it remained low in groups 2, 3 and 4 (38.4 ± 15.2, 45.7 ± 9.8 and 46.9 ± 11.2%, respectively). High DHA composition during induction/signaling phase and/or effector phase of photoreceptor cell apoptosis can delay the onset of apoptosis and counteract progression of MNU retinotoxicity in rat retina. DHA may play a role in the suppression of MNU-induced photoreceptor cell apoptosis in rat retina.
The Multifocal Pattern Electroretinogram in Chloroquine Retinopathy
Authors: Neubauer Aljoscha S. , Stiefelmeyer Sandra , Berninger Thomas , Arden Geoffrey B. , Rudolph Günther
Published: March 2004

Purpose: Optimal screening for ocular toxicity caused by chloroquine and hydroxychloroquine is still controversial. With the multifocal pattern electroretinogram (mfPERG), a new electrophysiological technique has recently become available to detect early changes of ganglion cells. In this study this new technique is applied to a series of 10 patients seen consecutively receiving long-term chloroquine medication. Methods: In 10 patients receiving chloroquine medication, clinical examination, Amsler visual field testing and computerized color vision testing were performed. If toxicity was suspected, automated perimetry was carried out. In addition, in all patients conventional pattern electroretinogram (PERG) and mfPERG testing were performed. Results: On clinical examination 8 patients showed no chloroquine-associated maculopathy, while 2 patients did. Of these 2, only 1 reported abnormalities when viewing the Amsler chart, while automated perimetry showed typical, ring-like paracentral scotomas in both affected patients and color vision was significantly abnormal. In the normal patients, 4 of 8 had a mild color vision disturbance, which correlated to age-related macular changes. The amplitudes of the PERG and the central (approximately 10°) responses of the mfPERG were markedly reduced in chloroquine maculopathy, while the latencies were unchanged. The peripheral rings of mfPERG (ranging to 48°) were not affected by chloroquine toxicity. Both PERG and mfPERG were less affected by age-related macular changes. Conclusions: The reduction of PERG and central mfPERG responses in chloroquine maculopathy may help with the early detection of toxicity.
Fcγ Receptors on Mast Cells: Activatory and Inhibitory Regulation of Mediator Release
Authors: Tkaczyk Christine , Okayama Yoshimichi , Metcalfe Dean D. , Gilfillan Alasdair M.
Published: March 2004

Mast cell activation and subsequent release of proinflammatory mediators are primarily a consequence of aggregation of the high affinity receptors for IgE (FcΕRI) on the mast cell surface following antigen-dependent ligation of FcΕRI-bound IgE. However, data obtained from rodent and human mast cells have revealed that IgG receptors (FcγR) can both promote and inhibit mast cell activation. These responses appear to be species and/or mast cell phenotype dependent. In CD34+-derived human mast cells exposed to interferon-γ, FcγRI is upregulated, FcγRII is expressed but not upregulated, and FcγRIII is not expressed. In contrast, in mouse mast cells, FcγRII and FcγRIII receptors are expressed, whereas FcγRI is not. Aggregation of FcγRI on human mast cells promotes mediator release in a manner generally similar to that observed following FcΕRI aggregation. Aggregation of FcγRIIb in mouse mast cells fails to influence cellular processes; however, when coligated with FcΕRI, signaling events thus activated downregulate antigen-dependent mediator release. These divergent responses are a consequence of different motifs contained within the cytosolic tails of the signaling subunits of these receptors and the specific signaling molecules recruited by these receptors following ligation. The studies described imply that data obtained in rodent models regarding the influence of FcγRs on mast cells may not be directly translatable to the human. The exploitation of FcγRs for a potential therapy for the treatment of allergic disorders is discussed in this context.
Predicting Nonepileptic Seizures Utilizing Seizure Frequency, EEG, and Response to Medication
Authors: Davis Bradley J.
Published: March 2004

The objective was to develop criteria that would prompt evaluation with video EEG monitoring in order to shorten the time to diagnosis of nonepileptic seizures. Over a period of 3 consecutive years, all patients being seen for seizures or the consideration of seizures meeting the following criteria were admitted for video EEG monitoring: (1) at least two events per week, (2) refractory to at least two medications, and (3) no prior EEG studies with epileptiform abnormalities after at least two attempts. A total of 13 patients met all three criteria, 11 of these patients had nonepileptic seizures, yielding a positive predictive value of 0.85. The median time from onset of symptoms until referral to the study institution was 3 years, with a range of 0–15 years. The median time from the first patient visit to a definitive diagnosis on video EEG monitoring was 1 month, with a range of 0–7 months. Patients meeting these three criteria frequently have nonepileptic seizures. These patients should undergo video EEG monitoring in a timely fashion to clarify the diagnosis.
Activation of Resistance Arteries with Endothelin-1: From Vasoconstriction to Functional Adaptation and Remodeling
Authors: Bakker Erik N.T.P. , Buus Carsten L. , VanBavel Ed , Mulvany Michael J.
Published: March 2004

Remodeling of resistance arteries is a key feature in hypertension. We studied the transition of vasoconstriction to remodeling in isolated rat skeletal muscle arterioles. Arterioles activated with 10 nM endothelin-1 showed functional adaptation when kept at low distension in a wire myograph setup, where contractile properties shifted towards a smaller lumen diameter after 1 day. Pressurized arteries kept in organoid culture showed physical inward remodeling after 3-day activation with 10 nM endothelin-1, characterized by a reduction in relaxed diameter without a change in the wall cross-sectional area (eutrophic remodeling). The relaxed lumen diameter (at 60 mm Hg) decreased from 169 ± 5 (day 0) to 155 ± 4 µm (day 3). An antibody directed to the β3-integrin subunit (but not one directed to the β1-integrin subunit) enhanced remodeling, from a reduction in relaxed diameter at 60 mm Hg of 15 ± 2.4 to 22 ± 1.8 µm (both on day 3). Collagen gel contraction experiments showed that the antibody directed to the β3-integrin subunit enhanced the compaction of collagen by smooth muscle cells, from 83 ± 1.5 to 68 ± 1.5% of the initial gel diameter. In conclusion, these data show that inward eutrophic remodeling is a response to sustained contraction, which may involve collagen reorganization through β3-integrins.