bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of CD163+ macrophages and local production of soluble CD163 with decreased lymphocyte activation in spondylarthropathy synovitis
Authors: Baeten Dominique , Jon Møller Holger , Delanghe Joris , Veys Eric M. , Moestrup Søren K. , De Keyser Filip
Published: May 2004

Objective

Since CD163+ macrophages are selectively increased in spondylarthropathy (SpA) synovitis, we investigated the role of CD163+ macrophages in synovial inflammation.

Methods

Synovial biopsy samples from 26 SpA and 23 rheumatoid arthritis (RA) patients were analyzed for macrophage and lymphocyte subsets. Synovial fluid (SF) samples were analyzed by Western blotting and enzyme‐linked immunosorbent assay for soluble CD163 (sCD163) and by flow cytometry for lymphocyte activation. We also analyzed sCD163 in sera from 100 SpA patients, 23 RA patients, 20 healthy controls, and 20 SpA patients treated with infliximab. Polymorphism of haptoglobin (Hp), the CD163 ligand, was determined in 130 SpA and 23 RA patients.

Results

CD163+ macrophages, but not CD68+ macrophages, were significantly increased in SpA versus RA synovium and in HLA–B27+ versus HLA–B27− SpA. Despite similar lymphocyte numbers, activated lymphocytes (CD69+) were significantly decreased in SpA versus RA patients, with an inverse correlation between CD163 and CD69 levels. Local production of sCD163 was evidenced by a 5–7‐fold higher level of sCD163 in SF than in serum and by the correlation with synovial lining CD163+ macrophages in SpA. SF sCD163 levels correlated directly with global inflammation but correlated inversely with CD69+ SF T lymphocytes in the synovium. In contrast, serum sCD163 levels were only moderately increased, did not correlate with SF sCD163 levels or parameters of inflammation, and were unaffected by infliximab therapy. The distribution of Hp polymorphism was not altered in SpA and was not related to CD163 expression.

Conclusion

Increased numbers of CD163+ macrophages in SpA synovium and local production of sCD163 are associated with global inflammation as well as impairment of T cell activation, suggesting a dual role for CD163+ macrophages in SpA synovitis.
A functional promoter haplotype of macrophage migration inhibitory factor is linked and associated with juvenile idiopathic arthritis
Authors: Donn Rachelle , Alourfi Zaynab , Zeggini Eleftheria , Lamb Rebecca , Jury Francine , Lunt Mark ,   the British Paediatric Rheumatology Study Group, Meazza Christina , De Benedetti Fabrizio , Thomson Wendy , Ray David
Published: May 2004

Objective

To establish linkage and replicate the association of macrophage migration inhibitory factor (MIF) with juvenile idiopathic arthritis (JIA).

Methods

Three hundred twenty‐one Caucasian simplex families from the UK were genotyped for polymorphisms of MIF using SNaPshot ddNTP primer extension, or by a fluorescently labeled primer method, and capillary gel electrophoresis. The functional significance of the promoter polymorphisms was studied using luciferase‐based reporter gene assays in human T lymphoblast and epithelial cell lines.

Results

MIF was linked and associated with JIA (P = 0.0016). Specifically, a 2‐point promoter haplotype, CATT7–MIF‐173*C, was found to be transmitted in excess (38 transmitted: 21 not transmitted) in the JIA patients. Conditional extended transmission disequilibrium test and pairwise extended transmission disequilibrium test predicted functional interaction between the 2 polymorphic positions. The interaction of the CATT repeat with MIF‐173*G/C was found to be specific to the cell type.

Conclusion

Replication of an association and linkage of MIF with JIA has been established. Functional interaction between the polymorphic positions on the linked haplotype has also been shown. The molecular mechanism of this interaction is currently being investigated.
Validation and clinical significance of the Childhood Myositis Assessment Scale for assessment of muscle function in the juvenile idiopathic inflammatory myopathies
Authors: Huber Adam M. , Feldman Brian M. , Rennebohm Robert M. , Hicks Jeanne E. , Lindsley Carol B. , Perez Maria D. , Zemel Lawrence S. , Wallace Carol A. , Ballinger Susan H. , Passo Murray H. , Reed Ann M. , Summers Ronald M. , White Patience H. , Katona Ildy M. , Miller Frederick W. , Lachenbruch Peter A. , Rider Lisa G. ,   for the Juvenile Dermatomyositis Disease Activity Collaborative Study Group
Published: May 2004

Objective

To examine the measurement characteristics of the Childhood Myositis Assessment Scale (CMAS) in children with juvenile idiopathic inflammatory myopathy (juvenile IIM), and to obtain preliminary data on the clinical significance of CMAS scores.

Methods

One hundred eight children with juvenile IIM were evaluated on 2 occasions, 7–9 months apart, using various measures of physical function, strength, and disease activity. Interrater reliability, construct validity, and responsiveness of the CMAS were examined. The minimum clinically important difference (MID) and CMAS scores corresponding to various degrees of physical disability were estimated.

Results

The intraclass correlation coefficient for 26 patients assessed by 2 examiners was 0.89, indicating very good interrater reliability. The CMAS score correlated highly with the Childhood Health Assessment Questionnaire (C‐HAQ) score and with findings on manual muscle testing (MMT) (rs = −0.73 and 0.73, respectively) and moderately with physician‐assessed global disease activity and skin activity, parent‐assessed global disease severity, and muscle magnetic resonance imaging (rs = −0.44 to −0.61), thereby demonstrating good construct validity. The standardized response mean was 0.81 (95% confidence interval 0.53, 1.09) in patients with at least 0.8 cm improvement on a 10‐cm visual analog scale for physician‐assessed global disease activity, indicating strong responsiveness. In bivariate regression models predicting physician‐assessed global disease activity, MMT remained significant in models containing the CMAS (P = 0.03) while the C‐HAQ did not (P = 0.4). Estimates of the MID ranged from 1.5 to 3.0 points on a 0–52‐point scale. CMAS scores corresponding to no, mild, mild‐to‐moderate, and moderate physical disability, respectively, were 48, 45, 39, and 30.

Conclusion

The CMAS exhibits good reliability, construct validity, and responsiveness, and is therefore a valid instrument for the assessment of physical function, muscle strength, and endurance in children with juvenile IIM. Preliminary data on MID and corresponding levels of disability should aid in the clinical interpretation of CMAS scores when assessing patients with juvenile IIM.
Antiinflammatory and analgesic effects of somatostatin released from capsaicin‐sensitive sensory nerve terminals in a Freund's adjuvant–induced chronic arthritis model in the rat
Authors: Helyes Zsuzsanna , Szabó Árpád , Németh József , Jakab Balázs , Pintér Erika , Bánvölgyi Ágnes , Kereskai László , Kéri György , Szolcsányi János
Published: May 2004

Objective

We previously demonstrated that somatostatin (SOM) released from the activated peripheral terminals of capsaicin‐sensitive primary sensory neurons inhibits acute inflammation and nociception. This study was undertaken to examine this systemic “sensocrine” function of neuronally derived somatostatin in chronic inflammation in the Freund's complete adjuvant (CFA)–induced arthritis model.

Methods

Arthritis of the tibiotarsal joint of Lewis rats was evoked by subcutaneous injection of CFA into the left hind paw and the tail root. For 3 weeks, the volume of the paws was measured by plethysmometry, and the mechanonociceptive thresholds were measured by esthesiometry. Plasma concentrations of SOM were determined by radioimmunoassay, and histologic studies of the joints were performed. To impair the function of capsaicin‐sensitive afferents, the capsaicin receptor (VR1/TRPV1) agonist resiniferatoxin (RTX) was injected subcutaneously (30, 70, and 100 μg/kg on 3 subsequent days) 7 days before CFA administration. The SOM receptor antagonist cyclosomatostatin (c‐SOM; 20 μg/kg) or, in another group, the synthetic heptapeptide agonist TT‐232 (2 × 50–400 μg/kg) was administered intraperitoneally every day.

Results

RTX pretreatment or c‐SOM injection significantly increased edema and mechanical hyperalgesia of both CFA‐treated and contralateral paws. The histologic score based on synovial thickening, cell infiltration, cartilage destruction, and bone erosion was also significantly higher both in the RTX‐ and the c‐SOM–injected groups. These parameters were dose‐dependently decreased by TT‐232. Plasma SOM‐like immunoreactivity increased 4‐fold on the twenty‐first day, and was inhibited by RTX pretreatment, as well as by daily administration of TT‐232.

Conclusion

Our data suggest that SOM released into the circulation from capsaicin‐sensitive afferents in response to prolonged activation exerts systemic antiinflammatory and analgesic effects. TT‐232 can open new perspectives in the treatment of chronic arthritis.
Antibodies to guanosine triphosphate misidentified as anti–double‐stranded DNA antibodies in a patient with antinuclear antibody–negative lupus, due to buckling of insolubilized assay DNA
Authors: Ma Chun Hung , Hui Joannie , Tang Janet Tsui Ying , Leung Danny Tze Ming , Chui Yiu Loon , Fok Tai Fai , Lim Pak‐Leong
Published: May 2004

Objective

To investigate why the serum of a pediatric patient with systemic lupus erythematosus was persistently (>30 months) and strongly positive for antibodies to double‐stranded DNA (dsDNA) as revealed by enzyme‐linked immunosorbent assay (ELISA), but yielded negative results on the antinuclear antibody test (HEp‐2 immunofluorescence [IF]).

Methods

The patient's antibodies were isolated on dsDNA and single‐stranded DNA (ssDNA) supports, which were then examined by dsDNA ELISA and HEp‐2 IF. Tests included the use of various inhibitors to determine the fine specificity of the antibodies. Other tests performed included immunoblotting, immunoprecipitation, Crithidia luciliae IF, and neutrophil IF.

Results

The antibodies isolated from the dsDNA and ssDNA supports were similar, in that they were of the IgG type, bound well in the dsDNA ELISA, and recognized a normally hidden nucleolar RNA antigen in HEp‐2 cells. With both the dsDNA ELISA and nucleolar antigens, inhibition studies revealed that the epitope recognized was guanosine 5′‐triphosphate (GTP). Binding of the antibodies was better to GTP than to guanosine 5′‐monophosphate or cytidylyl (3′‐5′) guanosine, and, in turn, was better than to guanosine, while N7‐methylated GTP was unreactive. The antibodies did not bind to dsDNA present in solution or in HEp‐2 or Crithidia cells, but bound transfer RNA well and recognized a cytoplasmic RNA antigen in neutrophils.

Conclusion

A new problem in dsDNA ELISA is revealed in the occurrence of a hitherto‐unknown and unusual buckling of the insolubilized DNA molecule, which, absent in dsDNA found in solution or in whole cells, presumably creates gaps of single‐strandedness in the molecule. A new antibody specific for GTP is described in this patient, which may be clinically important.
Macrophage migration inhibitory factor up‐regulates the expression of interleukin‐8 messenger RNA in synovial fibroblasts of rheumatoid arthritis patients: Common transcriptional regulatory mechanism between interleukin‐8 and interleukin‐1β
Authors: Onodera Shin , Nishihira Jun , Koyama Yoshikazu , Majima Tokifumi , Aoki Yoshimitsu , Ichiyama Hiroki , Ishibashi Teruo , Minami Akio
Published: May 2004

Objective

Interleukin‐8 (IL‐8) plays an important role in the migration of inflammatory cells into the synovium and joint fluids in rheumatoid arthritis (RA). This study was undertaken to investigate the IL‐8 inductive activity of the macrophage migration inhibitory factor (MIF) in RA synovial fibroblasts. The regulatory mechanism of IL‐8 was compared with that of IL‐1β.

Methods

MIF‐induced IL‐8 and IL‐1β transcriptional activation was studied in RA synovial fibroblasts by Northern blot analysis, enzyme‐linked immunosorbent assay, and electromobility shift assay. The effect of anti‐MIF antibody administration on murine passive collagen‐induced arthritis (CIA) was also evaluated by histologic examination and reverse transcriptase–polymerase chain reaction.

Results

MIF up‐regulated the IL‐8 messenger RNA (mRNA) and protein levels in a dose‐dependent manner. The IL‐8 mRNA up‐regulation started 1 hour poststimulation by MIF, and reached a maximum level at 6 hours. IL‐1β mRNA was also up‐regulated by MIF. The mRNA up‐regulation of IL‐8 and IL‐1β by MIF was inhibited by 2 tyrosine kinase inhibitors, a protein kinase C (PKC) inhibitor, an activator protein 1 (AP‐1) inhibitor, and by an NF‐κB inhibitor. A cAMP‐dependent kinase inhibitor did not inhibit it. MIF enhanced AP‐1 and NF‐κB binding activities in a dose‐dependent manner. Passive CIA enhanced mRNA levels of macrophage inflammatory protein 2 and cytokine‐induced neutrophil chemoattractants and, moreover, migration and proliferation of inflammatory cells within the synovium, which were suppressed by administration of an anti‐MIF antibody.

Conclusion

MIF may play an important role in the migration of inflammatory cells into the synovium of rheumatoid joints via induction of IL‐8. MIF up‐regulates IL‐8 and IL‐1β mRNA via tyrosine kinase–, PKC‐, AP‐1–, and NF‐κB–dependent pathways.
Progression of radiographic hip osteoarthritis over eight years in a community sample of elderly white women
Authors: Lane Nancy E. , Nevitt Michael C. , Hochberg Marc C. , Hung Yun‐Yi , Palermo Lisa
Published: May 2004

Objective

To describe progression over 8 years in a community‐based sample of elderly women with radiographic findings of hip osteoarthritis (RHOA) with or without hip pain.

Methods

Baseline and followup anteroposterior pelvic radiographs were obtained at a mean ± SD 8.3 ± 0.4 years of followup in women age ≥65 years at the baseline examination of the Study of Osteoporotic Fractures. We evaluated progression in 936 hips of 745 women with one or more baseline findings of RHOA: summary OA grade ≥2, minimum joint space (MJS) ≤1.5 mm, definite femoral or acetabular osteophytes, definite superolateral joint space narrowing (JSN), or moderate or worse superomedial JSN. We separately examined progression in hips with an MJS between 1.5 mm and 2.5 mm. Hip pain and lower extremity disability were assessed by questionnaire and examination. Measures of progression included an increase in summary grade of radiographic findings, increase in total osteophyte score, decrease in MJS of ≥0.5 mm, total hip replacement (THR), and increase in lower extremity disability score. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for baseline radiographic predictors of progression were estimated using general estimating equations.

Results

During followup, 12.9% of women with baseline RHOA underwent THR, and 22.8% had substantial worsening of lower extremity disability, while 64.6% of hips with RHOA showed radiographic progression or were replaced. Progression was greater by all measures in the 37% of hips and 47% of women with both RHOA and hip pain at baseline. Of hips with pain, 23.6% progressed to THR compared with 2.7% of hips without pain (OR 8.1 [95% CI 4.2, 15.4], P < 0.001), and MJS decreased ≥0.5 mm in 53.7% of hips with pain compared with 30.7% of hips without pain (OR 1.9 [95% CI 1.4, 2.6], P < 0.001). Women with hip pain were more likely to have worsened lower extremity disability (29.3% versus 17.6%; OR 1.8 [95% CI 1.2, 2.8], P = 0.0053). Hips with an MJS >1.5 mm and ≤2.5 mm (n = 1,868) had primarily superomedial narrowing and comparatively low rates of progression that did not differ by hip pain. Femoral osteophytes, superolateral JSN, and subchondral bone changes were independent predictors of progression.

Conclusion

Among women recruited from the community, radiographic and clinical progression was greater in those with symptomatic RHOA, but still substantially less frequent than previously reported for hip OA patients in clinical settings. Asymptomatic RHOA and hips with an isolated finding of mild JSN (MJS of 1.5 mm to 2.5 mm) were unlikely to progress over 8 years.
Association of killer cell immunoglobulin‐like receptors with scleroderma
Authors: Momot T. , Koch S. , Hunzelmann N. , Krieg T. , Ulbricht K. , Schmidt R. E. , Witte T.
Published: May 2004

Objective

Scleroderma is an autoimmune disorder of unknown etiology. A genetic contribution has been demonstrated, and genes influencing activation of the immune system have been potentially identified as candidate genes in this process. The repertoire of killer cell immunoglobulin‐like receptors (KIRs) that are involved in the activation of T cells and natural killer cells is highly variable. Recently, an association of KIR2DS2 with vasculitis in patients with rheumatoid arthritis has been reported. Because scleroderma is characterized by an involvement of the vascular system, we sought to determine whether KIR2DS2 is associated with scleroderma.

Methods

We typed 9 KIR genes in 102 patients with scleroderma and in 100 blood donors, using polymerase chain reaction on genomic DNA.

Results

Twelve patients with scleroderma, compared with only 2 blood donors, had KIR phenotypes characterized by the presence of the activating KIR2DS2 and the absence of the corresponding inactivating KIR2DL2 (P = 0.005).

Conclusion

The genetic combination of KIR2DS2+ and KIR2DL2− is associated with scleroderma.
Expression of interleukin‐21 receptor, but not interleukin‐21, in synovial fibroblasts and synovial macrophages of patients with rheumatoid arthritis
Authors: Jüngel Astrid , Distler Jörg H. W. , Kurowska‐Stolarska Mariola , Seemayer Christian A. , Seibl Reinhart , Forster Adrian , Michel Beat A. , Gay Renate E. , Emmrich Frank , Gay Steffen , Distler Oliver
Published: May 2004

Objective

To determine the role and expression of the cytokine/receptor pair interleukin‐21 (IL‐21)/IL‐21 receptor (IL‐21R) in rheumatoid arthritis (RA).

Methods

The expression of IL‐21R and IL‐21 was analyzed by TaqMan real‐time polymerase chain reaction (PCR) and in situ hybridization of synovial biopsy samples from patients with RA and osteoarthritis (OA). Double labeling by immunohistochemistry after in situ hybridization was performed with anti‐CD68 antibodies. The expression of IL‐21R at the protein level was confirmed by Western blotting. Stimulation experiments were performed with recombinant IL‐1β, tumor necrosis factor α (TNFα), platelet‐derived growth factor (PDGF), and transforming growth factor β (TGFβ). The role of IL‐21R in cartilage destruction was analyzed in the SCID mouse coimplantation model of RA.

Results

IL‐21R was found in total RNA extracts and in synovial biopsy samples from RA patients, whereas no expression or only minimal expression was seen in samples from OA patients. Double labeling indicated that both synovial macrophages and synovial fibroblasts expressed IL‐21R. Western blotting with anti–IL‐21R antibodies confirmed the expression of IL‐21R protein in RA synovial fibroblasts (RASFs). Of note, IL‐21 was not detectable by real‐time PCR and in situ hybridization in the same samples in vivo as in vitro. The level of expression of IL‐21R messenger RNA (mRNA) was not altered by stimulation with IL‐1β, TNFα, PDGF, or TGFβ. Interestingly, in the SCID mouse coimplantation model, RASFs did not maintain their expression of IL‐21R at sites of invasion into the cartilage. Similarly, IL‐21R mRNA was not expressed at sites of invasion into cartilage and bone in RA synovium.

Conclusion

Our data demonstrate that IL‐21R is expressed in RA synovium by RASFs and synovial macrophages. IL‐21R is associated with the activated phenotype of RASFs independently of the major proinflammatory cytokines IL‐1β and TNFα, but correlates negatively with the destruction of articular cartilage and bone.
Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate
Authors: Genovese Mark C. , Cohen Stanley , Moreland Larry , Lium Deborah , Robbins Sean , Newmark Richard , Bekker Pirow ,   for the 20000223 Study Group
Published: May 2004

Objective

To determine the potential for additive or synergistic effects of combination therapy with the selective anti–tumor necrosis factor α agent etanercept and the anti–interleukin‐1 agent anakinra.

Methods

Two hundred forty‐four patients in whom rheumatoid arthritis (RA) was active despite methotrexate therapy were treated with subcutaneous etanercept only (25 mg twice weekly), full‐dosage etanercept (25 mg twice weekly) plus anakinra (100 mg/day), or half‐dosage etanercept (25 mg once weekly) plus anakinra (100 mg/day) for 6 months in a double‐blind study at 41 centers in the US. Patients had never previously received anticytokine therapy. Patient response was measured with the American College of Rheumatology (ACR) core set criteria, a health‐related quality‐of‐life questionnaire, and the Disease Activity Score. Safety was assessed by the number of adverse events and clinical laboratory values. Plasma concentrations of both agents and antibody formation against both agents were also assessed.

Results

Combination therapy with etanercept plus anakinra provided no treatment benefit over etanercept alone, regardless of the regimen, but was associated with an increased safety risk. Thirty‐one percent of the patients treated with full‐dosage etanercept plus anakinra achieved an ACR 50% response, compared with 41% of the patients treated with etanercept only. This result was not statistically significant (P = 0.914). The incidence of serious infections (0% for etanercept alone, 3.7–7.4% for combination therapy), injection‐site reactions, and neutropenia was increased with combination therapy. Combination therapy had no effect on the pharmacokinetics or immunogenicity of either agent.

Conclusion

Combination therapy with etanercept and anakinra provides no added benefit and an increased risk compared with etanercept alone and is not recommended for the treatment of patients with RA.
Markers for type II collagen breakdown predict the effect of disease‐modifying treatment on long‐term radiographic progression in patients with rheumatoid arthritis
Authors: Landewé Robert , Geusens Piet , Boers Maarten , van der Heijde Désirée , Lems Willem , te Koppele Johan , van der Linden Sjef , Garnero Patrick
Published: May 2004

Objective

To investigate in a randomized clinical trial setting with an aggressive combination‐therapy arm and a mild‐monotherapy arm, whether therapy‐induced changes in urinary C‐terminal crosslinking telopeptide of type I collagen (CTX‐I) and type II collagen (CTX‐II) predict 5‐year radiographic progression in patients with rheumatoid arthritis (RA).

Methods

Patients had participated in the COBRA (Combinatietherapie Bij Reumatoïde Artritis) trial comparing aggressive step‐down combination therapy (the COBRA regimen, including temporary high‐dose prednisolone, temporary low‐dose methotrexate, and sulfasalazine [SSZ]) and mild monotherapy (SSZ). Urinary CTX‐I and CTX‐II levels were measured at baseline and 3, 6, 9, and 12 months after initiation of treatment. Radiographs were scored according to the modified Sharp/van der Heijde method (mean of 2 independent readers who were aware of the sequence). Individual long‐term radiographic progression was estimated, using baseline radiographs and all radiographs obtained during the followup period, by simple linear regression analysis (curve fitting).

Results

Both COBRA therapy and SSZ monotherapy produced a significant decrease in urinary CTX‐I and CTX‐II levels at 3 months, and this decrease was amplified at 6 months. COBRA therapy suppressed CTX‐II (change from baseline levels −36% and −43% at 3 and 6 months, respectively), but not CTX‐I, significantly better than did SSZ (−17% and −21% at 3 and 6 months, respectively) at 3 and 6 months. The magnitude of the decrease in urinary CTX‐II levels at 3 months significantly predicted long‐term (5‐year) radiographic progression (β = 0.48 [95% confidence interval (95% CI) 0.13, 0.83]). This effect was independent of the change in disease activity and inflammation indices at 3 months. Patients whose CTX‐II levels were normalized (<150 ng/mmoles of urinary creatinine) at 3 months had a significantly higher chance of radiographic stability (no progression over 5 years) than did patients whose CTX‐II levels were increased both at baseline and at 3 months (odds ratio 4.5 [95% CI 1.5, 13]).

Conclusion

The individual CTX‐II response measured after 3 months of therapy in patients with active RA who had increased CTX‐II levels at baseline independently predicts long‐term radiographic progression. Urinary CTX‐II levels may be used as early markers of treatment efficacy in patients with RA.
Familial Paget's disease in The Netherlands: Occurrence, identification of new mutations in the sequestosome 1 gene, and their clinical associations
Authors: Eekhoff E. W. M. , Karperien M. , Houtsma D. , Zwinderman A. H. , Dragoiescu C. , Kneppers A. L. J. , Papapoulos S. E.
Published: May 2004

Objective

To estimate the occurrence of familial Paget's disease of bone in The Netherlands, to examine the prevalence of mutations of the sequestosome 1 gene (SQSTM1) in identified families, and to assess potential genotype–phenotype associations.

Methods

We performed a case–control study of patients with Paget's disease and a mutation analysis of the SQSTM1 gene of index patients with familial disease and of the relatives of those with a mutation. Serum alkaline phosphatase (AP) activity was assessed, and bone scintigraphy was performed.

Results

Five percent of patients had at least 1 first‐degree relative with the disease, compared with 0.5% of the controls (relative risk 10; 95% confidence interval 1.3–75.6). In 38.9% of patients with familial disease, heterozygous mutations in the SQSTM1 gene were identified. These were the previously described P392L mutation, which was present in 22.2% of patients, and 3 new mutations, S399P, G425R, M404T, 9 of which were present in 3 different families. All mutations were located in the ubiquitin‐associated domain of the gene. There was a relationship between serum AP activity, as a marker of the disease, and the presence or absence of the G425R and P392L mutations, the subject's age, and the presence of Paget's disease.

Conclusion

Our data provide further evidence of a causal role of SQSTM1 gene mutations in the pathogenesis of Paget's disease and allow the design of a strategy based on measurements of serum AP activity and age for investigating asymptomatic relatives of patients with familial Paget's disease of bone.
Suppressive oligonucleotides protect against collagen‐induced arthritis in mice
Authors: Dong Li , Ito Shu‐ichi , Ishii Ken J. , Klinman Dennis M.
Published: May 2004

Objective

To examine whether systemic administration of oligonucleotides (ODNs), known to inhibit the production of proinflammatory cytokines, alters host susceptibility to collagen‐induced arthritis (CIA), a murine model of rheumatoid arthritis (RA).

Methods

CIA was induced by injecting DBA/1 mice with type II collagen (CII) in Freund's complete adjuvant, followed 3 weeks later by CII in Freund's incomplete adjuvant. The effect of suppressive ODNs on the incidence and severity of disease was monitored, as were immune correlates of CIA.

Results

Suppressive ODNs administered during the inductive phase of CIA significantly reduced the incidence and severity of arthritis. Treatment with suppressive ODNs significantly decreased serum titers of pathogenic IgG anti‐CII autoantibodies and interferon‐γ production by collagen‐reactive T cells.

Conclusion

Suppressive ODNs may be of therapeutic value in the treatment of RA, and potentially other autoimmune diseases.
International greenhouse gas emissions when global warming is a stochastic process
Authors: Wirl Franz
Published: May 2004

This paper integrates two different but crucial aspects of global warming: free riding and uncertainty. Although certainty equivalence does not hold, an analytical solution is obtained if ‘clean up’ (e.g. reforestation) is possible. Assuming realistically irreversible emissions, numerical methods are necessary to obtain the value function and the implied strategies, which are shown to be unique (for the calibrated parameters). Although uncertainty stresses the importance of conservation, the incentives to free ride are almost the same. Beyond the particular application, the paper shows how to analyze stochastic, dynamic games. Copyright © 2004 John Wiley & Sons, Ltd.
Structural characterization of the N‐terminal mineral modification domains from the molluscan crystal‐modulating biomineralization proteins, AP7 and AP24
Authors: Wustman Brandon A. , Morse Daniel E. , Evans John Spencer
Published: May 2004

The AP7 and AP24 proteins represent a class of mineral‐interaction polypeptides that are found in the aragonite‐containing nacre layer of mollusk shell (H. rufescens). These proteins have been shown to preferentially interfere with calcium carbonate mineral growth in vitro. It is believed that both proteins play an important role in aragonite polymorph selection in the mollusk shell. Previously, we demonstrated the 1–30 amino acid (AA) N‐terminal sequences of AP7 and AP24 represent mineral interaction/modification domains in both proteins, as evidenced by their ability to frustrate calcium carbonate crystal growth at step edge regions. In this present report, using free N‐terminal, Cα‐amide “capped” synthetic polypeptides representing the 1–30 AA regions of AP7 (AP7‐1 polypeptide) and AP24 (AP24‐1 polypeptide) and NMR spectroscopy, we confirm that both N‐terminal sequences possess putative Ca (II) interaction polyanionic sequence regions (2 × —DD— in AP7‐1, —DDDED— in AP24‐1) that are random coil‐like in structure. However, with regard to the remaining sequences regions, each polypeptide features unique structural differences. AP7‐1 possesses an extended β‐strand or polyproline type II‐like structure within the A11–M10, S12–V13, and S28–I27 sequence regions, with the remaining sequence regions adopting a random‐coil‐like structure, a trait common to other polyelectrolyte mineral‐associated polypeptide sequences. Conversely, AP24‐1 possesses random coil‐like structure within A1–S9 and Q14–N16 sequence regions, and evidence for turn‐like, bend, or loop conformation within the G10–N13, Q17–N24, and M29–F30 sequence regions, similar to the structures identified within the putative elastomeric proteins Lustrin A and sea urchin spicule matrix proteins. The similarities and differences in AP7 and AP24 N‐terminal domain structure are discussed with regard to joint AP7–AP24 protein modification of calcium carbonate growth. © 2004 Wiley Periodicals, Inc. Biopolymers 2004
Molecular dynamics simulations of HPr under hydrostatic pressure
Authors: Canalia Muriel , Malliavin Thérèse E.
Published: May 2004

The histidine‐containing protein (HPr) plays an important role in the phosphotransferase system (PTS). The deformations induced on the protein structure at high hydrostatic pressure values (4, 50, 100, 150, and 200 MPa) were previously (H. Kalbitzer, A. Görler, H. Li, P. Dubovskii, A. Hengstenberg, C. Kowolik, H. Yamada, and K. Akasaka, Protein Science 2000, Vol. 9, pp. 693–703) analyzed by NMR experiments: the nonlinear variations of the amide chemical shifts at high pressure values were supposed to arise from induced shifts in the protein conformational equilibrium. Molecular dynamics (MD) simulations are here performed, to analyze the protein internal mobility at 0.1 MPa, and to relate the nonlinear variations of chemical shifts observed at high pressure, to variations in conformational equilibrium. The global features of the protein structure are only slightly modified along the pressure. Nevertheless, the values of the Voronoi residues volumes show that the residues of α‐helices are more compressed that those belonging to the β‐sheet. The α‐helices are also displaying the largest internal mobility and deformation in the simulations. The nonlinearity of the 1H chemical shifts, computed from the MD simulation snapshots, is in qualitative agreement with the nonlinearity of the experimentally observed chemical shifts. © 2004 Wiley Periodicals, Inc. Biopolymers 2004
Residence Time Distribution in Granulation Drums on the Example of Industrial Carbon Black
Authors: Katzer M. , Pirl S. , Esser S. , Kopietz J. , Rieckmann T. , Behnisch J. , Klasen C.‐J.
Published: May 2004

The present work describes systematic investigations into dry granulation of industrial carbon black with special regard to the residence time characteristics, using a continuously operated semitechnical bead‐forming drum. A novel experimental method and a model for the determination of residence time distribution of carbon black in the bead‐forming drum have been developed and very good agreement of model and experiment has been demonstrated.
Stability Behavior of Liquid Jets under Gravity
Authors: Nonnenmacher S. , Piesche M.
Published: May 2004

The influence of gravity on the stability behavior of falling liquid strands without external excitation was investigated. To this end, a mathematic‐physical model was developed for the analysis of the stability behavior of liquid strands in the range of low to higher viscosity, the main emphasis being on gravity. The characteristics of the model are discussed and, finally, the stability criterion is derived for the quantitative determination of the point of disintegration.
Hydrate Formation during Pressure Release of Wet CO2,View‐Cell Observations
Authors: Ullrich A. , Eggers R.
Published: May 2004

The objective of this work is the evaluation of the blocking risk of pipelines by hydrate crystals in processing steps. Two topics were investigated: (I) hydrate formation during pressure release and isochore cooling and (II) the influence of a contact surface on hydrate formation. The investigated materials were steel, glass, and polytetrafluoroethylene (PTFE). Experiments were carried out in a 87 mL view‐cell to observe hydrate formation in the bulk CO2 phase, since crystals of that size can cause the problems mentioned. The starting conditions of all experiments were within the temperature range of T = 278–285 K and the pressure range of p = 6–20 MPa. The results of the experiments suggest that the major criterion for hydrate formation during pressure release is the degree of supersaturation. Visible hydrate formation can be observed at a minimum subcooling of ΔT = 7 K. With a starting temperature of T = 285 K and a starting pressure of p = 6 MPa no hydrate formation is observed. The surface properties of the material have no direct influence on the hydrate formation process. However, during pressure release hydrate crystals detach from hydrophobic materials like PTFE, whereas they stick to hydrophilic materials like glass and steel. Thus, the adhesion between hydrate crystals and hydrophilic surfaces is stronger than between hydrate crystals and hydrophobic surfaces.
Mixing and Crystallization Kinetics in Gas‐liquid Reactive Crystallization
Authors: Chen P.‐C. , Chen C.C. , Fun M.H. , Y Liao O. , Jiang J.J. , Wang Y.S. , Chen C.S.
Published: May 2004

A study of gas‐liquid reactive crystallization for CO2‐BaCl2‐H2O system was performed in a continuous flow crystallizer. The influences of mixing on the crystallization kinetics of barium carbonate crystals were investigated. The mixing parameters are stirrer speed, feed concentration, gas‐flow rate, pH of solution, addition rate of NaOH solution, and mean residence time. Under pH‐stat operation, the crystallization mechanism can be assessed by the addition rate of NaOH solution, which acts as an indicator for the absorption rate of carbon dioxide. Assuming a size‐independent agglomeration mechanism, the nucleation rate, growth rate and agglomeration kernel can be obtained, simultaneously, at steady state, by the method of moments. Evidence shows that feed concentration, feed rate, gas‐flow rate, and stirrer speed have a significant influence on the nucleation rates and mean particle sizes. This shows the effect of micromixing. The crystallization mechanism tends to be reaction limited when the feed concentration of barium chloride solution is higher than 5 mM, while at lower stirrer speeds and feed concentrations, the mechanism tends to be both mixing and reaction controlled. The growth rate depends on the mean supersaturation value and the pH of the solution and the mass‐transfer resistance cannot be completely eliminated in this work. For a monodispersal collision model, in the viscous sub‐range of turbulence, the agglomeration kernel can be expressed as β ∝ d3 $ϵ \bar$–1/4, showing a low efficiency of collision. The result is also demonstrated by the agglomeration kernel expression. Comparison with a liquid‐liquid‐mixing reactive crystallization system is also discussed.
Studies on the Hydrodynamics of Chaotic Bubbling in a Gas‐Liquid Bubble Column with a Single Nozzle
Authors: Liu M. , Hu Z.
Published: May 2004

In this work, the chaotic bubbling mechanism in a gas‐liquid bubble column with a single nozzle was investigated. The signal for the analysis was the time series of pressure fluctuations measured from a pressure transducer probe placed in the bubble column close to the nozzle. In order to study the bubbling process, statistical analysis, qualitative and quantitative nonlinear analyses were carried out for the pressure fluctuations. Power spectra used as standard statistical measures provided preliminary evidence that bubbling in the middle values of gas flow rates may be chaotic in nature. Phase plots provided a qualitative means of analyzing the fine geometry structure of the attractor reconstructed from the bubbling time signal. Positive finite estimates of the Kolmogorov entropy provided a quantitative evidence of behavior consistent with chaos. Besides previous diagnostic tools, the local nonlinear short‐term prediction was also used as a supplement method. It was found that the bubbling process exhibits a deterministic chaotic behavior in a certain range of the gas flow rate. When increasing the gas flow rate, the sequence of periodic bubbling, primary and advanced chaotic bubbling, and jetting or random bubbling were successively observed. However, no clear period doubling sequence leading to chaotic behavior was observed. The sharp loss of the ability to predict the pressure signal successfully with the nonlinear prediction method provides the strongest evidence of the presence of the chaotic bubbling. The variations of the nonlinear invariants, such as the Kolmogorov entropy and the correlation dimension together with the plot of the correlation integral with the operation conditions, might be developed as potential and effective quantitative tools for flow regime identification of the bubbling process.
Simulation of an Acid‐Based Starch Converter
Authors: Iranshahi A. , Hakimelahi H.R. , Sotudeh‐Gharebagh R. , Mostoufi N.
Published: May 2004

A mathematical model is proposed to simulate the starch converter. The converter was hydrodynamically divided into six zones and material and energy balances were established in each zone. Due to the fact that the converter is a laminar flow reactor, it was necessary to apply the equation oriented simulation approach to simulate the converter. Therefore, four partial differential equations were solved together by finite difference in each section. Thermophysical properties of the corresponding fluid were calculated by using various correlations and data from the literature. In order to predict accurate concentrations of glucose, the kinetics was determined with the aid of the data in the literature. A set of actual plant data from the industrial converter is used to validate the proposed model. The agreement between the model prediction and the experimental data is quite satisfactory and the model could be used to predict the performance of industrial converters at a wide range of operating conditions.
Utilization of a Two‐phase Reactor with Pre‐saturator for Multiphase Reactions
Authors: Battsengel B. , Datsevich L. , Jess A. , Münnich C. , Peter S. , Turek T.
Published: May 2004

The two‐phase reactor with pre‐saturator was investigated for the hydrogenation of 1‐octene and the hydrogenation of an adipic hexanediole‐oligoester. For low concentrations of the liquid reactant the reactor is a suitable system. For high concentrations a liquid recycle is necessary and although the residence time is higher the recycling might have a positive influence on the external mass transfer.
More Efficient Plant Design by Modularization?
Authors: Kampczyk B. , Hicking B. , Schmidt‐Traub H.
Published: May 2004

The software CAPD which was developed at the University of Dortmund, provides the possibility to quickly display a plant layout though its generation does not contain all the plant details. Through the utilization of a realistic placeholder for any equipment the plant layout can be optimized.
Design of Complex Distillation Columns by Overall‐Cost Optimization
Authors: Wenzel S. , Röhm H.‐J.
Published: May 2004

Compared with the conventional configuration, complex distillation columns make for a marked reduction of the energy requirements of multi‐component rectification systems. Whereas the control problems have, on the whole, been resolved, the ability to find the process‐technological optimum of a complex distillation system within a short space of time is still difficult. The aim of this paper is to reduce the time required for finding the optimum design with the aid of commercial standard software.
Experiment and Mathematical Modeling of Solid Formation at Spray Drying
Authors: Seydel P. , Sengespeick A. , Blömer J. , Bertling J.
Published: May 2004

The process of solid formation during spray drying has been described many times in the literature, however, a detailed mathematical description of the time‐dependent process concerning the structure of the particles as a function of substance and process parameters is still not available. In the present work, a time‐dependent and local modeling of the mass and energy transport processes during solid formation inside the droplet was carried out. The model was validated against reproducible experiments performed in a vertical pipe with single drop generation.
Process Concepts for the Transition Metal Catalyzed Syntheses of Formic Acid and Dimethylformamide Based on Carbon Dioxide
Authors: Behr A. , Ebbinghaus P. , Naendrup F.
Published: May 2004

In recent years, carbon dioxide has attracted increasing attention as raw material for chemical syntheses. The chemically inert carbon dioxide can be activated by homogeneous transition metal complex catalysts. This permits a number of various syntheses which, however, are only profitable if the catalyst separation and recycling can be carried out completely and simply. The development of process concepts for the syntheses of formic acid and dimethylformamide by the hydrogenation of carbon dioxide are presented here.
Investigations on the Regeneration Intensity of Different Back‐Pulse Systems for Surface Filters of Rigid Filter Media
Authors: Heidenreich S. , Haag W. , Mai R. , Leibold H. , Seifert H.
Published: May 2004

In order to improve the cleaning of rigid filter media, a new cleaning method was developed. The patented CPP (coupled pressure pulse) cleaning method is based on the principle that the cleaning system is directly coupled to the clean gas side of the filter elements. The newly developed CPP cleaning process is directly compared with a specific conventional jet‐pulse system and the efficiency and the advantages of the new method are demonstrated. It is impressively shown that with the CPP process, an excellent cleaning performance can be achieved.
A New Era for Chemical Apparatus Engineering?
Authors: Weiß E. , Praus S. , Rudolph J. , Lietzmann A. , Mense T.
Published: May 2004

The ACHEMA conference is an impressive exhibition on chemical apparatus engineering, closely connected with the epoch‐making developments of chemical and process engineering. It is most timely to think about new opportunities of development. Large‐scale plant engineering and general plant construction has experienced considerable improvement during the past decades. The effects of these changes are particularly perceptible in the economic sector of German apparatus engineering. Economic pressures have given an additional impetus to a considerable shrinking process. Chemical apparatus engineering will have to focus on two main pillars in the near future: highly qualified standard and innovative products. The latter must be developed in close cooperation with the economic sector of chemical engineering in order to put the hardware required for new technologies and process strategies on the market. This article names fields of manifestation of the general technical progress. The thrust is directed toward an elevated level of product quality that can be achieved from the point of view of apparatus engineering. These are properties that will finally lead to higher profitability. The signs for a new start of apparatus engineering are quite favorable, and this opportunity has to be seized. The ACHEMA conference as a location of exchange of experiences and an opportunity of critical assessment could be a source of ideas for future work.
Superstructure of Eu4Cd25: A Quasicrystal Approximant
Authors: Pay Gómez Cesar , Lidin Sven
Published: May 2004

The quasicrystal approximant Eu4Cd25, formerly designated EuCd6, was synthesized and characterized by means of single‐crystal X‐ray diffraction. Superstructure reflections corresponding to an F‐centered cubic unit cell with a doubled cell‐parameter relative to the I‐centered cubic sub‐cell could be observed in the diffraction data. This gives the largest cubic unit cell reported to date among binary alloys. The superstructure exhibits structural features that are found in all the RE–Cd6 approximants as well as a further ordering between vacant/occupied Cd8 cubes and oriented Cd4 tetrahedra, which causes the superstructure. A reversible high‐temperature phase‐transition was observed at 782 K by means of DSC.
Rational Design of the Pore System within the Framework Aluminium Alkylenediphosphonate Series
Authors: Harvey Howard G. , Slater Ben , Attfield Martin P.
Published: May 2004

We report here on the solvothermal synthesis and crystal structure of the hybrid organic–inorganic framework material Al2[O3PC3H6PO3](H2O)2F2⋅H2O (orthorhombic, Pmmn, a = 12.0591(2) Å, b = 19.1647(5) Å, c = 4.91142(7) Å, Z = 4), the second member of the Al2[O3PCnH2nPO3](H2O)2F2⋅H2O series. The structure consists of corrugated chains of corner‐sharing AlO4F2 octahedra in which alternating AlO4F2 octahedra contain two fluorine atoms in a trans or a cis configuration. The diphosphonate groups link the chains together through AlOPOAl bridges and through the propylene groups to form a three‐dimensional framework structure containing a one‐dimensional channel system. The linkage of the corrugated inorganic AlOP layers within the structure results in the formation of two types of channel that differ in size, shape and composition. The smaller channel is unoccupied; the larger channel is more elongated and contains two extra‐framework water molecules per unit cell. A computational investigation into the driving force that controls the stacking arrangement of the AlOP inorganic layers within this series of compounds reveals that the stacking is found to be controlled by thermodynamic factors, arising chiefly from the conformation of the organic linker molecule used to connect the inorganic sheets. It is found that the registration of the inorganic layers can be engineered by selecting an appropriate, simple organic spacer or linker alkyl chain, where an even number of carbon atoms in the alkyl chain directs formation of aligned, stacked, inorganic sheets (AAAAAA), and an odd number directs formation of unaligned, stacked sheets (ABABAB) and the formation of one or two channel types in the resultant structure, respectively. This combination of alkyl‐chain linkers in conjunction with corrugated inorganic layers is an effective tool to rationally design the pore system of hybrid framework materials.