Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
19956108 Analysis of 55 autoimmune disease and type II diabetes loci: further confirmation of chrom 2009 Dec A candidate gene study was conducted on 10 established type II diabetes genes and 45 genes associated with autoimmune diseases, including type I diabetes (T1D), in a maximum of 1410 affected sib-pair families assembled by the Type I Diabetes Genetics Consortium. Associations at P values <10(-3) were found for three known T1D regions at chromosomes 4q27, 12q13.2 and 12q24.13 (http://www.T1DBase.org). Support was obtained for a newly identified T1D candidate locus on chromosome 12q13.3-12q14.1 (rs1678536/KIF5A: P=8.1 x 10(-3); relative risk (RR) for minor allele=0.89, 95% CI=0.82-0.97), which has a separate association from the previously reported T1D candidate locus ERBB3/12q13.2-q13.3. Our new evidence adds to that previously published for the same gene region in a T1D case-control study (rs1678542; P=3.0 x 10(-4); odds ratio (OR)=0.92, 95% CI=0.88-0.96). This region, which contains many genes, has also been associated with rheumatoid arthritis.
21099117 Expression of αvβ8 integrin on dendritic cells regulates Th17 cell development and exper 2010 Dec Th17 cells promote a variety of autoimmune diseases, including psoriasis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. TGF-β is required for conversion of naive T cells to Th17 cells, but the mechanisms regulating this process are unknown. Integrin αvβ8 on DCs can activate TGF-β, and this process contributes to the development of induced Tregs. Here, we have now shown that integrin αvβ8 expression on DCs plays a critical role in the differentiation of Th17 cells. Th17 cells were nearly absent in the colons of mice lacking αvβ8 expression on DCs. In addition, these mice and the DCs harvested from them had an impaired ability to convert naive T cells into Th17 cells in vivo and in vitro, respectively. Importantly, mice lacking αvβ8 on DCs showed near-complete protection from experimental autoimmune encephalomyelitis. Our results therefore suggest that the integrin αvβ8 pathway is biologically important and that αvβ8 expression on DCs could be a therapeutic target for the treatment of Th17-driven autoimmune disease.
20676825 [The medial closed-wedge osteotomy of the distal femur for the treatment of unicompartment 2010 Jul OBJECTIVE: Shifting of the mechanical axis from the lateral to the medial compartment in patients with lateral osteoarthritis in combination with valgus deformity. INDICATIONS: Osteoarthritis of the lateral compartment in combination with valgus deformity of the (distal) femur. Posttraumatic and congenital valgus deformities of the (distal) femur. CONTRAINDICATIONS: Osteoarthritis of the medial compartment (>or=grade 3 on Outerbridge Scale). Total loss of the medial meniscus. Acute or chronic infections. Rheumatoid arthritis. Heavy smoking. Extension or flexion deficit>20 degrees. Poor soft-tissue conditions on site of surgery. SURGICAL TECHNIQUE: Optional: arthroscopy before osteotomy. Anteromedial skin incision, subvastus approach with blunt preparation around the vastus medialis muscle and separation of this muscle from the intermuscular septum. The posterior osteotomy is marked with Kirschner wires (OGD [osteotomy guiding device], Synthes, Switzerland, can be used optionally). The biplanar cut is marked on the bone with an electrocautery device. The bone cuts start with the posterior incomplete osteotomy, followed by the anterior biplanar cut. After finishing the osteotomy (three bone cuts!), the bone wedge can be removed. Closing the osteotomy should start very gently as a plastic deformation of the bone. A radiologic control of the leg alignment and the mechanical axis is achieved with an alignment rod (Synthes, Switzerland). The plate should be inserted under the vastus medialis muscle. It is very important, that the surgeon controls the correct anteromedial position of the plate at the distal femur (right and left version of the implant). Fixation of the plate with locking screws distally. Positioning of a lag screw in the dynamic hole directly above the osteotomy. Insertion of monocortical screws in the three remaining holes proximal of the lag screw. Finally, the lag screw is changed to a self-tapping bicortical locking head screw. X-ray control, wound closure. POSTOPERATIVE MANAGEMENT: Elastic bandage of the leg up to the thigh in the operating room. Change of the dressing on day 1 after surgery. Ice treatment. Walking on crutches starting day 1 after surgery. Physiotherapy and manual lymph drainage starting on day 1 after surgery. Partial weight bearing for the first 4-6 weeks after surgery. Suture removal after 10-12 days. X-ray control on day 3 and 6 weeks after surgery. Discharge possible, if wounds are dry (day 4-7). RESULTS: Between January 2005 and October 2008, 60 patients were treated with medial closed-wedge osteotomy of the distal femur (since 11/2006 only with biplanar osteotomy technique) at the Department of Trauma and Reconstructive Surgery, Diakoniekrankenhaus Henriettenstiftung Hannover, Germany. The average wedge size was 7.6 mm (4-13 mm). The mean age was 39.7 years (17-79 years). The patients had had 2.3 previous surgeries. The mean follow- up was 21 months (3-45 months). Freiling D, et al. Biplanare Osteotomie bei unikompartimentaler lateraler Kniegelenkarthrose Flexion was 126 degrees (95-140 degrees) preoperatively, and 128 degrees (105-140 degrees) postoperatively. 25 patients had at least 5 degrees extension deficit (5-15 degrees) before surgery, whereas ten patient did not reach the full extension at follow-up examination. The Tegner Activity Score increased from 2.8 (1-4) preoperatively to 5.6 (2-9) postoperatively, in IKDC (International Knee Documentation Committee) Score, 18 patients reached grade A, 27 grade B, nine grade C, and six grade D. The visual analog scale (VAS) score decreased from 6.8 (8-2) preoperatively to 3.1 (0-7) postoperatively. Seven patients had revision surgery (three times delayed union/nonunion of the osteotomy, one superficial and one deep infection, one hematoma, one fracture [proximal of the internal plate fixator] after a fall).
20012470 FOXO transcription factors and VEGF neutralizing antibody enhance antiangiogenic effects o 2010 Apr Resveratrol (trans-3,5,4'-trihydroxystilbene), a compound found largely in the skins of red grapes and wines, possesses anti-cancer and anti-angiogenic properties and protects the cardiovascular system. However, the molecular mechanisms by which resveratrol inhibits angiogenesis are currently subjects of intense investigation. The purpose of this study was to examine whether FOXO transcription factors mediate anti-angiogenic effects of resveratrol, and whether vascular endothelial growth factor (VEGF) neutralizing antibody can enhance these effects of resveratrol. Inhibition of PI3 kinase (PI3K)/AKT and MEK/ERK pathways synergistically inhibited migration and capillary tube formation of Human Umbilical Vein Endothelial Cells (HUVECs) and further enhanced the anti-angiogenic effects of resveratrol. Inhibitors of AKT and MEK kinase synergistically inhibited cytoplasmic FOXO3a phosphorylation, which was accompanied by its nuclear translocation in HUVECs. Interestingly, inhibition of PI3K/AKT and MEK/ERK pathways synergistically induced FOXO transcriptional activity and inhibited cell migration and capillary tube formation. Antiangiogenic effects of resveratrol were enhanced by inhibitors of AKT and MEK. Phosphorylation-deficient mutants of FOXOs induced FOXO transcriptional activity, inhibited HUVEC cell migration, and capillary tube formation, and also enhanced antiangiogenic effects of resveratrol. Finally, VEGF neutralizing antibody enhanced the anti-proliferative and anti-angiogenic effects of resveratrol. In conclusion, regulation of FOXO transcription factors by resveratrol may play an important role in angiogenesis which is critical for cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis, and cardiovascular disorders.
19491835 Developing valid and reliable health utilities in irritable bowel syndrome: results from t 2009 Aug OBJECTIVES: A "utility" is a measure of health-related quality of life (HRQOL) that ranges between 0 (death) and 1 (perfect health). Disease-targeted utilities are mandatory to conduct cost-utility analyses. Given the economic and healthcare burden of irritable bowel syndrome (IBS), cost-utility analyses will play an important role in guiding health economic decision-making. To inform future cost-utility analyses in IBS, we measured and validated the IBS utilities. METHODS: We analyzed data from Rome III IBS patients in the Patient Reported Observed Outcomes and Function (PROOF) Cohort-a longitudinal multi-center IBS registry. At entry, the patients completed a multi-attribute utility instrument (EuroQOL), bowel symptom items, IBS severity measurements (IBS Severity Scale (IBSSS), Functional Bowel Disease Severity Index (FBDSI)), HRQOL indexes (IBS quality-of-life instrument (IBS-QOL), Center for disease control-4 (CDC-4)), and the Worker Productivity Activity Index for IBS (WPAI). We repeated assessments at 3 months. RESULTS: There were 257 patients (79% women; age=43+/-15 years) at baseline and 85 at 3 months. The mean utilities in patients with severe vs. non-severe IBS were 0.70 and 0.80, respectively (P<0.001). There were no differences in utilities among IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), and mixed IBS (IBS-M) subgroups. EuroQOL utilities correlated with FBDSI (r=0.31; P<0.01), IBSSS (r=0.36; P<0.01), IBS-QOL (r=0.36; P<0.01), CDC-4 (r=0.44; P<0.01), WPAI presenteeism (r=0.16; P<0.01), abdominal pain (r=0.43; P<0.01), and distension (r=0.18; P=0.01). The utilities in patients reporting "considerable relief" of symptoms at 3 months vs. those without considerable relief were 0.78 and 0.73, respectively (P=0.02). CONCLUSIONS: EuroQOL utilities are valid and reliable in IBS. The utility of severe IBS (0.7) is similar to Class III congestive heart failure and rheumatoid arthritis. These validated utilities can be employed in future IBS cost-utility analyses.
19487969 Ron receptor tyrosine kinase negatively regulates TNFalpha production in alveolar macropha 2010 Feb The Ron receptor tyrosine kinase (TK) plays a regulatory role in the inflammatory response to acute lung injury induced by intranasal administration of bacterial LPS. Previously, we have shown that mice with a targeted deletion of the TK signaling domain of the Ron receptor exhibited more severe lung injury in response to intranasal LPS administration as evidenced by an increased leakage of albumin in the lungs and a greater thickening of the alveolar septa compared with wild-type mice. In addition, lung injury in the Ron TK-deficient (TK(-/-)) mice was associated with increased activation of the transcription factor, nuclear factor-kappaB (NF-kappaB), and significantly increased intrapulmonary expression of TNFalpha. TNFalpha, a multifunctional proinflammatory cytokine, is a central mediator in several disease states, including rheumatoid arthritis and sepsis. On the basis of the observation that TNFalpha production is increased in the Ron TK-/- mice and that macrophages are a major source of this cytokine, we hypothesized that the alterations observed in the Ron TK(-/-) mice may be due, in part, to Ron signaling, specifically in alveolar macrophages. To test this hypothesis, we used the wild-type and Ron TK(-/-) primary alveolar macrophages and the murine alveolar macrophage cell line, MH-S, to examine the effects of Ron activation on LPS-induced TNFalpha production and NF-kappaB activity. Here, we reported that Ron is expressed on alveolar macrophages and MH-S cells. Activation of Ron by its ligand, hepatocyte growth factor-like protein, decreases TNFalpha production in alveolar macrophages after LPS challenge. Decreased TNFalpha is associated with hepatocyte growth factor-like protein-induced decreases in NF-kappaB activation and increases in the NF-kappaB inhibitory protein, IkappaB. We also provided the first evidence for Ron as a negative regulator of Adam17, the metalloprotease involved in TNFalpha processing. These results indicate that Ron plays a critical role in regulation of alveolar macrophage signaling and validates this receptor as a target in TNFalpha-mediated pulmonary pathologies.
19662820 [Autoimmune diseases associated with transverse myelitis. Review]. 2009 Jun Transverse myelitis (TM) is an inflammatory process involving restricted areas of the spinal cord. The usually dramatic presentation with rapidly progressive symptoms involving motor, sensory and autonomic functions makes acute TM a medical emergency. Acute TM has been cited as a rare and unusual complication of systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS), but early diagnosis and aggressive treatment might improve the prognosis. This review of the literature (MEDLINE), showed that, within autoimmune diseases, acute transverse myelitis is mainly associated with SLE and SS. Previous studies seem to indicate that the presence of antiphospholipid antibodies might play a role in the etiology of TM. Although no uniform therapeutic protocol exists, and the prognosis is usually poor, early aggressive treatment (usually with EV pulses of methylprednisolone and cyclophosphamide) might improve the prognosis.
20506150 Detection of WA B cells in hepatitis C virus infection: a potential prognostic marker for 2010 Jul OBJECTIVE: An uncommon manifestation of hepatitis C virus (HCV) infection is systemic vasculitis associated with type II cryoglobulinemia (cryoglobulinemic vasculitis), a proliferative B cell disorder that transforms into B cell malignancy in 5-10% of patients. The monoclonal rheumatoid factors (mRF) that bear the WA cross-idiotype (Xid) are responsible for most cases of cryoglobulinemic vasculitis in patients with HCV infection. The purpose of this study was to determine whether WA B cells can be detected in asymptomatic patients with HCV infection, using sequence analysis of B cell clonal expansions (BCEs) to identify the WA Xid. METHODS: Asymptomatic patients with HCV infection and those without HCV infection as well as respective control patients with cryoglobulinemic vasculitis, whose serum was either negative or positive for WA mRF, were studied. BCEs were isolated in the patients' blood, and WA BCEs were identified by sequencing analysis. RESULTS: BCEs were detected in all control patients with cryoglobulinemic vasculitis, but only control patients with HCV infection had WA BCEs. None of the 33 asymptomatic patients without HCV infection had a BCE. WA BCEs were detected in 4 (7.4%) of 55 asymptomatic patients with HCV infection, in none of 14 patients with HCV infection and type III cryoglobulinemia, and in 5 (13.5%) of 37 patients with HCV infection and serum RF positivity. One patient with a WA BCE had splenic lymphoma markers and villous lymphocytes, and the villous lymphocytes were found to be WA B cells. CONCLUSION: By identification of the WA Xid, WA B cells can be detected in asymptomatic HCV-infected patients. WA B cells in asymptomatic patients with HCV infection may be a marker for the development of cryoglobulinemic vasculitis and associated B cell malignancies. The results of this study provide a basis for the development of the first practical clinical application of cross-idiotype analysis.
19565491 The CGGGG insertion/deletion polymorphism of the IRF5 promoter is a strong risk factor for 2009 Jul OBJECTIVE: Interferon regulatory factor 5 is a transcription factor involved in type I interferon (IFN) secretion. This study was undertaken to investigate whether a 5-bp (CGGGG insertion/deletion) promoter polymorphism is involved in genetic predisposition to primary Sjögren's syndrome (SS) and to assess the functional consequences of this polymorphism. METHODS: The exploratory cohort consisted of 185 patients with primary SS and 157 healthy controls, and the replication cohort consisted of 200 patients with primary SS and 282 healthy controls. Levels of IRF5 messenger RNA (mRNA) were assessed at baseline and after in vitro infection with reovirus in peripheral blood mononuclear cells (PBMCs) from 30 patients with primary SS and from salivary gland epithelial cells that had been cultured for 4 weeks from patients with primary SS or sicca symptoms. RESULTS: Carriage of the IRF5 4R CGGGG allele was associated with a greatly increased risk of primary SS in both cohorts (odds ratio 2.00 [95% confidence interval 1.5-2.7], P = 6.6 x 10(-6)). The CGGGG insertion/deletion polymorphism alone was sufficient to explain the association of primary SS with IRF5. The level of IRF5 mRNA in PBMCs depended significantly on genotype (P = 0.002) and was correlated with the levels of mRNA for the IFN-induced genes MX1 and IFITM1. Cultured salivary gland epithelial cells from patients carrying the 4R CGGGG IRF5 allele showed a high level of IRF5 mRNA (P = 0.04), which was amplified after reovirus infection (P = 0.026). CONCLUSION: Our findings indicate an association of the CGGGG insertion/deletion polymorphism of the IRF5 promoter with primary SS. Patients carrying the 4R CGGGG IRF5 allele had a high level of mRNA for IRF5 in PBMCs and salivary gland epithelial cells, mainly after in vitro viral infection. Patients with high levels of mRNA for IRF5 also had high levels of mRNA for type I IFN-induced genes in PBMCs.
19575332 Health-related quality of life in patients with primary Sjögren's syndrome: relationship 2009 OBJECTIVE: A cross-sectional study of 30 patients with primary Sjögren's syndrome (pSS) was performed to analyse the health-related quality of life and its relationship with serum levels of macrophage- and lymphocyte-derived cytokines. PATIENTS AND METHODS: Health-related quality of life was evaluated using the 36-item Short Form Health Survey (SF-36). Serum levels of interleukin (IL)-1beta, IL-6, IL-10, tumour necrosis factor (TNF)-alpha, and gamma-interferon (gamma-INF) were analysed by a sandwich immunoassay-based protein array system. RESULTS: Each of the eight scales of the SF-36 evaluating quality of life, as well as the physical composite score (PCS) and the mental composite score (MCS), showed a decrease in pSS patients. Similarly, patients with pSS showed significantly increased concentrations of each of the five cytokines analysed, when compared with the healthy control group (n = 20). In pSS patients, a significant negative correlation was detected between serum levels of IL-6 and the PCS of the SF-36. Those patients with concentrations of IL-6 higher than those of the healthy controls showed a significantly lower score in the dimensions of bodily pain and physical functioning, and in the PCS. CONCLUSIONS: Patients with pSS showed increased levels of several macrophage- and lymphocyte-derived cytokines, indicating the existence of an immune activation state. Serum levels of one of these cytokines, IL-6, were correlated with poor quality of life in these individuals.
20224179 Salivary gland and autoimmunity. 2009 Recent evidences suggest that the apoptotic pathway plays a central role in tolerazing T cells to tissue-specific self antigen, and may drive the autoimmune phenomenon in the salivary glands. We found that retinoblastoma-associated protein RbAp48 overexpression induces p53-mediated apoptosis in the salivary glands caused by estrogen deficiency. We demonstrated that transgenic (Tg) expression of RbAp48 resulted in the development of autoimmune exocrinopathy resembling Sjögren's syndrome (SS). CD4(+)T cell-mediated autoimmune lesions in the salivary glands were aggravated with age, in association with autoantibody productions. We obtained evidences that salivary epithelial cells can produce interferon-gamma (IFN-gamma) besides interleukin (IL)-18, which activates interferon regulatory factor-1 (IRF-1), and class II transactivator (CIITA). Indeed, the autoimmune lesions into Rag2(-/-) mice were induced by the adoptive transfer of lymph node cells from RbAp48-Tg mice. These results indicate a novel immunocompetent role of epithelial cells that can produce IFN-gamma, resulting in loss of local tolerance prior to developing gender-based autoimmunity. The studies reviewed the molecular mechanisms on the development of salivary gland autoimmunity, and gender-related differences in SS.
19644866 Fcgamma receptor-dependent expansion of a hyperactive monocyte subset in lupus-prone mice. 2009 Aug OBJECTIVE: Lupus-prone BXSB mice develop monocytosis characterized by selective accumulation of the Gr-1- monocyte subset. The aim of this study was to explore the possible role of activating IgG Fc receptors (FcgammaR) in the development of monocytosis and to characterize the functional phenotype of the Gr-1- subset that accumulates in lupus-prone mice bearing the NZB-type defective Fcgr2b allele for the inhibitory FcgammaRIIB. METHODS: The development of monocytosis was analyzed in BXSB and anti-IgG2a rheumatoid factor-transgenic C57BL/6 mice deficient in activating FcgammaR. Moreover, we assessed the expression levels of activating FcgammaR and inhibitory FcgammaRIIB on Gr-1+ and Gr-1- monocyte subsets in C57BL/6 mice bearing the C57BL/6-type or the NZB-type Fcgr2b allele. RESULTS: We observed monocytosis with expansion of the Gr-1- subset in anti-IgG2a-transgenic C57BL/6 mice expressing IgG2a, but not in those lacking IgG2a. Moreover, monocytosis barely developed in BXSB and anti-IgG2a-transgenic C57BL/6 mice deficient in activating FcgammaR. The Gr-1- subset that accumulated in lupus-prone mice displayed a unique hyperactive phenotype. It expressed very low levels of inhibitory FcgammaRIIB, due to the presence of the NZB-type Fcgr2b allele, but high levels of activating FcgammaRIV. This was in contrast to high levels of FcgammaRIIB expression and no FcgammaRIV expression on the Gr-1+ subset. CONCLUSION: Our results demonstrated a critical role of activating FcgammaR in the development of monocytosis and in the expansion of a Gr-1-FcgammaRIIB(low)FcgammaRIV+ hyperactive monocyte subset in lupus-prone mice. Our findings further highlight the importance of the NZB-type Fcgr2b susceptibility allele in murine lupus, the presence of which induces increased production of hyperactive monocytes as well as dysregulated activation of autoreactive B cells.
20662138 (64)Cu-1,4,7,10-Tetraazacyclododecane-N,N’,N’’,N’’’-tetraacetic acid agouti-re 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. The α(v)β(3) antagonists are being studied as antitumor and antiangiogenic agents, and the agonists are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). The peptide sequence Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). Most cyclic RGD peptides are composed of five amino acids. Haubner et al. (11) reported that various cyclic RGD peptides exhibit selective inhibition of binding (expressed as 50% inhibitory concentration (IC(50))) to α(v)β(3) (IC(50), 7–40 nM) but not to α(v)β(5) (IC(50), 600–4,000 nM) or α(IIb)β(3) (IC(50), 700–5,000 nM) integrins. Various radiolabeled cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). Only one cyclic RGD peptide, [(18)F]fluoropropionyl-galacto-c(-Arg-Gly-Asp-d-Phe-Lys) ([(18)F]-galacto-RGD), has been investigated for imaging expression of α(v)β(3) integrin in cancer patients with tumors. However, [(18)F]-galacto-RGD has been shown to have low tumor accumulation and low signal/background ratios. Cystine knot peptides (knottins) share a common disulfide-bonded framework and a triple-stranded β-sheet fold (13). The integrin-binding RGD motif was grafted into a knottin from the trypsin inhibitor II of the squash plant (Ecballium elaterium) to form proteolytic resistant knottin peptides. Knottin 2.5D (with three disulfide-bonds) was identified from a series of genetically engineered knottin peptides to have nanomolar binding to the α(v)β(3), α(v)β(5), and α(5)β(1) integrin receptors (14, 15). Knottin 2.5D was labeled with N-succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]SFB) to form 4-[(18)F]fluorobenzoyl-knottin 2.5D ([(18)F]FB-2.5D), which was evaluated for imaging tumor xenografts in mice with positron emission tomography (PET) (16). A truncated form of the agouti-related protein (AgRP), a 4-kDa knottin with four disulfide-bonds, was found to have high affinity for the α(v)β(3) integrin (17). AgRP-7C peptide was identified using the yeast-displayed AgRP library. Jiang et al. (18) evaluated (64)Cu-1,4,7,10-tetraazacyclododecane-N,N’,N’’,N’’’-tetraacetic acid agouti-related protein-7C ((64)Cu-DOTA-AgRP-7C) for PET imaging of α(v)β(3) integrin expression in tumors.
20067695 [Occipitocervical fixation: long-term follow-up in fifty-seven patients]. 2009 Dec PURPOSE OF THE STUDY: Occipitocervical fixation and spondylodesis is indicated in various cases of occipitocervical instability. The aim of this retrospective study was to evaluate the results of occipitocervical fixation at our institutions. MATERIAL: Between 1997 and 2007, a total of 57 patients underwent occipitocervical fixation (OC) there were 25 men and 32 women, from four to 77 years of age, with an average of 58.7 years. The patients were allocated to two groups according to the method of OC fixation used: tying wires or cables (group 1) screw-rod or screw-plate systems (group 2). Indications for OC fixation included trauma in 15, rheumatoid arthritis (RA) in 28, destruction due to psoriasis in one, tumour in eight, and congenital anomalies of the cervico-cranial junction in five patients. In five patients with tumour, OC fixation was completed with a transoral or transmandibular procedure. The C0-T 1 or C0-T 2 segments were fixed in 22 patients, C0-C2 segments in 14, C0-C3 segments in six, C0-C4 segments in two, C0-C5 segments in eight and C0-C6 segments in five patients. METHODS: In atlanto-occipital dislocation, comminuted fractures of the ;atlas or similar injuries, C0-C1-C2 segments were fused in congenital anomaly, the C0-to-lower cervical spine was fixed, with C1 being avoided. The RA patients were treated by fixation of the C0 to T1 or T2 segments. The atlas was fixed by the screw method of Goel, the C2 joint by that of Judet, or stable fusion of the two vertebrae was carried out by the Magerl transarticular technique. For the middle and lower cervical spine, lateral mass screw fixation by the Magerl method was used, and from C7 caudally the vertebrae were fixed transpedicularly. Occasionally, in small children in particular, a Ransford frame fixed with wires or cables was used. In principle, an extent of fixation as small as possible was employed. The patients were evaluated at a final follow-up ranging between 12 and 132 months after the primary surgery (average, 42.7 months). Indications for surgery and the method and extent of instrumentation were recorded. The evaluation included pain and neurological deficit assessment, radiographic evidence of the stability of fixation and bone union and intra-operative and early and late post-operative complications. RESULTS: Of the 57 patients, bone fusion was the objective of surgery in 52. Further five patients died of associated injuries or serious medical complications shortly after the operation. Of the remaining 47, bone union was achieved in 44 patients (93.6%). Pseudoarthrosis developed in three patients who, however, because of a higher age and minimal complaints did not require revision surgery. In terms of bone union, there was no difference between a short (C0-C2) and a long (C0-CX or C-T) fixation. No differences among fixation materials were found. The differences in percent bone union after spondylodesis between the tying-wire and screw-rod fixation systems were not statistically significant (p > 0.05). In the patients treated for RA, psoriasis or congenital anomaly, the Nurick scale score significantly improved at 2 years after surgery (p < 0.05). In comparison with the others, the RA patients had a significantly higher number of complications (p < 0.05). The patients treated for tumour showed a significant difference between the pre- and post-operative VAS values (p < 0.05). DISCUSSION: Of the patients with RA, psoriasis or congenital anomaly, 57.6% showed post-operative improvement in the Nurick scale score by 1-2 but never more than by 2. A decrease in pain intensity and neurological findings was recorded in 88.2% of the patients. This is in agreement with the results published in the international literature. In the patients treated for trauma, a high proportion (53.3%) had neurological deficit, which is unusually high for craniocervical injuries. This can be explained by the fact that OC fixation is used only in the most serious injuries. Of five patients with neurological deficit of Frankel grade A or B, three died and two required mechanical ventilation. Less serious neurological findings of Frankel grade C or D in three patients improved to a normal condition. CONCLUSIONS: Rigid OC fixation is a very effective method for the treatment of craniocervical junction instability. The currently used implants allow us to achieve high stability and efficiency of bone union. Regardless of the instrumentation used, fusion is achieved in more than 90%, and clinical improvement in more than 80% of the patients.
19808137 Pharmacokinetic and bioequivalence comparison between orally disintegrating and convention 2009 Aug BACKGROUND: Flurbiprofen, an NSAID, is used for the treatment of inflammation and pain caused by rheumatoid arthritis and osteoarthritis as well as soft-tissue injuries. A new orally disintegrating tablet (ODT) of flurbiprofen has recently been developed; this study was conducted to provide support for this drug to obtain marketing authorization in China. OBJECTIVE: The aim of the study was to compare the pharmacokinetic properties and bioequivalence of flurbiprofen 50-mg ODT (test) with a conventional flurbiprofen 50-mg tablet (reference) under fasting conditions in healthy volunteers. METHODS: This was a single-dose, randomized-sequence, open-label, 2-period crossover study. Healthy, nonsmoking Chinese male volunteers were randomly assigned to receive 150 mg (administered as three 50-mg tablets) of either the test or reference formulation of flurbiprofen, followed by a 7-day washout period and administration of the alternate formulation. Study drugs were administered after a 12-hour overnight fast. Blood samples were collected before dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after dosing. Serum flurbiprofen concentrations were analyzed using a validated nonstereospecific liquid chromatography/tandem mass spectrometry method. Pharmacokinetic parameters, including C(max), T(max), t(1/2), AUC(0-24), and AUC(0-infinity), were calculated and analyzed statistically. C(max), AUC(0-24), and AUC(0-infinity) were used to test for bioequivalence after natural logarithm (ln)-transformation. Tolerability was evaluated throughout the study by clinical assessments, vital sign monitoring, physical examinations, 12-lead ECG, clinical laboratory tests, and questioning subjects about adverse events (AEs). RESULTS: A total of 20 Chinese males (mean [SD] age, 21.4 [2.5] years [range, 19-28 years]; height, 174.4 [4.2] cm [range, 169-183 cm]; weight, 63.2 [5.1] kg [range, 56-78 kg]; body mass index, 20.8 [1.4] kg/m(2) [range, 19-24 kg/m(2)]) completed the study. No period or sequence effect was observed. The 90% CIs for the ln-transformed ratios of Cmax, AUC(0-24), and AUC(0-infinity) were 99.9% to 115.9%, 97.8% to 107.9%, and 100.3% to 110.9%, respectively, meeting the predetermined criteria for bioequivalence. Two subjects (10.0%) experienced 1 of 2 mild AEs (increase in total bilirubin and dizziness), which were not considered to be associated with study drug administration. CONCLUSIONS: This single-dose 150-mg (three 50-mg tablets) study of each formulation of flurbiprofen found that the test and reference products met the regulatory criteria for bioequivalence in these fasting healthy Chinese male volunteers. Both formulations were generally well tolerated. State Food and Drug Administration of China study registration number: 2005L04356.
19482216 Glucocorticoid resistance in inflammatory diseases. 2009 May 30 Glucocorticoid resistance or insensitivity is a major barrier to the treatment of several common inflammatory diseases-including chronic obstructive pulmonary disease and acute respiratory distress syndrome; it is also an issue for some patients with asthma, rheumatoid arthritis, and inflammatory bowel disease. Several molecular mechanisms of glucocorticoid resistance have now been identified, including activation of mitogen-activated protein (MAP) kinase pathways by certain cytokines, excessive activation of the transcription factor activator protein 1, reduced histone deacetylase-2 (HDAC2) expression, raised macrophage migration inhibitory factor, and increased P-glycoprotein-mediated drug efflux. Patients with glucocorticoid resistance can be treated with alternative broad-spectrum anti-inflammatory treatments, such as calcineurin inhibitors and other immunomodulators, or novel anti-inflammatory treatments, such as inhibitors of phosphodiesterase 4 or nuclear factor kappaB, although these drugs are all likely to have major side-effects. An alternative treatment strategy is to reverse glucocorticoid resistance by blocking its underlying mechanisms. Some examples of this approach are inhibition of p38 MAP kinase, use of vitamin D to restore interleukin-10 response, activation of HDAC2 expression by use of theophylline, antioxidants, or phosphoinositide-3-kinase-delta inhibitors, and inhibition of macrophage migration inhibitory factor and P-glycoprotein.
19420741 Role of sulfated O-glycans expressed by high endothelial venule-like vessels in pathogenes 2009 May Lymphocyte homing is mediated by a cascade of adhesive interactions between circulating lymphocytes and specialized endothelial cells comprising high endothelial venules (HEVs). Sulfated O-glycans expressed on HEVs, collectively called peripheral lymph node addressin (PNAd), interact with L-selectin expressed on lymphocytes, contributing to the initial step of the lymphocyte homing. In chronic inflammatory states, PNAd is induced on HEV-like vessels but absent in non-lymphoid tissues under normal conditions. Such HEV-like vessels have been observed in various chronic inflammatory diseases including rheumatoid arthritis, lymphocytic thyroiditis, Helicobacter pylori-associated chronic gastritis, and inflammatory bowel disease (IBD), and implicated in lymphocyte recruitment in those diseases. In H. pylori-associated chronic gastritis, PNAd-expressing HEV-like vessels are induced, and the progression of chronic inflammation is highly correlated with appearance of these vessels. Furthermore, eradication of H. pylori by antibiotics resulted in disappearance of PNAd. These results indicate that inhibition of PNAd formation could have therapeutic effect by attenuating lymphocyte recruitment. In ulcerative colitis (UC), PNAd-expressing HEV-like vessels are induced, preferentially in the active phase, and T cells, particularly CD4(+) T cells, are closely associated with these vessels, suggesting that T cell recruitment via PNAd-expressing HEV-like vessels plays at least a partial role in UC pathogenesis. Additionally, N-acetylglucosamine-6-O-sulfotransferase 1 (GlcNAc6ST-1) is suggested to be a candidate to regulate PNAd induction on HEV-like vessels in UC. These results provide a potential therapeutic strategy to treat UC by blocking T cell adhesion to PNAd-expressing HEV-like vessels. Inhibition or down-regulation of GlcNAc6ST-1 may be an alternative.
19407801 Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation. 2009 Apr 30 Gene silencing by double-stranded RNA, denoted RNA interference, represents a new paradigm for rational drug design. However, the transformative therapeutic potential of short interfering RNA (siRNA) has been stymied by a key obstacle-safe delivery to specified target cells in vivo. Macrophages are particularly attractive targets for RNA interference therapy because they promote pathogenic inflammatory responses in diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease and diabetes. Here we report the engineering of beta1,3-D-glucan-encapsulated siRNA particles (GeRPs) as efficient oral delivery vehicles that potently silence genes in mouse macrophages in vitro and in vivo. Oral gavage of mice with GeRPs containing as little as 20 microg kg(-1) siRNA directed against tumour necrosis factor alpha (Tnf-alpha) depleted its messenger RNA in macrophages recovered from the peritoneum, spleen, liver and lung, and lowered serum Tnf-alpha levels. Screening with GeRPs for inflammation genes revealed that the mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) is a previously unknown mediator of cytokine expression. Importantly, silencing Map4k4 in macrophages in vivo protected mice from lipopolysaccharide-induced lethality by inhibiting Tnf-alpha and interleukin-1beta production. This technology defines a new strategy for oral delivery of siRNA to attenuate inflammatory responses in human disease.
19362586 PARP inhibitors: new partners in the therapy of cancer and inflammatory diseases. 2009 Jul 1 Poly(ADP-ribose) polymerases (PARPs) are defined as cell signaling enzymes that catalyze the transfer of ADP-ribose units from NAD(+) to a number of acceptor proteins. PARP-1, the best characterized member of the PARP family, which currently comprises 18 members, is an abundant nuclear enzyme implicated in cellular responses to DNA injury provoked by genotoxic stress. PARP is involved in DNA repair and transcriptional regulation and is now recognized as a key regulator of cell survival and cell death as well as a master component of a number of transcription factors involved in tumor development and inflammation. PARP-1 is essential to the repair of DNA single-strand breaks via the base excision repair pathway. Inhibitors of PARP-1 have been shown to enhance the cytotoxic effects of ionizing radiation and DNA-damaging chemotherapy agents, such as the methylating agents and topoisomerase I inhibitors. There are currently at least five PARP inhibitors in clinical trial development. Recent in vitro and in vivo evidence suggests that PARP inhibitors could be used not only as chemo/radiotherapy sensitizers, but also as single agents to selectively kill cancers defective in DNA repair, specifically cancers with mutations in the breast cancer-associated genes (BRCA1 and BRCA2). PARP becomes activated in response to oxidative DNA damage and depletes cellular energy pools, thus leading to cellular dysfunction in various tissues. The activation of PARP may also induce various cell death processes and promotes an inflammatory response associated with multiple organ failure. Inhibition of PARP activity is protective in a wide range of inflammatory and ischemia-reperfusion-associated diseases, including cardiovascular diseases, diabetes, rheumatoid arthritis, endotoxic shock, and stroke. The aim of this review is to overview the emerging data in the literature showing the role of PARP in the pathogenesis of cancer and inflammatory diseases and unravel the solid body of literature that supports the view that PARP is an important target for therapeutic intervention in critical illness.
19201773 Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis. 2009 Jun OBJECTIVES: Genetic susceptibility is known to play a large part in the predisposition to the inflammatory bowel diseases (IBDs) known as Crohn's disease (CD) and ulcerative colitis (UC). The IL2/IL21 locus on 4q27 is known to be a common risk locus for inflammatory disease (shown in coeliac disease, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus and psoriasis), while the roles that interleukin 2 (IL2) and IL21 play in the immune response also make them attractive candidates for IBD. The objective of this study was to test for association between the IL2/IL21 locus and the IBDs. METHODS: The four single nucleotide polymorphisms (SNPs) in the IL2/IL21 locus most associated with coeliac disease were genotyped in 1590 subjects with IBD and 929 controls from The Netherlands, and then replicated in a North American cohort (2387 cases and 1266 controls) and an Italian cohort (805 cases and 421 controls), yielding a total of 4782 cases (3194 UC, 1588 CD) and 2616 controls. Allelic association testing and a pooled analysis using a Cochran-Mantel-Haenszel test were performed. RESULTS: All four SNPs were strongly associated with UC in all three cohorts and reached genome-wide significance in the pooled analysis (rs13151961 p = 1.35 x 10(-10), rs13119723 p = 8.60 x 10(-8), rs6840978 p = 3.0 7x 10(-8), rs6822844 p = 2.77 x 10(-9)). A moderate association with CD was also found in the pooled analysis (p value range 0.0016-9.86 x 10(-5)). CONCLUSIONS: A strong association for the IL2/IL21 locus with UC was found, which also confirms it as a general susceptibility locus for inflammatory disease.