bluuebunny/crossref_metadata_2025 huggingface dataset:
Endocrinology of Small-for-Gestational-Age Children: Recent Advances
Authors: de Zegher Francis
Published: November 2004

Over recent months, the links between prenatal growth restraint and postnatal endocrinology and metabolism have been strengthened and their spectrum has been broadened. Recent progress has come from complementary angles, including the following: (1) Small for gestational age (SGA) and the human genetics of insulin-like growth factor (IGF)-I and its receptor: (a) IGF-I receptor mutations [1]; (b) single copy of IGF-I receptor gene [2]; (c) IGF-I gene polymorphisms [3]. (2) Adrenarche and polycystic ovary syndrome: (a) prenatal and postnatal weight gain: opposite effects on adrenarche in girls and boys [4]; (b) metformin therapy in low-birth-weight girls to prevent progression from precocious pubarche to polycystic ovary syndrome [5]. (3) Gynecological and pregnancy complications in women born SGA: (a) hypergonadotropinaemia and small uterus-ovaries [6]; (b) identification of low maternal birth weight as a risk factor for: (i) gestational diabetes, (ii) pregnancy-induced hypertension (with SGA offspring) [7, 8]. (4) Growth hormone (GH) therapy for short children born SGA: (a) efficacy of long-term, continuous GH therapy [9]; (b) normal puberty in short GH-treated SGA children [10]. Our knowledge of SGA and post-SGA endocrinology and metabolism continues to expand swiftly. Children born SGA may continue to experience SGA consequences or correlates, and SGA adults may confer intergenerational SGA risk. Given the dynamics of this research frontier, it is anticipated that multiple facets of GH therapy in short SGA children will regularly be challenged in the future. May those questions be welcomed and may their responses ultimately lead to optimal GH regimens that benefit not only SGA children themselves but also, in due course, their progeny.
ECLAMC: The Latin-American Collaborative Study of Congenital Malformations
Authors: Castilla Eduardo E. , Orioli Iêda M.
Published: November 2004

Definition: ECLAMC (‘Estudio Colaborativo Latino Americano de Malformaciones Congénitas’) is a program for the clinical and epidemiological investigation of risk factors in the etiology of congenital anomalies in Latin-American hospitals, using a case-control methodological approach. It is a voluntary agreement among professionals lacking institutional base as well as designated budgets. ECLAMC has been usually funded by research-funding agencies rather than public health ministries. The National Research Councils of Argentina and Brazil have been the main sources of support during its 36 years of existence. Since vital and health statistics are unreliable in South America, ECLAMC collects all the information required for the denominators in a hospital-based sample of births. ECLAMC can be defined as a continental network of persons interested in research and prevention of birth defects. History and Evolution: From the institutional point of view, ECLAMC has had headquarters in diverse centers of Argentina and Brazil, but always as an independent research project, without a defined administrative link. ECLAMC began operating in 1967, as an investigation limited to the city of Buenos Aires, Argentina, and it gradually expanded until covering all the 10 countries of South America as well as Costa Rica and the Dominican Republic. Even though ECLAMC has maintained essentially the same original experimental design since 1967, due to the data accumulated by the program, the increasing experience as well as the development in science, technical modifications occurred including a DNA bank and a fully informatized data handling system. Since 1974 ECLAMC has been a founder member of the International Clearinghouse for Birth Defects Monitoring Systems; since 1994 a WHO Collaborating Center for the Prevention of Congenital Malformations, and since 2000 a collaborating member of the NIH Global Netwok for Women’s and Children’s Health Research. Methodology: The maternity hospital network of ECLAMC examines around 200,000 births per year. All major and minor anomalies diagnosed at birth in infants weighing 500 g or more are registered according to a manual of procedures. The next non-malformed baby of the same sex born in the same hospital is selected as a control subject for each case. Thus, a one-to-one healthy control group matched by sex, time and place of birth is obtained. As a system of epidemic surveillance, ECLAMC systematically observes the fluctuations in the frequencies of different malformations and, in the case of an alarm for a probable epidemic of a given malformation, at a given moment, and given area, it acts to identify its cause. As termination of pregnancy has severe legal restrictions in South America, prevention of birth defects should concentrate on primary, preconceptional and tertiary measures. Tertiary measures aim to avoid complications of the affected patients from the medical, psychological, and social standpoints.
Influence of Smoking on Serum and Milk of Mothers, and Their Infants’ Serum Insulin-Like Growth Factor-I and Insulin-Like Growth Factor Binding Protein-3 Levels
Authors: Ermis Bahri , Altinkaynak Konca , Yildirim Abdulkadir , Ozkan Behzat
Published: November 2004

Objective: To investigate the serum and milk in active-smoking and nonsmoking mothers, and their infants’ insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) levels. Design and Setting: A cohort study conducted at a tertiary medical center. Subjects: Forty-four mothers (age range: 21–34 years) and their newborns (7 days old) were enrolled in the study. Mothers were interviewed and classified according to their smoking status into one of two groups: the active-smoking mothers (n = 21) and the nonsmoking mothers (n = 23). Results: There was no difference noted in either IGF-I, IGFBP-3 or IGF-I/IGFBP-3 ratios in serum and milk of mothers, and their infants’ serum samples according to maternal smoking. Conclusion: This study demonstrated that maternal smoking (5–10 cigarettes/day) did not influence the maternal and infant serum levels of IGF-I and IGFBP-3 as well as the breast milk levels of these peptides.
Cervical Artery Dissection: A 5-Year Prospective Study in the Belluno District
Authors: Cimini N. , D’Andrea P. , Gentile M. , Berletti R. , Ferracci F. , Candeago R.M. , Conte F. , Moretto G.
Published: November 2004

Background: Artery dissection is an unusual cause of ischemic stroke, particularly frequent among young patients. The aim of this study was to collect epidemiological data on artery dissection in a hospital-based community, set up a diagnostic protocol and discover outcome predictors. Methods: Among patients suffering from cerebral infarction resident in our country, those with clinical and radiological features suggestive of artery dissection were selected. Risk factors, investigative techniques and treatment were evaluated. Patients were subjected to clinical examinations and were regularly tested neuradiologically. Results: Out of 895 ischemic stroke patients, 10 patients with cervical artery dissection (1.1%) were found. Seven patients were treated with anticoagulants and 3 received antiplatelet agents. One posttraumatic artery dissection patient died within a few days of the stroke. None of the patients suffered from a recurrence, while serious disability occurred in 4 of them. Conclusions: Artery dissection should be suspected in any cerebral infarction patient, especially in young patients without risk factors for cerebrovascular diseases. The treatment of choice consists of anticoagulants. An early clinical diagnosis, strongly supported by radiological tests, is mandatory to start the proper treatment and achieve the best possible outcome.
One Year of Clinical Experience in Postdilution Hemofiltration with Online Reinfusion of Regenerated Ultrafiltrate
Authors: Meloni Carlo , Ghezzi Paolo M. , Cipriani Silvia , Petroni Sandro , Del Poeta Giovanni , Rossini Bernardo , Rossi Valeria , Recino Gabriele , Suppo Giovanna , Cecilia Annalisa , Casciani Carlo U.
Published: November 2004

Background/Aims: Hemofiltrate reinfusion (HFR) is characterized by the use of regenerated ultrafiltrate as replacement fluid. We set up a new technique, postdilution HFR (PD-HFR), aiming at increasing purification efficiency, treatment tolerance and at reducing inflammatory states. Methods: We performed PD-HFR in 6 uremic patients during 1 year. Dialysis efficacy, dialyzer blood loss and the behavior of cytokines were evaluated. Results: No pyrogenic reactions or other adverse events were recorded. Treatment tolerance was excellent. We observed high urea extraction rates and optimal Kt/V values, high β2-microglobulin (β2m) extraction rates and a decrease in dialyzer blood loss; also IL-6 and TNF-α decreased significantly. Conclusions: Inversion of the standard HFR configuration has allowed us to improve the removal of both urea and β2m, and to decrease dialyzer blood loss, with an optimal tolerance. Moreover, the decrease in cytokine levels might attenuate the uremic microinflammatory state.
Radiosurgical Planning of Meningiomas: Compromises with Conformity
Authors: Rowe Jeremy G. , Walton Lee , Vaughan Paul , Malik Irfan , Radatz Matthias , Kemeny Andras
Published: November 2004

The radiosurgical planning of meningiomas frequently necessitates compromises between irradiating tumour and risking damage to adjacent structures. In selected cases, we resolved this by excluding part of the tumour from the prescription isodose volume. Most of these compromises or ‘suboptimal’ plans achieved growth control. Growth control could not be related to conformity indices or to various measures of the radiation dose received by the meningioma. Examining recurrences, 75% arose from dura outside the original treatment field. These findings are discussed in terms of dose prescription protocols and the use of conformity indices in planning. The importance of the dural origin of meningiomas is well established in surgical practice, as reflected by Simpson’s grades, but may be equally significant in radiosurgical practice.
Normalization of Negative T Waves in the Chronic Stage of Q Wave Anterior Myocardial Infarction as a Predictor of Myocardial Viability
Authors: Altun Armagan , Durmus-Altun Gulay , Birsin Atilla , Gultekin Aziz , Tatli Ersan , Ozbay Gultac
Published: November 2004

We investigated whether spontaneous normalization of negative T waves (TWN) on infarct-related ECG leads (IRLs) in the chronic phase of Q wave anterior myocardial infarction (MI) could be a predictor of residual viability in infarct areas. We prospectively studied 35 patients (age 60 ± 8.6 years) in the chronic phase of Q wave anterior MI. Spontaneous TWN (group A, n = 23) were defined as negative T waves that became upright (≧0.15 mV) in ≧2 IRLs. The presence of negative T waves (group B, n = 12) was defined as symmetric or biphasic negative T wave of ≧0.15 mV. All patients underwent same-day rest 201Tl-stress 99mTc sestamibi dual-isotope myocardial perfusion SPECT and 24-hour 201Tl reinjection imaging for ischemia and viability analysis. On scintigraphic examination, ischemic or viable myocardial segments were found in 18 patients (78%) with TWN and 4 patients (33%) of group B (p = 0.013). The use of TWN as a parameter had a marked influence on the sensitivity (82%), specificity (62%), positive (78%) and negative (67%) predictive values and accuracy (74%) of the diagnosis of viable myocardium. If we add the criterion of positive T waves in aVR with negative T waves to our criteria, we found that sensitivity (90%), positive (80%) and negative (80%) predictive values and accuracy (80%) increased. The results of our study suggest that analysis of TWN on IRLs is an accurate marker of residual viability and/or persistent peri-infarct ischemia in patients in the chronic stage of Q wave anterior MI, and therefore optimizes the diagnostic and therapeutic strategies after MI.
Dexamethasone-Induced Prenatal Alveolar Wall Thinning Is Associated with a Decrease in EIIIA+ Fibronectin Isoform in the Fetal Rat Lung
Authors: Arai Hirokazu , Kikuchi Wataru , Ishida Akira , Takada Goro
Published: November 2004

Background: Glucocorticoid hormones play an important role in architectural and biochemical lung maturation. Although much of the molecular mechanism of their action in the lung is not fully understood, glucocorticoids directly or indirectly regulate lung maturation. Indirect effects of glucocorticoids may involve the modulation of cell-cell or cell-matrix interactions. Fibronectin (FN) is the major constituent of the pulmonary extracellular matrix and exists in multiple isoforms arising from alternative RNA splicing. EIIIA is the major alternatively spliced segment, and its expression is regulated in a spatiotemporal and oncodevelopmental manner. Objectives: The present study focuses on the regulation of EIIIA-containing FN isoforms (referred to as EIIIA+ FN) by glucocorticoids in the developing lung. Methods: Dexamethasone (DEX) or saline was injected daily into pregnant rats from day 15 of gestation (term = day 22) until 24 h before sacrifice. The expression of EIIIA+ FN and proliferating cell nuclear antigen (PCNA), a biochemical marker for cell proliferation, was investigated in the fetal rat lung. Results: At day 20 of gestation (the canalicular stage), the DEX-treated lung showed a significant decrease in weight and saccular septal wall thickness, while the messenger RNA expression of the surfactant protein SP-B was increased in the DEX-treated lung, as compared with the control lung. The expression of EIIIA+ FN and PCNA around the distal airspaces was less extensive in the DEX-treated lung than in the control lung at day 20 of gestation. Conclusions: Given the finding in vitro that EIIIA+ FN regulated the cell cycle, our results suggest that the change of EIIIA+ FN expression in the DEX-treated lung affected pulmonary cell proliferation.
Macrophage Liver X Receptor Is Required for Antiatherogenic Activity of LXR Agonists
Authors: Levin Nancy , Bischoff Eric D. , Daige Chris L. , Thomas Diane , Vu Calvin T. , Heyman Richard A. , Tangirala Rajendra K. , Schulman Ira G.
Published: November 2004

Objective—

Complications of atherosclerotic cardiovascular disease due to elevated blood cholesterol levels are the major cause of death in the Western world. The liver X receptors, LXRα and LXRβ (LXRs), are ligand-dependent transcription factors that act as cholesterol sensors and coordinately control transcription of genes involved in cholesterol and lipid homeostasis as well as macrophage inflammatory gene expression. LXRs regulate cholesterol balance through activation of ATP-binding cassette transporters that promote cholesterol transport and excretion from the liver, intestine, and macrophage. Although LXR agonists are known to delay progression of atherosclerosis in mouse models, their ability to abrogate preexisting cardiovascular disease by inducing regression and stabilization of established atherosclerotic lesions has not been addressed.

Methods and Results—

We demonstrate that LXR agonist treatment increases ATP-binding cassette transporter expression within preexisting atherosclerotic lesions, resulting in regression of these lesions as well as remodeling from vulnerable to stable lesions and a reduction in macrophage content. Further, using macrophage-selective LXR-deficient mice created by bone marrow transplantation, we provide the first evidence that macrophage LXR expression is necessary for the atheroprotective actions of an LXR agonist.

Conclusions—

These data substantiate that drugs targeting macrophage LXR activity may offer therapeutic benefit in the treatment of atherosclerotic cardiovascular disease.
Decreased Binding of Annexin V to Endothelial Cells
Authors: Cederholm Anna , Svenungsson Elisabet , Jensen-Urstad Kerstin , Trollmo Christina , Ulfgren Ann-Kristin , Swedenborg Jesper , Fei Guo-Zhong , Frostegård Johan
Published: November 2004

Objective—

The cause of the exceedingly high risk of atherothrombosis in systemic lupus erythematosus (SLE) is not clear but antiphospholipid antibodies (aPL) and potentially antithrombotic annexin V have been implicated.

Methods and Results—

Twenty-six women (52±8.2 years) with SLE and a history of cardiovascular disease (CVD) (SLE cases) were compared with 26 women with SLE but no CVD (SLE controls) and 26 healthy women (population controls). Common carotid intima-media thickness (IMT) was determined by B-mode ultrasound as a surrogate measure of atherosclerosis. Annexin V binding to human umbilical vein endothelial cells (HUVECs) as determined by flow cytometry after 24-hour culture with plasma was decreased when plasma from SLE cases was used (SLE cases versus population controls:
P
=0.002; SLE cases versus SLE controls
P
=0.02). Antibodies against cardiolipin were among IgG antibodies causing decreased binding. There was a positive association between annexin V binding and IMT (
R
=0.73;
P
<0.001) among SLE cases. Immunohistochemical analysis revealed presence of annexin V in all human atherosclerotic plaques tested, especially at sites prone to rupture.

Conclusions—

Decreased annexin V binding to endothelium caused by antibodies may represent a novel mechanism of atherothrombosis. We hypothesize that even though annexin V may promote plaque growth at some disease stages, it may also stabilize plaque.
Enhanced Cellular Adenosine Uptake Limits Adenosine Receptor Stimulation in Patients With Hyperhomocysteinemia
Authors: Riksen Niels P. , Rongen Gerard A. , Boers Godfried H.J. , Blom Henk J. , van den Broek Petra H.H. , Smits Paul
Published: November 2004

Objective—

Endogenous adenosine has several cardioprotective effects. We postulate that in patients with hyperhomocysteinemia increased intracellular formation of S-adenosylhomocysteine decreases free intracellular adenosine. Subsequently, facilitated diffusion of extracellular adenosine into cells through dipyridamole-sensitive transporters is enhanced, limiting adenosine receptor stimulation. We tested this hypothesis in patients with classical homocystinuria (n=9, plasma homocysteine 93.1±24.7 μmol/L) and matched controls (n=8, homocysteine 9.1±1.0).

Methods and Results—

Infusion of adenosine (0.5, 1.5, 5.0, and 15.0 μg/min/dL forearm) into the brachial artery increased forearm blood flow, as measured with venous occlusion plethysmography, to 2.9±0.4, 4.3±0.5, 5.6±1.1, and 9.6±2.1 in the patients and to 2.8±0.6, 4.4±1.0, 9.0±1.7, and 17.0±3.1 mL/min/dL in controls (
P
<0.05). However, adenosine-induced vasodilation in the presence of dipyridamole (100 μg/min/dL) was similar in both groups (
P
=0.9). Additionally, in isolated erythrocytes, adenosine uptake was accelerated by incubation with homocysteine (half-time 6.4±0.3 versus 8.1±0.5 minutes,
P
<0.001) associated with increased intracellular formation of S-adenosylhomocysteine (
P
<0.0001).

Conclusions—

In hyperhomocysteinemia, adenosine-induced vasodilation is impaired but is restored by dipyridamole. Accelerated cellular adenosine uptake probably accounts for these observations. These impaired actions of adenosine could well contribute to the cardiovascular complications of hyperhomocysteinemia.
The Effect of Wind Shear and Curvature on the Gravity Wave Drag Produced by a Ridge
Authors: Teixeira Miguel A. C. , Miranda Pedro M. A.
Published: November 2004

The analytical model proposed by Teixeira, Miranda, and Valente is modified to calculate the gravity wave drag exerted by a stratified flow over a 2D mountain ridge. The drag is found to be more strongly affected by the vertical variation of the background velocity than for an axisymmetric mountain. In the hydrostatic approximation, the corrections to the drag due to this effect do not depend on the detailed shape of the ridge as long as this is exactly 2D. Besides the drag, all the perturbed quantities of the flow at the surface, including the pressure, may be calculated analytically.
Promoter trapping reveals significant differences in integration site selection between MLV and HIV vectors in primary hematopoietic cells
Authors: De Palma Michele , Montini Eugenio , de Sio Francesca R. Santoni , Benedicenti Fabrizio , Gentile Alessandra , Medico Enzo , Naldini Luigi
Published: November 2004

Recent reports have indicated that human immunodeficiency virus (HIV) and murine leukemia virus (MLV) vectors preferentially integrate into active genes. Here, we used a novel approach based on genetic trapping to rapidly score several thousand integration sites and found that MLV vectors trapped cellular promoters more efficiently than HIV vectors. Remarkably, 1 in 5 MLV integrations trapped an active promoter in different cell lines and primary hematopoietic cells. Such frequency was even higher in growth-stimulated lymphocytes. We show that the different behavior of MLV and HIV vectors was dependent on a different integration pattern within transcribed genes. Whereas MLV-based traps showed a strong bias for promoter-proximal integration leading to efficient reporter expression, HIV-based traps integrated throughout transcriptional units and were limited for expression by the distance from the promoter and the reading frame of the targeted gene. Our results indicate a strong propensity of MLV to establish transcriptional interactions with cellular promoters, a behavior that may have evolved to enhance proviral expression and may increase the insertional mutagenesis risk. Promoter trapping efficiency provides a convenient readout to assess transcriptional interactions between the vector and its flanking genes at the integration site and to compare integration site selection among different cell types and in different growth conditions.
Increased peripheral platelet destruction and caspase-3–independent programmed cell death of bone marrow megakaryocytes in myelodysplastic patients
Authors: Houwerzijl Ewout J. , Blom Nel R. , van der Want Johannes J. L. , Louwes Henk , Esselink Mariet T. , Smit Jan W. , Vellenga Edo , de Wolf Joost Th. M.
Published: November 2004

To investigate underlying mechanisms of thrombocytopenia in myelodysplastic syndrome (MDS), radiolabeled platelet studies were performed in 30 MDS patients with platelet counts less than 100 × 109/L. Furthermore, plasma thrombopoietin and glycocalicin index (a parameter of platelet or megakaryocyte destruction) were determined. Mean platelet life (MPL), corrected for the degree of thrombocytopenia, was reduced in 15 of 30 patients (4.3 ± 0.9 days [mean ± SD] vs 6.0 ± 1.3, P = .0003). Platelet production rate (PPR) was reduced in 25 of 30 patients (68 ± 34 × 109/d vs 220 ± 65, P < .0001). Thrombopoietin levels were not significantly correlated with the PPR. However, the glycocalicin index was significantly higher compared with controls (15 ± 16 vs 0.7 ± 0.2, P = .001) and significantly correlated with the PPR (P = .02, r = -0.5), but not with the MPL (P = 1.8). Ultrastructural studies demonstrated necrosis-like programmed cell death (PCD) in mature and immature megakaryocytes (n = 9). Immunohistochemistry of the bone marrow biopsies demonstrated no positive staining of MDS megakaryocytes for activated caspase-3 (n = 24) or cathepsin D (n = 21), while activated caspase-8 was demonstrated in a subgroup of patients (5/21) in less than 10% of megakaryocytes. These results indicate that the main cause of thrombocytopenia in MDS is caspase-3–independent necrosis-like PCD resulting in a decreased PPR in conjunction with an increased glycocalicin index.
Rapid and large amount of autocrine IL-3 production is responsible for mast cell survival by IgE in the absence of antigen
Authors: Kohno Masayuki , Yamasaki Sho , Tybulewicz Victor L. J. , Saito Takashi
Published: November 2004

Cross-linking FcϵRI on mast cells by immunoglobulin E (IgE) and antigen (Ag) initiates cascades leading to antiparasitic or allergic responses. It was recently reported that IgE without antigen, IgE(-Ag), actively promotes mast cell survival. Although we have demonstrated that the immunoreceptor tyrosine-based activation motif within FcRγ is essential for IgE(-Ag)–induced mast cell survival, the underlying mechanism remains still unclear. Here, we investigated the mechanism of IgE(-Ag)–induced survival using mast cells lacking several downstream molecules. Lyn and Syk were essential, whereas Fyn, Gab2, and the phosphoinositide 3-kinase–Akt pathway were not critical for survival. Failure of survival in FcRγ-/- bone marrow mast cells (BMMCs) was rescued by coculture with IgE-treated wild-type BMMCs, suggesting that survival is induced not directly through FcϵRI signals. We found that the survival is predominantly mediated by high production of interleukin 3 (IL-3), evidenced by severe impairment of survival by anti–IL-3 and in IL-3-/- BMMCs. The up-regulation of Bcl-xL/Bcl-2 by IgE was abrogated in IL-3-/- BMMCs, whereas the expression of histidine decarboxylase was normally induced. These results indicate that IL-3 plays a crucial role for IgE(-Ag)–induced mast cell survival, functioning in an autocrine manner by inducing the Bcl-xL/Bcl-2 via signal transducer and activator of transduction 5. We further suggest that IgE(-Ag)–mediated gene expression in mast cells is regulated at least 2 mechanisms: autocrine IL-3 dependent and independent.
Genetic analysis of SLC11A1 polymorphisms in multiple sclerosis patients
Authors: Comabella Manuel , Altet Laura , Peris Francesc , Villoslada Pablo , Sánchez Armand , Montalban Xavier
Published: November 2004

Solute carrier 11a1 (SLC11A1; formerly NRAMP1, where NRAMP stands for natural resistance-associated macrophage protein) is a proton/bivalent cation antiporter that localizes to late endosomes/lysosomes. SLC11A1 regulates macrophage functions that are of potential importance in the induction and/or maintenance of autoimmune diseases such as rheumatoid arthritis, type 1 diabetes and Crohn’s disease. We investigated SLC11A1 gene as a candidate gene for genetic susceptibility to multiple sclerosis (MS) in our population. Four SLC11A1 gene polymorphisms (5?GT repeat, D543N, 1729 -55del4 and 1729 -271del4) were analysed in a case-control study of 195 patients with MS and 125 control subjects. We found no evidence of association between SLC11A1 polymorphisms and MS susceptibility in the Spanish population.
Reliable screening for neuropsychological impairment in multiple sclerosis
Authors: Benedict Ralph HB , Cox Darcy , Thompson Laetitia L , Foley Fred , Weinstock-Guttman Bianca , Munschauer Frederick
Published: November 2004

In an earlier study, we developed the Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ) to assist in the screening for neuropsychological (NP) impairments. Self-report MSNQ scores correlated significantly with measures of depression, whereas informant-report MSNQ scores correlated with cognitive performance, but not depression. This study was criticized for use of a small sample and lack of data regarding normal performance and test -retest reliability. The present study was designed to replicate the earlier work with a larger sample of patients and normal controls obtained from multiple sites. We also evaluated the test -retest reliability and predictive validity of the MSNQ. The sample included 85 multiple sclerosis (MS) patients and 40 normal controls, matched on demographic variables. All participants completed the MSNQ and underwent NP testing. Thirty-four patients were re-examined at one week. Pearson and ANOVA techniques were utilized for univariate comparisons. Bayesian statistics were calculated to assess predictive validity. Patient self- and informant-report MSNQ scores differed from normal and test -retest reliability indices were high. Both self- and informant-reports were correlated with cognitive dysfunction and depression scales. Self-report MSNQ scores correlated more strongly with depression than cognitive performance, whereas the opposite pattern was observed with informant-report scores. Bayesian statistics showed that informant-report MSNQ scores predict cognitive impairment and patient self-report scores identify patients with cognitive impairment or depression. It is concluded that the MSNQ is useful, although patient self-reports may be exaggerated in depressed patients or reduced in patients with severe cognitive impairment.
Utilization of the auditory consonant trigram test to screen for cognitive impairment in patients with multiple sclerosis: comparison with the paced auditory serial addition test
Authors: Ozakbas S , Ormeci B , Akdede B B.Kivircik , Alptekin K , Idiman E
Published: November 2004

Several screening methods have been evaluated, but most of them are insensitive to MS-related cognitive impairment. The Auditory Consonant Trigram (ACT) test, which contains core features required for a working memory task, has been used to test neuro-cognitive function in different samples of patients to examine the status of working memory. The aim of the present study was to investigate the correlation between ACT and the Paced Auditory Serial Addition Test (PASAT), and the usefulness of ACT for evaluating the cognitive impairment in MS in a brief visit. A total of 109 consecutive patients with definite MS were included. The patients were administered ACT, PASAT and EDSS. Mean PASAT score and mean ACT score were 46.199-8.51 and 45.309-9.07, respectively. Correlations between EDSS and PASAT, and EDSS and ACTwere moderately strong. The correlation between ACT and PASATwas very strong (r=0.831, P<0.01). The mean time required to perform ACT was significantly shorter than PASAT (7.25±4.72 and 14.70±6.97 minutes, respectively). In conclusion, as a relatively brief measure of working memory, ACT was well accepted by MS patients and has a strong correlation with PASAT. Thus, ACT might be used for rapid evaluation of cognitive impairment in patients with multiple sclerosis.
Quality of life measures for the palliative care of people severely affected by multiple sclerosis: a systematic review
Authors: Gruenewald D A , Higginson I J , Vivat B , Edmonds P , Burman R E
Published: November 2004

Although there is increasing interest in measuring the quality of life (QoL) of people with multiple sclerosis (MS), relatively little is known about the issues of importance to people severely affected by MS. In the first of two systematic reviews, we searched the literature to identify measures that have been used to assess health-related QoL in people with MS, and described their measurement properties in terms of validity, reliability, responsiveness to change, and appropriateness for QoL assessment in people severely affected by MS. In the second review, we identified care domains important to people with MS, by reviewing survey, focus group and interview studies involving people with MS and/or their caregivers. Forty-six studies evaluating 12 disease-specific and ten generic QoL measures for patients, and one disease-specific measure for caregivers, satisfied all inclusion criteria. Sixteen focus group or interview studies and 51 questionnaire-based studies evaluated domains of care important to people with MS, and seven qualitative and 11 questionnaire-based studies assessed domains of care important to their caregivers. From these studies, we identified 15 domains of care important to people with MS and 12 domains important to caregivers. QoL measures differed markedly in their coverage of these care domains. Moreover, each measure fulfilled some but not all criteria of validity, reliability, responsiveness, and appropriateness. Further work is needed to clarify the domains of care relevant to people with severe MS, and to measure health-related QoL in this population.
Locus‐Specific Involvement of Anti‐Opioid Systems in Morphine Tolerance and Dependence
Authors: UEDA HIROSHI
Published: November 2004

Abstract: Opioid tolerance and addiction could be discussed as two types of plasticity or counteradaptation, at the cellular level and through neuronal circuits. Cellular counteradaptation mechanisms include receptor desensitization through phosphorylation and endocytosis and through altered gene expression. The former mechanisms are related to the acute tolerance mechanisms, while the latter to chronic one. From current studies, it is known that various phosphorylation steps, such as protein kinase C (PKC) and G protein‐coupled receptor (GPCR) kinase (GRK) regulate endocytosis. Of interest is that there are some differences in the physiological roles between opioid receptor endocytosis and other GPCR ones. Endocytosis of the opioid receptor is conceived as a recycling and resensitization step rather than the desensitization step. PKC phosphorylation inhibits endocytosis (PKC hypothesis). Therefore the PKC inhibitor attenuates acute analgesic tolerance. The agonist, which shows high‐endocytosis stimulation, therefore makes less significant tolerance liability (RAVE hypothesis). Chronic tolerance is more likely related to the mechanisms through plastic modulation of neuronal circuits, where anti‐opioidergic neurons are involved. The knockout mice lacking the receptors for anti‐opioidergic nociceptin/orphanin FQ (N/OFQ) or glutamatergic neurons show weak or no morphine tolerance and dependence. As their gene expression or protein expression increases during chronic morphine treatments, we propose the hypothesis that the enhanced anti‐opioid system may cause a counteradaptation to show tolerance and dependence. By a novel electroporation technique to deliver the receptor into the brain of knockout mice, we succeeded in determining the specific locus for the site of anti‐opioid (through GluRε1 or NR2A) action. All these results suggest that enhanced anti‐opioid systems may contribute to the development of morphine tolerance and dependence, and their contributions could be brain locus specific.
Methamphetamine and Brain Histamine: A Study Using Histamine‐Related Gene Knockout Mice
Authors: IWABUCHI KENTARO , KUBOTA YASUHIKO , ITO CHIHIRO , WATANABE TAKESHI , WATANABE TAKEHIKO , YANAI KAZUHIKO
Published: November 2004

Abstract: The central histamine (HA) neurons that originate from the posterior hypothalamus modulate a variety of physiological functions. In order to investigate the roles of brain histaminergic neuron system in the behavioral effects of methamphetamine (METH), we administrated METH repeatedly to l‐histidine decarboxylase (HDC)‐, histamine H1 receptor‐, H2 receptor‐gene knockout (KO) mice, H1/H2 receptor‐gene double KO mice, and wild type (WT) mice corresponding to each of them, and we measured locomotor activities. We also measured the contents of monoamines and amino acids in the brain of HDC‐gene KO and WT mice after a single administration of METH. METH‐induced locomotor hyperactivity and the development of behavioral sensitization were facilitated more in the HDC‐gene KO mice and H1/H2 gene double KO mice than the WT mice, suggesting that brain histamine has an inhibitory effect on the METH action through both H1 and H2 receptors. In addition, neurochemical study suggested the involvement of the GABAergic neuron system in the inhibitory effect of brain histamine.
Nootropic Nefiracetam Inhibits Proconvulsant Action of Peripheral‐Type Benzodiazepines in Epileptic Mutant EL Mice
Authors: NAKAMOTO YURIE , SHIOTANI TADASHI , WATABE SHIGEO , NABESHIMA TOSHITAKA , YOSHII MITSUNOBU
Published: November 2004

Abstract: Piracetam and structurally related nootropics are known to potentiate the anticonvulsant effects of antiepileptic drugs. It remains to be seen, however, whether these nootropics inhibit proconvulsant actions of many toxic agents including Ro 5‐4864, a specific agonist for peripheral‐type benzodiazepine receptors (PBR). The present study was designed to address this issue using EL mice, an animal model of epilepsy. In behavioral pharmacological experiments, EL mice were highly susceptible to convulsions induced by Ro 5‐4864 (i.p.) in comparison with nonepileptic DDY mice. Nefiracetam administered orally to EL mice inhibited spontaneous seizures. In DDY mice, convulsions induced by Ro 5‐4864 were prevented by nefiracetam when administered by i.v. injection. Aniracetam (i.v.) was partially effective, but piracetam and oxiracetam were ineffective as anticonvulsants. Binding assay for brain tissues revealed a higher density of mitochondrial PBR in EL mice compared with DDY mice. Binding of the PBR ligands Ro 5‐4864 to either EL or DDY mouse brain was inhibited by micromolar concentrations of these nootropic agents in the sequence of nefiracetam > aniracetam ≫ oxiracetam, piracetam. This rank order is identical to potency as anticonvulsants. These data suggest that nefiracetam may prevent toxic effects of PBR agonists through interacting with PBR.
Psychostimulants and Vesicle Trafficking: A Novel Mechanism and Therapeutic Implications
Authors: HANSON GLEN R. , SANDOVAL VERONICA , RIDDLE EVAN , FLECKENSTEIN ANNETTE E.
Published: November 2004

Abstract: The monoamine vesicular transporter 2 (VMAT‐2) has been associated with dopamine (DA) sequestration and protection against neurodegeneration caused by the intracellular oxidation of this monoamine. The data presented herein suggest that methylphenidate treatment enhances the amount of VMAT‐2 protein and possibly its activity in the presynaptic cytosol, where it is able to increase the sequestration of DA and likely protect against its instability. In contrast, methamphetamine (METH) has an opposite effect on cytosolic VMAT‐2 resulting in degradation of DA terminals. The fact that posttreatment of methylphenidate after a neurotoxic regimen of METH protects against resulting loss of DA parameters suggests that treatment with methylphenidate, or other DA transporter blockers, may be protective against degenerative disorders of DA pathways, such as Parkinson's disease.
Effects of “Legal X” Piperazine Analogs on Dopamine and Serotonin Release in Rat Brain
Authors: BAUMANN MICHAEL H. , CLARK ROBERT D. , BUDZYNSKI ALLISON G. , PARTILLA JOHN S. , BLOUGH BRUCE E. , ROTHMAN RICHARD B.
Published: November 2004

Abstract: 3,4‐Methylenedioxymethamphetamine (MDMA) is a popular illicit drug that evokes transporter‐mediated release of serotonin (5‐HT) and dopamine (DA) from nerve cells. Recently, drug users have ingested combinations of the piperazine analogs, 1‐benzylpiperazine (BZP) and 1‐(m‐trifluoromethylphenyl)piperazine (TFMPP), in an attempt to mimic the subjective effects of MDMA. In the present study, we compared neurochemical effects of MDMA, BZP, and TFMPP in rat brain. The ability of MDMA, BZP, and TFMPP to stimulate efflux of [3H]5‐HT and [3H]MPP+ (a DA transporter substrate) was determined in vitro using release assays in synaptosomes. The ability of these drugs to increase extracellular 5‐HT and DA in vivo was assessed using intracranial microdialysis in nucleus accumbens. MDMA stimulated transporter‐mediated release of 5‐HT (EC50= 58 nM) and MPP+ (EC50= 119 nM). BZP was a selective releaser of MPP+ (EC50= 175 nM), whereas TFMPP was a selective releaser of 5‐HT (EC50= 121 nM). MDMA injections (1 and 3 mg/kg, i.v.) increased dialysate 5‐HT and DA in a dose‐related manner, but actions on 5‐HT were predominant. BZP (3 and 10 mg/kg, i.v.) elevated dialysate DA and 5‐HT, while TFMPP (3 and 10 mg/kg, i.v.) elevated only 5‐HT. The coadministration of BZP plus TFMPP (BZP/TFMPP) produced marked elevations in extracellular 5‐HT and DA that mirrored the effects of MDMA. At the high dose of BZP/TFMPP (10 mg/kg, i.v.), the rise in dialysate DA exceeded the summed effects of the drugs alone. Our results support the hypothesis that the BZP/TFMPP combination mimics the neurochemical mechanism of MDMA, providing a basis for recreational use of these agents. Additionally, the findings suggest possible drug‐drug synergism when piperazine drugs are coadministered at high doses.
Effects of L‐745,870, a Dopamine D4 Receptor Antagonist, on Naloxone‐Induced Morphine Dependence in Mice
Authors: MAMIYA T , MATSUMURA T , UKAI M
Published: November 2004

Abstract: We examined whether dopamine D4 receptor is involved in morphine dependence in mice. Mice pretreated with morphine (10 mg/kg, s.c.) twice a day for 5 days showed withdrawal syndromes such as jumping, rearing, and forepaw tremors after the administration of naloxone (2 mg/kg, i.p.) on the sixth day. Such mice exhibited significant elevation of cAMP levels in the thalamus compared with the control mice. L‐745,870 (1 mg/kg, i.p.), a selective dopamine D4 receptor antagonist, pretreated with morphine on the sixth day, significantly attenuated the severity of withdrawal syndromes and the increase in cAMP levels after the administration of naloxone. These results suggest that (1) the elevation of cAMP levels is involved in the expression of morphine‐induced withdrawal syndromes, and (2) dopamine D4 receptor antagonistsinhibit the expression of morphine‐induced withdrawal syndromes accompanied with biochemical changes in mice. Furthermore, dopamine D4 receptor antagonists may be useful drugs for attenuating the expression of morphine dependence.
Role of γ‐Aminobutyric Acid (GABA) and Metabotropic Glutamate Receptors in Nicotine Reinforcement: Potential Pharmacotherapies for Smoking Cessation
Authors: MARKOU ATHINA , PATERSON NEIL E. , SEMENOVA SVETLANA
Published: November 2004

Abstract: Previous work indicated a role for GABA and glutamate in the reinforcing effects of drugs of abuse. The present studies assessed the effects of GABAergic and glutamatergic manipulations on the reinforcing effects of nicotine as assessed by intravenous nicotine self‐administration. Male Wistar rats were allowed to self‐administer either of two nicotine doses under a fixed ratio or a progressive ratio schedule of reinforcement. The effects of a glutamatergic compound on nicotine self‐administration in male DBA/2J mice were also explored. Finally, to assess for nonspecific effects of the drug manipulations, the effects of all test compounds on responding maintained by a food reinforcer were investigated. The pharmacological manipulations used were: γ‐vinyl‐GABA (vigabatrin or GVG), an irreversible inhibitor of GABA transaminase, the GABAB receptor agonists (−)baclofen and CGP44532, and the metabotropic glutamate receptor 5 (mGluR5) antagonist MPEP. GVG, CGP44532, and (−)baclofen dose‐dependently decreased nicotine self‐administration on the fixed‐ratio schedule, but also decreased food‐maintained responding. Furthermore, CGP44532 decreased breakpoints for nicotine and food at identical doses under the progressive‐ratio schedule. MPEP dose‐dependently decreased nicotine self‐administration with no effect on food‐maintained responding in rats. MPEP also decreased nicotine self‐administration in the mice. These results demonstrate that activation of GABAB receptors or blockade of mGluR5 decreased nicotine self‐administration. Although there was some selectivity for the effects of the GABAergic manipulations, there was clear selectivity of the effects of MPEP on nicotine‐ versus food‐maintained responding. Thus, compounds that increase GABAergic neurotransmission and antagonists at mGluR5 have potential as anti‐smoking medications for humans.
Prognostic Factors in Resected Stage I Non–Small-Cell Lung Cancer: A Multivariate Analysis of Six Molecular Markers
Authors: Lu Charles , Soria Jean-Charles , Tang Ximing , Xu Xiao-Chun , Wang Luo , Mao Li , Lotan Reuben , Kemp Bonnie , Bekele B. Nebiyou , Feng Lei , Hong Waun K. , Khuri Fadlo R.
Published: November 2004

Purpose

To analyze the prognostic significance of six molecular biomarkers (death-associated protein kinase [DAPK] promoter methylation, interleukin-10 [IL-10] protein expression, cyclooxygenase-2 [COX-2] mRNA expression, human telomerase reverse transcriptase catalytic subunit [hTERT] mRNA expression, retinoic acid receptor-beta [RAR-β] mRNA expression, and K-ras mutational status) in stage I non–small-cell lung cancer (NSCLC) patients.

Patients and Methods

Biomarker analyses were performed on tumors from 94 patients with stage I NSCLC who underwent surgical resection at our institution. A minimum follow-up period of 5 years was required. DAPK methylation was assessed by methylation-specific polymerase chain reaction (PCR). RAR-β, COX-2, and hTERT mRNA levels were determined by in situ hybridization with digoxigenin-labeled antisense riboprobes. K-ras mutation status was determined by the PCR–primer introduced restriction with enrichment for mutant alleles method. IL-10 protein expression was analyzed by immunohistochemistry using a polyclonal antihuman IL-10 antibody. Cancer-specific survival was analyzed with a Cox proportional hazards model. To identify independent prognostic factors, a stepwise selection method was used.

Results

DAPK methylation, IL-10 lack of expression, COX-2 expression, hTERT expression, RAR-β expression, and K-ras mutations were observed in 46.8%, 29.8%, 59.6%, 34.0%, 23.4%, and 34.0% of patients, respectively. In the final model, DAPK methylation and IL-10 lack of expression were significant negative prognostic factors for cancer-specific survival, whereas COX-2 expression was of borderline significance.

Conclusion

In this cohort of resected stage I NSCLC patients, molecular markers that independently predict cancer-specific survival have been identified. The prognostic roles of DAPK methylation, IL-10, and other biomarkers in NSCLC merit further investigation.
Colorectal Cancer With Mutation in BRAF, KRAS, and Wild-Type With Respect to Both Oncogenes Showing Different Patterns of DNA Methylation
Authors: Nagasaka Takeshi , Sasamoto Hiromi , Notohara Kenji , Cullings Harry M. , Takeda Masanori , Kimura Keigo , Kambara Takeshi , MacPhee Donald G. , Young Joanne , Leggett Barbara A. , Jass Jeremy R. , Tanaka Noriaki , Matsubara Nagahide
Published: November 2004

Purpose

BRAF mutations are common in sporadic colorectal cancers (CRCs) with a DNA mismatch repair (MMR) deficiency that results from promoter methylation of hMLH1, whereas KRAS mutations are common in MMR proficient CRCs associated with promoter methylation of MGMT. The aim of this study was to further investigate the link between genetic alterations in the RAS/RAF/ERK pathway and an underlying epigenetic disorder.

Patients and Methods

Activating mutations of BRAF and KRAS were identified and correlated with promoter methylation of 11 loci, including MINT1, MINT2, MINT31, CACNA1G, p16INK4a, p14ARF, COX2, DAPK, MGMT, and the two regions in hMLH1 in 468 CRCs and matched normal mucosa.

Results

BRAF V599E mutations were identified in 21 (9%) of 234 CRCs, and KRAS mutations were identified in 72 (31%) of 234 CRCs. Mutations in BRAF and KRAS were never found in the same tumor. CRCs with BRAF mutations showed high-level promoter methylation in multiple loci, with a mean number of methylated loci of 7.2 (95% CI, 6.6 to 7.9) among 11 loci examined (P < .0001). Tumors with KRAS mutations showed low-level promoter methylation, and CRCs with neither mutation showed a weak association with promoter methylation, with an average number of methylated loci of 1.8 (95% CI, 1.5 to 2.1) and 1.0 (95% CI, 0.79 to 1.3), respectively.

Conclusion

In CRC, the methylation status of multiple promoters can be predicted through knowledge of BRAF and, to a lesser extent, KRAS activating mutations, indicating that these mutations are closely associated with different patterns of DNA hypermethylation. These changes may be important events in colorectal tumorigenesis.