bluuebunny/crossref_metadata_2025 huggingface dataset:
Enrollment of Elderly Patients in Clinical Trials for Cancer Drug Registration: A 7-Year Experience by the US Food and Drug Administration
Authors: Talarico Lilia , Chen Gang , Pazdur Richard
Published: November 2004

Purpose

To analyze the age-related enrollment of cancer patients onto registration trials of new drugs or new indications approved by the US Food and Drug Administration from 1995 to 2002.

Patients and Methods

This study involved retrospective analyses of demographic data of cancer patients enrolled onto registration trials. The data on 28,766 cancer patients from 55 registration trials were analyzed according to age distributions of ≥ 65, ≥ 70, and ≥ 75 years. The rates of enrollment in each age group for each cancer were compared with the corresponding rates in the US cancer population. The age distributions of the US cancer population were derived from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute for the period 1995 to 1999 based on the 2000 US Census.

Results

The proportions of the overall patient populations aged ≥ 65, ≥ 70, and ≥ 75 years were 36%, 20%, and 9% compared with 60%, 46%, and 31%, respectively, in the US cancer population. Statistically significant under-representation of the elderly (P < .001) was noted in registration trials for all cancer treatment except for breast cancer hormonal therapies. Patients aged ≥ 70 years accounted for most of the under-representation.

Conclusion

Elderly were under-represented in the registration trials of new cancer therapies. Various strategies may be needed to evaluate cancer therapies for the elderly in prospective clinical trials and to improve cancer care in the elderly population.
Thickness Dependent Loss Function of Si with 0.14 eV Energy Resolution
Authors: Stöger‐Pollach M. , Hebert C. , Zandbergen H.W. , Schattschneider P.
Published: November 2004

Si band gap spectra were recorded by using electron energy loss spectrometry with very high energy resolution of 0.14 eV using a transmission electron microscope with a monochromated electron source. The shape of the spectra change with thickness, becoming indistinct at very thin regions. But even for higher thicknesses structureal evolution of the spectra can be observed. A comparison with band structure calculations is given, too.
An experimental study of acoustically enhanced NAPL dissolution in porous media
Authors: Vogler Eric T. , Chrysikopoulos Constantinos V.
Published: November 2004

The effects of acoustic waves on the dissolution of dense nonaqueous phase liquids in water saturated porous media are investigated. Experiments of trichloroethylene (TCE) ganglia dissolution within a water saturated column, packed with glass beads, are conducted. Acoustic waves with pressure amplitudes ranging from 0 to 1625 Pa and frequencies ranging from 0 to 285 Hz are employed to the interstitial fluid at the inlet of the packed column. Effluent dissolved TCE concentrations are observed to increase up to 120% in the presence of acoustic pressure waves compared to the case where TCE dissolution without acoustic waves is monitored. The observed effluent dissolved TCE concentration increase is attributed to enhanced mass flux at the TCE‐water interface, caused by acoustic waves. Highest dissolution rates occur at discrete frequencies suggesting resonance effects or the presence of standing waves. Although acoustic waves enhance TCE dissolution, they dissipate almost exponentially with distance from the acoustic source. © 2004 American Institute of Chemical Engineers AIChE J, 50: 3271–3280, 2004
Swelling and erosion affecting flavor release from glassy particles in water
Authors: Bouquerand P. E. , Maio S. , Normand V. , Singleton S. , Atkins D.
Published: November 2004

A model of flavor release from encapsulated flavor particles immersed in water has been developed that correlates well with experimental data. Flavor release from particles was determined by measuring both the quantities released from the particle to water and from water to air in the headspace. The model presented here predicts a very different release with time from the encapsulated flavor if the particle develops a hydrogel at the surface (swelling) compared to gradual erosion. Controlled heating showed more retention of flavor when the particle swells compared to a more rapid flavor release under conditions of particle erosion. © 2004 American Institute of Chemical Engineers AIChE J, 50: 3257–3270, 2004
Three new families with arterial tortuosity syndrome
Authors: Wessels Marja W. , Catsman‐Berrevoets Coriene E. , Mancini Grazia M.S. , Breuning Martijn H. , Hoogeboom Jeanette J.M. , Stroink Hans , Frohn‐Mulder Ingrid , Coucke Paul J. , Paepe Anne De , Niermeijer Martinus F. , Willems Patrick J.
Published: November 2004

Arterial tortuosity syndrome (ATS) is a rare condition with autosomal recessive inheritance characterized by connective tissue abnormalities. The most specific clinical findings are cardiovascular anomalies including tortuosity, lengthening, aneurysm, and stenosis formation of major arteries. Also ventricular hypertrophy is frequently present. Other anomalies are skin hyperextensibility and cutis laxa, joint laxity or contractures of the joints, and inguinal herniae. Histology shows disruption of elastic fibers of the media. These features suggest that ATS is a connective tissue disorder. A biochemical or molecular defect has not yet been identified. We describe here nine additional ATS patients from three consanguineous Moroccan families and review a total of 35 patients with this uncommon condition. © 2004 Wiley‐Liss, Inc.
Autoimmune disorders in Kabuki syndrome
Authors: Ming Jeffrey E. , Russell Karen L. , McDonald‐McGinn Donna M. , Zackai Elaine H.
Published: November 2004

Kabuki syndrome is associated with abnormalities in multiple organ systems. While many of the anomalies are congenital malformations, other clinical manifestations may not appear until later in childhood. Among these associated conditions, autoimmune abnormalities have been described in several patients. These include idiopathic thrombocytopenic purpura (ITP), hemolytic anemia, thyroiditis, and vitiligo. In this report, we describe five affected patients with autoimmune manifestations. Four patients had ITP, and two of these patients had concurrent hemolytic anemia. The fifth patient had vitiligo. Two of the patients with ITP had a chronic and relapsing course. Of note, some of these patients also had hypogammaglobulinemia. The autoimmune disorders may be manifestations of abnormal immune regulation. We conclude that Kabuki syndrome is associated with an increased incidence of autoimmune disorders. In addition, the presence of an underlying immune defect may predispose these children to a chronic course of these autoimmune conditions. © 2004 Wiley‐Liss, Inc.
Intellectual abilities and adaptive behavior of children and adolescents with Kabuki syndrome: A preliminary study
Authors: Mervis Carolyn B. , Becerra Angela M. , Rowe Melissa L. , Hersh Joseph H. , Morris Colleen A.
Published: November 2004

Very little is known about the intellectual abilities and adaptive behavior of individuals who have Kabuki syndrome, beyond the fact that most individuals with this syndrome have mental retardation. To fill this gap, we have completed psychological assessments of 11 children and adolescents with Kabuki syndrome. Results indicated that most of the participants functioned in the range of mild mental retardation, with both intellectual and adaptive behavior in the mildly deficient range and problem behaviors, if any, limited to mild difficulties with inattention and/or hyperactivity–impulsivity and mild problems with obsession/anxiety. At the lower extreme, one child evidenced severe mental retardation and profound adaptive behavior impairment accompanied by serious externalizing and internalizing problem behaviors. At the upper extreme, one adolescent had average intelligence and adaptive behavior, with problem behaviors well within the normal range for his chronological age. Most participants evidenced relative intellectual strengths in verbal and reasoning abilities and a relative weakness in visuospatial construction abilities. This pattern affected adaptive behavior as well, yielding a relative strength in Social Interaction and Communicative Skills and considerable weakness in Motor Skills and Personal Living Skills. © 2004 Wiley‐Liss, Inc.
Developmental outcome in Kabuki syndrome
Authors: Vaux Keith K. , Jones Kenneth L. , Jones Marilyn C. , Schelley Susan , Hudgins Louanne
Published: November 2004

Over the last 20 years, a wide spectrum of congenital anomalies have been described in association with Kabuki syndrome (KS). However, very little information is available on developmental outcome. As more individuals with this syndrome are recognized and reported, it appears that as many as one‐sixth may have normal intelligence. The purpose of this report is to describe the developmental outcome in 15 patients with KS, to determine whether a recognizable pattern of disabilities exist, and whether developmental outcome correlates with the presence of malformations. We ascertained 15 patients with KS from three dysmorphology and clinical genetics services in which developmental milestones and formal developmental testing were available. Based on these patients and a review of the literature, in the absence of major structural brain anomalies, the average intelligence quotient (IQ) in patients with this condition fall within the mild mental retardation range, however, specific developmental outcomes are widely variable, ranging from severe MR to normal intelligence. The presence or absence of hearing loss or major malformations, other than those involving the brain, was not predictive of developmental outcome. Published 2004 Wiley‐Liss, Inc.
Genotype–phenotype correlations for a wide spectrum of mutations in the Wilson disease gene (ATP7B)
Authors: Panagiotakaki Eleni , Tzetis Maria , Manolaki Nina , Loudianos Giorgos , Papatheodorou Athanasios , Manesis Emmanuel , Nousia‐Arvanitakis Sanda , V Syriopoulou , Kanavakis Emmanuel
Published: November 2004

Wilson disease (WND) is caused by mutations in the ATP7B gene and exhibits substantial allelic heterogeneity. In this study we report the results of molecular analyses of 20 WND families not described previously. When combined with our prior results, the cohort includes 93 index patients from 69 unrelated families. Twenty different mutations accounted for 86% of the WND chromosomes. The most frequent were p.H1069Q (35%), p.R969Q (12%), c.2530delA (7%), p.L936X (7%), p.Q289X (7%), and p.I1148T (3%). We also present here a detailed phenotypic assessment for patients whose molecular result was previously reported. Thirty cases were homozygous for 9 different mutations, 13 of which were homozygous for p.H1069Q, and 7 for p.R969Q. Mutations p.H1069Q and p.R969Q appeared to confer a milder disease as patients showed disease onset at a later age, and were associated with milder severity when found in trans with severe mutations. Predicted nonsense and frameshift mutations were associated with severe phenotypic expression with earlier disease onset and lower ceruloplasmin values. WND can be treated by copper‐chelation therapy, particularly if the disease is diagnosed before irreversible tissue damage occurs. Our results on the effect of predicted nonsense and frameshift mutations are especially important for early medical intervention in presymptomatic infants and children with these genotypes. © 2004 Wiley‐Liss, Inc.
Craniofacial structure in Marfan syndrome: A cephalometric study
Authors: De Coster Peter , Pauw Guy De , Martens Luc , De Paepe Anne
Published: November 2004

Marfan syndrome (MFS) is a connective tissue disorder with autosomal dominant inheritance. Mutations in the FBN1 gene cause deficient processing of fibrillin‐1, the main constituent of extracellular microfibrils, affecting tissues displaying elastic properties. Clinical manifestations are widespread and involve the skeletal, ocular, cardiovascular and pulmonary systems, skin and integumentum, and dura. A highly arched palate and retrognathia have been assigned to the symptoms with minor diagnostic specificity, although epidemiological data on prevalence are lacking yet. Twenty‐six patients with MFS (n = 26) were studied for craniofacial characteristics using cephalometric measurements on lateral cranial radiographs. The purposes of this study were (1) to compare cephalometric variables of MFS group with age‐ and sex‐matched population norms, and (2) to assess differences in palatal vault dimensions among adult MFS (n = 17) and matched controls (n = 32) by means of cephalometric measurements. Significant differences with population norms were found in the structures of the cranial base, the maxillary complex, the mandible body, and the relations of the jaws with respect to the cranial base and to each other. Palatal height and palatal length were significantly larger in MFS, and were significantly correlated to each other and to the height of the maxillo‐alveolar processus. The present data disprove in part previously reported findings, possibly due to biased patient selection in these studies or demographic differences. However, a strong correlation was found between maxillary/mandibular retrognathia, long face, highly arched palate, and MFS. A combination of both intrinsic genetic factors and environmental factors is suggested as a possible explanation for specific morphogenetic aspects of the craniofacial complex in MFS. © 2004 Wiley‐Liss, Inc.
NSAIDs increase survival in the Sandhoff disease mouse: Synergy with N‐butyldeoxynojirimycin
Authors: Jeyakumar Mylvaganam , Smith David A. , Williams Ian M. , Borja Mario Cortina , Neville David C. A. , Butters Terry D. , Dwek Raymond A. , Platt Frances M.
Published: November 2004

The GM2 gangliosidoses are caused by incomplete catabolism of GM2 ganglioside in the lysosome, leading to progressive storage and a neurodegenerative clinical course. An inflammatory response (microglial activation, macrophage infiltration, oxidative damage) has been found to be a consequence of GM2 storage in the brain, although it remains unclear whether this contributes to pathogenesis or disease progression. In this study, we treated Sandhoff disease mice with nonsteroidal antiinflammatory drugs (indomethacin, aspirin, and ibuprofen) and antioxidants (L‐ascorbic acid and α‐tochopherol acetate). The treated mice lived significantly longer than untreated littermates (12–23%, p < 0.0001) and showed a slower rate of disease progression (p < 0.001). When aspirin treatment was combined with substrate reduction therapy, synergy resulted (11%, p < 0.05) with a maximum improvement of 73% in survival (p < 0.00001). This study demonstrates that inflammation contributes to disease progression and identifies antiinflammatory and antioxidant therapies as a potential adjunctive approach to slow the clinical course of this and related disorders. Ann Neurol 2004;56:642–649
Cover Picture: Crystal Structure of Tricolorin A: Molecular Rationale for the Biological Properties of Resin Glycosides Found in Some Mexican Herbal Remedies (Angew. Chem. Int. Ed. 44/2004)
Authors: Rencurosi Anna , Mitchell Edward P. , Cioci Gianluca , Pérez Serge , Pereda‐Miranda Rogelio , Imberty Anne
Published: November 2004

In traditional Mexican farming the morning glory “heavenly blue” (Ipomea tricolor Cav.) is used as a cover crop. The structure of tricolorin A, one of several phytotoxic resin glycosides present in this plant, has now been determined crystallographically. The lipopolysaccharide contains one macrolactone ring and forms channel structures, which could be responsible for the biological activity of this compound, as reported by R. Pereda‐Miranda, A. Imberty, and co‐workers in their Communication on page 5918 ff.
Improvement in the mechanical properties of poly(3‐hydroxybutyrate‐co‐3‐hydroxyhexanoate) by preorientation
Authors: Hassan Mohamed K. , Abdel‐Latif Samir A. , El‐Roudi Omar M. , Sharaf Mohamed A. , Noda Isao , Mark James E.
Published: November 2004

Preoriented poly(3‐hydroxybutyrate‐co‐3‐hydroxyhexanoate) (Nodax™) films were obtained via the drawing of films to prestretching ratios ranging from 200 to 1000%. As expected, preorientation resulted in substantial improvements in the mechanical properties of the films from the corresponding increases in the amount and nature of the crystallinity present. Stress–strain curves in elongation showed a yield peak, which was relatively broad for the unoriented samples but became sharper, with a well‐defined neck, as the extent of preorientation was increased. In addition, the preoriented films had higher modulus, toughness, yield stress, and tensile strength values. The attribution of these changes in the mechanical properties to changes in the crystallinity was supported by X‐ray diffraction measurements. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 94: 2257–2262, 2004
Characteristics of poly(vinyl pyrrolidone)/poly(acrylic acid) interpolymer complex prepared by template polymerization of acrylic acid: Effect of reaction solvent and molecular weight of template
Authors: Chun Myung‐Kwan , Cho Chong‐Su , Choi Hoo‐Kyun
Published: November 2004

Poly(vinyl pyrrolidone) (PVP)/poly(acrylic acid) (PAA) interpolymer complexes were prepared, in ethanol or dimethylformamide (DMF), by template polymerization of acrylic acid in the presence of PVP (MW: 42.5 or 1100 K) used as the template. FTIR analysis showed that the complexes were formed through hydrogen bonding between the carboxyl groups of the PAA and the carbonyl groups of the PVP. The glass‐transition temperature (Tg) of the complex, prepared in ethanol, was higher than that of the component polymers, whereas the Tg of the complex, prepared in DMF, was located between that of the component polymers. The dissolution rate of the complex was affected by the molecular weight of the PVP and the reaction solvent. The release rate of ketoprofen from the complexes showed a pH dependency, and was slower at a lower pH. The ketoprofen release rate from the complex was controlled mainly by the dissolution rate of the complex above the pKa of PAA (4.75) and by the diffusion rate below the pKa. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 94: 2390–2394, 2004
Novel mucoadhesive polymer: Synthesis and mucoadhesion of poly[acrylic acid‐co‐poly(ethylene glycol) monomethylether monomethacrylate‐co‐dimethylaminoethyl methacrylate]
Authors: Xiang Jun , Li Xiaoling
Published: November 2004

This study was to design a mucoadhesive based on the biological and physicochemical properties of the buccal mucosa to achieve optimal mucoadhesion in the aqueous buccal environment. Since the buccal surface is negatively charged, a series of novel mucoadhesive poly[acrylic acid‐co‐poly(ethylene glycol) monomethylether monomethacrylate‐co‐dimethylaminoethyl methacrylate] [poly (AA‐PEGMM‐DMEMA)] were synthesized by incorporating the cationic monomer DMEMA into poly(AA‐PEGMM) to enhance the interactions between the mucohadhesive polymer and the buccal mucosa. The compositions of poly(AA‐PEGMM‐DMEMA) were varied by changing the content of DMEMA from 0 to 4.8 mol % while keeping the mole ratio of AA to PEGMM at a constant 9 : 1. It was found that the force of mucoadhesion of poly(AA‐PEGMM‐DMEMA) increased initially, as DMEMA content increased, and reached the maximum at 1% of DMEMA. Further increasing the content of DMEMA decreased the mucoadhesion. The polymers with 0.5 to 2.9% DMEMA appeared to have maximum mucoadhesion after prehydration for 5 min. An ATR–FTIR spectroscopy study revealed that intrapolymer interactions and intersurface interactions played opposite roles in the mucoadhesion performance of the polymers. Optimal mucoadhesion can be achieved by balancing these two interactions. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 94:2431–2437, 2004
On the potential of organoclay with respect to conventional fillers (carbon black, silica) for epoxidized natural rubber compatibilized natural rubber vulcanizates
Authors: Teh P. L. , Mohd Ishak Z. A. , Hashim A. S. , Karger‐Kocsis J. , Ishiaku U. S.
Published: November 2004

Onium modified montmorillonite (organoclay) was compounded with natural rubber (NR) in an internal mixer and cured by using a conventional sulfuric system. Epoxidized natural rubber with 50 mol % epoxidation (ENR 50) in 10 parts per hundred rubber (phr) was used as a compatibilizer in this study. For comparison purposes, two commercial fillers: carbon black (grade N330) and silica (grade vulcasil‐S) were used. Cure characteristics were carried out on a Monsanto MDR2000 Rheometer. Organoclay filled vulcanizate showed the lowest values of torque maximum, torque minimum, scorch, and cure times. The kinetics of cure reaction showed organoclay could behave as a cocuring agent. The mechanical testing of the vulcanizates involved the determination of tensile and tear properties. The improvement of tensile strength, elongation at break, and tear properties in organoclay filled vulcanizate were significantly higher compared to silica and carbon black filled vulcanizates. In terms of reinforcing efficiency (RE), organoclay exhibited the highest stiffness followed by silica and carbon black filled vulcanizates. Scanning electron microscopy revealed that incorporation of various types of fillers has transformed the failure mechanism of the resulting NR vulcanizates compared to the gum vulcanizates. Dynamic mechanical thermal analysis (DMTA) revealed that the stiffness and molecular relaxation of NR vulcanizates are strongly affected by the filler–rubber interactions. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 94: 2438–2445, 2004
Electrorheological behaviors of barium titanate/gelatin composite hydrogel elastomers
Authors: Gao Lingxiang , Zhao Xiaopeng
Published: November 2004

Electrorheological (ER) elastomers, based on a gelatin hydrogel as matrix in which barium titanate ER particles are dispersed, were investigated. The behavior of particles was observed by a microscopic method. The ER effects of the elastomers are described with the compression modulus as a function of both particle concentration and intensity of the externally applied electric field. The result demonstrates that the particles were aligned in the matrix under an externally applied dc electric field. Furthermore, it was found that alignment of the particles increases the elastomer's modulus. In addition, both the chain effect and filler effect of the particles can dominate the modulus. The peak of modulus appears when using the elastomer with a particle weight fraction of 1.5% because of the complex dominations of the two effects. In like manner, the largest incremental modulus appears. Based on the results, we found that the modulus of the elastomer cured under an electric field is greater than that without an electric field, and increases with the increasing field. Thus ER behavior of the elastomer can be controlled by the electric field intensity. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 94: 2517–2521, 2004
Identification and detection of the periostin gene in cardiac development
Authors: Norris Russell A. , Kern Christine B. , Wessels Andy , Moralez E. Iris , Markwald Roger R. , Mjaatvedt Corey H.
Published: November 2004

Periostin, a member of the fasciclin gene family, acts as a cell adhesion molecule through binding to cell surface integrins. Periostin expression has previously been shown to increase substantially following transforming growth factor β (TGF‐β) and bone morphogenetic protein stimulation. As these molecules are indispensable for cardiac development, we sought to clone the chicken ortholog of periostin and evaluate its spatiotemporal expression pattern during heart morphogenesis. We show by Northern analysis, whole mount and section in situ hybridization experiments that periostin is predominantly expressed in the developing endothelium of the ventricular trabeculae as well as in the endothelium and mesenchyme of the outflow tract and atrioventricular endocardial cushions. Cardiac expression continues into fetal development where periostin is seen predominantly in the valve leaflets and supporting chordae tendinae. © 2004 Wiley‐Liss, Inc.
Synthesis of Dimeric Trifluoromethoxyacridine‐derived Pathogen‐inactivating Nucleic Acid Intercalators
Authors: Csuk René , Raschke Christian , Göthe Gunnar , Reißmann Stefan
Published: November 2004

A series of antiviral active compounds consisting of an intercalating acridine‐derived part, a spacer region and a reactive EDTA‐derived conjugate was synthesized in an easy sequence. Thus, suitably mono‐protected 1, ω‐alkyldiamines gave, upon reaction with 9‐chloro‐2‐trifluoromethoxyacridine, followed by deprotection and reaction with EDTA dianhydride, the target molecules. Incorporation of their Fe(II) complexes in the presence of ascorbate gave a reduction of the phage titer of MS2 phages by several logarithmic decades.
Multimethodological approach to study and characterize Forum Novum (Vescovio, central Italy)
Authors: Gaffney V. , Patterson H. , Piro S. , Goodman D. , Nishimura Y.
Published: November 2004

The paper presents the results of an on‐going study of the Roman town and early medieval bishopric of Forum Novum at Vescovio in the middle Tiber valley to the north of Rome. The work forms part of the British School at Rome's Tiber Valley Project, which studies the changing landscapes of the middle Tiber valley as the hinterland of Rome through two millennia, from 1000 BC to AD 1000. At Forum Novum a range of remote sensing techniques are being combined with excavation to examine the extent and organization of a Roman town and its development through time.

From 1997 to 2001 a series of topographic and high‐resolution ground‐based remote sensing surveys took place at Forum Novum, which provide a basic map of the ancient centre. The integrated remote sensing surveys were carried out using the magnetic, geoelectric and ground‐penetrating radar (GPR) methods. The analysis of the gradiometric, resistivity and GPR time‐slice maps indicate that many structural foundations and walls of the buildings are still well preserved below the surface.

The results, which are presented and discussed in this paper, demonstrate the potential of remote sensing techniques for our understanding of the extent and organization of urban centres. In the case of Forum Novum, where much of the ancient centre lies under modern structures, GPR survey, in particular, proved fundamental. Further, the results of the georadar surveys permitted archaeologists to select key areas of the town for more detailed investigation through excavation. Copyright © 2004 John Wiley & Sons, Ltd.
Measurement of erythrocyte C4d and complement receptor 1 in systemic lupus erythematosus
Authors: Manzi Susan , Navratil Jeannine S. , Ruffing Margie J. , Liu Chau‐Ching , Danchenko Natalya , Nilson Sarah E. , Krishnaswami Shanthi , King Dale E. S. , Kao Amy H. , Ahearn Joseph M.
Published: November 2004

Objective

C4‐derived activation fragments are the only complement ligands present on the surfaces of normal erythrocytes. The significance of this observation is unknown, and the role of erythrocyte‐bound C4 (E‐C4) in human disease has not been explored. More than any other human disease, the pathogenesis of systemic lupus erythematosus (SLE) has been characterized by defects in clearance of complement‐bearing immune complexes via erythrocytes expressing complement receptor 1 (CR1). This study was undertaken to determine whether these functional defects might be reflected by abnormal patterns of E‐C4 and E‐CR1 expression on erythrocytes of patients with SLE.

Methods

We conducted a cross‐sectional study of 100 patients with SLE, 133 patients with other diseases, and 84 healthy controls. Erythrocytes were characterized by indirect immunofluorescence and by flow cytometry for determination of levels of C4d and CR1.

Results

Patients with SLE had higher levels of E‐C4d and lower levels of E‐CR1 than did patients with other diseases (P ≤ 0.001) or healthy controls (P ≤ 0.001). The test was 81% sensitive and 91% specific for SLE versus healthy controls and 72% sensitive and 79% specific for SLE versus other diseases, and it had an overall negative predictive value of 92%.

Conclusion

This is the first report of abnormal levels of E‐C4d in human disease. We found that abnormally high levels of E‐C4d and low levels of E‐CR1 are characteristic of SLE, and combined measurement of the 2 molecules has high diagnostic sensitivity and specificity for lupus. Determination of E‐C4d/E‐CR1 levels may be a useful addition to current tests and criteria for SLE diagnosis.
Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: A randomized, controlled trial
Authors: St. Clair E. William , van der Heijde Désirée M. F. M. , Smolen Josef S. , Maini Ravinder N. , Bathon Joan M. , Emery Paul , Keystone Edward , Schiff Michael , Kalden Joachim R. , Wang Ben , DeWoody Kimberly , Weiss Roberta , Baker Daniel ,   Active‐Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset Study Group
Published: November 2004

Objective

To compare the benefits of initiating treatment with methotrexate (MTX) and infliximab (anti–tumor necrosis factor α [anti‐TNFα] monoclonal antibody) with those of MTX treatment alone in patients with rheumatoid arthritis (RA) of ≤3 years' duration.

Methods

RA patients were eligible if they had active disease and no prior treatment with MTX or a TNFα inhibitor. One thousand forty‐nine patients were randomly assigned in a 4:5:5 ratio to 3 treatment groups: MTX–placebo, MTX–3 mg/kg infliximab, and MTX–6 mg/kg infliximab. MTX dosages were rapidly escalated to 20 mg/week, and infliximab or placebo infusions were given at weeks 0, 2, and 6, and every 8 weeks thereafter through week 46.

Results

At week 54, the median percentage of American College of Rheumatology improvement (ACR‐N) was higher for the MTX–3 mg/kg infliximab and MTX–6 mg/kg infliximab groups than for the MTX–placebo group (38.9% and 46.7% versus 26.4%, respectively; P < 0.001 for both comparisons). Patients in the MTX–3 mg/kg infliximab and MTX–6 mg/kg infliximab groups also showed less radiographic progression than those receiving MTX alone (mean ± SD changes in van der Heijde modification of the total Sharp score at week 54: 0.4 ± 5.8 and 0.5 ± 5.6 versus 3.7 ± 9.6, respectively; P < 0.001 for each comparison). In addition, physical function improved significantly more in the MTX–3 mg/kg infliximab and MTX–6 mg/kg infliximab groups than in the MTX–placebo group. Infliximab therapy was associated with a significantly higher incidence of serious infections, especially pneumonia.

Conclusion

For patients with active RA in its early stages, combination therapy with MTX and infliximab provides greater clinical, radiographic, and functional benefits than treatment with MTX alone.
Enhancement of collagen‐induced arthritis in mice genetically deficient in extracellular superoxide dismutase
Authors: Ross Aron D. , Banda Nirmal K. , Muggli Michele , Arend William P.
Published: November 2004

Objective

To examine the influence of superoxide on the severity of collagen‐induced arthritis (CIA) in mice.

Methods

CIA was induced in DBA/1J mice lacking the extracellular superoxide dismutase (EC‐SOD) gene (knockout [KO]) and in normal DBA/1J mice (wild‐type [WT]).

Results

The clinical disease activity score was significantly higher in EC‐SOD–KO mice than in WT mice between days 36 and 53, and the histologic scores for joint damage on day 53 increased 2‐fold or more in the EC‐SOD–KO mice. There were no significant differences between the 2 groups of mice in proliferation indices of spleen or lymph node cells in vitro after stimulation with type II collagen. Although both IgG1 and IgG2a anticollagen antibody levels increased in both groups of mice between days 21 and 53, there were no significant differences between the 2 groups. Lipopolysaccharide‐stimulated spleen cells from EC‐SOD–KO mice produced greater levels of tumor necrosis factor α (TNFα) over 48 hours in culture compared with cells from WT mice. Increased steady‐state levels of messenger RNA (mRNA) for interferon‐γ (IFNγ), TNFα, and interleukin‐1β (IL‐1β), and lower levels of IL‐1 receptor antagonist (IL‐1Ra) mRNA were present in the joints of the EC‐SOD–KO mice compared with the WT mice.

Conclusion

The absence of EC‐SOD leads to more severe CIA, which may be accompanied by enhanced production of the proinflammatory cytokines IFNγ, TNFα, and IL‐1β, and decreased production of the antiinflammatory cytokine IL‐1Ra in the joints.
Role of NF‐κB transcription factors in antiinflammatory and proinflammatory actions of mechanical signals
Authors: Agarwal Sudha , Deschner James , Long Ping , Verma Anupam , Hofman Cynthia , Evans Christopher H. , Piesco Nicholas
Published: November 2004

Objective

The mechanisms by which chondrocytes convert biomechanical signals into intracellular biochemical events are not well understood. In this study, we sought to determine the intracellular mechanisms of the magnitude‐dependent actions of mechanical signals.

Methods

Chondrocytes isolated from rabbit articular cartilage were grown on flexible membranes. Cells were subjected to cyclic tensile strain (CTS) of various magnitudes in the presence or absence of interleukin‐1β (IL‐1β), which was used as a proinflammatory signal for designated time intervals. The regulation of NF‐κB was measured by reverse transcriptase–polymerase chain reaction, electrophoretic mobility shift assay, and immunofluorescence.

Results

CTS of low magnitudes (4–8% equibiaxial strain) was a potent inhibitor of IL‐1β–dependent NF‐κB nuclear translocation. Cytoplasmic retention of NF‐κB and reduction of its synthesis led to sustained suppression of proinflammatory gene induction. In contrast, proinflammatory signals generated by CTS of high magnitudes (15–18% equibiaxial strain) mimicked the actions of IL‐1β and induced rapid nuclear translocation of NF‐κB subunits p65 and p50.

Conclusion

Magnitude‐dependent signals of mechanical strain utilize the NF‐κB transcription factors as common elements to abrogate or aggravate proinflammatory responses. Furthermore, the intracellular events induced by mechanical overload are similar to those that are initiated by proinflammatory cytokines in arthritis.
Prognostic importance of low body mass index in relation to cardiovascular mortality in rheumatoid arthritis
Authors: Kremers Hilal Maradit , Nicola Paulo J. , Crowson Cynthia S. , Ballman Karla V. , Gabriel Sherine E.
Published: November 2004

Objective

Various etiologic mechanisms have been implicated in the observed increase in cardiovascular mortality in rheumatoid arthritis (RA). Body mass index (BMI) is associated with cardiovascular mortality in the general population. This study compared the effect of BMI on cardiovascular mortality in a population‐based cohort of subjects with RA with that in a cohort of individuals without RA from the same population.

Methods

The RA cohort comprised all members of an incidence cohort of Rochester, Minnesota residents ages ≥18 years who were first diagnosed with RA (by the American College of Rheumatology 1987 criteria) from 1955 through 1994. An age‐ and sex‐matched comparison cohort of subjects without RA was assembled. Both cohorts were followed up longitudinally through their complete (inpatient, outpatient) medical records beginning at age 18 years and continuing until death, migration, or January 1, 2001, and the details of weight and height changes during this period were recorded. High BMI was defined as a BMI >30 kg/m2 and low BMI as <20 kg/m2. Cox regression models were used to estimate the effect of BMI on cardiovascular mortality after accounting for traditional cardiac risk factors and malignancies.

Results

RA subjects with low BMI at incidence had a significantly higher risk of cardiovascular death (hazard ratio [HR] 3.34, 95% confidence interval [95% CI] 2.23–4.99) compared with non‐RA subjects with normal BMI, after adjusting for age, sex, personal cardiac history, smoking status, and presence of diabetes, hypertension, and malignancies. RA subjects with normal BMI at incidence who experienced low BMI during followup also had a higher risk of cardiovascular death (HR 2.09, 95% CI 1.50–2.92) when compared with non‐RA subjects who maintained normal BMI throughout followup.

Conclusion

Among patients with RA, low BMI is associated with a significantly increased risk of cardiovascular death.
Serum cytokine profiles in relapsing polychondritis suggest monocyte/macrophage activation
Authors: Stabler Thomas , Piette Jean‐Charles , Chevalier Xavier , Marini‐Portugal Andre , Kraus Virginia B.
Published: November 2004

Objective

There is evidence that autoimmunity plays a significant role in the pathogenesis of relapsing polychondritis (RP). This study was designed to investigate circulating levels of various cytokines in relation to the etiology of this rare disorder, and to compare the pattern of cytokine elevations in RP with that in another autoimmune disease, rheumatoid arthritis (RA).

Methods

Serum from 22 patients with active RP and an equal number of age‐ and sex‐matched healthy controls and RA patients were available for analysis. The following cytokines were measured: interleukin‐1β (IL‐1β), IL‐2, IL‐4, IL‐5, IL‐6, IL‐7, IL‐8, IL‐10, IL‐12, IL‐13, IL‐17, interferon‐γ (IFNγ), tumor necrosis factor α, granulocyte colony‐stimulating factor (G‐CSF), granulocyte–macrophage colony‐stimulating factor (GM‐CSF), monocyte chemoattractant protein 1 (MCP‐1), and macrophage inflammatory protein 1β (MIP‐1β). Results were analyzed by nonparametric Mann‐Whitney test with Holm stepdown adjustment for multiple testing.

Results

The levels of 3 of these cytokines showed significant differences between RP patients and controls. Compared with controls, mean serum levels of MCP‐1, MIP‐1β, and IL‐8 were all much higher in patients with active RP. In contrast, RA patients showed a more general increase in all cytokines measured, with much higher levels of IL‐2, IL‐4, IL‐5, IL‐6, IL‐7, IL‐10, IL‐13, IFNγ, G‐CSF, GM‐CSF, MCP‐1, and MIP‐1β compared with controls.

Conclusion

Levels of 3 serum cytokines were significantly higher in RP patients than in age‐ and sex‐matched controls. One of these 3 cytokines, IL‐8, was not significantly elevated in RA samples. Overall, in RP, a more discrete group of cytokines exhibited significantly increased levels than was found in RA. Each of the 3 cytokines that were elevated in RP is a proinflammatory chemokine, characteristic of activation of the monocyte and macrophage lineage, and in the case of IL‐8, also of neutrophils. These data suggest a major role for a cell‐mediated immune response in the pathophysiology of RP.
The relationship of antiresorptive drug use to structural findings and symptoms of knee osteoarthritis
Authors: Carbone Laura D. , Nevitt Michael C. , Wildy Kathryn , Barrow Karen D. , Harris Fran , Felson David , Peterfy Charles , Visser Marjolein , Harris Tamara B. , Wang Benjamin W. E. , Kritchevsky Stephen B. ,   Health, Aging and Body Composition Study
Published: November 2004

Objective

To examine the cross‐sectional association between use of medications that have a bone antiresorptive effect (estrogen, raloxifene, and alendronate) and both the structural features of knee osteoarthritis (OA), assessed by magnetic resonance imaging (MRI) and radiography, and the symptoms of knee OA in elderly women.

Methods

Women in the Health, Aging and Body Composition Study underwent MRI and radiography of the knee if they reported symptoms of knee OA, and women without significant knee symptoms were selected as controls. MR images of the knee were assessed for multiple features of OA using the Whole‐Organ MRI scoring method, and radiographs were read for Kellgren and Lawrence grade and individual features of OA. Concurrent medication use and knee symptoms were assessed by interview, and knee pain severity was evaluated using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).

Results

There were 818 postmenopausal women from whom we obtained MR images of the knee and data on medication use. Among these women, 214 (26.2%) were receiving antiresorptive drugs. We found no significant association between overall use of antiresorptive drugs and the presence of knee pain and radiographic changes of OA of the knee. Use of alendronate, but not estrogen, was associated with less severity of knee pain as assessed by WOMAC scores. Both alendronate use and estrogen use were associated with significantly less subchondral bone attrition and bone marrow edema–like abnormalities in the knee as assessed by MRI, as compared with women who had not received these medications.

Conclusion

Elderly women being treated with alendronate and estrogen had a significantly decreased prevalence of knee OA–related subchondral bone lesions compared with those reporting no use of these medications. Alendronate use was also associated with a reduction in knee pain according to the WOMAC scores.
Inhibition of adjuvant‐induced arthritis by DNA vaccination with the 70‐kd or the 90‐kd human heat‐shock protein: Immune cross‐regulation with the 60‐kd heat‐shock protein
Authors: Quintana Francisco J. , Carmi Pnina , Mor Felix , Cohen Irun R.
Published: November 2004

Objective

Adjuvant arthritis can be induced in Lewis rats by immunization with Mycobacterium tuberculosis (Mt). The mycobacterial 65‐kd heat‐shock protein (Hsp65) is targeted by arthritogenic T cells. However, Hsp65 and the mycobacterial 71‐kd heat‐shock protein are also recognized by T cells that can down‐regulate adjuvant‐induced arthritis (AIA). We have recently demonstrated that vaccination with human Hsp60 DNA inhibits AIA. The present study was undertaken to analyze the role of the T cell responses to self HSP molecules other than Hsp60 in the control of AIA.

Methods

Lewis rats were immunized with DNA vaccines coding for human Hsp70 or Hsp90 (Hsp70 plasmid [pHsp70] or pHsp90), and AIA was induced. The T cell response to Mt, Hsp60, Hsp70, and Hsp90 (proliferation and cytokine release) was studied, and the T cell response to Hsp60 was mapped with overlapping peptides.

Results

The Hsp70 or Hsp90 DNA vaccines shifted the arthritogenic T cell response from a Th1 to a Th2/3 phenotype and inhibited AIA. We detected immune crosstalk between Hsp70/90 and Hsp60: both the Hsp70 and Hsp90 DNA vaccines induced Hsp60‐specific T cell responses. Similarly, DNA vaccination with Hsp60 induced Hsp70‐specific T cell immunity. Epitope mapping studies revealed that Hsp60‐specific T cells induced by pHsp70 vaccination reacted with known regulatory Hsp60 epitopes.

Conclusion

T cell immunity to Hsp70 and to Hsp90, like Hsp60‐specific immunity, can modulate the arthritogenic response in AIA. In addition, our results suggest that the regulatory mechanisms induced by Hsp60, Hsp70, and Hsp90 are reinforced by an immune network that connects their reactivities.
Flachdecken mit Vorspannung ohne Verbund nach DIN 1045‐1: Praxisnahe Hinweise zu Entwurf und Bemessung
Authors: Morgen Karl , Nölting Diedrich , Wollrab Ekkehard
Published: November 2004

Zum Jahresende 2004 läuft die Übergangsfrist für die seit September 2002 eingeführte Bemessungsnorm DIN 1045 für Tragwerke aus Beton, Stahlbeton und Spannbeton aus. Ein wesentlicher Aspekt des neuen Regelwerks ist die Aufhebung der normativen Trennung für die Bemessung von Stahlbeton‐ und Spannbetonbauteilen. Im Hinblick darauf und unter Berücksichtigung der nationalen Entwicklungen auf dem Gebiet des Spannbetonbaus erscheint es absehbar, daß auch in Deutschland im Hochbau vermehrt vorgespannte Bauteile ausgeführt werden. Von besonderem Interesse für Bauherren, Architekten und entwerfende Ingenieure ist dabei die Perspektive, intern verbundlos verlegte Spannglieder zur Realisierung unterzugsfreier, weitgespannter Deckentragwerke zu verwenden. Insbesondere für schlanke Decken mit großen Spannweiten und erhöhten Anforderungen an die Begrenzung der vertikalen Bauteilverformungen bietet diese Bauart wesentliche Vorteile gegenüber Stahlbetondecken. Der vorliegende Beitrag soll die Entwicklung in diesem Bereich unterstützen, indem aufbauend auf dem heutigen Kenntnisstand praxisorientierte Hinweise zum Entwurf und zur Bemessung von Flachdecken mit Vorspannung ohne Verbund nach DIN 1045‐1 gegeben werden.
Development of an ultrahigh‐temperature process for the enzymatic hydrolysis of lactose. III. Utilization of two thermostable β‐glycosidases in a continuous ultrafiltration membrane reactor and galacto‐oligosaccharide formation under steady‐state conditions
Authors: Petzelbauer Inge , Splechtna Barbara , Nidetzky Bernd
Published: November 2004

Hydrolysis of lactose by hyperthermophilic β‐glycosidases from the archaea Sulfolobus solfataricus (SsβGly) and Pyrococcus furiosus (CelB) was carried out at 70°C in a continuous stirred‐tank reactor (CSTR) coupled to a 10‐kDa cross‐flow ultrafiltration module to recycle the enzyme. Recirculation rates of ≥1 min−1, reaction of proteins with reducing sugars, and enzyme adsorption onto the membrane are major “operational” factors of enzyme inactivation in the CSTR. They cause the half‐life times of SsβGly and CelB to be reduced two‐ and eight‐fold, respectively, the average value for both enzymes now being ∼5 to 7 days. Using lactose at initial concentrations of 45 and 170 g/L, the CSTR was operated at a constant conversion level of ∼80% for more than 2 weeks without the occurrence of microbial contamination. The productivities for the SsβGly‐catalyzed conversion of lactose were determined at different dilution rates and initial substrate concentrations, and exceed by a factor of ≤2 those observed with CelB under otherwise identical conditions. This difference reflects the approximately eight‐fold stronger product inhibition of CelB by D‐glucose. While the maximum total galacto‐oligosaccharide production (90–100 mM) at 170 g/L lactose in the CSTR was not different from that in the batch reactor (CelB) or was greater by ∼25% (SsβGly), continuous and batchwise reactions with both enzymes differed markedly with regard to relative proportions of the individual saccharide components present at 80% substrate conversion. The CSTR yielded an up to four‐fold greater ratio of disaccharides to trisaccharides concomitant with a 5‐ to 30‐fold larger relative proportion of β‐D‐Galp‐(1→3)‐D‐Glc in the product mixture. The results show that apart from continuous hydrolysis of lactose at 70°C, a CSTR charged with SsβGly or CelB and operated at steady‐state conditions could be a useful reaction system for the production of galacto‐oligosaccharides in which composition is narrower and more easily programmable, in terms of the individual components contained, as compared to the batchwise reaction. © 2002 John Wiley & Sons, Inc. Biotechnol Bioeng 77: 394–404, 2002; DOI 10.1002/bit.10106
Kinetic studies on elemental sulfur oxidation by Acidithiobacillus ferrooxidans: Sulfur limitation and activity of free and adsorbed bacteria
Authors: Ceskova Pavla , Mandl Martin , Helanova Sarka , Kasparovska Jitka
Published: November 2004

The kinetics of sulfur oxidation by Acidithiobacillus ferrooxidans in shaking flasks and a 10‐L reactor was studied. The observed linearity of growth and sulfur oxidation was explained by sulfur limitation. Total cell yield was not significantly different for exponential growth as compared to growth during the sulfur‐limiting phase. Kinetic studies of sulfur oxidation by growing and nongrowing bacteria indicated that both free and adsorbed bacteria oxidize sulfur. Changes in the number of free bacteria rather than cells adsorbed on sulfur were better predictors of the kinetics of sulfur oxidation, indicating that the free bacteria were performing sulfur oxidation. The active growth phase always followed adsorption of bacteria on sulfur; however, the special metabolic role of adsorbed bacteria was unclear. Their activity in sulfur solubilization was considered. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 78: 24–30, 2002; DOI 10.1002/bit.10172