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ID PMID Title PublicationDate abstract
20191588 Juvenile idiopathic arthritis and HLA class I and class II interactions and age-at-onset e 2010 Jun OBJECTIVE: The aim of this study was to quantitate risk and to examine heterogeneity for HLA at high resolution in patients with the most common subtypes of juvenile idiopathic arthritis (JIA), IgM rheumatoid factor-negative polyarticular JIA and oligoarticular JIA. Use of 4-digit comprehensive HLA typing enabled great precision, and a large cohort allowed for consideration of both age at disease onset and disease subtype. METHODS: Polymerase chain reaction-based high-resolution HLA typing for class I and class II loci was accomplished for 820 patients with JIA and 273 control subjects. Specific HLA epitopes, potential interactions of alleles at specific loci and between loci (accounting for linkage disequilibrium and haplotypic associations), and an assessment of the current International League of Associations for Rheumatology classification criteria were considered. RESULTS: An HLA-DRB1/DQB1 effect was shown to be exclusively attributable to DRB1 and was similar between patients with oligoarticular JIA and a younger subgroup of patients with polyarticular JIA. Furthermore, patients with polyarticular JIA showed age-specific related effects, with disease susceptibility in the group older than age 6 years limited to an effect of the HLA-DRB1*08 haplotype, which is markedly different from the additional susceptibility haplotypes, HLA-DRB1*1103/1104, found in the group with oligoarticular JIA and the group of younger patients with polyarticular JIA. Also in contrast to findings for oligoarticular JIA, patients with polyarticular arthritis had no evidence of an HLA class I effect. Markers associated with a reduced risk of disease included DRB1*1501, DRB1*0401, and DRB1*0701. DRB1*1501 was shown to reduce risk across the whole cohort, whereas DRB1*0401 and DRB1*0701 were protective for selected JIA subtypes. Surprisingly, the disease predisposition mediated by DPB1*0201 in individuals without any disease-predisposing DRB1 alleles was great enough to overcome even the very strong protective effect observed for DRB1*1501. CONCLUSION: Inherited HLA factors in JIA show similarities overall as well as differences between JIA subtypes.
21314616 Novel mutants of human tumor necrosis factor with dominant-negative properties. 2010 Dec Tumor necrosis factor (TNF) is a polyfunctional cytokine, one of the key mediators of inflammation and innate immunity. On the other hand, systemic or local TNF overexpression is typical of such pathological states as rheumatoid arthritis, psoriasis, Crohn's disease, septic shock, and multiple sclerosis. Neutralization of TNF activity has a marked curative effect for some diseases; therefore, the search for various TNF blockers is a promising field of protein engineering and biotechnology. According to the previously developed concept concerning the possibility of designing dominant-negative mutants, the following TNF variants have been studied: TNFY87H + A145R, TNFY87H + A96S + A145R, and TNFV91N + A145R. All of these form inactive TNF heterotrimers with the native protein. The ability of mutants to neutralize the effect of TNF was investigated. The addition of mutants to the native protein was shown to provide a concentration-dependent suppression of TNF cytotoxicity against the mouse fibroblast cell line L929. Thus, novel inhibitors of human TNF can be engineered on the basis of these muteins.
21193642 Interstitial lung diseases after leflunomide use in nephropathy: an analysis of reported c 2011 Apr BACKGROUND: Leflunomide (LEF)-induced interstitial lung disease (ILD) has been reported in patients with rheumatoid arthritis. In China, LEF is used off-label for the treatment of nephropathy. METHODS: Systemic review of the Chinese literature from 1999 to June 2010 for case reports and case series of LEF-induced ILD in nephropathy patients. RESULTS: We identified seven cases of LEF-induced ILD (three males and four females), with an average age of 45.9 years (range: 9-69 years). Six cases had primary nephrotic syndrome and one had Henoch-Schoenlein purpura. Four cases had diagnoses of renal pathology. Five patients were given loading doses of LEF, followed by a maintenance dose of 10-30 mg/day. The mean duration of LEF use was 62.9 ± 33.0 days (range: 20-120 days). The mean accumulated dose of LEF was 1192.5 mg (range: 830-1800 mg). LEF therapy was considered effective in four patients. Four patients died (57.1%), three of whom had developed fevers. All three male patients died and both of the young patients died. The mean duration of LEF treatment was 83 days for patients who died and 37 days for survivors. CONCLUSIONS: LEF-induced ILD in patients with nephropathy usually occurred after ∼2 months of treatment and an accumulated dose of 1192.5 mg. Duration of LEF use, male sex, young age and fever seemed to increase the risk of mortality.
21124072 Monoclonal antibody therapy in multiple sclerosis: Paradigm shifts and emerging challenges 2010 Nov Therapeutic approaches to multiple sclerosis (MS) are based on altering the functions of the immune system, either by using broad immunosuppressive drugs used for transplantation rejection and rheumatology, or by modulating them more discreetly with beta interferon and synthetic amino-acid copolymers. These strategies are only partially successful, have important safety and tolerability limitations, and have shown to be mostly effective in earlier stages of the disease, in which acute relapses dominate the clinical picture. For progressive phenotypes of MS there are currently no effective therapeutic options. As very specific and potent immunosuppressive agents, monoclonal antibodies (mAbs) may offer considerable advantages over other therapies for MS. During the last decade, anti-a4 integrin natalizumab became the first approved mAb for treatment of relapsing MS, after convincingly demonstrating clinically significant effects on two large Phase 3 trials. Moreover, the concept of disease remission was introduced for the first time, to describe patients that show no signs of clinical or imaging markers of disease activity during therapy with natalizumab. Of the mAbs under development for MS, alemtuzumab and rituximab have also shown promising evidence of effectiveness, and potentially expanded the therapeutic horizon to reversal of disease progression in early relapsing patients, and progressive patients who previously had not been studied. However, the appearance of progressive multifocal leukoencephalopathy (PML) in natalizumab-treated MS patients, as well as in patients with lymphoma, lupus and rheumatoid arthritis treated with rituximab, and autoimmune-type complications in alemtuzumab-treated MS patients underlines the fact that extended efficacy comes with significant clinical risks. The challenge is then how best to utilize therapies that have evidently superior efficacy in a chronic disease of young adults, to obtain the best benefit-risk ratio, and how to monitor and prevent emergent safety concerns.
21110879 The association between hip fracture and hip osteoarthritis: a case-control study. 2010 Nov 26 BACKGROUND: There have been reports both supporting and refuting an inverse relationship between hip fracture and hip osteoarthritis (OA). We explore this relationship using a case-control study design. METHODS: Exclusion criteria were previous hip fracture (same side or contralateral side), age younger than 60 years, foreign nationality, pathological fracture, rheumatoid arthritis and cases were radiographic examinations were not found in the archives. We studied all subjects with hip fracture that remained after the exclusion process that were treated at Akureyri University Hospital, Iceland 1990-2008, n = 562 (74% women). Hip fracture cases were compared with a cohort of subjects with colon radiographs, n = 803 (54% women) to determine expected population prevalence of hip OA. Presence of radiographic hip OA was defined as a minimum joint space of 2.5 mm or less on an anteroposterior radiograph, or Kellgren and Lawrence grade 2 or higher. Possible causes of secondary osteoporosis were identified by review of medical records. RESULTS: The age-adjusted odds ratio (OR) for subjects with hip fracture having radiographic hip OA was 0.30 (95% confidence interval [95% CI] 0.12-0.74) for men and 0.33 (95% CI 0.19-0.58) for women, compared to controls. The probability for subjects with hip fracture and hip OA having a secondary cause of osteoporosis was three times higher than for subjects with hip fracture without hip OA. CONCLUSION: The results of our study support an inverse relationship between hip fractures and hip OA.
21067953 Vitamin D and inflammation. 2010 Dec Calcitriol, or 1,25-dihydroxyvitamin D3 (1,25(OH)(2)D3) is a well-known endocrine regulator of calcium homeostasis. More recently, local calcitriol production by immune cells was shown to exert autocrine or paracrine immunomodulating effects. Immune cells that produce calcitriol also express the vitamin D receptor (VDR) and the enzymes needed to metabolize vitamin D3 (1α-, 25-, and 24-hydroxylases). Studies of animal models and cell cultures showed both direct and indirect immunomodulating effects involving the T cells, B cells, and antigen-presenting cells (dendritic cells and macrophages) and affecting both innate and adaptive immune responses. The overall effect is a switch from the Th1/Th17 response to the Th2/Treg profile. The immunomodulating effects of vitamin D may explain the reported epidemiological associations between vitamin D status and a large number of autoimmune and inflammatory diseases. Such associations have been suggested by observational studies not only in rheumatoid arthritis, lupus, inflammatory bowel disease, and type 1 diabetes; but also in infections, malignancies, transplant rejection, and cardiovascular disease. In animal models for these diseases, vitamin D supplementation has been found to produce therapeutic effects. Thus, vitamin D is a key focus for public health efforts and may hold promise for the treatment of dysimmune diseases.
20962430 Cyclophilin A: promising new target in cardiovascular therapy. 2010 Nov Cyclophilin A (CyPA) has been studied as a multifunctional protein that is upregulated in a variety of inflammatory conditions, such as rheumatoid arthritis, autoimmune disease, and cancer. CyPA has been classified as an immunophilin and has a variety of intracellular functions, including intracellular signaling, protein trafficking, and the regulation of other proteins activity. Besides its intracellular functions, CyPA is a secreted molecule that has a physiological and pathological role in cardiovascular diseases, making it a potential biomarker and mediator in cardiovascular diseases, such as vascular stenosis, atherosclerosis, and abdominal aortic aneurysms.
20889595 Increased risk of autoimmune disease in families with Wegener's granulomatosis. 2010 Dec OBJECTIVE: The etiology of Wegener's granulomatosis (WG) is unknown. Susceptibility genes for WG that also affect the risks of other autoimmune/inflammatory diseases have been identified, indicating the existence of shared interdisease genetic susceptibilities. To determine the effect, on a population level, of shared susceptibility on disease risk, we assessed the occurrence of autoimmune/inflammatory disease in first-degree relatives of patients with WG. METHODS: In the Swedish Hospital Discharge Register we identified 2288 individuals discharged with the diagnosis of WG between 1970 and 2003. Through linkage to the Swedish Multi-generation Register we identified 787 parents, 1212 siblings, and 3650 children of these patients. From the Register of Total Population we identified 10 controls for each patient with WG, and 65,000 of their first-degree relatives. Through linkage to the nationwide Outpatients Register, we identified autoimmune/inflammatory disease among all relatives. Relative risks were estimated as hazard ratio (HR) using Cox regression. The study period was 2001-2006. RESULTS: Biological first-degree relatives of patients with WG were at a moderately increased risk of any autoimmune/inflammatory disease (HR 1.32, 95% CI 1.18-1.49), including specific associations with, for example, multiple sclerosis (HR 1.92, 95% CI 1.16-3.16), Sjögren's syndrome (HR 2.00, 95% CI 1.07-3.73), and seropositive rheumatoid arthritis (HR 1.54, 95% CI 1.09-2.19). CONCLUSION: Relatives of patients with WG are at increased risk of being diagnosed with other autoimmune/inflammatory diseases, indicating shared susceptibility between WG and other auto-immune/inflammatory disease.
20550597 Do patient experiences on priority aspects of health care predict their global rating of q 2010 Sep BACKGROUND: Patient-given global ratings are frequently interpreted as summary measures of the patient perspective, with limited understanding of what these ratings summarize. Global ratings may be determined by patient experiences on priority aspects of care. OBJECTIVES: (i) identify patient priorities regarding elements of care for breast cancer, hip- or knee surgery, cataract surgery, rheumatoid arthritis and diabetes, (ii) establish whether experiences regarding priorities are associated with patient-given global ratings, and (iii) determine whether patient experiences regarding priorities are better predictors of global ratings than experiences concerning less important aspects of care. SETTING AND PARTICIPANTS: Data collected for the development of five consumer quality index surveys - disease-specific questionnaires that capture patient experiences and priorities - were used. RESULTS: Priorities varied: breast cancer patients for example, prioritized rapid access to care and diagnostics, while diabetics favoured dignity and appropriate frequency of tests. Experiences regarding priorities were inconsistently related to global ratings of care. Regression analyses indicated that demographics explain 2.4-8.4% of the variance in global rating. Introducing patient experiences regarding priorities increased the variance explained to 21.1-35.1%; models with less important aspects of care explained 11.8-23.2%. CONCLUSIONS: Some experiences regarding priorities are strongly related to the global rating while others are poorly related. Global ratings are marginally dependent on demographics, and experiences regarding priorities are somewhat better predictors of global rating than experiences regarding less important elements. As it remains to be fully determined what global ratings summarize, caution is warranted when using these ratings as summary measures.
20490513 [Neuroendocrine immune interactions in rheumatic diseases]. 2010 Jun Clinical observations in chronic inflammatory diseases have demonstrated the significant influence of neuroendocrine mechanisms on the immune system: (1) Amelioration of rheumatoid arthritis during pregnancy; (2) preponderance of women versus men with respect to autoimmune diseases; (3) negative effects of ovulation-inducing therapy, oral contraceptives, and hormone replacement therapy; (4) protective effect of hemiplegia; (5) influence of psychological stress on inflammation; and (6) influence of circadian rhythms on inflammatory symptoms.The effects of different hormones and neurotransmitters on the immune system are influenced by: (1) the immune stimulus (foreign antigens or autoantigens) and subsequent antigen-specific immune responses, (2) the cell types involved during different phases of the disease, (3) the target organ with its specific microenvironment, (4) the timing of hormone or neurotransmitter increase in relation to the disease course, (5) the concentration of hormones and neurotransmitters, (6) the variability in expression of receptors depending on the microenvironment and the cell type, and (7) the intra- and extracellular peripheral metabolism of hormones and neurotransmitters leading to important biologically active metabolites with quite different anti- and proinflammatory functions.The circadian rhythm of disease-related symptoms with a peak in the early morning hours confirms that the neuroendocrine system has a strong influence on these chronic immune/inflammatory diseases. The influence is transmitted by the circadian fluctuation in the activity of hormonal and neuronal pathways linking the brain to immune cell activation.These considerations could lead to novel therapeutic strategies for rheumatic diseases in the future.
20415310 Simultaneous acute rotator cuff tear and distal biceps rupture in a strongman competitor. 2010 Apr Acute rotator cuff tear is commonly associated with tearing of the proximal biceps tendon, but has never been reported to occur simultaneously with a distal biceps tendon rupture. A 38-year-old right-hand-dominant strongman competitor attempted a 300-pound overhead axle press and experienced immediate pain in the right shoulder and elbow. He had no known systemic risk factors for tendon ruptures including hyperparathyroidism, hemodialysis, alcoholism, rheumatoid arthritis, statin medications, fluoroquinolones, and steroid use.Right shoulder magnetic resonance imaging (MRI) showed a full-thickness supraspinatus tear with 3 cm of retraction. There was minimal fatty infiltration of the supraspinatus on the sagittal cuts consistent with acute rupture. The subscapularis was intact. The long head of the biceps tendon had mild medial subluxation but was completely within the bicipital groove. Right elbow MRI showed a complete distal biceps tendon rupture. Thirteen days after his injury, the patient underwent arthroscopic supraspinatus repair and proximal biceps tenodesis. Distal biceps tendon repair was performed using the modified 2-incision muscle-splitting technique. At 24-month follow-up, the patient was pain free and had returned to full activity including weightlifting but had not returned to strongman competition.This is the first report of simultaneous acute full thickness ruptures of the rotator cuff and distal biceps tendon. This case report underscores the importance of a complete physical examination and a high index of suspicion for additional concomitant injuries, particularly in athletes with unusually high stresses to the body.
20412815 Over-expression of IL-33 leads to spontaneous pulmonary inflammation in mIL-33 transgenic 2010 Jul 8 IL-33 plays an important role in inflammatory diseases including hypersensitive diseases like asthma, autoimmune diseases like rheumatoid arthritis, cardiovascular diseases like heart failure and neurodegenerative diseases like Alzheimer's disease. Here we reported the generation of an IL-33 transgenic mouse, in which mouse IL-33 full-length cDNA was controlled under the CMV promoter. The transgenic IL-33 was released as a cleaved form with molecular weight of 18kDa in pulmonary, nephritic, cardiac and pancreatic tissues in transgenic mice and the pI of 18kDa peptide was about pH 3-5 on the 2D PAGE which was similar with the activated peptide of IL-33. Histological analysis showed massive airway inflammation with infiltration of eosinophils around bronchi and small blood vessels, hyperplasia of goblet cells and accumulation of mucus-like material in pulmonary tissue of transgenic mice. An increase of IL-5, IL-8, IL-13 and IgE was detected in bronchoalveolar lavage fluid (BALF) of transgenic mice, which are inflammatory factors. These findings suggest transgenic IL-33 could be cleaved and secreted in an activated form and play an important role in the pathogenesis of pulmonary inflammation.
20192998 Suppressive functions of activated B cells in autoimmune diseases reveal the dual roles of 2010 Jan B lymphocytes contribute to immunity through production of antibodies, antigen presentation to T cells, and secretion of cytokines. B cells are generally considered in autoimmune diseases as drivers of pathogenesis. This view is certainly justified, given the successful utilization of the B cell-depleting reagent rituximab in patients with rheumatoid arthritis or other autoimmune pathologies. In a number of cases, however, the depletion of B cells led to an exacerbation of symptoms in patients with autoimmune disorders. In a similar manner, mice lacking B cells can develop an aggravated course of disease in several autoimmune models. These paradoxical observations are now explained by the concept that activated B cells can suppress immune responses through the production of cytokines, especially interleukin-10. Here, we review the stimulatory signals that induce interleukin-10 secretion and suppressive functions in B cells and the phenotype of the B cells with such characteristics. Finally, we formulate a model explaining how this process of immune regulation by activated B cells can confer advantageous properties to the immune system in its combat with pathogens. Altogether, this review proposes that B-cell-mediated regulation is a fundamental property of the immune system, with features of great interest for the development of new cell-based therapies for autoimmune diseases.
20068402 Molecular construction and optimization of anti-human IL-1alpha/beta dual variable domain 2009 Jul Signal transduction through the interleukin-1 receptor (IL-1R) pathway mediates a strong pro-inflammatory response, which contributes to a number of human diseases such as rheumatoid arthritis. Within the IL-1 family, IL-1alpha and IL-1beta are both agonistic ligands for IL-1R, whereas IL-1 receptor antagonist (IL-1ra) is an endogenous antagonist that binds to IL-R, but does not signal. Therefore, the ideal therapeutic strategy would be blocking both IL-1alpha and IL-1beta, but not IL-1ra. However, due to low sequence homology between the three members of the family, it has been exceedingly difficult to identify potent therapeutic agents, e.g., monoclonal antibodies (mAbs), that selectively recognize both IL-1alpha and IL-1beta, but not IL-1ra. Currently, several anti-IL-1 therapeutic agents in clinical development either inhibit only IL-1beta (i.e., anti-IL-1beta mAb), or recognize all three ligands (i.e., anti-IL-1R mAb or IL-1R Trap). We have recently developed a novel dual variable domain immunoglobulin (or DVD-Ig) technology that enables engineering the distinct specificities of two mAbs into a single functional, dual-specific, tetravalent IgG-like molecule. Based on this approach, we have developed anti-human IL-1alpha/beta DVD-Ig molecules using several pairs of monoclonal antibodies with therapeutic potential, and present a case study for optimal design of a DVD-Ig agent for a specific target pair combination.
20018048 Inference of disease associations with unmeasured genetic variants by combining results fr 2009 Dec 15 Results from whole-genome association studies of many common diseases are now available. Increasingly, these are being incorporated into meta-analyses to increase the power to detect weak associations with measured single-nucleotide polymorphisms (SNPs). Imputation of genotypes at unmeasured loci has been widely applied using patterns of linkage disequilibrium (LD) observed in the HapMap panels, but there is a need for alternative methods that can utilize the pooled effect estimates from meta-analyses and explore possible associations with SNPs and haplotypes that are not included in HapMap.By a weighted average technique, we show that association results for common SNPs in an observed data set can be scaled and combined to infer the effect of a genetic variant that has been measured only in an independent reference data set. We show that the ratio p(R-1)/[1 + p(R-1)], where R is the relative risk associated with a measured or unmeasured allele of frequency p, is appropriately scaled by 1/D' and weighted in proportion to r2, both common measures of LD being derived from the reference data set.We illustrate this computationally simple method by combining the results of a genome-wide association screen from the North American Rheumatoid Arthritis Consortium with LD measures from the British 1958 Birth Cohort, and explore the validity of underlying assumptions about the generalizability of LD from one population to another, and from healthy subjects to subjects with clinical disease.
19880327 Suppressing IL-32 in monocytes impairs the induction of the proinflammatory cytokines TNFa 2010 Feb Targeting major proinflammatory cytokines such as IL-1beta and TNFalpha is of great interest in patients with chronic inflammatory diseases, including rheumatoid arthritis, colitis, and psoriasis. The cytokine Interleukin (IL)-32 induces proinflammatory cytokines such as TNFalpha, IL-1beta, IL-6, and chemokines. We previously used an IL-32 ligand-affinity column to purify proteinase 3, which is abundantly expressed in neutrophil and monocytic leukocytes but not in other cell types, and found that IL-32 is mainly produced by monocytic leukocytes. This evidence suggested that silencing endogenous IL-32 by short hairpin RNA (shRNA) in monocytic cells might reveal the precise function of endogenous IL-32. Indeed, lipopolysaccharide (LPS)- or phorbol myristate acetate (PMA)-induced proinflammatory cytokine production was significantly inhibited in shRNA/IL-32 stable clones as compared to control clones. Furthermore, macrophages in PMA-differentiated shRNA/IL-32 stable clones displayed remarkably impaired LPS- and IL-1beta-induced proinflammatory cytokine production. These data suggest that IL-32 is not only involved in host defense against pathogens, but also might play a role in chronic inflammatory diseases. IL-32 production leads to major proinflammatory cytokine production during the initial immune response.
19876783 PI3K isoforms as drug targets in inflammatory diseases: lessons from pharmacological and g 2009 Nov Inflammation protects the body against infection and injury, but it is a process that can become dysregulated with deleterious consequences, including the development of rheumatoid arthritis, inflammatory bowel disease, psoriasis and multiple sclerosis. In recent years, inflammation has also been demonstrated to play a key role in other widely prevalent diseases not previously considered to have inflammatory etiologies, such as Alzheimer's disease, cardiovascular diseases and cancer. The current anti-inflammatory therapies such as steroids, NSAIDs and antihistamines are mainly based on inhibiting the synthesis or action of inflammatory mediators. The more recently developed biopharmaceuticals (eg, TNFalpha-neutralizing therapies, and anti-IgE and anti-CD20 antibodies) follow a similar therapeutic strategy. However, both the established anti-inflammatory therapies and the more recent biopharmaceutical innovations have shortcomings and there remains a need for the identification and validation of new anti-inflammatory drug targets. This review focuses on the description of the data indicating that PI3K isoforms control inflammation at many levels, from the generation of inflammatory cells to the migration and function of these cells. More specifically, the contribution of the gamma and delta isoforms of PI3K to the immune processes that underpin inflammatory responses, as well as their potential as therapeutic targets, are evaluated.
19859796 Sulfasalazine induces apoptosis of HBx-expressing cells in an NF-kappaB-independent manner 2010 Feb The Hepatitis B virus (HBV) is a causative agent of acute chronic hepatitis, cirrhosis, and hepatocarcinoma. The Hepatitis B virus X protein (HBx) has pleiotypic functions in the regulation of proliferation and apoptosis. It has been suggested that the anti-inflammatory drug sulfasalazine, which is commonly used to treat rheumatoid arthritis and inflammatory bowel disease, inhibits nuclear factor NF-kappaB and induces cell death in HBx-expressing liver cells. In this study, we demonstrate that sulfasalazine induces cell death via apoptosis in HBx-expressing liver cells, as evidenced by characteristic changes in nuclear morphology, cleavage of poly (ADP-ribose) polymerase (PARP), caspase-3 and caspase-9, and activation of caspase-3. We also demonstrate that inhibition of NF-kappaB by siRNA fails to induce apoptosis of HBx-expressing liver cells, indicating that sulfasalazine modulates apoptosis of HBx-expressing cells in an NF-kappaB-independent manner.
19761564 Evaluation of a large-scale biomedical data annotation initiative. 2009 Sep 17 BACKGROUND: This study describes a large-scale manual re-annotation of data samples in the Gene Expression Omnibus (GEO), using variables and values derived from the National Cancer Institute thesaurus. A framework is described for creating an annotation scheme for various diseases that is flexible, comprehensive, and scalable. The annotation structure is evaluated by measuring coverage and agreement between annotators. RESULTS: There were 12,500 samples annotated with approximately 30 variables, in each of six disease categories - breast cancer, colon cancer, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Type 1 diabetes mellitus (DM). The annotators provided excellent variable coverage, with known values for over 98% of three critical variables: disease state, tissue, and sample type. There was 89% strict inter-annotator agreement and 92% agreement when using semantic and partial similarity measures. CONCLUSION: We show that it is possible to perform manual re-annotation of a large repository in a reliable manner.
19653802 Phenylalanine 4-monooxygenase and the role of endobiotic metabolism enzymes in xenobiotic 2009 Oct Phenylalanine 4-monooxygenase is the key enzyme in the sulfoxidation of the thioether drug S-carboxymethyl-l-cysteine and its thioether metabolites, S-methyl-l-cysteine, N-acetyl-S-carboxymethyl-l-cysteine and N-acetyl-S-methyl-l-cysteine in humans, and a number of other mammalian species. The kinetics constants of the sulfoxidation reaction (K(m), V(max) and CL(E)) have been investigated in cytosolic fractions derived from rat and human liver, in cytosolic fractions of HepG2 cells and using both human and mouse cDNA expressed phenylalanine 4-monooxygenase. Differences in K(m), V(max) and CL(E) of S-carboxymethyl-l-cysteine have been seen in HepG2 cells and human and mouse cDNA expressed phenylalanine 4-monooxygenase when compared to both rat and human hepatic cytosolic fractions. The association of the genetic polymorphism in the sulfoxidation of S-carboxymethyl-l-cysteine is highlighted with particular reference to this biotransformation reaction as being a biomarker of disease susceptibility in Parkinson's, Alzheimer's and motor neurone diseases and in rheumatoid arthritis. The possible underlying molecular genetics of the sulfoxidation polymorphism is also discussed in relation to the known allelic frequencies of phenylalanine 4-monooxygenase. Finally, the new found role phenylalanine 4-monooxygenase plays in xenobiotic metabolism is discussed.