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ID PMID Title PublicationDate abstract
19633969 Effect of ethnic origin (Caucasians versus Turks) on the prevalence of rheumatic diseases: 2009 Nov The objective of this study was to compare the prevalence of musculoskeletal complaints and rheumatic disorders in Caucasians and Turks in an identical environment. Subjects were selected randomly for an interview from Tehran's 22 districts. The Community Oriented Program for Control of Rheumatic Diseases questionnaire was filled in, positive cases were examined, and if needed, laboratory or X-ray tests were performed. A total of 4,096 houses were visited, and 10,291 persons were interviewed. They were 71.4% Caucasians and 23.1% Turks with similar distribution of age and gender. Musculoskeletal complaints of the past 7 days were detected in 40.8% of Caucasians and 45.5% of Turks (p < 0.001). In Caucasians, the total of musculoskeletal complaints in men was 33.8% (95% CI, 31.4-36.2%) versus 48.3% in women (95% CI, 45.7-50.8%). In Turks, the total of musculoskeletal complaints in men was 36.6% (95% CI, 32.2-41.1%) versus 55.8% in women (95% CI, 55.8-60.6%). The data of Caucasians versus Turks were as follows: knee pain 20.2% (95% CI, 18.2-22.1) versus 24.1% (95% CI, 20.5-27.6), with p < 0.001; dorso-lumbar spine pain 15.1% (95% CI, 13.6-16.6) versus 18.4% (95% CI, 15.1-21.8), with p < 0.001; shoulder pain 10.7% (95% CI, 9.4-11.9) versus 12.3% (95% CI, 9.7-14.8), with p = 0.025; osteoarthritis 14.1% (95% CI, 12.8-15.2) versus 16.4% (95% CI, 14.3-18.6), p = 0.04; and knee osteoarthritis 12.3% (95% CI, 11.8-14.1) versus 15.3% (95% CI, 13.3-17.4), with p < 0.001). There were no significant differences regarding the prevalence of soft tissue rheumatism, rheumatoid arthritis, ankylosing spondylitis, Behcet's disease, fibromyalgia, and gout. Although musculoskeletal complaints were more frequent in Turks than in Caucasians, the prevalence of rheumatic disorders was rather similar except for knee osteoarthritis.
19530981 The hepatic safety and tolerability of the cyclooxygenase-2 selective NSAID celecoxib: poo 2009 Aug OBJECTIVE: To assess the hepatic safety and tolerability of celecoxib versus placebo and three commonly prescribed nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). RESEARCH DESIGN AND METHODS: This was a retrospective, pooled analysis of a 41-study dataset involving patients with osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, chronic low back pain, and Alzheimer's disease. Criteria for selection of studies were: (1) Randomized, parallel-group design and planned treatment duration of > or =2 weeks (2) > or =1 placebo or NSAID comparator (3) > or =1 arm with celecoxib at total daily dose of > or =200 mg (4) Data available as of October 31, 2004 Data were pooled by treatment and subject from the safety analysis population of included studies. Treatment-emergent hepatobiliary adverse events (AEs) were compared for celecoxib <200 mg/day (943 patients), 200 mg/day (12 008 patients), 400 mg/day (7380 patients), and 800 mg/day (4602 patients); placebo (4057 patients); diclofenac 100-150 mg/day (7639 patients); naproxen 1000 mg/day (2953 patients); and ibuprofen 2400 mg/day (2484 patients). Hepatobiliary laboratory abnormalities were also analyzed. RESULTS: There were no cases of liver failure, treatment-related liver transplant, or treatment-related hepatobiliary death. Incidence of serious hepatic AEs was low, with 13 (0.05%) serious hepatic AEs among 24 933 celecoxib-treated patients, and 16 (0.21%) among 7639 diclofenac-treated patients. No patients receiving celecoxib or any nonselective NSAID met criteria for Hy's rule (alanine aminotransferase [ALT] > or =3 x upper limit of normal [ULN] with bilirubin > or =2 x ULN). The incidence of notable (> or =5 x ULN) and severe (> or =10 x ULN) ALT elevations was similar for all treatment groups except diclofenac. Significantly fewer hepatobiliary AEs were reported for celecoxib (any dose; 1.11%) than for diclofenac (vs. 4.24%, p < 0.0001); for ibuprofen (vs. 1.53%, p = 0.06) and placebo (vs. 0.89%, p = 0.21) the incidence of AEs was comparable to celecoxib. LIMITATIONS: A number of limitations should be considered when evaluating the results: findings were limited by the quality and reporting of the studies selected; difficulty in estimating the incidence of AEs due to the low frequency of events; acetaminophen not included as an active comparator. CONCLUSIONS: In this pooled analysis, the incidence of hepatic AEs in patients treated with celecoxib was similar to that for both placebo-treated patients and patients treated with ibuprofen or naproxen, but lower than for diclofenac.
18971939 CD226 Gly307Ser association with multiple autoimmune diseases. 2009 Jan Genome-wide association studies provide insight into multigenic diseases through the identification of susceptibility genes and etiological pathways. In addition, the identification of shared variants among autoimmune disorders provides insight into common disease pathways. We previously reported an association of a nonsynonymous single nucleotide polymorphism (SNP) rs763361/Gly307Ser in the immune response gene CD226 on chromosome 18q22 with type 1 diabetes (T1D) susceptibility. Here, we report efforts toward identifying the causal variant by exonic resequencing and tag SNP mapping of the 18q22 region in both T1D and multiple sclerosis (MS). In addition to the analysis of newly available samples in T1D (2088 cases and 3289 controls) and autoimmune thyroid disease (AITD) (821 cases and 1920 controls), resulting in strong support for the Ser(307) association with T1D (P=3.46 x 10(-9)) and continued potential evidence for AITD (P=0.0345), we provide evidence for association of Gly307Ser with MS (P=4.20 x 10(-4)) and rheumatoid arthritis (RA) (P=0.017). The Ser(307) allele of rs763361 in exon 7 of CD226 predisposes to T1D, MS, and possibly AITD and RA, and based on the tag SNP analysis, could be the causal variant.
18771438 Identification of the most active interleukin-32 isoform. 2009 Apr Cytokines are crucial in host defence against pathogens such as bacteria, viruses, fungi and parasites. A newly described cytokine, interleukin-32 (IL-32), induces various proinflammatory cytokines (tumour necrosis factor-alpha, IL-1beta, IL-6) and chemokines in both human and mouse cells through the nuclear factor-kappaB and p38 mitogen-activated protein kinase inflammatory signal pathway. The IL-32 primarily acts on monocytic cells rather than T cells. In an attempt to isolate the IL-32 soluble receptor, we used an IL-32 ligand-affinity column to purify neutrophil proteinase 3, which is a serine proteinase involved in many inflammatory diseases. IL-32 has biological activity associated with Mycobacterium tuberculosis and chronic proinflammatory diseases such as rheumatoid arthritis. IL-32 is transcribed as six alternative splice variants and the biological activity of each individual isoform remains unknown. Here, we cloned the complementary DNA of the four IL-32 isoforms (alpha, beta, gamma and delta) that are the most representative IL-32 transcripts. To produce recombinant protein with a high yield, the amino acids of two cysteine residues were mutated to serine residues, because serine residues are not conserved among different species. The multi-step purified recombinant IL-32 isoform proteins were assessed for their biological activities with different cytokine assays. The gamma isoform of IL-32 was the most active, although all isoforms were biologically active. The present study will provide a specific target to neutralize endogenous IL-32, which may contribute to basic and clinical immunology.
20945564 4-[(18)F]Fluorobenzoyl-knottin 2.5D. 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 used for imaging, [(18)F]fluoropropionyl-galacto-c(Arg-Gly-Asp-d-Phe-Lys) ([(18)F]-galacto-RGD), has been investigated for measuring 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 trypsin inhibitor II of the squash plant (Ecballium elaterium). Knottin 2.5D (with three disulfide bonds; (GCPQGRGDWAPTSCSQDSDCLAGCVCGPNGFCG-NH(2)) 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) and evaluated for positron emission tomography (PET) imaging of tumor xenografts in mice (16).
20638987 Estrogen and glucocorticoid regulate osteoblast differentiation through the interaction of 2010 Aug 30 Imbalanced functions between osteoclasts and osteoblasts are involved in inflammatory bone damage. The clinical effectiveness of blocking TNF-alpha in treatment of active rheumatoid arthritis established the significance of TNF-alpha in the pathogenesis. In the present study, we investigated the cellular mechanism by which estrogen and glucocorticoid interact in osteoblastic differentiation regulated by BMP and TNF-alpha using mouse myoblastic C2C12 cells. The expression of estrogen receptors, (ER)alpha and ERbeta, and glucocorticoid receptor (GCR) was significantly increased by BMP-2 treatment regardless of the presence of estradiol and dexamethasone. Estradiol, but not dexamethasone, enhanced BMP-induced Runx2 and osteocalcin expression in C2C12 cells. In addition, TNF-alpha suppressed BMP-2-induced Runx2 and osteocalcin expression, and estradiol and dexamethasone reversed the TNF-alpha effects on BMP-2-induced Runx2 expression. Dexamethasone also abolished osteocalcin expression induced by BMP-2. Interestingly, BMP-2-induced Smad1/5/8 phosphorylation and Id-1 promoter activity were enhanced by estradiol pretreatment. On the other hand, dexamethasone suppressed BMP-2-induced Smad1/5/8 activation. TNF-alpha-induced SAPK/JNK activity was suppressed by estradiol, while NFkappaB phosphorylation was inhibited by dexamethasone. Of note, the inhibitory effects of TNF- on BMP-2-induced Runx2 and osteocalcin expression were reversed by SAPK/JNK inhibition regardless of the presence of estradiol. The estradiol effects that enhance BMP-2-induced Runx2 and osteocalcin mRNA expression were restored by antagonizing ER, and moreover, membrane-impermeable estradiol-BSA failed to enhance the BMP-2-induced osteoblastic differentiation. Thus, estrogen and glucocorticoid are functionally involved in the process of osteoblast differentiation regulated by BMPs and TNF-alpha. BMP-2 increases the sensitivities of ERs and GCR, whereas estrogen and glucocorticoid differentially regulate BMP-Smad and TNF-alpha signaling.
20081827 The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors. 2010 Feb Deregulation of the phosphoinositide-3-OH kinase (PI(3)K) pathway has been implicated in numerous pathologies including cancer, diabetes, thrombosis, rheumatoid arthritis and asthma. Recently, small-molecule and ATP-competitive PI(3)K inhibitors with a wide range of selectivities have entered clinical development. In order to understand the mechanisms underlying the isoform selectivity of these inhibitors, we developed a new expression strategy that enabled us to determine to our knowledge the first crystal structure of the catalytic subunit of the class IA PI(3)K p110 delta. Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI(3)K inhibitors reveal that selectivity toward p110 delta can be achieved by exploiting its conformational flexibility and the sequence diversity of active site residues that do not contact ATP. We have used these observations to rationalize and synthesize highly selective inhibitors for p110 delta with greatly improved potencies.
19969058 Bee venom suppresses PMA-mediated MMP-9 gene activation via JNK/p38 and NF-kappaB-dependen 2010 Feb 17 ETHNOPHARMACOLOGICAL RELEVANCE: Bee venom has been used for the treatment of inflammatory diseases such as rheumatoid arthritis and for the relief of pain in traditional oriental medicine. AIM OF THE STUDY: The purpose of this study is to elucidate the effects of bee venom on MMP-9 expression and determine possible mechanisms by which bee venom relieves or prevents the expression of MMP-9 during invasion and metastasis of breast cancer cells. We examined the expression and activity of MMP-9 and possible signaling pathway affected in PMA-induced MCF-7 cells. MATERIAL AND METHODS: Bee venom was obtained from the National Institute of Agricultural Science and Technology of Korea. Matrigel invasion assay, wound-healing assay, zymography assay, western blot assay, electrophoretic mobility shift assay and luciferase gene assay were used for assessment. RESULTS: Bee venom inhibited cell invasion and migration, and also suppressed MMP-9 activity and expression, processes related to tumor invasion and metastasis, in PMA-induced MCF-7 cells. Bee venom specifically suppressed the phosphorylation of p38/JNK and at the same time, suppressed the protein expression, DNA binding and promoter activity of NF-kappaB. The levels of phosphorylated ERK1/2 and c-Jun did not change. We also investigated MMP-9 inhibition by melittin, apamin and PLA(2), representative single component of bee venom. We confirmed that PMA-induced MMP-9 activity was significantly decreased by melittin, but not by apamin and phospholipase A(2). These data demonstrated that the expression of MMP-9 was abolished by melittin, the main component of bee venom. CONCLUSION: Bee venom inhibits PMA-induced MMP-9 expression and activity by inhibition of NF-kappaB via p38 MAPK and JNK signaling pathways in MCF-7 cells. These results indicate that bee venom can be a potential anti-metastatic and anti-invasive agent. This useful effect may lead to future clinical research on the anti-cancer properties of bee venom.
19591173 RAGE expression and NF-kappaB activation attenuated by extracellular domain of RAGE in hum 2009 Nov The receptor for advanced-glycation-end-products (RAGE) has been implicated as a pro-inflammatory factor in chronic inflammatory conditions such as diabetes mellitus and rheumatoid arthritis. The aim of this study was to investigate the inhibitory effect of the soluble-RAGE (sRAGE), the extracellular domain of RAGE, on RAGE expression and NF-kappaB translocation in human-salivary gland-cell-lines (HSG). Cells were stimulated with agonist S100A4, fusion protein of RAGE encompassing the extracellular domain of RAGE (ex-RAGE), ex-RAGE followed by S100A4, or S100A4 followed by ex-RAGE. Our study indicates that RAGE expression was highest at 150 microg/microl of S100A4 and efficiently down-regulated by 1.8-fold (P < 0.05) when ex-RAGE was incubated prior to agonist S100A4. RAGE protein was also consistently down-regulated by 20-40% with pre-incubation of ex-RAGE. More importantly, nuclear translocation of p65 and p52 of NF-kappaB by S100A4 was inhibited in the presence of ex-RAGE, confirming anti-inflammatory function of ex-RAGE. In conclusion, ex-RAGE down-regulates RAGE expression and inhibits p65 and p52 activation in HSG, providing evidence that ex-RAGE functions as a "decoy" to RAGE-ligand interaction and thus potentially dampening inflammatory conditions.
19233601 Risk factors related to the failure of venous leg ulcers to heal with compression treatmen 2009 May BACKGROUND: Compression therapy is the most widely used treatment for venous leg ulcers and it was used in different forms for more than 400 years. Published healing rates of venous ulcers obtained with compression therapy vary widely from 40-95%. According to numerous studies, it has been suggested that the application of external pressure to the calf muscle raises the interstitial pressure resulting in improved venous return and reduction in the venous hypertension. Several risk factors have been identified to be correlated with the failure of venous leg ulcers to heal with compression therapy (longer ulcer duration; large surface area; fibrinous deposition present on >50% of the wound surface and an Ankle Brachial Pressure Index (ABPI) of <0.85. METHODS: An open prospective single-center study was performed in order to determine possible risk factors associated with the failure of venous ulcers to heal when treated with multi-layer high compression bandaging system for 52 weeks. In the study, 189 patients (101 women, 88 men; mean age 61 years) with venous leg ulcers (ulcer surface >5 cm(2); duration >3 months) were included. The study excluded patients with arterial disease (ABPI <0.8), heart insufficiency with ejection fraction (EF) <35, pregnancy, cancer disease, rheumatoid arthritis, and diabetes. Based on clinical opinion and available literature, the following were considered as potential risk factors: sex, age, ulceration surface, time since ulcer onset, previous operations, history of deep vein thrombosis, body mass index (BMI), reduction in calf circumference >3 cm during the first 50 days of treatment, walking distance during the day <200 meters, calf:ankle circumference ratio <1.3, fixed ankle joint, history of surgical wound debridement, >50% of wound covered with fibrin, depth of the wound >2 cm. RESULTS: Within 52 weeks of limb-compression therapy, 24 (12.7%) venous ulcers had failed to heal. A small ulceration surface (<20 cm(2)), the duration of the venous ulcer <12 months, a decrease in calf circumference of more than 3 cm, and emergence of new skin islets on >10% of wound surface during the first 50 days of treatment were favorable prognostic factors for ulcer healing. A large BMI (>33 kg/m(2)), short walking distance during the day (<200 m), a history of wound debridement, and ulcers with deepest presentation (>2 cm) were indicators of slow healing. Calf:ankle circumference ratio <1.3, fixed ankle joint, and reduced ankle range of motion were the only independent parameters associated with non-healing (P < .001). CONCLUSION: The results obtained in this study suggest that non-healing venous ulcers are related to the impairment of the calf muscle pump.
19008314 Tumor necrosis factor-related apoptosis-inducing ligand inhibits experimental autoimmune t 2009 Apr There have been several reports that TNF-related apoptosis-inducing ligand (TRAIL) has the ability to suppress the development of experimental autoimmune diseases, including a mouse model of experimental autoimmune encephalomyelitis, a rabbit model of rheumatoid arthritis, type 1 diabetes mellitus, in mice and experimental autoimmune thyroiditis (EAT) in mice. However, the mechanism underlying TRAIL effect is not well defined. In the present study, we specifically examined TRAIL effects on CD4(+)CD25(+) regulatory T cells. CD4(+)CD25(+) T cells prepared from mouse thyroglobulin (mTg)-immunized CBA/J mice proliferate in the presence of TRAIL and dendritic cells in vitro. These CD4(+)CD25(+) T cells included both CD4(+)CD25(+)CD45RB(Low) (regulatory) and CD4(+)CD25(+)CD45RB(High) (effector) T cells. Our results demonstrated that mTg-immunized mice treated with TRAIL showed significant increases in the number of CD4(+)CD25(+)CD45RB(Low) T cells compared with mice immunized with mTg alone. CD4(+)CD25(+)CD45RB(Low) T cells expressed much higher levels of the forkhead family transcription factor, IL-10, and TGFbeta1 than CD4(+)CD25(+)CD45RB(High) T cells, and these cells can completely suppress the proliferation of the mTg-primed splenocytes in lower concentrations than the unfractionated CD4(+)CD25(+) T cells. Furthermore, transfer of these cells into CBA/J mice prior to mTg-primed splenocyte injection could markedly reduce the frequency and severity of EAT development. CD4(+)CD25(+)CD45RB(Low) T cells were more effective at suppressing histological thyroiditis than unfractionated cells. These results indicated that TRAIL can increase the number of mTg-specific CD4(+)CD25(+)CD45RB(Low) T cells, inhibiting autoimmune responses and preventing the progression of EAT. These findings reveal a novel mechanism by which TRAIL could inhibit autoimmune disease.
21029974 Distribution of Z-scores in a University cohort with an emphasis on "high" bone mineral de 2010 Oct High bone mineral density (BMD) is currently not defined by the International Society for Clinical Densitometry with a specific Z-score cutoff; however, it has been suggested that a Z-score greater than or equal to 2.5 is not normal. Institutional Review Board approval was obtained. We evaluated a University dual-energy X-ray absorptiometry database over the previous 24 mo to define Z-score distributions. A Z-score greater than or equal to 2.5 was selected as the outcome event of interest in a logistic regression for adjusted odds ratio. The covariates were height; weight; body mass index (BMI); gender; menopausal status; use of female hormones; presence of insufficiency fractures after 50 yr of age; previous fractures; previous surgeries (back surgeries, vertebroplasty, or kyphoplasty); transplant history; presence of long-term chronic conditions (asthma, lupus, rheumatoid arthritis, or cystic fibrosis); eating disorder; current use of glucocorticoids; smoking status; and current and past use of osteoporosis pharmacological therapies. The study included a total of 8216 patients; 7212 (87.8%) were females, and 1044 (12.2%) were males. In the total population, 13.6% had a Z-score greater than or equal to 2.5 at the lumbar spine, femoral neck, or total hip. Only 0.2% of the males and 0.8% of the females had a Z-score greater than or equal to 2.5 at all 3 sites. The 97.5th percentiles for Z-scores in our population for men and women, respectively, were 3.4 and 3.9 at the lumbar spine, 1.5 and 2.1 at the femoral neck, and 1.6 and 2.2 at the total hip. The 99th percentile for Z-scores for men and women, respectively, were 4.9 and 4.7 at the lumbar spine, 2.4 and 2.7 at the femoral neck, and 2.2 and 2.7 at the total hip. At the lumbar spine, female gender and weight were found to be risk factors for a high Z-score (≥ 2.5). The use of glucocorticoids, bone-active medications, BMI, and smoking were significantly less likely to predict a lumbar spine Z-score greater than or equal to 2.5. A high total-hip Z-score is predicted by increasing weight, whereas those patients using bone-active medications were less likely to have high BMD at the total hip. At the femoral neck, there were no significant risk factors related to a Z-score greater than or equal to 2.5; those taking bone-active medications were significantly less likely to have a high Z-score. These data suggest that a high Z-score is common at 1 or more sites. Further research about the criteria for the diagnosis of high BMD is warranted.
19956032 Biomechanical assessment of bilateral C1 laminar hook and C1-2 transarticular screws and b 2009 Dec STUDYDESIGN: In vitro biomechanical test was conducted to compare the stability of 5 different atlantoaxial posterior fusion techniques. OBJECTIVE: To evaluate the biomechanical stability of an atlas laminar hook combined with transarticular (TA) screws relative to 4 different conventional fusion techniques. SUMMARY OF BACKGROUND DATA: The atlantoaxial instability caused by fractures, rheumatoid arthritis, congenital deformity, or traumatic lesions of the transverse ligament often result in acute or chronic spinal cord compression, a possible threat to a patient's life. Posterior atlantoaxial fixations are used to reconstruct the stability of atlantoaxial articulation. Conventional posterior atlantoaxial fixations are associated with high rates of pseudoarthrosis and carry the potential risk of neurologic complication. TA screw fixation can provide an excellent biomechanical stability. As a modified 3-point fixation technique, the bilateral C1-2 TA screws have been combined with C1 laminar hook and bone grafts. This modified technique had carried good clinical outcomes. METHODS: Eight human specimens (C0-C4) were loaded nondestructively with pure moments and the range of motion at the level of C1-C2 was measured. Eight specimens were implanted with each of the following techniques, respectively: Gallie fixation, C1-2 TA screw fixation combined with Gallie fixation, C1-2 TA screw fixation, C1 laminar hook combined with C1-2 TA screw fixation plus bone grafts, and the C1 lateral mass screws in the atlas combined with C2 isthmic screws in axis. RESULTS: Although the C1-2 TA screws best restricted lateral bending and axial rotation, the modified 3-point fixation technique additionally restricted flexion-extension and provided the excellent stability. Differences in axial rotation and lateral bending (with + or - 1.5 Nm load) were observed when the 3-point fixation techniques (TA + Gallie and TA + hook) were compared with atlas lateral mass screws in the atlas combined with isthmic screws in axis. CONCLUSIONS: The modified C1 laminar hook combined with C1-2 TA screws and bone graft fixation provided the best biomechanical stability. The C1 lateral mass screws in the atlas combined with isthmic screws in axis fixation is a sound alternative when the C1-2 TA screw fixation is not feasible.
19837766 Effects of alendronate on bone metabolism in glucocorticoid-induced osteoporosis measured 2009 Nov Osteoporosis represents a significant side effect of glucocorticoid therapy, and alendronate has been reported to prevent this glucocorticoid-induced osteoporosis. Functional imaging with (18)F-fluoride PET allows quantitative analysis of bone metabolism in specific skeletal regions. However, only a few studies have quantitatively determined bone turnover and metabolism in glucocorticoid-induced osteoporosis by radiologic imaging techniques including PET. The aim of this study was to examine changes in regional bone remodeling and turnover as measured by (18)F-fluoride PET, the relationship between these measured changes and conventional bone metabolism parameters, and the effect of alendronate treatment. METHODS: The study group consisted of 24 postmenopausal women (mean age, 59.7 y) who had various diseases, excluding rheumatoid arthritis, and had been treated with 10 mg or more of oral glucocorticoids (prednisolone equivalent) per day for more than 6 mo. Treatment with 5 mg of alendronate per day began at the time of study entry and continued for 12 mo. (18)F-fluoride PET was performed at baseline, 3 mo, and 12 mo to determine localized bone turnover, and the results were compared with other bone metabolism parameters. RESULTS: Lumbar spine standardized uptake values (SUVs) were significantly lower (P < 0.05) in the osteoporotic group (T-score < or = -2.5) than in the group that was healthy or osteopenic (T-score > -2.5). Patients treated with alendronate for 12 mo exhibited significant decreases in serum bone-specific alkaline phosphate (P < 0.05), urinary N-telopeptide for type I collagen (P < 0.01), lumbar spine SUV (P < 0.01), and femoral neck SUV (P < 0.01) in association with a gradual increase in bone mineral density (BMD) of the lumbar spine relative to the baseline value (P < 0.05). Although there was a significant correlation between BMD and SUV in the lumbar spine at baseline (P < 0.05), there was no correlation between the 2 variables at 12 mo of treatment with alendronate. CONCLUSION: Alendronate treatment resulted in significant decreases in bone metabolism and turnover in the lumbar spine. It also led to an increase in BMD of the lumbar spine in patients with glucocorticoid-induced osteoporosis. Our findings suggest that antiresorptive therapy has a direct bone-metabolism effect on skeletal kinetics in glucocorticoid-induced osteoporosis at the clinically important site of the lumbar spine.
19626040 Follow-up examination of linkage and association to chromosome 1q43 in multiple sclerosis. 2009 Oct Multiple sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disease affecting >4,00,000 individuals in the United States. Population and family-based studies have suggested that there is a strong genetic component. Numerous genomic linkage screens have identified regions of interest for MS loci. Our own second-generation genome-wide linkage study identified a handful of non-major histocompatibility complex regions with suggestive linkage. Several of these regions were further examined using single-nucleotide polymorphisms (SNPs) with average spacing between SNPs of approximately 1.0 Mb in a dataset of 173 multiplex families. The results of that study provided further evidence for the involvement of the chromosome 1q43 region. This region is of particular interest given linkage evidence in studies of other autoimmune and inflammatory diseases including rheumatoid arthritis and systemic lupus erythematosus. In this follow-up study, we saturated the region with approximately 700 SNPs (average spacing of 10 kb per SNP) in search of disease-associated variation within this region. We found preliminary evidence to suggest that common variation within the RGS7 locus may be involved in disease susceptibility.
19293841 The interaction index, a novel information-theoretic metric for prioritizing interacting g 2009 Oct We developed an information-theoretic metric called the Interaction Index for prioritizing genetic variations and environmental variables for follow-up in detailed sequencing studies. The Interaction Index was found to be effective for prioritizing the genetic and environmental variables involved in GEI for a diverse range of simulated data sets. The metric was also evaluated for a 103-SNP Crohn's disease dataset and a simulated data set containing 9187 SNPs and multiple covariates that was modeled on a rheumatoid arthritis data set. Our results demonstrate that the Interaction Index algorithm is effective and efficient for prioritizing interacting variables for a diverse range of epidemiologic data sets containing complex combinations of direct effects, multiple GGI and GEI.
19289577 Normally occurring NKG2D+CD4+ T cells are immunosuppressive and inversely correlated with 2009 Apr 13 The NKG2D receptor stimulates natural killer cell and T cell responses upon engagement of ligands associated with malignancies and certain autoimmune diseases. However, conditions of persistent NKG2D ligand expression can lead to immunosuppression. In cancer patients, tumor expression and shedding of the MHC class I-related chain A (MICA) ligand of NKG2D drives proliferative expansions of NKG2D(+)CD4(+) T cells that produce interleukin-10 (IL-10) and transforming growth factor-beta, as well as Fas ligand, which inhibits bystander T cell proliferation in vitro. Here, we show that increased frequencies of functionally equivalent NKG2D(+)CD4(+) T cells are inversely correlated with disease activity in juvenile-onset systemic lupus erythematosus (SLE), suggesting that these T cells may have regulatory effects. The NKG2D(+)CD4(+) T cells correspond to a normally occurring small CD4 T cell subset that is autoreactive, primed to produce IL-10, and clearly distinct from proinflammatory and cytolytic CD4 T cells with cytokine-induced NKG2D expression that occur in rheumatoid arthritis and Crohn's disease. As classical regulatory T cell functions are typically impaired in SLE, it may be clinically significant that the immunosuppressive NKG2D(+)CD4(+) T cells appear functionally uncompromised in this disease.
19748983 TLR3 ligand polyinosinic:polycytidylic acid induces IL-17A and IL-21 synthesis in human Th 2009 Oct 1 TLR3 and TLR9 recognize the pathogen-associated microbial patterns dsRNA and unmethylated DNA, respectively. The recent discovery that these receptors also recognize endogenous ligands from necrotic material has drawn increased attention to their involvement in autoimmunity. Th cell cytokines IL-17A and IL-21 have been assigned with pivotal roles in the regulation of such autoimmune diseases. IL-17A is the hallmark cytokine of the recently discovered proinflammatory Th cell subset T(H)17. By contrast, the expression of IL-21 does not seem to be limited to a single distinct Th cell subset. We investigated the expression of IL-17A and IL-21 in human CD4+ T cells in response to stimulation with the TLR3 ligand polyinosinic:polycytidylic acid (poly(I:C)) and the TLR9 ligand CpG. We discovered that poly(I:C) induced synthesis of both IL-17A and IL-21. Moreover, we found that poly(I:C) was able to drive the differentiation of naive Th cells into an IL-21 but not into an IL-17A-producing phenotype and did this without affecting the levels of transcription factors T-bet, GATA-3, or retinoic acid receptor-related orphan receptor C. Finally, we found that the IL-21-producing cells that were differentiated in response to poly(I:C) expressed the chemokine receptor CXCR3, which is important in the recruitment of T cells into inflamed joints in rheumatoid arthritis. This is the first report to show that the TLR3 ligand poly(I:C) can directly induce the synthesis of IL-17A and IL-21 and drive differentiation of human naive CD4+ T cells.
20422155 Bone health-related factors and the use of bisphosphonates in community setting--15-year f 2011 Jan The present study investigated the bone health related factors that were associated with the use of bisphosphonates (BP) among 2,050 postmenopausal Finnish women. Low BMD + low trauma energy fracture was the strongest determinant of BP use, while other secondary causes of osteoporosis were less strongly related with BP use. BP use was associated with reduced femoral neck (FN) and lumbar spine (LS) bone loss rate. INTRODUCTION: The aim was to identify bone health related factors associated with the use of BP in a community setting. METHODS: A population-based sample of 2,050 Finnish postmenopausal women was measured with dual X-ray absorptiometry at the FN and LS in 1989, 1994, 1999 and 2004, and information on osteoporosis risk factors, including low-trauma energy fractures, were collected with postal inquiries. Self-reported use of BP in 2004 was considered as the end point variable. RESULTS: Among BP users, 12% had T-score > -2.0 SD and no fracture during follow-up (FU). In women without any bone medication, 26% had T-score < -2.0 SD or low-trauma energy fracture or both during the FU. In BP users, a significant reduction in FN and LS bone loss rate, cumulative with duration of use, was observed in ANCOVA (p < 0.001). Among BP users, there was a significantly higher proportion of women with several independent risk factors for osteoporosis and more spine and humerus fractures but less ankle fractures. T-score < -2 SD combined with low-trauma energy fracture was significantly related to the use of BPs (p < 0.001, OR = 15.96) and T-score < -2 SD was a stronger predictor of BP use (p < 0.001, OR = 13.29) than fracture (p > 0.05, OR = 1.35) in multivariate logistic regression. Other factors related with BP use were vitamin D use (p = 0.001, OR = 2.27), high number of medications (p < 0.001, OR = 1.26) and rheumatoid arthritis (p < 0.05, OR 2.55). CONCLUSIONS: These findings reveal the recent bone health-related indications for BP prescription.
19718038 Interferon regulatory factor-8 regulates bone metabolism by suppressing osteoclastogenesis 2009 Sep Bone metabolism results from a balance between osteoclast-driven bone resorption and osteoblast-mediated bone formation. Diseases such as periodontitis and rheumatoid arthritis are characterized by increased bone destruction due to enhanced osteoclastogenesis. Here we report that interferon regulatory factor-8 (IRF-8), a transcription factor expressed in immune cells, is a key regulatory molecule for osteoclastogenesis. IRF-8 expression in osteoclast precursors was downregulated during the initial phase of osteoclast differentiation induced by receptor activator of nuclear factor-kappaB ligand (RANKL), which is encoded by the Tnfsf11 gene. Mice deficient in Irf8 showed severe osteoporosis, owing to increased numbers of osteoclasts, and also showed enhanced bone destruction after lipopolysaccharide (LPS) administration. Irf8-/- osteoclast precursors underwent increased osteoclastogenesis in response to RANKL and tumor necrosis factor-alpha (TNF-alpha). IRF-8 suppressed osteoclastogenesis by inhibiting the function and expression of nuclear factor of activated T cells c1 (NFATc1). Our results show that IRF-8 inhibits osteoclast formation under physiological and pathological conditions and suggest a model where downregulation of inhibitory factors such as IRF-8 contributes to RANKL-mediated osteoclastogenesis.