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ID PMID Title PublicationDate abstract
21484575 Interleukin-targeted therapy for metabolic syndrome and type 2 diabetes. 2011 Interleukin-1β Interleukin-1β (IL-1β) is a key regulator of the body's inflammatory response and is produced after infection, injury, and an antigenic challenge. Cloned in 1984, the single polypeptide IL-1β has been shown to exert numerous biological effects. It plays a role in various diseases, including autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases, and Type 1 diabetes, as well as in diseases associated with metabolic syndrome such as atherosclerosis, chronic heart failure, and Type 2 diabetes. The macrophage is the primary source of IL-1β, but epidermal, epithelial, lymphoid, and vascular tissues also synthesize IL-1. Recently, IL-1β production and secretion have also been reported from pancreatic islets. Insulin-producing β-cells β-cells within the pancreatic islets are specifically prone to IL-β-induced destruction and loss of function. Macrophage-derived IL-1β production in insulin-sensitive organs leads to the progression of inflammation inflammation and induction of insulin resistance in obesity. This chapter explains the mechanisms involved in the inflammatory response during diabetes progression with specific attention to the IL-1β signal effects influencing insulin action and insulin secretion insulin secretion . We highlight recent clinical studies, rodent and in vitro experiments with isolated islets using IL-1β as a potential target for the therapy of Type 2 diabetes.
21347995 Chemical constituents and pharmacological properties of Poria cocos. 2011 May Poria cocos (Polyporaceae) is a saprophytic fungus that grows in diverse species of Pinus. Its sclerotium, called fu-ling or hoelen, is used in traditional Chinese and Japanese medicine for its diuretic, sedative, and tonic effects. Various studies of this fungus have demonstrated its marked anti-inflammatory activity in different experimental models of acute and chronic inflammation. It is widely used as a constituent of many preparations in Asian medicine, but the number of research papers on its clinical properties is insufficient for establishing its efficacy and safety from a scientific point of view. In this review, we have compiled all the published data concerning the chemistry, pharmacology, and clinical uses of this drug in order to evaluate its clinical interest for future use against various pathologies in which inflammation and immunodepression are implicated. We selected the papers for review on the basis of their ethnopharmacological relevance, using the most relevant databases for the biomedical sciences. Studies on various fungus extracts as well as on the major phytochemical compounds (polysaccharides and triterpenoids) present in Poria cocos comprised the principal objectives of this review. In several of the studies reviewed, the inhibitory effects of triterpenes on phospholipase A (2) (PLA (2)) have been clearly demonstrated. In addition, the inhibitory effects of Poria cocoson the secretion of different cytokines from human peripheral blood monocytes have also been described. Triterpenoids are known to have a pivotal influence on certain diseases such as rheumatoid arthritis, psoriasis, autoimmune uveitis, septic shock, and possibly bronchial asthma, while polysaccharides can potentiate the immune response. Reviewing the literature, we found that polysaccharides from Poria cocos enhanced the secretion of immune stimulators and suppressed the secretion of immune suppressors, thus potentiating the immune response. In addition, they showed antitumor activity against different cancer cell lines. This activity is associated with their capacity to inhibit angiogenesis by downregulating both NF- κB and the induction of NF- κB/Rel translocation.
21279517 Comorbidity profile of poliomyelitis survivors in a Chinese population: a population-based 2011 Jun Previous reports of comorbid conditions in poliomyelitis survivors mainly focused on some disease categories, such as respiratory diseases, gastrointestinal diseases, psychiatric diseases, neurological diseases and cancer. Data regarding a wide spectrum of medical comorbidities in patients with poliomyelitis is still sparse. This study aimed to investigate and profile the wide range of comorbidities among the survivors of paralytic poliomyelitis in a Chinese population. In total, 2,032 paralytic poliomyelitis patients were selected as the study group and the comparison group consisted of 10,160 randomly selected enrollees. The comorbidities for analysis were based on a modified version of the Elixhauser Comorbidity Index. Conditional logistic regression analyses were computed to investigate the risk of comorbidities for these two groups. As compared to controls, patients with paralytic poliomyelitis had significantly higher prevalence of hypertension, ischemic heart disease, hyperlipidemia, congestive heart failure, cardiac arrhythmias, peripheral vascular disorder, stroke, paralysis, migraines, Parkinson's disease, rheumatoid arthritis, ankylosing spondylitis, pulmonary circulation disorders, chronic pulmonary disease, liver disease, peptic ulcers, hepatitis B or C, deficiency anemias, depression, and lymphoma. Most of the differences are of clinical interest, ORs often being between 2 and 3. No significant difference between poliomyelitis patients and controls was observed in the prevalence of SLE, tuberculosis, alcohol abuse and drug abuse. Our findings demonstrate that survivors of paralytic poliomyelitis in Taiwan are at higher risk of having multiple medical comorbidities although some potential confounding factors including educational level, marital status, obesity and physical activity are not available in our database. The pattern is generally consistent with previous observations from Western populations. Nevertheless, we found several novel associations which have rarely, if ever, been reported previously.
22946016 Antinociceptive, anti-inflammatory and acute toxicity effects of juglans regia L. Leaves i 2011 Jan BACKGROUND: Juglans regia leaves have been used in folk medicine to alleviate inflammatory diseases. This study investigates the antinociceptive, anti-Inflammatory and acute toxicity effects of Juglans regia L. leaves in mice. METHODS: 351 Male and female albino mice were divided into negative (saline), positive (morphine or diclofenac) controls as well as test groups (n=6-8). The acute (intraperitoneally) toxicity was evaluated for 2 days. Antinociceptive activities were done using hot-plate and writhing tests. Anti-inflammatory effects were studied using xylene induced ear edema and cotton pellet tests. RESULTS: The LD50 values of J. regia aqueous and ethanolic extrats were 5.5 and 3.3 g/kg, respectively. The aqueous (2.87 and 1.64 g/kg) and ethanolic (2.044 and 1.17 g/kg) extracts showed antinociceptive activity in hot-plate test. The pretreatment of naloxone (2 mg/kg, s.c.) did not inhibit the extracts activities. The extracts exhibited antinociceptive activity in writhing test, which were not blocked by naloxone. In xylene test, both extracts showed anti-inflammatory activity in some doses. The extracts showed anti-inflammatory activity against the chronic inflammation. CONCLUSION: J. regia leaves demonstrated antinociceptive effect through non-opioid receptors and anti-inflammatory effect against acute and chronic inflammation. The extracts of J. regia could be considered as a promising analgesic and anti-inflammatory agents against diseases such as rheumatoid arthritis.
21161563 Lactoferrin inhibits the inflammatory and angiogenic activation of bovine aortic endotheli 2011 May OBJECTIVE: Lactoferrin (Lf) is known to have anti-cancer and anti-inflammatory activities; however, its therapeutic mechanism has not been defined. In this study, to explain the therapeutic mechanism of Lf, we examined the effect of Lf on endothelial cell activation, leukocyte integration, and angiogenesis in vitro. METHODS: Endothelia-leukocyte adhesion assays were used to assess primary cultures of bovine aortic endothelial cells (BAECs) activation following LPS treatment. The mRNA expression of ICAM-1 and proinflammatory cytokines was measured using RT-PCR. Each step of angiogenesis was evaluated in vitro, including endothelial cell proliferation, migration, and tube formation. Proliferation was examined using WST-1 and BrdU incorporation assays, while wound migration assays were used to evaluate cell migration; capillary-like tube formation assays on Matrigel were used to assess tube formation. RESULTS: Lf reduced the adhesion of human monocyte-like THP-1 cells to BAECs by 45%. Lf also reduced mRNA expression of ICAM-1 and proinflammatory cytokines in BAECs. Lf significantly inhibited BAEC proliferation, migration, and tube formation. CONCLUSIONS: Lf exerted a potent effect on BAEC activation, suggesting that it might function via an endothelia-based mechanism in the treatment of various diseases, including rheumatoid arthritis and cancer.
21159896 Concordance study of 3 direct-to-consumer genetic-testing services. 2011 Mar BACKGROUND: Several companies offer direct-to-consumer (DTC) genetic testing to evaluate ancestry and wellness. Massive-scale testing of thousands of single-nucleotide polymorphisms (SNPs) is not error free, and such errors could translate into misclassification of risk and produce a false sense of security or unnecessary anxiety in an individual. We evaluated 3 DTC services and a genomics service that are based on DNA microarray or solution genotyping with hydrolysis probes (TaqMan® analysis) and compared the test results obtained for the same individual. METHODS: We evaluated the results from 3 DTC services (23andMe, deCODEme, Navigenics) and a genomics-analysis service (Expression Analysis). RESULTS: The concordance rates between the services for SNP data were >99.6%; however, there were some marked differences in the relative disease risks assigned by the DTC services (e.g., for rheumatoid arthritis, the range of relative risk was 0.9-1.85). A possible reason for this difference is that different SNPs were used to calculate risk for the same disease. The reference population also had an influence on the relative disease risk. CONCLUSIONS: Our study revealed excellent concordance between the results of SNP analyses obtained from different companies with different platforms, but we noted a disparity in the data for risk, owing to both differences in the SNPs used in the calculation and the reference population used. The larger issues of the utility of the information and the need for risk data that match the user's ethnicity remain, however.
21120503 Comparative proteome analysis of peripheral blood mononuclear cells in systemic lupus eryt 2012 Mar To identify and quantify protein profiles from peripheral blood mononuclear cells (PBMC) of systemic lupus erythematosus (SLE) patients with isobaric Tagging for Relative and Absolute protein Quantification (iTRAQ)-based proteomic technology and to find differentially expressed proteins in SLE. PBMC were collected from patients of six stable SLE, six active SLE, six rheumatoid arthritis (RA), and six healthy donors. After protein extraction and concentration, the pooled protein content was labeled with iTRAQ reagents and then subjected to multiple chromatographic fractionation and tandem mass spectrometry. ProteinPilotâ„¢ 3.0 software and a database of IPI (International Protein Index) human 3.62 were used for database searching and statistical analysis. A total of 452 proteins were identified. Of these, 67 unique proteins were observed twofold or more alteration in levels across groups. The proteins determined support existing knowledge and uncover novel biomarker candidates. These results indicate that iTRAQ-based technology can serve as a useful aid for identification and quantification proteins from PBMC.
21868085 The cryoglobulinaemias. 2012 Jan 28 Cryoglobulins are immunoglobulins that precipitate in vitro at temperatures less than 37°C and produce organ damage through two main pathways: vascular sludging (hyperviscosity syndrome, mainly in type I cryoglobulinaemia) and immune-mediated mechanisms (principally vasculitis, in mixed cryoglobulinaemia). Cryoglobulinaemia is associated with many illnesses, which can be broadly grouped into infections, autoimmune disorders, and malignancies; the most common cause is infection with hepatitis C virus. Mixed cryoglobulinaemic syndrome is diagnosed when a patient has typical organ involvement (mainly skin, kidney, or peripheral nerve) and circulating cryoglobulins. Cutaneous purpura is the most common manifestation of cryoglobulinaemic vasculitis. The most frequently affected internal organs are the peripheral nerves, kidneys, and joints. The course varies widely and prognosis is influenced by both cryoglobulinaemic damage to vital organs and by comorbidities associated with underlying diseases. More than 90% of cases of cryoglobulinaemia have a known underlying cause; therefore treatment is focused on the cause of the disorder rather than merely symptomatic relief. Studies suggest that both combined or sequential antiviral therapies and targeted biological treatments might be more effective than monotherapy.
21178699 Long-term use of hydroxypropyl cellulose ophthalmic insert to relieve symptoms of dry eye 2011 Jan OBJECTIVES: To report a case in which hydroxypropyl cellulose ophthalmic inserts were successfully used for the treatment of dry eye disease in a contact lens (CLs) wearer for more than 25 years. METHODS: Review of clinical findings in a female CL wearer with dry eye spanning more than 30 years. The patient was diagnosed with the Sjögren syndrome and demonstrated inadequate lacrimation as assessed by Schirmer testing. Slitlamp examination demonstrated bilateral corneal stippling with fluorescein and signs of superior limbic keratoconjunctivitis. RESULTS: Initially, the patient's symptoms improved with infrequent use of artificial tears. As the signs and symptoms of dry eye disease worsened, the patient initiated therapy with once-daily hydroxypropyl cellulose ophthalmic inserts. Punctal plugs and updating to increasingly oxygen-permeable soft CLs, in combination with continued use of the inserts, largely controlled the signs and symptoms of dry eye disease during a 25-year period. Simultaneous use of the hydroxypropyl cellulose ophthalmic inserts and CLs was well tolerated without any significant side effects or changes in visual acuity. CONCLUSIONS: Dry eye is a chronic disease often requiring long-term management. In this case, daily use of hydroxypropyl cellulose ophthalmic inserts effectively treated autoimmune dry eye, providing symptomatic relief, and resulted in improved objective measures of disease severity across several decades. Such an experience is consistent with the available evidence-based data for hydroxypropyl cellulose ophthalmic inserts and supports their use in clinical practice for the treatment of moderate-to-severe dry eye disease.
22516995 [Expression of osteopontin in labial glands of patients with primary Sjögren's syndrome]. 2012 Apr 18 OBJECTIVE: To investigate the mRNA transcription and protein expression of osteopontin (OPN) and to analyze the possible role of OPN in primary Sjögren's syndrome (pSS). METHODS: In this study, 24 patients with pSS were selected and diagnosed according to the American-European Consensus Group criteria. The control group was composed of 14 subjects. Total RNA from labial glands was extracted. The target gene and β-actin acted as templates to perform reverse transcript polymerase chain reaction (RT-PCR). Then mRNA expression of the target gene were semi-quantitated by the OD ratio of the target gene to β-actin bands on gel under densitometry. Immunohistocheical analysis was used to determine the expression of proteins of the target genes in labial glands from patients and healthy control. RESULTS: In contrast to the control group, the mRNA transcription and protein level of the target genes in labial glands in pSS patients were significantly increased statistically (P<0.05). Spearman and Pearson rank correlation coefficients were used for analyzing the correlation of lymphocytes foci-score (LFS) with OPN expressions, the level of the mRNA transcription (0.407, P=0.049) and protein expression of OPN (0.476, P=0.039) was positively correlated with the LFS. Immunohistochemistry detected that OPN protein was not only mainly expressed in intracytoplasm of the gland duct, but also in infiltrated lymphocytes. CONCLUSION: OPN is higher expressed in the basal and surface of labial glands of pSS patients, which may contribute to the destruction of labial glands.
22859354 Disease-modifying antirheumatic drug use in the treatment of juvenile idiopathic arthritis 2012 Sep OBJECTIVE: To characterize disease-modifying antirheumatic drug (DMARD) use for children with juvenile idiopathic arthritis (JIA) in the United States and to determine patient factors associated with medication use. METHODS: We analyzed cross-sectional baseline enrollment data from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry from May 2010 through May 2011 for children with JIA. Current and prior medication use was included. We used parsimonious backward stepwise logistic regression models to calculate OR to estimate associations between clinical patient factors and medication use. RESULTS: We identified 2748 children with JIA with a median disease duration of 3.9 years from 51 US clinical sites. Overall, 2023 (74%) had ever received a nonbiologic DMARD and 1246 (45%) had ever received a biologic DMARD. Among children without systemic arthritis, methotrexate use was most strongly associated with uveitis (OR 5.2, 95% CI 3.6-7.6), anticitrullinated protein antibodies (OR 4.5, 95% CI 1.7-12), and extended oligoarthritis (OR 4.1, 95% CI 2.5-6.6). Among children without systemic arthritis, biologic DMARD use was most strongly associated with rheumatoid factor (RF)-positive polyarthritis (OR 4.3, 95% CI 2.9-6.6), psoriatic arthritis (PsA; OR 3.0, 95% CI 2.0-4.4), and uveitis (OR 2.8, 95% CI 2.1-3.7). Among children with systemic arthritis, 160 (65%) ever received a biologic DMARD; tumor necrosis factor inhibitor use was associated with polyarthritis (OR 2.5, 95% CI 3.8-16), while interleukin 1 inhibitor use was not. CONCLUSION: About three-quarters of all children with JIA in the CARRA Registry received nonbiologic DMARD. Nearly one-half received biologic DMARD, and their use was strongly associated with RF-positive polyarthritis, PsA, uveitis, and systemic arthritis.
22818907 The relation between visual performance and clinical ocular manifestations in Stevens-John 2012 Sep PURPOSE: To investigate the relation between visual function, clinical findings, and visual symptoms in Stevens-Johnson syndrome (SJS) and to compare the results with Sjögren syndrome (SS) patients and normal subjects. DESIGN: Cross-sectional comparative study. METHODS: One hundred fifteen eyes of 59 consecutive patients with SJS and toxic epidermal necrolysis (TEN), 208 eyes of 104 healthy normal subjects, and 132 eyes of 66 SS patients were investigated in this multicenter study. All study subjects underwent tear function and ocular surface examinations, Landolt and functional visual acuity examinations, and the Japanese version of the NEI VFQ-25 (National Eye Institute Visual Function Questionnaire). RESULTS: The mean ocular surface grading scores were significantly higher and the mean score of all 12 NEI VFQ subscales was significantly lower in the SJS patients compared to the SS patients and the normal subjects (P < .05). The conventional and functional logarithm of minimal angle of resolution (logMAR) visual acuities in SJS patients with minimal corneal complications were significantly higher and the mean total composite NEI VFQ scores were lower compared to SS patients. The conventional and functional logMAR visual acuities and the mean ocular surface grading scores in SJS with aqueous deficiency were significantly higher and the mean total composite NEI VFQ scores were lower compared to SS patients. Strong correlations between best-corrected logMAR functional visual acuities and either ocular surface grading scores or the composite NEI VFQ-25 scores were observed. CONCLUSIONS: The functional visual acuity examination reflects the severity of clinical ocular surface findings and vision-related quality of life more than the standard conventional visual acuity in SJS.
22530364 [Histological investigations in ambulatory oral surgery practice]. 2012 Mar In the practice of oral surgery correspondence with the pathologist is required in order to identify the lesions in question by histologic examination. By current legal regulations the histological evaluation of removed tissues is mandatory. In the presentation the authors process the data obtained in their Department since 2008. Coincidence of the clinical and histological diagnosis is analysed statistically such is the occurrence of various types of oral mucosa lesions and cysts. In cases of presumed malignancy the biopsies were carried out in a department with adequate oncological background. In indications of autoimmun deseases mainly in cases of Sjögren's syndrome the Department has been requested to carry out minor salivary gland biopsies. Statistical analysis of the findings of the minor salivary gland biopsies will also be discussed. The histological diagnoses have been provided by Prof. Zsuzsanna Suba MD, DMD, PhD of the Semmelweis University, Department of Oral and Maxillofacial Surgery, Oral Pathology Unit. In order of prevalence the most common histologically verified lesions were: radicular cyst, fibromas and granulation tissue. In 84.5% of the cases the histological findings confirmed the clinical diagnoses. In 44,5% of the cases Sjögren's syndrome was verified by the minor salivary gland biopsy. Although in most cases the histological examination supported the clinical diagnoses, close cooperation of the oral surgeon and pathologist is essential.
21965486 The effect of electronic health records on the use of clinical care guidelines for patient 2011 Oct BACKGROUND: The emergence of health information technology provides an opportunity for health care providers to improve the quality and safety of dental care, particularly for patients with medically complex conditions. METHODS: The authors randomized each of 15 dental clinics (HealthPartners, Bloomington, Minn.) to one of three groups to evaluate the impact of two clinical decision support (CDS) approaches during an 18-month study period. In the first approach--provider activation through electronic dental records (EDRs)--a flashing alert was generated at the dental visit to identify patients with medically complex conditions and to direct the dental care provider to Web-based personalized care guidelines. In the second approach--patient activation through personal health records--a secure e-mail was generated or a letter was mailed to patients before dental visits encouraging them to ask their dental care provider to review the care guidelines specific to their medical conditions. RESULTS: The authors evaluated the rate of reviewing care guidelines among 102 providers. Participants in the provider and patient activation groups increased their use of the system during the first six months, which had a generalized effect of increasing use of the guidelines for all patients, even if they were not part of the study (P < .05). The study results showed that provider activation was more effective than was patient activation. However, providers did not sustain their high level of use of the system, and by the end of the study, the rate of use had returned to baseline levels despite participants' continued receipt of electronic alerts. CONCLUSIONS: The study results demonstrated that review of clinical care guidelines for patients with medically complex conditions can be improved with CDS systems that involve the use of electronic health records. CLINICAL IMPLICATIONS: As the U.S. population ages, dentists must be vigilant in adapting care for patients with medically complex conditions to ensure therapeutic safety and effectiveness. Expanded use of CDS via EDRs can help dental care providers achieve this objective.
21481003 Effects of gustatory stimulants of salivary secretion on salivary pH and flow in patients 2011 Nov OBJECTIVES: To compare salivary pH changes and stimulation efficacy of two different gustatory stimulants of salivary secretion (GSSS) in patients with primary Sjögren syndrome. SETTING: Portuguese Institute for Rheumatological Diseases. DESIGN: Double-blind randomized controlled trial. SUBJECTS: Eighty patients were randomized to two intervention groups. Sample size was calculated using an alpha error of 0.05 and a beta of 0.20. MATERIALS AND METHODS: Participants were randomly assigned to receive a new GSSS containing a weaker malic acid, fluoride and xylitol or a traditionally citric acid-based one. Saliva collection was obtained by established methods at different times. The salivary pH of the samples was determined with a pH meter and a microelectrode. MAIN OUTCOME MEASURES: Salivary pH variations and counts of subjects with pH below 4.5 for over 1 min and stimulated salivary flow were the main outcome measures. RESULTS: Both GSSS significantly stimulated salivary output without significant differences between the two groups. The new gustatory stimulant of salivary secretion presented an absolute risk reduction of 52.78% [33.42-72.13 (95% CI)] when compared with the traditional one. CONCLUSIONS: In Xerostomic Primary Sjögren syndrome patients, gustatory stimulants of salivary secretion based on acid mail only with fluoride and xylitol present similar salivary stimulation capacity when compared to citric acid-based ones, besides significantly reducing the number of salivary pH drops below 4.5. This could be related to a diminished risk for dental erosion and should be confirmed with further studies.
21428963 Inflammation: a role for NR4A orphan nuclear receptors? 2011 Apr Inflammation is paradoxical; it is essential for protection following biological, chemical or physical stimuli, but inappropriate or misdirected inflammation is responsible for tissue injury in a variety of inflammatory diseases. The polarization of immune cells is critical in controlling the stages of inflammatory response. The acute phase of inflammation is characterized by a T-lymphocyte:Th2 cytokine profile and involves a co-ordinated migration of immune cells to the site of injury where production of cytokines and acute-phase proteins brings about healing. However, persistent inflammation can result in inappropriate and prolonged T-lymphocyte:Th1 cytokine-mediated action and reaction of self-molecules, leading to a chronic phase in diseases such as RA (rheumatoid arthritis), Ps (psoriasis) and atherosclerosis. The inflammatory response is also controlled by activated macrophage cells, with classically activated (M1) cells producing a wide variety of pro-inflammatory mediators, while alternatively activated (M2) macrophages participate in anti-inflammatory response. Members of the NR4A subfamily (NR4A1/NUR77, NR4A2/NURR1 and NR4A3/NOR1) of orphan NRs (nuclear receptors) have emerged as key transcriptional regulators of cytokine and growth factor action in diseases affecting our aging population. As ligand-independent and constitutively active receptors, the activity of these transcription factors is tightly controlled at the level of expression, post-translational modification and subcellular localization. NR4A subfamily members are aberrantly expressed in inflamed human synovial tissue, psoriatic skin, atherosclerotic lesions, lung and colorectal cancer cells. Significantly, prolonged or inappropriate inflammatory responses contribute to the pathogenesis of these diseases. In activated cells, NR4A receptors are rapidly and potently induced, suggesting that these receptors may act as important transcriptional mediators of inflammatory signals. NR4A receptors may contribute to the cellular processes that control inflammation, playing a critical part in the contribution of chronic inflammation or they may have a protective role, where they may mediate pro-resolution responses. Here, we will review the contribution of the NR4A orphan NRs to integration of cytokine signalling in inflammatory disorders.
22851707 Endothelial cells and fibroblasts amplify the arthritogenic type I IFN response in murine 2012 Sep 1 Localized elevation in type I IFN has been uniquely linked to the severe Lyme arthritis that develops in C3H mice infected with the spirochete Borrelia burgdorferi. In this study, the dynamic interactions that result in generation of these responses were further examined in C3H mice carrying the type I IFN receptor gene ablation, which effectively blocks all autocrine/paracrine signaling crucial to induction of downstream effectors. Reciprocal radiation chimeras between C3H and IFNAR1⁻/⁻ mice implicated both radiation-sensitive and radiation-resistant cells of the joint tissue in the proarthritic induction of type I IFN. Ex vivo analysis of cells from the naive joint revealed CD45⁺ cells residing in the tissue to be uniquely capable of initiating the type I IFN response to B. burgdorferi. Type I IFN responses were analyzed in real time by lineage sorting of cells from infected joint tissue. This demonstrated that myeloid cells, endothelial cells, and fibroblasts were responsible for propagating the robust IFN response, which peaked at day 7 postinfection and rapidly resolved. Endothelial cells and fibroblasts were the dominant sources of IFN signature transcripts in the joint tissue. Fibroblasts were also the major early source of chemokines associated with polymorphonuclear leukocyte and monocyte/macrophage infiltration, thus providing a focal point for arthritis development. These findings suggest joint-localized interactions among related and unrelated stromal, endothelial, and myeloid cell lineages that may be broadly applicable to understanding the pathogeneses of diseases associated with type I IFN signature, including systemic lupus erythematosus and some rheumatoid arthritides.
22414631 Fibromyalgia, mood disorders, and intense creative energy: A1AT polymorphisms are not alwa 2012 Dec Persons with single copies of common alpha-1-antitrypsin polymorphisms such as S and Z are often considered "silent carriers". Published evidence however supports a complex behavioral phenotype or trait - intense creative energy ("ICE")-associated with A1AT polymorphisms. We now confirm that phenotype and present an association of fibromyalgia syndrome (FMS) and A1AT in a consecutive series of neurological patients. This is a retrospective case control series of 3176 consecutive patients presenting to Duke University Memory Clinic (747 patients) and to regional community-based Caldwell Hospital Neurology and Memory center (2429 patients). Work-up included medical history and examination, psychological evaluation, and genetic analysis. Chronic widespread pain (CWP) or FMS were diagnosed according to clinical guidelines, mostly as secondary diagnoses. Neurological patients carrying A1AT polymorphisms were common (ca 16% prevalence) and carriers had significantly higher use of inhaler and anxiolytic medications. Patients with ICE phenotype had a significantly higher proportion of A1AT polymorphisms (42%) compared to non-ICE patients (13%). Presence of CWP or FMS was common (14-22%) with average age at presentation of 56 years old and mostly female gender (82%). Patients with CWP/FMS had again significantly higher proportion of A1AT polymorphisms (38%) compared to other neurological patients (13%). Patients with anxiety disorders, bipolar I or bipolar II disorders or PTSD also had increased proportion of A1AT polymorphisms and significant overlap with ICE and FMS phenotype. Significant reductions in CWP/FMS prevalence are seen in apolipoprotein E4 carriers and methylene tetrahydrofolate reductase (MTHFR) mutation homozygotes. Since ICE phenotype is reported as a lifelong behavioral attribute, the presumption is that A1AT carriers have fundamental differences in brain development and inflammatory response. In support of this concept is finding those persons reporting a diagnosis of juvenile rheumatoid or idiopathic arthritis (JRA, JIA) had a significantly high proportion of A1AT polymorphisms (63%), suggesting a spectrum for JRA to later FMS presentations. Likewise, persons reporting a history of attention deficit disorder (ADD) had an increased proportion of A1AT polymorphisms (26%) compared to non-ADD persons (13%). Toxic environmental exposures are common (23%) and associated with diagnoses of PSP, PPA, FTD, FTD-PD, PD and ADVD. A1AT carriers were increased in cases of toxic exposure and PSP, PPA and FTD-PD. Our findings support the ICE behavioral phenotype for A1AT polymorphism carriers and the reported association with anxiety and bipolar spectrum disorders. We now extend that phenotype to apparent vulnerability to inflammatory muscle disease in a spectrum from JRA to fibromyalgia (FMS) and specific behavioral subsets of ADD, PTSD, and specific late onset neurological syndromes (FTD-PD and PPA). High and low risk FMS subsets can be defined using A1AT, MTHFR and APOE genotyping. Clinical diagnoses associated with A1AT polymorphisms included fibromyalgia, JRA/JIA, bipolar disorder, PTSD, primary progressive aphasia and FTDPD, but not most Alzheimer Disease subtypes. These results support an extended phenotype for A1AT mutation carriers beyond liver and lung vulnerability to selective advantages: ICE phenotype and disadvantages: fibromyalgia, affective disorders, and selected late onset neurological syndromes.
22637724 Durable pharmacological responses from the peptide ShK-186, a specific Kv1.3 channel inhib 2012 Sep The Kv1.3 channel is a recognized target for pharmaceutical development to treat autoimmune diseases and organ rejection. ShK-186, a specific peptide inhibitor of Kv1.3, has shown promise in animal models of multiple sclerosis and rheumatoid arthritis. Here, we describe the pharmacokinetic-pharmacodynamic relationship for ShK-186 in rats and monkeys. The pharmacokinetic profile of ShK-186 was evaluated with a validated high-performance liquid chromatography-tandem mass spectrometry method to measure the peptide's concentration in plasma. These results were compared with single-photon emission computed tomography/computed tomography data collected with an ¹¹¹In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugate of ShK-186 to assess whole-blood pharmacokinetic parameters as well as the peptide's absorption, distribution, and excretion. Analysis of these data support a model wherein ShK-186 is absorbed slowly from the injection site, resulting in blood concentrations above the Kv1.3 channel-blocking IC₅₀ value for up to 7 days in monkeys. Pharmacodynamic studies on human peripheral blood mononuclear cells showed that brief exposure to ShK-186 resulted in sustained suppression of cytokine responses and may contribute to prolonged drug effects. In delayed-type hypersensitivity, chronic relapsing-remitting experimental autoimmune encephalomyelitis, and pristane-induced arthritis rat models, a single dose of ShK-186 every 2 to 5 days was as effective as daily administration. ShK-186's slow distribution from the injection site and its long residence time on the Kv1.3 channel contribute to the prolonged therapeutic effect of ShK-186 in animal models of autoimmune disease.
22761804 An intense and short-lasting burst of neutrophil activation differentiates early acute myo 2012 BACKGROUND: Neutrophils are involved in thrombus formation. We investigated whether specific features of neutrophil activation characterize patients with acute coronary syndromes (ACS) compared to stable angina and to systemic inflammatory diseases. METHODS AND FINDINGS: The myeloperoxidase (MPO) content of circulating neutrophils was determined by flow cytometry in 330 subjects: 69 consecutive patients with acute coronary syndromes (ACS), 69 with chronic stable angina (CSA), 50 with inflammation due to either non-infectious (acute bone fracture), infectious (sepsis) or autoimmune diseases (small and large vessel systemic vasculitis, rheumatoid arthritis). Four patients have also been studied before and after sterile acute injury of the myocardium (septal alcoholization). One hundred thirty-eight healthy donors were studied in parallel. Neutrophils with normal MPO content were 96% in controls, >92% in patients undergoing septal alcoholization, 91% in CSA patients, but only 35 and 30% in unstable angina and AMI (STEMI and NSTEMI) patients, compared to 80%, 75% and 2% of patients with giant cell arteritis, acute bone fracture and severe sepsis. In addition, in 32/33 STEMI and 9/21 NSTEMI patients respectively, 20% and 12% of neutrophils had complete MPO depletion during the first 4 hours after the onset of symptoms, a feature not observed in any other group of patients. MPO depletion was associated with platelet activation, indicated by P-selectin expression, activation and transactivation of leukocyte β2-integrins and formation of platelet neutrophil and -monocyte aggregates. The injection of activated platelets in mice produced transient, P-selectin dependent, complete MPO depletion in about 50% of neutrophils. CONCLUSIONS: ACS are characterized by intense neutrophil activation, like other systemic inflammatory syndromes. In the very early phase of acute myocardial infarction only a subpopulation of neutrophils is massively activated, possibly via platelet-P selectin interactions. This paroxysmal activation could contribute to occlusive thrombosis.