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ID PMID Title PublicationDate abstract
17048275 Vaccination against IL-17 suppresses autoimmune arthritis and encephalomyelitis. 2006 Nov Interleukin 17 is a T cell-derived cytokine that induces the release of pro-inflammatory mediators in a wide range of cell types. Recently, a subset of IL-17-producing T helper cells (Th17) distinct from Th1 and Th2 cells has been described, which constitutes a new T cell polarization state. Aberrant Th17 responses and overexpression of IL-17 have been implicated in a number of autoimmune disorders including rheumatoid arthritis and multiple sclerosis. Molecules blocking IL-17 such as IL-17-specific monoclonal antibodies have proved to be effective in ameliorating disease in animal models. Hitherto, active immunization targeting IL-17 is an untried approach. Herein we explore the potential of neutralizing IL-17 by active immunization using virus-like particles conjugated with recombinant IL-17 (IL-17-VLP). Immunization with IL-17-VLP induced high levels of anti-IL-17 antibodies thereby overcoming natural tolerance, even in the absence of added adjuvant. Mice immunized with IL-17-VLP had lower incidence of disease, slower progression to disease and reduced scores of disease severity in both collagen-induced arthritis and experimental autoimmune encephalomyelitis. Active immunization against IL-17 therefore represents a novel therapeutic approach for the treatment of chronic inflammatory diseases.
16971957 A distinct inflammatory gene expression profile in patients with psoriatic arthritis. 2006 Oct Psoriatic arthritis (PsA) is a systemic inflammatory condition featuring polyarthritis associated with psoriasis. Apart from clinical indicators, few biomarkers exist to aid in the diagnosis and management of PsA. We hypothesized that whole blood gene expression profiling would provide new diagnostic markers and/or insights into pathogenesis of the disease. We compared whole blood gene expression profiles in PsA patients and in age-matched controls. We identified 310 differentially expressed genes, the majority of which are upregulated in PsA patients. The PsA expression profile does not significantly overlap with profiles derived from patients with rheumatoid arthritis or systemic lupus erythematosus. Logistic regression identified two lymphocyte-specific genes (zinc-finger protein 395 and phosphoinositide-3-kinase 2B) that discriminate PsA patients from normal controls. In addition, a highly coregulated cluster of overexpressed genes implicated in protein kinase A regulation strongly correlates with erythrocyte sedimentation rate. Other clusters of coregulated, yet suppressed genes in PsA patient blood include molecules involved in T-cell signaling. Finally, differentially expressed genes in PsA fall into diverse functional categories, but many downregulated genes belong to a CD40 signaling pathway. Together, the data suggest that gene expression profiles of PsA patient blood contain candidate novel disease markers and clues to pathogenesis.
18612926 Adiponectin mitigates the severity of arthritis in mice with collagen-induced arthritis. 2008 Jul OBJECTIVE: Adiponectin (AD) is considered an inflammation modulator. In this study, we investigated the effect of AD on rheumatoid arthritis (RA) using a collagen-induced arthritis (CIA) mouse model and RA synovial fibroblasts (RASF). METHODS: Fifteen DBA/1 mice were divided into three groups. All mice, except the control group, were injected with type II collagen. AD was intra-articularly injected in the left hind legs after arthritis development (the AD-treated group). The severity of the arthritis was measured using an arthritis score and paw thickness. A histopathological assessment of joint sections was performed by haematoxylin/eosin (H&E) staining. Tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and matrix metalloproteinase (MMP)-3 expression was evaluated by immunohistochemical staining in the CIA mice. Synovial tissue was obtained from four RA patients during total joint replacement. RASF cultures were established from this tissue. RASF were pretreated with AD and stimulated by TNFalpha or IL-1beta. TNFalpha, IL-1beta, IL-6, and MMP-3 production was measured by enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR). RASF proliferation was evaluated using the MTT assay. RESULTS: AD significantly mitigated the severity of the arthritis and histopathological findings indicative of RA in CIA mice. TNFalpha, IL-1beta, and MMP-3 expression decreased, but IL-6 expression in AD-treated joint tissues increased. Moreover, AD reduced TNFalpha, IL-1beta, and MMP-3 expression in stimulated RASF and increased IL-6 expression in IL-1beta-stimulated RASF. AD significantly inhibited IL-1beta-induced RASF proliferation, despite increased IL-6 expression. CONCLUSION: These data suggest that AD may play an anti-inflammatory role in the pathophysiology of RA.
17185416 Ethanol prevents development of destructive arthritis. 2007 Jan 2 Environmental factors are thought to play a major role in the development of rheumatoid arthritis. Because the use of ethanol is widespread, we assessed the role of ethanol intake on the propensity to develop chronic arthritis. Collagen type II-immunized mice were given water or water containing 10% (vol/vol) ethanol or its metabolite acetaldehyde. Their development of arthritis was assessed, as well as the impact of ethanol on leukocyte migration and activation of intracellular transcription factors. Mice exposed daily to this dose of ethanol did not display any liver toxicity, and the development of erosive arthritis was almost totally abrogated. In contrast, the antibody-mediated effector phase of collagen-induced arthritis was not influenced by ethanol exposure. Also, the major ethanol metabolite, acetaldehyde, prevented the development of arthritis. This antiinflammatory and antidestructive property of ethanol was mediated by (i) down-regulation of leukocyte migration and (ii) up-regulation of testosterone secretion, with the latter leading to decreased NF-kappaB activation. We conclude that low but persistent ethanol consumption delays the onset and halts the progression of collagen-induced arthritis by interaction with innate immune responsiveness.
16670827 Use of antibodies recognizing cyclic citrullinated peptide in the differential diagnosis o 2007 Apr OBJECTIVE: To determine the prevalence of anti-cyclic citrullinated peptide (CCP) antibodies in systemic sclerosis (SSc) and to assess any association between the presence of anti-CCP, radiographic features, and clinical manifestations. MATERIALS AND METHODS: Anti-CCP antibodies and rheumatoid factor (RF) were tested in serum samples from 75 patients with SSc (64 women and 11 men), with a mean age of 59.4 years (range 24-85) with either diffuse (dcSSc) and limited (lcSSc) cutaneous involvement. As a control group, 22 age- and sex-matched healthy controls (HCs) were examined. Standard radiographs of the hands and wrists were examined in each patient. RESULTS: The presence of anti-CCP was found in sera of 10.6% (8/75) patients with SSc (lcSSc 3 of 44, 6.8%; dcSSc 5 of 31, 16.1%). None of the HCs was positive for anti-CCP. The positivity of RF was observed in 19 of 75 (25.3%) SSc patients (lcSSc 10 of 44, 22.7%; dcSSc 9 of 31, 29%). Statistically significant association was found between anti-CCP positivity and the presence of arthritis (p<0.0001) and marginal erosions (p=0.001). CONCLUSION: Our data show that joint involvement is a common presenting feature of SSc. In this report, we show that anti-CCP antibodies can be detected also in patients with SSc, but they are generally less commonly present than in adults with rheumatoid arthritis (RA). Thus, the finding of high titers of anti-CCP antibodies may help to define the diagnosis of overlap syndrome SSc/RA and facilitate diagnosis and appropriate treatment.
18241229 Oestrogen exhibits type II collagen protective effects and attenuates collagen-induced art 2008 Apr As anti-inflammatory treatments used in rheumatoid arthritis, such as glucocorticoids, often result in secondary detrimental effects on bone health, the objective of this study was to investigate the effects of oestrogen therapy (ET) on the development and activity of collagen-induced arthritis (CIA) in rats, with a focus on assessment of chondroprotective effects using biomarkers of type II collagen degradation. Forty female Lewis rats were allocated into four intervention groups: (i) control + vehicle; (ii) CIA + vehicle; (iii) CIA + ET; and (iv) CIA + prednisolone. During the 28-day intervention period we monitored body weight, time-point of disease onset, incidence of manifest disease and paw volume. Levels of the type II collagen degradation marker (CTX-II) were measured in serum. At euthanasia, hind paws were isolated, extracted for proteins and measured for the concentration of CTX-II. Matrix metalloproteinase (MMP) activity was evaluated using gelatinase zymography. Oestrogen treatment delayed the time-point of disease onset and reduced the incidence and degree of manifest immunoarthritis significantly, assessed by macroscopic evaluation of hind paw inflammation and paw volume. Measures of serum or tissue levels of CTX-II showed significantly reduced type II collagen degradation elicited by oestrogen treatment. In alignment, a decreased activity of MMP-2 and MMP-9 was found in the paw protein extracts. We have demonstrated that the anti-inflammatory effect of ET is linked to chondroprotective effects in an animal model of systemic immunoarthritis. As ET has positive rather than negative effects on bone health in contrast to prednisolone, these observations may be important for potential combination therapy.
17117102 Prominent premalar and cheek swelling: a sign of thyroid-associated orbitopathy. 2006 Nov PURPOSE: To describe prominent premalar and cheek swelling as a previously undescribed clinical feature of thyroid-associated orbitopathy (TAO). DESIGN: Retrospective interventional case series. METHODS: A retrospective case review of patients with prominent premalar and/or cheek swelling and TAO was undertaken. All patients who presented from March 2002 to February 2005 with complaints of premalar and/or cheek swelling in TAO were analyzed. RESULTS: Six female patients between the ages of 28 and 66 years (average, 44.2 years) who had complaints of prominent premalar and/or cheek swelling and TAO were included in the study, among 326 new patients with TAO (incidence: 1.84%). Five of the 6 patients had Graves hyperthyroidism. One initially had Hashimoto thyroiditis, which converted to Graves hyperthyroidism. In all cases, TAO preceded the thyroid disease or developed simultaneously (average time from TAO to thyroid disease was 3.0 months). No patient had received corticosteroids before premalar and/or cheek swelling. The premalar and/or cheek swelling was bilateral in all cases, but 2 of 6 were asymmetric. No diurnal fluctuation or tenderness in premalar and/or cheek swelling was noted. All improved incompletely over several months. Brow, eyelid swelling, and orbital-fat hypertrophy on radiologic examination was coincidentally noted in 5 of 6 cases. Pretibial myxedema was noted in one case. One case was associated with another autoimmune disease (rheumatoid arthritis). CONCLUSIONS: Prominent premalar and cheek swelling should be considered among the clinical features of TAO. The true incidence will become apparent as we question and examine patients more carefully regarding this entity and as we review premorbid photographs.
17497607 [Septic arthritis of the wrist]. 2007 Apr BACKGROUND: Septic arthritis of the wrist is correlated with a high morbidity. To show diagnostic and therapeutic options we reviewed the patients treated with wrist infections at our institution for one year. METHODS: The data of ten patients who were treated for septic arthritis of the wrist in 2003 and 2004 were collected in a retrospective survey. Etiology, risk factors, microorganism and resistance data were recorded. RESULTS: Six infections were of an iatrogenic nature (four following surgery, one joint puncture and one joint injection). In nine cases there was a single arthritis of the wrist. One patient had oligoarthritis. In four cases Staphylococcus aureus, in one Proteus mirabilis and in one Pseudomonas aeroginosa were identified. In four cases, no microorganism could be identified. Two of the patients suffered from diabetes mellitus, one had rheumatoid arthritis. There was no significant elevation in the white blood cell count with 9.2 (4.5 - 12.5) x 10 (9)/L. Arthroscopic debridement and synovialectomy could be performed in one case. In the other cases open surgery was necessary. In four cases partial bone resection was required. Local antibiotics were installed in eight cases. All infections healed. In nine patients the joint was immobilized with an external fixation device. All patients received systemic antibiotics. Four wrists ended in an arthrodesis, one in a four-corner fusion. On average, two (1 - 6) surgical interventions were necessary per patient. The six patients without an arthrodesis had a range of motion in extension/flexion of 30-0-24 degrees. CONCLUSION: Surgical treatment is sufficient in septic arthritis of the wrist. However, an early diagnosis and therapeutic intervention are essential to avoid a permanent disability.
17254348 Gene therapy with an improved doxycycline-regulated plasmid encoding a tumour necrosis fac 2007 Inhibition of tumour necrosis factor (TNF)-alpha with biological molecules has proven an effective treatment for rheumatoid arthritis, achieving a 20% improvement in American College of Rheumatology score in up to 65% of patients. The main drawback to these and many other biological treatments has been their expense, which has precluded their widespread application. Biological molecules could alternatively be delivered by gene therapy as the encoding DNA. We have developed novel plasmid vectors termed pGTLMIK and pGTTMIK, from which luciferase and a dimeric TNF receptor II (dTNFR) are respectively expressed in a doxycycline (Dox)-regulated manner. Regulated expression of luciferase from the self-contained plasmid pGTLMIK was examined in vitro in a variety of cell lines and in vivo following intramuscular delivery with electroporation in DBA/1 mice. Dox-regulated expression of luciferase from pGTLMIK of approximately 1,000-fold was demonstrated in vitro, and efficient regulation was observed in vivo. The vector pGTTMIK encoding dTNFR was delivered by the same route with and without administration of Dox to mice with collagen-induced arthritis. When pGTTMIK was delivered after the onset of arthritis, progression of the disease in terms of both paw thickness and clinical score was inhibited when Dox was also administered. Vectors with similar regulation characteristics may be suitable for clinical application.
18204462 Dcir deficiency causes development of autoimmune diseases in mice due to excess expansion 2008 Feb The dendritic cell immunoreceptor (official gene symbol Clec4a2, called Dcir here) is a C-type lectin receptor expressed mainly in dendritic cells (DCs) that has a carbohydrate recognition domain in its extracellular portion and an immunoreceptor tyrosine-based inhibitory motif, which transduces negative signals into cells, in its cytoplasmic portion. We found high Dcir expression in the joints of two mouse rheumatoid arthritis models. Because the structural characteristics of Dcir suggest that it may have an immune regulatory role, and because autoimmune-related genes are mapped to the DCIR locus in humans, we generated Dcir-/- mice to learn more about the pathological roles of this molecule. We found that aged Dcir-/- mice spontaneously develop sialadenitis and enthesitis associated with elevated serum autoantibodies. Dcir-/- mice showed a markedly exacerbated response to collagen-induced arthritis. The DC population was expanded excessively in aged and type II collagen-immunized Dcir-/- mice. Upon treatment with granulocyte-macrophage colony-stimulating factor, Dcir-/- mouse-derived bone marrow cells (BMCs) differentiated into DCs more efficiently than did wild-type BMCs, owing to enhanced signal transducer and activator of transcription-5 phosphorylation. These observations indicate that Dcir is a negative regulator of DC expansion and has a crucial role in maintaining the homeostasis of the immune system.
17522095 The antioxidant vitamins A, C, E and selenium in the treatment of arthritis: a systematic 2007 Aug OBJECTIVE: To systematically review the evidence from randomized clinical trials (RCTs) for the effectiveness of the antioxidant vitamins A, C, E or selenium or their combination in the treatment of arthritis. METHODSL: A systematic search of computerized databases from inception to September 2006 for relevant RCTs, application of pre-defined inclusion/exclusion criteria and independent data extraction by two authors. Methodological quality was assessed using the Jadad scale. RESULTS: The searches identified 20 unique RCTs meeting the inclusion criteria: 11 in inflammatory arthritis and 9 in osteoarthritis (OA). The studies included are generally of poor quality. They fall into three main clusters: selenium for rheumatoid arthritis (n = 5); vitamin E for inflammatory arthritis (n = 5) and vitamin E for OA (n = 7). One RCT suggests superiority of vitamin E over placebo and three RCTs suggest equivalence between vitamin E and diclofenac in the treatment of inflammatory arthritis. In OA, four RCTs compared vitamin E with placebo. Two shorter-term studies were positive and two longer-term studies were negative. Two further RCTs suggest equivalence between vitamin E and diclofenac in the treatment of OA. Findings for selenium, vitamin A and a combination product in inflammatory arthritis and for vitamin A, and a combination product in OA were negative. An isolated positive result for vitamin C in OA is of doubtful clinical significance. CONCLUSIONS: Clinical trials testing the efficacy of vitamin E in the treatment of OA and inflammatory arthritis have been methodologically weak and have produced contradictory findings. There is presently no convincing evidence that selenium, vitamin A, vitamin C or the combination product selenium ACE is effective in the treatment of any type of arthritis.
17135447 TGF-beta type I receptor kinase inhibitor down-regulates rheumatoid synoviocytes and preve 2007 Feb Rheumatoid arthritis (RA) is characterized by hypertrophic synovial tissues comprising excessively proliferating synovial fibroblasts and infiltrating inflammatory cells. Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that regulates cell growth, inflammation and angiogenesis by acting on various cell types. In RA synovial tissues, TGF-beta is expressed at high levels. However, the precise role of TGF-beta in RA remains unclear. We herein demonstrated a causal link between the TGF-beta-induced RA synovial cell proliferation and induction of platelet-derived growth factor (PDGF)-AA. In addition, TGF-beta induced IL-6 and vascular endothelial growth factor (VEGF) production by RA synovial fibroblasts associated with nuclear factor-kappa B activation. These effects of TGF-beta on RA synovial fibroblasts were suppressed by TGF-beta type I receptor kinase inhibitor HTS466284. Furthermore, HTS466284 significantly prevented anti-collagen type II antibody-induced arthritis in mice according to the clinical manifestations, histology, tumor necrosis factor-alpha, PDGF and VEGF expression and 5-bromo-2'-deoxyuridine incorporation. These in vitro and in vivo results suggest that TGF-beta plays a role in the development of synovial hyperplasia consisting of synovial cell proliferation, inflammation and angiogenesis. The blockade of TGF-beta signaling may thus become an additional strategy for the treatment of RA.
17764057 Computed tomographic imaging in connective tissue diseases. 2007 Aug The connective tissue diseases are a group of autoimmune mediated disorders characterized by multiorgan damage. High-resolution computed tomography (HRCT) plays an important role in identifying patients with respiratory involvement. Although there is some overlap, typical HRCT appearances are increasingly recognized for each of the major connective tissue diseases and are described in detail in this review (rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjögren syndrome, polymyositis/dermatomyositis, mixed connective tissue disease). The clinical utility of HRCT is discussed with respect to the detection of disease, diagnosis, staging of disease severity, prognostic evaluation, and monitoring of disease progression. The difficult problem of establishing the clinical significance of CT abnormalities is also addressed.
17599735 Interferon-gamma protects against the development of structural damage in experimental art 2007 Jul OBJECTIVE: Local interaction between soluble mediators within the inflamed synovium is a key factor that governs the pathologic outcome of inflammatory arthritides. Our aim was to investigate the interplay between the Th1 lymphokine interferon-gamma (IFNgamma) and pivotal cytokines that drive rheumatoid arthritis (RA) pathology (interleukin-1beta [IL-1beta] and tumor necrosis factor alpha [TNFalpha]) in modulating inflammation and arthritis in vitro and in vivo. METHODS: Monarticular antigen-induced arthritis (AIA) was initiated in IFNgamma-deficient (IFNgamma(-/-)) mice and age-matched wild-type (IFNgamma(+/+)) mice. Joint swelling was measured and histologic analysis was performed in order to assess changes in both inflammatory and degenerative parameters in vivo. In vitro, the influence of IFNgamma in regulating IL-1beta- and TNFalpha-driven CXCL8 and CCL2 production was quantified by enzyme-linked immunosorbent assay. RESULTS: In murine AIA, both inflammatory and degenerative arthritis parameters were significantly exacerbated in the absence of IFNgamma. IFNgamma appeared to be a crucial factor in regulating CXCR2+ neutrophil influx in the joint. In in vitro studies using RA fibroblast-like synoviocytes, IFNgamma modulated both IL-1beta- and TNFalpha-driven chemokine synthesis, resulting in the down-regulation of CXCL8 production. CONCLUSION: IFNgamma exerts antiinflammatory, chondroprotective, and antiosteoclastogenic effects in murine AIA through a mechanism that involves the regulation of chemokine synthesis and local neutrophil recruitment. These studies suggest a potential therapeutic role of modulating IFNgamma signaling in the treatment of inflammatory arthritides.
21783751 Prevention of collagen-induced arthritis in mice by Cervus korean TEMMINCK var. mantchuric 2007 Mar The effect of water extract of deer antler (DAA) prepared from the pilose antler of Cervus korean TEMMINCK var. mantchuricus Swinhoe (Nokyong) on collagen-induced mouse rheumatoid arthritis (RA) model was studied. Identification of common DAA capable of affording protection or modulating the onset and severity of arthritis may have important human health implications. DAA has been shown to possess anti-inflammatory and anti-carcinogenic properties in experimental animals. In this study, we determined the effect of DAA-injection on collagen-induced arthritis in mice. In three independent experiments, mice given DAA in water exhibited significantly reduced incidence of arthritis (30-45%) as compared with mice not given DAA in water (86-98%). The arthritis index also was significantly lower in DAA-injected animals. Western blot analysis showed a marked reduction in the expression of inflammatory mediators such as cyclooxygenase 2, IFN-γ, and tumor necrosis factor α in arthritic joints of DAA-injected mice. The neutral endopeptidase activity was approximately six-fold higher in arthritic joints of non-DAA-injected mice in comparison to non-arthritic joints of unimmunized mice, whereas it was only two-fold higher in the arthritic joints of DAA-injected mice. Additionally, total IgG and type II collagen-specific IgG levels were lower in serum and arthritic joints of DAA-injected mice. Taken together our studies suggest that DAA may be useful in the prevention of onset and severity of arthritis.
16855156 Circadian rhythms: glucocorticoids and arthritis. 2006 Jun Circadian rhythms are driven by biological clocks and are endogenous in origin. Therefore, circadian changes in the metabolism or secretion of endogenous glucocorticoids are certainly responsible in part for the time-dependent changes observed in the inflammatory response and arthritis. More recently, melatonin (MLT), another circadian hormone that is the secretory product of the pineal gland, has been found implicated in the time-dependent inflammatory reaction with effects opposite those of cortisol. Interestingly, cortisol and MLT show an opposite response to the light. The light conditions in the early morning have a strong impact on the morning cortisol peak, whereas MLT is synthesized in a strictly nocturnal pattern. Recently, a diurnal rhythmicity in healthy humans between cellular (Th1 type) or humoral (Th2 type) immune responses has been found and related to immunomodulatory actions of cortisol and MLT. The interferon (IFN)-gamma/interleukin (IL)-10 ratio peaked during the early morning and correlated negatively with plasma cortisol and positively with plasma MLT. Accordingly, the intensity of the arthritic pain varies consistently as a function of the hour of the day: pain is greater after waking up in the morning than in the afternoon or evening. The reduced cortisol and adrenal androgen secretion, observed during testing in rheumatoid arthritis (RA) patients not treated with glucocoticoids, should be clearly considered as a "relative adrenal insufficiency" in the presence of a sustained inflammatory process, and allows Th1 type cytokines to be produced in higher amounts during the late night. In conclusion, the right timing (early morning) for the glucocorticoid therapy in arthritis is fundamental and well justified by the circadian rhythms of the inflammatory mechanisms.
17514770 Inflammation-inducible anti-TNF gene expression mediated by intra-articular injection of s 2007 Jul BACKGROUND: The tumor necrosis factor (TNF)-alpha plays a central role in rheumatoid arthritis (RA) and current biotherapies targeting TNF-alpha have a major impact on RA treatment. The long-term safety concerns associated with the repetitive TNF blockade prompt optimization of therapeutic anti-TNF approaches. Since we recently demonstrated that intra-articular gene transfer using a recombinant adeno-associated virus serotype 5 (rAAV5) efficiently transduces arthritic joints, we evaluate its effect on collagen-induced arthritis (CIA) when encoding TNF antagonists. METHODS: Recombinant AAV5 vectors encoding the human TNFRp55 extracellular domain fused to the Fc region of mice IgG1 (TR1) or a small molecular weight dimeric human TNFRp75 extracellular domain (TR2), under two different promoters, the CMV or a chimeric NF-kappaB-based promoter inducible by inflammation, were injected into mouse CIA joints. RESULTS: Best protection against arthritis was obtained with the rAAV5 encoding the TR1, as reflected by delayed disease onset, decreased incidence and severity of joint damage. This effect was associated with a transient expression of the anti-TNF agent when expressed under a NF-kappaB-responsive promoter, only detectable during disease flare, while the antagonist expression was rapidly increased and stable when expressed from a CMV promoter. Importantly, using the intra-articular administration of the rAAV5-NF-kappaB-TR1 vector, we observed a striking correlation between local TR1 expression and inflammation. CONCLUSIONS: These findings strongly support the feasibility of improving the safety of anti-TNF approaches for the treatment of arthritis by local rAAV5-mediated gene expression under an inflammation-responsive promoter, able to provide a limited, transient and therapeutically relevant expression of anti-TNF compounds.
18576344 Cartilage oligomeric matrix protein induction of chronic arthritis in mice. 2008 Jul OBJECTIVE: To develop a new mouse model for arthritis using cartilage oligomeric matrix protein (COMP) and to study the role of major histocompatibility complex (MHC) and Ncf1 genes in COMP-induced arthritis (COMPIA). METHODS: Native (pentameric) and denatured (monomeric) COMP purified from a rat chondrosarcoma was injected into mice with Freund's adjuvant to induce arthritis. C3H.NB, C3H.Q, B10.P, B10.Q, (B10.Q x DBA/1)F1, (BALB/c x B10.Q)F1, Ncf1 mutated, H-2Aq, H-2Ap, and human DR4+-transgenic mice were used. Anti-COMP antibodies and COMP levels in the immune sera were analyzed, and passive transfer of arthritis with purified immune sera was tested. RESULTS: Immunization with rat COMP induced a severe, chronic, relapsing arthritis, with a female preponderance, in the mice. The disease developed in C3H.NB mice, but not in B10.P mice, although they share the same MHC haplotype. Both H-2q and H-2p MHC haplotypes allowed the initiation of COMPIA. Using H-2Aq-transgenic and H-2Ap-transgenic mice, we demonstrated a role of both the Aq and Ep class II molecules in this model. Interestingly, the introduction of a mutation in the Ncf1 gene, which is responsible for the reduced oxidative burst phenotype, into the COMPIA-resistant B10.Q mouse strain rendered them highly susceptible to arthritis. In addition, the transfer of anti-COMP serum was found to induce arthritis in naive mice. Mice transgenic for the rheumatoid arthritis (RA)-associated DR4 molecule were found to be highly susceptible to COMPIA. CONCLUSION: Using rat COMP, we have developed a new and unique mouse model of chronic arthritis that resembles RA. This model will be useful as an appropriate and alternative model for studying the pathogenesis of RA.
17475983 Twenty years of recombinant human growth hormone in children: relevance to pediatric care 2007 May Recombinant human growth hormone has revolutionized the management of children and adolescents with growth hormone deficiency and other growth disorders, but clinical and ethical controversies remain regarding diagnostic approach, optimal recombinant human growth hormone dose and duration, and expected outcomes. Management of pubertal and transitioning patients with growth hormone deficiency has also commanded increased attention. Recent clinical studies that demonstrate the positive health benefits of recombinant human growth hormone in children with cystic fibrosis, inflammatory bowel disease, and juvenile rheumatoid arthritis have not yet clarified issues about patient selection and appropriate long-term use. An understanding of current recombinant human growth hormone indications and controversies can facilitate patient evaluation and expedite referral for potential treatment. This review summarizes current indications for recombinant human growth hormone use, discusses clinical challenges, and provides recommendations for pediatricians caring for children who may be appropriate candidates for recombinant human growth hormone therapy.
16601456 Echocardiographic measures of diastolic function in pediatric heart disease. 2006 May PURPOSE OF REVIEW: The past year has seen a continued evolution in the echocardiographic assessment of diastolic function in children. This paper reviews published studies from the past year that have helped characterize diastolic function using echocardiography in children. RECENT FINDINGS: Characterization of diastolic function using Doppler and Doppler tissue imaging in the normal infant and child was a primary focus of pediatric echocardiographic investigation. These technologies appear to hold significant promise as tools to improve understanding of diastolic function in the normal child as the heart matures. Diastolic function in children with congenital heart disease has also been better characterized using these tools, specifically in patients with atrial septal defects, tetralogy of Fallot, single ventricle physiology, and following cardiac transplantation. Finally, diastolic function in acquired heart disease or with systemic disease in the child has been evaluated using echocardiography, with recent reports describing findings in children with dilated cardiomyopathy, chronic renal disease, obesity, type I diabetes, juvenile rheumatoid arthritis, obstructive sleep apnea, and after anthracycline exposure for childhood cancer. SUMMARY: Pediatric echocardiography has clearly become the primary tool for describing and characterizing diastolic function in infants and children both with and without heart disease. It is becoming an important noninvasive diastolic monitoring tool that allows serial assessment of pathologic diastolic disease in both primary myocardial and systemic disease states.