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ID PMID Title PublicationDate abstract
23147107 Neuronal IL-17 receptor upregulates TRPV4 but not TRPV1 receptors in DRG neurons and media 2013 Jan In addition to the proinflammatory cytokines tumor necrosis factor-α, interleukin-6 and interleukin-1ß, the cytokine interleukin-17 (IL-17) is considered an important mediator of autoimmune diseases such as rheumatoid arthritis. Because tumor necrosis factor-α and interleukin-1ß have the potential to influence the expression of transduction molecules such as transient receptor potential vanilloid 1 (TRPV1) in dorsal root ganglion (DRG) neurons and thus to contribute to pain we explored in the present study whether IL-17A activates DRG neurons and influences the expression of TRPV1. The IL-17A receptor was visualized in most neurons in dorsal root ganglion (DRG) sections as well as in cultured DRG neurons. Upon long-term exposure to IL-17A, isolated and cultured rat DRG neurons showed a significant upregulation of extracellular-regulated kinase (ERK) and nuclear factor κB (NFκB). Long-term exposure of neurons to IL-17A did not upregulate the expression of TRPV1. However, we found a pronounced upregulation of transient receptor potential vanilloid 4 (TRPV4) which is considered a candidate transduction molecule for mechanical hyperalgesia. Upon the injection of zymosan into the paw, IL-17A-deficient mice showed less mechanical hyperalgesia than wild type mice but thermal hyperalgesia was not attenuated in IL-17A-deficient mice. These data show, therefore, a particular role of IL-17 in mechanical hyperalgesia, and they suggest that this effect is linked to an activation and upregulation of TRPV4.
23063343 Factor structure and psychometric properties of the resilience scale in a spanish chronic 2012 Nov The concept of resilience is receiving increasing attention in the field of chronic pain. It has been shown to play a protective role in patients with osteoarthritis, fibromyalgia, and rheumatoid arthritis. Despite this finding, no resilience measurements have been validated in chronic pain populations. The Resilience Scale (RS) is a well-known instrument that has been used to assess resilience in studies conducted in the general population. When used in chronic pain samples, this scale presented the highest internal consistency compared to other resilience scales. The main aim of this study was to provide data on the factor structure, reliability, and validity of the RS in a sample of chronic musculoskeletal pain patients (n = 300). Factor analyses revealed a single-factor solution of 18 items (RS-18), which accounted for 52.43% of the total variance of this scale. The RS-18 shows good reliability (internal consistency and stability) and construct validity. This scale has the advantage of excluding items closely related to functional disability and impairment. Furthermore, the RS-18 significantly correlated with several pain-related variables (ie, catastrophizing, pain acceptance, active and passive pain coping, anxiety, depression, pain-related anxiety, disability, functioning, impairment, and pain intensity). Clinicians and researchers are thus provided with a valid and reliable instrument to assess resilience in chronic pain populations. PERSPECTIVE: This article presents the first resilience questionnaire (RS-18) for chronic pain patients. The instrument obtained shows good reliability and validity. The results provide health-care professionals and researchers with a measure of resilience in chronic pain patients that excludes items related to functional disability.
22960092 Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review. 2012 Dec OBJECTIVE: Although osteoarthritis (OA) is considered a non-inflammatory condition, it is widely accepted that synovial inflammation is a feature of OA. However, the role of immune cells and their cytokines in OA is largely unknown. This narrative systematic review summarizes the knowledge of inflammatory properties, immune cells and their cytokines in synovial tissues (STs) of OA patients. DESIGN: Broad literature search in different databases was performed which resulted in 100 articles. RESULTS: Of 100 articles 33 solely investigated inflammation in OA ST with or without comparison with normal samples; the remaining primarily focussed on rheumatoid arthritis (RA) ST. Studies investigating different severity stages or cellular source of cytokines were sparse. OA ST displayed mild/moderate grade inflammation when investigated by means of haematoxylin and eosin (H&E) staining. Most frequently found cells types were macrophages, T cells and mast cells (MCs). Overall the number of cells was lower than in RA, although the number of MCs was as high as or sometimes even higher than in RA ST. Cytokines related to T cell or macrophage function were found in OA ST. Their expression was overall higher than in normal ST, but lower than in RA ST. Their cellular source remains largely unknown in OA ST. CONCLUSION: Inflammation is common in OA ST and characterized by immune cell infiltration and cytokine secretion. This inflammation seems quantitatively and qualitatively different from inflammation in RA. Further research is needed to clarify the role of inflammation, immune cells and their cytokines in the pathogenesis of OA.
22926910 [Interstitial lung disease in patients with primary biliary cirrhosis]. 2012 Primary biliary cirrhosis (PBC) is a chronic autoimmune disorder of unknown etiology. The disease affects middle-aged women and is characterized by the destruction of the intralobular bile ducts that causes consequent cholestasis. AMA is a hallmark of PBC, composed mostly of IgG and IgM class. The M2 antibody is the most specific one, with sensitivity range of 54-98% depending on type of test used. PBC is often accompanied by other autoimmune diseases, such as Sjögrens syndrome, thyroiditis, rheumatoid arthritis, dermatomyositis, polymyositis. Interstitial lung disease (ILD) has been reported in patients with primary biliary cirrhosis but its frequency and nature are poorly understood. We report pulmonary involvement in the course of PBC in 4 middle-aged women. Histopatological examination of lung specimens was available in three patients: two presented with sarcoid - like granulomas, one with lymphocytic interstitial pneumonia (LIP). In one patient the diagnosis of pulmonary fibrosis was based on clinical and radiological features. Because of abnormal pulmonary function tests (PFT) results all the patients were treated with prednisone, one, additionally with azathioprine. The treatment was successful in all of the patients.
22878429 FabryScan: a screening tool for early detection of Fabry disease. 2012 Nov Fabry disease, an X-linked lipid storage disorder, is associated early morbidity and mortality. Since enzyme replacement therapy is available, accurate detection of unrecognized cases is important. Characteristic early symptoms are recurrent episodes of burning and lancinating pain in the distal extremities associated with small fiber neuropathy. The aim was to develop and validate an easy diagnostic questionnaire in combination with three simple bedside tests, the "FabryScan", for the detection of Fabry disease in patients with chronic extremity pain. Questions related to relevant clinical characteristics of Fabry disease (mainly related to pain) were compiled by Fabry specialists and pain experts. Furthermore, three bedside tests assessing sensory small and large fiber function were established. The provisional version was tested in a prospective multicenter trial of 138 patients with chronic extremity pain due to Fabry disease (n = 55), painful polyneuropathy (n = 40), and rheumatoid arthritis (n = 43). Identification of the most discriminant combinations of items for Fabry disease and their calculation of sensitivity and specificity were based on multivariate analyses. We retained only 10 questions and three bedside tests for the final version of the FabryScan. A cut-off score of 12/33 (corresponding to the number of positive points) resulted in a high proportion of correctly identified patients (76 %) with a sensitivity of 88 % and a specificity of 87 %. The FabryScan is a combination of a brief and simple questionnaire with three simple bedside tests with good discriminative value for the identification of Fabry patients in patients with chronic extremity pain.
22875700 The effect of neutralizing antibodies on the sustainable efficacy of biologic therapies: w 2012 Sep Over the last decade, biologic therapeutic proteins have advanced the treatment of diseases such as rheumatoid arthritis (RA). Therapeutic antibodies such as infliximab, adalimumab, rituximab, tocilizumab, golimumab, certolizumab pegol, the receptor construct etanercept, and abatacept, an anticluster of differentiation (CD)80/anti-CD86 fusion protein, are used as treatment for RA and ankylosing spondylitis (AS). Infliximab, adalimumab, golimumab, certolizumab pegol, and etanercept are inhibitors of tumor necrosis factor (TNF), a key regulator of inflammation. Left untreated, progression of rheumatic diseases due to inflammation can lead to irreversible joint damage and serious disability. One limitation for the use of therapeutic antibodies is immunogenicity, the induction of antibodies by the adaptive immune system in response to foreign substances. The development of antidrug antibodies (ADAs) has a varying impact on the clinical efficacy of biologic agents for the treatment of RA and AS, depending on whether the ADAs are neutralizing or non-neutralizing. Studies have indicated that neutralizing ADAs are associated with a reduced efficacy, decreased drug survival, increased instances of dose escalation, and adverse events. Comparison studies of anti-TNF biologics have demonstrated that each drug has a different sustained efficacy profile depending on immunogenicity. The purpose of this review is to provide rheumatologists with information regarding the effect of neutralizing antibodies on the sustainable efficacy of anti-TNF biologic therapies. This information will be of value to practicing rheumatologists in Africa and the Middle East who should take into account the potential for changes in the efficacy and safety of biologic therapies and closely monitor patients under their care.
24783003 Alcohol consumption as a risk factor for autoimmune thyroid disease: a prospective study. 2012 Jul BACKGROUND: Alcohol consumption has been identified as a protective factor for some autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus. OBJECTIVE: We hypothesized that alcohol consumption would reduce the risk of developing autoimmune thyroid disease (AITD). STUDY DESIGN: Two nested case-control studies in the prospective Amsterdam AITD cohort. Follow-up was 5 years, with annual assessments. In study A, we compared alcohol consumption between cases (subjects who during follow-up remained euthyroid but developed thyroid peroxidase antibodies (TPO-Ab), called event) and controls (subjects who remained euthyroid and TPO-Ab-negative). In study B, we compared alcohol consumption between cases (subjects who during follow-up developed overt hypothyroidism, called event) and controls (subjects who did not develop overt hypothyroidism). For each case, 2 controls were selected, matched for age, duration of follow-up and smoking behavior at baseline and at the time of event. RESULTS: In study A, alcohol consumption did not differ between cases and controls at any time point. In study B, the number of subjects consuming >10 units of alcohol per week was not different between cases and controls at study entrance (8.3 vs. 14.5%, NS), but lower at 1 year before (5.3 vs. 19.7%, p = 0.041) and at the time of event (6.7 vs. 23.7%, p = 0.044); respective odds ratios are 0.54 (0.14-2.06), 0.23 (0.05-1.04) and 0.23 (0.05-1.06). CONCLUSION: Alcohol consumption is not associated with de novo development of TPO-Ab, but is lower in subjects who developed overt hypothyroidism. The data suggest alcohol consumption may protect against overt autoimmune hypothyroidism.
22683424 Circulating microRNAs as candidate biomarkers in patients with systemic lupus erythematosu 2012 Sep Aberrant expression of microRNAs (miRNAs) has been identified in various diseases. Recent studies demonstrated that miRNAs can be detected in the circulation and serve as potential biomarkers of various diseases. Moreover, the detection of circulating miRNAs can provide important novel information concerning diseases. In this study, a miRNA profile was used to determine the aberrantly expressed circulating miRNAs in patients with systemic lupus erythematosus (SLE) compared with patients with rheumatoid arthritis (RA) and healthy controls (HCs). To further confirm the microarray data, we identified 8 miRNAs (miR-126, miR-21, miR-451, miR-223, miR-16, miR-125a-3p, miR-155, and miR-146a) by real-time quantitative PCR (qRT-PCR) in 20 healthy controls and in 55 patients, of whom 30 patients were diagnosed with SLE and 25 were diagnosed with RA. Consistent with the microarray data, miR-126 was specifically enriched only in the blood of the SLE patients, but 4 other miRNAs (miR-21, miR-451, miR-223, and miR-16) were upregulated in the patients with SLE and were also significantly increased in the patients with RA. In contrast, miR-125a-3p, miR-155, and miR-146a showed a trend toward significantly reduced levels in the patients with SLE. In addition, to further estimate the potential roles of these differentially expressed circulating miRNAs in the pathogenesis of SLE, we used a bioinformatics exploratory analysis and identified a number of significantly enriched pathways, which implied that most dysregulated circulating miRNAs might be involved in various signal transduction pathways and cell interactions, particularly the mitogen-activated protein kinase signaling pathway. Based on these findings, we postulate that aberrantly expressed plasma miRNAs could be attractive as candidates for putative biomarkers of SLE and may help elucidate the possible pathogenesis of SLE.
22647863 Prevalence of musculoskeletal diseases in Guatemala, Central America: the COPCORD study of 2012 Jun BACKGROUND: Guatemala is a multiethnic, multilingual, and multicultural country. We have evaluated 2 different ethnic groups from (1) San Juan Sacatepéquez County (SJSC), a rural population (30% illiterate), with 65% from Kaqchiquel ethnic group; and (2) Zone 5 of Guatemala City (Z5GC), an urban population (6.6% illiterate), with 95.5% mestizos. OBJECTIVE: This study aimed to measure simultaneously the prevalence of rheumatic diseases in these 2 Guatemalan populations, both located in the State of Guatemala. METHODS: A convenience sample of 4000 inhabitants 15 years and older was selected in each group. The Core Community Oriented Program for Control of Rheumatic Diseases Questionnaire was used in this survey. Phase 1 was for screening (identification of study subjects), phase 2 was for obtaining information from subjects with musculoskeletal complaints, and phase 3 was for rheumatologic diagnostic purposes. Phases 1 and 2 were performed by 6 interviewers. Phase 3 was completed by 4 rheumatologists. RESULTS: In phase I, 8000 subjects were identified in both groups. In phase II, 949 subjects reported musculoskeletal complaints: 371 (39%) in Z5GC and 578 (61%) in SJSC. In phase III, 419 patients were clinically evaluated: 141 (34%) in Z5GC and 278 (66%) in SJSC. The most prevalent musculoskeletal diseases were (1) osteoarthritis, (2) soft tissue rheumatism, (3) rheumatoid arthritis, (4) low back pain, and (5) arthralgias of unknown etiology. Osteoarthritis and soft tissue rheumatism were significantly more common in the rural population. CONCLUSIONS: The most prevalent musculoskeletal diseases in Guatemala seem to be similar to those in most previous Community Oriented Program for Control of Rheumatic Diseases studies. Most subjects were still working. Further studies examining medical care received and impact on function can now be of interest.
22491915 Increased risk of anterior uveitis following herpes zoster: a nationwide population-based 2012 Apr OBJECTIVE: To investigate the relationship between herpes zoster (HZ) and the subsequent risk of anterior uveitis during the year following an HZ diagnosis, using a nationwide population-based data set. METHODS: This study used the Taiwan National Health Insurance Research Database. The study cohort consisted of 314,405 patients who received a diagnosis of HZ. The comparison cohort comprised 943,215 randomly selected patients. We tracked each patient for a 1-year period from their index ambulatory care visit to identify those who subsequently received a diagnosis of anterior uveitis. Stratified Cox proportional hazard regressions were performed to compute the adjusted 1-year uveitis-free survival rate, after adjusting for patient's age, sex, and geographic region and the presence of rheumatoid arthritis, psoriasis, mumps, systemic lupus erythematosus, tuberculosis, ankylosing spondylitis, and human immunodeficiency syndrome/AIDS. RESULTS: During the 1-year follow-up period, 2515 (0.2%) of 1,257,620 sampled patients were diagnosed with anterior uveitis: 908 from the study cohort (0.3% of the patients with HZ) and 1607 from the comparison cohort (0.2% of patients without HZ). After adjusting for potential confounders, the hazard ratio of anterior uveitis during the 1-year follow-up period was 1.67 for patients with HZ (P < .001) compared with the comparison cohort. In addition, the hazard ratio of anterior uveitis for patients with HZ ophthalmicus was 13.06 (P < .001) when compared with patients without HZ. CONCLUSIONS: The risk of anterior uveitis increased in the year following a diagnosis of HZ. We suggest that patient eye condition be evaluated following diagnosis with HZ.
22435926 Spondylodiscitis: standards of current treatment. 2012 May BACKGROUND: Spinal infections are an important clinical problem that often require aggressive medical therapy, and sometimes even surgery. Known risk factors are advanced age, diabetes mellitus, rheumatoid arthritis, immunosuppression, alcoholism, long-term steroid use, concomitant infections, poly-trauma, malignant tumor, and previous surgery or invasive procedures (discography, chemonucleolysis, and surgical procedures involving or adjacent to the intervertebral disc space). The most common level of involvement is at the lumbar spine, followed by the thoracic, cervical and sacral levels: lesions at the thoracic spine tend to lead more frequently to neurological symptoms. OBJECTIVE: The aim of the current paper is to describe current evidence-based standards of therapy in the management of SD by emphasizing pharmacological therapy and principles and indications for bracing and surgery. METHODS: A PubMed and Google Scholar search using various forms and combinations of the key words: spondylodiscitis, spine, infection, therapy, surgery, radiology, treatment. Reference citations from publications identified in the literature search were reviewed. Publications highlighted in this article were extracted based on relevancy to established, putative, and emerging diagnostic and therapeutic standards, either conservative (antibiotic therapy and bracing) or surgical. FINDINGS: To date, conservative therapy, based on targeted antibiotic therapy plus bracing, represents the mainstay in the management of SD. Proper diagnosis and tailored therapy can improve clinical results and decrease the chance of failure. Surgery should be an option only for patients with complications of this disease, namely deformity, neural compression and neurological compromise. Current standards in the setting of SD are continuously evolving, as can be seen in the recent advances in the field of radiological diagnostics, and the use of growth factors and cell-therapy strategies to promote infection eradication and bone healing after surgery.
22408231 Increased risk of uveitis in coeliac disease: a nationwide cohort study. 2012 Jun BACKGROUND: Case reports suggest a potential association between coeliac disease (CD) and uveitis, but larger well-controlled studies are lacking. The aim of this study was therefore to examine the risk of uveitis in patients with biopsy-verified CD. METHODS: Small intestinal biopsy reports performed between July 1969 and February 2008 were collected from all (n=28) pathology departments in Sweden. From these reports, 29,044 patients with CD (equals villous atrophy, Marsh 3) were identified. Uveitis was defined according to relevant International Classification of Disease codes in the Swedish National Patient Register. Cox regression was used to estimate HR for uveitis in individuals with CD compared with those in reference individuals matched for age, sex, county and calendar year. RESULTS: During follow-up, 148 patients with CD developed uveitis (expected count 112), corresponding to a HR of 1.32 (95% CI 1.10 to 1.58). The absolute risk of uveitis was 50/100,000 person-years in CD. The risk estimate did not change more than marginally when adjusted for type 1 diabetes, rheumatoid arthritis and autoimmune thyroid disease (HR 1.30; 95% CI 1.08 to 1.56). The risk of uveitis remained significantly increased even 5 years after CD diagnosis (HR 1.31; 95% CI 1.04 to 1.64). CONCLUSION: A moderately increased risk of uveitis was found in patients with biopsy-verified CD. CD might be considered in patients with uveitis of unknown aetiology.
22387224 Fyn positively regulates the activation of DAP12 and FcRγ-mediated costimulatory signals 2012 Jun Osteoclasts (OCs) are the only bone-resorbing cells and are critically involved in various bone-associated diseases, including osteoporosis and rheumatoid arthritis. Differentiation of OCs from bone marrow macrophage cells (BMMs) is regulated by RANK and the adaptor protein (DAP12/FcRγ)-mediated costimulatory signals. However, it is unknown how RANKL/RANK signal stimulates phosphorylation of DAP12/FcRγ to initiate the costimulatory signals. As reported here, we found that OC differentiation and acquisition of bone resorption capacity were suppressed in RANKL-stimulated Fyn(-/-) or Fyn-siRNA-transfected BMMs, but could be restored by overexpression of Fyn kinase in Fyn(-/-) BMMs. However, the RANKL-stimulated proliferation of BMMs was unaffected by the absence of Fyn. In addition, RANKL-stimulated Fyn(-/-) BMMs no longer exhibited the optimal induction of typical OC markers such as NFATc1, c-Fos, c-Src, TRAF6, and cathepsin K or costimulatory signals such as the activating phosphorylations of Syk, PLCγ2, and Gab2. These were restored by overexpression of Fyn in Fyn(-/-) BMMs. Immunoprecipitation studies also indicated that the adaptor proteins DAP12/FcRγ and Syk interacted with RANK during RANKL stimulation in BMMs in a Fyn-dependent manner. Phosphorylation of the DAP12/FcRγ and the recruitment of Syk by DAP12/FcRγ were suppressed in Fyn(-/-) BMMs. This is the first demonstration that Fyn relays the initial RANK/RANKL signal to the ITAM-containing adaptors DAP12/FcRγ for OC differentiation.
22260531 The impact of Porphyromonas gingivalis lipids on apoptosis of primary human chondrocytes. 2012 The role of oral bacterial infections including periodontal disease in the pathogenesis of rheumatoid arthritis (RA) has gained increasing interest. Among the major periodontal pathogens, Porphyromonas gingivalis has been mostly associated with RA pathogenesis. The aim of this study was to analyze the effect of P. gingivalis total lipid (TL) fraction and dihydroceramides, as potent virulence factors, on human primary chondrocytes. Primary chondrocyte cultures were incubated with P. gingivalis phosphoglycerol dihydroceramide (PG DHC) lipids, the TL fraction or phosphoethanolamine dihydroceramide. Cell morphology changes were determined by phase contrast light microscopy. Early and late apoptosis cell analysis was performed by Annexin-V, active caspases, and 7-Aminoactinomycin D staining, and examined by flow cytometry, and cell necrosis was evaluated by lactate dehydrogenase release. Procaspase-3 activation was determined by Western blot analysis. Microscopic analysis showed altered cell morphology and cell shrinkage following incubation with P. gingivalis TLs and PG DHC lipids. Flow cytometry demonstrated an increase of Annexin-V positive and active caspases positive chondrocytes after incubation with TL and PG DHC fractions but not after phosphoethanolamine dihydroceramide (control lipid) treatment or in untreated control cells. Furthermore, Western blot analysis showed an early cleavage of procaspase-3 after 1 hr. Significant lactate dehydrogenase release following incubation with P. gingivalis lipids was demonstrated. The present data demonstrate that P. gingivalis lipids promote apoptosis in primary human chondrocytes, and thereby may contribute to the joint damage seen in the pathogenesis of RA.
22260029 [Polymorphism of the 5R-5-hydroxytriptolide]. 2011 Nov 5R-5-hydroxytriptolide (LLDT-8) is a new drug candidate which is in clinical trial treating rheumatoid arthritis. Polymorph screening of the compound was carried out in this study. Polymorph of LLDT-8 was prepared by evaporative crystallization and antisolvent crystallization methods and was characterized by powder X-ray diffraction (p-XRD), infrared spectrometry (IR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TG). It was found that p-XRD patterns, DSC curves, TG curves and IR spectra of the LLDT-8 samples prepared by the above recrystallization methods were all consistent. The 20 of main peaks in the p-XRD patterns appeared at 7.58 degrees, 8.14 degrees, 8.66 degrees, 15.46 degrees, 16.46 degrees, 29.54 degrees, 31.16 degrees and 38.26 degrees, while the infrared absorption peaks appeared at 3 471.3, 2 962.2, 2 887.0, 1 762.6, 1 677.8, 1 432.9, 1 365.4, 1 247.7, 1 080.0, 1 031.7 and 877.5 cm(-1). LLDT-8 was decomposed at 271.2 degrees C based on the determination from DSC and TG. It was showed in single crystal X-ray diffraction study that LLDT-8 crystal was monoclinic with the space group being P2 (1). The cell parameters were found to be: a = 11.460 1 (11), b = 6.320 5 (6), c = 13.028 1 (12), alpha = 90.00, beta = 115.557 (2) and gamma = 90.00. The crystal was a hydrogen-bonded dimmer. The slurry experiments, which were further conducted in solvents with different polarities, confirmed the stability of solid state of LLDT-8 based on the p-XRD determination. The polymorph of LLDT-8 made assurance of its efficacy consistence during its clinical trials.
22193289 Progesterone and autoimmune disease. 2012 May Sexual dimorphism in human immune systems is most apparent in the female predominance of certain autoimmune diseases (ADs) like systemic lupus erythematosus (SLE). Epidemiologic, observational and experimental evidence strongly suggest sex steroids are important modulators of genetic risk in human AD. In this regard, the roles of progesterone (Pg), an immunomodulatory female sex steroid, are poorly understood. Several lines of investigation indicate Pg and synthetic progestins impact risk of AD and immune-mediated injury in different ways depending on their concentrations and their engagement of various Pg receptors expressed in immune organs, immune cells or tissues targeted by immune attack. At low physiologic levels, Pg may enhance interferon-alpha (IFN-α) pathways important in SLE pathogenesis. Commonly used synthetic progestins may have the opposite effect. At pregnancy levels, Pg may suppress disease activity in rheumatoid arthritis (RA) and multiple sclerosis (MS) via inhibition of T helper type 1 (Th1) and Th17 pathways and induction of anti-inflammatory molecules. Importantly, Pg's immunomodulatory effects differ from those of estrogens and androgens. An additional layer of complexity arises from apparent interdependence of sex hormone signaling pathways. Identifying mechanisms by which Pg and other sex steroids modulate risk of AD and immune-mediated injury will require clarification of their cellular and molecular targets in vivo. These future studies should be informed by recent genetic discoveries in human AD, particularly those revealing their sex-specific genetic associations.
22153851 Co-delivery of antigen and a lipophilic anti-inflammatory drug to cells via a tailorable n 2012 Feb 15 Nanotechnology promises new drug carriers that can be tailored to specific applications. Here we report a new approach to drug delivery based on tailorable nanocarrier emulsions (TNEs), motivated by a need to co-deliver a protein antigen and a lipophilic drug for specific inhibition of nuclear factor kappa B (NF-κB) in antigen presenting cells (APCs). Co-delivery for NF-κB inhibition holds promise as a strategy for the treatment of rheumatoid arthritis. We used a highly surface-active peptide (SAP) to prepare a nanosized emulsion having defined surface properties predictable from the SAP sequence. Incorporating the lipophilic drug into the oil phase at the time of emulsion formation enabled its facile packaging. The SAP is depleted from bulk during emulsification, allowing simple subsequent addition of the drug-loaded oil-in-water emulsion to a solution of protein antigen. Decoration of emulsion surface with antigen was achieved via electrostatic deposition. In vitro data showed that the TNE prepared this way was internalized and well-tolerated by model APCs, and that good suppression of NF-κB expression was achieved. This work reports a new type of nanotechnology-based carrier, a TNE, which can potentially be tailored for co-delivery of multiple therapeutic components, and can be made using simple methods using only biocompatible materials.
22024571 Cysteine cathepsins: from structure, function and regulation to new frontiers. 2012 Jan It is more than 50 years since the lysosome was discovered. Since then its hydrolytic machinery, including proteases and other hydrolases, has been fairly well identified and characterized. Among these are the cysteine cathepsins, members of the family of papain-like cysteine proteases. They have unique reactive-site properties and an uneven tissue-specific expression pattern. In living organisms their activity is a delicate balance of expression, targeting, zymogen activation, inhibition by protein inhibitors and degradation. The specificity of their substrate binding sites, small-molecule inhibitor repertoire and crystal structures are providing new tools for research and development. Their unique reactive-site properties have made it possible to confine the targets simply by the use of appropriate reactive groups. The epoxysuccinyls still dominate the field, but now nitriles seem to be the most appropriate "warhead". The view of cysteine cathepsins as lysosomal proteases is changing as there is now clear evidence of their localization in other cellular compartments. Besides being involved in protein turnover, they build an important part of the endosomal antigen presentation. Together with the growing number of non-endosomal roles of cysteine cathepsins is growing also the knowledge of their involvement in diseases such as cancer and rheumatoid arthritis, among others. Finally, cysteine cathepsins are important regulators and signaling molecules of an unimaginable number of biological processes. The current challenge is to identify their endogenous substrates, in order to gain an insight into the mechanisms of substrate degradation and processing. In this review, some of the remarkable advances that have taken place in the past decade are presented. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.
21972766 Locked versus nonlocked plate fixation for hallux MTP arthrodesis. 2011 Jul BACKGROUND: Dorsal plate fixation is used commonly for arthrodesis of the hallux first metatarsophalangeal (MTP) joint. Custom dorsal plates incorporating locking technology have been developed recently for applications in the foot to provide relative ease of application and theoretically superior mechanical properties. The purpose of this study is to compare the radiographic and clinical outcomes of patients undergoing hallux MTP joint arthrodesis using a locked plate, or a nonlocked plate. MATERIALS AND METHODS: We compared consecutive patients who underwent hallux MTP arthrodesis for a variety of diagnoses with either a precontoured locked titanium dorsal plate (Group 1) or a precontoured, nonlocked stainless steel plate (Group 2). All patients were evaluated with radiographs, visual analog pain scale, American Orthopaedic Foot and Ankle Society (AOFAS) hallux score, and a detailed patient satisfaction survey. RESULTS: There were 73 feet in Group 1 and 107 feet in Group 2. There was a trend toward a higher nonunion rate in Group 1 compared to Group 2. When considering only patients without rheumatoid arthritis (RA), the union rate was significantly higher in Group 2 compared to Group 1. Hardware failure and the overall complication rate was equivalent between the two Groups. CONCLUSION: As locked plate technology continues to gain popularity for procedures in the foot, it is important that clinical outcomes are reported. Locked titanium plates were associated with higher nonunion rates. Improved plate design, patient selection, and an understanding of plate biomechanics in this unique loading environment may optimize future outcomes for hallux MTP arthrodesis.
21841730 Prophylaxis of hepatitis B reactivation with immunosuppressive therapy in rheumatic diseas 2011 Apr Reactivation of infection with hepatitis B virus (HBV) is a potentially serious complication of immunosuppression, which can be identified and efficiently prevented. There have been an increasing number of cases of HBV reactivation in patients receiving immunosuppression in the context of rheumatic diseases such as rheumatoid arthritis or systemic lupus erythematosus. The recommendations in this area should be individualized taking into account two aspects: immunosuppressive regimens used (high or low risk of reactivation) and the different stages of HBV infection: chronic hepatitis B, inactive HBV carrier, occult hepatitis B infection defined by HB surface antigen (HBsAg) negative and antibody anti-HB core (anti-HBc) positive. In patients with rheumatic diseases that will start high-risk immunosuppressive drugs, we propose a universal screening with serological tests for hepatitis B (HBsAg, anti-HBs and anti-HBc). Patients with chronic hepatitis B (HBsAg positive, HBV DNA ≥ 2000 IU/ml, elevated ALT) should initiate antiviral therapy. Inactive HBV carriers (HBsAg positive, HBV DNA <2000 IU / ml, normal aminotransferases) exposed to high risk immunosuppressive therapy should undergo prophylaxis of HBV reactivation. Prophylaxis should be started 2 to 4 weeks before the beginning of immunosuppressive therapy and maintained for at least 6 to 12 months after its suspension. It is recommended to use entecavir or tenofovir as first line antiviral agents. In inactive HBsAg carriers under low-risk immunosuppressive therapy and patients with HBsAg negative/anti-HBc positive (HBV infection in the past), the strategy should be monitoring of viral reactivation with aminotransferases and HBV DNA determination in every 6 months.