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ID PMID Title PublicationDate abstract
20177421 In silico and in vitro pharmacogenetics: aldehyde oxidase rapidly metabolizes a p38 kinase 2011 Feb The clinical development of a candidate p38 kinase inhibitor was terminated because of its unexpectedly rapid clearance in human subjects. Its short half-life and metabolic profile in human beings were vastly different from that in rats, dogs, and monkeys characterized during routine pre-clinical studies. Mice generated the predominant drug (4-hydroxylated) metabolite produced in human beings, which was not found in other species. The data from a murine in vitro drug biotransformation assay that used liver extracts from 14 inbred mouse strains were analyzed by haplotype-based computational genetic analysis. This led to the identification of aldehyde oxidase-1 (AOX1) as the enzyme responsible for the rapid metabolism of this drug. Specific enzyme inhibitors and expressed recombinant enzymes were used to confirm that AOX catalyzed the formation of the 4-hydroxylated drug metabolite in mouse and man. Genetic variation within Aox1 regulated the level of hepatic Aox1 mRNA, AOX1 protein, and enzyme activity among the inbred strains. Thus, computational murine pharmacogenetic analysis can facilitate the identification and characterization of drug metabolism pathways that are differentially utilized by humans and other species.
20492549 Risk-managed production of bioactive recombinant proteins using a novel plant virus vector 2011 Jan A plant viral vector has the potential to efficiently produce recombinant proteins at a low cost in a short period. Although recombinant proteins can be also produced by transgenic plants, a plant viral vector, if available, may be more convenient when urgent scale-up in production is needed. However, it is difficult to use a viral vector in open fields because of the risk of escape to the environment. In this study, we constructed a novel viral vector system using a movement-defective Cucumber mosaic virus (CMV) vector, which is theoretically localized in the inoculated cells but infects systemically only with the aid of the transgenic helper plant that complements viral movement, diminishing the risk of viral proliferation. Interestingly, the helper plant systemically infected with the vector gave strong cross-protection against challenge inoculation with wild-type CMVs. Using CMV strains belonging to two discrete CMV groups (subgroups I and II), we also improved the system to prevent recombination between the vector and the transgene transcript in the helper plant. We here demonstrate the expression of an anti-dioxin single chain variable fragment (DxscFv) and interleukin-1 receptor antagonist (IL1-Ra) in Nicotiana benthamiana by this viral vector confinement system, which is applicable for many useful high-quality recombinant proteins.
22492023 A series of patients on anti-TNF therapy referred to a multidisciplinary lung cancer servi 2013 Mar BACKGROUND: Biological therapies have significantly improved the quality of life of patients with aggressive collagen vascular diseases. Blocking TNF activity may potentially confer a higher malignant potential for patients. AIMS: To identify patients to whom anti-TNF therapies were recently prescribed and were referred to a multidisciplinary lung cancer service. METHODS: Retrospective review of patients over an 18-month period who were referred to a multidisciplinary lung cancer service. RESULTS: Three patients who underwent recent anti-TNF therapies and presented with solid organ tumours. All had significant additional risks for cancer including smoking and family history and active connective tissue diseases with a past history of immunosuppressive therapies. CONCLUSIONS: Our series highlights the potential malignant risk of anti-TNF theraphy to a general medical audience.
21111629 Lymphotoxin α stimulates proliferation and pro-inflammatory cytokine secretion of rheumat 2011 Feb OBJECTIVE: TNFα plays a crucial role in rheumatoid arthritis (RA) by stimulating fibroblast-like synoviocytes (FLS). Lymphotoxin α (LTα) is a pro-inflammatory cytokine with significant homology to TNFα. We compared the effects of both cytokines on cultured RA FLS. METHODS: Receptor expression on RA FLS was analyzed by FACS. Cells were stimulated with LTα or TNFα and proliferation was measured by [3H]thymidine incorporation and secretion of inflammatory cytokines and metalloproteinase 3 by ELISA. Activation of MAP kinases and Akt was analyzed by Western blotting. Nuclear translocation of NFκB was visualized by immunofluorescence. RESULTS: 60-80% and 30-50% of the RA FLS tested expressed TNF receptors I and II, respectively, and 70-75% expressed HVEM. LTα induced RA FLS proliferation at the same level of TNFα, which was blocked by etanercept. Both LTα and TNFα induced activation of MAP kinases ERK1/2 and p38 as well as Akt. 95-98% of FLS showed nuclear translocation of NFκB after stimulation with either cytokines. LTα and TNFα were potent to induce secretion of IL-6, IL-8 and metalloproteinase 3 in FLS. CONCLUSION: LTα is as effective as TNFα in stimulating RA FLS. Blocking both cytokines might allow a better control of inflammation and synovial proliferation in RA.
22641591 Association of HLA-DRB5*01 with protection against cutaneous manifestations of rheumatoid 2012 May OBJECTIVE: To evaluate the frequency of HLA classes I and II and their association with the cutaneous manifestation of rheumatoid vasculitis (RV) in Brazilian patients. PATIENTS AND METHODS: During one year we selected 130 patients with rheumatoid arthritis (RA) classified according to the American College of Rheumatology, 1987. All patients underwent a clinical and laboratory questionnaire to exclude other causes of cutaneous vasculopathy (neoplasia, infections, illicit drug use, diabetes mellitus, and tobaccoism). Seventy-three patients with any risk factor for other causes of vasculopathy were excluded. Fifty-seven without risk factors for other causes of vasculopathy were included in the study, 17 with RV according to Scott and Bacon's criteria, 1984. Demographic data, time of RA diagnosis, disease activity (DAS28), presence of rheumatoid factor, and anti-cyclic citrullinated peptide antibodies were analyzed. The HLA alleles were typed using the DNA-amplified polymerase chain reaction with low-resolution hybridization and sequence-specific primers. RESULTS: The comparison between the 40 patients without RV and the 17 patients with RV showed an increased frequency of HLA-B*14 (Pc = 0.168) and HLA-Cw*08 (Pc = 0.084) in patients with RV and an increased frequency of HLA-DRB5*01 (Pc = 0.048) in patients without RV. CONCLUSION: The HLA-DRB5*01 may confer protection against that extra-articular manifestation of RA.
21506984 TNF alpha antagonist-induced lupus-like syndrome: report and review of the literature with 2011 May BACKGROUND:   In patients with various autoimmune and rheumatic diseases, a drug-induced lupus-like syndrome (DILS) has been reported with the use of adalimumab, cerrolizumab pegol, etanercept, and infliximab. OBJECTIVE:   To review clinical characteristics of patients who develop tumor necrosis factor (TNF) alpha antagonist-induced lupus-like syndrome (TAILS) and review implications for further TNF alpha antagonist therapy. MATERIALS AND METHODS:  We describe a 62-year-old woman with rheumatoid arthritis who developed a pruritic photo-distributed rash two months after the initiation of etanercept therapy. Her skin biopsy showed lupus erythematosus, and she had positive serum ANA, anti-Sjogren's syndrome A (SSA)/Ro, and anti-Sjogren's syndrome B (SSB)/La antibodies. Her symptoms resolved after discontinuation of the drug, topical and systemic corticosteroids, and hydroxychloroquine sulfate. Subsequently, her rheumatoid arthritis was treated with golimumab for six months without recurrence of skin lesions. Published reports of individuals who have developed TAILS and those who have continued treatment with alternative TNF alpha antagonists are reviewed. RESULTS:   TAILS is most commonly associated with the use of etanercept and infliximab. It occurs most often in women in the fifth decade of life. Onset of symptoms ranges from less than one month to more than four years. Syndrome-associated cutaneous lesions and induction of autoantibodies are common. There is no definitively established mechanism of pathogenesis. Treatment can include discontinuation of the drug, corticosteroids, immunosuppressives, and hydroxychloroquine sulfate. To date, 10 patients with TAILS have continued therapy with an alternative TNF alpha antagonist without recurrence of lupus symptoms. CONCLUSIONS: Development of a DILS after one TNF alpha antagonist does not preclude continued treatment with an alternative TNF alpha antagonist.
22090298 [Investigation of Epstein-Barr virus and herpes simplex virus markers by serological and m 2011 Oct Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) which are autoimmune diseases usually questioned for their association with many infectious agents have etiopathogenesis related to genetic, immunologic, hormonal and even environmental factors. The most commonly attributed etiologic agents are herpes group viruses. The aim of this study was to investigate the role of Epstein-Barr virus (EBV) and herpes simplex (HSV) viruses in the etiology of RA and SLE. A total of 137 patients (87 RA and 50 SLE; mean age: 33 ± 12 years) who were admitted to Eskisehir Osmangazi University Medical Faculty Rheumatology Department between January 2007-January 2008 and diagnosed according to 1987 ACR (American College of Rheumatology) criteria have been included in the study, together with 50 healthy blood donors (mean age: 35 ± 14 years) as control group. Serum samples obtained from all of the cases were tested for EBV VCA-IgG, VCA-IgM, EA/D-IgG and EBNA-IgG (Trinity Biotech, USA); IgM and IgG antibodies against HSV-1 and HSV-2 by ELISA method (Dia-Pro Diagnostic, Italy), and the presence of viral nucleic acids in blood samples were investigated by real-time quantitative polymerase chain reaction (RTPCR; Qiagen, USA). EBV VCA-IgM was negative in all of the RA, SLE and control group patients. VCA-IgG positivity were 98% and 96%, and for EBNA-IgG 98.5% and 100%, in patient and control groups, respectively. There was no statistically significant difference between the groups regarding VCA-IgG and EBNA- IgG positivity (p> 0.05). On the other hand, EBV EA/D-IgG positivity rate found in the SLE group (34%) was significantly higher than RA (7%) and control (12%) groups (p< 0.001 and p< 0.05, respectively). There was no significant difference between RA and control groups in terms of EA/D-IgG positivity (p> 0.05). Regarding herpes simplex virus serology, HSV1-IgG seropositivity were 99% and 94% and HSV2-IgG positivity were 8% and 12% in the patient and control groups, respectively. There was no statistically significant difference between the groups according to the positivity rates of IgM and IgG specific for HSV-1 and HSV-2 (p> 0.05). All of the cases were found negative in terms of EBV, HSV-1 and HSV- 2 DNAs according to double-checked RT-PCR results. In conclusion, no significant difference was determined for EBV and HSV serologic markers in RA and SLE patients compared to the control group. However, significantly higher rate of EBV EA/D-IgG positivity in SLE patients might have indicated a possible association between SLE and EBV infection. Larger scale, prospective studies including examination of the synovial fluid/tissue samples are required to enlighten the association between SLE and EBV.
23019102 Genetic and expression analysis of SNPs in the human deoxyribonuclease II: SNPs in the pro 2012 Sep Five SNPs in the human DNase II gene have been reported to be associated with rheumatoid arthritis (RA). Genotype and haplotype analysis of 14 SNPs, nine SNPs of which reported in the NCBI dbSNP database in addition to these five SNPs, was performed in healthy subjects. The enzymatic activities of the amino acid substituted DNase II corresponding to each SNP and serum DNase II in healthy Japanese, and promoter activities derived from each haplotype of the RA-related SNPs were measured. Significant correlations between genotype in each RA-related SNP and enzymatic activity levels were found; alleles associated with RA exhibited a reduction in serum DNase II activity. Furthermore, the promoter activities of each reporter construct corresponding to predominant haplotypes in three SNPs in the promoter region of the gene exhibited significant correlation with levels of serum DNase II activity. These findings indicate these three SNPs could alter the promoter activity of DNASE2, leading to a decline in DNase II activity in the serum through gene expression. Since the three SNPs in the promoter region of the DNase II gene could affect in vivo DNase II activity through reduction of the promoter activity, it is feasible to identify these SNPs susceptible to RA.
21262368 Osteoarthritis-like damage of cartilage in the temporomandibular joints in mice with autoi 2011 Apr OBJECTIVE: To study temporomandibular joint (TMJ) involvement in an autoimmune murine model of rheumatoid arthritis (RA), a disease characterized by inflammatory destruction of the synovial joints. Although TMJ dysfunction is frequently found in RA, TMJ involvement in RA remains unclear, and TMJ pathology has not been studied in systemic autoimmune animal models of RA. METHODS: Proteoglycan (PG) aggrecan-induced arthritis (PGIA) was generated in genetically susceptible BALB/c mice. TMJs and joint tissues/cartilage were harvested for histological and immunohistochemical analyses and RNA isolation for quantitative polymerase chain-reaction. Serum cytokine levels were measured in mice with acute or chronic arthritis, and in non-arthritic control animals. RESULTS: Despite the development of destructive synovitis in the limbs, little or no synovial inflammation was found in the TMJs of mice with PGIA. However, the TMJs of arthritic mice showed evidence of aggrecanase- and matrix metalloproteinase-mediated loss of glycosaminoglycan-containing aggrecan, and in the most severe cases, structural damage of cartilage. Serum levels of pro-inflammatory cytokines, including interleukin (IL)-1β, were elevated in arthritic animals. Expression of the IL-1β gene was also high in the inflamed limbs, but essentially normal in the TMJs. Local expression of genes encoding matrix-degrading enzymes (aggrecanases and stromelysin) was upregulated to a similar degree in both the limbs and the TMJs. CONCLUSION: We propose that constantly elevated levels of catabolic cytokines, such as IL-1β, in the circulation (released from inflamed joints) create a pro-inflammatory milieu within the TMJ, causing local upregulation of proteolytic enzymes and subsequent loss of aggrecan from cartilage.
21640054 Clinical presentation and salivary gland histopathology of paediatric primary Sjögren's s 2011 May OBJECTIVES: Explore the presentation, diagnostic criteria and exocrine gland histopathology of paediatric primary Sjögren's syndrome (PPSjS). METHODS: A case series of 8 children is reported and American-European Consensus Group (AECG-2002) criteria were examined, as well as minor labial salivary and lachrymal gland biopsies, which were scored by a pathologist blinded to outcome. For all cases, connective tissue diseases and parotid-related infectious disease were excluded. RESULTS: Age at onset varied from 5-13 years old; 6 were females, all followed from diagnosis up to the last visit (1-10 years). The main features at presentation were recurrent tender parotid swelling and sialectasis imaging, with decreased salivary function assessed by Tc-99 scintigraphy. Mild sicca symptoms were observed in 4/8 cases. Systemic features, including fatigue, myalgia, arthritis, tenosynovitis, joint contractures, transient Raynaud's and high ESR, were recorded at onset. Autoantibody profile was unremarkable for diagnosis, while lymphocytic infiltration of labial salivary glands and sialectasis were observed in all biopsies (8/8). In lachrymal glands, massive lymphocytic infiltration and lymphocytic gastritis were observed during complementary assessment. Flares were treated with low dose steroids and long-term use of hydroxychloroquine (5/8), although only 3/8 fulfilled AECG-2002 diagnostic criteria, throughout the disease course. CONCLUSIONS: PPSjS is rare, slowly progressive and its early presentation is variable. Standardised diagnostic algorithms should include recurrent parotid swelling and early diagnosis should rely mostly on salivary and lachrymal gland histopathology in this age group.
22391030 Glutamate-based depression GBD. 2012 May We describe a new term: glutamate-based depression (GBD). GBD is defined as a chronic depressive illness associated with environmental stress and diseases associated with altered glutamate neurotransmission. We hypothesize that glutamate-induced over-activation of extrasynaptic NMDA receptors in the subgenual cingulate area called Brodmann's 25 plays an important role in the etiology of depression and may be responsible for the high incidence of co-morbid depression associated in diseases with glutamate etiology. While depression is a syndrome with multiple possible etiologies, we propose that a disruption in glutamatergic neurotransmission may underline a substantial proportion of clinically observed depression. The high rates of depressive symptoms associated with various disorders in which altered glutamatergic functions have been identified, may suggest a common pathophysiological mechanism is underlying the diverse clinical presentations.
21335610 Toll-like receptor 4 signalling is specifically TGF-beta-activated kinase 1 independent in 2011 Jul OBJECTIVE: Activated synovial fibroblasts are key players in the pathogenesis of RA by driving inflammation and joint destruction. Numerous molecules including cytokines and Toll-like receptor (TLR) ligands induce pro-inflammatory signalling and gene expression through a hierarchical network of kinases. Upstream mitogen-activated protein kinase kinase kinases (MAP3Ks) represent an attractive target for RA treatment. In this study, we sought to determine the role of the MAP3K TGF-β-activated kinase 1 (TAK1) in cytokine and TLR-mediated signalling. METHODS: TAK1 activity was inhibited using either a small molecule inhibitor or lentivirally overexpressed kinase-inactive TAK1-K63W mutant in murine embryonic and human dermal and synovial fibroblasts. Fibroblasts were stimulated with IL-1, TNF, TLR2 or TLR4 agonists and responses were evaluated using transcriptional reporters, western blotting and analysis of gene expression of collagenases (MMP3 and MMP13), cytokines (IL-1β and IL-6) and chemokines (IL-8 and MCP-1). RESULTS: TAK1 inhibition abrogated cytokine- and TLR-induced nuclear factor-κB (NF-κB) and Saa3-promoter reporter activation in murine and human dermal fibroblasts. In synovial fibroblasts, TAK1 regulated IL-1 and TNF-mediated NF-κB, but not Saa3-promoter reporter activation. Inducible mRNA expression of cytokines, collagenases and chemokines, except MCP-1, was TAK1 dependent for IL-1, TNF and TLR2 signalling. Unexpectedly, TLR4-mediated NF-κB reporter activation and inducible mRNA expression was fully TAK1 independent. Accordingly, NF-κB p65 and p38 MAPK phosphorylation was unaffected by TAK1 inhibition. CONCLUSION: In general, TAK1 crucially regulates IL-1 and TNF signalling in fibroblasts. Interestingly, TLR4 signalling is specifically TAK1 independent in synovial fibroblasts. Consequently, therapeutic TAK1 inhibition in arthropathies may not dampen the damage-associated molecular pattern-mediated TLR4 activation of synovial fibroblasts.
21291650 Dermatologic manifestations of Sjögren syndrome. 2011 Jan Sjögren syndrome (SS) is a chronic autoimmune inflammatory disease that involves primarily the exocrine glands, resulting in their functional impairment. SS typically presents as dry eyes (xerophthalmia) and dry mouth (xerostomia). This process can manifest either as the independent phenomenon of primary SS or as secondary SS when found in the context of another autoimmune process, most commonly rheumatoid arthritis or systemic lupus erythematosus. Nearly half of the patients with SS develop cutaneous manifestations, which may include dry skin (xeroderma), palpable and nonpalpable purpura, and/or urticaria-like lesions. These cutaneous manifestations have been underemphasized because they are often overshadowed by the more prominent sicca symptoms. However, certain skin findings are of paramount clinical and prognostic importance as they confer an increased risk for the development of life-threatening conditions, including multisystem vasculitis and non-Hodgkin lymphoma.OBJECTIVE AND CONCLUSIONS:In this review, the cutaneous manifestations of primary SS are discussed, with an emphasis on those findings that portend an increased risk of mortality.
21337319 RNA sensors in human osteoarthritis and rheumatoid arthritis synovial fibroblasts: immune 2011 Jun OBJECTIVE: The aim of this study was to analyze both the constitutive and induced expression and function of double-stranded RNA (dsRNA; Toll-like receptor 3 [TLR-3], retinoic acid-inducible gene I [RIG-I], and melanoma differentiation-associated gene 5 [MDA5]) and single-stranded RNA (ssRNA; TLR-7) receptors in osteoarthritis (OA) and rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS), by studying the transcription factors involved and the subsequent effects on antiviral interferon-β (IFNβ), the proinflammatory CXCL8 chemokine, and matrix metalloproteinase 3 (MMP-3). An additional goal was to study the effect of vasoactive intestinal peptide (VIP). METHODS: The expression of TLR-3, TLR-7, RIG-I, and MDA5 in cultured FLS was studied by reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and Western blotting. Transcription factors were studied using the ELISA-based TransAM transcription factor kit. The expression of IFNβ, CXCL8 (interleukin-8), and MMP-3 was analyzed by RT-PCR and ELISA. RESULTS: FLS expressed TLR-3, TLR-7, RIG-I, and MDA5. The expression of TLR-3 and RIG-I was higher in RA FLS, while the expression of TLR-7 and MDA5 was higher in OA FLS. Stimulation with poly(I-C) induced the activation of IFN regulatory factor 3 (IRF-3), NF-κB, and activator protein 1 (AP-1) c-Jun as well as the subsequent production of IFNβ, CXCL8, and MMP-3. VIP reduced the activation of IRF-3 and the production of IFNβ in both OA and RA FLS. Imiquimod induced the activation of NF-κB, AP-1 c-Fos, and AP-1 c-Jun and the synthesis of CXCL8 and MMP-3. VIP significantly diminished MMP-3 production only in imiquimod-treated RA FLS. CONCLUSION: The results of this study revealed a prominent function of FLS in the recognition of both dsRNA and ssRNA, which may be present in the joint microenvironment. This study also advances the healing function of the endogenous neuroimmune peptide VIP, which inhibited TLR-3-, RIG-I-, MDA5-, and TLR-7-mediated stimulation of antiviral, proinflammatory, and joint destruction mediators.
21346002 Metabolism of the c-Fos/activator protein-1 inhibitor T-5224 by multiple human UDP-glucuro 2011 May We developed 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl} propionic acid (T-5224) as a novel inhibitor of the c-Fos/activator protein-1 for rheumatoid arthritis therapy. We predicted the metabolism of T-5224 in humans by using human liver microsomes (HLM), human intestinal microsomes (HIM), recombinant human cytochrome P450 (P450), and UDP-glucuronosyltransferases (UGTs). T-5224 was converted to its acyl O-glucuronide (G2) by UGT1A1 and UGT1A3 and to its hydroxyl O-glucuronide (G3) by several UGTs, but it was not metabolized by the P450s. A comparison of the intrinsic clearances (CL(int)) between HLM and HIM suggested that the glucuronidation of T-5224 occurs predominantly in the liver. UGT1A1 showed a higher k(cat)/K(m) value than UGT1A3 for G2 formation, but a lower k(cat)/K(m) value than UGT1A3 for G3 formation. A high correlation was observed between G2 formation activity and UGT1A1-specific activity (β-estradiol 3-glucuronidation) in seven individual HLM. A high correlation was also observed between G2 formation activity and UGT1A1 content in the HLM. These results strongly suggest that UGT1A1 is responsible for G2 formation in human liver. In contrast, no such correlation was observed with G3 formation, suggesting that multiple UGT isoforms, including UGT1A1 and UGT1A3, are involved in G3 formation. G2 is also observed in rat and monkey liver microsomes as a major metabolite of T-5224, suggesting that G2 is not a human-specific metabolite. In this study, we obtained useful information on the metabolism of T-5224 for its clinical use.
22734277 Cement spacer as definitive management for postoperative ankle infection. 2012 Mar BACKGROUND: Postoperative infection can be a devastating complication of ankle replacement and arthrodesis surgery. Management consists of eradication of the infection and either, revision of the initial surgery or some form of salvage procedure. There are instances however when the patient is asymptomatic, medically unfit, or the local tissue is too tenuous to warrant performing additional surgery. We conducted a retrospective review of the outcome of the use of an antibiotic impregnated cement spacer as the definitive procedure in this kind of patient. METHODS: There were nine patients with post operative deep ankle infection following surgery who did not undergo subsequent revision surgery. The initial surgeries were either total ankle replacement (TAR) (n = 6) or ankle arthrodesis (n = 3). The indications for the retention of the cement spacer were patients who were asymptomatic following insertion of the cement spacer, did not desire further surgery, or were medically unfit for further surgery. The patients all underwent removal of hardware or implants, debridement, and insertion of an antibiotic impregnated cement spacer. Six weeks of intravenous antibiotics were administered according to culture sensitivity results. Patients were followed up closely for complications (wound dehiscence, spacer migration, bone loss), resolution of infection, functionality, and satisfaction. RESULTS: The average time of cement spacer retention was 20.1 months, ranging from 6 to 62 months. The most common infecting organisms were Staph. Aureus (n = 3) and Staph. Epidermidis (n = 3). One patient had wound complications, possibly due to the proximity of the cement spacer to the anterior skin surface. One patient had a repeat infection at 52 months. The most common co-morbidities were rheumatoid arthritis (n = 3) and diabetes (n = 2). At final followup, seven patients still had a retained cement spacer and two had subsequent below knee amputations (BKA) performed as a result of delayed complications. Review of the X-rays revealed two patients with loosening and migration of the cement spacer. No patients had signs of excessive bone loss. All patients with a retained antibiotic cement spacer were mobile and able to perform basic activities of daily living with minimal discomfort. CONCLUSION: The long-term use of antibiotic impregnated cement spacers following postoperative ankle infection is a reasonable option in the low demand patient with surgical or medical co-morbidities.
21539877 Post-thymic regulation of CD5 levels in human memory T cells is inversely associated with 2011 Aug Immunologic memory is a critical feature of the adaptive immune system to fight recurrent infections. However, the mechanisms that shape the composition and function of the human memory T-cell pool remain incompletely understood. We here demonstrate that post-thymic human T-cell differentiation was associated with the downregulation, but not loss, of the inhibitory molecule CD5. The sensitivity of human CD8(+) and CD4(+) memory T cells to interleukin (IL)-15 was inversely associated with the level of CD5 expression. CD5 expression was downregulated by IL-15-mediated signaling in vitro and CD5(lo) memory T cells accumulated in the bone marrow. Persistent antigenic stimulation, as in the case of cytomegalovirus infection and rheumatoid arthritis (RA), was also associated with an increased number of CD5(lo) memory T cells. In conclusion, CD5 may be a useful marker to identify memory T-cell subsets with distinct responsiveness to the homeostatic cytokine IL-15.
22339472 Discovery of the macrocycle (9E)-15-(2-(pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-tr 2012 Mar 22 Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly soluble 14l was selected as the optimal compound. Oral efficacy in the murine collagen-induced arthritis (CIA) model for rheumatoid arthritis (RA) supported 14l as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compound 14l (SB1578) was progressed into development and is currently undergoing phase 1 clinical trials in healthy volunteers.
22562976 TLR9 agonist CpG enhances protective nasal HSP60 peptide vaccine efficacy in experimental 2012 Oct OBJECTIVES: Peptide-based immune tolerance induction is considered an attractive treatment option for autoimmune diseases. The authors have developed a novel method that can enhance the induction of protective peptide-specific T-cell responses, using a rat arthritis model. The authors focused on the Toll-like receptor 9 ligand CpG, which was shown to stimulate regulatory T-cell proliferation when added to plasmacytoid dendritic cells (pDC) using in-vitro cultures. METHODS: The peptide used is a heat shock protein 60 epitope (p1) that elicits tolerogenic peptide-specific immune responses in human arthritis patients and was recently shown to have protective capacity as a bystander antigen in the rat adjuvant arthritis model. Rats were treated with three nasal doses of p1, CpG or a combination of p1 and CpG. Antigen-presenting cells were studied in nose-draining lymph nodes (mandibular lymph nodes; MLN) after nasal treatment, and T-cell responses were analysed in joint-draining lymph nodes after arthritis induction. RESULTS: Nasal co-administration of p1/CpG significantly augmented the arthritis-protective effect of p1, while CpG treatment alone did not. Co-treatment of p1/CpG increased both the number and activation status of pDC in draining MLN, which was accompanied by amplified p1-specific T-cell proliferation and interleukin (IL)-10 production. During early arthritis, p1-specific IL-10 production was identified at the site of inflammation. P1 and p1/CpG-treated rats showed a greater amount of CD4+FoxP3+ regulatory T cells in the joint-draining lymph nodes, which correlated with lower arthritis scores. CONCLUSIONS: These clinical and immunological data suggest the use of CpG as a potent adjuvant for mucosal peptide-specific immune therapy in arthritis.
22440999 Sensorineural hearing loss--a common finding in early-onset type 2 diabetes mellitus. 2012 Jul OBJECTIVE: To evaluate the prevalence and potential associations of hearing impairment in patients 30 to 50 years old with diabetes diagnosed before age 40 years-early-onset type 2 diabetes mellitus (T2DM). METHODS: The study cohorts consisted of 46 consecutive patients with early-onset T2DM and 47 age-matched control subjects with rheumatoid arthritis. All study subjects completed clinical, serologic, and auditory assessments. RESULTS: The patients with T2DM had a mean age of 42 ± 6 years and a mean disease duration of 11 ± 6 years. Microalbuminuria was present in 26.1%, proliferative retinopathy in 26.1%, and symptomatic peripheral neuropathy in 23.9%. The prevalence of unilateral or bilateral hearing loss was significantly higher in the patients with T2DM than in the patients with rheumatoid arthritis (21.7% versus 6.4%, respectively; P = .01). Most cases of hearing loss were mild and involved high or acute tones. After multivariate analysis with adjustment for age, there was a significant association between hearing loss and hemoglobin A1c (odds ratio, 1.3; 95% confidence interval, 1.02 to 1.81; P = .035). In the patients with T2DM, the lengthening of the brainstem response was not significantly increased; however, the wave morphologic features were abnormal and the reproducibility was poor in both ears in 11 patients (24%). CONCLUSION: Patients with early-onset T2DM and poor glycemic control have an increased prevalence of subclinical hearing loss and impaired auditory brainstem responses. Hearing impairment may be an underrecognized complication of diabetes.