bluuebunny/crossref_metadata_2025 huggingface dataset:
Epileptic seizures cause extended postictal cerebral vascular dysfunction that is prevented by HO-1 overexpression
Authors: Parfenova Helena , Carratu Pierluigi , Tcheranova Dilyara , Fedinec Alex , Pourcyrous Massroor , Leffler Charles W.
Published: January 2005

The extended postictal state is characterized by neurological problems in patients. Inadequate blood supply to the brain and impaired cerebral autoregulation may contribute to seizure-induced neuronal damage. Recent evidence in newborn pigs indicates that activation of the antioxidative enzyme heme oxygenase (HO) at the onset of seizures is necessary for increased cerebral blood flow during the ictal episode and for normal cerebral vascular functioning during the immediate postictal period. We hypothesized that seizures cause prolonged postictal cerebral vascular dysfunction that can be accentuated by HO inhibition and rescued by HO overexpression. Cerebral vascular responses to endothelium-dependent (hypercapnia, bradykinin) and -independent (isoproterenol, sodium nitroprusside) stimuli were assessed 48 h after bicuculline-induced seizures in: 1) saline-control newborn piglets, 2) HO-inhibited animals (HO was inhibited by tin protoporphyrin, SnPP, 3 mg/kg iv), and 3) HO-overexpressing piglets (HO-1 was upregulated by cobalt protoporphyrin, CoPP, 50 mg/kg ip). Extended alterations of HO expression in cerebral microvessels were confirmed by measuring CO production and inducible HO (HO-1) and constitutive HO (HO-2) proteins. Our data provide evidence that seizures cause a severe, sustained, postictal cerebral vascular dysfunction as reflected by impaired vascular reactivity to physiologically relevant dilators. During the delayed postictal state, vascular reactivity to all dilator stimuli was reduced in saline control and, to a greater extent, in HO-inhibited animals. In CoPP-treated piglets, no reduction in postictal cerebral vascular reactivity was observed. These findings may indicate that CoPP prevents postictal cerebral vascular dysfunction by upregulating HO-1, a finding that might have implications for preventing postictal neurological complications.
Modification of sarcolemmal Na+-K+-ATPase and Na+/Ca2+exchanger expression in heart failure by blockade of renin-angiotensin system
Authors: Shao Qiming , Ren Bin , Elimban Vijayan , Tappia Paramjit S. , Takeda Nobuakira , Dhalla Naranjan S.
Published: January 2005

The activities of both sarcolemmal (SL) Na+-K+-ATPase and Na+/Ca2+exchanger, which maintain the intracellular cation homeostasis, have been shown to be depressed in heart failure due to myocardial infarction (MI). Because the renin-angiotensin system (RAS) is activated in heart failure, this study tested the hypothesis that attenuation of cardiac SL changes in congestive heart failure (CHF) by angiotensin-converting enzyme (ACE) inhibitors is associated with prevention of alterations in gene expression for SL Na+-K+-ATPase and Na+/Ca2+exchanger. CHF in rats due to MI was induced by occluding the coronary artery, and 3 wk later the animals were treated with an ACE inhibitor, imidapril (1 mg·kg−1·day−1), for 4 wk. Heart dysfunction and cardiac hypertrophy in the infarcted animals were associated with depressed SL Na+-K+-ATPase and Na+/Ca2+exchange activities. Protein content and mRNA levels for Na+/Ca2+exchanger as well as Na+-K+-ATPase α1-, α2- and β1-isoforms were depressed, whereas those for α3-isoform were increased in the failing heart. These changes in SL activities, protein content, and gene expression were attenuated by treating the infarcted animals with imidapril. The beneficial effects of imidapril treatment on heart function and cardiac hypertrophy as well as SL Na+-K+-ATPase and Na+/Ca2+exchange activities in the infarcted animals were simulated by enalapril, an ACE inhibitor, and losartan, an angiotensin receptor antagonist. These results suggest that blockade of RAS in CHF improves SL Na+-K+-ATPase and Na+/Ca2+exchange activities in the failing heart by preventing changes in gene expression for SL proteins.
Smad1 expression and function during mouse embryonic lung branching morphogenesis
Authors: Chen Cheng , Chen Hui , Sun Jianping , Bringas Pablo , Chen Yuhua , Warburton David , Shi Wei
Published: January 2005

Bone morphogenetic protein (BMP) 4 plays very important roles in regulating developmental processes of many organs, including lung. Smad1 is one of the BMP receptor downstream signaling proteins that transduce BMP4 ligand signaling from cell surface to nucleus. The dynamic expression patterns of Smad1 in embryonic mouse lungs were examined using immunohistochemistry. Smad1 protein was predominantly detected in peripheral airway epithelial cells of early embryonic lung tissue [embryonic day 12.5 (E12.5)], whereas Smad1 protein expression in mesenchymal cells increased during mid-late gestation. Many Smad1-positive mesenchymal cells were localized adjacent to large airway epithelial cells and endothelial cells of blood vessels, which colocalized with a molecular marker of smooth muscle cells (α-smooth muscle actin). The biological function of Smad1 in early lung branching morphogenesis was then studied in our established E11.5 lung explant culture model. Reduction of endogenous Smad1 expression was achieved by adding a Smad1-specific antisense DNA oligonucleotide, causing ∼20% reduction of lung epithelial branching. Furthermore, airway epithelial cell proliferation and differentiation were also inhibited when endogenous Smad1 expression was knocked down. Therefore, these data indicate that Smad1, acting as an intracellular BMP signaling pathway component, positively regulates early mouse embryonic lung branching morphogenesis.
In vitro and in vivo regulation of transepithelial lung alveolar sodium transport by serine proteases
Authors: Planès Carole , Leyvraz Céline , Uchida Tokujiro , Angelova Milena Apostolova , Vuagniaux Grégoire , Hummler Edith , Matthay Michael , Clerici Christine , Rossier Bernard
Published: January 2005

The amiloride-sensitive epithelial sodium channel (ENaC) constitutes a rate-limiting step for sodium (Na+) and water absorption across lung alveolar epithelium. Recent reports suggested that ENaC is regulated by membrane-bound extracellular serine proteases, such as channel-activating proteases (CAPs). The objectives of this study were to examine the role of serine proteases in the regulation of transepithelial alveolar Na+and water transport in vitro and in vivo and the expression of CAPs in rodent distal lung. In vitro experiments showed that inhibition of endogenous serine proteases by apical aprotinin 1) decreased ENaC-mediated currents in primary cultures of rat and mouse alveolar epithelial cells without affecting the abundance nor the electrophoretic migration pattern of biotinylated α- and β-ENaC expressed at the cell surface and 2) suppressed the increase in amiloride-sensitive short-circuit current induced by the β2-agonist terbutaline. RT-PCR experiments indicated that CAP1, CAP2, and CAP3 mRNAs were expressed in mouse alveolar epithelial cells, whereas CAP1 was also expressed in alveolar macrophages recovered by bronchoalveolar lavage. CAP1 protein was detected by Western blotting in rat and mouse alveolar epithelial cells, alveolar macrophages and bronchoalveolar lavage fluid. Finally, in vivo experiments revealed that intra-alveolar treatment with aprotinin abolished the increase in Na+-driven alveolar fluid clearance (AFC) induced by terbutaline in an in situ mouse lung model, whereas trypsin potentiated it. These results show that endogenous membrane-bound and/or secreted serine proteases such as CAPs regulate alveolar Na+and fluid transport in vitro and in vivo in rodent lung.
Surfactant phospholipid DPPC downregulates monocyte respiratory burst via modulation of PKC
Authors: Tonks Alex , Parton Joan , Tonks Amanda J. , Morris Roger H. K. , Finall Alison , Jones Kenneth P. , Jackson Simon K.
Published: January 2005

Pulmonary surfactant phospholipids have been shown previously to regulate inflammatory functions of human monocytes. This study was undertaken to delineate the mechanisms by which pulmonary surfactant modulates the respiratory burst in a human monocytic cell line, MonoMac-6 (MM6). Preincubation of MM6 cells with the surfactant preparations Survanta, Curosurf, or Exosurf Neonatal inhibited the oxidative response to either lipopolysaccharide (LPS) and zymosan or phorbol 12-myristate 13-acetate (PMA) by up to 50% ( P < 0.01). Preincubation of MM6 cells and human peripheral blood monocytes with dipalmitoyl phosphatidylcholine (DPPC), the major phospholipid component of surfactant, inhibited the oxidative response to zymosan. DPPC did not directly affect the activity of the NADPH oxidase in a MM6 reconstituted cell system, suggesting that DPPC does not affect the assembly of the individual components of this enzyme into a functional unit. The effects of DPPC were evaluated on both LPS/zymosan and PMA activation of protein kinase C (PKC), a ubiquitous intracellular kinase, in MM6 cells. We found that DPPC significantly inhibited the activity of PKC in stimulated cells by 70% ( P < 0.01). Western blotting experiments demonstrated that DPPC was able to attenuate the activation of the PKCδ isoform but not PKCα. These results suggest that DPPC, the major component of pulmonary surfactant, plays a role in modulating leukocyte inflammatory responses in the lung via downregulation of PKC, a mechanism that may involve the PKCδ isoform.
Keratinocyte growth factor therapy in murine oleic acid-induced acute lung injury
Authors: Ulrich K. , Stern M. , Goddard M. E. , Williams J. , Zhu J. , Dewar A. , Painter H. A. , Jeffery P. K. , Gill D. R. , Hyde S. C. , Geddes D. M. , Takata M. , Alton E. W. F. W.
Published: January 2005

Alveolar type II (ATII) cell proliferation and differentiation are important mechanisms in repair following injury to the alveolar epithelium. KGF is a potent ATII cell mitogen, which has been demonstrated to be protective in a number of animal models of lung injury. We have assessed the effect of recombinant human KGF (rhKGF) and liposome-mediated KGF gene delivery in vivo and evaluated the potential of KGF as a therapy for acute lung injury in mice. rhKGF was administered intratracheally in male BALB/c mice to assess dose response and time course of proliferation. SP-B immunohistochemistry demonstrated significant increases in ATII cell numbers at all rhKGF doses compared with control animals and peaked 2 days following administration of 10 mg/kg rhKGF. Protein therapy in general is very expensive, and gene therapy has been suggested as a cheaper alternative for many protein replacement therapies. We evaluated the effect of topical and systemic liposome-mediated KGF-gene delivery on ATII cell proliferation. SP-B immunohistochemistry showed only modest increases in ATII cell numbers following gene delivery, and these approaches were therefore not believed to be capable of reaching therapeutic levels. The effect of rhKGF was evaluated in a murine model of OA-induced lung injury. This model was found to be associated with significant alveolar damage leading to severe impairment of gas exchange and lung compliance. Pretreatment with rhKGF 2 days before intravenous OA challenge resulted in significant improvements in Po2, Pco2, and lung compliance. This study suggests the feasibility of KGF as a therapy for acute lung injury.
An analysis of wine festival attendees’ motivations: A synergy of wine, travel and special events?
Authors: Yuan Jingxue Jessica , Cai Liping A. , Morrison Alastair M. , Linton Sally
Published: January 2005

As special-interest tourism, wine tourism is becoming increasingly important for wine-growing regions. But wine marketers are faced with a paucity of empirical data when examining wine tourists’ characteristics and behaviour. This issue needs to be addressed if marketers want to implement more effective strategies to target the market. Visiting wine festivals is an important component in the complete construct of wine tourism. What might have motivated the participants to visit such an event has become critical for wine-growing destinations when they attempt to use wine festivals to promote the wineries and regions. This research study used a survey instrument specially designed to test participants’ motivations to attend a regional wine festival in a Midwestern state in the USA. Both festival and wine tourism motivations were integrated in the measurement scale. The findings showed that attendees were motivated by a variety of factors which were associated with the focus on the different elements incorporated in the theme of the festival — a synergy of wine, travel and special event. Wine festivals can be used as a vehicle to attract younger people to become more interested in wine. They create a good venue to tap into future target markets for wine tourism development.
Scottish tourism: Scenarios and vision
Authors: Yeoman Ian , Lederer Peter
Published: January 2005

In order to understand the potential for tourism in Scotland, it is important to look beyond the near future. Four scenarios have been created that paint contrasting pictures of Scottish tourism in 2015. The ‘Dynamic’ scenario creates a £10bn tourism economy with tourism being the number-one industry in Scotland. The ‘Weekend Get away’ sees tourism based upon consumerism and play. The value of tourism in this scenario is £7.6bn. ‘Yesterday’s Destination’ means tourism is based upon the past, and the industry is found to be too complacent. An uncompetitve industry means that growth is only 1 per cent per annum and valued at £5.1bn. Finally, ‘Exclusive Scotland’ means that the Scottish economy has failed as deflation has taken the soul out of the country but favourable exchange rates mean that international high-spending tourists flock to exclusive resorts. Tourism in this scenario is a £2.6bn industry. These four scenarios follow different paths and are driven by different circumstances. But within all of the scenarios, tourism exists. The opportunity for Scotland is to maximise its potential in order that tourism is Scotland’s first and everlasting industry.

The paper begins with a commentary by Peter Lederer.
Turning scenarios into a strategy map: Our ambition for Scottish tourism
Authors: Hay Brian , Yeoman Ian
Published: January 2005

VisitScotland has set out a vision for the Scottish tourism industry in which tourism will be the ‘first and everlasting industry’ of Scotland. This vision is driven by an ambition to increase tourism revenue by 50 per cent within the next ten years. In order to achieve that objective, a strategy map is used to provide direction that sets out the size and shape of the industry.

A constructivist interpretation paradigm and a cognitive mapping methodology are used to bring structure to the phenomenon of tourism futures by using a software package called Decision Explorer. This paper describes tourism being shaped by changes in demographics and in monetary policy. The consumer will be price-sensitive and/or sophisticated. Scotland will be recognised as a leisure destination rather than a tourism destination, with revenue growth much more likely to be derived from retail and leisure activities rather than the traditional sectors of accommodation and transport. But as tourism develops in Scotland, faster growth will be seen from European and short-haul markets compared to traditional long-haul markets. Shifts in demand as a result of demographic changes will result in visitors staying more with friends rather than with relatives, particularly in urban locations. A decreasing labour supply will result in more dependency on labour substitutes and the newer technologies.
On the destruction of kaolinite and gibbsite by phenylphosphonic, phenylphosphinic and phenylarsonic acids: evidence for the formation of new Al compounds
Authors: Gardolinski J. E. F. C. , Lagaly G. , Czank M.
Published: January 2005

Kaolinite and synthetic γ-Al(OH)3 (gibbsite or hydrargillite) were reacted with phenylphosphonic, phenylphosphinic and 2-nitrophenol-4-arsonic acids. The products were studied by powder X-ray diffraction, transmission electron microscopy/selected area electron diffraction/ energy dispersive X-ray/Fourier transform infrared and simultaneous thermogravimetric/differential thermal analysis. The acids were not intercalated but, instead, easily destroyed the structure of the minerals. Lamellar Al phenylphosphonate and aluminium phenylphosphinate and phenylarsonate with polymeric linear-chain structures were formed from kaolinite. The reaction between gibbsite and the same acids yielded almost identical products. No evidence of formation of grafted kaolinite derivatives after the reaction with phenylphosphonic acid was found.
Long-term in vitro transformation of 2-line ferrihydrite to goethite/hematite at 4, 10, 15 and 25°C
Authors: Schwertmann U. , Stanjek H. , Becher H.-H.
Published: January 2005

2-line ferrihydrite stored in water at ambient temperatures from 4 to 25°C and at ten different pH values between 2.5 and 12 for up to 10–12 y transformed to both goethite and hematite at all temperatures and pH values except at pH 12 where only goethite was formed. The rate and degree of transformation (20–100%) increased with increasing pH and temperature. The hematite/ (hematite+goethite) ratio varied between 0 and ~0.8, increased with increasing temperature and showed a strong maximum at pH 7–8 which increased from 0.1–0.2 at 4°C to 0.7–0.8 at 25°C. The maximum coincides with the zero point of charge of ferrihydrite where its solubility and, thus, its via-solution transformation rate to goethite are minimal. We assume, therefore, that in this pH-range the (slower) via-solution transformation to hematite can more efficiently compete with that to goethite.
Microstructures and interlayering in pyrophyllite from the Coastal Range of central Chile: evidence of a disequilibrium assemblage
Authors: Ruiz Cruz M. D. , Morata D. , Puga E. , Aguirre L. , Vergara M.
Published: January 2005

Pyrophyllite from a Triassic sedimentary formation from the Coastal Range of Chile has been investigated by transmission/analytical electron microscopy (TEM/AEM). The mineral assemblage includes pyrophyllite, muscovite, paragonite, a kaolin mineral, boehmite, rutile and hematite. The textures indicate that the protolith was a volcanoclastic rock. Petrographic evidence, chemistry, and the mineral assemblage suggest the intense leaching of the parent rock by a weathering process, before the metamorphic episode, to create the protolith for the pyrophyllite. Pyrophyllite always grows from the kaolin mineral, and both phases show close orientation relationships. The presence of parallel intergrowths of pyrophyllite and muscovite indicate that muscovite also grew from the kaolin mineral. Nevertheless, the composition of muscovite suggests that this phase must also form from another precursor, probably Al smectite. The AEM data and textural relationships between pyrophyllite and muscovite reveal the presence of two generations of muscovite and suggest that Na-rich muscovite recrystallized into a Na-free muscovite and paragonite.
The accurate crystal chemistry of ferric smectites from the lateritic nickel ore of Murrin Murrin (Western Australia). II. Spectroscopic (IR and EXAFS) approaches
Authors: Gaudin A. , Petit S. , Rose J. , Martin F. , Decarreau A. , Noack Y. , Borschneck D.
Published: January 2005

Fe-rich smectites from lateritic weathering profiles have previously been studied by XRD, ICP-AES, SEM-EDX and TEM-EDX analyses (Gaudinet al., 2004). These smectites exhibit intermediate chemistries between five end-members: Al-Fe beidellites, Al-Fe montmorillonites and Mg+Ni-saponite. The spectroscopic study by FTIR and XAS of these smectites reveals that: (1) tetrahedral Fe3+is near or below the detection limit (0.05 cation for 4Si); (2) the large chemical variability is due to substitution of the three major cations (Fe, Al, Mg) within adjacent octahedra; (3) Ni is not concentrated in another clay phase such as Ni-kerolite and is located in the octahedral sheets of smectite; (4) octahedral cations are not randomly distributed but ordered in separated Fe, Al, Mg, Ni clusters; (5) the Mg-Ni saponite end-member actually appears as small trioctahedral clusters of Mg and Ni distributed within the dioctahedral smectite.
Variations in the chemical composition of illite from five geothermal fields: a possible geothermometer
Authors: Battaglia S.
Published: January 2005

Previous attempts to use illite as a geothermometer have failed: no general relation between the mineral's chemical composition and temperature of crystallization has been found. Here, chemical compositions of 27 illite samples from five different geothermal fields (the data on four of which were drawn from the literature) were compared with their crystallization temperatures. As previously reported by Cathelineau (1988), the K content was found to be the only variable yielding a suitable correlation, but only when applied to one geothermal field; when various geothermal systems were considered, the correlation weakened considerably. Introduction of a correction algorithm to the K content of the illite has made it possible to draw a single line to fit the data from all the studied samples, yielding a good correlation coefficient (r = 0.84).
Gap-junction channels inhibit transverse propagation in cardiac muscle
Authors: Sperelakis Nicholas , Ramasamy Lakshminarayanan
Published: January 2005

The effect of adding many gap-junctions (g-j) channels between contiguous cells in a linear chain on transverse propagation between parallel chains was examined in a 5 × 5 model (5 parallel chains of 5 cells each) for cardiac muscle. The action potential upstrokes were simulated using the PSpice program for circuit analysis. Either a single cell was stimulated (cell A1) or the entire chain was stimulated simultaneously (A-chain). Transverse velocity was calculated from the total propagation time (TPT) from when the first AP crossed a Vm of -20 mV and the last AP crossed -20 mV. The number of g-j channels per junction was varied from zero to 100, 1,000 and 10,000 (Rgj of ∞, 100 MΩ, 10 MΩ, 1.0 MΩ, respectively). The longitudinal resistance of the interstitial fluid (ISF) space between the parallel chains (Rol2) was varied between 200 KΩ (standard value) and 1.0, 5.0, and 10 MΩ. The higher the Rol2 value, the tighter the packing of the chains. It was found that adding many g-j channels inhibited transverse propagation by blocking activation of all 5 chains, unless Rol2 was greatly increased above the standard value of 200 KΩ. This was true for either method of stimulation. This was explained by, when there is strong longitudinal coupling between all 5 cells of a chain awaiting excitation, there must be more transfer energy (i.e., more current) to simultaneously excite all 5 cells of a chain.
Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients
Authors: Wegman Pia , Vainikka Linda , Stål Olle , Nordenskjöld Bo , Skoog Lambert , Rutqvist Lars-Erik , Wingren Sten
Published: January 2005

Background

Tamoxifen is widely used as endocrine therapy for oestrogen-receptor-positive breast cancer. However, many of these patients experience recurrence despite tamoxifen therapy by incompletely understood mechanisms. In the present report we propose that tamoxifen resistance may be due to differences in activity of metabolic enzymes as a result of genetic polymorphism. Cytochrome P450 2D6 (CYP2D6) and sulfotransferase 1A1 (SULT1A1) are polymorphic and are involved in the metabolism of tamoxifen. The CYP2D6*4 and SULT1A1*2 genotypes result in decreased enzyme activity. We therefore investigated the genotypes of CYP2D6 and SULT1A1 in 226 breast cancer patients participating in a trial of adjuvant tamoxifen treatment in order to validate the benefit from the therapy.

Methods

The patients were genotyped using PCR followed by cleavage with restriction enzymes.

Results

Carriers of the CYP2D6*4 allele demonstrated a decreased risk of recurrence when treated with tamoxifen (relative risk = 0.28, 95% confidence interval = 0.11–0.74, P = 0.0089). A similar pattern was seen among the SULT1A1*1 homozygotes (relative risk = 0.48, 95% confidence interval = 0.21–1.12, P = 0.074). The combination of CYP2D6*4 and/or SULT1A1*1/*1 genotypes comprised 60% of the patients and showed a 62% decreased risk of distant recurrence with tamoxifen (relative risk = 0.38, 95% confidence interval = 0.19–0.74, P = 0.0041).

Conclusion

The present study suggests that genotype of metabolic enzymes might be useful as a guide for adjuvant endocrine treatment of postmenopausal breast cancer patients. However, results are in contradiction to prior hypotheses and the present sample size is relatively small. Findings therefore need to be confirmed in a larger cohort.
Brachial neuropathy after immunosuppression and stem cell transplantation for multiple sclerosis
Authors: Walker Melanie , Zunt Joseph R , Kraft George H
Published: January 2005

We present a case of brachial neuritis in an adult male who underwent high-dose immunosuppressive therapy and autologous stem cell transplantation (SCT) for primary progressive multiple sclerosis (MS). Brachial neuropathy following SCT has not previously been reported in patients with MS. The etiology of peripheral nerve dysfunction following SCT remains obscure.
Responsiveness of the Multiple Sclerosis Impairment Scale in comparison with the Expanded Disability Status Scale
Authors: Ravnborg M , Blinkenberg M , Sellebjerg F , Ballegaard M , Larsen S Helweg , Sørensen P Soelberg
Published: January 2005

The Multiple Sclerosis Impairment Scale (MSIS) is a measure of accumulated deficits assessed by means of a standard neurological examination. We compared the responsiveness of the MSIS with that of the Expanded Disability Status Scale (EDSS). We reviewed 4300 records collected systematically from 1995 to 2003 and identified 534 patients who had clinically definite multiple sclerosis and had had at least two clinical assessments with a time interval of 2-5 years. The rate of deterioration was significantly higher on the MSIS than on the EDSS. The annualized change in EDSS exhibited a maximum at baseline EDSS 4 and a subsequent rapid decline at higher baseline EDSS, while the annualized change in MSIS was fairly stable over a wide middle range of baseline MSIS. The variance of the annualized change in EDSS fluctuated markedly between the baseline EDSS categories, being highest at baseline EDSS 2, while the variance of the annualized change in MSIS was stable. The study indicates that the responsiveness of the MSIS is better than that of the EDSS in terms of both magnitude and stability over the range of measurement.
Randomized study of once-weekly interferon β-1a therapy in relapsing multiple sclerosis: three-year data from the OWIMS study
Authors: Freedman M S , Francis G S , Sanders E ACM , Rice G PA , O'Connor P , Comi G , Duquette P , Metz L , Murray T J , Bouchard J-P , Abramsky O , Pelletier J , O'Brien F ,   OWIMS Study Group,   University of British Columbia MS/MRI Research Group
Published: January 2005

Background: Once weekly interferon β-1a for multiple sclerosis (OWIMS) demonstrated modest, but significant, magnetic resonance imaging (MRI) benefit of once-weekly (qw) interferon (IFN) β-1a at 48 weeks, but no significant effect on relapses. Objective: An OWIMS extension permitted assessment of longer-term efficacy/safety of qw IFN β-1a in relapsing-remitting multiple sclerosis (RRMS). Methods: Placebo patients were rerandomized to IFN β-1a, 22 or 44 mcg qw, for two additional 48-week intervals. Primary outcome was MRI lesion activity. Relapse rate and other MRI measures were secondary outcomes. Results: After three years, median (mean) T2 lesion count/patient/scan was 1.3 (2.6) for 44 mcg, 1.7 (3.3) for 22 mcg, 1.7 (3.4) for placebo/22 mcg, 2.0 (3.6) for placebo/44 mcg (all differences not significant). Annualized relapse rates were lowest for 44 mcg (0.77) versus other groups (0.83-0.86, not significant). Persistent neutralizing antibodies did not affect relapse rates, but MRI active lesions were increased in antibody-positive patients receiving 44 mcg compared to antibody negative patients. Conclusions: In RRMS, once weekly IFN β-1a, particularly 44 mcg, can induce a significant MRI, but not relapse, effect, compared with placebo. No significant dose effect was seen. In contrast to the significant effect observed with three-times-weekly dosing of subcutaneous IFN β-1a compared with placebo, this study confirms the lack of meaningful clinical benefit with once-weekly dosing.
Treatment patterns of multiple sclerosis patients: a comparison of veterans and non-veterans using the NARCOMS registry
Authors: Lo Albert C , Hadjimichael Olympia , Vollmer Timothy L
Published: January 2005

Multiple sclerosis (MS) is a chronic illness of the central nervous system, with a highly variable clinical course. Available therapies are only partially effective and as a consequence treatment patterns between patients can be varied. Longitudinal databases consisting of large cohorts where successive and sequential data is collected may reveal disease and treatment characteristics not apparent when data is gathered during clinical trials that consist usually of relatively homogeneous patients followed for short durations. We analysed data from the North American Research Committee on Multiple Sclerosis registry, a self-reported database, to assess MS patient characteristics and treatment patterns, with a focus on veterans. We show that the Veteran Healthcare Administration (VHA) system of medical centres care for a greater number of patients with higher average disability but not necessarily patients who report primary progressive or actively worsening disease. We also show that the VHA medical centres appear to better provide multidisciplinary care, particularly in the areas of social work, physical therapy and urology. In general, treatment patterns for symptomatic therapies follow similar patterns across veterans and non-veterans groups. Treatment patterns for immunomodulatory agents suggest that VHA veterans use IMA less frequently than either non-VHA veterans or non-veterans.
Utility and barriers to performance of the ankle brachial index in primary care practice
Authors: Mohler Emile R , Treat-Jacobson Diane , Reilly Muredach P , Cunningham Kelly E , Miani Mark , Criqui Michael H , Hiatt William R , Hirsch Alan T
Published: January 2005

Peripheral arterial disease is prevalent, associated with increased cardiovascular morbidity and mortality, and is underdiagnosed. Nevertheless, systematic efforts to provide early office-based peripheral arterial disease detection are not routinely implemented in office practice. The PARTNERS Program implemented the ankle brachial index (ABI) measurement in primary care outpatient clinics in order to model practical dissemination of this technique and thus improve office-based peripheral arterial disease detection. The objective of this study was to identify clinician-defined factors that were perceived to foster acceptance of, or create barriers to, the use of the ABI in office practice. The ABI Utilization Survey was administered to primary care clinicians who participated in the PARTNERS Program, as well as to additional primary care clinicians who participated in the PARTNERS Preceptorship. The survey assessed six parameters: pre- and post-participation office ABI utilization; perceived clinical utility of the ABI; perceived value of the ABI data relative to other commonly used office disease detection methods; feasibility of implementing office-based ABI testing; definition of factors limiting utilization of the ABI in office practice; and the role of office staff in performing the ABI test. Survey data were obtained from 886 respondents. A total of 68% of respondents did not measure the ABI prior to participation in the PARTNERS Program. After Program participation, the frequency of office ABI use increased from 12% to 43% weekly and 13% to 39% monthly. The few participants who reported using the ABI only once a year (annually) did not significantly change after the program. Most clinicians believed that the ABI was useful in the diagnosis and management of both symptomatic (96%) and asymptomatic (89%) peripheral arterial disease. Moderate to major barriers to use of the ABI included time constraints (56%), lack of reimbursement (45%), and staff availability (45%). Nearly all (88%) clinicians believed that it was feasible to incorporate ABI into daily practice. Overall, most clinicians (57 75%) believed that ABI was equal to, or more useful, than other widely available and reimbursed screening tests in preserving their patients’ health. In conclusion, the ABI was perceived by primary care clinicians to be a clinically useful diagnostic test. Limited reimbursement and time were identified as the primary barriers to its widespread use. Once learned, most clinicians stated that the ABI would continue to be frequently used in their office practice. The ABI is a simple peripheral arterial disease detection tool that can be successfully applied in primary care office practices.
Abnormal monocyte recruitment and collateral artery formation in monocyte chemoattractant protein-1 deficient mice
Authors: Voskuil Michiel , Hoefer Imo E , van Royen Niels , Hua Jing , de Graaf Stijn , Bode Christoph , Buschmann Ivo R , Piek Jan J
Published: January 2005

Monocyte chemoattractant protein 1 (MCP-1) has been shown to be effective for the stimulation of collateral artery formation in small and large animal models. The availability of a genetic knockout mouse enables evaluation of the importance of the role of MCP-1 in the natural course of collateral artery growth. In a total of 21 MCP-1 = as well as 13 of the appropriate genetic background controls (f129Sv=JXC57Bl=6JgF1), a femoral artery ligation was performed. Subsequently, a polyethylene catheter, connected to an osmotic minipump, was inserted retrogradely into the occluded femoral artery with the tip pointing upstream. Using this technique, PBS (MCP-1 =: n 1/4-13 and C57Bl=6J: n 1/4-13) or MCP-1 (JE; MCP-1 =: n 1/4-8) was delivered intra-arterially. Seven days after ligation, determination of hind limb flow was assessed by controlled tissue perfusion using differently labeled fluorescent microspheres. MCP-1 = mice exhibited a reduction of hind limb flow of 32.9-9.2% of the unligated hind limb, compared with 55.4-6.8% in C57Bl=6J mice (p <0.01). MCP-1= mice that underwent a subsequent ‘rescue’ treatment with MCP-1 showed a restoration of flow to a level of 47.4-9.8% (p 1/4 NS compared with PBS-treated C57Bl/6J). Specific immunohistochemical staining for monocytes (MOMA-2: MCP-1 =, n 1/4-5 and C57Bl/6J, n 1/4-5) showed a reduced number of monocytes around developing collateral arteries in the MCP-1 = mice. In conclusion, our data show that the absence of MCP-1 causes a strong reduction in flow restoration after femoral artery occlusion, coinciding with a reduced monocyte attraction, emphasizing the central role of this chemokine in the multifactorial process of collateral artery formation.
Skeletal muscle metabolic changes in peripheral arterial disease contribute to exercise intolerance: a point-counterpoint discussion
Authors: Brass Eric P , Hiatt William R , Green Simon
Published: January 2005

Patients with claudication have a marked impairment in exercise performance. Several factors contribute to this limitation, including reductions in large vessel blood flow and oxygen delivery as well as metabolic abnormalities in skeletal muscle. The relative contribution of these factors and their role in the pathophysiology of the exercise limitation is discussed using a point-counterpoint approach. Future directions for research conclude the discussion.
The Integrated Role of Desferrioxamine and Phenserine Targeted to an Iron‐Responsive Element in the APP‐mRNA 5′‐Untranslated Region
Authors: VENTI AMANDA , GIORDANO TONY , EDER PAUL , BUSH ASHLEY I. , LAHIRI DEBOMOY K. , GREIG NIGEL H. , ROGERS JACK T.
Published: January 2005

Abstract: The Alzheimer's amyloid precursor protein (APP) is the metalloprotein that is cleaved to generate the pathogenic Aβ peptide. We showed that iron closely regulated the expression of APP by 5′‐untranslated region (5′‐UTR) sequences in APP mRNA. Iron modulated APP holoprotein expression by a pathway similar to iron control of the translation of the ferritin‐L and ‐H mRNAs by iron‐responsive elements in their 5′‐UTRs. APP gene transcription is also responsive to copper deficit where the Menkes protein depleted fibroblasts of copper to suppress transcription of APP through metal regulatory and copper regulatory sequences upstream of the APP 5′ cap site. APP is a copper‐zinc metalloprotein and chelation of Fe3+ by desferrioxamine and Cu2+ by clioquinol appeared to provide effective therapy for the treatment of AD in limited patient studies. We have introduced an RNA‐based screen for small APP 5′‐UTR binding molecules to identify leads that limit APP translation (but not APLP‐1 and APLP‐2) and amyloid Aβ peptide production. A library of 1200 drugs was screened to identify lead drugs that limited APP 5′‐UTR‐directed translation of a reporter gene. The efficacy of these leads was confirmed for specificity in a cell‐based secondary assay to measure the steady‐state levels of APP holoprotein relative to APLP‐1/APLP‐2 by Western blotting. Several chelators were identified among the APP 5′‐UTR directed leads consistent with the presence of an IRE stem‐loop in front of the start codon of the APP transcript. The APP 5′‐UTR‐directed drugs—desferrioxamine (Fe3+ chelator), tetrathiomolybdate (Cu2+ chelator), and dimercaptopropanol (Pb2+ and Hg2+ chelator)—each suppressed APP holoprotein expression (and lowered Aβ peptide secretion). The novel anticholinesterase phenserine also provided “proof of concept” for our strategy to target the APP 5′‐UTR sequence to identify “anti‐amyloid” drugs. We further defined the interaction between iron chelation and phenserine action to control APP 5′‐UTR‐directed translation in neuroblastoma (SY5Y) transfectants. Phenserine was most efficient to block translation under conditions of intracellular iron chelation with desferrioxamine suggesting that this anticholinesterase operated through an iron (metal)‐dependent pathway at the APP 5′‐UTR site.
BACE1 Gene Expression and Protein Degradation
Authors: ZHOU WEIHUI , QING HONG , TONG YIGANG , SONG WEIHONG
Published: January 2005

Abstract: Deposition of amyloid β protein in the brain is the major pathological feature of Alzheimer's disease. Amyloid β protein is generated from β‐amyloid precursor protein by β‐secretase and γ‐secretase. Proteolytic processing of amyloid precursor protein at the β site by BACE1 is essential to generate amyloid β protein. BACE1, the major β‐secretase involved in cleaving amyloid precursor protein, has been identified as a type 1 membrane‐associated aspartyl protease. In this study, we found that BACE1 gene expression is controlled by a TATA‐less promoter. BACE1 gene expression is tightly regulated at the transcriptional level and the transcription factor Sp1 plays an important role in regulation of BACE1 to process amyloid precursor protein generating amyloid β protein. Furthermore, we found that BACE1 protein is ubiquitinated, and the degradation of BACE1 proteins and amyloid precursor protein processing are regulated by the ubiquitin‐proteasome pathway.
Microglia as a Potential Bridge between the Amyloid β‐Peptide and Tau
Authors: KITAZAWA MASASHI , YAMASAKI TRITIA R. , LAFERLA FRANK M.
Published: January 2005

Abstract: Inflammation is a critical component of the pathogenesis of Alzheimer's disease (AD), consisting of the activation of both microglia and astrocytes. Activated microglia and reactive astrocytes are found in and around extraneuronal amyloid‐β plaques and are thought to facilitate the clearance of these deposits from the brain parenchyma. However, mounting evidence indicates that chronic activation of microglia, presumably via the secretion of cytokines and reactive molecules, may exacerbate plaque pathology as well as enhance the hyperphosphorylation of tau and the subsequent development of neurofibrillary tangles. Thus, suppression of microglial activity in AD brain has been considered as a potential treatment of AD and may slow the disease progression. Along these lines, anti‐inflammatory drugs, particularly nonsteroidal anti‐inflammatory drugs (NSAIDs), lessen the effects of AD pathology. In this review, we discuss the molecular mechanism of inflammatory responses in AD brain as well as animal models, and current therapies using NSAIDs, antioxidants, and immunotherapy as neuroprotective strategies for AD.
Inflammation and the Degenerative Diseases of Aging
Authors: McGEER PATRICK L. , McGEER EDITH G.
Published: January 2005

Abstract: Chronic inflammation is associated with a broad spectrum of neurodegenerative diseases of aging. Included are such disorders as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis, the Parkinson‐dementia complex of Guam, all of the tauopathies, and age‐related macular degeneration. Also included are such peripheral conditions as osteoarthritis, rheumatoid arthritis, atherosclerosis, and myocardial infarction. Inflammation is a two‐edged sword. In acute situations, or at low levels, it deals with the abnormality and promotes healing. When chronically sustained at high levels, it can seriously damage viable host tissue. We describe this latter phenomenon as autotoxicity to distinguish it from autoimmunity. The latter involves a lymphocyte‐directed attack against self proteins. Autotoxicity, on the other hand, is determined by the concentration and degree of activation of tissue‐based monocytic phagocytes. Microglial cells are the brain representatives of the monocyte phagocytic system. Biochemically, the intensity of their activation is related to a spectrum of inflammatory mediators generated by a variety of local cells. The known spectrum includes, but is not limited to, prostaglandins, pentraxins, complement components, anaphylotoxins, cytokines, chemokines, proteases, protease inhibitors, adhesion molecules, and free radicals. This spectrum offers a huge variety of targets for new anti‐inflammatory agents. It has been suggested, largely on the basis of transgenic mouse models, that stimulating inflammation rather than inhibiting it can be beneficial in such diseases as AD. If this were the case, administration of NSAIDs, or other anti‐inflammatory drugs, would be expected to exacerbate conditions such as AD, PD, and atherosclerosis. However, epidemiological evidence overwhelmingly demonstrates that the reverse is true. This indicates that, at least in these diseases, the inflammation is harmful. So far, advantage has not been taken of opportunities indicated by these epidemiological studies to treat AD and PD with appropriate anti‐inflammatory agents. Based on this evidence, classical NSAIDs are the most logical choice. Dosage, though, must be sufficient to combat the inflammation. Analysis of mRNA levels of inflammatory mediators indicates that the intensity of inflammation is considerably higher in AD hippocampus and in PD substantia nigra than in osteoarthritic joints. Thus, full therapeutic doses of NSAIDs, or combinations of anti‐inflammatory agents, are needed to achieve the suggested neurological benefits.
Neuroprotection from Complement‐Mediated Inflammatory Damage
Authors: KULKARNI AMOD P. , KELLAWAY LAURIE A. , LAHIRI DEBOMOY K. , KOTWAL GIRISH J.
Published: January 2005

Abstract: Several neurodegenerative disorders, such as multiple sclerosis, Alzheimer's disease, and Parkinson's disease, are associated with inflammatory damage. The complex process of neuroinflammation involves various components of the immune system and the central nervous system. Particularly, brain astrocytes and microglial cells generate several inflammatory mediators like cytokines, leukotrienes, superoxide radicals, eicasonoids, and the components of the complement cascade. Complement plays an important role in the etiology of most of the neuroinflammatory disorders. To prevent long‐term dysfunction inflammation in the central nervous system must be modulated with neuroprotective agents such as nonsteroidal anti‐inflammatory drugs, steroids, phenolic thiazoles, nitrones, catechins, nitric oxide synthetase inhibitors, flavonoids, and phosphodiesterase inhibitors. Few drugs are found to be effective and their therapeutic benefit is hampered by side effects. Most of the neuroprotective agents are free radical scavengers and many inhibit only one or two aspects of inflammation. The complement inhibitory activity of most of these agents is either unknown or not established. Thus, there is doubt regarding their therapeutic value in most of the inflammatory disorders in which complement plays a major role. In this context the role of a multifunctional protein, vaccinia virus complement control protein (VCP), is quite significant as it may play a pivotal role in the treatment of several neuroinflammatory disorders. VCP is known to inhibit both complement pathways involved in inflammation. It is also known to inhibit cytokines and chemokines in inflammation. Our recent studies on rats demonstrate that VCP administration inhibits macrophage infiltration, reduces spinal cord destruction, and improves motor skills associated with spinal cord injury, establishing VCP as a strong candidate for neuroprotection. Thus, complement inhibitors such as VCP can serve as neuroprotective agents in inflammation associated with several neurodegenerative disorders.
The Degeneration of Dopamine Neurons in Parkinson's Disease: Insights from Embryology and Evolution of the Mesostriatocortical System
Authors: VERNIER PHILIPPE , MORET FREDERIC , CALLIER SOPHIE , SNAPYAN MARINA , WERSINGER CHRISTOPHE , SIDHU ANITA
Published: January 2005

Abstract: Parkinson's disease (PD) is, to a large extent, specific to the human species. Most symptoms are the consequence of the preferential degeneration of the dopamine‐synthesizing cells of the mesostriatal‐mesocortical neuronal pathway. Reasons for that can be traced back to the evolutionary mechanisms that shaped the dopamine neurons in humans. In vertebrates, dopamine‐containing neurons and nuclei do not exhibit homogenous phenotypes. In this respect, mesencephalic dopamine neurons of the substantia nigra and ventral tegmental area are characterized by a molecular combination (tyrosine hydroxylase, aromatic amino acid decarboxylase, monoamine oxidase, vesicular monoamine transporter, dopamine transporter—to name a few), which is not found in other dopamine‐containing neurons of the vertebrate brain. In addition, the size of these mesencephalic DA nuclei is tremendously expanded in humans as compared to other vertebrates. Differentiation of the mesencephalic neurons during development depends on genetic mechanisms, which also differ from those of other dopamine nuclei. In contrast, pathophysiological approaches to PD have highlighted the role of ubiquitously expressed molecules such as a‐synuclein, parkin, and microtubule‐associated proteins. We propose that the peculiar phenotype of the dopamine mesencephalic neurons, which has been selected during vertebrate evolution and reshaped in the human lineage, has also rendered these neurons particularly prone to oxidative stress, and thus, to the fairly specific neurodegeneration of PD. Numerous evidence has been accumulated to demonstrate that perturbed regulation of DAT‐dependent dopamine uptake, DAT‐dependent accumulation of toxins, dysregulation of TH activity as well as high sensitivity of DA mesencephalic neurons to oxidants are key components of the neurodegeneration process of PD. This view points to the contribution of nonspecific mechanisms (α‐synuclein aggregation) in a highly specific cellular environment (the dopamine mesencephalic neurons) and provides a robust framework to develop novel and rational therapeutic schemes in PD.