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ID PMID Title PublicationDate abstract
19625220 Folate/homocysteine phenotypes and MTHFR 677C>T genotypes are associated with serum levels 2009 Oct Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that recruits monocytes into the subendothelial cell layer in atherosclerotic lesions. Elevated homocysteine (hyperhomocysteinemia), which is usually associated with low-folate status, is a known risk factor for many pathologies with inflammatory etiologies. The present study was undertaken to examine whether there are associations between MCP-1 concentrations and folate/Hcy phenotype or methylenetetrahydrofolate reductase (MTHFR) 677C>T genotype in healthy young adults. In females, MCP-1 concentrations were positively correlated with Hcy and negatively correlated with both serum and red blood cell folate; female smokers and MTHFR 677T carriers had particularly elevated MCP-1 concentrations. Similar relationships were not seen in males. These findings may have implications for understanding the female predominance observed for a range of autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis.
19571080 All-polyethylene compared with metal-backed tibial components in total knee arthroplasty a 2009 Jul BACKGROUND: Several studies have described equivalent performance on radiostereometric analysis at two years for metal-backed compared with all-polyethylene stemmed tibial implants. The purpose of this study was to determine the ten-year survivorship results of these two designs from a large randomized controlled trial. METHODS: Patients who were fifty years old or more, with no history of infection, and were undergoing primary total knee arthroplasty were randomized at the time of surgery to receive either an all-polyethylene or a metal-backed tibial component. Patients were assessed preoperatively and at one, three, five, eight, and ten years postoperatively. All assessments included a clinical history, a physical examination, and a radiographic evaluation. A total of 510 consecutive patients (566 knees) were recruited from August 1993 to January 1997. The mean age of the patients at the time of the index arthroplasty was 69.3 years, and 299 (59%) were women. The primary diagnosis was osteoarthritis for 458 knees (80.9%) and rheumatoid arthritis for 108 knees (19.1%). RESULTS: Two hundred and ninety-three patients returned for the ten-year follow-up evaluation. A total of twenty-eight knees had been revised. Ten-year survivorship, with revision for any reason (or the time at which patients were documented as requiring revision but were unfit for surgery) as the end point, was 94.5% (95% confidence interval, 90.4% to 96.8%) for the all-polyethylene design and 96% (95% confidence interval, 92.6% to 97.8%) for the metal-backed design. Ten-year survivorship, with aseptic failure as the end point, was 97% (95% confidence interval, 93.3% to 98.7%) for the all-polyethylene design and 96.8% (95% confidence interval, 93.6% to 98.4%) for the metal-backed design. On the basis of the numbers available at ten years, there was no significant difference in survivorship between the two designs (p > 0.05). CONCLUSIONS: The long-term results demonstrate excellent survivorship, with revision as the end point, for both the metal-backed and the all-polyethylene tibial component designs with no differences noted between the two.
19234579 Direct quantitation of omega-3 fatty acid intake of Canadian residents of a long-term care 2009 Feb An increased dietary intake of n-3 highly unsaturated fatty acids (HUFA; >or=20 carbons, >or=3 carbon-carbon double bonds), particularly eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3), is associated with the decreased risk and incidence of several morbidities afflicting the elderly, including cognitive decline, dementia, rheumatoid arthritis, and macular degeneration. In this study, the dietary intake and blood levels of fatty acids were directly determined in residents of a retirement home or assisted living phase of a continuum of care facility for Canadian seniors. Finger-tip-prick blood samples, 3-day food duplicates, and 3-day food records were collected. The fatty acid composition of food duplicates and blood was determined by gas chromatography. Fifteen participants (7 male, 8 female; 87.1 +/- 4.8 years of age) completed the protocol. The daily intake of EPA and DHA combined, determined directly, was 70 mg (95% CI, 41-119) or 0.036% of total energy (95% CI, 0.022-0.058). In finger-tip-prick blood, the percent of n-3 HUFA in total HUFA of whole blood, a biomarker of n-3 polyunsaturated fatty acid status, was 28.8 +/- 5.2%. Correlations between daily n-3 HUFA intake and n-3 HUFA in blood were not significant (r = 0.14; n = 15), but became significant after the removal of 2 participants who appeared to consume fish irregularly (r = 0.59; n = 13). The n-3 HUFA intake and corresponding n-3 HUFA blood levels of Canadian long-term care residents are lower than levels estimated to prevent several morbidities associated with aging.
19166876 New advances in musculoskeletal pain. 2009 Apr Non-malignant musculoskeletal pain is the most common clinical symptom that causes patients to seek medical attention and is a major cause of disability in the world. Musculoskeletal pain can arise from a variety of common conditions including osteoarthritis, rheumatoid arthritis, osteoporosis, surgery, low back pain and bone fracture. A major problem in designing new therapies to treat musculoskeletal pain is that the underlying mechanisms driving musculoskeletal pain are not well understood. This lack of knowledge is largely due to the scarcity of animal models that closely mirror the human condition which would allow the development of a mechanistic understanding and novel therapies to treat this pain. To begin to develop a mechanism-based understanding of the factors involved in generating musculoskeletal pain, in this review we present recent advances in preclinical models of osteoarthritis, post-surgical pain and bone fracture pain. The models discussed appear to offer an attractive platform for understanding the factors that drive this pain and the preclinical screening of novel therapies to treat musculoskeletal pain. Developing both an understanding of the mechanisms that drive persistent musculoskeletal pain and novel mechanism-based therapies to treat these unique pain states would address a major unmet clinical need and have significant clinical, economic and societal benefits.
21092187 Fabry disease. 2010 Nov 22 Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A activity. FD is pan-ethnic and the reported annual incidence of 1 in 100,000 may underestimate the true prevalence of the disease. Classically affected hemizygous males, with no residual α-galactosidase A activity may display all the characteristic neurological (pain), cutaneous (angiokeratoma), renal (proteinuria, kidney failure), cardiovascular (cardiomyopathy, arrhythmia), cochleo-vestibular and cerebrovascular (transient ischemic attacks, strokes) signs of the disease while heterozygous females have symptoms ranging from very mild to severe. Deficient activity of lysosomal α-galactosidase A results in progressive accumulation of globotriaosylceramide within lysosomes, believed to trigger a cascade of cellular events. Demonstration of marked α-galactosidase A deficiency is the definitive method for the diagnosis of hemizygous males. Enzyme analysis may occasionnally help to detect heterozygotes but is often inconclusive due to random X-chromosomal inactivation so that molecular testing (genotyping) of females is mandatory. In childhood, other possible causes of pain such as rheumatoid arthritis and 'growing pains' must be ruled out. In adulthood, multiple sclerosis is sometimes considered. Prenatal diagnosis, available by determination of enzyme activity or DNA testing in chorionic villi or cultured amniotic cells is, for ethical reasons, only considered in male fetuses. Pre-implantation diagnosis is possible. The existence of atypical variants and the availability of a specific therapy singularly complicate genetic counseling. A disease-specific therapeutic option - enzyme replacement therapy using recombinant human α-galactosidase A - has been recently introduced and its long term outcome is currently still being investigated. Conventional management consists of pain relief with analgesic drugs, nephroprotection (angiotensin converting enzyme inhibitors and angiotensin receptors blockers) and antiarrhythmic agents, whereas dialysis or renal transplantation are available for patients experiencing end-stage renal failure. With age, progressive damage to vital organ systems develops and at some point, organs may start to fail in functioning. End-stage renal disease and life-threatening cardiovascular or cerebrovascular complications limit life-expectancy of untreated males and females with reductions of 20 and 10 years, respectively, as compared to the general population. While there is increasing evidence that long-term enzyme therapy can halt disease progression, the importance of adjunctive therapies should be emphasized and the possibility of developing an oral therapy drives research forward into active site specific chaperones.
20844157 Risk factors for venous thromboembolism in patients undergoing total hip replacement and r 2010 Sep 15 BACKGROUND: Data on the risk factors for venous thromboembolism among patients undergoing total hip replacement and receiving pharmacological thromboprophylaxis are limited. The purpose of this study was to examine potential patient-related risk factors for venous thromboembolism following total hip replacement in a nationwide follow-up study. METHODS: Using medical databases, we identified all patients who underwent primary total hip replacement and received pharmacological thromboprophylaxis in Denmark from 1995 to 2006. The outcome measure was hospitalization with venous thromboembolism within ninety days of surgery. We considered age, sex, indication for primary total hip replacement, calendar year of surgery, and comorbidity history as potential risk factors. RESULTS: The overall rate of hospitalization for venous thromboembolism within ninety days following a primary total hip replacement was 1.02% (686 hospitalizations after 67,469 procedures) at a median of twenty-two days. The incidence of symptomatic deep venous thrombosis and of nonfatal pulmonary embolism was 0.7% (499 of 67,469) and 0.3% (205 of 67,469), respectively. The incidence of death due to venous thromboembolism or from all causes was 0.05% (thirty-eight patients) and 1.0% (678 patients), respectively. Patients with rheumatoid arthritis had a reduced relative risk for venous thromboembolism compared with patients with primary osteoarthritis (adjusted relative risk = 0.47; 95% confidence interval, 0.25 to 0.90). Patients with a high score on the Charlson comorbidity index had an increased relative risk for venous thromboembolism compared with patients with a low score (adjusted relative risk = 1.45; 95% confidence interval, 1.02 to 2.05). Patients with a history of cardiovascular disease (relative risk = 1.40; 95% confidence interval, 1.15 to 1.70) or prior venous thromboembolism (relative risk = 8.09; 95% confidence interval, 6.07 to 10.77) had an increased risk for venous thromboembolism compared with patients without that history. CONCLUSIONS: The cumulative incidence of a venous thromboembolism within ninety days of surgery among patients with total hip replacement receiving pharmacological thromboprophylaxis was 1%. This information on the associated risk factors could be used to better anticipate the risk of venous thromboembolism for an individual patient.
20810916 Plasma gelsolin modulates cellular response to sphingosine 1-phosphate. 2010 Dec Hypogelsolinemia is observed in patients with different states of acute or chronic inflammation such as sepsis, rheumatoid arthritis, and multiple sclerosis. In animal models of sepsis, repletion of plasma gelsolin reduces septic mortality. However, the functions of extracellular gelsolin and the mechanisms leading to its protective nature are poorly understood. Potential mechanisms involve gelsolin's extracellular actin scavenging function or its ability to bind bioactive lipids or proinflammatory mediators, which would limit inflammatory responses and prevent tissue damage. Here we report that human plasma gelsolin binds to sphingosine 1-phosphate (S1P), a pleiotropic cellular agonist involved in various immune responses, and to its synthetic structural analog FTY720P (Gilenya). The fluorescence intensity of a rhodamine B-labeled phosphatidylinositol 4,5-bisphosphate binding peptide derived from gelsolin and the optical density of recombinant human plasma gelsolin (rhpGSN) were found to decrease after the addition of S1P or FTY720P. Gelsolin's ability to depolymerize F-actin also decreased progressively with increasing addition of S1P. Transient increases in phosphorylation of extracellular signal-regulated kinase in bovine aortic endothelial cells (BAECs) after S1P treatment were inhibited by rhpGSN. The ability of S1P to increase F-actin content and the elastic modulus of primary astrocytes and BAECs was also prevented by rhpGSN. Evaluation of S1P and gelsolin levels in cerebrospinal fluid reveals a low concentration of gelsolin and a high concentration of S1P in samples obtained from patients suffering from lymphatic meningitis. These findings suggest that gelsolin-mediated regulation of S1P bioactivity may be important to maintain immunomodulatory balance at inflammatory sites.
20808933 Extreme evolutionary disparities seen in positive selection across seven complex diseases. 2010 Aug 17 Positive selection is known to occur when the environment that an organism inhabits is suddenly altered, as is the case across recent human history. Genome-wide association studies (GWASs) have successfully illuminated disease-associated variation. However, whether human evolution is heading towards or away from disease susceptibility in general remains an open question. The genetic-basis of common complex disease may partially be caused by positive selection events, which simultaneously increased fitness and susceptibility to disease. We analyze seven diseases studied by the Wellcome Trust Case Control Consortium to compare evidence for selection at every locus associated with disease. We take a large set of the most strongly associated SNPs in each GWA study in order to capture more hidden associations at the cost of introducing false positives into our analysis. We then search for signs of positive selection in this inclusive set of SNPs. There are striking differences between the seven studied diseases. We find alleles increasing susceptibility to Type 1 Diabetes (T1D), Rheumatoid Arthritis (RA), and Crohn's Disease (CD) underwent recent positive selection. There is more selection in alleles increasing, rather than decreasing, susceptibility to T1D. In the 80 SNPs most associated with T1D (p-value <7.01 x 10(-5)) showing strong signs of positive selection, 58 alleles associated with disease susceptibility show signs of positive selection, while only 22 associated with disease protection show signs of positive selection. Alleles increasing susceptibility to RA are under selection as well. In contrast, selection in SNPs associated with CD favors protective alleles. These results inform the current understanding of disease etiology, shed light on potential benefits associated with the genetic-basis of disease, and aid in the efforts to identify causal genetic factors underlying complex disease.
20701403 Tramadol/paracetamol fixed-dose combination: a review of its use in the management of mode 2010 Tramadol/paracetamol 37.5 mg/325 mg (Tramacet, Zaldiar, Ixprim, Kolibri) is an orally administered fixed-dose combination of the atypical opioid tramadol and paracetamol, which is indicated in the EU for the symptomatic treatment of moderate to severe pain. This article reviews the pharmacological properties, clinical efficacy and tolerability of tramadol/paracetamol in adults with moderate to severe pain. Fixed-dose tramadol/paracetamol is a rapidly-acting, longer-duration, multimodal analgesic, which is effective and generally well tolerated in patients with moderate to severe pain. In several well designed, clinical studies, single- or multiple-dose tramadol/paracetamol was effective in providing pain relief in adult patients with postoperative pain after minor surgery, musculoskeletal pain (acute, subacute or chronic), painful diabetic peripheral neuropathy or migraine pain. It was also effective as an add-on analgesic in patients who were experiencing moderate to severe musculoskeletal pain (e.g. osteoarthritis or rheumatoid arthritis pain) despite ongoing NSAID and/or disease-modifying antirheumatic drug therapy. Moreover, in patients with postoperative pain, ankle sprain pain or subacute lower back pain, the analgesic efficacy of tramadol/paracetamol was better than that of paracetamol, generally similar to, or better than that, of tramadol, and generally similar to that of ibuprofen or the fixed-dose combinations hydrocodone/paracetamol, codeine/paracetamol and codeine/paracetamol/ibuprofen. In addition, the analgesic efficacy of tramadol/paracetamol did not differ significantly from that of gabapentin in patients with chronic pain associated with diabetic peripheral neuropathy. Tramadol/paracetamol had no additional tolerability issues relative to its components and, overall, the tolerability profile of tramadol/paracetamol was generally similar to that of other active comparators (fixed-dose combinations or single-agents); however, incidences of some adverse events were lower in tramadol/paracetamol than in active comparator recipients. Although additional comparative and long-term studies would help to definitively position tramadol/paracetamol with respect to other analgesics, available clinical data suggest that tramadol/paracetamol is a useful treatment option for providing multimodal analgesia in patients with moderate to severe pain.
20432243 VEGF-A expression in osteoclasts is regulated by NF-kappaB induction of HIF-1alpha. 2010 May 15 Large osteoclasts (10+ nuclei), predominant in rheumatoid arthritis and periodontal disease, have higher expression of proteases and activating receptors and also have increased resorptive activity when compared to small (2-5 nuclei) osteoclasts. We hypothesized that large and small osteoclasts activate different signaling pathways. A Signal Transduction Pathway Finder Array was used to compare gene expression of large and small osteoclasts in RAW 264.7-derived osteoclasts. Expression of vascular endothelial growth factor A (Vegfa) was higher in large osteoclasts and this result was confirmed by RT-PCR. RT-PCR further showed that RANKL treatment of RAW cells induced Vegfa expression in a time-dependent manner. Moreover, VEGF-A secretion in conditioned media was also increased in cultures with a higher proportion of large osteoclasts. To investigate the mechanism of Vegfa induction, specific inhibitors for the transcription factors NF-kappaB, AP-1, NFATc1, and HIF-1 were used. Dimethyl bisphenol A, the HIF-1alpha inhibitor, decreased Vegfa mRNA expression, whereas blocking NF-kappaB, AP-1, and NFATc1 had no effect. Furthermore, the NF-kappaB inhibitor gliotoxin inhibited Hif1alpha mRNA expression. In conclusion, VEGF-A gene and protein expression are elevated in large osteoclasts compared to small osteoclasts and this increase is regulated by HIF-1. In turn, Hif1alpha mRNA levels are induced by RANKL-mediated activation of NF-kappaB. These findings reveal further differences in signaling between large and small osteoclasts and thereby identify novel therapeutic targets for highly resorptive osteoclasts in inflammatory bone loss.
20156139 Merging traditional Chinese medicine with modern drug discovery technologies to find novel 2010 Mar Traditional Chinese Medicines (TCM) are rapidly gaining attention in the West as sources of new drugs, dietary supplements and functional foods. However, lack of consistent manufacturing practices and quality standards, fear of adulteration, and perceived deficiencies in scientific validation of efficacy and safety impede worldwide acceptance of TCM. In addition, Western pharmaceutical industries and regulatory agencies are partial toward single ingredient drugs based on synthetic molecules, and skeptical of natural product mixtures. This review concentrates on three examples of TCM-derived pharmaceuticals and functional foods that have, despite these usual obstacles, risen to wide acceptance in the West based on their remarkable performance in recent scientific investigations. They are: Sweet wormwood (Artemisia annua), the source of artemisinin, which is the currently preferred single compound anti-malarial drug widely used in combination therapies and recently approved by US FDA; Thunder god vine (Tripterygium wilfordii) which is being developed as a botanical drug for rheumatoid arthritis; and green tea (Camellia sinensis) which is used as a functional beverage and a component of dietary supplements.
20091657 Effect of cyclosporine on blood pressure. 2010 Jan 20 BACKGROUND: Cyclosporine is an immunosuppressive agent used for different autoimmune diseases. The official Canadian indications for cyclosporine are solid organ transplantation, bone marrow transplantation, psoriasis, rheumatoid arthritis and nephritic syndrome (e-CPS 2008). The expanding range of indications for cyclosporine therapy will lead to more patients receiving chronic therapy with possible side effects, hypertension being one of the most common. Therefore it is essential to know the magnitude of increase of blood pressure (BP) associated with cyclosporine in order to appropriately manage patients receiving the drug. OBJECTIVES: The primary objective of this systematic review is to evaluate the effect of cyclosporine on blood pressure, compared to placebo in randomized trials. SEARCH STRATEGY: We searched The Cochrane Central Register of Controlled Trials (CENTRAL) and bibliographic databases, including MEDLINE (2000-2008) and EMBASE (1980-2008). SELECTION CRITERIA: Selection was made using double-blind, randomized, controlled trials comparing cyclosporine to placebo. All patients treated with cyclosporine were included without restriction by type of disease or by age and sex. DATA COLLECTION AND ANALYSIS: Blood pressure measurements in any setting and by any means were acceptable including the auscultatory or oscillometric method with a preference for the sitting position. Mean blood pressure results were entered as mean change from placebo and standard error of the mean (SEM). If blood pressure data was provided at different times after the initiation of cyclosporine therapy the weighted mean BP change from placebo from all measurements was used. MAIN RESULTS: The search yielded 1340 citations, of which 17 trials met the inclusion criteria. We created dose-ranges according to the usual dose administration recommended by the manufacturer and allocated the 17 included trials to the corresponding dose-range. The results demonstrate a highly statistically significant increase in blood pressure associated with cyclosporine. There appears to be a dose-related effect with lower doses (1-4 mg/kg/d) increasing mean BP by an average of 5 mmHg and higher doses (>10 mg/kg/d) increasing mean BP by 11 mmHg on average. Furthermore in 3 trials the effect appears to be similar after a single dose as with chronic therapy. AUTHORS' CONCLUSIONS: Cyclosporine statistically significantly increases blood pressure compared to placebo in a dose-related fashion. The magnitude of increase in blood pressure is clinically significant and increases the risk of stroke, myocardial infarction, heart failure and other adverse cardiovascular events associated with elevated BP. Consequently prescribers should try to find the lowest effective dose in all patients receiving cyclosporine chronically.
20641917 (68)Ga-1,4,7-Triazacyclononane-1,4-7-triacetic acid-Glu-[15-amino-4,7,10,13-tetraoxapentad 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 of the cyclic RGD peptides are composed of five amino acids. Various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) (50% inhibition concentration (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 (11). Various radiolabeled cyclic RGD peptides and peptidominetics have been found to have high accumulation in tumors in mice (12, 13). Out of these developments [(18)F]Galacto-c(RGDfK) has been evaluated in a number of clinical studies for imaging of α(v)β(3) in cancer patients (14-19). Liu et al. (20) used 1,4,7-triazacyclononane-1,4-7-triacetic acid (NOTA) as a bifunctional chelator for labeling Glu-[15-amino-4,7,10,13-tetraoxapentadecanoic acid-cyclo(RGDfK)](2) (P(4)-RGD2) to form ((68)Ga-NOTA-P(4)-RGD2) for positron emission tomography (PET) imaging of α(v)β(3) receptors in nude mice bearing human glioblastoma U87MG tumors.
20641458 (68)Ga-1,4,7-Triazacyclononane-1,4-7-triacetic acid-Glu-[Gly-Gly-Gly-c(Arg-Gly-Asp-D-Phe-L 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 of the cyclic RGD peptides are composed of five amino acids. Various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) (50% inhibition concentration (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 (11). Various radiolabeled cyclic RGD peptides and peptidominetics have been found to have high accumulation in tumors in mice (12, 13). Out of these developments [(18)F]Galacto-c(RGDfK) has been evaluated in a number of clinical studies for imaging of α(v)β(3) in cancer patients (14-19). Li et al. (20) used 1,4,7-triazacyclononane-1,4-7-triacetic acid (NOTA) as a bifunctional chelator for labeling Glu-[Gly-Gly-Gly-cyclo(RGDfK)](2) (G(3)-RGD2) to form ((68)Ga-NOTA-G(3)-RGD2) for positron emission tomography (PET) imaging of α(v)β(3) receptors in nude mice bearing human glioblastoma U87MG tumors.
20641262 (68)Ga-1,4,7-Triazacyclononane-1,4-7-triacetic acid-Glu-[c(Arg-Gly-Asp-D-Tyr-Lys)](2). 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 of the cyclic RGD peptides are composed of five amino acids. Haubner et al. (11) reported that various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) (50% inhibition concentration (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 and peptidominetics have been found to have high accumulation in tumors in mice (12, 13). Out of these developments [(18)F]Galacto-c(RGDfK) has been evaluated in a number of clinical studies for imaging of α(v)β(3) in cancer patients (14-19). Li et al. (20) used 1,4,7-triazacyclononane-1,4-7-triacetic acid (NOTA) as a bifunctional chelator for labeling Glu-[cyclo(RGDyK)](2) (RGD2) to form ((68)Ga-NOTA-RGD2) for positron emission tomography (PET) imaging of α(v)β(3) receptors in nude mice bearing human glioblastoma U87MG tumors.
19838346 Trans-iliac-sacral-iliac-bar procedure to treat insufficiency fractures of the sacrum. 2009 Jul BACKGROUND: Osteoporosis is an increasing problem attributed to the greater longevity of the population and the incidence of fractures related to osteoporosis. The presence of osteoporotic bone, comorbidities, and functional status of the patient require adequate solutions to improve the clinical outcome of sacral insufficiency fractures. Conservative treatment by means of prolonged bed rest and analgesics are associated with increased risks and complications. A sacroplasty significantly improves the functional outcome. We describe the trans-iliac-sacral-iliac-bar (TISIB) procedure and our clinical experience to treat insufficiency fractures of the sacrum. MATERIALS AND METHODS: The records of 19 consecutive patients with a mean age of 71.7 years (range: 57-82 years) who had been managed with a TISIB procedure from 2005 till 2007 were reviewed retrospectively. There were 15 females and 4 males. Predisposing factors for sacral insufficiency fractures were osteoporosis (n = 12, 63%), radiotherapy (n = 6, 32%), and rheumatoid arthritis (n =1). Diagnosis with a mean delay of 3.7 months was mainly made by CT. All patients were preoperatively and at follow-up assessed by means of the visual analogue score (VAS), analgesic consumption, and the ability to perform activities of daily living (ADLs) using a 5-point pain scale: 1, without pain; 2, mild pain; 3, moderate pain; 4, severe pain and, 5 unable to perform ADLs because of pain. RESULTS: The average duration of postoperative follow-up was 9 months (range: 3-24.5 months). No neurological complications occurred during the surgery. A postoperative radiographic study showed a well-positioned bar in every case. The mean VAS improved 44.7 mm (preoperative: 67.8; at follow-up: 23.2). Fifteen patients (79%) consumed narcotic analgesics before surgery, and only one (5%) at follow-up; two patients (10%) consumed NSAIDS before surgery and three (15%) after. Two patients (10%) consumed minor analgesics before, and 11 (58%) after the procedure. Finally, four patients (21%) were not taking any analgesics at follow-up. Before surgery, 9 patients (47%) were able to perform ADLs with a pain score of 4; 6 (32%) with a score of 3, and 4 (21%) a score of 2. At follow-up 1 (5%) did have a score of 4; 1 (5%) a score of 3, 8 (42%) a score of 2 and 9 (47%) a pain score of 1. CONCLUSION: A TISIB PROCEDURE RELIES ON THE PRINCIPLES OF FRACTURE TREATMENT: fracture stabilisation and compression. The incapacitating problem of an insufficiency fracture of the sacrum can be elegantly solved by means of this minimally invasive procedure. A near-immediate improvement is noticed when looking at the VAS score, analgesics consumption, and the ability to perform ADLs.
19542371 Tristetraprolin is required for full anti-inflammatory response of murine macrophages to I 2009 Jul 15 IL-10 is essential for inhibiting chronic and acute inflammation by decreasing the amounts of proinflammatory cytokines made by activated macrophages. IL-10 controls proinflammatory cytokine and chemokine production indirectly via the transcription factor Stat3. One of the most physiologically significant IL-10 targets is TNF-alpha, a potent proinflammatory mediator that is the target for multiple anti-TNF-alpha clinical strategies in Crohn's disease and rheumatoid arthritis. The anti-inflammatory effects of IL-10 seem to be mediated by several incompletely understood transcriptional and posttranscriptional mechanisms. In this study, we show that in LPS-activated bone marrow-derived murine macrophages, IL-10 reduces the mRNA and protein levels of TNF-alpha and IL-1alpha in part through the RNA destabilizing factor tristetraprolin (TTP). TTP is known for its central role in destabilizing mRNA molecules containing class II AU-rich elements in 3' untranslated regions. We found that IL-10 initiates a Stat3-dependent increase of TTP expression accompanied by a delayed decrease of p38 MAPK activity. The reduction of p38 MAPK activity releases TTP from the p38 MAPK-mediated inhibition, thereby resulting in diminished mRNA and protein levels of proinflammatory cytokines. These findings establish that TTP is required for full responses of bone marrow-derived murine macrophages to IL-10.
19345587 Autotaxin structure-activity relationships revealed through lysophosphatidylcholine analog 2009 May 1 Autotaxin (ATX) catalyzes the hydrolysis of lysophosphatidylcholine (LPC) to form the bioactive lipid lysophosphatidic acid (LPA). LPA stimulates cell proliferation, cell survival, and cell migration and is involved in obesity, rheumatoid arthritis, neuropathic pain, atherosclerosis and various cancers, suggesting that ATX inhibitors have broad therapeutic potential. Product feedback inhibition of ATX by LPA has stimulated structure-activity studies focused on LPA analogs. However, LPA displays mixed mode inhibition, indicating that it can bind to both the enzyme and the enzyme-substrate complex. This suggests that LPA may not interact solely with the catalytic site. In this report we have prepared LPC analogs to help map out substrate structure-activity relationships. The structural variances include length and unsaturation of the fatty tail, choline and polar linker presence, acyl versus ether linkage of the hydrocarbon chain, and methylene and nitrogen replacement of the choline oxygen. All LPC analogs were assayed in competition with the synthetic substrate, FS-3, to show the preference ATX has for each alteration. Choline presence and methylene replacement of the choline oxygen were detrimental to ATX recognition. These findings provide insights into the structure of the enzyme in the vicinity of the catalytic site as well as suggesting that ATX produces rate enhancement, at least in part, by substrate destabilization.
19143814 Several loci in the HLA class III region are associated with T1D risk after adjusting for 2009 Feb AIM: Several studies have indicated that genes in the human leucocyte antigen (HLA) region additional to the HLA class II DRB1-DQB1 contribute to type 1 diabetes (T1D) susceptibility. The aim of this study was to assess if markers in the class III Major Histocompatibility Complex (MHC) region are associated with T1D after accounting for linkage disequilibrium (LD) with DRB1-DQB1. METHODS: We investigated 356 single nucleotide polymorphisms (SNPs) in the class III region covering 1.1 megabases in two subsets of data: 289 Human Biological Data Interchange (HBDI) Caucasian families and 597 additional Caucasian families collected by the Type 1 Diabetes Genetics Consortium (T1DGC). Analysis conditioning on DRB1-DQB1 was performed using the overall conditional genotype method. RESULTS: Thirteen SNPs replicated in both subsets of the data and showed evidence of an additional effect on disease risk. Although some of the SNPs are in tight LD with each other, at least six of the associations were not because of LD with other class III markers. The strongest association within class III markers was with rs2395106 that maps 5' to the NOTCH4 gene, which has also been implicated in susceptibility to rheumatoid arthritis. The second association was with rs707915 mapping to the MSH5 gene, in a block of six markers significantly associated with T1D after adjusting for LD with DR-DQ. In total, six-independent associations within class III were observed although results were not adjusted for LD with class I. CONCLUSIONS: Our data confirm that the class III region is involved in T1D susceptibility and suggest that more than one gene in the region is involved.
21130161 Essential role of neutrophil mobilization in concanavalin A-induced hepatitis is based on 2011 Mar Neutrophil depleted mice are protected from concanavalin A-mediated hepatitis, showing that neutrophils are critical for cellular liver damage. Interleukin-6 has pro- and anti-inflammatory properties and mediates neutrophil recruitment in diseases such as rheumatoid arthritis. In classic signaling, interleukin-6 binds to the membrane-bound interleukin-6-receptor and initiates signaling via gp130. In interleukin-6 trans-signaling, the agonistic soluble interleukin-6-receptor can form a soluble interleukin-6/interleukin-6-receptor complex and stimulate cells which only express gp130 but no interleukin-6-receptor. Interleukin-6 trans-signaling was shown to be important for liver regeneration and development of liver adenomas. Here, we show that blocking classic interleukin-6 signaling but not interleukin-6 trans-signaling reduced concanavalin A-induced liver damage in mice, with reduced liver STAT3 phosphorylation and liver neutrophil accumulation. However, the level of neutrophil-attracting chemokine KC is only reduced by inhibition of interleukin-6 trans-signaling. Analysis of circulating neutrophils after concanavalin A challenge revealed that classic interleukin-6 signaling is required for the mobilization of blood neutrophils. Reduced neutrophil infiltration was accompanied by increased levels of hepatoprotective monocyte chemoattractant protein-1 and reduced level of hepatodestructive interleukin-4. Abrogated classic interleukin-6 signaling in concanavalin A-mediated hepatitis exhibited liver-protective effects indicating that interleukin-6 classic but not interleukin-6 trans-signaling is responsible for liver damage. Classic interleukin-6 signaling is required to mount an efficient neutrophilia during concanavalin A-induced immune response, which might have clinical implications in the regard that blocking global interleukin-6 signaling pathways is a treatment option in different chronic inflammatory diseases.