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ID PMID Title PublicationDate abstract
27089192 Case 229: Burn-related Global Ankylosis of Interphalangeal Joints with Associated Acrooste 2016 May History A 50-year-old woman presented with a 6-month history of polyarthralgia involving the left and right hands, wrists, elbows, ankles, and knees. Her pain was not associated with morning stiffness but did worsen over the course of the day. She denied experiencing fevers, chills, or mouth ulcers. She did not report paresthesias or blue discoloration of her fingers when they were exposed to cold. Her family history was remarkable for an aunt who died of systemic lupus erythematosus and for a brother with arthritis. Her medical history was remarkable for vitamin D deficiency, hypertension, and rehabilitation for burns. At clinical examination, she had mild tenderness to palpation of her joints, without associated erythema, swelling, or crepitus. Healed skin grafts were also noted. Blood chemistry tests revealed a rheumatoid factor of 8.5 IU/mL (normal range, 0-13.9 IU/mL), an erythrocyte sedimentation rate of 2 mm/hr (normal range, 0-40 mm/hr), and a C-reactive protein value of 0.4 mg/L (3.8 nmol/L) (normal range, 0-4.9 mg/L [0-46.7 nmol/L]). Antinuclear antibodies test results were negative. Radiography of the right and left hands was performed.
27795505 Detection of IFN-γ+IL-17+ cells in salivary glands of patients with Sjögren's syndrome a 2016   Objective: Th17 cells, which mainly produce interleukin (IL)-17, have been suggested to play a critical role in the pathogenesis of autoimmune diseases. The plasticity of Th17 cells, in which these cells shift to a Th1 phenotype in the presence of IL-12, has recently been reported. However, the role of IL-17 in Sjögren's syndrome (SS) and Mikulicz's disease (MD) currently remains unknown. PATIENTS AND METHODS: The submandibular salivary gland and lymph node of a MD patient and the salivary glands of 15 SS patients were collected. IFN-γ+ cells, IL-17+ cells, and IFN-γ+IL-17+ cells were detected by immunohistochemical staining. RESULTS: IFN-γ+ cells, IL-17+ cells, and IFN-γ+IL-17+ cells were detected in the submandibular salivary gland and lymph node of the MD patient and salivary glands of the 15 SS patients. DISCUSSION: IFN-γ+IL-17+cells in the salivary glands of patients were speculated to be Th1/Th17 cells in the present study. Th1/Th17 cells are known to be derived from Th17 cells and differentiate into Th1 cells, and IL-17-derived Th1 cells have been suggested to induce the deterioration of juvenile idiopathic arthritis (JIA). Thus, Th1/Th17 cells may play an important role in the pathogenesis of SS and MD. CONCLUSION: IFN-γ+, IFN-γ+IL-17+, and IL-17+ cells were detected in the submandibular salivary gland and lymph node of a MD patient and the salivary glands of 15 SS patients.
27798262 Autoimmune manifestations in aged mice arise from early-life immune dysregulation. 2016 Oct 19 Autoantibodies can be present years to decades before the onset of disease manifestations in autoimmunity. This finding suggests that the initial autoimmune trigger involves a peripheral lymphoid component, which ultimately drives disease pathology in local tissues later in life. We show that Sjögren's syndrome manifestations that develop in aged NOD.H-2h4 mice were driven by and dependent on peripheral dysregulation that arose in early life. Specifically, elimination of spontaneous germinal centers in spleens of young NOD.H-2h4 mice by transient blockade of CD40 ligand (CD40L) or splenectomy abolished Sjögren's pathology of aged mice. Strikingly, a single injection of anti-CD40L at 4 weeks of age prevented tertiary follicle neogenesis and greatly blunted the formation of key autoantibodies implicated in glandular pathology, including anti-muscarinic receptor antibodies. Microarray profiling of the salivary gland characterized the expression pattern of genes that increased with disease progression and showed that early anti-CD40L greatly repressed B cell function while having a broader effect on multiple biological pathways, including interleukin-12 and interferon signaling. A single prophylactic treatment with anti-CD40L also inhibited the development of autoimmune thyroiditis and diabetes in NOD.H-2h4 and nonobese diabetic mice, respectively, supporting a key role for CD40L in the pathophysiology of several autoimmune models. These results strongly suggest that early peripheral immune dysregulation gives rise to autoimmune manifestations later in life, and for diseases predated by autoantibodies, early prophylactic intervention with biologics may prove efficacious.
27076615 Imbalanced Rab3D versus Rab27 increases cathepsin S secretion from lacrimal acini in a mou 2016 Jun 1 The mechanism responsible for the altered spectrum of tear proteins secreted by lacrimal gland acinar cells (LGAC) in patients with Sjögren's Syndrome (SS) remains unknown. We have previously identified increased cathepsin S (CTSS) activity as a unique characteristic of tears of patients with SS. Here, we investigated the role of Rab3D, Rab27a, and Rab27b proteins in the enhanced release of CTSS from LGAC. Similar to patients with SS and to the male nonobese diabetic (NOD) mouse model of SS, CTSS activity was elevated in tears of mice lacking Rab3D. Findings of lower gene expression and altered localization of Rab3D in NOD LGAC reinforce a role for Rab3D in suppressing excess CTSS release under physiological conditions. However, CTSS activity was significantly reduced in tears of mice lacking Rab27 isoforms. The reliance of CTSS secretion on Rab27 activity was supported by in vitro findings that newly synthesized CTSS was detected in and secreted from Rab27-enriched secretory vesicles and that expression of dominant negative Rab27b reduced carbachol-stimulated secretion of CTSS in cultured LGAC. High-resolution 3D-structured illumination microscopy revealed microdomains of Rab3D and Rab27 isoforms on the same secretory vesicles but present in different proportions on different vesicles, suggesting that changes in their relative association with secretory vesicles may tailor the vesicle contents. We propose that a loss of Rab3D from secretory vesicles, leading to disproportionate Rab27-to-Rab3D activity, may contribute to the enhanced release of CTSS in tears of patients with SS.
26332048 TLR-7 and -9 Stimulation of Peripheral Blood B Cells Indicate Altered TLR Signalling in Pr 2015 Dec Primary Sjögren's syndrome (pSS) is a chronic, inflammatory autoimmune disease characterised by lymphocytic infiltrations in the exocrine glands, resulting in destruction of salivary and lacrimal glands. B cells have an important role in the disease, as detection of autoantibodies against SSA/Ro or SSB/La is one of the diagnostic criteria, being found in a majority of the patients. Toll-like receptors (TLR) are pattern recognition receptors. TLR-7 and -9 are found in endosomes and bind microbial nucleic acids. We have previously shown that pSS patients and healthy controls have similar expression pattern of TLR-7 and -9 in various B-cell populations. In this study we further analysed the responsiveness of B cells upon TLR stimulation. B cells isolated from peripheral blood of 21 pSS patients and 18 healthy controls were stimulated with TLR-7 and -9 ligands for 24 h before being analysed for the expression of certain surface markers and intracellular cytokine levels by flow cytometry. Secreted cytokines were measured by a multiplex cytokine assay. Patients with pSS had more naïve and less preswitched memory B cells compared to controls in unstimulated as well as via TLR-7 stimulated cells. Unstimulated and via TLR-7 stimulated B cells from pSS patients also had fewer IL-10(+) preswitched memory B cells. Moreover, TLR-7 and -9 stimulated B cells of pSS patients secreted increased amounts of several cytokines. B cells of pSS patients show a different responsiveness upon stimulation of TLR-7 and -9 compared to controls.
25727287 NOD.H-2h4 mice: an important and underutilized animal model of autoimmune thyroiditis and 2015 NOD.H-2h4 mice express the K haplotype on the NOD genetic background. They spontaneously develop thyroiditis and Sjogren's syndrome, but they do not develop diabetes. Although autoimmune thyroid diseases and Sjogren's syndrome are highly prevalent autoimmune diseases in humans, there has been relatively little emphasis on the use of animal models of these diseases for understanding basic mechanisms involved in development and therapy of chronic organ-specific autoimmune diseases. The goal of this review is to highlight some of the advantages of NOD.H-2h4 mice for studying basic mechanisms involved in development of autoimmunity. NOD.H-2h4 mice are one of relatively few animal models that develop organ-specific autoimmune diseases spontaneously, i.e., without a requirement for immunization with antigen and adjuvant, and in both sexes in a relatively short period of time. Thyroiditis and Sjogren's syndrome in NOD.H-2h4 mice are chronic autoimmune diseases that develop relatively early in life and persist for the life of the animal. Because the animals do not become clinically ill, the NOD.H-2h4 mouse provides an excellent model to test therapeutic protocols over a long period of time. The availability of several mutant mice on this background provides a means to address the impact of particular cells and molecules on the autoimmune diseases. Moreover, to our knowledge, this is the only animal model in which the presence or absence of a single cytokine, IFN-γ, is sufficient to completely inhibit one autoimmune thyroid disease, with a completely distinct autoimmune thyroid disease developing when it is absent.
25660200 The diffuse infiltrative lymphocytosis syndrome (DILS). A comprehensive review. 2015 May The Diffuse Infiltrative Lymphocytosis Syndrome (DILS) is a rare multisystemic syndrome described in HIV-infected patients. It is characterised by CD8(+) T-cell lymphocytosis associated with a CD8(+) T-cell infiltration of multiple organs. DILS is usually seen in uncontrolled or untreated HIV infection but can also manifest itself independently of CD4(+) T-cell counts. The syndrome may present as a Sjögren-like disease that generally associates sicca signs with bilateral parotiditis, lymphadenopathy, and extraglandular organ involvement. The latter may affect the lungs, nervous system, liver, kidneys, and digestive tract. Anomalies of the respiratory system are often identified as lymphocytic interstitial pneumonia. Facial nerve palsy, aseptic meningitis or polyneuropathy are among the more frequent neurological features. Hepatic lymphocytic infiltration, lymphocytic interstitial nephropathy and digestive tract lymphocytic infiltration account for more rarely noted complications. Sicca syndrome, organomegaly and/or organ dysfunction associated with polyclonal CD8(+) T-cell organ-infiltration are greatly suggestive of DILS in people living with HIV. Labial salivary gland biopsy is therefore helpful when the focus score is equal or greater than 1 (or Chisholm Score ≥ 3). Primary Sjögren syndrome, chronic HCV or HTLV1 infection, graft versus host disease, IgG4-related disease, and immune reconstitution inflammatory syndrome are among the differential diagnoses that need to be considered. Treatment consists in highly active anti-retroviral therapy (HAART), which is usually effective in resolving clinical signs and symptoms. Steroids, however, may also be occasionally required when organ infiltration does not respond to HAART. This review should provide an insight into this rare entity complicating the course of HIV infection.
25590841 Serum IgG subclasses in autoimmune diseases. 2015 Jan To characterize serum IgG subclass levels in several autoimmune diseases, including primary Sjogren syndrome (pSS), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and primary biliary cirrhosis (PBC). We aimed to analyze serum IgG subclass distribution and to test whether serum IgG4 levels are elevated in these diseases. Serum IgG subclass levels from 102 pSS, 102 SSc, 100 SLE, and 59 PBC patients, as well as 40 healthy controls (HCs), were measured using the immunonephelometric assay. The distribution of IgG subclasses among these autoimmune diseases was analyzed. In this cross-sectional study, serum IgG1 (IgG1/IgG) and/or IgG3 (IgG3/IgG) were significantly increased, compared with those in HCs. Only 6.34% of patients had levels of serum IgG4 >135 mg/dL. There were no significant differences in the frequency of elevated serum IgG4 levels between patients and HC. In pSS, serum IgG1 levels were much higher than those in other disease groups, whereas serum IgG2 and IgG3 levels were most prominently increased in PBC. A strikingly different serum IgG subclass distribution was detected in patients with autoimmune diseases compared with HCs. Serum IgG subclass levels also showed distinct characteristics among different autoimmune diseases. Serum IgG4 levels in these patients were lower or not much higher than those in HCs, which differed from IgG4-related diseases.
26462481 Expert opinion in the management of aqueous Deficient Dry Eye Disease (DED). 2015 Oct 13 BACKGROUND: Dry eye disease (DED) affects millions of people worldwide. There are a variety of new treatments beyond traditional therapies such as preservative free artificial tears. Here, we conduct a survey to identify the most common treatments used among specialists and assess their interest in newer therapies. METHODS: An international survey was distributed to dry eye researchers and expert practitioners via an internet survey. The survey data collected were analyzed with descriptive statistics. RESULTS: One hundred and fifteen respondents completed the survey; of these, 66 % were cornea specialists. The most commonly prescribed topical treatments included cyclosporine A (CSA) 0.05 % (71/104, 68 %), fluorometholone (FML) 0.1 % (59/99, 60 %), loteprednol etabonate 0.5 % (50/99, 51 %), and autologous serum eye drops (ASD; 48/97, 49 %). The most commonly prescribed non-topical medications included essential fatty acid supplements (72/104, 69 %), low-dose doxycycline (oral; 61/100, 61 %), and flaxseed supplements (32/96, 33 %) as well as punctal plugs (76/102, 75 %). Respondents reported treatment with topical corticosteroids for 2 to 8 weeks (46/86, 53 %), followed by less than 2 weeks (24/86, 28 %) and with topical CSA between 2 to 8 weeks (45/85, 53 %) followed by 2 to 6 months (24/85, 28 %). The top three signs and symptoms reported to indicate treatment response were, in order, fluorescein staining of the cornea, reduction in foreign body sensation, and reduction in burning sensation. CONCLUSION: This survey offers insight into current expert opinion in the treatment of DED. The results of this survey are hypothesis generating and will aid in the design of future clinical studies.
27461134 Mucosal-associated invariant T cells are reduced and functionally immature in the peripher 2016 Oct The frequencies, immunophenotype, and function of mucosal-associated invariant T (MAIT) cells were studied in patients with primary Sjögren syndrome (pSS) and healthy controls. MAIT cells were significantly decreased in the peripheral blood (PB) of patients with pSS. Vα7.2(+) MAIT cells were detected in the salivary gland tissue from pSS patients, but not in controls, indicating that the reduction of MAIT cells in PB might be due to migration into the target tissue. Furthermore, the residual peripheral blood MAIT cells in pSS patients showed altered immunophenotype and function. While MAIT cells from controls were almost exclusively CD8(+) and expressed an effector memory immunophenotype, in pSS patients they were enriched in CD4(+) and naïve subpopulations. Consistently, the functional studies demonstrated that MAIT cells from pSS showed a lower level of activation with reduced expression of CD69 and CD154 (CD40L), and a lower production of TNF and IFN-γ. In summary, our findings demonstrate that MAIT cells were reduced and phenotypically and functionally altered in PB of pSS patients. The altered function of MAIT cells in target tissues from pSS patients may result in dysregulation of mucosal immunity leading to microbial damage of mucosal surfaces and subsequent initiation of autoimmune response.
27343959 The practical evaluation and management of patients with symptoms of a sore burning mouth. 2016 Jul There are many etiologic factors to consider in a patient who presents with symptoms or sensations of a sore burning mouth. These range from local causes within the oral cavity to underlying systemic disease, including psychologic factors. This paper aims to describe the different clinical presentations and to outline a systematic approach to the evaluation and management of such patients. The clinician will be directed to the relevant diagnosis by following the traditional medical model of taking a focused history, performing a thorough clinical examination, considering the potential differential diagnoses, and requesting pertinent and appropriate investigations. The various differential diagnoses and broad treatment options will also be discussed and outlined. This paper will not, however, discuss burning mouth syndrome (oral dysesthesia), which is a diagnosis of exclusion, whereby the oral mucosa is clinically normal and there are no identifiable medical or dental causes to account for the patient's symptoms.
25780886 Cyclosporine A Suppresses the Activation of the Th17 Cells in Patients with Primary Sjögr 2015 Apr Primary Sjögren's syndrome (pSS) is a common autoimmune disease involving abnormal Th17 activation. The aim of the current study was to investigate the immunosuppression effect of Cyclosporine A (Cys A), a potent immunosuppressor on the proliferation and activation of T cells, on the activation of Th17 cells. Blood samples from both inactive and active pSS patients as well as healthy controls were collected and serum and peripheral blood mononuclear cells (PBMCs) were collected and tested for IL-17 and RORγt expression. Subsequently, PBMCs were treated in vitro with Cys A in a series of doses and incubation time and the effect of Cys A on inhibiting Th17 activation was tested by measuring IL-17 and RORγt expression. IL-17 in both serum and PBMCs as well as RORγt in PBMCs from active pSS patients were significantly elevated on both the mRNA and protein levels comparing to those from both inactive pSS patients and healthy controlCys A in the final concentration of 80ng/ml and the treatment time of 24h showed strong inhibition effect on the expression of IL-17 and RORγt in PBMCs from active pSS patients. However, Cys A in various doses and incubation times did not show much impact on inhibiting IL-17 as well as RORγt expression in PBMCs from healthy donors and inactive pSS patients. Cys A possesses the capability in immunosuppressing the activation of Th17 cells, suggesting that Cys A may be a potential treatment for pSS and maybe other autoimmune diseases.
26399281 Diminished salivary epidermal growth factor secretion: a link between Sjögren's syndrome 2016 OBJECTIVES: Healthy human labial salivary glands produce epidermal growth factor (EGF). In Sjögren's syndrome (SS), EGF staining is diminished. SS is also associated with chronic autoimmune corpus gastritis. We therefore hypothesized that EGF secretion would be diminished in SS and that this could affect gastric target cells. METHODS: Salivary EGF secretion in SS was compared to that in healthy controls using an enzyme-linked immunosorbent assay (ELISA). EGF receptor (EGFR) immunoreactive cells in the gastric corpus of healthy human subjects were analysed using immunostaining. RESULTS: Salivary secretion of EGF was diminished in SS patients (232.4, range 52.6-618.4, vs. 756.6, range 105.3-1631.6 pg/min, p = 0.002). Proton-pump positive parietal cells were mostly EGFR immunoreactive whereas very few pepsinogen I (PGI)-positive cells were EGFR positive. CONCLUSIONS: As EGF is relatively acid resistant, salivary gland-derived EGF might participate in an exo/endocrine mode of parietal cell maintenance in the gastric corpus. Deficiency of salivary gland-derived EGF in SS patients may cause impairment of gastric parietal cells resulting in exposure of immunogenic cryptic antigens and loss of immunological self-tolerance.
26364546 Primary biliary cirrhosis. 2015 Oct 17 Primary biliary cirrhosis is a chronic cholestatic liver disease characterised by destruction of small intrahepatic bile ducts, leading to fibrosis and potential cirrhosis through resulting complications. The serological hallmark of primary biliary cirrhosis is the antimitochondrial antibody, a highly disease-specific antibody identified in about 95% of patients with primary biliary cirrhosis. These patients usually have fatigue and pruritus, both of which occur independently of disease severity. The typical course of primary biliary cirrhosis has changed substantially with the introduöction of ursodeoxycholic acid (UDCA). Several randomised placebo-controlled studies have shown that UDCA improves transplant-free survival in primary biliary cirrhosis. However, about 40% of patients do not have a biochemical response to UDCA and would benefit from new therapies. Liver transplantation is a life-saving surgery with excellent outcomes for those with decompensated cirrhosis. Meanwhile, research on nuclear receptor hormones has led to the development of exciting new potential treatments. This Seminar will review the current understanding of the epidemiology, pathogenesis, and natural history of primary biliary cirrhosis, discuss management of the disease and its sequelae, and introduce research on new therapeutic options.
26242856 Efficacy and safety of belimumab given for 12 months in primary Sjögren's syndrome: the B 2015 Dec OBJECTIVE: To report the efficacy and safety of long-term treatment of SS with belimumab, targeting the B-cell-activating factor. METHODS: Patients with primary SS were included in the BELISS open-label phase II study, a 1-year open-label trial, if they were positive for anti-SSA or anti-SSB antibodies and had systemic complications or persistent salivary gland enlargement or early disease or biomarkers of B-cell activation. They received belimumab, 10 mg/kg i.v., at weeks 0, 2 and 4 and then every 4 weeks; if response was observed at week 28, or if the clinician and the patient agreed to continue the study in the absence of side effects, treatment was continued for 1 year. Efficacy and safety were analysed during the 1-year period of treatment. RESULTS: Among the 30 patients recruited, 28 were evaluated at week 28 as already reported. Nineteen terminated the 52-week study, 15 of them being responders and 4 non-responders at week 28. Thirteen of the 15 responders at week 28 also responded at week 52 (86.7%). The improvement in the EULAR Sjögren's Syndrome Disease Activity Index and EULAR Sjögren's Syndrome Patient Reported Index scores observed at week 28 showed a trend to further improvement at week 52, and the amelioration of peculiar EULAR Sjögren's Syndrome Disease Activity Index domains (glandular, lymphadenopathy, articular) appeared of particular relevance. The decrease in biomarkers of B-cell activation observed at week 28 persisted unchanged until week 52, with RF decreasing further. Salivary flow, Schirmer's test and the focus score of salivary biopsy did not change. Safety of treatment was good. CONCLUSION: Long-term treatment with belimumab may be beneficial in SS. Randomized, double-blind, controlled studies in larger populations are encouraged.
25617429 American Society of Nephrology quiz and questionnaire 2014: acid-base and electrolyte diso 2015 Mar 6 The Nephrology Quiz and Questionnaire remains an extremely popular session for attendees of the Annual Kidney Week Meeting of the American Society of Nephrology. Once again, in 2014 the conference hall was overflowing with audience members and eager quiz participants. Topics covered by the expert discussants included electrolyte and acid-base disorders, glomerular disease, ESRD/dialysis, and transplantation. Complex cases from each of these categories along with single-best-answer questions were prepared and submitted by the panel of experts. Before the meeting, program directors of United States nephrology training programs and nephrology fellows answered the questions using an Internet-based questionnaire. During the live session, members of the audience tested their knowledge and judgment on a series of case-oriented questions prepared and discussed by the experts. They compared their answers in real time using audience response devices with the answers of the nephrology fellows and training program directors. The correct and incorrect answers were then discussed after the audience responses and the results of the questionnaire were displayed. As always, the audience, lecturers, and moderators enjoyed this educational session. This article recapitulates the acid-base and electrolyte disorders portion of the session and reproduces its educational value for the readers of the Clinical Journal of the American Society of Nephrology. Enjoy the clinical cases and expert discussions.
25183206 IL-26 is overexpressed in chronically HCV-infected patients and enhances TRAIL-mediated cy 2015 Sep OBJECTIVE: Interleukin-26 (IL-26) is a member of the IL-10 cytokine family, first discovered based on its peculiar expression by virus-transformed T cells. IL-26 is overexpressed in chronic inflammation (rheumatoid arthritis and Crohn's disease) and induces proinflammatory cytokines by myeloid cells and some epithelial cells. We thus investigated the expression and potential role of IL-26 in chronic HCV infection, a pathology associated with chronic inflammation. DESIGN: IL-26 was quantified in a cohort of chronically HCV-infected patients, naive of treatment and its expression in the liver biopsies investigated by immunohistochemistry. We also analysed the ability of IL-26 to modulate the activity of natural killer (NK) cells, which control HCV infection. RESULTS: The serum levels of IL-26 are enhanced in chronically HCV-infected patients, mainly in those with severe liver inflammation. Immunohistochemistry reveals an intense IL-26 staining in liver lesions, mainly in infiltrating CD3+ cells. We also show that NK cells from healthy subjects and from HCV-infected patients are sensitive to IL-26. IL-26 upregulates membrane tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) expression on CD16- CD56(bright) NK cells, enabling them to kill HCV-infected hepatoma cells, with the same efficacy as interferon (IFN)-α-treated NK cells. IL-26 also induces the expression of the antiviral cytokines IFN-β and IFN-γ, and of the proinflammatory cytokines IL-1β and TNF-α by NK cells. CONCLUSIONS: This study highlights IL-26 as a new player in the inflammatory and antiviral immune responses associated with chronic HCV infection.
26549477 Biological activity of a small molecule indole analog, 1-[(1H-indol-3-yl)methylene]-2-phen 2016 Jan 25 A synthetic small molecule, 1-[(1H-indol-3-yl)methylene]-2-phenylhydrazine (HMPH) was conveniently synthesised by a one-step reaction, purified and characterised by chromatographic and spectroscopic methods. HMPH scavenged free radicals and inhibited lipopolysaccharide (LPS)-induced ROS generation and NO release in RAW-264.7 cells without signs of any detectable cytotoxicity. HMPH inhibited lipid peroxidation (LPO) with IC50 of 135 ± 9 as against 58 ± 8 μM for α-tocopherol. Further, HMPH (>50 μM) significantly reduced the LPS-induced TNF-α release in mouse peritoneal macrophages and in human peripheral blood mononuclear cells (PBMCs). HMPH did not show any visible signs of toxicity in rats up to 400 mg/kg/intraperitoneal and 2000 mg/kg/oral. HMPH at 25 and 50 mg/kg attenuated neutrophil infiltration in air-pouch lavage and bronchoalveolar lavage (BAL) in rat models. HMPH also reduced myeloperoxidase (MPO), nitrite and TNF-α in air-pouch lavage in addition to MPO in plasma. HMPH reduced acute paw-inflammation in carrageenan-induced paw-edema. HMPH consistently decreased both ipsilateral and contralateral paw inflammation, minimised the clinical scores of arthritis, prevented body weight (B.wt.) loss, attenuated serum C-reactive protein (C-RP) and rheumatoid factors (RF) in rat model of adjuvant-induced arthritis. Histopathology and radio-graphical reports show that HMPH reduced bone erosion in both ipsilateral and contralateral paw joints. Failure to inhibit COX suggests that effectiveness of HMPH in both acute and chronic inflammation is mediated by a multimodal mechanism involving modulation of immunity, attenuating TNF-α, protecting bone attrition and reducing oxidative stress.
27836987 RANKL induces Bach1 nuclear import and attenuates Nrf2-mediated antioxidant enzymes, there 2017 Feb Reactive oxygen species (ROS) play a role in intracellular signaling during osteoclastogenesis. We previously reported that transcriptional factor nuclear factor E2-related factor 2 (Nrf2) was exported from the nucleus to the cytoplasm by receptor activator of nuclear factor-κB ligand (RANKL), and that Nrf2 negatively regulated osteoclastogenesis via antioxidant enzyme up-regulation. Knockout mice of BTB and CNC homology 1 (Bach1)-the competitor for Nrf2 in transcriptional regulation-was known to attenuate RANKL-mediated osteoclastogenesis, although the mechanism remains unclear. Therefore, we hypothesized that RANKL could be involved in the nuclear translocation of Bach1, which would attenuate Nrf2-mediated antioxidant enzymes, thereby augmenting intracellular ROS signaling in osteoclasts. RANKL induced Bach1 nuclear import and Nrf2 nuclear export. Induction of Bach1 nuclear export increased Nrf2 nuclear import, augmented antioxidant enzyme expression, and, thus, diminished RANKL-mediated osteoclastogenesis via attenuated intracellular ROS signaling. Finally, an in vivo mouse bone destruction model clearly demonstrated that induction of Bach1 nuclear export inhibited bone destruction. In this study, we report that RANKL favors osteoclastogenesis via attenuation of Nrf2-mediated antioxidant enzyme expression by competing with Bach1 nuclear accumulation. Of importance, induction of Bach1 nuclear export activates Nrf2-dependent antioxidant enzyme expression, thereby attenuating osteoclastogenesis. Bach1 nuclear export might be a therapeutic target for such bone destructive diseases as rheumatoid arthritis, osteoporosis, and periodontitis.-Kanzaki, H., Shinohara, F., Itohiya, K., Yamaguchi, Y., Katsumata, Y., Matsuzawa, M., Fukaya, S., Miyamoto, Y., Wada, S., Nakamura, Y. RANKL induces Bach1 nuclear import and attenuates Nrf2-mediated antioxidant enzymes, thereby augmenting intracellular reactive oxygen species signaling and osteoclastogenesis in mice.
27178283 Time trends in osteoporosis risk factor profiles: a comparative analysis of risk factors, 2016 Oct The aim of this article was to identify prevalent osteoporosis risk factors, medications and comorbidities associated with bone mineral density (BMD). Furthermore to evaluate changes in risk factor profiles over 12 years. 6285 women consecutively referred to an osteoporosis specialist clinic were included. Information of potential risk factors was obtained by questionnaire and clinical examination. Additional information on medication use, comorbidities and fractures were obtained from national registries. An association (<0.05) between well-known risk factors negatively influencing bone health was established in a real-life setting. The prevalence of osteoporosis and proportion of patient's having comorbidity's associated with osteoporosis were increasing during the inclusion period (start 23.8 %, end 29.7 %). Increasing age (OR = 1.05), current smoking (OR = 1.18), estrogen deficiency (OR = 1.7), hyperthyroidism (OR = 1.5), previous major osteoporotic fracture (OR = 1.7), former osteoporosis treatment (OR = 3.5), higher BMI (OR = 0.87), use of calcium supplementation (OR = 1.2), high exercise level (OR = 0.7), and use of thiazide diuretics (OR = 0.7) were identified as predictors of osteoporosis by DXA. Rheumatoid arthritis (OR = 2.4) and chronic pulmonary disease (OR = 1.5) was associated with site-specific osteoporosis by DXA at the total hip. Current use of loop diuretics (OR = 1.7) and glucocorticoid use (OR = 1.04-1.06) were associated with both total hip and femoral neck T-score <-2.5. Our data confirms an independent negative association with BMD of many established risk factors, certain comorbidities, and medications. Exercise level, use of loop diuretics, and prevalent chronic pulmonary disease, risk factors not included in fracture risk calculators were associated with osteoporosis by DXA. Time trends indicate risk profile is dynamic, with increasing focus on secondary osteoporosis.