bluuebunny/crossref_metadata_2025 huggingface dataset:
Quaternary Ammonium Compounds
Authors: Dery Maurice
Published: July 2004

Most quaternary ammonium compounds produced in the United States are formulated into consumer products. The largest markets for quaternaries are fabric softening, hair care, bactericidal and germicidal applications, and for manufacture of organoclays. When one of the alkyl groups contains around 10 carbon atoms, the molecules exhibit surface‐active properties. Physical properties are determined by the chemical structure of the material. Reactions include eliminations, displacements, and rearrangements. There are also many biologically important quaternaries.

Most quaternaries are biodegradable. Quaternaries are prepared by the reaction of a tertiary amine with an alkylating agent. Commercial production from natural fats and oils, α‐olefins, and fatty alcohols is described. Quaternized esteramines are gaining market share in Western Europe. Other classes of quaternaries include phase‐transfer catalysts, polyamine‐based quaternaries, and perfluorinated quaternaries.
Investigation of the human serotonin receptor geneHTR3Bin bipolar affective and schizophrenic patients
Authors: Frank Bernd , Niesler Beate , Nöthen Markus M. , Neidt Helge , Propping Peter , Bondy Brigitta , Rietschel Marcella , Maier Wolfgang , Albus Margot , Rappold Gudrun
Published: July 2004

The neurotransmitter serotonin (5‐hydroxytryptamine, 5‐HT) mediates a multitude of central nervous functions by activating 5‐HT receptor subtypes. A dysfunction of serotonergic neurotransmission is considered to play a major role in the pathophysiology of complex neuropsychiatric disorders. In our study, a mutation screen of the serotonin receptor geneHTR3Bwas carried out to explore a putative contribution to the etiology of bipolar affective disorder (BPAD) and schizophrenia (SZ). Screening of 49 patients suffering from BPAD, 78 patients with SZ and 62 control individuals revealed eleven sequence variations including a 3 bp deletion within the 5′UTR (5′ untranslated region), four exonic and five intronic SNPs as well as a point mutation in the 3′UTR ofHTR3B. Four of these sequence variations have not been described previously. Statistical computation rated most variants as probably non‐disease related polymorphisms. However, IVS6 + 31C > T, IVS6 + 40C > A, and 1386T > C were solely detected in bipolar affective patients and in none of the controls. Interestingly, we observed a significant underrepresentation of the 3 bp deletion −100_−102delAAG in an extended sample of 162 bipolar affected patients compared to controls (allele‐wise: 8% vs. 15%,P = 0.006, OR = 0.49, 95% CI: 0.3–0.82; genotype‐wise: 15,5% vs. 29,0%,P = 0.005, OR = 0.45, 95% CI: 0.26–0.77). We suggest that this deletion may influence translational efficiency, thereby possibly affecting the development of bipolar affective disease. © 2004 Wiley‐Liss, Inc.
Mapping genes of complex psychiatric diseases in Daghestan genetic isolates
Authors: Bulayeva Kazima B. , Leal Suzanne M. , Pavlova Tatiana A. , Kurbanov Ruslan M. , Glatt Stephen J. , Bulayev Oleg A. , Tsuang Ming T.
Published: July 2004

Genetic isolates, which provide outstanding opportunities for identification of susceptibility genes for complex diseases, can be classified as primary (having an ancient demographic history in a stable environment) or secondary (having a younger demographic history) Neel [1992: Minority populations: Genetics, demography, and health, pp. 1–13]. Daghestan contains 26 out of 50 indigenous Caucasus ethnicities that have been in existence for hundreds of generations in the same highland region. The ethnic groups are subdivided into numerous primary isolates. The founder effect and gene drift in these primary isolates may have caused aggregation of specific haplotypes with limited numbers of pathogenic alleles and loci in some isolates relative to others. These are expressed as inter‐population differences in lifetime prevalence and features of certain complex clinical phenotypes and in patterns of genetic linkage and linkage disequilibrium (LD). Stable highland and ethnic‐cultural environments have led to increased penetrance and a reduced number of phenocopies, which typically hamper the identification of any susceptibility genes for complex diseases. Owing to these characteristics of the primary isolates, a comparative linkage study in the primary isolates allows us to define the number of susceptibility genes for any complex disease and to identify the source of variability and non‐replication of linkage analysis results. As part of an ongoing study, seven extended schizophrenia and one nonspecific mental retardation kindreds have been ascertained from Daghestan isolates. Lifetime morbid risk for schizophrenia in the isolates varied from 0 to 5%. A genome scan with markers spaced 10 cM apart was carried out on these pedigrees and linkage analysis was performed using descent graph methods, as implemented in Simwalk2. To identify regions containing susceptibility genes within these kindreds, we followed up those regions with non‐parametric and parametric linkage analyses, with the choice of genetic model guided by the results obtained in the NPL. While the analyses are ongoing, the most positive findings were made in different isolated pedigrees on chromosomes 17p11, 3q24, and 22q for schizophrenia and on chromosome 12q for nonspecific mental retardation. © 2004 Wiley‐Liss, Inc.
Allelic and haplotypic association of GABRA2 with alcohol dependence
Authors: Covault Jonathan , Gelernter Joel , Hesselbrock Victor , Nellissery Maggie , Kranzler Henry R.
Published: July 2004

Alcohol dependence is a highly prevalent disorder that is associated with serious morbidity and mortality. Because the GABAA neurotransmitter receptor is an important mediator for several behavioral effects of alcohol, genes encoding GABA‐related proteins are functional candidates to influence risk of alcohol dependence. Two genome‐wide scans showed linkage of alcohol dependence to a region on chromosome 4p, which contains a cluster of genes encoding GABAA receptor subunits. A recent effort to fine map that region showed a haplotypic association of alcohol dependence to the gene encoding the GABAA receptor α‐2 subunit (GABRA2). We examined 10 single nucleotide polymorphisms (SNPs) spanning the coding region of this gene in samples of European American subjects with alcohol dependence (n = 446), and controls (n = 334) screened to exclude substance use disorders. There was evidence of association to alcohol dependence for seven adjacent markers spanning 98,000 bp in the middle and 3′‐portion of the GABRA2 gene (range of P‐values = 0.008–0.03). When the subset of the alcohol‐dependent subjects excluding those with a diagnosis of cocaine or opioid dependence or major depressive episode (n = 198) was examined, the strength of the association was increased across these 7 SNPs (range of P‐values = 0.002–0.007). Two common haplotypes in this region accounted for 90.8% of chromosomes. The more common haplotype was present in 55.6% of control group chromosomes versus 48.2% of alcohol‐dependent subjects (P = 0.007) and 45.8% of subjects with alcohol dependence but no co‐morbid drug dependence or depression (P = 0.003). These findings replicate and extend recently reported findings, which together underscore the potential contribution of polymorphic variation at the GABRA2 locus to the risk for alcohol dependence. © 2004 Wiley‐Liss, Inc.
Simple and complex genetics of colorectal cancer susceptibility
Authors: Baglioni Silvana , Genuardi Maurizio
Published: July 2004

There are several hereditary conditions associated with an increased risk of colorectal cancer (CRC). These include well‐characterized autosomal dominant syndromes, such as familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). A novel autosomal recessive form of FAP, caused by mutations in the base excision repair gene MYH, has recently been recognized. This discovery has provided further evidence for the importance of DNA repair mechanisms in CRC development, already documented by the involvement of the mismatch repair in HNPCC. Additional CRC‐predisposing conditions, such as hyperplastic polyposis and hereditary mixed polyposis syndrome, are being outlined. Heterogeneity of genetic mechanisms has important consequences for counseling and surveillance in hereditary CRC. Nevertheless, classical mendelian conditions represent only a minor share of the total CRC population burden. Alleles of the same genes that are involved in hereditary syndromes might also act as low penetrance variants, as shown for APC 1307K in the Ashkenazi. However, the level of complexity of multifactorial CRC is such that current tools appear inadequate to pinpoint all the involved components. A combination of different strategies, including careful clinical observation, analysis of homogeneous patient populations, and critical evaluation of data derived from experimental models, along with methodological improvements in nucleic acid analysis, will probably be necessary to unravel the basis of nonmendelian CRC. Once this is achieved, it will be possible to realize the ultimate goal of targeted CRC prevention, with the adoption of measures tailored according to individual risk levels. © 2004 Wiley‐Liss, Inc.
Inherited predisposition to cancer: A historical overview
Authors: Lynch Henry T. , Shaw Trudy G. , Lynch Jane F.
Published: July 2004

The hereditary predisposition to cancer dates historically to interest piqued by physicians as well as family members wherein striking phenotypic features were shown to cluster in families, inclusive of the rather grotesque cutaneous findings in von Recklinghausen's neurofibromatosis, which date back to the sixteenth century. The search for the role of primary genetic factors was heralded by studies at the infrahuman level, particularly on laboratory mouse strains with strong susceptibility to carcinogen‐induced cancer, and conversely, with resistance to the same carcinogens. These studies, developed in the 19th and 20th centuries, continue today. This article traces the historical aspects of hereditary cancer dealing with identification and ultimate molecular genetic confirmation of commonly occurring cancers, particularly of the colon in the case of familial adenomatous polyposis and its attenuated form, both due to the APC germline mutation; the Lynch syndrome due to mutations in mismatch repair genes, the most common of which were found to be MSH2, MLH1, and MSH6 germline mutations; the hereditary breast‐ovarian cancer syndrome with BRCA1 and BRCA2 germline mutations; the Li‐Fraumeni (SBLA) syndrome due to the p53 mutation; and the familial atypical multiple mole melanoma in association with pancreatic cancer due to the CDKN2A (p16) germline mutation. These and other hereditary cancer syndromes have been discussed in some detail relevant to their characterization, which, for many conditions, took place in the late 18th century and, in the more modern molecular genetic era, during the past two decades. Emphasis has been placed upon the manner in which improved cancer control will emanate from these discoveries. © 2004 Wiley‐Liss, Inc.
Unravelling the genetics of prostate cancer
Authors: Edwards Stephen M. , Eeles Rosalind A.
Published: July 2004

This review describes what is currently known about the genetics of prostate cancer. Traditionally, the genetics of a suspected inherited cancer predisposition have generally been thought of in terms of a single, high‐risk gene with a dominant mode of inheritance. Such a gene might be observed in families, as has been documented in familial breast cancer (BRCA1/2), familial colorectal cancer (HNPCC), retinoblastoma (RB1), and Wilms tumor (WT1). This review investigates the evidence for the existence, first of familial prostate cancer, and second, for the presence of such a high‐risk gene in those families by epidemiological and experimental approaches. Another current area of interest in prostate cancer is the investigation of the contribution of common lower penetrance genes to the disease. This alternative approach has become popular, as it raises the issue of frequently seen genetic variations such as single nucleotide polymorphisms (SNPs) having relevance to the risk of developing the disease. Finally, this article will explore the way forward, with emphasis on worldwide collaboration from teams attempting to find the genes responsible for the disease and investment in new technologies that will aid in their discovery. © 2004 Wiley‐Liss, Inc.
Developmental changes in the shape of the supralaryngeal vocal tract in chimpanzees
Authors: Nishimura Takeshi
Published: July 2004

The hyoid bone and larynx in human neonates are positioned as high as in other mammals. However, during postnatal life, they descend relative to the hard palate more rapidly compared with the horizontal growth of the oral cavity. This process is completed through the descent of the laryngeal skeleton relative to the hyoid, and through the descent of the hyoid relative to the cranial base. Thus, the human supralaryngeal vocal tract (SVT) develops to form a two‐tube configuration with equally long horizontal and vertical parts. Longitudinal studies on living chimpanzee infants show that the descent of the larynx is more rapid than the horizontal growth of the oral cavity. This is primarily attributed to the descent of their larynges relative to the hyoid bone, but this is not accompanied by the descent of the hyoid. The present study, using embalmed specimens of chimpanzees, also shows that the horizontal and vertical parts of the SVT grow in chimpanzees similarly to humans during infancy. However, in chimpanzees, the horizontal part of the SVT grows greatly, whereas the vertical part of the SVT grows only slightly during the juvenile period. As a result, the chimpanzee larynx does not descend rapidly relative to the oral elongation during that period. Such differences may be related to the structural and morphological development of the facial skeleton and mandible, which affects prognathism and hyoid descent. These results support the hypothesis that the descent of the larynx evolved in at least two steps during hominoid evolution. Am J Phys Anthropol 126:193–204, 2005. © 2004 Wiley‐Liss, Inc.
Correspondence between enamel hypoplasia and odontometric bilateral asymmetry in Australian twins
Authors: Corruccini Robert S. , Townsend Grant C. , Schwerdt Wendy
Published: July 2004

Four aspects of enamel hypoplasia of the maxillary central incisor and mandibular canine (hypoplasia presence, width, cumulative width, and crown position) were correlated with directional and fluctuating measures of bilateral odontometric asymmetry in a large panel (n = 950) of South Australian twins. Hypoplasia and asymmetry are thought to reflect general developmental disruption, but they show few correlations beyond the expected statistical type I error. This may relate to differences in their specific etiology, the composite nature of overall crown dimensions, a general lack of stress, and the extended period of formation of dental crowns. In contrast, asymmetry is marginally more detectable in a subsample separated according to hypoplastic teeth, suggesting that correspondence may be clearer in comparisons at the population rather than individual level. The most notable difference is the greater variability of asymmetry measures in hypoplastic individuals. Am J Phys Anthropol 126:177–182, 2005. © 2004 Wiley‐Liss, Inc.
Study of polyethylene solution fractionation and resulting fractional crystallization behavior
Authors: Kong Jie , Fan Xiaodong , Jia Mei
Published: July 2004

Solution fractionation for four different polyethylenes including high‐density polyethylene (HDPE), low‐density polyethylene (LDPE), linear low‐density polyethylene (LLDPE), and very low‐density polyethylene (VLDPE) are conducted by stepwise controlling both the temperature and the amount of precipitant. The size exclusion chromatograph (SEC) measurements indicate that solution fractionation technique can successfully separate all the polyethylene samples in accordance with their molecular weight and molecular‐weight distributions. In addition, infrared spectroscopy analysis shows that the degree of short‐chain branching for each fraction of each polyethylene varies with the fraction's molecular weight. The effect of the molecular weight with different short‐chain branching on each fraction's crystallinity represents the characteristics of chain components for different polyethylenes. The crystallinities of HDPE, LLDPE, and LDPE decrease with the increase in their molecular weights; however, for VLDPE, its crystallinity increases with the increase in the molecular weight. The research revealed that the degree of short‐chain branching, together with the molecular weight, can greatly affect the crystallinity of polyethylene. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 93: 2542–2549, 2004
Cementum‐like tissue deposition on the resorbed enamel surface of human deciduous teeth prior to shedding
Authors: Sahara Noriyuki , Ozawa Hidehiro
Published: July 2004

Prior to the shedding of human deciduous teeth, odontoclastic resorption takes place at the pulpal surface of the coronal dentin, and this resorption occasionally extends coronally from the dentinoenamel junction into the enamel. After the end of resorption, however, the resorbed enamel surface is repaired by the deposition of a cementum‐like tissue. Using this phenomenon as an observation model, in this study we examined the sequence of cellular and extracellular/matrix events involved in the enamel resorption repair by light and electron microscopy. As the odontoclast terminated its resorption activity, it detached from the resorbed enamel surface; thereafter, numerous mononuclear cells were observed along the resorbed enamel surface. Most of these mononuclear cells made close contact with the resorbed enamel surface, and coated pits or patches were observed on their plasma membrane facing this surface. Furthermore, they frequently contained thin needle‐ or plate‐like enamel crystals in their cytoplasmic vacuoles as well as secondary lysozomes. Following the disappearance of these monononuclear cells, the resorbed enamel surface now displayed a thin coat of organic matrix. Ultrastructurally, this organic layer was composed of a reticular and/or granular organic matrix, but contained no collagen fibrils. Energy‐dispersive X‐ray microanalysis of this thin organic layer in undecalcified sections revealed small spectral peaks of Ca and P. Cementum‐like tissue initially formed along this thin organic layer, increased in width, and appeared to undergo mineralization as time progressed. The results of our observations demonstrate that regardless of type of matrix of dental hard tissues, tooth repair may be coupled to tooth resorption, and suggest that mononuclear cells and an organic thin layer found on the previously resorbed enamel surface may play an important role in the repair process initiated after resorption of the enamel. © 2004 Wiley‐Liss, Inc.
Etanercept in Sjögren's syndrome: A twelve‐week randomized, double‐blind, placebo‐controlled pilot clinical trial
Authors: Sankar Vidya , Brennan Michael T. , Kok Marc R. , Leakan Rose Anne , Smith Janine A. , Manny Joan , Baum Bruce J. , Pillemer Stanley R.
Published: July 2004

Objective

To assess the safety and potential efficacy of etanercept in the treatment of Sjögren's syndrome (SS).

Methods

This pilot study was a 12‐week randomized, double‐blind, placebo‐controlled trial of etanercept, with 14 subjects in each group. Patients received 25 mg of etanercept or placebo (vehicle) by twice‐weekly subcutaneous injection. Patients met the American‐European Consensus Group criteria for SS. The primary outcome required at least 20% improvement from baseline values for at least 2 of the following 3 domains: subjective or objective measures of dry mouth, subjective or objective measures of dry eyes, and IgG level or erythrocyte sedimentation rate (ESR).

Results

Of the 14 patients taking etanercept, 11 had primary SS and 3 had SS secondary to rheumatoid arthritis. Baseline measures did not differ between the 2 groups. Three etanercept‐treated patients and 1 placebo‐treated patient did not complete the trial. Five etanercept‐treated patients and 3 placebo‐treated patients showed improvement from baseline in the primary outcome variable at 12 weeks, but the difference was not statistically significant. There were no significant differences between the groups for changes in subjective measures of oral or ocular symptoms (by visual analog scale), the IgG level, Schirmer I test result, van Bijsterveld score, or salivary flow. At 12 weeks, the ESR had decreased in the etanercept group compared with baseline (P = 0.004); however, the mean reduction was only 18.6%.

Conclusion

We found no evidence to suggest that treatment with etanercept at a dosage of 25 mg twice weekly for 12 weeks was clinically efficacious in SS. A larger trial will be necessary to definitively address the efficacy of etanercept in the treatment of SS.
Genetic studies in familial ankylosing spondylitis susceptibility
Authors: Zhang Ge , Luo Jingchun , Bruckel Jane , Weisman Michael A. , Schumacher H. Ralph , Khan Muhammad A. , Inman Robert D. , Mahowald Maren , Maksymowych Walter P. , Martin Tammy M. , Yu David T. Y. , Stone Millicent , Rosenbaum James T. , Newman Patricia , Lee Juwon , McClain Jo A. , West O. Clark , Jin Li , Reveille John D.
Published: July 2004

Objective

To define the genetic basis of susceptibility to ankylosing spondylitis (AS), especially non–major histocompatibility complex (MHC) genes.

Methods

The study group comprised 244 affected sibling pairs from 180 pedigrees of primarily European ancestry. Sibling pairs were concordant for AS by the modified New York criteria and had available sacroiliac radiographs. The subjects were genotyped for 400 markers in ABI PRISM linkage map MD‐10 and for 17 additional markers on chromosomes 6p, 6q, and 11q (including HLA–B, DRB1, DQA1, DQB1, and DPB1 alleles). Two‐point and multipoint nonparametric linkage (NPL) analyses were conducted using the NPL statistic and 1‐parameter allele‐sharing model logarithm of odds (LOD) scores, calculated using the Allele‐Sharing Model (ASM) computer program.

Results

Linkage of the MHC region was supported by both 2‐point and multipoint analyses, with the strongest peak (45.90 cM) in the MHC at the HLA–DRB1 locus (NPL score 8.720, ASM LOD score 20.49; P = 6.8 × 10−20 for 2‐point analysis). A second region was found to have positive linkage at the q arm of chromosome 6 (D6S441) in 2‐point analysis; this was supported by a 39.13‐cM region (135.58–174.71 cM) in multipoint analysis, with the smallest P value (4.2 × 10−3) at 166.39 cM. A third region was found on chromosome 11q, with the strongest evidence for linkage for D11S4094 at 123 cM (NPL score 2.235, ASM LOD score 1.939) and, on transmission disequilibrium test analysis, D11S4090 at 105.74 cM (P = 6.2 × 10−5). Linkage in this area was supported by multipoint analysis, spanning 22.19 cM continuously from 101.68 cM to 123.87 cM, with the strongest peak at 112.33 cM (P = 0.014); this was confirmed by subsequent fine mapping studies.

Conclusion

Thus, this genome‐wide scan implicates, in addition to the MHC, regions outside the MHC in AS susceptibility, especially on chromosomes 6q and 11q.
Diagnostic value of magnetic resonance imaging of the forefeet in early rheumatoid arthritis when findings on imaging of the metacarpophalangeal joints of the hands remain normal
Authors: Ostendorf Benedikt , Scherer Axel , Mödder Ulrich , Schneider Matthias
Published: July 2004

Objective

To investigate the diagnostic role of magnetic resonance imaging (MRI) of the forefeet in patients with early rheumatoid arthritis (RA) in whom findings on MR images of the hands are normal and conventional radiographs of the hands and feet do not show erosions.

Methods

The study group comprised 25 patients with early RA (disease duration of <12 months) in whom erosions were not demonstrated on conventional radiographs of the hands and feet. These patients underwent MRI of the clinically dominant hand to detect signs of arthritis. If results of MRI of the hand were normal according to the Outcome Measures in Rheumatology Clinical Trials (OMERACT) RA‐MRI scoring system (RAMRIS), MRI of the dominant forefoot was performed. The MRI protocol comprised coronal and sagittal T1‐weighted spin‐echo (before and after administration of contrast medium), coronal fat‐suppressed short tau inversion recovery sequences, coronal and sagittal T2‐weighted turbo spin‐echo sequences, and axial fat‐suppressed T1‐weighted spin‐echo sequences after administration of contrast medium. MRI of the forefeet was analyzed on the basis of a modified RAMRIS.

Results

MRI revealed pathologic findings in the hands of 15 of 25 patients (edema in 9 patients, synovitis in 12, erosions in 6, defects in 3). In 10 patients with a mean disease duration of 9.4 weeks, hand MRI scans were normal according to RAMRIS. Four of these 10 patients had tenosynovitis of the finger flexor tendons (there was no OMERACT criterion for tenosynovitis). RAMRIS analysis of the corresponding MRI scans of the forefeet of these patients revealed signs of edema in 7 patients, synovitis in all 10 patients (at the third metatarsophalangeal [MTP] joint in 7, at the fourth MTP joint in 6, at the first MTP joint in 4, and at the fifth MTP joint in 2 patients), tenosynovitis of the foot flexor tendons in 2 patients, erosions at the second and third MTP joints in 1 patient, and a single defect at the first MTP joint in 1 patient.

Conclusion

RAMRIS analysis of MRI scans of the forefeet detected synovitis and bone edema in patients with early RA in whom MRI of the finger joints was normal. MRI of the forefeet contributes an additional tool aimed at earlier and more accurate diagnosis and thus might allow an earlier decision to start appropriate medication in patients with early RA.
Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis
Authors: Van Gaalen Floris A. , Van Aken Jill , Huizinga Tom W. J. , Schreuder Geziena M. Th. , Breedveld Ferdinand C. , Zanelli Eric , Van Venrooij Walther J. , Verweij Cornelis L. , Toes René E. M. , De Vries René R. P.
Published: July 2004

Objective

The functional role of HLA class II molecules in the pathogenesis of rheumatoid arthritis (RA) is unclear. HLA class II molecules are involved in the interaction between T and B lymphocytes required for long‐lived B cell responses and generation of high‐affinity IgG antibodies. We undertook this study to investigate the relationship between HLA class II gene polymorphisms and RA‐specific IgG antibodies against cyclic citrullinated peptides (anti‐CCP antibodies).

Methods

High‐resolution HLA–DR and DQ typing and anti–CCP‐2 antibody testing were performed on 268 RA patients from the Early Arthritis Clinic cohort at the Department of Rheumatology of the Leiden University Medical Center. The presence of anti‐CCP antibodies was analyzed in carriers of the different DR and DQ alleles. Disease progression was measured over a period of 4 years by scoring radiographs of the hands and feet using the Sharp/van der Heijde method.

Results

Carriership of the individual alleles HLA–DRB1*0401, DRB1*1001, DQB1*0302, and DQB1*0501 was associated with the presence of anti‐CCP antibodies. Carriers of DQ–DR genotypes containing proposed RA susceptibility alleles were significantly more often anti‐CCP antibody positive. Carriership of one or two HLA–DRB1 shared epitope (SE) alleles was significantly associated with production of anti‐CCP antibodies (odds ratio [OR] 3.3, 95% confidence interval [95% CI] 1.8–6.0 and OR 13.3, 95% CI 4.6–40.4, respectively). An increased rate of joint destruction was observed in SE+, anti‐CCP+ patients (mean Sharp score 7.6 points per year) compared with that in SE−, anti‐CCP+ patients (2.4 points per year) (P = 0.04), SE+, anti‐CCP− patients (1.6 points per year) (P < 0.001), and SE−, anti‐CCP− patients (1.6 points per year) (P < 0.001).

Conclusion

HLA class II RA susceptibility alleles are associated with production of anti‐CCP antibodies. Moreover, more severe disease progression is found in RA patients with both anti‐CCP antibodies and SE alleles.
Ultrasonography of the metatarsophalangeal joints in rheumatoid arthritis: Comparison with magnetic resonance imaging, conventional radiography, and clinical examination
Authors: Szkudlarek Marcin , Narvestad Eva , Klarlund Mette , Court‐Payen Michel , Thomsen Henrik S. , Østergaard Mikkel
Published: July 2004

Objective

To compare ultrasonography (US) with magnetic resonance imaging (MRI), conventional radiography, and clinical examination in the evaluation of bone destruction and signs of inflammation in the metatarsophalangeal (MTP) joints of patients with rheumatoid arthritis (RA).

Methods

Two hundred MTP joints of 40 patients with RA and 100 MTP joints of 20 healthy control subjects were assessed with B‐mode US, contrast‐enhanced MRI, conventional radiography, and clinical examination for signs of bone destruction and joint inflammation.

Results

With MRI considered the reference method, the sensitivity, specificity, and accuracy of US for the detection of bone erosions were 0.79, 0.97, and 0.96, respectively, while the corresponding values for radiography were 0.32, 0.98, and 0.93. The sensitivity, specificity, and accuracy of US for the detection of synovitis were 0.87, 0.74, and 0.79, while for clinical examination, the corresponding values were 0.43, 0.89, and 0.71. Erosive disease was identified in 26 patients by US, compared with 20 patients by MRI and 11 patients by radiography. Evaluation by US indicated signs of inflammation in 36 patients, while MRI and clinical examination revealed signs of inflammation in 31 patients and 20 patients, respectively. US and MRI volume‐based gradings of synovitis showed intraclass correlation coefficients of 0.56–0.72 (P < 0.0001). The MRI and radiographic visualizations of US‐detected bone changes were closely related to their size‐based gradings on US.

Conclusion

US enables detection and grading of destructive and inflammatory changes in the MTP joints of patients with RA. By comparison with MRI, US was found to be markedly more sensitive and accurate than clinical examination and conventional radiography. Considering the early and frequent involvement of the MTP joints, evaluation of these joints by US may be of major clinical importance in RA.
Involvement of chemokines and Th1 cytokines in the pathogenesis of mucocutaneous lesions of Behçet's disease
Authors: Ben Ahmed M. , Houman H. , Miled M. , Dellagi K. , Louzir H.
Published: July 2004

Objective

To investigate a possible pathogenic role of cytokines in Behçet's disease (BD) by focusing on the analysis of cytokine gene expression within mucocutaneous BD lesions.

Methods

The study group comprised 20 patients with active BD. In this group, a set of chemokines as well as Th1 and Th2 cytokines in biopsy specimens obtained from oral and genital ulcers, pseudofolliculitis lesions, and lesions at the site of pathergy testing were studied using real‐time quantitative reverse transcriptase–polymerase chain reaction.

Results

We observed important increases in the expression of interleukin‐8 (IL‐8) (∼700‐fold), monocyte chemoattractant protein 1 (∼65‐fold), interferon‐γ (∼71‐fold), and IL‐12 (∼69‐fold) messenger RNA in BD lesions compared with normal skin. Except for IL‐10 (∼75‐fold increase), Th2 cytokines (i.e., IL‐4 and IL‐13) were absent.

Conclusion

Our data suggest a direct role of Th1 lymphocytes in the pathogenesis of mucocutaneous BD lesions.
Etanercept treatment of psoriatic arthritis: Safety, efficacy, and effect on disease progression
Authors: Mease Philip J. , Kivitz Alan J. , Burch Francis X. , Siegel Evan L. , Cohen Stanley B. , Ory Peter , Salonen David , Rubenstein Joel , Sharp John T. , Tsuji Wayne
Published: July 2004

Objective

Etanercept has been shown to improve the articular and cutaneous manifestations of psoriatic arthritis (PsA). In this study, we further evaluated the safety, efficacy, and effect on radiographic progression of etanercept in patients with PsA.

Methods

Patients with PsA (n = 205) were randomized to receive placebo or 25 mg etanercept subcutaneously twice weekly for 24 weeks. Patients continued to receive blind‐labeled therapy in a maintenance phase until all had completed the 24‐week phase, then could receive open‐label etanercept in a 48‐week extension. Efficacy and safety were evaluated at 4, 12, and 24 weeks and at 12‐week intervals thereafter. Radiographs of the hands and wrists were assessed at baseline and 24 weeks, at entry to the open‐label phase, and after 48 weeks in the study.

Results

Etanercept significantly reduced the signs and symptoms of PsA and psoriasis. At 12 weeks, 59% of etanercept patients met the American College of Rheumatology 20% improvement criteria for joint response, compared with 15% of placebo patients (P < 0.0001), and results were sustained at 24 and 48 weeks. At 24 weeks, 23% of etanercept patients eligible for psoriasis evaluation achieved at least 75% improvement in the Psoriasis Area and Severity Index, compared with 3% of placebo patients (P = 0.001). Radiographic disease progression was inhibited in the etanercept group at 12 months; the mean annualized rate of change in the modified total Sharp score was −0.03 unit, compared with +1.00 unit in the placebo group (P = 0.0001). Etanercept was well tolerated.

Conclusion

Etanercept reduced joint symptoms, improved psoriatic lesions, inhibited radiographic progression, and was well tolerated in patients with PsA.
Outer surface lipoproteins ofBorrelia burgdorferivary in their ability to induce experimental joint injury
Authors: Batsford Stephen , Dunn John , Mihatsch Michael
Published: July 2004

Objective

To examine the ability of bacterial lipoproteins from the spirocheteBorrelia burgdorferito cause in vivo tissue injury (arthritis).

Methods

Outer surface proteins (OSPs) fromB burgdorferiwere used in a rat model of antigen‐induced allergic arthritis. Intraarticular challenge with recombinant OspA, OspB, and OspC in nonlipidated (peptide) and lipidated forms was performed in the left knee joint; the contralateral joint received buffer as control. Inflammation was monitored by technetium scintigraphy and histology.

Results

Nonlipidated (peptide) OspA, OspB, and OspC did not induce arthritis; the only exception was polymerized OspA, which was tested in preimmunized rats. Lipidated OspA from 2 different strains and lipidated OspC induced severe arthritis, whereas lipidated OspB failed to induce injury. A synthetic analog of the OSP lipid modification, lipopeptide Pam3Cys‐Ser‐Lys4‐OH, either alone or coupled to bovine serum albumin, also failed to induce injury. Injury did not develop in control groups that were given the appropriate buffers or lipopolysaccharide. This showed that lipidated borrelial OSPs can be potent arthritogens but vary greatly with respect to their injury‐inducing potential. The possession of a lipid modification is essential but is not sufficient to render an OSP arthritogenic.

Conclusion

This is the first study to demonstrate that individual lipoproteins fromB burgdorferican induce experimental joint injury in vivo. These results may help elucidate the pathogenesis of Lyme arthritis and, above all, underline the importance of bacterial lipoproteins as major virulence factors.
Amplification of the synovial inflammatory response through activation of mitogen‐activated protein kinases and nuclear factor κB using ligation of CD40 on CD14+ synovial cells from patients with rheumatoid arthritis
Authors: Harigai Masayoshi , Hara Masako , Kawamoto Manabu , Kawaguchi Yasushi , Sugiura Tomoko , Tanaka Michi , Nakagawa Miki , Ichida Hisae , Takagi Kae , Higami‐Ohsako Satomi , Shimada Katsuhiko , Kamatani Naoyuki
Published: July 2004

Objective

To determine the signal transduction pathways in CD14+ synovial cells from patients with rheumatoid arthritis (RA) after CD40 ligation, and to examine their role in amplifying synovial inflammation in affected joints.

Methods

Expression of messenger RNA was analyzed using quantitative reverse transcription–polymerase chain reaction. Cytokines and chemokines were measured using enzyme‐linked immunosorbent assay. Activation of kinases was detected using Western blotting. Nuclear translocation of NF‐κB was examined using immunohistochemistry. CD14+ synovial cells were enriched using magnetic cell sorting. Fibroblast‐like synoviocytes (FLS) were obtained by passaging primary synovial cell culture.

Results

Stimulation of CD14+ synovial cells from RA patients by recombinant soluble CD154 (rsCD154) significantly induced expression of tumor necrosis factor α (TNFα), interleukin‐1α (IL‐1α), and IL‐1β. CD14+ RA synovial cells stimulated with rsCD154 plus interferon‐γ (IFNγ) induced significantly higher production of IL‐6, IL‐8, and monocyte chemoattractant protein 1 by FLS compared with unstimulated CD14+ synovial cells, through TNFα‐, IL‐1α−, and IL‐1β–mediated pathways. Stimulation with rsCD154 plus IFNγ induced the activation of ERK‐1/2, p38 MAPK, and NF‐κB. Specific inhibitors of MAPK/ERK‐1/2 kinases and p38 MAPK significantly reduced the production of TNFα and IL‐1β by rsCD154 plus IFNγ–stimulated CD14+ synovial cells, and also inhibited production of these cytokines by freshly isolated synovial cells from RA patients.

Conclusion

These data indicate that the CD40–CD154 interaction activates the ERK, p38, and NF‐κB pathways in CD14+ synovial cells from RA patients to produce TNFα, IL‐1α, and IL‐1β, which in turn amplifies inflammatory responses by stimulating FLS. Inhibition of the CD40–CD154 interaction or its signal transduction pathways would be a strong and efficient strategy for the management of synovial inflammation in RA.
Association of the CT60 marker of the CTLA4 gene with systemic lupus erythematosus
Authors: Torres Belén , Aguilar Francisco , Franco Ernesto , Sánchez Elena , Sánchez‐Román Julio , Alonso Juan Jiménez , Núñez‐Roldán Antonio , Martín Javier , Francisca González‐Escribano María
Published: July 2004

Objective

To investigate the possible association of the CT60A/G marker with systemic lupus erythematosus (SLE) in Spanish patients, and to identify the possible CTLA4 haplotype responsible for the association, taking into account other polymorphisms described at positions −1722T/C, −319C/T, +49A/G, and the microsatellite (AT)n in the 3′‐untranslated region (3′‐UTR) of the CTLA4 gene.

Methods

Genotyping of CT60 was performed in 395 patients with SLE and 293 healthy controls using polymerase chain reaction (PCR)–restriction fragment length polymorphism analysis. Genotyping of the rest of the dimorphisms has been previously reported. Genotyping of microsatellite polymorphism (AT)n in the 3′‐UTR was performed using PCR with a fluorescence‐labeled primer.

Results

With regard to CT60A/G, the frequency of the AA genotype was significantly decreased among the SLE patients (18.7% versus 28.3% in the control group; P = 0.003, corrected P [Pcorr] = 0.009, odds ratio [OR] = 0.58, 95% confidence interval [95% CI] 0.40–0.85). In other words, the frequency of individuals bearing the G phenotype was increased in the patient group compared with the control group (81.2% versus 71.7%; P = 0.003, Pcorr = 0.006, OR = 1.71, 95% CI 1.18–2.49). The distribution of allele frequency was also significantly different between patients and controls (P = 0.01, Pcorr = 0.02, OR [for allele G] = 1.32, 95% CI 1.06–1.65). After combining the data on the different polymorphisms, 2 neutral haplotypes were found: +49A;(AT)7;CT60A and +49G;(AT)8–19;CT60G. In addition, a susceptibility haplotype was found: +49A;(AT)>19;CT60G.

Conclusion

The 3′‐UTR of the CTLA4 gene is involved in susceptibility to SLE.
Varus–valgus alignment in the progression of patellofemoral osteoarthritis
Authors: Cahue September , Dunlop Dorothy , Hayes Karen , Song Jing , Torres Leah , Sharma Leena
Published: July 2004

Objective

To test the hypotheses that lateral patellofemoral (PF) osteoarthritis (OA) progression is more common than medial PF OA progression, that varus alignment increases the likelihood of medial PF OA progression, and that valgus alignment increases the likelihood of lateral PF OA progression.

Methods

Patients with knee OA were recruited from the community. Inclusion criteria were definite osteophyte presence (i.e., Kellgren/Lawrence radiographic grade ≥2) in 1 or both knees and at least some difficulty with knee‐requiring activity. Varus–valgus alignment (the angle formed by the intersection of the mechanical axes of the femur and tibia) was measured on a full‐limb radiograph at baseline. To assess PF OA progression, weight‐bearing skyline views of the PF compartment were obtained at baseline and at 18‐month followup. Knees with the highest grade of PF narrowing at baseline were excluded from analysis. Logistic regression and generalized estimating equations were used; odds ratios (ORs) were adjusted for age, sex, and body mass index.

Results

Lateral PF OA progression, which occurred in 120 (30%) of 397 knees, was more common than was medial PF OA progression, which occurred in 60 knees (15%). Varus (versus nonvarus) alignment increased the odds of PF OA progression isolated to the medial PF compartment (adjusted OR 1.85, 95% confidence interval [95% CI] 1.00–3.44). Valgus alignment increased the odds of PF OA progression isolated to the lateral compartment (adjusted OR 1.64, 95% CI 1.01–2.66).

Conclusion

Lateral PF OA progression was more common than medial progression, and varus–valgus alignment influenced the likelihood of PF OA progression in a compartment‐specific manner. Interventions that address the stress imposed by alignment on the PF compartments may delay PF OA progression and should be developed.
International consensus on preliminary definitions of improvement in adult and juvenile myositis
Authors: Rider Lisa G. , Giannini Edward H. , Brunner Hermine I. , Ruperto Nicola , James‐Newton Laura , Reed Ann M. , Lachenbruch Peter A. , Miller Frederick W.
Published: July 2004

Objective

To use a core set of outcome measures to develop preliminary definitions of improvement for adult and juvenile myositis as composite end points for therapeutic trials.

Methods

Twenty‐nine experts in the assessment of myositis achieved consensus on 102 adult and 102 juvenile paper patient profiles as clinically improved or not improved. Two hundred twenty‐seven candidate definitions of improvement were developed using the experts' consensus ratings as a gold standard and their judgment of clinically meaningful change in the core set of measures. Seventeen additional candidate definitions of improvement were developed from classification and regression tree analysis, a data‐mining decision tree tool analysis. Six candidate definitions specifying percentage change or raw change in the core set of measures were developed using logistic regression analysis. Adult and pediatric working groups ranked the 13 top‐performing candidate definitions for face validity, clinical sensibility, and ease of use, in which the sensitivity and specificity were ≥75% in adult, pediatric, and combined data sets. Nominal group technique was used to facilitate consensus formation.

Results

The definition of improvement (common to the adult and pediatric working groups) that ranked highest was 3 of any 6 of the core set measures improved by ≥20%, with no more than 2 worse by ≥25% (which could not include manual muscle testing to assess strength). Five and 4 additional preliminary definitions of improvement for adult and juvenile myositis, respectively, were also developed, with several definitions common to both groups. Participants also agreed to prospectively test 6 logistic regression definitions of improvement in clinical trials.

Conclusion

Consensus preliminary definitions of improvement were developed for adult and juvenile myositis, and these incorporate clinically meaningful change in all myositis core set measures in a composite end point. These definitions require prospective validation, but they are now proposed for use as end points in all myositis trials.
Retardation of joint damage in patients with early rheumatoid arthritis by initial aggressive treatment with disease‐modifying antirheumatic drugs: Five‐year experience from the FIN‐RACo study
Authors: Korpela Markku , Laasonen Leena , Hannonen Pekka , Kautiainen Hannu , Leirisalo‐Repo Marjatta , Hakala Markku , Paimela Leena , Blåfield Harri , Puolakka Kari , Möttönen Timo
Published: July 2004

Objective

To evaluate the long‐term frequency of disease remissions and the progression of joint damage in patients with early rheumatoid arthritis (RA) who were initially randomized to 2 years of treatment with either a combination of 3 disease‐modifying antirheumatic drugs (DMARDs) or a single DMARD.

Methods

In this multicenter prospective followup study, a cohort of 195 patients with early, clinically active RA was randomly assigned to treatment with a combination of methotrexate, sulfasalazine, hydroxychloroquine, and prednisolone or with a single DMARD (initially, sulfasalazine) with or without prednisolone. After 2 years, the DMARD and prednisolone treatments became unrestricted, but were still targeted toward remission. The long‐term effectiveness was assessed by recording the frequency of remissions and the extent of joint damage seen on radiographs of the hands and feet obtained annually up to 5 years. Radiographs were assessed by the Larsen score.

Results

A total of 160 patients (78 in the combination group and 82 in the single group) completed the 5‐year extension study. At 2 years, 40% of the patients in the combination‐DMARD group and 18% in the single‐DMARD group had achieved remission (P < 0.009). At 5 years, the corresponding percentages were 28% and 22% (P not significant). The median Larsen radiologic damage scores at baseline, 2 years, and 5 years in the combination‐DMARD and single‐DMARD groups were 0 and 2 (P = 0.50), 4 and 12 (P = 0.005), and 11 and 24 (P = 0.001), respectively.

Conclusion

Aggressive initial treatment of early RA with the combination of 3 DMARDs for the first 2 years limits the peripheral joint damage for at least 5 years. Our results confirm the earlier concept that triple therapy with combinations of DMARDs contributes to an improved long‐term radiologic outcome in patients with early and clinically active RA.
Expression and function of RANK in human monocyte chemotaxis
Authors: Mosheimer Birgit A. , Kaneider Nicole C. , Feistritzer Clemes , Sturn Daniel H. , Wiedermann Christian J.
Published: July 2004

Objective

RANKL, a member of the tumor necrosis factor superfamily, is a central regulator of osteoclast recruitment and activation. Whether RANKL affects monocyte locomotion in vitro via RANK and a possible signaling pathway were investigated.

Methods

Monocytes were obtained from venous blood of healthy donors. Cell migration was studied by micropore filter assays. The signaling mechanisms required for RANKL‐dependent migration were tested using signaling enzyme blockers and Western blot analyses. Expression of RANK messenger RNA (mRNA) in monocytes was demonstrated by reverse transcriptase–polymerase chain reaction, and receptor expression on cell surface was investigated by fluorescence‐activated cell sorting analyses.

Results

RANKL significantly stimulated monocyte chemotaxis via activation of phosphatidylinositol 3‐kinase, phosphodiesterase, and Src kinase. The effect on migration was inhibited by osteoprotegerin, which is the decoy receptor for RANKL. Expression of RANK receptor mRNA was shown, and synthesis of RANK in monocytes was suggested by the detection of RANK immunoreactivity on the cell surface.

Conclusion

These data suggest that RANK is expressed by monocytes whose activation by RANKL stimulates directed migration involving phosphatidylinositol 3‐kinase, phosphodiesterase, and Src kinases.