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ID PMID Title PublicationDate abstract
25547857 Rapidly destructive arthrosis of the shoulder joints: radiographic, magnetic resonance ima 2015 Jun BACKGROUND: Rapidly destructive arthrosis of the humeral head is a rare condition with an elusive pathophysiologic mechanism. In this study, radiographic and histopathologic findings were analyzed to determine the clinical characteristics of this rare condition. METHODS: We retrospectively analyzed 189 patients who underwent total shoulder arthroplasty from January 2001 to August 2012. Among them, 9 patients showed a particular pattern of rapid collapse of the humeral head on plain radiography and magnetic resonance imaging (MRI) within 12 months from symptom onset. Patients with trauma, rheumatoid arthritis, steroid intake, neurologic osteoarthropathy, osteonecrosis, renal osteoarthropathy, or gout were excluded. RESULTS: All patients were women, with a mean age of 72.0 years (range, 63-85 years). The right side was involved in 7 cases and the left in 2 cases. The mean duration of humeral head collapse was 5.6 months (range, 2-11 months) from the onset of shoulder pain. Plain radiographs of all patients showed a unique pattern of humeral head flattening, which appeared like a clean surgical cut with bone debris around the humeral head. MRI findings revealed significant joint effusion and bone marrow edema in the humeral head, without involvement of the glenoid. Pathologic findings showed both fragmentation and regeneration of bone matrix, representing fracture healing. CONCLUSION: The important features of rapidly destructive shoulder arthrosis are unique flattened humeral head collapse with MRI showing massive joint effusion and bone marrow edema in the remnant humeral head. This condition should be considered in the differential diagnosis of elderly women with insidious shoulder pain.
27957592 [Lateral unicompartmental knee arthroplasty - a challenge]. 2017 Feb OBJECTIVE: Joint surface replacement in the lateral compartment by unicondylar knee arthroplasty. INDICATIONS: Lateral unicompartmental osteoarthritis of the knee joint, avascular necrosis of the lateral femoral condyle. CONTRAINDICATIONS: Full thickness cartilage defect in the central part of the medial compartment or in the medial aspect of the patellofemoral joint. Instability/contracture of cruciate and collateral ligaments, valgus deformity >15°, valgus deformity not passively correctable, flexion deformity >15°, an intraoperative flexion <100°, failed upper tibial osteotomy, rheumatoid arthritis. SURGICAL TECHNIQUE: Leg positioning in leg holder. Minimally invasive parapatellar lateral arthrotomy. Exposure of the lateral compartment and removal of osteophytes. Attachment of the tibial saw guide. Horizontal cut 7-8 mm below the original tibial plateau with protection of the lateral collateral ligament. Vertical saw cut via an incision in the central aspect of the patellar ligament with an internal rotation of 20°. Femoral preparation. Insertion of the intramedullary rod, positioning of the femoral drill guide directing to the anterior superior iliac spine and drilling the holes. Insertion of the posterior resection guide. Saw cut with protection of the lateral collateral ligament. Insertion of the 0 mm spigot and first milling. Measurement of the extension gap. Insertion of the corresponding spigot (never use a spigot >5 mm). Milling and insertion of the trial components. Application of the anti-impingement guide and anterior and posterior resection of bone. Final preparation of the tibial plateau. Cementing of the components. POSTOPERATIVE MANAGEMENT: Mobilization under full weight-bearing with two crutches. RESULTS: With a mean follow-up of 1.7-4 years, the dislocation rate is about 0-6.6%. Revision-free survival is 90-98%.
27942232 Prevalence of different pain categories based on pain spreading on the bodies of older adu 2016 BACKGROUND AND OBJECTIVE: There is limited knowledge about the prevalence of pain and its relation to comorbidities, medication, and certain lifestyle factors in older adults. To address this limitation, this cross-sectional study examined the spreading of pain on the body in a sample of 6611 subjects ≥65 years old (mean age = 75.0 years; standard deviation [SD] = 7.7) living in southeastern Sweden. METHODS: Sex, age, comorbidities, medication, nicotine, alcohol intake, and physical activity were analyzed in relation to the following pain categories: local pain (LP) (24.1%), regional pain medium (RP-Medium) (20.3%), regional pain heavy (RP-Heavy) (5.2%), and widespread pain (WSP) (1.7%). RESULTS: RP-Medium, RP-Heavy, and WSP were associated more strongly with women than with men (all p<0.01). RP-Heavy was less likely in the 80-84 and >85 age groups compared to the 65-69 age group (both p<0.01). Traumatic injuries, rheumatoid arthritis/osteoarthritis, and analgesics were associated with all pain categories (all p<0.001). An association with gastrointestinal disorders was found in LP, RP-Medium, and RP-Heavy (all p<0.01). Depressive disorders were associated with all pain categories, except for LP (all p<0.05). Disorders of the central nervous system were associated with both RP-Heavy and WSP (all p<0.05). Medication for peripheral vascular disorders was associated with RP-Medium (p<0.05), and hypnotics were associated with RP-Heavy (p<0.01). CONCLUSION: More than 50% of older adults suffered from different pain spread categories. Women were more likely to experience greater spreading of pain than men. A noteworthy number of common comorbidities and medications were associated with increased likelihood of pain spread from LP to RP-Medium, RP-Heavy, and WSP. Effective management plans should consider these observed associations to improve functional deficiency and decrease spreading of pain-related disability in older adults.
27929705 SNAPIN is critical for lysosomal acidification and autophagosome maturation in macrophages 2017 Feb We previously observed that SNAPIN, which is an adaptor protein in the SNARE core complex, was highly expressed in rheumatoid arthritis synovial tissue macrophages, but its role in macrophages and autoimmunity is unknown. To identify SNAPIN's role in these cells, we employed siRNA to silence the expression of SNAPIN in primary human macrophages. Silencing SNAPIN resulted in swollen lysosomes with impaired CTSD (cathepsin D) activation, although total CTSD was not reduced. Neither endosome cargo delivery nor lysosomal fusion with endosomes or autophagosomes was inhibited following the forced silencing of SNAPIN. The acidification of lysosomes and accumulation of autolysosomes in SNAPIN-silenced cells was inhibited, resulting in incomplete lysosomal hydrolysis and impaired macroautophagy/autophagy flux. Mechanistic studies employing ratiometric color fluorescence on living cells demonstrated that the reduction of SNAPIN resulted in a modest reduction of H(+) pump activity; however, the more critical mechanism was a lysosomal proton leak. Overall, our results demonstrate that SNAPIN is critical in the maintenance of healthy lysosomes and autophagy through its role in lysosome acidification and autophagosome maturation in macrophages largely through preventing proton leak. These observations suggest an important role for SNAPIN and autophagy in the homeostasis of macrophages, particularly long-lived tissue resident macrophages.
27829665 The role of common protective alleles HLA-DRB1*13 among systemic autoimmune diseases. 2017 Jan Associations between human leukocyte antigen (HLA) and susceptibility to systemic autoimmune diseases have been reported. The predisposing alleles are variable among ethnic groups and/or diseases. On the other hand, some HLA alleles are associated with resistance to systemic autoimmune diseases, including systemic sclerosis, systemic lupus erythematosus and rheumatoid arthritis. Interestingly, DRB1*13 alleles are the protective alleles shared by multiple autoimmune diseases. DRB1*13:01 allele is protective in European populations and DRB1*13:02 in Japanese. Because alleles in multiple HLA loci are in strong linkage disequilibrium, it is difficult to determine which of the protective alleles is functionally responsible for the protective effects. Thus far, association studies suggested that DRB1*13:02 represents at least one of the causally associated protective factors against multiple systemic autoimmune diseases in the Japanese population. The protective effect of DRB1*13 alleles appears to overcome the predisposing effect of the susceptible alleles in heterozygous individuals of DRB1*13 and the susceptible allele. A gene dosage effect was observed in the associations of DRB1*13:02 with the protection from systemic autoimmune diseases; thus homozygous individuals are more effectively protected from the systemic autoimmune diseases than heterozygotes. DRB1*13:02 also confers protection against organ-specific autoimmune diseases and some infectious diseases. Several hypotheses can be proposed for the molecular mechanisms of the protection conferred by DRB1*13, some of which can explain the dominant effect of DRB1*13 molecules over the susceptible alleles, but the actual protective function of DRB1*13 requires further study. Understanding of the protective mechanisms of DRB1*13 may lead to the identification of targets for the curative treatment of systemic autoimmune diseases.
27542772 STAMS: STRING-assisted module search for genome wide association studies and application t 2016 Dec 15 MOTIVATION: Analyzing genome wide association data in the context of biological pathways helps us understand how genetic variation influences phenotype and increases power to find associations. However, the utility of pathway-based analysis tools is hampered by undercuration and reliance on a distribution of signal across all of the genes in a pathway. Methods that combine genome wide association results with genetic networks to infer the key phenotype-modulating subnetworks combat these issues, but have primarily been limited to network definitions with yes/no labels for gene-gene interactions. A recent method (EW_dmGWAS) incorporates a biological network with weighted edge probability by requiring a secondary phenotype-specific expression dataset. In this article, we combine an algorithm for weighted-edge module searching and a probabilistic interaction network in order to develop a method, STAMS, for recovering modules of genes with strong associations to the phenotype and probable biologic coherence. Our method builds on EW_dmGWAS but does not require a secondary expression dataset and performs better in six test cases. RESULTS: We show that our algorithm improves over EW_dmGWAS and standard gene-based analysis by measuring precision and recall of each method on separately identified associations. In the Wellcome Trust Rheumatoid Arthritis study, STAMS-identified modules were more enriched for separately identified associations than EW_dmGWAS (STAMS P-value 3.0 × 10(-4); EW_dmGWAS- P-value = 0.8). We demonstrate that the area under the Precision-Recall curve is 5.9 times higher with STAMS than EW_dmGWAS run on the Wellcome Trust Type 1 Diabetes data. AVAILABILITY AND IMPLEMENTATION: STAMS is implemented as an R package and is freely available at https://simtk.org/projects/stams CONTACT: rbaltman@stanford.eduSupplementary information: Supplementary data are available at Bioinformatics online.
27467817 Targeting Tumor Necrosis Factor-α with Adalimumab: Effects on Endothelial Activation and 2016 OBJECTIVE: It is well known that atherosclerotic inflammatory vascular disease is critically driven by oxidized lipids and cytokines. In this regard, tumor necrosis factor (TNF)-α is known as a crucial mediator of early pro-atherosclerotic events. Epidemiologic data suggest that blockade of TNF-α has beneficial effects on vascular outcomes in patients with rheumatoid arthritis, however, detailed mechanistic studies are still lacking. This study aims to elucidate effects of TNF-α blockade by adalimumab-which is approved for several inflammatory disorders-on endothelial activation and monocyte adhesion under pro-atherosclerotic conditions. METHODS AND RESULTS: Phorbol myristate acetate (PMA) differentiated THP-1 macrophages were stimulated with oxidized low density lipoprotein and subsequent analysis of this conditioned media (oxLDL CM) revealed a strong release of TNF-α. The TNF-α rich supernatant led to activation of human umbilical vein endothelial cells (HUVEC) as shown by enhanced expression of major adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin which was suppressed by the TNF-α inhibitor adalimumab. Accordingly, adalimumab effectively prevented THP-1 monocyte adhesion to endothelial cells under static as well as under flow conditions. Furthermore, adalimumab suppressed endothelial leakage as shown by Evan's blue diffusion across a confluent endothelial monolayer. Of note, after intraperitoneal injection we detected abundant deposition of fluorophore-labelled adalimumab in atherosclerotic plaques of hypercholesterolemic mice. CONCLUSION: Our results show that adalimumab prevents major inflammatory effects of TNF-α on endothelial activation, endothelial monocyte adhesion, endothelial leakage and therefore extends the therapeutic options of adalimumab to limit vascular inflammation.
27396605 Malondialdehyde and 4-hydroxy-2-hexenal are formed during dynamic gastrointestinal in vitr 2016 Aug 10 Marine long-chain polyunsaturated fatty acids (LC n-3 PUFA) are associated with reduced risk for inflammatory diseases, such as cardiovascular diseases and rheumatoid arthritis. These fatty acids, however, are rapidly oxidized, generating highly reactive malondialdehyde (MDA), 4-hydroxy-2-hexenal (HHE) and 4-hydroxy-2-nonenal (HNE). These oxidation products may interact with DNA and proteins, thus possibly leading to impaired cell functions. Little is known about the formation of MDA, HHE and HNE in fish oil in the gastrointestinal (GI) tract. In this study, the effect of dynamic in vitro digestion of cod liver oil on the generation of MDA, HHE and HNE was evaluated using the TNO Gastro-Intestinal Model (tiny-TIM). Effects of pre-formed oxidation products, pre-emulsification of the oil, and addition of oxidants (EDTA and hemoglobin, Hb) on GI oxidation were evaluated. Formation of aldehydes occurred during GI digestion. However, only emulsified oil fortified with 11.5 μM Hb oxidized to a degree that overcame the dilution induced by gastric secretion, which caused increased aldehyde concentrations in gastric lumen up to 90 min. The maximum levels of aldehydes generated in this study were 24.5 μM MDA, 1.6 μM HHE and 0.07 μM HNE. Oils containing different amounts of pre-formed lipid oxidation products maintained the same oxidation ranking order during digestion, even though the relative changes were not directly proportional. Emulsification of the oil had an unclear effect in the gastric phase, but a pro-oxidative effect in the intestinal phase. In general, higher aldehyde levels were reached in the intestinal lumen than in the initial meal, demonstrating that GI digestion promotes oxidation. Hence, epithelial cells may be exposed to elevated amounts of reactive aldehydes for several hours after a meal containing fish oil.
27259542 Group-combined P-values with applications to genetic association studies. 2016 Sep 15 MOTIVATION: In large-scale genetic association studies with tens of hundreds of single nucleotide polymorphisms (SNPs) genotyped, the traditional statistical framework of logistic regression using maximum likelihood estimator (MLE) to infer the odds ratios of SNPs may not work appropriately. This is because a large number of odds ratios need to be estimated, and the MLEs may be not stable when some of the SNPs are in high linkage disequilibrium. Under this situation, the P-value combination procedures seem to provide good alternatives as they are constructed on the basis of single-marker analysis. RESULTS: The commonly used P-value combination methods (such as the Fisher's combined test, the truncated product method, the truncated tail strength and the adaptive rank truncated product) may lose power when the significance level varies across SNPs. To tackle this problem, a group combined P-value method (GCP) is proposed, where the P-values are divided into multiple groups and then are combined at the group level. With this strategy, the significance values are integrated at different levels, and the power is improved. Simulation shows that the GCP can effectively control the type I error rates and have additional power over the existing methods-the power increase can be as high as over 50% under some situations. The proposed GCP method is applied to data from the Genetic Analysis Workshop 16. Among all the methods, only the GCP and ARTP can give the significance to identify a genomic region covering gene DSC3 being associated with rheumatoid arthritis, but the GCP provides smaller P-value. AVAILABILITY AND IMPLEMENTATION: http://www.statsci.amss.ac.cn/yjscy/yjy/lqz/201510/t20151027_313273.html CONTACT: liqz@amss.ac.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
27019110 Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets 2016 May Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with human complex traits. However, the genes or functional DNA elements through which these variants exert their effects on the traits are often unknown. We propose a method (called SMR) that integrates summary-level data from GWAS with data from expression quantitative trait locus (eQTL) studies to identify genes whose expression levels are associated with a complex trait because of pleiotropy. We apply the method to five human complex traits using GWAS data on up to 339,224 individuals and eQTL data on 5,311 individuals, and we prioritize 126 genes (for example, TRAF1 and ANKRD55 for rheumatoid arthritis and SNX19 and NMRAL1 for schizophrenia), of which 25 genes are new candidates; 77 genes are not the nearest annotated gene to the top associated GWAS SNP. These genes provide important leads to design future functional studies to understand the mechanism whereby DNA variation leads to complex trait variation.
26821519 [Analysis of Cases with Elevated Blood (1->3)-β-D-glucan in Relation to an Infection Mark 2015 Nov (1->3)-β-D-glucan (BDG) is a constituent of the fungal cell wall and its blood level is known as a marker of fungal infection including pneumocystis pneumonia (PCP). Meanwhile, peripheral blood neutrophil CD64 expression (CD64) is upregulated in various infections. We analyzed patients with positive BDG (cut off 11.0 pg/mL) and those whose CD64 was measured simultaneously. In patients who visited our hospital from 2005 to 2011, BDG was measured in 3,960 samples. The number of positive samples were 441 obtained from 185 patients. In patients with positive BDG, the initial BDG was 24.3 [16.4-70.5] pg/mL (median [interquartile range]). Positive BDG samples were derived mainly from the department of Rheumatology or that of Allergy and Respirology. Common primary diseases were rheumatoid arthritis (RA) or other connective tissue diseases, followed by malignancy, none (only abnormal chest X-ray) and bronchial asthma. The rates of afebrile patients, patients on immunosuppressive therapy and those with a normal range of white blood cell count were 63.7%, 50.9% and 40.8%, respectively. The main causes of positive BDG were PCP (n = 38, 20.5%) and non-PCP mycosis (n = 48, 25.9%, including 26 cases of aspergillosis). Others (99 patients, 53.6%) had positive BDG of unknown origin and 53 of them ameliorated spontaneously, most of whom could have been examples of pseudo-positive BDG. The number of deceased patients was 57 (30.8%) consisting of 9 PCP, 16 non-PCP mycosis and others. The median initial positive BDG levels in patients with PCP, non-PCP mycosis and others were 49.9, 28.9 and 19.7pg/mL, respectively. The positive rate of CD64 (cut off 2,000 molecules/cell) measured simultaneously with initial positive BDG was 77.8%. In RA patients with PCP, 94.7% of them had positive CD64 and the levels of CD64 were significantly higher than those in RA patients with bacterial pneumonia (median 9,386 vs 4,399 molecules/cell) in that same period. The positive rate of CD64 was lower in patients with positive BDG of unknown origin than those with PCP or non-PCP mycosis, which implies positive CD64 can exclude pseudo-positive BDG. Immunosuppressed patients often exhibit positive BDG. Simultaneous measurement of BDG and CD64, a quick pan-infection marker, assists the decision whether the positive BDG is true or false-positive.
26784322 Frequency of Comorbidities and Their Association with Clinical Disability and Relapse in M 2016 BACKGROUND: Multiple sclerosis (MS) patients may be at an increased risk of comorbidities due to the debilitating and chronic nature of the disease. An increased understanding of comorbidities and disease course in MS may provide new insights and enhance MS management. We aimed at investigating the frequency of comorbidities and their associations with clinical disability and relapse in MS. METHODS: A prospective cohort of 198 MS patients was followed during 2002-2005 and queried about specific doctor-diagnosed comorbidities. In Australia, the MS cohort was compared to the 2007 general population with regard to the prevalence of comorbidities. Multilevel mixed-effects linear regression was used to assess the difference in subsequent disability between those who reported comorbidities and those who did not. The association of comorbidities with the hazard of relapse was assessed using survival analysis. RESULTS: The age-standardised prevalence of hypertension, dyslipidaemia, asthma, psoriasis, eczema and anaemia was significantly higher in the MS cohort compared to that in the general Australian population. The level of disability (Multiple Sclerosis Severity Score) in those who reported overweight/obesity (β: 0.76 (95% CI 0.04-1.48), p = 0.037), or dyslipidaemia (β: 1.05 (95% CI 0.07-2.02), p = 0.036) was significantly higher compared to those who did not report these comorbidities, even after adjustment for potential confounders. There were no significant associations between comorbidities and change in disability. For relapse analyses, rheumatoid arthritis and anaemia were associated with more than threefold (hazard ratio, HR 3.70 (95% CI 1.80-7.58), p < 0.001) and twofold (HR 2.04 (95% CI 1.11-3.74), p = 0.022) increased risk of subsequent relapse respectively. CONCLUSIONS: The prevalence of some comorbidities was higher in MS patients and associated with greater disability and relapse risk. Treatment of these comorbidities in patients with MS has the potential to improve disease course and help in the understanding of the prognosis and outcomes of MS.
26748647 Effects of Fostamatinib on the Pharmacokinetics of Oral Contraceptive, Warfarin, and the S 2016 Mar BACKGROUND AND OBJECTIVES: Fostamatinib is a spleen tyrosine kinase inhibitor that has been investigated as therapy for rheumatoid arthritis and immune thrombocytopenic purpura. The present studies assessed the potential for pharmacokinetic interaction between fostamatinib and the commonly prescribed medications oral contraceptive (OC), warfarin, and statins (rosuvastatin, simvastatin) in healthy subjects. METHODS: The OC study was a crossover study over two 28-day treatment periods (Microgynon(®) 30 plus placebo or fostamatinib). Concentrations of OC constituents (ethinyl estradiol/levonorgestrel) were measured. Effects on warfarin pharmacokinetics and pharmacodynamics were assessed (21-day study). Warfarin was administered on days 1 and 14, fostamatinib on days 8-20. The statin study was a two-period, fixed-sequence study of the effects of fostamatinib on exposure to rosuvastatin or simvastatin (single doses). Safety was assessed throughout. RESULTS: Fostamatinib co-administration with OC increased exposure to ethinyl estradiol [area under the plasma concentration-time curve at steady state (AUCss) 28% [confidence interval (CI 90%) 21-36]; maximum plasma concentration (Cmax) at steady state (Cmax,ss) 34% (CI 26-43)], but not levonorgestrel (AUCss 5%; Cmax,ss -3%), while exposure to luteinizing hormone and follicle-stimulating hormone decreased (≈ 20%). Fostamatinib did not affect the pharmacokinetics/pharmacodynamics of warfarin to a clinically relevant extent, but caused an upward trend in AUC for both R- and S-warfarin [18% (CI 13-23) and 13% (CI 7-19)]. Fostamatinib increased rosuvastatin AUC by 96% (CI 78-115) and Cmax by 88% (CI 69-110), and increased simvastatin acid AUC by 74% (CI 50-102) and Cmax by 83% (CI 57-113). CONCLUSION: Fostamatinib exhibits drug-drug interactions when co-administered with OC, simvastatin, or rosuvastatin, with the AUC of statins almost doubling. Fostamatinib did not exhibit a clinically relevant DDI on warfarin.
26627497 Evaluation of a follow-up protocol for patients on chloroquine and hydroxychloroquine trea 2016 Jan OBJECTIVE: To review the problems found after a new follow-up protocol for patients on chloroquine and hydroxychloroquine treatment. METHOD: Retrospective study was conducted between May 2012 and January 2013 on the clinical files, retinographies, fundus auto-fluorescence (FAF) images, and central-10 degree visual fields (VF) of patients who were referred to the Ophthalmology Department as they had started treatment with hydroxychloroquine. RESULTS: One hundred twenty-six patients were included; 94.4% were referred from the Rheumatology Department and 5.6% from Dermatology. Mean age was 59.7 years, and 73.8% were women. All of them were on hydroxychloroquine treatment, and 300mg was the most frequent daily dose. Rheumatoid arthritis was the most common diagnosis (40.5%), followed by systemic lupus erythematosus (15.9%). The mean Snellen visual acuity was 0.76, and 26 patients had lens opacities. The VF were normal in 97 patients, 8 had mild to moderate defects with no definite pattern, and in 9 the results were unreliable. Of the 51 patients older than 65years, 16 (31.4%) had altered or unreliable VF. The FAF was normal in 104 patients (82.5%), and abnormal, but consistent with ophthalmoscopic features, in 12 patients (pathological myopia, age related changes, early, middle or late age-related macular degeneration). CONCLUSIONS: Visual fields as a reference test for the diagnosis of AP toxicity are not quite reliable for patients over 65. Therefore, the FAF is recommended as primary test, perhaps combined with another objective test, such as SD-OCT instead of VF.
26578971 Pathophysiological significance of the two-pore domain K(+) channel K2P5.1 in splenic CD4( 2015 The alkaline pH-activated, two-pore domain K(+) channel K2P5.1 (also known as TASK2/KCNK5) plays an important role in maintaining the resting membrane potential, and contributes to the control of Ca(2+) signaling in several types of cells. Recent studies highlighted the potential role of the K2P5.1 K(+) channel in the pathogenesis of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. The aim of the present study was to elucidate the pathological significance of the K2P5.1 K(+) channel in inflammatory bowel disease (IBD). The degrees of colitis, colonic epithelial damage, and colonic inflammation were quantified in the dextran sulfate sodium-induced mouse IBD model by macroscopic and histological scoring systems. The expression and functional activity of K2P5.1 in splenic CD4(+) T cells were measured using real-time PCR, Western blot, and fluorescence imaging assays. A significant increase was observed in the expression of K2P5.1 in the splenic CD4(+) T cells of the IBD model. Concomitant with this increase, the hyperpolarization response induced by extracellular alkaline pH was significantly larger in the IBD model with the corresponding intracellular Ca(2+) rises. The expression of K2P5.1 was higher in CD4(+)CD25(-) T cells than in CD4(+)CD25(+) regulatory T cells. The knockout of K2P5.1 in mice significantly suppressed the disease responses implicated in the IBD model. Alternations in intracellular Ca(2+) signaling following the dysregulated expression of K2P5.1 were associated with the disease pathogenesis of IBD. The results of the present study suggest that the K2P5.1 K(+) channel in CD4(+)CD25(-) T cell subset is a potential therapeutic target and biomarker for IBD.
26504855 Autoimmune Conditions in 235 Hemochromatosis Probands with HFE C282Y Homozygosity and Thei 2015 We performed a retrospective study of autoimmune conditions (ACs) in 235 hemochromatosis probands at diagnosis by analyzing age, sex, ACs, history of first-degree family members with ACs (FH), diabetes, heavy ethanol consumption, elevated serum ALT/AST, nonalcoholic fatty liver disease, viral hepatitis, cirrhosis, iron removed to achieve iron depletion (QFe), and positivity for human leukocyte antigen (HLA) haplotypes A (∗) 01, B (∗) 08; A (∗) 02, B (∗) 44; A (∗) 03, B (∗) 07; A (∗) 03, B (∗) 14; and A (∗) 29, B (∗) 44. There were 138 men (58.7%). Median followup was 19.6 y. One or more of 19 ACs were diagnosed in each of 35 probands (14.9%). Prevalences of Hashimoto's thyroiditis, rheumatoid arthritis, and ankylosing spondylitis were 8.1% (95% CI: [5.1, 12.5]), 1.7% [0.6, 4.6], and 0.0085 [0.0015, 0.0337], respectively. Eighteen probands (7.7%) had a FH. Eight probands with ACs had 9 family members with ACs. In a logistic regression, ACs were less likely in men (odds ratio (OR) 0.3 [0.1, 0.6]) and more likely in probands with a FH (OR 4.1 [1.4, 11.8]). Overall ACs risk was not significantly associated with QFe or HLA haplotypes. Estimated survival of probands with and without ACs did not differ significantly. We conclude that ACs are common in hemochromatosis probands, especially women and probands with a FH.
26499405 Niclosamide inhibits the inflammatory and angiogenic activation of human umbilical vein en 2015 Dec OBJECTIVE: Niclosamide is known to have anti-cancer and anti-inflammatory activities; however, its therapeutic mechanism has not been defined. In this study, to explain the therapeutic mechanism of niclosamide, we examined the effect of niclosamide on endothelial cell activation,leukocyte integration, proliferation, migration and angiogenesis in vitro. METHODS: Endothelia-leukocyte adhesion assays were used to assess primary cultures of human umbilical vein endothelial cells’ (HUVECs) activation following TNF-α treatment. Each step of angiogenesis was evaluatedin vitro, including endothelial cell proliferation, migration and tube formation. Proliferation was examined using EdU assays, while wound migration assays and transwell assays were used to evaluate cell migration; cord like structure formation assays on Matrigel were used to assess tube formation. In vivo matrigel plug assay was used to assess angiogenesis. The protein expression was measured using western blot. RESULTS: Niclosamide reduced the adhesion of human monocyte cells to HUVECs. Niclosamide also reduced protein expression of VCAM-1 and ICAM1 in HUVECs.Niclosamide significantly inhibited HUVEC proliferation,migration and cord-like structure formation. Niclosamide also suppresses VEGF-induced angiogenesis in vivo.Niclosamide attenuated IKK-mediated activation of NF-κB pathway in TNFα-induced endothelial cells. Niclosamide also suppresses VEGF-induced endothelial VEGFR2 activation and downstream P-AKT, P-mTOR and P-p70S6K. CONCLUSIONS: Niclosamide exerted a potent effect on HUVECs activation, suggesting that it might function via an endothelia-based mechanism in the treatment of various diseases, including rheumatoid arthritis and cancer.
26224827 Triceps-sparing ulnar approach for total elbow arthroplasty. 2015 Aug To prevent insufficiency of the triceps after total elbow arthroplasty, we have, since 2008, used a triceps-sparing ulnar approach. This study evaluates the clinical results and post-operative alignment of the prosthesis using this approach. We reviewed 25 elbows in 23 patients. There were five men and 18 women with a mean age of 69 years (54 to 83). There were 18 elbows with rheumatoid arthritis, six with a fracture or pseudoarthrosis and one elbow with osteoarthritis. Post-operative complications included one intra-operative fracture, one elbow with heterotopic ossification, one transient ulnar nerve palsy, and one elbow with skin necrosis, but no elbow was affected by insufficiency of the triceps. Patients were followed for a mean of 42 months (24 to 77). The mean post-operative Japanese Orthopaedic Association Elbow Score was 90.8 (51 to 100) and the mean Mayo Elbow Performance score 93.8 (65 to 100). The mean post-operative flexion/extension of the elbow was 135°/-8°. The Manual Muscle Testing score of the triceps was 5 in 23 elbows and 2 in two elbows (one patient). The mean alignment of the implants examined by 3D-CT was 2.8° pronation (standard deviation (sd) 5.5), 0.3° valgus (sd 2.7), and 0.7° extension (sd 3.2) for the humeral component, and 9.3° pronation (sd 9.7), 0.3° valgus (sd 4.0), and 8.6° extension (sd 3.1) for the ulnar component. There was no radiolucent line or loosening of the implants on the final radiographs. The triceps-sparing ulnar approach allows satisfactory alignment of the implants, is effective in preventing post-operative triceps insufficiency, and gives satisfactory short-term results.
26204326 Microemulsions mediated effective delivery of methotrexate hydrogel: more than a tour de f 2016 Methotrexate (MTX), a well known drug for the treatment of cancer and rheumatoid arthritis, has gained prominence in the treatment of psoriasis over the period of years. However, the present mode of systemic administration through oral or parenteral route has always proposition, full of compromises. The toxicity of drug to the vital organs and physiological environment is the major concern. Also, its poor skin penetration is one major problem. Hence novel system based on lipid carriers has been considered here to overcome the barriers. Microemulsions (MEs) were prepared using pseudo-ternary phase diagram (PTPD) and they were characterized for various parameters such as size, shape (cryo-SEM), PDI, zeta potential, etc. The chosen MEs system (optimized) was then incorporated into secondary vehicles and characterized for rheological behavior, texture profile analysis, in vitro release, ex vivo permeation and drug distribution into different layers of skin. The developed formulations were further evaluated in ex vivo and in vivo such as cell line study, imiquimod-induced psoriatic model, allergic contact dermatitis, rat tail model (% orthokeratosis) and safety test (Draize test). The MEs based MTX gel has shown its potential in locating the drug at the desired domain of stratum corneum, epidermal and dermal layers of skin and reducing systemic absorption. Our results are suggestive of MEs potential as a novel carrier for topical delivery of MTX in topical therapeutic and safety approaches. In conclusion, developed MEs-based hydrogel has shown promising results in achieving effective delivery of MTX.
26155968 Incidence and risk factors for heterotopic ossification after total hip arthroplasty: a me 2015 Sep BACKGROUND: This study aims to quantitatively summarize risk factors associated with heterotopic ossification after total hip arthroplasty. METHODS: The computerized and additional manual searches were performed in Medline, Embase, CNKI, and Cochrane central database (all through March 2014) for potential studies. Studies eligible had to meet the quality assessment criteria by Newcastle-Ottawa Scale and to evaluate the risk factors for heterotopic ossification after total hip arthroplasty. Two reviewers independently extracted the relevant data and any disagreement was solved by consensus. Stata11.0 was used to perform all the statistical analyses. RESULTS: Fourteen studies involving 6468 cases with total hip arthroplasty and 1939 heterotopic ossification (HOs) (30.0 %) were eligible and included in this meta-analysis. Our meta-analysis identified the significant increased risk factors for HO were male gender [odds ratio (OR) 2.11; 95 % confidence interval (CI) 1.80-2.48)], cemented implant (OR 1.48; 95 % CI 1.00-2.17), bilateral operations (OR 1.74; 95 % CI 1.24-2.45), ankylosing spondylitis (OR 1.90; 95 % CI 1.07-3.37) and ankylosed hip (OR 9.85; 95 % CI 2.61-37.24). Rheumatoid arthritis was protective for the development of HO (OR 0.51; 95 % CI 0.33-0.80). The other variables including age, use of NSAIDs, femoral neck fracture, previous hip fracture, hypertrophic osteoarthritis and osteophytes were identified not as the risk factors for development of HO (P > 0.05). CONCLUSION: Patients involved with the above-mentioned medical conditions should be carefully paid close attention by surgeons to reduce HO after total hip arthroplasty. LEVEL OF EVIDENCE: Level II, meta-analysis.