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ID PMID Title PublicationDate abstract
27993633 Davallia bilabiata exhibits anti-angiogenic effect with modified MMP-2/TIMP-2 secretion an 2017 Jan 20 ETHNOPHARMACOLOGICAL RELEVANCE: Davallia bilabiata Hosokawa (D. bilabiata), also called GuSuiBu, is popularly used as a substitute for Drynaria fortunei J. Sm for rheumatoid and degenerative arthritis in traditional Chinese medicine. Little is known about the underlying mechanisms of anti-angiogenesis responsible for arthritis in D. bilabiata which needs to be elucidated. AIM OF THE STUDY: The present study is intended to investigate the anti-angiogenic effect of D. bilabiata associated with the modulation of matrix metalloproteinases (MMPs) and down regulation of vascular endothelial growth factor (VEGF) ligand/receptors both in vivo and in vitro. MATERIALS AND METHODS: We investigated the potential anti-angiogenic effect of D. bilabiata by the in vivo neovascularization of chick chorioallantoic membranes (CAM) assay, and the in vitro migration and matrix-induced tube formation assay using human umbilical vascular endothelial cells (HUVECs). The expressions of MMP-2, TIMP-2, RECK and VEGF/VEGFR were analyzed by real-time RT-PCR or Western blot method. RESULTS: One major compound from water extract of D. bilabiata was identified as Epicatechin 3-O-β-D-allopyranoside. D. bilabiata was confirmed to inhibit in vivo angiogenesis by CAM assay. D. bilabiata also exhibited in vitro anti-angiogenic and anti-regrowth effects as demonstrated by tube formation assay, transwell migration assay and wound healing assay. The mRNA expressions of MMP-2, and MMP-14 were decreased. On the contrary, tissue inhibitor of metalloproteinase-2 (TIMP-2), reversion-inducing cysteine-rich protein with kazal motifs (RECK) were increased by D. bilabiata. The extracellular MMP-2 activity was found to be reduced both in vitro and in vivo by D. bilabiata as determined by gelatin zymography. Results from western blot analysis and ELISA further demonstrated the decrease of MMP-2 and increase of TIMP-2 secretion after D. bilabiata treatment. The gene expressions of VEGF-A, -B, -C, -D and VEGFR-1, -2, -3 were all inhibited by D. bilabiata. CONCLUSION: We concluded that the anti-angiogenic effect of D. bilabiata was associated with the decreased MMP-2 activity mediated by the upregulation of TIMP-2 and RECK, and the suppression of VEGF/VEGFRs expression.
20301357 WAS-Related Disorders. 1993 CLINICAL CHARACTERISTICS: The WAS-related disorders, which include Wiskott-Aldrich syndrome, X-linked thrombocytopenia (XLT), and X-linked congenital neutropenia (XLN), are a spectrum of disorders of hematopoietic cells, with predominant defects of platelets and lymphocytes caused by pathogenic variants in WAS. WAS-related disorders usually present in infancy. Affected males have thrombocytopenia with intermittent mucosal bleeding, bloody diarrhea, and intermittent or chronic petechiae and purpura; eczema; and recurrent bacterial and viral infections, particularly of the ear. At least 40% of those who survive the early complications develop one or more autoimmune conditions including hemolytic anemia, immune thrombocytopenic purpura, immune-mediated neutropenia, rheumatoid arthritis, vasculitis, and immune-mediated damage to the kidneys and liver. Individuals with a WAS-related disorder, particularly those who have been exposed to Epstein-Barr virus (EBV), are at increased risk of developing lymphomas, which often occur in unusual, extranodal locations including the brain, lung, or gastrointestinal tract. Males with XLT have thrombocytopenia with small platelets; other complications of Wiskott-Aldrich syndrome, including eczema and immune dysfunction, are usually mild or absent. Males with XLN have congenital neutropenia, myeloid dysplasia, and lymphoid cell abnormalities. DIAGNOSIS/TESTING: The diagnosis of a WAS-related disorder is established in a male proband with both congenital thrombocytopenia (<70,000 platelets/mm(3)) and small platelets, in addition to at least one of the following features: eczema, recurrent bacterial or viral infections, autoimmune disease(s), malignancy, reduced WASP expression in a fresh blood sample, abnormal antibody response to polysaccharide antigens and/or low isohemagglutinins, or positive maternal family history of a WAS-related disorder. Identification of a hemizygous WAS pathogenic variant on molecular genetic testing is necessary to confirm the diagnosis. MANAGEMENT: Treatment of manifestations: Treatment options depend on an individual's predicted disease burden; hematopoietic cell transplantation (HCT) is the only known curative treatment. Topical steroids for eczema; antibiotics for infected eczema; judicious use of immunosuppressants for autoimmune disease; granulocyte colony stimulating factor (G-CSF) and appropriate antibiotics for neutropenia. Prevention of primary manifestations: Pneumocystis jiroveci (formerly known as Pneumocystis carinii pneumonia, or PCP) prophylaxis with Bactrim(®) (trimethoprim-sulfamethoxazole) or pentamidine, intravenous immunoglobulin (IVIgG) replacement therapy, routine childhood "non-live" immunizations; judicious use of platelet transfusions for significant bleeding and surgical procedures. Surveillance: Routine monitoring of blood counts and adequacy of IVIgG replacement therapy. Agents/circumstances to avoid: Circumcision of at-risk newborn males who have thrombocytopenia; use of medications that interfere with platelet function. Defer elective procedures until after HCT. Evaluation of relatives at risk: Evaluation of at-risk newborn males so that morbidity and mortality can be reduced by early diagnosis and treatment. GENETIC COUNSELING: WAS-related disorders are inherited in an X-linked manner. If the mother is a carrier of a WAS pathogenic variant, the chance of transmitting the pathogenic variant in each pregnancy is 50%: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers. Males will pass the pathogenic variant to all of their daughters and none of their sons. Female carriers of a WAS pathogenic variant are usually asymptomatic and have no immunologic or biochemical markers of the disorder. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant has been identified in the family.
27043267 Identification of N-phenyl-2-(N-phenylphenylsulfonamido)acetamides as new RORγ inverse ag 2016 Jun 30 Retinoic acid receptor-related orphan receptors (RORs) are ligand-dependent transcriptional factors and members of the nuclear receptor superfamily. RORs regulate inflammation, metabolic disorders and circadian rhythm. RORγ is a promising therapeutic drug target for treating Th17-mediated autoimmune diseases. In our study, we performed structure-based virtual screening and ligand-based virtual screening targeting the RORγ ligand-binding domain and successfully identified N-phenyl-2-(N-phenylphenylsulfonamido) acetamides as a type of RORγ inverse agonist. Among the 28 purchased compounds, C11 was confirmed to be active with micromolar IC50 values in both an AlphaScreen assay (62.58 μM) and a cell-based reporter gene assay (4.54 μM). Structure-guided optimization of the compound C11 led to the identification of compound 39, which significantly enhanced RORγ inhibition with an IC50 value of 630 nM. The RORγ antagonism of 39 was 7-fold higher than that of hit compound C11. These results represent a promising starting point for developing potent small molecule RORγ inverse agonists for the treatment of autoimmune diseases, such as rheumatoid arthritis, psoriasis, and multiple sclerosis.
26750564 Downregulation of Organic Anion Transporting Polypeptide (OATP) 1B1 Transport Function by 2016 Mar 7 Organic anion transporting polypeptide (OATP) 1B1 mediates the hepatic uptake of many drugs including lipid-lowering statins. Decreased OATP1B1 transport activity is often associated with increased systemic exposure of statins and statin-induced myopathy. Antimalarial drug chloroquine (CQ) is also used for long-term treatment of rheumatoid arthritis and systemic lupus erythematosus. CQ is lysosomotropic and inhibits protein degradation in lysosomes. The current studies were designed to determine the effects of CQ on OATP1B1 protein degradation, OATP1B1-mediated transport in OATP1B1-overexpressing cell line, and statin uptake in human sandwich-cultured hepatocytes (SCH). Treatment with lysosome inhibitor CQ increased OATP1B1 total protein levels in HEK293-OATP1B1 cells and in human SCH as determined by OATP1B1 immunoblot. In HEK293-FLAG-tagged OATP1B1 stable cell line, co-immunofluorescence staining indicated that intracellular FLAG-OATP1B1 is colocalized with lysosomal associated membrane glycoprotein (LAMP)-2, a marker protein of late endosome/lysosome. Enlarged LAMP-2-positive vacuoles with FLAG-OATP1B1 protein retained inside were readily detected in CQ-treated cells, consistent with blocking lysosomal degradation of OATP1B1 by CQ. In HEK293-OATP1B1 cells, without pre-incubation, CQ concentrations up to 100 μM did not affect OATP1B1-mediated [(3)H]E217G accumulation. However, pre-incubation with CQ at clinically relevant concentration(s) significantly decreased [(3)H]E217G and [(3)H]pitavastatin accumulation in HEK293-OATP1B1 cells and [(3)H]pitavastatin accumulation in human SCH. CQ pretreatment (25 μM, 2 h) resulted in ∼1.9-fold decrease in Vmax without affecting Km of OATP1B1-mediated [(3)H]E217G transport in HEK293-OATP1B1 cells. Pretreatment with monensin and bafilomycin A1, which also have lysosome inhibition activity, significantly decreased OATP1B1-mediated transport in HEK293-OATP1B1 cells. Pharmacoepidemiologic studies using data from the U.S. Food and Drug Administration Adverse Event Reporting System indicated that CQ plus pitavastatin, rosuvastatin, and pravastatin, which are minimally metabolized by the cytochrome P450 enzymes, led to higher myopathy risk than these statins alone. In summary, the present studies report novel findings that lysosome is involved in degradation of OATP1B1 protein and that pre-incubation with lysosomotropic drug CQ downregulates OATP1B1 transport activity. Our in vitro data in combination with pharmacoepidemiologic studies support that CQ has potential to cause OATP-mediated drug-drug interactions.
26132828 Structure and mechanism of a bacterial host-protein citrullinating virulence factor, Porph 2015 Jul 1 Citrullination is a post-translational modification of higher organisms that deiminates arginines in proteins and peptides. It occurs in physiological processes but also pathologies such as multiple sclerosis, fibrosis, Alzheimer's disease and rheumatoid arthritis (RA). The reaction is catalyzed by peptidylarginine deiminases (PADs), which are found in vertebrates but not in lower organisms. RA has been epidemiologically associated with periodontal disease, whose main infective agent is Porphyromonas gingivalis. Uniquely among microbes, P. gingivalis secretes a PAD, termed PPAD (Porphyromonas peptidylarginine deiminase), which is genetically unrelated to eukaryotic PADs. Here, we studied function of PPAD and its substrate-free, substrate-complex, and substrate-mimic-complex structures. It comprises a flat cylindrical catalytic domain with five-fold α/β-propeller architecture and a C-terminal immunoglobulin-like domain. The PPAD active site is a funnel located on one of the cylinder bases. It accommodates arginines from peptide substrates after major rearrangement of a "Michaelis loop" that closes the cleft. The guanidinium and carboxylate groups of substrates are tightly bound, which explains activity of PPAD against arginines at C-termini but not within peptides. Catalysis is based on a cysteine-histidine-asparagine triad, which is shared with human PAD1-PAD4 and other guanidino-group modifying enzymes. We provide a working mechanism hypothesis based on 18 structure-derived point mutants.
27482468 Integrative genomics analyses unveil downstream biological effectors of disease-specific p 2016 Functionally altered biological mechanisms arising from disease-associated polymorphisms, remain difficult to characterize when those variants are intergenic, or, fall between genes. We sought to identify shared downstream mechanisms by which inter- and intragenic single nucleotide polymorphisms (SNPs) contribute to a specific physiopathology. Using computational modeling of 2 million pairs of disease-associated SNPs drawn from genome wide association studies (GWAS), integrated with expression Quantitative Trait Loci (eQTL) and Gene Ontology functional annotations, we predicted 3,870 inter-intra and inter-intra SNP pairs with convergent biological mechanisms (FDR<0.05). These prioritized SNP pairs with overlapping mRNA targets or similar functional annotations were more likely to be associated with the same disease than unrelated pathologies (OR>12). We additionally confirmed synergistic and antagonistic genetic interactions for a subset of prioritized SNP pairs in independent studies of Alzheimer's disease (entropy p=0.046), bladder cancer (entropy p=0.039), and rheumatoid arthritis (PheWAS case-control p<10(-4)). Using ENCODE datasets, we further statistically validated that the biological mechanisms shared within prioritized SNP pairs are frequently governed by matching transcription factor binding sites and long-range chromatin interactions. These results provide a "roadmap" of disease mechanisms emerging from GWAS and further identify candidate therapeutic targets among downstream effectors of intergenic SNPs.
27896669 Detection of autoantibodies to DSF70/LEDGFp75 in Mexican Hispanics using multiple compleme 2017 Dec PURPOSE: Antinuclear autoantibodies (ANA) targeting the dense fine speckled antigen DFS70, also known as lens epithelium-derived growth factor p75 (LEDGF/p75), are attracting attention due to their low frequency in systemic rheumatic diseases but increased frequency in clinical laboratory referrals and healthy individuals (HI). These ANA specifically recognize the stress protein DFS70/LEDGFp75, implicated in cancer, HIV-AIDS, and inflammation. While their frequency has been investigated in various ethnic populations, there is little information on their frequency among Hispanics/Latinos. In this study, we determined the frequency of anti-DFS70/LEDGFp75 autoantibodies in Mexican Hispanics using multiple detection platforms. METHODS: The frequency of anti-DFS70/LEDGFp75 antibodies was determined in 171 individuals, including 71 dermatomyositis (DM) patients, 47 rheumatoid arthritis (RA) patients, 30 obesity (OB) patients, and 23 HI. Antibody detection was achieved using four complementary assay platforms: indirect immunofluorescence, Western blotting, ELISA, and chemiluminescent immunoassay. RESULTS: We detected relatively low frequencies of anti-DFS70/LEDGFp75 antibodies in patients with DM (1.4%), RA (4.3%), and OB (6.6%), and elevated frequency (17.4%) in HI. A strong concordance between the different antibody detection platforms was observed. CONCLUSIONS: The low frequency of anti-DFS70/LEDGFp75 antibodies in Mexican patients with rheumatic diseases, but relatively higher frequency in HI, is consistent with previous observations with non-Hispanic populations, suggesting that geographic differences or ethnicity do not influence the frequency of these autoantibodies. Our results also highlight the importance of confirmatory assays for the accurate detection of these autoantibodies. Future studies with larger cohorts of healthy Hispanics/Latinos are needed to confirm if their anti-DFS70/LEDGFp75 antibody frequencies are significantly higher than in non-Hispanics.
27149370 Plasma Surfactant Protein-D, Matrix Metalloproteinase-7, and Osteopontin Index Distinguish 2016 Nov 15 RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease (ILD) characterized by abnormal extracellular matrix (ECM) remodeling. We hypothesized that ECM remodeling might result in a plasma profile of proteins specific for IPF that could distinguish patients with IPF from other idiopathic ILDs. OBJECTIVES: To identify biomarkers that might assist in distinguishing IPF from non-IPF ILD. METHODS: We developed a panel of 35 ECM, ECM-related, and lung-specific analytes measured in plasma from 86 patients with IPF (derivation cohort) and in 63 patients with IPF (validation cohort). Comparison groups included patients with rheumatoid arthritis-associated ILD (RA-ILD; n = 33), patients with alternative idiopathic ILDs (a-ILD; n = 41), and healthy control subjects (n = 127). Univariable and multivariable logistic regression models identified biomarkers that differentiated patients with IPF from those with a-ILD. Both continuous and diagnostic threshold versions of biomarkers were considered; thresholds were chosen to maximize summed diagnostic sensitivity and specificity in univariate receiver-operating characteristic curve analysis. A diagnostic score was created from the most promising analytes. MEASUREMENTS AND MAIN RESULTS: Plasma surfactant protein (SP)-D > 31 ng/ml, matrix metalloproteinase (MMP)-7 > 1.75 ng/ml, and osteopontin > 6 ng/ml each significantly distinguished patients with IPF from patients with a-ILD, both individually and in a combined index. The odds ratio for IPF when at least one analyte in the index exceeded the threshold was 4.4 (95% confidence interval, 2.0-9.7; P = 0.0003). When at least two analytes were elevated, the odds ratio for IPF increased to 5.0 (95% confidence interval, 2.2-11.5; P = 0.0002). CONCLUSIONS: A biomarker index of SP-D, MMP-7, and osteopontin enhanced diagnostic accuracy in patients with IPF compared with those with non-IPF ILD. Our data suggest that this biomarker index may improve diagnostic confidence in IPF.
26657290 Auranofin-mediated inhibition of PI3K/AKT/mTOR axis and anticancer activity in non-small c 2016 Jan 19 Auranofin, a gold complex that has been used to treat rheumatoid arthritis in clinics and has documented pharmacokinetic and safety profiles in humans, has recently been investigated for its anticancer activity in leukemia and some solid cancers. However, auranofin's single agent activity in lung cancer is not well characterized. To determine whether auranofin has single agent activity in lung cancer, we evaluated auranofin's activity in a panel of 10 non-small cell lung cancer (NSCLC) cell lines. Cell viability analysis revealed that auranofin induced growth inhibition in a subset of NSCLC cell lines with a half maximal inhibitory concentration (IC50) below 1.0 μM. Treatment with auranofin elicited apoptosis and necroptosis in auranofin-sensitive cell lines. Moreover, the susceptibility of NSCLC cells to auranofin was inversely correlated with TXNRD1 expression in the cells. Transient transfection of the TXNRD1-expressing plasmid in auranofin-sensitive Calu3 cells resulted in partial resistance, indicating that high TXNRD level is one of causal factors for resistance to auranofin. Further mechanistic characterization with proteomic analysis revealed that auranofin inhibits expression and/or phosphorylation of multiple key nodes in the PI3K/AKT/mTOR pathway, including S6, 4EBP1, Rictor, p70S6K, mTOR, TSC2, AKT and GSK3. Ectopic expression of TXNRD1 partially reversed auranofin-mediated PI3K/AKT/mTOR inhibition, suggesting that TXNRD1 may participate in the regulation of PI3K/AKT/mTOR pathway. Administration of auranofin to mice with xenograft tumors derived from NSCLC cells significantly suppressed tumor growth without inducing obvious toxic effects. Our results demonstrated feasibility of repurposing auranofin for treatment of lung cancer.
26258640 Deficient angiogenesis in redox-dead Cys17Ser PKARIα knock-in mice. 2015 Aug 10 Angiogenesis is essential for tissue development, wound healing and tissue perfusion, with its dysregulation linked to tumorigenesis, rheumatoid arthritis and heart disease. Here we show that pro-angiogenic stimuli couple to NADPH oxidase-dependent generation of oxidants that catalyse an activating intermolecular-disulphide between regulatory-RIα subunits of protein kinase A (PKA), which stimulates PKA-dependent ERK signalling. This is crucial to blood vessel growth as 'redox-dead' Cys17Ser RIα knock-in mice fully resistant to PKA disulphide-activation have deficient angiogenesis in models of hind limb ischaemia and tumour-implant growth. Disulphide-activation of PKA represents a new therapeutic target in diseases with aberrant angiogenesis.
25555357 Lignans and aromatic glycosides from Piper wallichii and their antithrombotic activities. 2015 Mar 13 ETHNOPHARMACOLOGICAL RELEVANCE: Piper wallichii (Miq.) Hand.-Mazz. is a medicinal plant used widely for the treatment of rheumatoid arthritis, inflammatory diseases, cerebral infarction and angina in China. Previous study showed that lignans and neolignans from Piper spp. had potential inhibitory activities on platelet aggregation. In the present study, we investigated the chemical constituents of Piper wallichii and their antithrombotic activities, to support its traditional uses. MATERIALS AND METHODS: The methanolic extract of the air-dried stems of Piper wallichii was separated and purified using various chromatographic methods, including semi-preparative HPLC. The chemical structures of the isolates were determined by detailed spectroscopic analysis, and acidic hydrolysis in case of the new glycoside 2. Determination of absolute configurations of the new compound 1 was facilitated by calculated electronic circular dichroism using time-dependent density-functional theory. All compounds were tested for their inhibitory effects on platelet aggregation induced by platelet activating factor (PAF) in rabbits׳ blood model, from which the active ones were further evaluated the in vivo antithrombotic activity in zebrafish model. RESULTS: A new neolignan, piperwalliol A (1), and four new aromatic glycosides, piperwalliosides A-D (2-5) were isolated from the stems of Piper wallichii, along with 25 known compounds, including 13 lignans, six aromatic glycosides, two phenylpropyl aldehydes, and four biphenyls. Five known compounds (6-10) showed in vitro antiplatelet aggregation activities. Among them, (-)-syringaresinol (6) was the most active compound with an IC50 value of 0.52 mM. It is noted that in zebrafish model, the known lignan 6 showed good in vivo antithrombotic effect with a value of 37% at a concentration of 30 μM, compared with the positive control aspirin with the inhibitory value of 74% at a concentration of 125μM. CONCLUSION: This study demonstrated that lignans, phenylpropanoid and biphenyl found in Piper wallichii may be responsible for antithrombotic effect of the titled plant.
27798154 ICOS-Ligand Triggering Impairs Osteoclast Differentiation and Function In Vitro and In Viv 2016 Nov 15 Osteoblasts, osteocytes, and osteoclasts (OCs) are involved in the bone production and resorption, which are crucial in bone homeostasis. OC hyperactivation plays a role in the exaggerated bone resorption of diseases such as osteoporosis, rheumatoid arthritis, and osteolytic tumor metastases. This work stems from the finding that OCs can express B7h (ICOS-Ligand), which is the ligand of the ICOS T cell costimulatory molecule. Because recent reports have shown that, in endothelial, dendritic, and tumor cells, B7h triggering modulates several activities of these cells, we analyzed the effect of B7h triggering by recombinant ICOS-Fc on OC differentiation and function. The results showed that ICOS-Fc inhibits RANKL-mediated differentiation of human monocyte-derived OC-like cells (MDOCs) by inhibiting the acquirement of the OC morphology, the CD14(-) cathepsin K(+) phenotype, and the expression of tartrate-resistant acid phosphatase, OSCAR, NFATc1, and DC-STAMP. Moreover, ICOS-Fc induces a reversible decrease in the sizes of cells and nuclei and cathepsin K expression in mature MDOCs. Finally, ICOS-Fc inhibits the osteolytic activities of MDOCs in vitro and the development of bone loss in ovariectomized or soluble RANKL-treated mice. These findings open a novel field in the pharmacological use of agonists and antagonists of the ICOS-B7h system.
26363864 Reverse Epidemiology of Traditional Cardiovascular Risk Factors in the Geriatric Populatio 2015 Nov 1 Traditional risk factors of cardiovascular death in the general population, including body mass index (BMI), serum cholesterol, and blood pressure (BP), are also found to relate to outcomes in the geriatric population, but in an opposite direction. Some degrees of elevated BMI, serum cholesterols, and BP are reportedly associated with lower, instead of higher, risk of death among the elderly. This phenomenon is termed "reverse epidemiology" or "risk factor paradox" (such as obesity paradox) and is also observed in a variety of chronic disease states such as end-stage renal disease requiring dialysis, chronic heart failure, rheumatoid arthritis, and AIDS. Several possible causes are hypothesized to explain this risk factor reversal: competing short-term and long-term killers, improved hemodynamic stability in the obese, adipokine protection against tumor necrosis factor-α, lipoprotein protection against endotoxins, and lipophilic toxin sequestration by the adipose tissue. It is possible that the current thresholds for intervention and goal levels for such traditional risk factors as BMI, serum cholesterol, and BP derived based on younger populations do not apply to the elderly, and that new levels for such risk factors should be developed for the elderly population. Reverse epidemiology of conventional cardiovascular risk factors may have a bearing on the management of the geriatric population, thus it deserves further attention.
25776919 Optimal clearance of Sporothrix schenckii requires an intact Th17 response in a mouse mode 2015 Aug The discovery of Th17 cells, along with many other Th cell subsets in the recent years, has expanded the Th1/Th2 paradigm that had persisted since its proposition by Mosmann in 1986. Defined by the characteristic expression of the transcription factor retinoic-related orphan receptor γt (RORγt) and production of IL-17A (IL-17), Th17 cells are powerful inducers of tissue inflammation with a recognized role against extracellular bacteria and fungi. Despite this, the interest in their study came from the pivotal role they play in the development and maintenance of major chronic inflammatory conditions such as multiple sclerosis, rheumatoid arthritis and Crohn's disease, hence they have been the target of promising new anti-Th17 therapies. Accordingly, the identification of opportunistic pathogens whose clearance relies on the Th17 response is of huge prophylactic importance. As shown here for the first time, this applies to Sporothrix schenckii, a thermo-dimorphic fungus and the causative agent of sporotrichosis. Our results show that both Th17 and Th1/Th17 mixed cells are developed during the S. schenckii systemic mice infection, which also leads to augmented production of IL-17 and IL-22. Also, by using an antibody-mediated IL-23 depletion model, we further demonstrate that optimal fungal clearance, but not survival, depends on an intact Th17 response.
27723989 [Extrahepatic manifestations of HCV infection]. 2016 Fall Extrahepatic manifestations of hepatitis C virus infection (HCV) are very common. The most common of these is mixed cryoglobulinaemia. Anti-HCV antibodies and viral ribonucleic acid, HCV RNA, can be found in the cryoprecipitates, together with the rheumatoid factor. Cryoglobulins consist of a complex of immunoglobulins that in vitro precipitate upon the cooling bellow the human body temperature. Vasculitis is caused by the deposition of such immune complexes in the small blood vessels. A link with the HCV infection is considered to be established with membranoproliferative glomerulonephritis, leukocytoclastic vasculitis, lymphoproliferative disorders (in particular B cell lymphoma), Sjögren and sicca syndrome, lichen planus, porfyria cutanea tarda and diabetes mellitus. Very probable is the relationship of chronic HCV infection and thyroid disease, arthralgias, otherwise unexplained fatigue and autoimmune hepatitis.Key words: direct acting antivirals - extrahepatic manifestations - chronic hepatitis C - mixed cryoglobulinaemia.
27772553 CAV3 mutation in a patient with transient hyperCKemia and myalgia. 2016 Nov Mutations in caveolin-3 (CAV3) can lead to different clinical phenotypes affecting skeletal or cardiac muscles. Here, we describe a patient with Klinefelter syndrome, ulcerative colitis and Sjögren syndrome, who developed transient hyperCKemia, myalgia and mild muscular weakness. Using whole exome sequencing (WES), a missense mutation G169A was found in the CAV3 gene. In addition, we identified a homozygous frameshift deletion in MS4A12 that may contribute to inflammatory bowel disease, further demonstrating usefulness of WES in dual molecular diagnoses.
26704822 [Indication for total knee arthroplasty: evidence mapping]. 2015 BACKGROUND: Joint replacement surgery is one of the most often performed routine procedures for the treatment of knee osteoarthritis in Germany. Currently, there is no consensus on indication criteria for total knee arthroplasty (TKA). OBJECTIVES: The topic indication for TKA was processed using six guiding questions concerning: 1) Common practice in determining the indication for TKA; 2) Inclusion criteria in clinical trials; 3) Treatment goals/goal criteria; 4) Predictors for goal attainment; 5) Economic aspects of determining a TKA indication; 6) Guidelines of the "Working Group of Scientific Medical Societies" (AWMF) in other areas. METHODS: The evidence mapping was conducted by systematically searching Medline via Ovid, the Cochrane Library, through hand searching national guidelines and selected journals as well as the AWMF guideline portal. RESULTS OF THE GUIDING QUESTIONS: 1) In Germany there is currently no consented guideline regarding indications for TKA surgery. 2) Indication criteria for clinical trials are: diagnosed osteoarthritis of the knee, limitations of age and BMI. The most common criteria for exclusion include rheumatoid/inflammatory arthritis, secondary diagnoses and allergies. 3) As yet, no international initiatives have been identified which, by involving all relevant stakeholders, have reached consensus regarding the indication criteria for TKA. 4) A variety of predictors were identified with effects on individual treatment goals acting in different directions. 5) Very few studies were identified concerning economic aspects of determining TKA indication. 6) Comparable AWMF guidelines are currently not available. CONCLUSION: The findings of this study suggest that specific systematic reviews are needed to explore the following questions: What are the treatment goals of a TKA intervention? For whom are these relevant? And how are they measured? Continuous analyses are recommended in the field of predictors for a positive TKA outcome.
27841110 Pre-treatment clinical assessment in head and neck cancer: United Kingdom National Multidi 2016 May This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. This paper provides recommendations on the pre-treatment clinical assessment of patients presenting with head and neck cancer. Recommendations • Comorbidity data should be collected as it is important in the analysis of survival, quality of life and functional outcomes after treatment as well as for comparing results of different treatment regimens and different centres. (R) • Patients with hypertension of over 180/110 or associated target organ damage, should have antihypertensive medication started pre-operatively as per British Hypertension Society guidelines. (R) • Rapidly correcting pre-operative hypertension with beta blockade appears to cause higher mortality due to stroke and hypotension and should not be used. (R) • Patients with poorly controlled or unstable ischaemic heart disease should be referred for cardiology assessment pre-operatively. (G) • Patients within one year of drug eluting stents should be discussed with the cardiologist who was responsible for their percutaneous coronary intervention pre-operatively with regard to cessation of antiplatelet medication due to risk of stent thrombosis. (G) • Patients with multiple recent stents should be managed in a centre with access to interventional cardiology. (G) • Surgery after myocardial infarction should be delayed if possible to reduce mortality risk. (R) • Patients with critical aortic stenosis (AS) should be considered for pre-operative intervention. (G) • Clopidogrel should be discontinued 7 days pre-operatively; warfarin should be discontinued 5 days pre-operatively. (R) • Patients with thromboembolic disease or artificial heart valves require heparin therapy to bridge peri-operative warfarin cessation, this should start 2 days after last warfarin dose. (R) • Cardiac drugs other than angotensin-converting enzyme inhibitors and angiotensin II antagonists should be continued including on the day of surgery. (R) • Angotensin-converting enzyme inhibitors and angiotensin II antagonists should be withheld on the day of surgery unless they are for the treatment of heart failure. (R) • Post-operative care in a critical care area should be considered for patients with heart failure or significant diastolic dysfunction. (R) • Patients with respiratory disease should have their peri-operative respiratory failure risk assessed and critical care booked accordingly. (G) • Patients with severe lung disease should be assessed for right heart disease pre-operatively. (G) • Patients with pulmonary hypertension and right heart failure will be at extraordinarily high risk and should have the need for surgery re-evaluated. (G) • Perioperative glucose readings should be kept within 4-12 mmol/l. (R) • Patients with a high HbA1C facing urgent surgery should have their diabetes management assessed by a diabetes specialist. (G) • Insulin-dependent diabetic patients must not omit insulin for more than one missed meal and will therefore require an insulin replacement regime. (R) • Patients taking more than 5 mg of prednisolone daily should have steroid replacement in the peri-operative period. (R) • Consider proton pump therapy for patients taking steroids in the peri-operative phase if they fit higher risk criteria. (R) • Surgery within three months of stroke carries high risk of further stroke and should be delayed if possible. (R) • Patients with rheumatoid arthritis should have flexion/extension views assessed by a senior radiologist pre-operatively. (R) • Patients at risk of post-operative cognitive dysfunction and delirium should be highlighted at pre-operative assessment. (G) • Patients with Parkinson's disease (PD) must have enteral access so drugs can be given intra-operatively. Liaison with a specialist in PD is essential. (R) • Intravenous iron should be considered for anaemia in the urgent head and neck cancer patient. (G) • Preoperative blood transfusion should be avoided where possible. (R) • Where pre-operative transfusion is essential it should be completed 24-48 hours pre-operatively. (R) • An accurate alcohol intake assessment should be completed for all patients. (G) • Patients considered to have a high level of alcohol dependency should be considered for active in-patient withdrawal at least 48 hours pre-operatively in liaison with relevant specialists. (R) • Parenteral B vitamins should be given routinely on admission to alcohol-dependent patients. (R) • Smoking cessation, commenced preferably six weeks before surgery, decreases the incidence of post-operative complications. (R) • Antibiotics are necessary for clean-contaminated head and neck surgery, but unnecessary for clean surgery. (R) • Antibiotics should be administered up to 60 minutes before skin incision, as close to the time of incision as possible. (R) • Antibiotic regimes longer than 24 hours have no additional benefit in clean-contaminated head and neck surgery. (R) • Repeat intra-operative antibiotic dosing should be considered for longer surgeries or where there is major blood loss. (R) • Local antibiotic policies should be developed and adhered to due to local resistance patterns. (G) • Individual assessment for venous thromboembolism (VTE) risk and bleeding risk should occur on admission and be reassessed throughout the patients' stay. (G) • Mechanical prophylaxis for VTE is recommended for all patients with one or more risk factors for VTE. (R) • Patients with additional risk factors of VTE and low bleeding risk should have low molecular weight heparin at prophylactic dose or unfractionated heparin if they have severe renal impairment. (R).
25851902 Thiobenzothiazole-modified Hydrocortisones Display Anti-inflammatory Activity with Reduced 2015 May 22 Glucocorticoids signal through the glucocorticoid receptor (GR) and are administered clinically for a variety of situations, including inflammatory disorders, specific cancers, rheumatoid arthritis, and organ/tissue transplantation. However, glucocorticoid therapy is also associated with additional complications, including steroid-induced diabetes. We hypothesized that modification of the steroid backbone is one strategy to enhance the therapeutic potential of GR activation. Toward this goal, two commercially unavailable, thiobenzothiazole-containing derivatives of hydrocortisone (termed MS4 and MS6) were examined using 832/13 rat insulinoma cells as well as rodent and human islets. We found that MS4 had transrepression properties but lacked transactivation ability, whereas MS6 retained both transactivation and transrepression activities. In addition, MS4 and MS6 both displayed anti-inflammatory activity. Furthermore, MS4 displayed reduced impact on islet β-cell function in both rodent and human islets. Similar to dexamethasone, MS6 promoted adipocyte development in vitro, whereas MS4 did not. Moreover, neither MS4 nor MS6 activated the Pck1 (Pepck) gene in primary rat hepatocytes. We conclude that modification of the functional groups attached to the D-ring of the hydrocortisone steroid molecule produces compounds with altered structure-function GR agonist activity with decreased impact on insulin secretion and reduced adipogenic potential but with preservation of anti-inflammatory activity.
26970039 Validity of PROMIS physical function measured in diverse clinical samples. 2016 May OBJECTIVES: To evaluate the validity of the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function measures using longitudinal data collected in six chronic health conditions. STUDY DESIGN AND SETTING: Individuals with rheumatoid arthritis (RA), major depressive disorder (MDD), back pain, chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF), and cancer completed the PROMIS Physical Function computerized adaptive test or fixed-length short form at baseline and at the end of clinically relevant follow-up intervals. Anchor items were also administered to assess change in physical function and general health. Linear mixed-effects models and standardized response means were estimated at baseline and follow-up. RESULTS: A total of 1,415 individuals participated (COPD n = 121; CHF n = 57; back pain n = 218; MDD n = 196; RA n = 521; cancer n = 302). The PROMIS Physical Function scores improved significantly for treatment of CHF and back pain patients but not for patients with MDD or COPD. Most of the patient subsamples that reported improvement or worsening on the anchors showed a corresponding positive or negative change in PROMIS Physical Function. CONCLUSION: This study provides evidence that the PROMIS Physical Function measures are sensitive to change in intervention studies where physical function is expected to change and able to distinguish among different clinical samples. The results inform the estimation of meaningful change, enabling comparative effectiveness research.