bluuebunny/crossref_metadata_2025 huggingface dataset:
Leishmania major-mediated prevention of programmed cell death induction in infected macrophages is associated with the repression of mitochondrial release of cytochrome c
Authors: Akarid Khadija , Arnoult Damien , Micic-Polianski Juliette , Sif Jamila , Estaquier Jérôme , Ameisen Jean Claude
Published: April 2004

Leishmania are obligate, intracellular parasites of macrophages in their vertebrate hosts, including humans, in which they cause disease. Here, we report that in vitro infection with Leishmania major protects murine bone marrow-derived macrophages against programmed cell death (PCD) induced by deprival of macrophage-colony stimulating factor and delays PCD caused by treatment with staurosporine, a broad inducer of PCD. This preventive effect was observed in macrophages from L. major-susceptible BALB/c and L. major-resistant C57BL/6 mice, indicating that repression of PCD did not depend on genetic background-specific regulation of T helper cell type 1 (Th1)/Th2 cytokine secretion. Prevention of effector caspase activation and PCD was associated with a repression of mitochondrial release of cytochrome c and did not involve the nuclear factor-κB pathway. The capacity of L. major to delay PCD induction in the infected macrophages may have implications for Leishmania pathogenesis by favoring the invasion of its host and the persistence of the parasite in the infected cells.
A new role for monoamine oxidases in the modulation of macrophage-inducible nitric oxide synthase gene expression
Authors: Vega Antonio , Chacón Pedro , Monteseirín Javier , El Bekay Rajaa , Álvarez Moisés , Alba Gonzalo , Conde José , Martín-Nieto José , Bedoya Francisco J , Pintado Elizabeth , Sobrino Francisco
Published: April 2004

This report focuses on the modulatory role of endogenous H2O2 on lipopolysaccharide (LPS)/interferon-γ (IFN-γ)-induced inducible nitric oxide synthase (NOS2) gene expression in rat peritoneal macrophages. Exogenously added H2O2 was initially found to inhibit the synthesis of NOS2, which prompted us to assess the effect of the activity of monoamine oxidase (MAO) and semicarbazide-sensitive amine oxidase (SSAO) as H2O2-forming enzymes on NOS2 gene expression. In the presence of their substrates, tyramine for MAO and benzylamine for SSAO, intracellular synthesis of H2O2 took place with concomitant inhibition of LPS/IFN-γ-induced NOS2 protein synthesis, as detected by Western blotting, flow cytometry, and immunofluorescence microscopy analyses. Pargyline and semicarbazide, specific inhibitors of MAO and SSAO, respectively, canceled this negative effect of MAO substrates on NOS2 expression. In the presence of Fe2+ and Cu2+ ions, inhibition of NOS2 expression was enhanced, suggesting the participation in this regulation of species derived from Fenton chemistry. In addition, the negative effect of H2O2, generated by MAOs, was found to be exerted on NOS2 mRNA levels. These data offer a new insight in the control of NOS2 expression through the intracellular levels of H2O2 and other reactive oxygen species (ROS). The hypothesis can be raised that the inhibition of NOS by H2O2 could constitute a protective mechanism against the cytotoxic consequences of the activation of ROS-generating enzymes, thus providing a new, singular role for the MAO family of proteins.
Autoperfused mouse flow chamber reveals synergistic neutrophil accumulation through P-selectin and E-selectin
Authors: Smith Michael L , Sperandio Markus , Galkina Elena V , Ley Klaus
Published: April 2004

To study rolling of mouse neutrophils on P- and E-selectins in whole blood and without cell isolation, we constructed an autoperfused flow chamber made from rectangular microslides (0.2×2 mm) perfused from a carotid artery catheter. A differential pressure transducer served to measure wall shear stress. Green fluorescent neutrophils rolled on P-selectin but not E-selectin coated at 50 ng/ml, with some rolling on E-selectin at 150 ng/ml. However, when P- and E-selectins were coimmobilized, the resulting number of rolling neutrophils was sixfold and fourfold higher than on P- or E-selectin alone. Velocity and flux analysis shows that P-selectin initiates neutrophil rolling, and a small amount of E-selectin, unable to capture many neutrophils, reduces the rolling velocity of all neutrophils by more than 90%. The unexpected synergism between E- and P-selectins explains why neutrophil recruitment is enhanced when both selectins are expressed.
Leukocyte circulation: one-way or round-trip? Lessons from primary immunodeficiency patients
Authors: Badolato Raffaele
Published: April 2004

The identification of chemokines has profoundly changed the way we interpret the immune response, elucidating the mechanism by which inflammatory cells are recruited to the site of infection by local secretion of chemoattractants such as CXC chemokine ligand 8 (CXCL8)/interleukin-8, chemokine ligand 2 (CCL2)/monocyte chemoattractant protein 1. This novel view of the immune response has been remodeled further following observations that lymphoid tissue development derives from the coordinated secretion of homeostatic chemokines such as CCL19, CCL21, and CXCL13, which mediate recruitment and clustering of the cells involved in lymphoid organogenesis. The study of primary immunodeficiencies has demonstrated that the number of circulating leukocytes is dependent on migration amongst bone marrow, blood circulation, and inflamed tissues. Defects of leukocyte adhesion and chemotaxis as a result of mutations of β2-integrins lead to abnormal leukocytosis and susceptibility to skin infections, as observed in leukocyte adhesion deficiency. Conversely, neutropenia in children with myelokathexis is a result of leukocyte retention in the bone marrow because of the mutations of CXC chemokine receptor 4, which affect the capacity of cells to recirculate between blood and bone marrow. Moreover, the identification of the genetic basis of primary immunodeficiencies has shown that many primary immunodeficiencies such as Wiskott-Aldrich syndrome and common variable immunodeficiencies are characterized by altered migration of leukocytes and/or disregulation of cellular response to chemokines. This paper will be focused on the interpretation of primary immunodeficiencies as defects in leukocyte circulation between blood and primary and secondary organs.
Prostaglandin E2 receptors EP2 and EP4 are up-regulated in peritoneal macrophages and joints of pristane-treated mice and modulate TNF-α and IL-6 production
Authors: Akaogi Jun , Yamada Hidehiro , Kuroda Yoshiki , Nacionales Dina C , Reeves Westley H , Satoh Minoru
Published: April 2004

Prostaglandin E2 (PGE2) can have pro- or anti-inflammatory effects, depending on engagement of different PGE2 receptor (EP) subtypes. The role of EPs in regulating autoimmune inflammation was studied in the murine arthritis/lupus model induced by pristane. Peritoneal macrophages were isolated (biomagnetic beads) from BALB/c, DBA/1, or C57BL/6 mice treated with pristane (intraperitoneally, 3 months earlier) or thioglycolate (3 days earlier) or with untreated controls. EPs, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) mRNA expression was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). Cells were cultured unstimulated or stimulated with lipopolysaccharide (LPS) or LPS + interferon-γ in combination with EP subtype-specific agonists. Tumor necrosis factor α (TNF-α) and interleukin (IL)-6 production was tested by enzyme-linked immunosorbent assay (culture supernatant) and flow cytometry. TNF-α mRNA levels also were examined. High levels of EPs (EP4/2>EP1>EP3), iNOS, and COX-2 mRNA were expressed in peritoneal macrophages from pristane-treated but not untreated or thioglycolate-treated mice (RT-PCR). TNF-α production was inhibited 50–70% at 2–24 h by EP4/2 agonists, whereas IL-6 was enhanced up to ∼220%. TNF-α inhibition is mediated partly via the protein kinase A pathway and partly via IL-6. Intracellular TNF-α staining was inhibited 20% by EP4/2 agonists. TNF-α mRNA levels were inhibited 50–70% at 2–24 h, indicating that TNF-α inhibition was partly at the level of transcription. EP1/3 agonists had little effect. Synovial cells from mice with pristane-induced arthritis (DBA/1) also expressed EP2/4, and the EP2/4 agonist inhibited TNF-α production. PGE2 can modulate inflammatory reactions via the EP2/4 receptor through its regulation of TNF-α and IL-6. Modification of EP signaling may be a new therapeutic strategy in inflammatory/autoimmune diseases.
Identification of two immunogenic domains of the prion protein—PrP—which activate class II-restricted T cells and elicit antibody responses against the native molecule
Authors: Gregoire Sylvie , Logre Caroline , Metharom Pat , Loing Estelle , Chomilier Jacques , Rosset Martine Bruley , Aucouturier Pierre , Carnaud Claude
Published: April 2004

Recent reports suggest that immunity against the prion protein (PrP) retards transmissible spongiform encephalopathies progression in infected mice. A major obstacle to the development of vaccines comes from the fact that PrP is poorly immunogenic, as it is seen as self by the host immune system. Additional questions concern the immune mechanisms involved in protection and the risk of eliciting adverse reactions in the central nervous system of treated patients. Peptide-based vaccines offer an attractive strategy to overcome these difficulties. We have undertaken the identification of the immunogenic regions of PrP, which trigger helper T cells (Th) associated with antibody production. Our results identify two main regions, one between the structured and flexible portion of PrP (98–127) and a second between α 1 and α 2 helix (143–187). Peptides (30-mer) corresponding to these regions elicit class II-restricted Th cells and antibody production against native PrP and could therefore be of potential interest for a peptide-based vaccination.
Sensitivity analysis of a new room model integrating phenomena of air temperature distribution in controller tests
Authors: Riederer P , Marchio D
Published: April 2004

Room models, currently used for controller tests, assume the room air to be perfectly mixed. Considering the results of a study of temperature conditions in real rooms, equipped with different HVAC systems, a new model is developed, assuming a non-uniform temperature distribution in a room. The proposed model is based on the zonal modelling approach where the room air is divided into several sub-volumes. This approach allows taking into account various convective phenomena, which are imposed by the HVAC systems and have an impact on the test of HVAC controllers. The temperatures in the occupant zone as well as at typical sensor positions are the main outputs of the new model. The model has already been validated for different HVAC systems such as radiator, convector and fan-coil unit in heating and cooling mode. The model including a large number of correlations this paper deals with the sensitivity of the results on its main parameters. The paper starts with a general presentation of sensitivity of the main equations used in the model, followed by simulations demonstrating the impact of these parameters on the results. This sensitivity analysis is necessary to evaluate the pertinence of using virtual laboratory tests to compare controllers.
Simplified models for direct and indirect contact cooling towers and evaporative condensers
Authors: Lebrun J , Silva C Aparecida , Trebilcock F , Winandy E
Published: April 2004

This paper presents a simplified method of analysing the combined heat and mass transfer phenomena in direct and indirect contact cooling towers and evaporative condensers. The theoretical basis of the model is Merkel's theory. The cooling towers, evaporative condensers and fluid coolers are considered as members of a classical heat exchanger family, working in wet regime. Here, the air side heat and mass transfer processes are governed by the same basic process. This paper shows that a `unified' theoretical treatment may be applied to all three evaporative exchangers. The key difference in the theory for each type relates to these exchangers unique characteristic, the global heat transfer coefcient AU, or the corresponding thermal resistances of the fluids. Specific correlations for the calculation of AU or of the equivalent thermal resistances, considering the influence of the water and air flow rates entering the exchangers, are discussed. An example for each case is shown, illustrating the validation of the models with catalogue data.
Uncertainty in model-based condition monitoring
Authors: Buswell R A , Wright J A
Published: April 2004

Model-based techniques for automated condition monitoring of HVAC systems have been under development for some years. The generation of false alarms has been identified as a principal factor affecting the potential usefulness of condition monitoring in HVAC applications. Results from the application of these methods to systems installed in real buildings have highlighted the difficulty in selecting good alarm thresholds that balance robustness (lack of false alarms) and sensitivity (early detection). This paper demonstrates that this balance can be met in a transparent and analytical manner, through the application of uncertainty analysis. The paper discusses the sources of uncertainty associated with component models and system measurements. A condition monitoring scheme applied to a typical HVAC cooling coil subsystem installed in a real building is presented. Faults are artificially introduced into the system and are used in conjunction with fault-free operation to demonstrate the sensitivity and robustness of the scheme. The principle conclusions drawn by the paper consider the likely minimum magnitudes of faults that can be detected in typical HVAC systems, without false alarm generation. More broadly however, the paper demonstrates that the issue of uncertainty affects all aspects of system monitoring, modelling and control.
Connectionism, HPSG signs and SLA representations: specifying principles of mapping between form and function
Authors: Mellow J. Dean
Published: April 2004

A current limitation of the connectionist approach to second language acquisition (SLA) research is that it does not, to my knowledge, include complex linguistic representations. This article proposes a partial solution to this limitation by motivating and illustrating specific analyses that utilize the sign-based representations developed within Head-driven Phrase Structure Grammar (HPSG). To motivate the proposed representations, the article applies them to an analysis of four types of mappings between form and function: one-to-one, primed redundancy, nonprimed redundancy and polyfunctional. The paper summarizes representative SLA data that indicate how these mappings may appear in second language (L2) production. Key properties of HPSG analyses are discussed, indicating how they are consistent with connectionist assumptions. Sign-based representations of the four types of mappings are then provided, including several modifications to HPSG formalisms. The article concludes with a discussion of future directions.
`To be a native speaker means not to be a nonnative speaker’
Authors: Han ZhaoHong
Published: April 2004

The construct of the native speaker is germane to second language acquisition (SLA) research; it underlies, and permeates, a significant bulk of SLA theory construction and empirical research. Nevertheless, it is one of the least investigated (and for that matter, least understood) concepts in the field. Even a cursory reading of the major SLA literature would not yield one readily available definition that captures the essential uses that have been made of the concept: including, but not limited to, setting the native speaker as a goal or a model for SLA or using the native speaker as a yardstick to measure second language knowledge. As is, the concept remains assumed-based on common sense observation and intuition-rather than exposed to scientific inquiry. In this article I would like to draw attention to this pivotal yet much neglected concept by reviewing Davies (1991; 2003) on the native speaker. A by no means exhaustive account, the books outline principal parameters for considering the native speaker concept, thereby providing a useful basis for further inquiry.
Nephrotoxicity and its prevention by catechin in ferric nitrilotriacetate promoted oxidative stress in rats
Authors: Chopra Kanwaljit , Singh Devinder , Chander Vikas
Published: April 2004

Intraperitoneal injection of ferric nitrilotriacetate (Fe-NTA) to rats and mice results in iron-induced free radical injury and cancer in kidneys. This study was designed to investigate the effect of catechin, a bioflavonoid with antioxidant potential, on Fe-NTA-induced nephrotoxicity in rats. Four groups were employed in the present study. Group I served as control group, Group II animals received Fe-NTA (8 mg iron/kg body weight i.p.), Group III animals were given 40 mg/kg catechin p.o. twice a day for 4 days and on the 5th day Fe-NTA was challenged, and Group IV animals received catechin alone for 4 days. Renal function was assessed by measuring plasma creatinine and blood urea nitrogen. The oxidative stress was measured by renal malondialdehyde levels, reduced glutathione levels and by enzymatic activity of catalase, glutathione reductase and superoxide dismutase. One hour after a single intraperitoneal (i.p.) injection of Fe-NTA (8 mg iron/kg), a marked deterioration of renal architecture, renal function and severe oxidative stress was observed. Pretreatment of animals with catechin markedly attenuated renal dysfunction, reduced elevated thiobarbituric acid reacting substances (TBARS), restored the depleted renal antioxidant enzymes and normalized the renal morphological alterations. These results clearly demonstrate the role of oxidative stress and its relation to renal dysfunction, and suggest a protective effect of catechin on Fe-NTA-induced nephrotoxicity in rats.
Effect of lipoic acid on the oxidoreductive status of red blood cells in rats subject to oxidative stress by chronic administration of adriamycin
Authors: Malarkodi K P , Sivaprasad R , Varalakshmi P
Published: April 2004

One of the most intriguing phenomena observed during adriamycin (ADR) toxicity has been attributed to ADR-induced oxidative stress. The study was aimed to assess the protective effect of lipoic acid (LA) against ADR induced damage to erythrocytes. Male albino rats (Wistar strain) were subjected to ADR (1 mg/kg body weight/day i.v.) once a week for a period of 12 weeks. Haematological indices like haemoglobin levels (Hb) and haematocrit (Ht) were also lowered along with a marked increase in the activities of serum glutamate pyruvate transaminase (SGPT) and serum glutamate oxaloacetate transaminase (SGOT). These rats demonstrated enhanced erythrocyte membrane lipid peroxidation (LPO) and an onslaught in the antioxidant defence armoury, witnessed by lowered activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), vitamin A, vitamin C and vitamin E. Rats administered with ADR showed a marked decline in the activities of membrane-bound ATPases. Abnormal LPO and decreased deformability led to increased osmotic fragility of the red blood cells. Pretreatment with LA (35 mg/kg body weight/day i.p.) 24 hours prior to the administration of ADR once a week for a period of 12 weeks was effective in counteracting these biochemical disturbances, thereby minimizing the toxic side effects of ADR.
Omeprazole treatment: genotoxicity biomarkers, and potential to induce CYP1A2 activity in humans
Authors: Sinués Blanca , Fanlo Ana , Bernal Marĺa Luisa , Val Marta , Mayayo Esteban
Published: April 2004

Omeprazole is one of the most used acid-suppressing medications. This fact emphasizes the questions concerning the safety of this compound. Healthy volunteers (n-33) were included in this prospective study. All study subjects were analysed for their CYP2C19 genotype. Of the 33 individuals, 24 were homozygous for the wild type CYP2C19*1 allele, 7 were heterozygous for theCYP2C19*2 variant allele, and 2 were homozygous for the CYP2C19*2 variant allele. Before and after 14 days of omeprazole treatment at a daily dose of 20 mg, one blood sample was taken from each individual to determine five cytogenetic biomarkers of genotoxicity: chromosome aberrations, micronuclei, proliferating rate index, sister chromatid exchanges, and mitotic index. The only significant change was that of a weak increase in micro nuclei count after treatment in relation to baseline values (day 0) (P-0.026). To assess the potential of omeprazole to induce P450 CYP1A2, the urinary ratio AFMU-1X-1U/17U in the interval of 4 / 5 hours after caffeine intake was calculated twice (days 0 and 15), using the caffeine test in 27 of the 33 individuals. This result suggests that omeprazole does not increase CYP1A2 activity after 14 days of treatment.
Exercise capacity, disability and leisure physical activity of subjects with multiple sclerosis
Authors: Romberg A , Virtanen A , Aunola S , Karppi S-L , Karanko H , Ruutiainen J
Published: April 2004

The purpo se of the present study was to examine exercise capacity and its relationship to neurological disability as measured using the Expanded Disability Status Scale (EDSS) and to leisure physical activity in subjects with multiple sclerosis (MS). Thirty-four men and 61 women (mean age 44±6.7 years, mean disease duration 5.7±6.4 years) with mild to moderate disability (EDSS range 1.0- 5.5) participated. They underwent an incremental exercise test on a leg cycling ergometer. Leisure physical activity was measured using a questionnaire. Peak oxygen uptake (VO 2peak) in men was 27.0±5.2 mL/kg/min, and in women 21.7±5.5 mL/kg/min. The disability correlated inversely with the VO 2peak both in men (r = -0.50, P =0.004) and in women (r = -0.25, P =0.05). No correlation between disease duration and VO 2peak was found. In a multivariate regression analysis, neurological disability was confirmed as a predictor of VO 2peak. No evidence of a relationship between leisure physical activity and VO 2peak was found. A main finding was that disability and exercise capacity are inter-related, even in subjects who are not severely handicapped (84% had an EDSS of B-4.0). The level of disability should be taken into account in the planning of aerobic exercise programs for fully ambulatory MS subjects.
Win 55212-2, a cannabinoid receptor agonist, attenuates leukocyte/endothelial interactions in an experimental autoimmune encephalomyelitis model
Authors: Ni Xiang , Geller Ellen B , Eppihimer Michael J , Eisenstein Toby K , Adler Martin W , Tuma Ronald F
Published: April 2004

Multiple sclerosis (MS) is the most common of the immune demyelinating disorders of the central nervous system (C NS). Leukocyte/endothelial interactions are important steps in the progression of the disease and substances that interfere with these activities have been evaluated as potential therapeutic agents. C annabinoid receptor agonists have been shown to downregulate immune responses and there is preliminary evidence that they may slow the progress of MS. The purpo se of this investigation was to determine how cannabinoid recepto r agonists interfere with leukocyte rolling and adhesion. This was investigated in an experimental autoimmune encephalo myelitis (EAE) model using six to eight week old C 57BL/6 mice. Mouse myelin oligodendrocyte protein and pertussis toxin were used to induce EAE. WIN 55212-2, C B1 and C B2 antagonist were given. By use of in vivo intravital microscopy, leukocyte/endothelial interactio ns were evaluated via a cranial window implanted two days before. The results demonstrated that EAE increases leukocyte rolling and firm adhesion in the brain, and that this increased leukocyte/endothelial interactio n can be attenuated by administration of WIN 55212-2. Furthermore, use of the selective antagonists for the C B1 recepto r (SR 141716A) and the C B2 receptor (SR144528) in this study demonstrated that the cannabinoid’s inhibitory effects on leukocyte/endothelial interactions can be mediated by activating C B2 receptor.
Interferon β-1a in relapsing multiple sclerosis: four-year extension of the European IFNβ-1a Dose-C omparison Study
Authors: Clanet M , Kappos L , Hartung H-P , Hohlfeld R ,   The European IFNβ-1a Dose-Comparison Study Investigators
Published: April 2004

Background: Multiple sclerosis (MS) is a chronic disease requiring long-term monitoring of treatment. Objective: To assess the four-year clinical efficacy of intramuscular (IM) IFNb-1a in patients with relapsing MS from the European IFNb-1a Dose-C omparison Study. Methods: Patients who completed 36 months of treatment (Part 1) of the European IFNb-1a Dose-C omparison Study were given the option to continue double-blind treatment with IFNb-1a 30 mcg or 60 mcg IM once weekly (Part 2). Analyses of 48-month data were performed on sustained disability progression, relapses, and neutralizing antibody (NA b) formation. Results: O f 608/802 subjects who completed 36 months of treatment, 493 subjects continued treatment and 446 completed 48 months of treatment and follow-up. IFNb-1a 30 mcg and 60 mcg IM once weekly were equally effective for up to 48 months. There were no significant differences between doses over 48 months on any of the clinical endpoints, including rate of disability progression, cumulative percentage of patients who progressed (48% and 43%, respectively), and annual relapse rates; relapses tended to decrease over 48 months. The incidence of patients who were positive for NAbs at any time during the study was low in both treatment groups. Conclusion: C ompared with 60-mcg IM IFNb-1a once weekly, a dose of 30 mcg IM IFNb-1a once weekly maintains the same clinical efficacy over four years.
Cytokine mRNA expression in patients with multiple sclerosis and fatigue
Authors: Flachenecker Peter , Bihler Irene , Weber F , Gottschalk M , Toyka Klaus V , Rieckmann Peter
Published: April 2004

Background: Fatigue is one of the most common disabling symptoms in patients with multiple sclerosis (MS), but the putative role of proinflammatory cytokines remains to be elucidated. Methods: Thirty-seven patients (27 women, 10 men) with relapsing-remitting (n =29) and secondary progressive (n =8) MS, aged 41.0 ± 10.2 years, were studied. Fatigue was assessed by Krupp’s Fatigue Severity Scale (FSS). C ytokine mRNA expression for interferon (IFN)-g, tumor necro sis factor (TNF)-a and interleukin (IL)-10 were measured by real time RT PC R. A utonomic function was evaluated by standard tests for parasympathetic and sympathetic function, as well as by serum levels of norepinephrine and epinephrine. Results: Median levels of TNF-a mRNA expression were significantly higher in MS patients with (FSS]-4.0 and]-5.0, n=26 and n=14, respectively) than in those without fatigue (FSSB-4.0, n =11). No differences were seen for IFN-g and IL-10 mRNA expression. C ytokine levels were not correlated to autonomic tests or to serum catecho lamine levels. Conclusions: These results suggest that TNF-a, as a principal proinflammatory mediator, is associated with MS-related fatigue. This is in support of a patho genic role of the MS-related inflammatory process in the development of fatigue.
Multiple sclerosis and alcohol: a study of problem drinking
Authors: Quesnel Susan , Feinstein Anthony
Published: April 2004

Multiple sclerosis (MS) patients are known to be at increased risk from mood disorders and suicidal ideation. A lthough these are often associated with alcohol disorders, the drinking habits of MS patients have not been well studied to date. O ur study assessed drinking patterns in 140 MS patients, focusing on a possible link between problem drinking and mood and anxiety disorders. Lifetime psychiatric diagnoses were ascertained using the Structured C linical Interview for DSM-IV disorders (SCID-IV). Results demonstrate that one in six MS patients drink to excess over the course of their lifetime. Those with a history of problem drinking display a higher lifetime prevalence of anxiety (P =0.006), but not mood disorders. There were also significant associations between problem drinking and a lifetime prevalence of suicidal ideation (P =0.006), substance abuse (P =0.001), and a family history of mental illness (P =0.008). C linicians should be aware of the possibility of problem drinking in MS patients, and how this may complicate the course of their disease. C lues to problem drinking in MS patients are the presence of a positive family history of mental illness and prominent anxiety.
Influence of C C R5 δ32 polymorphism on multiple sclerosis susceptibility and disease course
Authors: Silversides J A , Heggarty S V , McDonnell G V , Hawkins S A , Graham C A
Published: April 2004

The C C R5 chemokine receptor has been implicated in the patho genesis of multiple sclerosis (MS). We carried out an allelic association study using a deletion polymorphism in the coding region of the C C R5 gene in 331 relapsing-remitting (RR) and secondary progressive (SP) MS patients, 108 primary progressive (PP) MS patients and 230 healthy controls. O f the 331 RR and SPMS patients, 172 were recruited from specialist clinics and 159 from a population survey. Disease severity was assessed clinically using the Expanded Disability Status Scale (EDSS) and used to calculate a progression index for each patient (defined as EDSS divided by duration of disease). No significant difference in distribution of the C C R5 d32 allele was observed between the 331 RR/SPMS patients and controls, between the 108 PPMS patients and controls or between the PPMS and RR/SPMS groups. Furthermore, no differences in rate of disease progression were detected between carriers and noncarriers of the d32 allele. In the population-based group of RR/SPMS patients, carriage of the C C R5 d32 polymorphism was associated with a lower age at disease onset (mean age 26.562 versus 31.065 years, P =0.003). However, no significant differences in age of onset were present in the PPMS group or in a second RRMS population. These results suggest that the C C R5 d32 polymorphism is not a major determinant of susceptibility to develop MS in the population under study, and conflict with a previously reported association between C C R5 d32 carriage and a better prognosis.
Progressive change in primary progressive multiple sclerosis normal-appearing white matter: a serial diffusion magnetic resonance imaging study
Authors: Schmierer Klaus , Altmann Daniel R , Kassim Nadja , Kitzler Hagen , Kerskens Christian M , Doege Claudia A , Aktas Orhan , Lünemann Jan D , Miller David H , Zipp Frauke , Villringer Arno
Published: April 2004

In spite of marked disability, patients with primary progressive multiple sclerosis (PPMS) display smaller lesion volumes on conventional magnetic resonance imaging (MRI) compared with other forms of multiple sclerosis (MS). Hence, damage to the normal-appear ing brain tissue (NA BT) may play an important role in explaining the patho genesis of disability in PPMS. Diffusion-weighted MRI (DW-MRI) probes water diffusion in vivo that can be altered by patho logic changes. Using DW-MRI we investigated diffusion in the NA BT of 15 patients with PPMS over one year. The average apparent diffusion coefficient (A DC av) was measured in 10 regions of interest located in the normal- appearing thalamus and the normal-appearing white matter (NAWM). Six healthy subjects served as a reference. In contrast to healthy subjects, patients with PPMS showed an increment within 12 months of the A DC av in NAWM which was associated with an increase of the T2- and T1-lesion volumes. The A DC av in frontal NAWM was associated with disability as measured by the MS Functio nal C omposite Measure. Serial DW-MRI depicts progressive changes in the NAWM of patients with PPMS. O ur preliminary findings suggest that the processes causing structural damage in NAWM and lesions in patients with PPMS are partially linked and that changes of water diffusion in NAWM depicted by DW-MRI are clinically relevant.
Diffusion tensor imaging in multiple sclerosis: a tool for monitoring changes in normal-appearing white matter
Authors: Cassol Emmanuelle , Ranjeva Jean-Philippe , Ibarrola Danielle , Mékies Claude , Manelfe Claude , Clanet Michel , Berry Isabelle
Published: April 2004

Our objectives were to determine the reproducibility of diffusion tensor imaging (DTI) in volunteers and to evaluate the ability of the method to monitor longitudinal changes occurring in the normal-appearing white matter (NAWM) of patients with multiple sclerosis (MS). DTI was performed three-mo nthly for one year in seven MS patients: three relapsing-remitting (RRMS), three secondary progressive (SPMS) and one relapsing SP. They were selected with a limited cerebral lesion load. Seven age- and sex-matched controls also underwent monthly examinations for three months. Diffusivity and anisotropy were quantified over the segmented whole supratentorial white matter, with the indices of trace (Tr) and fractional anisotropy (FA). Results obtained in volunteers show the reproducibility of the method. Patients had higher trace and lower anisotropy than matched controls (P B-0.0001). O ver the follow-up, both Tr and FA indicated a recovery after the acute phase in RRMS and a progressive shift towards abnormal values in SPMS. A lthough this result is not statistically significant, it suggests that DTI is sensitive to microscopic changes occurring in tissue of normal appearance in conventional images and could be useful for monitoring the course of the disease, even though it was unable to clearly distinguish between the various physiopathological processes involved.
Genotypes at the APOE and SCA2 loci do not predict the course of multiple sclerosis in patients of Portuguese origin
Authors: Santos Mónica , do Carmo Costa Maria , Rio Maria Edite , Sá Maria José , Monteiro Marta , Valença Angela , Sá Alfredo , Dinis José , Figueiredo José , de Almeida Luís Bigotte , Valongueiro António , Coelho Isabel , Matamá Maria Teresa , Pinto-Basto Jorge , Sequeiros Jorge , Maciel Patrícia
Published: April 2004

Multiple sclerosis (MS) is a demyelinating disease that affects about one in 500 young Europeans. In order to test the previously proposed influence of the A PO E and SC A 2 loci on susceptibility to MS, we studied these loci in 243 Portuguese patients and 192 healthy controls and both parents of 92 patients. We did not detect any significant difference when A PO E and SC A 2 allele frequencies of cases and controls were compared, or when we compared cases with different forms of the disease. Disequilibrium of transmission was tested for both loci in the 92 trios, and we did not observe segregation distortion. To test the influence of the A PO E o4 and SC A 2 22 C AGs alleles on severity of disease, we compared age at onset and progression rate between groups with and without those alleles. We did not observe an association of the o4 or the 22 C AG s alleles with rate of progression in our total patient population; allele o4 was associated with increased rate of progression of MS in a subset of patients with less than 10 years of the disease. However, globally in the Portuguese population, the A PO E and SC A2 genes do not seem to be useful in the clinical context as prognostic markers of this disorder.
The potential role of angiotensin-converting enzyme inhibition in peripheral arterial disease
Authors: Hirsch Alan T , Duprez Daniel
Published: April 2004

Peripheral arterial disease (PAD) is associated with significant morbidity and mortality, and yet remains under-recognized and under-treated. Atherosclerosis is the most common cause of lower extremity PAD and pharmacological interventions that alter this central pathogenic role of atherosclerosis may alter the natural history of PAD. There is growing evidence that the renin-angiotensin system (RAS) is a significant mediator of this disease process and that treatment with angiotensin-converting enzyme (ACE) inhibitors is associated with vasculoprotective effects that are independent of the antihypertensive properties of these agents. Numerous lines of evidence suggest that ACE inhibitors directly inhibit the atherosclerotic process and improve vascular endothelial function. In patients with PAD, ACE inhibitors have been shown to improve peripheral circulation as measured by peripheral arterial blood pressure and by increases in peripheral blood flow. Preliminary evidence suggests that ACE inhibitors might improve clinical symptoms in patients with PAD. Recent evidence has confirmed that ACE inhibition is associated with a decrease in morbidity and mortality in patients with arterial disease without left ventricular dysfunction; this benefit was at least as great for the subset of patients with PAD. Overall, these data support a significant role for the RAS in the pathogenesis of all atherosclerotic diseases (including PAD) and suggest that the benefit is independent of the blood pressure lowering properties of these agents. These studies suggest that ACE inhibitor therapy should be considered in the routine management of individuals with PAD, regardless of whether they have hypertension or left ventricular dysfunction.
Inflammatory status and endothelial function in asymptomatic and symptomatic peripheral arterial disease
Authors: Silvestro Antonio , Scopacasa Francesco , Ruocco Aldo , Oliva Gabriella , Schiano Vittorio , Zincarelli Carmela , Brevetti Gregorio
Published: April 2004

Peripheral arterial disease (PAD) is a predictor of cardiovascular risk. However, it is unknown whether PAD severity influences inflammatory status and endothelial function, which play a major role in atherosclerosis. Accordingly, we measured brachial artery flow-mediated dilation (FMD), and plasma levels of several inflammatory markers in 15 control subjects, and 19 asymptomatic and 19 symptomatic PAD patients. Each symptomatic patient was matched to an asymptomatic patient for age, sex, risk factors, presence of cardiovascular disease, and pharmacological treatments. Asymptomatic patients had similar inflammatory profiles as controls, but lower median FMD (11.7% vs 8.5%, p < 0.01). Compared with asymptomatic patients, symptomatic patients had higher median C-reactive protein (1.5mg=l vs 6.0 mg=l, p < 0.05) and interleukine-6 (1.5 pg=ml vs 3.5 pg=ml, p < 0.05), and lower FMD (8.5% vs 5.1%, p < 0.01). In the 38 PAD patients, the ankle=brachial pressure index correlated positively with FMD (p < 0.01), and negatively with C-reactive protein (p < 0.05), soluble intercellular adhesion molecule-1 (p < 0.05) and soluble vascular cell adhesion molecule-1 (p < 0.05). Thus, in PAD, endothelial function and inflammatory status are related to the severity of the circulatory impairment. This finding may contribute to the explanation of the increasingly poor prognosis with increased PAD severity.
The pivotal role of matrix metalloproteinases in the development of human abdominal aortic aneurysms
Authors: Liapis Christos D , Paraskevas Kosmas I
Published: April 2004

Abdominal aortic aneurysms (AAAs) represent a chronic degenerative condition and impart the risk of a life-threatening episode of rupture. Chronic inflammation and destructive remodeling of the extracellular matrix of the aortic wall constitute trademarks of this entity. Multiple studies have implicated a group of locally produced matrix endopeptidases-the matrix metalloproteinases (MMPs)-as the main culprits of this process. For this reason, extensive research on the Identification of the role of these enzymes, as well as possible alternative pharmacological treatments of AAAs, has taken place during the last few years. The exact role of the several members of the group of metalloproteinases has already been discovered, and conservative therapeutic strategies oriented towards these agents have been suggested, but a Definite treatment plan is still a controversial topic. The possible role of a genetic predisposition to AAAs is another crucial topic that remains to be determined, as it would render the confrontation of this condition much more efficient.
Effect of alcohol on endothelial function in healthy subjects
Authors: Vlachopoulos Charalambos , Tsekoura Dorothea , Tsiamis Eleftherios , Panagiotakos Demosthenes , Stefanadis Christodoulos
Published: April 2004

While studies have shown that red wine improves endothelial function, the effect of pure alcohol, the common denominator of all alcoholic beverages, on endothelial function has not been defined. The effect of oral intake of alcohol (one ounce - a dose corresponding to two drink equivalents) on flow-mediated dilatation of the brachial artery was studied in 12 healthy subjects using high-resolution ultrasonography according to a randomized, sham procedure-controlled, single-blind protocol. Alcohol produced a significant vasodilatation of the brachial artery at resting conditions. Furthermore, it led to a significant increase of the brachial artery diameter at reactive hyperemia; however, the percentage flow-mediated dilatation did not change. This study shows, for the first time, that acute moderate intake of alcohol has a potent dilating effect on large arteries both at resting and at reactive hyperemic conditions, without affecting flow-mediated dilatation as a percentage. This may be useful for explaining the divergent effect of different alcoholic beverages on endothelial function and provides valuable insight into the mechanisms involved in the vascular effects of alcohol.
Lower extremity peripheral arterial disease in hospitalized patients with coronary artery disease
Authors: Dieter Robert S , Tomasson Jon , Gudjonsson Thorbjorn , Brown Roger L , Vitcenda Mark , Einerson Jean , McBride Patrick E
Published: April 2004

The prevalence of coronary artery disease (CAD) in patients with peripheral arterial disease (PAD) has been well defined. However, the prevalence of PAD in hospitalized patients with CAD has not been defined. The ankle-brachial index (ABI) is a useful non-invasive tool to screen for PAD. The aim of our study was to assess the prevalence of PAD in hospitalized patients with CAD by measuring the ABI. The study was conducted at the University of Wisconsin Hospital and Clinics inpatient Cardiovascular Medicine Service. Medically stable patients with CAD were invited to participate prior to hospital discharge. Data regarding cardiovascular risk factors, history of previous PAD, physical examination, and ABI were collected. An ABI less than or equal to 0.9 or a history of previous lower extremity vascular invention was considered to be indicative of significant PAD. A total of 100 patients (66 men and 34 women) were recruited. Forty patients were found to have PAD (mean ABI in nonrevascularized patients with PAD = 0.67). By measuring the ABI, 37 (25 men) were positive for PAD and three had an ABI corrected with previous revascularization. Of these patients, 21 (52.5%) had previously documented PAD. Patients with PAD were older (p = 0.003), had a greater smoking history (p = 0.002), were more likely to have diabetes (p = 0.012), hypertension (p = 0.013) and a trend towards more dyslipidemia (p = 0.055). In conclusion, hospitalized patients with CAD are likely to have concomitant PAD. Risk factors for PAD in this patient population include advanced age, history of smoking, diabetes, hypertension, dyslipidemia and abnormal pulse examination. Identification of patients with PAD by measuring the ankle-brachial index is easily done.
Peripheral veins: influence of gender, body mass index, age and varicose veins on cross-sectional area
Authors: Kröger K , Ose C , Rudofsky G , Roesener J , Weiland D , Hirche H
Published: April 2004

To investigate changes in the size of the deep and superficial venous systems associated with gender, age, body mass index and varicose veins, changes to the cross-sectional area of the femoral and the long saphenous veins were analysed in the Duesseldorf=Essen civil servant study population. Between December 1989 and July 1993 a total of 9935 employees were recruited; 9261 were then evaluated for this analysis. Diameters of the long saphenous and femoral veins were determined 2-3 cm distal to the confluence in lying (after 15 min rest) and standing (after 5 min) positions. Cross-sectional areas (CSA) were calculated. A total of 63% of all people were assigned to CEAP (clinical, etiological, anatomical pathophysiological) class 0, 27% to class 1, 8.5% to class 2, while 1.5% belonged to higher CEAP classes. In people without varicose veins (CEAP class 0) the CSA of the femoral and long saphenous veins were smaller in females than in males. In people with a normal body mass index (BMI) (20-25) the mean CSA of the femoral and long saphenous veins in a standing position was similar from the third up to the sixth decade of life. The volume increase due to a standing position expressed as the absolute increase in CSA of the femoral and long saphenous veins was not age-related, either. The relative volume increase expressed as a ratio remained unchanged with age. There was a strong relationship between the CSA of both veins and increasing BMI. In a lying position, the CSA of the femoral and long saphenous veins increased only slightly with increasing CEAP classes. In a standing position, the CSA of both veins increased even in CEAP class 1 (p < 0.001). In a stepwise multivariate regression analysis, the CSA of both veins in a standing position was not age-related but associated with BMI, CEAP classes and gender. The absolute increase in CSA was influenced by all four variables, but BMI and gender were most important. In Conclusion, this study shows that aging is not necessarily associated with an increase in venous CSA of the deep and superficial venous system. BMI is the most important determinant for an increase in CSA in standing position. Varicosity of the superficial venous system is always associated with similar changes in the deep venous system.
Effect of sildenafil on arterial stiffness and wave reflection
Authors: Vlachopoulos Charalambos , Hirata Kozo , O’Rourke Michael F
Published: April 2004

While sildenafil (Viagra) is widely prescribed for erectile dysfunction, its effect on arterial function is not established. The elastic properties of the aorta, as well as the magnitude and timing of wave reflection, are important factors for efficient performance of the cardiovascular system and have been identified as prognosticators of cardiovascular risk. A total of 24 subjects with coronary artery disease, of whom 14 were hypertensives, aged 69 8 years, were studied in a randomized, placebo-controlled, double-blind, cross-over design. Measurements lasted for 3 h after the sildenafil intake (50 mg, p.o.) or placebo. Aortic elastic properties were evaluated with carotid-femoral pulse wave velocity; wave reflection was evaluated with augmentation index and augmented pressure of the aortic pressure waveform. Pulse wave velocity decreased significantly (by 0.65 m/s, p = 0.005), denoting a decrease in aortic stiffness. Augmentation index and augmented pressure decreased significantly (by 4.47% absolute and by 4.01 mmHg; p < 0.001 and p = 0.001, respectively), denoting a decreased effect of wave reflection from the periphery. Aortic pulse pressure decreased significantly (by 6.74 mmHg, p < 0.05). An active effect of the drug on aortic wall appears to contribute to the decrease in pulse wave velocity, although other mechanisms such as a decrease of blood pressure and autonomic reflexes could also have contributed. The effect of sildenafil lasted throughout the study (3 h), being evident 30 min after drug intake. In conclusion, this study shows, for the first time, that sildenafil has a favorable effect on aortic stiffness and wave reflection in patients with coronary artery disease. This finding may have important implications for cardiovascular performance and exercise capacity during intercourse.