bluuebunny/crossref_metadata_2025_split huggingface dataset:
Steady‐state pharmacokinetics and safety of donepezil HCl in subjects with moderately impaired renal function
Authors: Nagy Christa F. , Kumar Dinesh , Cullen Edward I. , Bolton W. Kline , Marbury Thomas C. , Gutierrez Maria J. , Hutman H. Wayne , Pratt Raymond D. 
Published: October 2004

AimsTo characterize the pharmacokinetic, pharmacodynamic and safety profiles of donepezil in subjects with moderate renal impairment and matched healthy controls during single‐dose and multiple‐dose phases.MethodsThis open‐label study enrolled subjects with moderate renal impairment (creatinine clearance [CLCr] 17–33 ml min−1 1.73 m−2 body surface area) and age, weight and sex‐matched healthy controls. A single‐dose (5 mg donepezil) phase was followed by a 23‐day multiple dose (5 mg day−1 donepezil) steady‐state phase. The pharmacokinetic and pharmacodynamic parameters of donepezil were determined for up to 144 h after the first dose and 168 h after the last dose.ResultsThirty‐six subjects were enrolled, 19 renally impaired and 17 healthy controls. All pharmacokinetic and pharmacodynamic parameters were similar between groups after a single dose of donepezil (Cmax 5.17 ± 0.36 and 6.07 ± 0.49 ng ml−1; AUC0−24 76.05 ± 5.54 and 77.45 ± 4.49 ng·h ml−1; mean maximum percentage inhibition [Imax] red blood cell (RBC) AChE activity 32.07 ± 2.00 and 31.69 ± 2.45%; for subjects with renal impairment and healthy subjects, respectively). Pharmacokinetic parameters under steady‐state conditions did not differ between renally impaired and healthy subjects (CSS 20.83 ± 1.78 and 18.38 ± 1.52 ng ml−1; AUC0−24 500.0 ± 42.8 and 441.1 ± 36.4 ng·h ml−1; degree of accumulation [RA] 6.98 ± 0.59 and 5.94 ± 0.53; for subjects with renal impairment and healthy subjects, respectively). Main pharmacodynamic parameters were also similar in renally impaired and healthy subjects at steady state (average percentage inhibition [ISS] RBC AChE activity 65.11 ± 2.52 and 60.62 ± 2.95, respectively). Protein binding was also similar between groups (% free donepezil 23.54 ± 1.96 and 20.23 ± 0.64, respectively). Donepezil was well tolerated by both groups.ConclusionsThese results indicate that the pharmacokinetics of donepezil are not altered after dosing to steady state, and that donepezil can be administered safely to subjects with moderate renal impairment.
Interferon-γ-modified dendritic cells suppress B cell function and ameliorate the development of experimental autoimmune myasthenia gravis
Authors: ADIKARI S B , LIAN H , LINK H , HUANG Y-M , XIAO B-G 
Published: October 2004

SUMMARYThis study was designed to investigate the therapeutic effects of interferon (IFN)-γ-modulated dendritic cells (DC) in experimental autoimmune myasthenia gravis (EAMG). We induced EAMG in Lewis rats by immunization with Torpedo nicotinic acetylcholine receptor (nAChR) and adjuvant. On day 33 post-immunization (p.i.), splenic DC were prepared, exposed to IFN-γ alone (IFN-γ-DC) or to IFN-γ in combination with 1-methyl-DL-tryptophan (1-MT), the specific inhibitor of indoleamine 2,3-dioxygenase (IDO) (IFN-γ + 1-MT-DC), and injected subcutaneously into rats with incipient EAMG on day 5 p.i. A control group of EAMG rats received naive DC on day 5 p.i., while another group received 1-MT every other day, intraperitoneally (p.i.), from days 5 to 41 p.i. The severity of clinical signs of EAMG was reduced dramatically in IFN-γ-DC-treated rats compared to rats receiving naive DC, IFN-γ + 1-MT-DC or 1-MT alone. The number of plasma cells secreting nAChR antibodies was reduced and the expression of B cell activation factor (BAFF) on splenic and lymph node mononuclear cells (MNC) was down-regulated in rats treated with IFN-γ-DC. In vitro co-culture of MNC derived from EAMG rats with IFN-γ-DC produced relatively few cells secreting nAChR antibodies. Addition of 1-MT to the co-culture significantly increased the number of cells secreting nAChR antibodies. We conclude that IFN-γ-DC reduced the number of plasma cells secreting nAChR antibodies in an IDO-dependent manner and ameliorated the development of EAMG in Lewis rats.
Circulating monocytes in patients with acute coronary syndromes lack sufficient interleukin-10 production after lipopolysaccharide stimulation
Authors: VAN HAELST P L , TERVAERT J W COHEN , BIJZET J , BALJÉ-VOLKERS C , MAY J F , LANGEVELD B , GANS R O B 
Published: October 2004

SUMMARYAcute coronary syndromes (ACS) are associated with inflammation resulting from monocyte activation. We sought for differences in the production of pro- and anti-inflammatory cytokines by monocytes from patients with ACS. C-reactive protein (CRP) and neopterin were measured in 22 patients with acute coronary syndromes, 50 patients with stable vascular disease and 22 healthy controls. Production of tumour necrosis factor (TNF)-α and interleukin (IL)-10 was determined after, respectively, 6 and 24 h of incubation of full blood with lipopolysaccharide (LPS). Levels of CRP [median, interquartile range (IQR)][1·5 mg/l (0·8–4·5) ACS patient versus 2·1 (0·9–3·6) stable disease versus 0·4 (0·3–1·2) healthy controls] (P &lt; 0·001) and neopterin [7·4 nmol/l (6·0–8·7) ACS patient versus 7·1(6·0–8·9) stable disease versus 6·4 (5·6–7·3) healthy controls] (P = 0·07) were higher in both the patient groups. IL-10 production after LPS stimulation was greatly reduced in patients with acute coronary syndromes (16 175 pg/ml, 7559–28 470 pg/ml) as opposed to patients with stable disease (28 379 pg/ml, 12 601–73 968 pg/ml) and healthy controls (63 830 pg/ml, 22 040–168 000 pg/ml) (P = 0·003). TNF-α production was not signiﬁcantly different between the groups [7313 pg/ml (4740–12 615) ACS patient versus 11 002 (5913–14 190) stable disease versus 8229 (5225–11 364) healthy controls] (P = 0·24). Circulating monocytes in unstable coronary syndromes produce equal amounts of TNF-α but less IL-10 after stimulation with LPS in vitro as compared with healthy controls. We hypothesize that, in acute coronary syndromes, the production proinflammatory cytokines is not counterbalanced by anti-inflammatory cytokines such as IL-10.
Autoantibody against matrix metalloproteinase-3 in patients with systemic sclerosis
Authors: NISHIJIMA C , HAYAKAWA I , MATSUSHITA T , KOMURA K , HASEGAWA M , TAKEHARA K , SATO S 
Published: October 2004

SUMMARY
Systemic sclerosis (SSc) is characterized by multi-organ fibrosis with an autoimmune background. Although autoantibodies are detected frequently in SSc patients, the role of autoantibody in the development of fibrosis remains unknown. Connective tissue homeostasis is a balance between the synthesis and degradation of the extracellular matrix (ECM); ECM degradation is regulated mainly by matrix metalloproteinases (MMPs). Anti-MMP-1 antibody is suggested to inhibit MMP-1 and be involved in the development of the fibrosis in SSc. However, the accumulation of various ECM components in the tissue of SSc cannot be explained by the anti-MMP-1 antibody alone. In this study, we examined the presence  or  levels of antibody to MMP-3, a protein which degrades various ECM components relevant to SSc fibrosis. Enzyme-linked immunosorbent assay (ELISA) using human recombinant MMP-3 revealed that IgG anti-MMP-3 autoantibody levels were elevated significantly in the sera from SSc patients, but not in patients with active systemic lupus erythematosus or dermatomyositis. IgG and IgM anti-MMP-3 antibody levels were significantly higher in diffuse cutaneous SSc, a severe form, than those in limited cutaneous SSc. Consistently, IgG anti-MMP-3 antibody levels correlated significantly with fibrosis of the skin, lung and renal blood vessels. The presence of IgG anti-MMP-3 autoantibody in sera from SSc patients was confirmed by immunoblotting analysis. Remarkably, MMP-3 activity was inhibited by IgG anti-MMP-3 antibody. These results suggest that anti-MMP-3 antibody is a serological marker that reflects the severity of SSc and also suggest that it may contribute to the development of fibrosis by inhibiting MMP-3 activity and reducing the ECM turnover.
Increased CCR4 expression on circulating CD4+ T cells in ankylosing spondylitis, rheumatoid arthritis and systemic lupus erythematosus
Authors: YANG P T , KASAI H , ZHAO L J , XIAO W G , TANABE F , ITO M 
Published: October 2004

SUMMARYPrevious studies have suggested that CCR4 is particularly important in the selective recruitment of various subsets of leucocytes in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In this study, we examined the percentage of CD4+/CCR4+ T cells within circulating lymphocytes in active ankylosing spondylitis (AS), RA and SLE patients. The clinical significance of CCR4 expression as well as possible associations between the expression and serum levels of tumour necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-10 were also examined. Our results showed that the percentage of CD4+/CCR4+ T cells was significantly elevated in AS and RA patients as compared with normal controls. The percentage was also significantly higher in SLE patients who had received no treatment with glucocorticoids or cytotoxic drugs (untreated SLE) than that in controls. In addition, the percentage of CD4+/CCR4+ T cells showed significant positive correlations with the Bath ankylosing spondylitis disease activity index (BASDAI) in AS and with the SLE disease activity index (SLEDAI) in untreated SLE. Of all the cytokines examined, the elevated serum IL-10 level was closely correlated with the percentage of CD4+/CCR4+ T cells in AS, RA and untreated SLE. These results suggest that CCR4 may be crucial in the pathogenesis of AS, RA and SLE. The percentage of CD4+/CCR4+ T cells can serve as a useful marker for the activity of AS and untreated SLE.
Glycolytic enzymes associated with the cell surface of Streptococcus pneumoniae are antigenic in humans and elicit protective immune responses in the mouse
Authors: LING E , FELDMAN G , PORTNOI M , DAGAN R , OVERWEG K , MULHOLLAND F , CHALIFA-CASPI V , WELLS J , MIZRACHI-NEBENZAHL Y 
Published: October 2004

SUMMARY
Streptococcus pneumoniae is a leading cause of otitis media, sinusitis, pneumonia, bacteraemia and meningitis worldwide. The drawbacks associated with the limited number of various capsular polysaccharides that can be included in the polysaccharide-based vaccines focuses much attention on pneumococcal proteins as vaccine candidates. We extracted an enriched cell wall fraction from S. pneumoniae WU2. Approximately 150 soluble proteins could be identified by 2D gel electrophoresis. The proteins were screened by 2D-Western blotting using sera that were obtained longitudinally from children attending day-care centres at 18, 30 and 42 months of age and sera from healthy adult volunteers. The proteins were further identified using matrix-assisted laser desorption ionization-time of flight mass spectrometry. Seventeen proteins were antigenic in children and adults, of which 13 showed an increasing antibody response with age in all eight children analysed. Two immunogenic proteins, fructose–bisphosphate aldolase (FBA) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and a control protein with known low immunogenicity, heat shock protein 70 (DnaK), were expressed in Escherichia coli, purified and used to immunize mice. Mouse antibodies elicited to the recombinant (r) FBA and rGAPDH were cross-reactive with several genetically unrelated strains of different serotypes and conferred protection to respiratory challenge with virulent pneumococci. In addition, the FBA used in this study (NP_345117) does not have a human ortholog and warrants further investigation as a candidate for a pneumococcal vaccine. In conclusion, the immunoproteomics based approach utilized in the present study appears to be a suitable tool for identification of novel S. pneumoniae vaccine candidates.
Targets and methods for the detection of processed animal proteins in animal feedstuffs
Authors: Muldoon Mark T. , Onisk Dale V. , Brown Michael C. , Stave James W. 
Published: October 2004

SummaryBovine spongiform encephalopathy (BSE), or ‘mad cow disease’, is one of several transmissable spongiform encephalopathies (TSEs) known to affect certain mammals and is spread through the ingestion of infected animal tissue. It is believed that the inadvertent contamination of meat and bone meal (MBM) with infected animal tissue and the subsequent use of this material as a feed supplement contributed to the spread of the disease in cattle. As a result, the use of processed animal proteins (PAPs) in animal feeds is regulated in many parts of the world. Although feed testing is the only definitive means to certify compliance, regulatory compliance often relies solely on paper certification. Recently, rapid methods have become available that can be used by regulators to determine compliance during routine inspections. We describe a rapid, immunochromatographic strip test that can detect 0.1% MBM in animal feed. The test takes 15 min to perform and large numbers of samples can be screened for PAPs simultaneously.
Comparative analysis of Palm and wearable computers for Participatory Simulations
Authors: Klopfer Eric , Yoon Susan , Rivas Luz 
Published: October 2004

Abstract Recent educational computer‐based technologies have offered promising lines of research that promote social constructivist learning goals, develop skills required to operate in a knowledge‐based economy (Roschelle et al. 2000), and enable more authentic science‐like problem‐solving. In our research programme, we have been interested in combining these aims for curricular reform in school science by developing innovative and progressive hand‐held and wearable computational learning tools. This paper reports on one such line of research in which the learning outcomes of two distinct technological platforms (wearable computers and Palm hand‐helds) are compared using the same pedagogical strategy of Participatory Simulations. Participatory Simulations use small wearable or hand‐held computers to engage participants in simulations that enable inquiry and experimentation (Colella 2000) allowing students to act out the simulation themselves.The study showed that the newer and more easily distributable version of Participatory Simulations on Palms was equally as capable as the original Tag‐based simulations in engaging students collaboratively in a complex problem‐solving task. We feel that this robust and inexpensive technology holds great promise for promoting collaborative learning as teachers struggle to find authentic ways to integrate technology into the classroom in addition to engaging and motivating students to learn science.
A comparison of parallelism in interface designs for computer‐based learning environments
Authors: Min Rik , Yu Tao , Spenkelink Gerd , Vos Hans 
Published: October 2004

AbstractIn this paper we discuss an experiment that was carried out with a prototype, designed in conformity with the concept of parallelism and the Parallel Instruction theory (the PI theory). We designed this prototype with five different interfaces, and ran an empirical study in which 18 participants completed an abstract task. The five basic designs were based on hypotheses of the PI theory that for solving tasks on screens all task relevant information must be in view on a computer monitor, as clearly as possible. The condition with two parallel frames and the condition with one long web page appeared to be the best design for this type of task, better than window versions that we normally use for our computer simulations on the web. We do not only describe the results of the abstract task in the five conditions, but we also discuss the results from the perspective of concrete, realistic tasks with computer simulations. The interface with two parallel frames is the best solution here, but also the interface with long web pages (‘virtual parallelism’) is a great favourite in practice when doing realistic tasks.
Impairment of coronary circulation by acute hyperhomocysteinaemia and reversal by antioxidant vitamins
Authors: Coppola A. , Astarita C. , Liguori E. , Fontana D. , Oliviero M. , Esposito K. , Coppola L. , Giugliano D. 
Published: October 2004

Abstract.Objective.  To evaluate the effect of acute hyperhomocysteinaemia with and without antioxidant vitamins pretreatment on coronary circulation and circulating chemokine levels.Design.  Observer‐blinded, randomized crossover study.Setting.  This study was conducted at a university hospital and at a general hospital in Italy.Subjects.  Sixteen healthy hospital staff volunteers (nine men, seven women), aged 26–40 years.Interventions.  Subjects were given each three loads in random order at 1‐week intervals: oral methionine, 100 mg kg−1 in fruit juice; the same methionine load immediately following ingestion of antioxidant vitamin E, 800 IU, and ascorbic acid, 1000 mg; and methionine‐free fruit juice (placebo).Main outcome measures.  Coronary flow velocity reserve (CFVR), assessed by noninvasive transthoracic Doppler echocardiography, blood pressure, heart rate, lipid and glucose, monocyte chemoattractant protein‐1 (MCP‐1) and interleukin‐8 (IL‐8) parameters evaluated at baseline and 4 h following ingestion of the loads.Results.  The oral methionine load increased plasma homocysteine from 12.8 ± 1.8 to 33.3 ± 3.4 μmol L−1 at 4 h (P < 0.001). A similar increase was observed with same load plus vitamins (P < 0.001) but not with placebo (P = 0.14). Circulating MCP‐1 and IL‐8 levels rose after the methionine load (P < 0.001), but not after placebo or methionine plus vitamins. The methionine load significantly reduced CFVR (decrease, 26 ± 8.2%; P < 0.001). The methionine load with ingestion of vitamins partially prevented the impairment of CFVR (decrease, 11 ± 4%; P < 0.001).Conclusion.  Our data suggest that acute hyperhomocysteinaemia reduces CFVR and increases plasma MCP‐1 and IL‐8 levels in healthy subjects. Pretreatment with antioxidant vitamin E and ascorbic acid prevents the effects of hyperhomocysteinaemia, suggesting an oxidative mechanism.
A population‐based intervention study on elevated serum levels of methylmalonic acid and total homocysteine in elderly people: results after 36 months of follow‐up
Authors: Björkegren K. , Svärdsudd K. 
Published: October 2004

Abstract.Objectives.  To study the effects of vitamin B12 and folic acid treatment on haematological measures, reported symptoms and clinical findings over a 3‐year period.Design.  A longitudinal two‐cohort study.Setting.  A mid‐Swedish community.Subjects.  A 20% random sample of persons 70 years or older in a defined geographical area were invited to a survey (n = 266). Sixty‐nine persons who had serum cobalamin <300 pmol L−1 and serum methylmalonic acid (MMA) ≥0.37 μmol L−1 or serum total homocysteine (tHcy) ≥15 μmol L−1 and who had no vitamin B12 or folic acid substitution were selected for treatment.Main outcome measures.  Serum cobalamin, folate, MMA and tHcy. Presence of gastrointestinal, neurological, psychiatric and some other symptoms, obtained by questionnaire, and Mini Mental State Examination (MMSE) score, vibration sense measurement and findings at a physical examination.Results.  After combined vitamin B12–folic acid treatment, all persons normalized their serum tHcy and MMA levels and the effect remained after 3 years. The study design allowed separation of pure vitamin B12 deficiencies from folate and combined deficiencies. There was a tendency towards improvement of vibration sense, especially in the long nerve paths, and improvement of neurological symptoms and oral mucosa findings. No improvement was seen for other symptoms, reflex activity or MMSE score.Conclusions.  Vitamin treatment of elderly people in the early phase of the condition may reverse damage that otherwise would become irreversible. If initiated, the treatment should be combined with vitamin B12 and folic acid.
Hormone therapy and mortality during a 14‐year follow‐up of 14 324 Norwegian women
Authors: Graff‐Iversen S. , Hammar N. , Thelle D. S. , Tonstad S. 
Published: October 2004

Abstract.Objectives.  We evaluated mortality from cardiovascular disease (CVD), coronary heart disease (CHD) and all causes in relation to use of any hormone therapy (HT) and HT with oestradiol and norethisterone or levonorgestrel.Design.  Population‐based cohort study.Setting and subjects.  Women in three Norwegian counties were invited to a health survey in 1985–88 and 82.8% participated. In all 14 324 post‐ or perimenopausal women aged 35–62 years, including 702 HT users with a mean age of 48.8 years, were followed for 14 years.Results.  Women using HT had mortality from all causes and CVD comparable with that of nonusers. The relative risk (RRs) for CVD mortality amongst all women were 0.69 (95% CI: 0.35–1.33) for users of HT, and 0.96 (95% CI: 0.43–2.17) for users of HT with norethisterone or levonorgestrel. Amongst women free of self‐reported cardiovascular health problems at baseline all‐cause, CVD and CHD mortality tended to be lower amongst users of HT whilst HT use was linked with increased mortality amongst women with cardiovascular health problems.Conclusions.  In this cohort of women around the usual age of menopause all‐cause or CVD mortality amongst users of HT, most often oestradiol combined with norethisterone or levonorgestrel, was not markedly different from that of nonusers. Early CHD events amongst HT users prior to the baseline survey, together with selective inclusion of healthy subjects, may in part explain protective effects of HT on CHD reported from previous observational studies.
Beyond bone mineral density: can existing clinical risk assessment instruments identify women at increased risk of osteoporosis?
Authors: Wehren L. E. , Siris E. S. 
Published: October 2004

Abstract.Objective.  Although osteoporosis and fragility fracture are common amongst postmenopausal women, the extent of risk varies, and measurement of bone mineral density (BMD) is the standard tool used to diagnose and assess fracture risk. Rates of diagnosis remain relatively low, and several groups have developed instruments to help identify individuals who would most benefit from BMD testing. In this paper, we review and compare the performance of these instruments to identify those most useful in the primary care setting.Design.  Review of screening instruments comprised osteoporosis clinical risk factors and comparison of the sensitivity and specificity of these algorithms.Results.  Validated instruments have varying complexity, but similar sensitivity and specificity for identifying individuals who are likely to have low BMD. The area under the receiver operating characteristic curve ranges from 0.75 (SOFSURF) to 0.81 (SCORE). The simplest of the instruments (OST) uses only age and weight and has an AUC of 0.79.Conclusions.  The Osteoporosis Self‐assessment Tool, the simplest of the instruments, performs as well as more complex tools and, because of its simplicity, may be the most useful means for the busy clinician to identify postmenopausal women who would most benefit from BMD testing.