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ID PMID Title PublicationDate abstract
27833373 Evaluation of antinociceptive and antirheumatic activity of Grangea maderaspatana (L.) Poi 2015 Oct INTRODUCTION: Grangea maderaspatana (L.) Poir. (Asteraceae), a popular Indian medicinal plant is traditionally used for rheumatism in the knee joint and pain in the muscles. AIM: To investigate antinociceptive and antirheumatic activity of G. maderaspatana (L.) Poir. using experimental models. MATERIALS AND METHODS: Antinociceptive activity of methanolic extract of G. maderaspatana (L.) Poir. (GMME) (500 mg/kg, 1000 mg/kg, p.o.) was evaluated in rats using tail flick test. Anti-inflammatory and anti-arthritic activity of GMME (1000 mg/kg, p.o.) was evaluated using carrageenan-induced rat paw edema and complete Freund's adjuvant (CFA)- induced arthritis models. The degree of arthritis was evaluated by hind paw swelling, body weight changes, arthritic index, erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), and C-reactive protein (CRP) supported by histopathology of ankle joints. RESULTS: GMME treatment showed a significant increase in the latency for tail flick and provided significant protection against carrageenan-induced rat paw edema. 21 days treatment of GMME significantly inhibited paw edema found to be induced by arthritis by CFA in rats. Further, GMME treatment also reversed arthritic index and loss of body weight and reduced CFA-induced rise of ESR, RF, and CRP significantly in rats. Histopathological study of ankle joint revealed that GMME inhibited edema formation and cellular infiltration induced by CFA. CONCLUSIONS: GMME possesses antinociceptive, anti-inflammatory, and antirheumatic activities.
26018160 Pentosan Polysulfate: a Novel Glycosaminoglycan-Like Molecule for Effective Treatment of A 2015 Aug Arthritogenic alphaviruses such as Ross River virus (RRV) and chikungunya virus (CHIKV) cause large-scale epidemics of severe musculoskeletal disease and have been progressively expanding their global distribution. Since its introduction in July 2014, CHIKV now circulates in the United States. The hallmark of alphavirus disease is crippling pain and inflammation of the joints, a similar immunopathology to rheumatoid arthritis. The use of glycans as novel therapeutics is an area of research that has increased in recent years. Here, we describe the promising therapeutic potential of the glycosaminoglycan (GAG)-like molecule pentosan polysulfate (PPS) to alleviate virus-induced arthritis. Mouse models of RRV and CHIKV disease were used to characterize the extent of cartilage damage in infection and investigate the potential of PPS to treat disease. This was assessed using histological analysis, real-time PCR, and fluorescence-activated cell sorting (FACS). Alphaviral infection resulted in cartilage destruction, the severity of which was alleviated by PPS therapy during RRV and CHIKV clinical disease. The reduction in cartilage damage corresponded with a significant reduction in immune infiltrates. Using multiplex bead arrays, PPS treatment was found to have significantly increased the anti-inflammatory cytokine interleukin-10 and reduced proinflammatory cytokines, typically correlated with disease severity. Furthermore, we reveal that the severe RRV-induced joint pathology, including thinning of articular cartilage and loss of proteoglycans in the cartilage matrix, was diminished with treatment. PPS is a promising new therapy for alphavirus-induced arthritis, acting to preserve the cartilage matrix, which is damaged during alphavirus infection. Overall, the data demonstrate the potential of glycotherapeutics as a new class of treatment for infectious arthritis. IMPORTANCE: The hallmark of alphavirus disease is crippling pain and joint arthritis, which often has an extended duration. In the past year, CHIKV has expanded into the Americas, with approximately 1 million cases reported to date, whereas RRV continues to circulate in the South Pacific. Currently, there is no licensed specific treatment for alphavirus disease, and the increasing spread of infection highlights an urgent need for therapeutic intervention strategies. Pentosan polysulfate (PPS) is a glycan derivative that is orally bioavailable, has few toxic side effects, and is currently licensed under the name Elmiron for the treatment of cystitis in the United States. Our findings show that RRV infection damages the articular cartilage, including a loss of proteoglycans within the joint. Furthermore, treatment with PPS reduced the severity of both RRV- and CHIKV-induced musculoskeletal disease, including a reduction in inflammation and joint swelling, suggesting that PPS is a promising candidate for drug repurposing for the treatment of alphavirus-induced arthritis.
27330028 Autophagy-linked FYVE containing protein WDFY3 interacts with TRAF6 and modulates RANKL-in 2016 Sep Recently, autophagy-related proteins were shown to regulate osteoclast mediated bone resorption, a critical process in autoimmune diseases such as rheumatoid arthritis. However, the role of autophagy-linked FYVE containing protein, WDFY3, in osteoclast biology remains elusive. WDFY3 is a master regulator in selective autophagy for clearing ubiquitinated protein aggregates and has been linked with rheumatoid arthritis. Herein, we used a series of WDFY3 transgenic mice (Wdfy3(lacZ) and Wdfy3(loxP)) to investigate the function of WDFY3 in osteoclast development and function. Our data demonstrate that WDFY3 is highly expressed at the growth plate of neonatal mice and is expressed in osteoclasts in vitro cultures. Osteoclasts derived from WDFY3 conditional knockout mice (Wdfy3(loxP/loxP)-LysM-Cre(+)) demonstrated increased osteoclast differentiation as evidenced by higher number and enlarged size of TRAP(+) multinucleated cells. Western blot analysis also revealed up-regulation of TRAF6 and an increase in RANKL-induced NF-κB signaling in WDFY3-deficient bone marrow-derived macrophages compared to wild type cultures. Consistent with these observations WDFY3-deficient cells also demonstrated an increase in osteoclast-related genes Ctsk, Acp5, Mmp9 and an increase of dentine resorption in in vitro assays. Importantly, in vivo RANKL gene transfer exacerbated bone loss in WDFY3 conditional knockout mice, as evidenced by elevated serum TRAP, CTX-I and micro-CT analysis of distal femurs compared to wild type littermates. Taken together, our data highlight a novel role for WDFY3 in osteoclast development and function, which can be exploited for the treatment of musculoskeletal diseases.
26948765 Effects of sodium selenite on c-Jun N-terminal kinase signalling pathway induced by oxidat 2016 May The c-Jun N-terminal kinases (JNK) are members of the mitogen-activated protein kinase family and are activated by environmental stress. Se plays an important role in the biological pathways by forming selenoprotein. Selenoproteins have been shown to exhibit a variety of biological functions including antioxidant functions and maintaining cellular redox balance, and compromise of such important proteins would lead to oxidative stress and apoptosis. We examined the expression levels of JNK in Kashin-Beck disease (KBD) patients, tested the potential protective effects of sodium selenite on tert-butyl hydroperoxide (tBHP)-induced oxidative injury and apoptosis in human chondrocytes as well as its underlying mechanism in this study. We produced an oxidative damage model induced by tBHP in C28/I2 human chondrocytes to test the essential anti-apoptosis effects of Se in vitro. The results indicated that the expression level of phosphorylated JNK was significantly increased in KBD patients. Cell apoptosis was increased and molecule expressions of the JNK signalling pathway were activated in the tBHP-injured chondrocytes. Na2SeO3 protected against tBHP-induced oxidative stress and apoptosis in cells by increasing cell viability, reducing reactive oxygen species generation, increasing Glutathione peroxidase (GPx) activity and down-regulating the JNK pathway. These results demonstrate that apoptosis induced by tBHP in chondrocytes might be mediated via up-regulation of the JNK pathway; Na2SeO3 has an effect of anti-apoptosis by down-regulating the JNK signalling pathway.
26274612 Targeting Atp6v1c1 Prevents Inflammation and Bone Erosion Caused by Periodontitis and Reve 2015 Periodontal disease (Periodontitis) is a serious disease that affects a majority of adult Americans and is associated with other systemic diseases, including diabetes, rheumatoid arthritis, and other inflammatory diseases. While great efforts have been devoted toward understanding the pathogenesis of periodontitis, there remains a pressing need for developing potent therapeutic strategies for targeting this pervasive and destructive disease. In this study, we utilized novel adeno-associated virus (AAV)-mediated Atp6v1c1 knockdown gene therapy to treat bone erosion and inflammatory caused by periodontitis in mouse model. Atp6v1c1 is a subunit of the V-ATPase complex and regulator of the assembly of the V0 and V1 domains of the V-ATPase complex. We demonstrated previously that Atp6v1c1 has an essential function in osteoclast mediated bone resorption. We hypothesized that Atp6v1c1 may be an ideal target to prevent the bone erosion and inflammation caused by periodontitis. To test the hypothesis, we employed AAV RNAi knockdown of Atp6v1c1 gene expression to prevent bone erosion and gingival inflammation simultaneously. We found that lesion-specific injection of AAV-shRNA-Atp6v1c1 into the periodontal disease lesions protected against bone erosion (>85%) and gingival inflammation caused by P. gingivalis W50 infection. AAV-mediated Atp6v1c1 knockdown dramatically reduced osteoclast numbers and inhibited the infiltration of dendritic cells and macrophages in the bacteria-induced inflammatory lesions in periodontitis. Silencing of Atp6v1c1 expression also prevented the expressions of osteoclast-related genes and pro-inflammatory cytokine genes. Our data suggests that AAV-shRNA-Atp6v1c1 treatment can significantly attenuate the bone erosion and inflammation caused by periodontitis, indicating the dual function of AAV-shRNA-Atp6v1c1 as an inhibitor of bone erosion mediated by osteoclasts, and as an inhibitor of inflammation through down-regulation of pro-inflammatory cytokine expression. This study demonstrated that Atp6v1c1 RNAi knockdown gene therapy mediated by AAV-shRNA-Atp6v1c1 is a promising novel therapeutic approach for the treatment of bone erosion and inflammatory related diseases, such as periodontitis and rheumatoid arthritis.
25969732 Prevalence of rheumatoid arthritis in low- and middle-income countries: A systematic revie 2015 Jun BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disorder that affects the small joints of the body. It is one of the leading causes of chronic morbidity in high-income countries, but little is known about the burden of this disease in low- and middle-income countries (LMIC). METHODS: The aim of this study was to estimate the prevalence of RA in six of the World Health Organization's (WHO) regions that harbour LMIC by identifying all relevant studies in those regions. To accomplish this aim various bibliographic databases were searched: PubMed, EMBASE, Global Health, LILACS and the Chinese databases CNKI and WanFang. Studies were selected based on pre-defined inclusion criteria, including a definition of RA based on the 1987 revision of the American College of Rheumatology (ACR) definition. RESULTS: Meta-estimates of regional RA prevalence rates for countries of low or middle income were 0.40% (95% CI: 0.23-0.57%) for Southeast Asian, 0.37% (95% CI: 0.23-0.51%) for Eastern Mediterranean, 0.62% (95% CI: 0.47-0.77%) for European, 1.25% (95% CI: 0.64-1.86%) for American and 0.42% (95% CI: 0.30-0.53%) for Western Pacific regions. A formal meta-analysis could not be performed for the sub-Saharan African region due to limited data. Male prevalence of RA in LMIC was 0.16% (95% CI: 0.11-0.20%) while the prevalence in women reached 0.75% (95% CI: 0.60-0.90%). This difference between males and females was statistically significant (P < 0.0001). The prevalence of RA did not differ significantly between urban and rural settings (P = 0.353). These prevalence estimates represent 2.60 (95% CI: 1.85-3.34%) million male sufferers and 12.21 (95% CI: 9.78-14.67%) million female sufferers in LMIC in the year 2000, and 3.16 (95% CI: 2.25-4.05%) million affected males and 14.87 (95% CI: 11.91-17.86%) million affected females in LMIC in the year 2010. CONCLUSION: Given that majority of the world's population resides in LMIC, the number of affected people is substantial, with a projection to increase in the coming years. Therefore, policy makers and health-care providers need to plan to address a significant disease burden both socially and economically.
24629182 Low free testosterone is associated with loss of appendicular muscle mass in Japanese comm 2015 Mar AIM: Sarcopenia accelerates frailty syndrome, and adversely affects activities of daily living and quality of life. The aim of the present study was to assess longitudinal relationships between baseline androgen and muscle mass changes in Japanese women. METHODS: Data were collected from 539 community-dwelling, Japanese women aged 40-79 years at baseline who participated in both baseline and follow-up examinations of a longitudinal study of aging (mean duration 8.3 years). Appendicular skeletal muscle mass was measured with dual-energy X-ray absorptiometry at baseline and follow-up examinations. The cut-off point for sarcopenia was a skeletal muscle index (appendicular skeletal muscle mass/height(2) ) <5.46 kg/m(2) . Participants with sarcopenia at baseline were excluded. Thus, 430 women were included. Total testosterone, free testosterone and dehydroepiandrosterone-sulphate were measured by radioimmunoassay at baseline. The androgens were categorized into three groups by serum levels. Multiple logistic regression models were fit to determine the associations between androgens and sarcopenia while controlling for baseline age, body mass index, leisure-time physical activity, nutritional intakes (total energy, total protein, vitamin D), serum C-reactive protein levels, medical histories (heart disease, osteoporosis, rheumatoid arthritis), menopause and smoking habit. RESULTS: The fully adjusted odds ratio of sarcopenia for the low-free testosterone group (<0.7 pg/mL) compared with the high-free testosterone group (≥1.2 pg/mL) was 3.59 (95% confidence interval 1.25-10.34). Sarcopenia was not significantly related to total testosterone or dehydroepiandrosterone-sulphate. CONCLUSION: A low-free testosterone level appears to be a significant predictor of the risk for loss of appendicular muscle in Japanese women.
27433429 Comparative Sensitivity of Intraoperative Motor Evoked Potential Monitoring in Predicting 2016 Aug STUDY DESIGN: Retrospective review. OBJECTIVE: Intraoperative motor evoked potential (MEP) monitoring in spine surgery may assist surgeons in taking corrective measures to prevent neurologic deficits. The efficacy of monitoring MEPs intraoperatively in patients with myelopathy from nondegenerative causes has not been quantified. We compared the sensitivity and specificity of intraoperative MEP monitoring in patients with myelopathy caused by nondegenerative processes to patients with degenerative cervicothoracic spondylotic myelopathy (CSM). METHODS: We retrospectively reviewed our myelopathy surgical cases during a 1-year period to identify patients with degenerative CSM and CSM of nondegenerative causes and collected data on intraoperative MEP changes and postoperative new deficits. Categorical variables were analyzed by Fisher exact test. Receiver operator curves assessed intraoperative MEP monitoring performance in the two groups. RESULTS: In all, 144 patients were identified: 102 had degenerative CSM and 42 had CSM of nondegenerative causes (24 extra-axial tumors, 12 infectious processes, 5 traumatic fractures, and 1 rheumatoid arthritis). For degenerative CSM, there were 11 intraoperative MEP alerts and 7 new deficits (p < 0.001). The corresponding sensitivity was 71% and the specificity was 94%. In the nondegenerative group, there were 11 intraoperative MEP alerts and 3 deficits, which was not significant (p > 0.99). The sensitivity (33%) and specificity (74%) were lower. Among patients with degenerative CSM, the model performed well for predicting postoperative deficits (area under the curve [AUC] 0.826), which appeared better than the nondegenerative group, although it did not reach statistical significance (AUC 0.538, p = 0.16). CONCLUSIONS: Based on this large retrospective analysis, intraoperative MEP monitoring in surgery for nondegenerative CSM cases appears to be less sensitive to cord injury and less predictive of postoperative deficits when compared with degenerative CSM cases.
27382576 New Alternatives for Autoimmune Disease Treatments: Physicochemical and Clinical Comparabi 2016 Etanercept is a recombinant fusion protein approved for the treatment of TNF-α mediated diseases such as rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, and ankylosing spondylitis. Herein, we present an evaluation of the physicochemical and biological properties of a biosimilar etanercept and its reference product followed by a clinical study in patients diagnosed with RA intended to demonstrate comparability of their immunomodulatory activity. Identity analyses showed a total correspondence of the primary and higher-order structure between the two products. In regard to intrinsic heterogeneity, both products showed to be highly heterogenous; however the biosimilar etanercept exhibited similar charge and glycan heterogeneity intervals compared to the reference product. Apoptosis inhibition assay also showed that, despite the high degree of heterogeneity exhibited by both products, no significant differences exist in their in vitro activity. Finally, the clinical assessment conducted in RA-diagnosed patients did not show significant differences in the evaluated pharmacodynamic markers of both products. Collectively, the results from the comparability exercise provide convincing evidence that the evaluated biosimilar etanercept can be considered an effective alternative for the treatment of RA.
25976154 Serum IL-33 levels are increased in patients with psoriasis. 2016 Mar BACKGROUND: Interleukin (IL)-33 is a recently identified cytokine, which is a member of the IL-1 family and binds to a heterodimeric receptor comprising ST2 (suppression of tumorigenicity 2) and IL-1 receptor accessory protein. Serum levels of IL-33 have been reported to be upregulated in various T helper (Th)1/Th17-mediated diseases, such as rheumatoid arthritis and inflammatory bowel disease. IL-33 expression is increased in lesional skin in patients with psoriasis, but serum levels in patients with psoriasis have not yet been studied. AIM: To study serum IL-33 levels in patients with psoriasis, a Th1/Th17-mediated skin disease, before and after anti-tumour necrosis factor (TNF)-α therapy. METHODS: Serum IL-33 levels were measured in patients with psoriasis vulgaris (PV), psoriatic arthritis (PsA) or pustular psoriasis (PP), and compared with those of healthy controls. Associations between serum IL-33 levels and serum TNF-α, IL-6, vascular endothelial growth factor and C-reactive protein levels were also studied. In addition, the effect of IL-33 stimulation on IL-6, IL-8, TNF-α and VEGF secretion by human keratinocyte was analysed. RESULTS: Serum IL-33 levels in patients with PV, PsA and PP were significantly higher than those in healthy controls. Serum IL-33 levels correlated with serum TNF-α levels in patients with psoriasis, and decreased after anti-TNF-α therapy. IL-33 stimulated IL-6 and IL-8 secretion by human keratinocytes. CONCLUSIONS: These results suggest that serum IL-33 levels generally reflect increased inflammation in patients with psoriasis.
27298338 VX-509 (Decernotinib)-Mediated CYP3A Time-Dependent Inhibition: An Aldehyde Oxidase Metabo 2016 Aug (R)-2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (VX-509, decernotinib) is an oral Janus kinase 3 inhibitor that has been studied in patients with rheumatoid arthritis. Patients with rheumatoid arthritis often receive multiple medications, such as statins and steroids, to manage the signs and symptoms of comorbidities, which increases the chances of drug-drug interactions (DDIs). Mechanism-based inhibition is a subset of time-dependent inhibition (TDI) and occurs when a molecule forms a reactive metabolite which irreversibly binds and inactivates drug-metabolizing enzymes, potentially increasing the systemic load to toxic concentrations. Traditionally, perpetrating compounds are screened using human liver microsomes (HLMs); however, this system may be inadequate when the precipitant is activated by a non-cytochrome P450 (P450)-mediated pathway. Even though studies assessing competitive inhibition and TDI using HLM suggested a low risk for CYP3A4-mediated DDI in the clinic, VX-509 increased the area under the curve of midazolam, atorvastatin, and methyl-prednisolone by approximately 12.0-, 2.7-, and 4.3-fold, respectively. Metabolite identification studies using human liver cytosol indicated that VX-509 is converted to an oxidative metabolite, which is the perpetrator of the DDIs observed in the clinic. As opposed to HLM, hepatocytes contain the full complement of drug-metabolizing enzymes and transporters and can be used to assess TDI arising from non-P450-mediated metabolic pathways. In the current study, we highlight the role of aldehyde oxidase in the formation of the hydroxyl-metabolite of VX-509, which is involved in clinically significant TDI-based DDIs and represents an additional example in which a system-dependent prediction of TDI would be evident.
26142477 Auranofin efficacy against MDR Streptococcus pneumoniae and Staphylococcus aureus infectio 2015 Sep BACKGROUND: Auranofin is an FDA-approved, gold-containing compound in clinical use for the oral treatment of rheumatoid arthritis and has been recently granted by the regulatory authorities due to its antiprotozoal properties. METHODS: A reprofiling strategy was performed with a Streptococcus pneumoniae phenotypic screen and a proprietary library of compounds, consisting of both FDA-approved and unapproved bioactive compounds. Two different multiresistant S. pneumoniae strains were employed in a sepsis mouse model of infection. In addition, an MRSA strain was tested using both the thigh model and a mesh-associated biofilm infection in mice. RESULTS: The repurposing approach showed the high potency of auranofin against multiresistant clinical isolates of S. pneumoniae and Staphylococcus aureus in vitro and in vivo. Efficacy in the S. pneumoniae sepsis model was obtained using auranofin by the oral route in the dose ranges used for the treatment of rheumatoid arthritis. Thioglucose replacement by alkyl chains showed that this moiety was not essential for the antibacterial activity and led to the discovery of a new gold derivative (MH05) with remarkable activity in vitro and in vivo. CONCLUSIONS: Auranofin and the new gold derivative MH05 showed encouraging in vivo activity against multiresistant clinical isolates of S. pneumoniae and S. aureus. The clinical management of auranofin, alone or in combination with other antibiotics, deserves further exploration before use in patients presenting therapeutic failure caused by infections with multiresistant Gram-positive pathogens. Decades of clinical use mean that this compound is safe to use and may accelerate its evaluation in humans.
25666883 Can Tocilizumab Decrease Cartilage Oligomeric Matrix Protein Levels and Disease Activity i 2015 Feb 9 Serum cartilage oligomeric matrix protein (COMP) level is a new marker of joint destruction in patients with rheumatoid arthritis (RA), and a new means of identifying patients with progressive joint damage. To evaluate the effect of tocilizumab (TCZ) on serum COMP levels, and whether there is any difference in this effect between patients failing on anti-TNF treatment and those failing on disease-modifying anti-rheumatic drugs (DMARDs). Fifty-one patients with long-standing RA (42 F, 9 M; mean age 62±14 years; disease duration 4.5±1.2 years) unresponsive to DMARDs and anti-TNF drugs were treated with TCZ 8 mg/kg/month. Serum COMP levels were measured by means of an ELISA at baseline and after six months of TCZ treatment; the patents' DAS28 scores and levels of RF (IgM, IgG, IgA), anti-CCP autoantibodies, ESR, CRP and IL-6 were evaluated at the same times. After six months of TCZ treatment, there was a significant decrease from baseline in ESR (46.1 [28.7-68.9] vs 34.3 [4.1- 58.8] mm/h, P <0.0001), CRP (2.2 [0.8-4.4] vs 1.3 [0.7-3.8] mg/dL, P <0.0001), TNF-α (21.3 [7.6-29.8] vs 17.4 [3.4-28.6] pg/mL, P=0.0408), IL-6 (6.9 [3.5-9.6] vs 3.4 [3.0-9.6] pg/mL, p<0.0001); anti-CCP (55.1 [30.2-273.0] vs 54.7 [30.1- 269.8] IU/mL, P=0.9683), RF-IgM (142.0 [48.0-260.0] vs 138.0 [42.0-243.0] IU/mL, P=0.4828), RF-IgA (81.0 [20-140] vs 108.0 [20-175] U/mL, P=0.0003), and RF-IgG (65.2 [30-158] vs 58.3 [38.0-158.0] U/mL, P=0.2671). There was also a significant decrease in DAS28 scores (4.3 [3.2-5.9] vs 3.7 [2.3-5.4], P <0.0001), and a non-significant decrease in serum COMP levels (0.95 [0.04-2.90] vs 0.98 [0.05-2.36] μg/mL; P = 0.9856). A decrease in serum COMP levels was observed in the patients failing on anti-TNF treatment or anti-DMARDs without any difference. TCZ therapy in patients with long-standing RA is associated with a significant decrease in ESR, CRP, IL-6, TNF and DAS28 values, and a decrease in serum COMP levels, particularly in patients failing on previous anti-TNF therapy. These findings suggest that TCZ has an effect on cartilage joint destruction after only six months of treatment.
27206706 Cross-Disease Transcriptomics: Unique IL-17A Signaling in Psoriasis Lesions and an Autoimm 2016 Sep Transcriptome studies of psoriasis have identified robust changes in mRNA expression through large-scale analysis of patient cohorts. These studies, however, have analyzed all mRNA changes in aggregate, without distinguishing between disease-specific and nonspecific differentially expressed genes (DEGs). In this study, RNA-seq meta-analysis was used to identify (1) psoriasis-specific DEGs altered in few diseases besides psoriasis and (2) nonspecific DEGs similarly altered in many other skin conditions. We show that few cutaneous DEGs are psoriasis specific and that the two DEG classes differ in their cell type and cytokine associations. Psoriasis-specific DEGs are expressed by keratinocytes and induced by IL-17A, whereas nonspecific DEGs are expressed by inflammatory cells and induced by IFN-γ and tumor necrosis factor. Peripheral blood mononuclear cell-derived DEGs were more psoriasis specific than cutaneous DEGs. Nonetheless, peripheral blood mononuclear cell DEGs associated with major histocompatibility complex class I and natural killer cells were commonly downregulated in psoriasis and other autoimmune diseases (e.g., multiple sclerosis, sarcoidosis, and juvenile rheumatoid arthritis). These findings demonstrate "cross-disease" transcriptomics as an approach to gain insights into the cutaneous and noncutaneous psoriasis transcriptomes. This highlighted unique contributions of IL-17A to the cytokine network and uncovered a blood-based gene signature that links psoriasis to other diseases of autoimmunity.
27405175 [Preparation and evaluation of intra-articular injectable sinomenine hydrochloride-loaded 2016 Jan Phytantriol (PT), ethanol (ET) and water were used to prepare in situ cubic liquid crystal (ISV2). The pseudo-ternary phase diagram of PT-ET-water was constructed and isotropic solution formulations were chosen for further optimization. The physicochemical properties of isotropic solution formulations were evaluated to optimize the composition of ISV2. In situ hexagonal liquid crystals (ISH2) were prepared based on the composition of ISV2 with the addition of vitamin E acetate (VitEA) and the amount of VitEA was optimized by in vitro release behavior. The phase structures of liquid crystalline gels formed by ISV2 and ISH2 in excess water were confirmed by crossed polarized light microscopy and small angle X-ray scattering, respectively. Rheological properties of ISV2 and ISH2 were studied by a DHR-2 rheometer. In vitro drug release studies were conducted by using a dialysis membrane diffusion method. Pharmacokinetics was investigated by determination of sinomenine hydrochloride (SMH) concentration in synovial membrane after intra-articular injection of SMH-loaded ISH2 in adjuvant-induced arthritis rats. The optimal ISV2 (PT/ET/water, 64 : 16 : 20, w/w/w) loaded with 6 mg x g(-1) of SMH showed a suitable pH, injectable and formed a cubic liquid crystalline gel in situ with minimum water absorption in the shortest time. The optimal ISV2 was able to sustain the drug release for 144 h. The optimal ISH2 system was prepared by addition of 5% VitEA into PT in the optimal ISV2 system. This ISH2 (PT/VitEA/ET/water, 60.8 : 3.2 : 16 : 20, w/w/w/w) was an injectable isotropic solution with suitable pH. The new ISH2 was able to sustain the drug release for more than 240 h. Local pharmacokinetics study indicated that the retention time and AUC(0-∞) of ISH2 group were increased significantly compared with that of SMH solution group and the AUC(0-∞) of ISH2 group was 6.01 times higher than that of SMH solution group. The developed ISH2 was suitable for intra-articular injection that may apply to patients in the treatment of rheumatoid arthritis.
26945816 Brief Report: Peripheral Osteolysis in Adults Linked to ASAH1 (Acid Ceramidase) Mutations: 2016 Sep OBJECTIVE: To establish a diagnosis and provide counseling and treatment for 3 adult patients from one family presenting with peripheral osteolysis. METHODS: Following clinical and radiographic assessment, exome sequencing, targeted gene resequencing, and determination of enzyme activity in cultured fibroblasts were performed. RESULTS: The proband (age 40 years) had a history of episodic fever and pain in childhood that subsided around puberty. He and 2 of his older sisters (ages 58 and 60 years, respectively) showed adult-onset progressive shortening of fingers and toes with redundancy of the overlying skin. Radiographs showed severe osteolysis of the distal radius and ulna, carpal bones, metacarpal bones, and phalanges. Sequencing of the known genes for recessively inherited osteolysis, MMP2 and MMP14, failed to show pathogenic mutations. Exome sequencing revealed compound heterozygosity for mutations c.505T>C (p.Trp169Arg) and c.760A>G (p.Arg254Gly) in ASAH1, the gene coding for acid ceramidase. Sanger sequencing confirmed correct segregation in the family, and enzyme activity in fibroblast cultures from the patients was reduced to ∼8% of that in controls, confirming a diagnosis of Farber's disease. CONCLUSION: Our findings indicate that hypomorphic mutations in ASAH1 may result in an osteoarticular phenotype with a juvenile phase resembling rheumatoid arthritis that evolves to osteolysis as the final stage in the absence of neurologic signs. This observation delineates a novel type of recessively inherited peripheral osteolysis and illustrates the long-term skeletal manifestations of acid ceramidase deficiency (Farber's disease) in what appear to be the oldest affected individuals known so far.
26633291 Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. 2016 Jan Cytokines are major drivers of autoimmunity, and biologic agents targeting cytokines have revolutionized the treatment of immune-mediated diseases. Despite the effectiveness of these drugs, they do not induce complete remission in all patients, prompting the development of alternative strategies - including targeting of intracellular signal transduction pathways downstream of cytokines. Many cytokines that bind type I and type II cytokine receptors are critical regulators of immune-mediated diseases and employ the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway to exert their effect. Pharmacological inhibition of JAKs blocks the actions of type I/II cytokines, and within the past 3 years therapeutic JAK inhibitors, or Jakinibs, have become available to rheumatologists. Jakinibs have proven effective for the treatment of rheumatoid arthritis and other inflammatory diseases. Adverse effects of these agents are largely related to their mode of action and include infections and hyperlipidemia. Jakinibs are currently being investigated for a number of new indications, and second-generation selective Jakinibs are being developed and tested. Targeting STATs could be a future avenue for the treatment of rheumatologic diseases, although substantial challenges remain. Nonetheless, the ability to therapeutically target intracellular signalling pathways has already created a new paradigm for the treatment of rheumatologic disease.
25502930 Indications and outcomes for use of Montgomery cannulas. 2015 Feb IMPORTANCE: To our knowledge, we report the first series to analyze use of the Montgomery cannula as an airway management tool for indications other than obstructive sleep apnea. OBJECTIVES: To analyze the use and outcomes of Montgomery cannula placement for airway management and to identify indications for placement. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of 20 patients who received a Montgomery cannula from 2003 through 2012 at the University of Iowa Hospitals and Clinics. INTERVENTION: Montgomery cannula placement. MAIN OUTCOMES AND MEASURES: Indications for cannula placement, comorbidities, body mass index, reasons for failure of cannula use, and complications. RESULTS: Indications included glottic stenosis (n = 7), obstructive sleep apnea (n = 5), bilateral vocal cord paralysis (n = 4), subglottic stenosis (n = 4), supraglottic swelling after radiation or chemoradiation therapy (n = 4), bulbar dystonia with paradoxical vocal cord motion (n = 1), vocal cord fixation secondary to rheumatoid arthritis and gastroesophageal reflux disease (n = 1), and airway obstruction associated with seizure disorder (n = 1). Comorbidities included obesity or overweight (n = 14), gastroesophageal reflux disease (n = 9), hypertension (n = 7), and diabetes mellitus (n = 6). Fifteen patients successfully used a Montgomery cannula, including all patients with 3 or fewer comorbidities. Five patients required replacement with a Jackson tracheostomy tube due to persistent tracheostomal granulation tissue (n = 2), feeling safer with the tracheostomy tube (n = 1), a posterior scar band causing airway obstruction (n = 1), and inability to care for the cannula because of poor manual dexterity from arthritis (n = 1). The mean (range) body mass index of successful and unsuccessful users was 27.5 (18.2-37.7) and 33.8 (24.1-42.7), respectively. Complications included the cannula being blocked by adipose tissue (n = 2) or pushed posteriorly into the airway (n = 2). The Montgomery cannula was used as a successful decannulation tool in 4 patients-with the cannula serving as an interim airway management tool leading to tracheostome closure. CONCLUSIONS AND RELEVANCE: We identified features associated with successful use of the cannula and an additional indication for a Montgomery cannula as a step-down management tool for decannulation.
27022516 STIFF ELBOW TREATMENT BY INTERPOSING ARTHROPLASTY ASSOCIATED TO HINGED EXTERNAL FIXATOR. 2009 Jan OBJECTIVE: Assess the results of the elbow/fascia lata interposing arthroplasty technique associated to the use of a hinged external fixator in the treatment of stiff elbow. METHODS: Between 2001 and 2006, five cases of stiff elbow were operated and followed up by the Shoulder and Elbow Group of the Santa Casa Misericórdia de São Paulo Medical Sciences School, establishing the following as inclusion criteria: patients with below-functional elbow range of motion associated to degeneration on that joint, for whom total prosthesis had not been indicated. Patients' ages ranged from 21 to 55 years (mean: 38). Male gender was prevalent (four cases), and, in all cases, the dominant side was operated. Concerning etiology, two cases of infectious arthritis sequels, one post-trauma sequel, and two rheumatoid arthritis were found. Preoperative range of motion ranged from 20° to 30° of flexion-extension; in two cases, fixed contracture existed in flexion at 30° and 65°. The patients were assessed according to Bruce-modified AMA criteria. RESULTS: The mean follow up time was 54 months. All patients showed improvement of the Bruce index, which, preoperatively, was 43.5, increasing to 88.2 postoperatively. We found two excellent cases, one good, one fair, and one poor. CONCLUSION: Fascia lata interposing arthroplasty associated to the use of a dynamic external fixator on stiff elbows is a feasible alternative for patients not indicated to total elbow arthroplasty.
26933146 Defining conditions where long-term glucocorticoid treatment has an acceptably low level o 2016 Jun There is convincing evidence for the known and unambiguously accepted beneficial effects of glucocorticoids at low dosages. However, the implementation of existing recommendations and guidelines on the management of glucocorticoid therapy in rheumatic diseases is lagging behind. As a first step to improve implementation, we aimed at defining conditions under which long-term glucocorticoid therapy may have an acceptably low level of harm. A multidisciplinary European League Against Rheumatism task force group of experts including patients with rheumatic diseases was assembled. After a systematic literature search, breakout groups critically reviewed the evidence on the four most worrisome adverse effects of glucocorticoid therapy (osteoporosis, hyperglycaemia/diabetes mellitus, cardiovascular diseases and infections) and presented their results to the other group members following a structured questionnaire for final discussion and consensus finding. Robust evidence on the risk of harm of long-term glucocorticoid therapy was often lacking since relevant study results were often either missing, contradictory or carried a high risk of bias. The group agreed that the risk of harm is low for the majority of patients at long-term dosages of ≤5 mg prednisone equivalent per day, whereas at dosages of >10 mg/day the risk of harm is elevated. At dosages between >5 and ≤10 mg/day, patient-specific characteristics (protective and risk factors) determine the risk of harm. The level of harm of glucocorticoids depends on both dose and patient-specific parameters. General and glucocorticoid-associated risk factors and protective factors such as a healthy lifestyle should be taken into account when evaluating the actual and future risk.