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ID PMID Title PublicationDate abstract
24171693 An insight on human skin penetration of diflunisal: lipogel versus hydrogel microemulsion. 2015 Jan Diflunisal is a NSAID used in acute and long term management of pain and inflammation associated with osteoarthritis, rheumatoid arthritis and symptoms of primary dysmenorrhea. However, its oral use is associated with side effects such as peptic ulceration, dyspepsia, gastrointestinal disturbances and bleeding. The aim of this work was to develop lecithin organogels (LO) transdermal delivery system for diflunisal and to study its human skin penetration ability in comparison with an optimized microemulsion-based hydrogel. Ternary phase diagrams were constructed using butyl lactate as an organic solvent and two commercial grades of lecithin. The formation of gel phase was lecithin concentration dependent with Phosholipion 85 G being capable of forming organogels at lower lecithin concentration than Lipoid S75. The gels prepared using butyl lactate were able to tolerate higher amounts of water than could be incorporated in the lipogels prepared with other organic solvents. All the investigated gels possessed acceptable physical properties and were able to deliver diflunisal through human skin. The lipogels delivered higher total drug amount through the skin than the hydrogel. The composition of lecithin seemed to have some effect on the skin permeability enhancement ability of the lipogel. Lecithin containing higher amount of phosphatidyl ethanolamine could provide better transdermal delivery. The elaborated lecithin organogels are potential carriers that create a good opportunity for transdermal delivery of diflunisal overcoming the side effects associating its oral route.
24015655 [Clinical effect of posterior atlanto axial vertebra internal fixation for treatment of in 2013 Jun OBJECTIVE: To explore radiographic results and clinical effects of posterior atlanto axial vertebra internal fixation in treating instability of occipitocervical. METHODS: The clinical data of 155 patients with instability of occipitocervical treated by posterior atlanto axial vertebra internal fixation were respectively analyzed from September 2005 to January 2011. There were 68 males and 87 females, ranging in age from 6 to 75 years old with an average of 45.6 years old. Of them, 53 cases were fresh odontoid fractures(Aderson type II C), 30 cases were os odontoideum, 20 cases were old odontoid fractures, 18 cases were unstable atlas fractures, 12 cases were atlanto axial rotatory dislocation, 11 cases were atlanto axial dislocation after rheumatoid arthritis, and 11 cases were basilar invagination. Radiographic results were evaluated in terms of atlas pedicle screw fixation, bone healing and bone graft fusion. Clinical effect evaluation included relief of pain in the occipital-cervical region by VAS score and JOA score. RESULTS: Totally 300 screws were set through atlas pedicle screw fixation in 150 patients. Five patients receivde hook fixation. Postoperative CT showed ideal nailing were 275 (91.7%),acceptable nailing were 14 (4.7%) and unacceptable nailing were 11 (3.6%). All patients were followed up, and the duration ranged from 16 to 40 months with an average of 25.4 months. The fresh fractures healed and 140 cases got bone graft fusion. Preoperative VAS and JOA score were respectively improved from (7.2 +/- 1.1), (7.3 +/- 2.4) to (3.2 +/- 1.1), (13.3 +/- 2.4) at the latest follow-up. CONCLUSION: Posterior atlanto axial vertebra internal fixation in treating instability of occipitocervical can effectively recover physiological curvature of cervical, provide mechanical stability, and obtain good clinical effect. For the young patients who require further activity, posterior fixation and non-fusion technology is a good choose, which can avoid bone graft.
23936387 A possible mechanism behind autoimmune disorders discovered by genome-wide linkage and ass 2013 Celiac disease is a common autoimmune disorder characterized by an intestinal inflammation triggered by gluten, a storage protein found in wheat, rye and barley. Similar to other autoimmune diseases such as type 1 diabetes, psoriasis and rheumatoid arthritis, celiac disease is the result of an immune response to self-antigens leading to tissue destruction and production of autoantibodies. Common diseases like celiac disease have a complex pattern of inheritance with inputs from both environmental as well as additive and non-additive genetic factors. In the past few years, Genome Wide Association Studies (GWAS) have been successful in finding genetic risk variants behind many common diseases and traits. To complement and add to the previous findings, we performed a GWAS including 206 trios from 97 nuclear Swedish and Norwegian families affected with celiac disease. By stratifying for HLA-DQ, we identified a new genome-wide significant risk locus covering the DUSP10 gene. To further investigate the associations from the GWAS we performed pathway analyses and two-locus interaction analyses. These analyses showed an over-representation of genes involved in type 2 diabetes and identified a set of candidate mechanisms and genes of which some were selected for mRNA expression analysis using small intestinal biopsies from 98 patients. Several genes were expressed differently in the small intestinal mucosa from patients with celiac autoimmunity compared to intestinal mucosa from control patients. From top-scoring regions we identified susceptibility genes in several categories: 1) polarity and epithelial cell functionality; 2) intestinal smooth muscle; 3) growth and energy homeostasis, including proline and glutamine metabolism; and finally 4) innate and adaptive immune system. These genes and pathways, including specific functions of DUSP10, together reveal a new potential biological mechanism that could influence the genesis of celiac disease, and possibly also other chronic disorders with an inflammatory component.
23836909 Neutralizing nanobodies targeting diverse chemokines effectively inhibit chemokine functio 2013 Aug 30 Chemokine receptors and their ligands play a prominent role in immune regulation but many have also been implicated in inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, allograft rejection after transplantation, and also in cancer metastasis. Most approaches to therapeutically target the chemokine system involve targeting of chemokine receptors with low molecular weight antagonists. Here we describe the selection and characterization of an unprecedented large and diverse panel of neutralizing Nanobodies (single domain camelid antibodies fragment) directed against several chemokines. We show that the Nanobodies directed against CCL2 (MCP-1), CCL5 (RANTES), CXCL11 (I-TAC), and CXCL12 (SDF-1α) bind the chemokines with high affinity (at nanomolar concentration), thereby blocking receptor binding, inhibiting chemokine-induced receptor activation as well as chemotaxis. Together, we show that neutralizing Nanobodies can be selected efficiently for effective and specific therapeutic treatment against a wide range of immune and inflammatory diseases.
23799623 Aspirin antagonizes the cytotoxic effect of methotrexate in lung cancer cells. 2013 Sep Methotrexate (MTX) has been widely used for the treatment of cancer and rheumatoid arthritis (RA). Aspirin (ASA) is a non-selective cyclooxygenase (COX) inhibitor that contributes to the treatment of inflammatory conditions such as RA. It has been observed that the antitumor effect of ASA can be attributed to inhibition of cell cycle progression, induction of apoptosis and inhibition of angiogenesis. In the present study, we revealed that the treatment with a combination of MTX and ASA resulted in antagonism of the cytotoxic effect as demonstrated by SRB and colony formation assays. ASA alleviated the MTX-mediated S phase accumulation and recovered the G1 phase. MTX-mediated accumulation of the S phase marker cyclin A was also alleviated by ASA. Notably, FAS protein levels were upregulated by MTX in A549 cells. The antagonism of MTX efficacy caused by ASA was accompanied by altered expression of caspase-3, Bcl-2 and FAS but not dihydrofolate reductase (DHFR). This suggests that the alteration of caspase-3, Bcl-2 and FAS was involved in the antagonism between ASA and MTX. Exogenously added folic acid reversed the MTX-mediated DHFR inhibition following either MTX or MTX + ASA treatments. Most importantly, we demonstrated for the first time that the commonly used non-steroidal anti-inflammatory drug for headache ASA and possibly other COX-1/2 inhibitors can produce a strong antagonistic effect on the growth inhibition of lung cancer cells when administered in combination with MTX. The clinical implication of our finding is obvious, i.e., the clinical efficacy of MTX therapy can be compromised by ASA and their concomitant use should be avoided.
23734776 Association of IFIH1 rs1990760 polymorphism with susceptibility to autoimmune diseases: a 2013 Nov Published data on the association between the IFIH1 rs1990760 polymorphism and multiple autoimmune diseases are controversial and inconclusive. To more precisely estimate the association between the IFIH1 rs1990760 polymorphism and susceptibility to autoimmune diseases, a meta-analysis was conducted. Studies examining the association of the IFIH1 rs1990760 polymorphism with autoimmune diseases were exhaustively searched using PubMed, Web of Science and a review of the references. A total of 19 studies with 26 comparisons including 8 type 1 diabetes (T1D), 5 systemic lupus erythematosus (SLE), 5 Graves' disease (GD), 2 multiple sclerosis (MS), 2 rheumatoid arthritis (RA), 2 Hashimoto's thyroiditis (HT), 2 autoimmune Addison's disease (AAD) were available for this meta-analysis. Meta-analysis was performed for genotype T/T + T/C (dominant model), genotype T/T (recessive model) and T-allele in fixed or random-effects models. The overall odds ratios (ORs) and 95% confidence intervals (CIs) for T-allele were T1D (OR = 1.184, 95% CI = 1.142-1.229), SLE (OR = 1.143, 95% CI = 1.073-1.217), MS (OR = 1.181, 95% CI = 1.062-1.313) and RA (OR = 1.115, 95% CI = 1.004-1.239), respectively. For T1D and SLE, significant association was observed in the population of European ancestry, but not in the Asian population. This meta-analysis demonstrates that the IFIH1 rs1990760 T-allele confers susceptibility to T1D, SLE, MS and RA and suggests that the IFIH1 rs1990760 polymorphism might have no effect on GD and AAD. Our result provides further evidence for the notion of common gene underlying multiple autoimmune diseases.
23701550 Hypusine modification of the ribosome-binding protein eIF5A, a target for new anti-inflamm 2014 Inflammation is part of an important mechanism triggered by the innate immune response that rapidly responds to invading microorganisms and tissue injury. One important elicitor of the inflammatory response is the Gram-negative bacteria component lipopolysaccharide (LPS), which induces the activation of innate immune response cells, the release of proinflammatory cytokines, such as interleukin 1 and tumor necrosis factor α(TNF-α), and the cellular generation of nitric oxide (NO) by the inducible nitric oxide synthase (iNOS). Although essential to the immune response, uncontrolled inflammatory responses can lead to pathological conditions, such as sepsis and rheumatoid arthritis. Therefore, identifying cellular targets for new anti-inflammatory treatments is crucial to improving therapeutic control of inflammation-related diseases. More recently, the translation factor eIF5A has been demonstrated to have a proinflammatory role in the release of cytokines and the production of NO. As eIF5A requires and essential and unique modification of a specific residue of lysine, changing it to hypusine, eIF5A is an interesting cellular target for anti-inflammatory treatment. The present study reviews the literature concerning the anti-inflammatory effects of inhibiting eIF5A function. We also present new data showing that the inhibition of eIF5A function by the small molecule GC7 significantly decreases TNF-α release without affecting TNF-α mRNA levels. We discuss the mechanisms by which eIF5A may interfere with TNF-α mRNA translation by binding to and regulating the function of ribosomes during protein synthesis.
23555007 Sinomenine protects against lipopolysaccharide-induced acute lung injury in mice via adeno 2013 Sinomenine (SIN) is a bioactive alkaloid extracted from the Chinese medicinal plant Sinomenium acutum, which is widely used in the clinical treatment of rheumatoid arthritis (RA). However, its role in acute lung injury (ALI) is unclear. In this study, we investigate the role of SIN in lipopolysaccharide (LPS)-induced ALI in mice. After ALI, lung water content and histological signs of pulmonary injury were attenuated, whereas the PaO2/FIO2 (P/F) ratios were elevated significantly in the mice pretreated with SIN. Additionally, SIN markedly inhibited inflammatory cytokine TNF-α and IL-1β expression levels as well as neutrophil infiltration in the lung tissues of the mice. Microarray analysis and real-time PCR showed that SIN treatment upregulated adenosine A(2A) receptor (A(2A)R) expression, and the protective effect of SIN was abolished in A(2A)R knockout mice. Further investigation in isolated mouse neutrophils confirmed the upregulation of A(2A)R by SIN and showed that A(2A)R-cAMP-PKA signaling was involved in the anti-inflammatory effect of SIN. Taken together, these findings demonstrate an A(2A)R-associated anti-inflammatory effect and the protective role of SIN in ALI, which suggests a potential novel approach to treat ALI.
23475901 Generation and characterization of fully human monoclonal antibodies against human Orai1 f 2013 May Calcium entry into T cells following antigen stimulation is crucial for nuclear factor of activated T cells (NFAT)-mediated T cell activation. The movement of calcium is mediated by calcium release-activated calcium (CRAC) channels. There are two key components of this channel: Orai1 is the pore-forming subunit located in the plasma membrane, and stromal interaction molecule 1 (STIM1) functions as a Ca(2+) sensor in the endoplasmic reticulum. A subset of human patients carry mutations in either STIM1 or Orai1 that affect protein function or expression, resulting in defective store-operated Ca(2+) influx and CRAC channel function, and impaired T cell activation. These patients suffer from a hereditary form of severe combined immune deficiency syndrome, highlighting the importance of the CRAC channel for T lymphocyte function in humans. Since autoreactive T cells play an important role in the development of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and organ transplantation, Orai1 becomes an attractive therapeutic target for ameliorating autoimmune disease. We developed a novel approach to inhibiting CRAC function by generating high-affinity fully human monoclonal antibodies to human Orai1. These antibodies inhibited ICRAC current, store-operated Ca(2+) influx, NFAT transcription, and cytokine release. These fully human antibodies to human Orai1 may represent a novel therapeutic approach for the treatment of autoimmunity.
23400861 Significance of antibodies against the native ribosomal P protein complex and recombinant 2013 Mar BACKGROUND: This study aimed to evaluate autoantibodies against the native ribosomal P complex (anti-Rib-P(C)) and recombinant ribosomal P proteins (anti-Rib-P0, anti-Rib-P1, anti-Rib-P2) for their prevalence, diagnostic relevance and clinical associations in a Chinese cohort with systemic lupus erythematosus (SLE). METHODS: Anti-Rib-P, anti-dsDNA and anti-Smith antigen (Sm) antibodies were analyzed in sera from 198 patients with SLE, 33 with rheumatoid arthritis, 61 with Sjögren's syndrome and 70 healthy individuals by means of ELISA. RESULTS: Antibody prevalences were 29.8% (anti-Rib-P(C)), 33.3% (anti-Rib-P0), 42.9% (anti-Rib-P1) and 34.3% (anti-Rib-P2), at a specificity of 99%. Among SLE patients lacking anti-dsDNA and anti-Sm, 27.8% showed positive for at least one of the investigated anti-Rib-P types. The serological hit rate provided by anti-dsDNA/anti-Sm detection (72.7%) was increased upon parallel testing for anti-Rib-P(C) (77.3%) or anti-Rib-P0/P1/P2 (80.3%). Anti-Rib-P positivity was associated with disease activity, neuropsychiatric events, lupus nephritis, skin rash, lymphocytopenia, increased erythrocyte sedimentation rates, decreased complement C3/C4 and elevated IgA/IgG levels. CONCLUSION: Based on these results, antibodies against ribosomal P proteins are important complementary parameters to anti-dsDNA and anti-Sm, and should be considered for inclusion in the classification criteria for SLE. The diagnostic value of anti-Rib-P0/P1/P2 is diagnostically superior to that of anti-Rib-P(C).
25582999 [High resolution peripheral quantitative computed tomography for the assessment of morphol 2015 Jul High resolution peripheral quantitative computed tomography (HR-pQCT) is a new technology commercially available for less than 10 years that allows performing in vivo assessment of bone parameters. HR-pQCT assesses the trabecular thickness, trabecular separation, trabecular number and connectivity density and, in addition, cortical bone density and thickness and total bone volume and density in high-definition mode, which additionally allows obtaining digital constructs of bone microarchitecture. The application of mathematics to captured data, a method called finite element analysis (FEA), allows the estimation of the physical properties of the tissue, simulating supported loads in a non-invasive way. Thus, HR-pQCT simultaneously acquires data previously provided separately by dual energy x-ray absorptiometry (DXA), magnetic resonance imaging and histomorphometry, aggregating biomechanical estimates previously only possible in extracted tissues. This method has a satisfactory reproducibility, with coefficients of variation rarely exceeding 3%. Regarding accuracy, the method shows a fair to good agreement (r(2) = 0.37-0.97). The main clinical application of this method is in the quantification and monitoring of metabolic bone disorders, more fully evaluating bone strength and fracture risk. In rheumatoid arthritis patients, this allows gauging the number and size of erosions and cysts, in addition to joint space. In osteoarthritis, it is possible to characterize the bone marrow edema-like areas that show a correlation with cartilage breakdown. Given its high cost, HR-pQCT is still a research tool, but the high resolution and efficiency of this method reveal advantages over the methods currently used for bone assessment, with a potential to become an important tool in clinical practice.
25482338 Buccal mucosal delivery of a potent peptide leads to therapeutically-relevant plasma conce 2015 Feb 10 Stichodactyla helianthus neurotoxin (ShK) is an immunomodulatory peptide currently under development for the treatment of autoimmune diseases, including multiple sclerosis and rheumatoid arthritis by parenteral administration. To overcome the low patient compliance of conventional self-injections, we have investigated the potential of the buccal mucosa as an alternative delivery route for ShK both in vitro and in vivo. After application of fluorescent 5-Fam-ShK to untreated porcine buccal mucosa, there was no detectable peptide in the receptor chamber using an in vitro Ussing chamber model. However, the addition of the surfactants sodium taurodeoxycholate hydrate or cetrimide, and formulation of ShK in a chitosan mucoadhesive gel, led to 0.05-0.13% and 1.1% of the applied dose, respectively, appearing in the receptor chamber over 5h. Moreover, confocal microscopic studies demonstrated significantly enhanced buccal mucosal retention of the peptide (measured by mucosal fluorescence associated with 5-Fam-ShK) when enhancement strategies were employed. Administration of 5-Fam-ShK to mice (10mg/kg in a mucoadhesive chitosan-based gel (3%, w/v) with or without cetrimide (5%, w/w)) resulted in average plasma concentrations of 2.6-16.2nM between 2 and 6h, which were substantially higher than the pM concentrations required for therapeutic activity. This study demonstrated that the buccal mucosa is a promising administration route for the systemic delivery of ShK for the treatment of autoimmune diseases.
25460501 LIGHT/TNFSF14 increases osteoclastogenesis and decreases osteoblastogenesis in multiple my 2014 Dec 30 LIGHT, a TNF superfamily member, is involved in T-cell homeostasis and erosive bone disease associated with rheumatoid arthritis. Herein, we investigated whether LIGHT has a role in Multiple Myeloma (MM)-bone disease. We found that LIGHT was overproduced by CD14+ monocytes, CD8+ T-cells and neutrophils of peripheral blood and bone marrow (BM) from MM-bone disease patients. We also found that LIGHT induced osteoclastogenesis and inhibited osteoblastogenesis. In cultures from healthy-donors, LIGHT induced osteoclastogenesis in RANKL-dependent and -independent manners. In the presence of a sub-optimal RANKL concentration, LIGHT and RANKL synergically stimulated osteoclast formation, through the phosphorylation of Akt, NFκB and JNK pathways. In cultures of BM samples from patients with bone disease, LIGHT inhibited the formation of CFU-F and CFU-OB as well as the expression of osteoblastic markers including collagen-I, osteocalcin and bone sialoprotein-II. LIGHT indirectly inhibited osteoblastogenesis in part through sclerostin expressed by monocytes. In conclusion, our findings for the first time provide evidence for a role of LIGHT in MM-bone disease development.
25402257 The use of natural language processing of infusion notes to identify outpatient infusions. 2015 Jan PURPOSE: Outpatient infusions are commonly missing in Veterans Health Affairs (VHA) pharmacy dispensing data sets. Currently, Healthcare Common Procedure Coding System (HCPCS) codes are used to identify outpatient infusions, but concerns exist if they correctly capture all infusions and infusion-related data such as dose and date of administration. We developed natural language processing (NLP) software to extract infusion information from medical text infusion notes. The objective was to compare the sensitivity of three approaches to identify infliximab administration dates and infusion doses against a reference standard established from the Veterans Affairs rheumatoid arthritis (VARA) registry. METHODS: We compared the sensitivity and positive predictive value (PPV) of NLP to that of HCPCS codes in identifying the correct date and dose of infliximab infusions against a human extracted reference standard. RESULTS: The sensitivity was 0.606 (0.585-0.627) for HCPCS alone, 0.858 (0.842-0.873) for NLP alone, and 0.923 (0.911-0.934) for the two methods combined, with a PPV of 0.735 (0.716-0.754), 0.976 (0.969-0.983), and 0.957 (0.948-0.965) for each method, respectively. The mean dose of infliximab was 433 mg in the reference standard, 337 mg from HCPCS, 434 mg from NLP, and 426 mg from the combined method. CONCLUSIONS: HCPCS codes alone are not sufficient to accurately identify infliximab infusion dates and doses in the VHA system. The use of NLP significantly improved the sensitivity and PPV for estimating infusion dates and doses, especially when combined with HCPCS codes.
25002114 Predictors of in-hospital mortality in coronary artery dissection: Findings from the Natio 2015 BACKGROUND: The pathophysiology of coronary artery dissection (CD) remains poorly under-stood and little is known about the factors predicting mortality in these patients. We aimed to study the epidemiology of CD and predictors of mortality in these patients. METHODS: All patients diagnosed with CD in the Nationwide Inpatient Sample 2009-2010 database using International Classification of Diseases ninth revision 414.12 were included in the study. Chronic conditions included in the analysis were diabetes mellitus, hypertension, hyperlipidemia, coronary artery disease (CAD), obesity, alcohol use, smoking, heart failure and ventricular arrhythmias. Non-cardiovascular conditions were connective tissue disorders, fibromuscular dysplasia, Ehlers-Danlos syndrome, Marfan's syndrome, sarcoidosis, Crohn's disease, polycystic kidney disease, rheumatoid arthritis, vasculitis including giant cell arteritis, polyarteritis nodosa and Takayasu's disease, cocaine use, early or premature labor. RESULTS: The prevalence of CD in the United States was 0.02% (n = 11,255), based on the hospital admissions reviewed in the database. The mean age was 63.25 years with women (64.62 years) being older than men (62.25 years) (p < 0.001). In-hospital mortality rate was 4.2%, with women (5.5%) having higher mortality than men (3.2%) (p = 0.009). Ventricular arrhythmias (OR 5.86, p < 0.001) predicted higher mortality, while hyperlipidemia (OR 0.26, p < 0.001) and CAD (OR 0.31, p = 0.001) predicted lower mortality in multivariate analysis. CONCLUSIONS: Our study demonstrated that CD was more prevalent in men but women had higher mortality than men. Age, heart failure and ventricular arrhythmias were independent predictors of increased mortality but hyperlipidemia CAD predicted lower mortality in patients with CD.
24798501 Reconstitution of the peripheral B lymphocyte compartment in patients with ANCA-associated 2014 Sep While in patients with rheumatoid arthritis B-cell repopulation starts within 9 months after rituximab (RTX) therapy, a delayed B-cell repopulation was reported in some RTX-treated patients with ANCA-associated vasculitides (AAV). To date, the frequency of AAV patients with impaired peripheral B-cell regeneration and the mechanisms leading to the constricted regenerative capacity are unknown. We analyzed the B-cell repopulation kinetic in 37 AAV patients treated with RTX followed by maintenance immunosuppressants. We report on serum concentrations of the B-cell-activating factor BAFF, immunoglobulins and B-cell subpopulations in patients that relapsed after RTX. B-cells were re-detectable in only one patient within 9 months after RTX. In 14 patients (41%), B-cell repopulation started later, after a mean observation time of 21 months. Only seven of these patients had detectable B-cells within the first year after RTX. Twenty patients (59%) had no B-cell reconstitution within the observation period. BAFF was increased in RTX-treated AAV patients compared to healthy controls and correlated inversely with peripheral B-cell numbers, IgG- and IgA concentrations. Immunoglobulin concentrations declined significantly after RTX and the IgG concentration correlated with B-cell numbers. Thirteen patients relapsed after RTX. Relapses occurred exclusively either after B-cell reconstitution had started or were accompanied by rising ANCA titres. In relapsed patients, the B-lymphocyte compartment consisted mainly of switched memory B-cells. Our data indicate that RTX treatment can induce secondary immunodeficiency in AAV, with hypogammaglobulinemia and long-lasting B-lymphopenia. Further studies are needed to define the pathophysiology of the impaired B-cell development in RTX-treated AAV patients.
24741591 Adipokines, metabolic syndrome and rheumatic diseases. 2014 The metabolic syndrome (MetS) is a cluster of cardiometabolic disorders that result from the increasing prevalence of obesity. The major components of MetS include insulin resistance, central obesity, dyslipidemia, and hypertension. MetS identifies the central obesity with increased risk for cardiovascular diseases (CVDs) and type-2 diabetes mellitus (T2DM). Patients with rheumatic diseases, such as rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, and ankylosing spondylitis, have increased prevalence of CVDs. Moreover, CVD risk is increased when obesity is present in these patients. However, traditional cardiovascular risk factors do not completely explain the enhanced cardiovascular risk in this population. Thus, MetS and the altered secretion patterns of proinflammatory adipokines present in obesity could be the link between CVDs and rheumatic diseases. Furthermore, adipokines have been linked to the pathogenesis of MetS and its comorbidities through their effects on vascular function and inflammation. In the present paper, we review recent evidence of the role played by adipokines in the modulation of MetS in the general population, and in patients with rheumatic diseases.
24661968 An integrated strategy based on UPLC-DAD-QTOF-MS for metabolism and pharmacokinetic studie 2014 May 14 ETHNOPHARMACOLOGICAL RELEVANCE: Saussurea laniceps Hand.-Mazz. (SL) has long been used under the herbal name Tibetan "Snow Lotus" for the treatment of rheumatoid arthritis, stomachache and dysmenorrhea in Tibetan folk medicine. Since herbal medicine (HM) is a synergistical system with multiple components, both of the metabolism and pharmacokinetic studies of HM are interdependent. This study aimed to develop an integrated strategy based on the UPLC-DAD-QTOF-MS technique for metabolism and pharmacokinetic studies of HM. MATERIAL AND METHODS: SL was used here as a test herb to verify the feasibility of the proposed strategy. SL was administered to rats, then, the blood plasma, urine and feces were analyzed to determine the metabolic profiles. Using our strategy, umbelliferone and scopoletin were evaluated to be the key bioactive components. Their pharmacokinetic parameters were measured and biotransformation pathways were elucidated. RESULTS: After oral administration of SL to rats, 17 components in blood, 10 components in urine and 2 components in feces were identified and characterized using our UPLC-DAD-QTOF-MS method. Umbelliferone, scopoletin and their metabolites were found to be the major components involved in the metabolism process. Literature reports also suggest that umbelliferone and scopoletin are responsible for the therapeutic effects of SL, thus these two components were selected as the active markers for pharmacokinetic study. In the test of validity, the established method presented good linearity with R(2)>0.99. The relative standard deviation value was below 13.9% for precision, and recovery studies for accuracy were found to be within the range 91.8-112.5%. CONCLUSION: The present strategy offers, simultaneously, precision in quantitative analysis (metabolism study) and accuracy in quantitative analysis (pharmacokinetic study) with greater efficiency and less costs, which is therefore reliably used for integrated metabolism and pharmacokinetic studies of HM.
24556593 18F-FDG PET scanning in pulmonary amyloidosis. 2014 Apr (18)F-FDG PET plays an important role in the evaluation of patients with lung malignancies but can lead to false-positive and false-negative results. Very little is known about (18)F-FDG PET scanning in amyloidosis. METHODS: A computer-assisted search of medical records was conducted to identify subjects with pulmonary amyloidosis (confirmed by biopsy) who were seen at the Mayo Clinic during a 15-y period between January 1, 1997, and December 31, 2011, and had a PET scan available for current review. RESULTS: Eighteen patients were diagnosed to have amyloidosis by lung biopsy (15 surgical, 2 transthoracic needle, and 1 bronchoscopic). The mean age of the patients was 64.8 y (range, 32-80 y). Seventeen patients had primary amyloidosis, including 5 with Sjögren syndrome, 1 with rheumatoid arthritis, and 1 with multiple myeloma. The most common abnormal findings on the chest CT scan were pulmonary nodules (n = 14), followed by cysts (n = 6) and reticular opacities (n = 4). Eight patients had positive (18)F-FDG PET results (intrathoracic (18)F-FDG uptake), including 4 patients with coexisting mucosa-associated lymphoid tissue lymphoma (maximal standardized uptake value [SUVmax] range, 3.1-6.7) and 1 patient with a pleural plasmacytoma (SUVmax, 7.2); the remaining 3 patients had amyloid only (SUVmax range, 2.1-3.2). Ten patients with negative PET results included 3 additional patients with mucosa-associated lymphoid tissue lymphoma. CONCLUSION: Positive (18)F-FDG PET results, especially with an SUVmax of more than 3, in patients with pulmonary amyloidosis should raise suspicion about associated lymphoma or plasmacytoma, but negative PET results do not exclude the presence of such neoplasms.
24424131 In silico study of 1-(4-Phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl) ethanones derivatives as 2014 Feb 1 C-C chemokine receptor type 1 (CCR1) is a chemokine receptor with seven transmembrane helices and it belongs to the G-Protein Coupled receptor (GPCR) family. It plays an important role in rheumatoid arthritis, organ transplant rejection, Alzheimer's disease and also causes inflammation. Because of its role in disease processes, CCR1 is considered to be an important drug target. In the present study, we have performed three dimensional Quantitative Structure activity relationship (3D-QSAR) studies on a series of 1-(4-Phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl) ethanone derivatives targeting CCR1. Homology modeling of CCR1 was performed based on a template structure (4EA3) which has a high sequence identity and resolution. The highest active molecule was docked into this model. Ligand-based and Receptor-based quantitative structure-activity relationship (QSAR) study was performed and CoMFA models with reasonable statistics was developed for both ligand-based (q(2)=0.606; r(2)=0.968) and receptor-guided (q(2)=0.640; r(2)=0.932) alignment methods. Contour map analyses identified favorable regions for high affinity binding. The docking results highlighted the important active site residues. Tyr113 was found to interact with the ligand through hydrogen bonding. This residue has been considered responsible for anchoring ligands inside the active site. Our results could also be helpful to understand the inhibitory mechanism of 1-(4-Phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl) ethanone derivatives thereby to design more effective ligands in the future.