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ID PMID Title PublicationDate abstract
21824732 Extracellular cyclophilin A may be a potential target to protect against myocardial reperf 2011 Nov Myocardial reperfusion injury is increasingly recognized as an inflammatory process, characterized by neutrophil recruitment and subsequently excessive release of pro-inflammatory factors. Recently, the extracellular cyclophilin A (CypA) has been showed to play an important role in initiation and development of inflammation by chemo trafficking of leukocytes into inflamed tissues, eliciting massive release of pro-inflammatory cytokines, and inducing production of matrix metalloproteinases. Also, the agents targeting CypA have been demonstrated to promise anti-inflammatory effects in the different experimental models of inflammatory diseases including acute lung injury, rheumatoid arthritis, and atherosclerosis. Therefore, we hypothesize that the extracellular CypA may in some way implicated in the pathogenesis of reperfusion-induced inflammatory process, and the specific inhibitors of the extracellular CypA can provide a protection against the myocardial reperfusion injury.
21605031 α-Secretase in Alzheimer's disease and beyond: mechanistic, regulation and function in th 2012 Feb Proteases regulate numerous physiological functions in all living organisms. Because of their contribution to βAPP processing, α-, β- and γ-secretases have focused particular attention of researchers in the field of Alzheimer's disease (AD) during the past 20 years. Whereas the β-secretase BACE1 and the heterotetrameric presenilin-dependent γ- secretase complex were identified between 1995 and 2002, α-secretase activity was attributed to previously described ADAM10 and ADAM17, two members of the type I integral membrane protein family called ADAMs (A Disintegrin And Metalloprotease). ADAM10 and/or ADAM17 target numerous substrates through various modes of action. This review focuses on the complex physiology of these α-secretases and will document their contribution to cancers, diabetes, rheumatoid arthritis, and prion diseases besides their well characterized role in Alzheimer's disease.
21584243 Helminth parasites and the modulation of joint inflammation. 2011 There is an urgent need to develop better therapeutics for autoimmune and autoinflammatory diseases, of which musculoskeletal disorders such as rheumatoid arthritis are particularly prevalent and debilitating. Helminth parasites are accomplished masters at modifying their hosts' immune activity, and so attention has focused on rodent-helminth model systems to uncover the workings of the mammalian immune response to metazoan parasites, with the hope of revealing molecules and/or mechanisms that can be translated into better treatments for human autoimmune and idiopathic disorders. Substantial proof-of-principal data supporting the concept that infection with helminth parasites can reduce the severity of concomitant disease has been amassed from models of mucosal inflammation. Indeed, infection with helminth parasites has been tried as a therapy in inflammatory bowel disease, and there are case reports relating to other conditions (e.g., autism); however, the impact of infection with parasitic helminths on musculoskeletal diseases has not been extensively studied. Here, we present the view that such a strategy should be applied to the amelioration of joint inflammation and review the literature that supports this contention.
21490773 Methotrexate in atherogenesis and cholesterol metabolism. 2011 Methotrexate is a disease-modifying antirheumatic drug commonly used to treat inflammatory conditions such as rheumatoid arthritis which itself is linked to increased cardiovascular risk. Treatments that target inflammation may also impact the cardiovascular system. While methotrexate improves cardiovascular risk, inhibition of the cyclooxygenase (COX)-2 enzyme promotes atherosclerosis. These opposing cardiovascular influences may arise from differing effects on the expression of proteins involved in cholesterol homeostasis. These proteins, ATP-binding cassette transporter (ABC) A1 and cholesterol 27-hydroxylase, facilitate cellular cholesterol efflux and defend against cholesterol overload. Methotrexate upregulates expression of cholesterol 27-hydroxylase and ABCA1 via adenosine release, while COX-2 inhibition downregulates these proteins. Adenosine, acting through the A(2A) and A(3) receptors, may upregulate proteins involved in reverse cholesterol transport by cAMP-PKA-CREB activation and STAT inhibition, respectively. Elucidating underlying cardiovascular mechanisms of these drugs provides a framework for developing novel cardioprotective anti-inflammatory medications, such as selective A(2A) receptor agonists.
21466448 Biologic drugs for analgesia: redefining the opportunity. 2011 Oct Chronic pain conditions present a huge burden on modern society. Both inflammatory and neuropathic pain are poorly treated in man; the majority of patients do not benefit from adequate pain relief, and side effects of currently used treatments are common. Discovery and development of novel therapies remains an imperative, but the ability to genuinely test the efficacy of novel therapies is often limited by effects at targets other than intended, particularly with novel small molecule approaches. Approaches which limit these off-target activities, and thus avoid the commonest cause of terminating development of new therapeutics may provide a greater ability to genuinely test targets of choice clinically, and here, biologic therapeutics provide such an opportunity; in the major class of biologic therapies, monoclonal antibodies, inherent exquisite selectivity is intrinsic to their nature. Antibody therapeutics have been developed successfully in the immunology and cancer fields, and recent progress in analgesia suggests that these therapeutics may transform treatment paradigms in a similar manner to that observed within, for example, the rheumatoid arthritis space. In addition, opportunities with other biologic approaches, such as peptides, further broadens the potential to bring forward genuinely novel approaches to pain. In this review, the current status of biologic therapies, as well as future opportunities are reviewed.
21426466 Scurvy: historically a plague of the sailor that remains a consideration in the modern int 2011 Mar We report the case of the case of a 56 year old female with sepsis on a background of rheumatoid arthritis and steroid use manifesting with overt clinical features of scurvy. Ascorbic acid assays were able to demonstrate severe deficiency and confirm a diagnosis of scurvy. Clinical resolution of signs and symptoms following commencement of vitamin C replacement was rapid. The intensivist and dietitian need to consider this diagnosis even in the first world setting, particularly in the presence of sepsis, inflammatory conditions, steroid use and importantly malnutrition.
21387119 Status epilepticus associated with borage oil ingestion. 2011 Jun The use of herbal and complementary medicine is common. Many herbal products are known to produce serious adverse effects. Borage oil is derived from the seeds of the borage plant (Borago officinalis) an abundant source of gamma-linolenic acid (GLA), and Borage oil has been promoted as a treatment for rheumatoid arthritis, atopic dermatitis, diabetic neuropathy, and menopause-related symptoms. We report a case of status epilepticus in a patient who consumed borage oil for one week.
21384158 Th22 in inflammatory and autoimmune disease: prospects for therapeutic intervention. 2011 Jul T helper cell 22 (Th22) is a new subset of T cells clearly separate from Th17 and other known T cell subsets with distinct gene expression and function. With the CCR6 + CCR4 + CCR10 + phenotype and aryl hydrocarbon receptor as the key transcription factor, Th22 subsets produce cytokines such as IL-22, whose function depends on the activation of signal transduction and activators of transcription 3. IL-22 was up-regulated in Rheumatoid arthritis, Crohn's disease, Psoriasis, and atopic dermatitis patients whereas it was down-regulated in the serum of patients with sarcoidosis and systemic lupus erythematosus. Furthermore, it has been demonstrated that IL-22 may have promise as a potential therapeutic for chronic inflammatory diseases, and treatment with recombinant cytokine or gene therapy delivery of IL-22 may alleviate tissue destruction during inflammatory responses. In summary, Th22 cell plays an important and complicated role in inflammatory and autoimmune disease.
21318047 A Nonsecosteroidal Vitamin D Receptor Modulator Ameliorates Experimental Autoimmune Enceph 2011 Jan 26 Vitamin D receptor (VDR) agonists are currently the agents of choice for the treatment of psoriasis, a skin inflammatory indication that is believed to involve an autoimmune component. 1,25-dihydroxyvitamin D3 [1,25-(OH)(2)D(3)], the biologically active metabolite of vitamin D, has shown efficacy in animal autoimmune disease models of multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and type I diabetes. However, the side effect of 1,25-(OH)(2)D(3) and its synthetic secosteroidal analogs is hypercalcemia, which is a major impediment in their clinical development for autoimmune diseases. Hypercalcemia develops as a result of the action of VDR agonists on the intestine. Here, we describe the identification of a VDR modulator (VDRM) compound A that was transcriptionally less active in intestinal cells and as a result exhibited less calcemic activity in vivo than 1,25-(OH)(2)D(3). Cytokine analysis indicated that the VDRM not only modulated the T-helper cell balance from Th1 to Th2 effector function but also inhibited Th17 differentiation. Finally, we demonstrate that the oral administration of compound A inhibited the induction and progress of experimental autoimmune encephalomyelitis in mice without causing hypercalcemia.
21185106 Wnt signaling in macrophages: augmenting and inhibiting mycobacteria-induced inflammatory 2011 Jun Wnt proteins are secreted, palmitoylated glycoproteins with multiple functions in cell proliferation and migration as well as tissue organization. They are best known for their role in embryonic development and tissue homeostasis. In the last years, Wnt signaling was also shown to be involved in the regulation of inflammatory processes: Wnt5a is induced in human macrophages in response to mycobacteria and conserved bacterial structures and contributes to the regulation of pro-inflammatory cytokines via its receptor Frizzled (Fzd) 5. Wnt5a is also induced in other infectious and inflammatory diseases such as tuberculosis, sepsis, psoriasis, rheumatoid arthritis and atherosclerosis. In contrast, Wnt3a, a ligand of Fzd1, is constitutively expressed by bronchial epithelial cells and mediates anti-inflammatory effects on mycobacteria-infected macrophages via the Wnt/beta-Catenin signaling pathway. This pathway suppresses the activity of GSK3beta, a well known regulator of NF-kappaB-dependent gene transcription. Here we review recent data on immunomodulatory activities of Wnt proteins. Additional experiments using exogenous Wnt homologs further support the notion that TLR/NF-kappaB and Wnt signaling are functionally interconnected.
21094504 Molecular analyses of the Chinese herb Leigongteng (Tripterygium wilfordii Hook.f.). 2011 Jan Tripterygium wilfordii Hook.f., known as Leigongteng (Thunder God Vine) in traditional Chinese medicine, has attracted much attention for its applications in relieving autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus, and for treating cancer. Molecular analyses of the ITS and 5S rDNA sequences indicate that T. hypoglaucum and T. doianum are not distinct from T. wilfordii, while T. regelii should be recognized as a separate species. The results also demonstrate potential value of rDNA sequence data in forensic detection of adulterants derived from Celastrus angulatus in commercial samples of Leigongteng.
23259458 Membranoproliferative glomerulonephritis complicating Waldenström's macroglobulinemia. 2012 Dec 21 BACKGROUND: Lymphoproliferative disorders causing paraproteinemia can be associated with various kidney injuries including the deposition of monoclonal immunoglobulins (Ig). A known glomerular manifestation of Waldenström's macroglobulinemia is characterized by prominent intracapillary hyaline thrombi and lack of conspicuous glomerular proliferation. The present case was special in 2 aspects: 1. the diagnosis of glomerulonephritis was unexpected before renal biopsy, 2. the prominent glomerular proliferation paired with large intracapillary hyaline thrombi is uncommon in Waldenström's macroglobulinemia-associated glomerulonephritis. CASE PRESENTATION: A 73-year-old Caucasian woman with a long-standing history of rheumatoid arthritis and Waldenström's macroglobulinemia was admitted for acute renal failure (ARF), which initially was presumed to be the consequence of extrarenal causes. Proteinuria and hematuria were only mild. In renal core biopsy, a membranoproliferative glomerulonephritis (MPGN) and prominent intracapillary hyaline monoclonal IgM thrombi were found in addition to acute tubular necrosis. Of note, the patient's history was positive for purpuric skin changes, suspicious for cryoglobulinemia. However, serological tests for cryoglobulins were repeatedly negative. The ARF resolved before the start of immunomodulatory therapy for Waldenström's macroglobulinemia. CONCLUSION: The presence of MPGN with prominent hyaline thrombi in the context of Waldenström's macroglobulinemia is uncommon and can be oligosymptomatic. We discuss this case in the context of previous literature and classifications suggested for monoclonal Ig-related renal pathologies.
23237056 Chronic leg ulcers in adult patients with rheumatological diseases - a 7-year retrospectiv 2014 Dec Chronic leg ulcers in patients with rheumatological diseases can cause significant morbidity. We performed a retrospective case review to describe the epidemiology, clinical features and outcome of chronic leg ulcers in this group of patients. Twenty-nine patients with underlying rheumatological conditions, such as, rheumatoid arthritis (15 patients), systemic lupus erythematosus (8 patients), overlap syndromes (3 patients), systemic sclerosis (1 patient) and ankylosing spondylitis (1 patient) were included. The ulcers were mostly located around the ankle (55·2%) and calves (37·9%). The predominant aetiology of the ulcers, in decreasing order of frequency, was venous disease, multifactorial, vasculitis or vasculopathy, infective, pyoderma gangrenosum, ischaemic microangiopathy and iatrogenic. Treatment modalities included aggressive wound bed preparation, compression therapy (17 patients), changes in immunosuppressive therapy (15 patients), hyperbaric oxygen therapy (4 patients) and cellular skin grafting (2 patients). Management of chronic leg ulcers in rheumatological patients is challenging and the importance of careful clinicopathological correlation and treatment of the underlying cause cannot be overemphasised.
23166560 A Case of Peritoneal Tuberculosis Developed after Infliximab Therapy for Refractory RA. 2012 Oct Recently, interferon gamma releasing assay has been recommended to compensate the tuberculin skin test (TST) for screening for latent tuberculosis infection (LTBI). Although it improved the detection of LTBI before treatment with tumor necrosis factor blocker, its application to immune suppressed patients is limited. We report a case of peritoneal tuberculosis (TB) developed in a patient who tested positive for TST and QuantiFERON-TB Gold (QFT-G) before infliximab therapy, to emphasize the importance of monitoring during treatment. A 52-year-old woman presented with abdominal distension. She had been diagnosed with seropositive rheumatoid arthritis six years ago. She had started taking infliximab six months ago. All screening tests for TB were performed and the results of all were negative. At admission, the results of repeated TST and QFT-G tests were positive. Histopathological examination confirmed peritoneal TB. The patient started anti-TB therapy and the symptoms were relieved.
22773721 Agranulocytosis from levamisole-adulterated cocaine. 2012 Jul INTRODUCTION: Afebrile neutropenia with an absolute neutrophil count (ANC) of zero in a nonimmunocompromised individual is unusual. Outlined is a case of agranulocytosis likely due to levamisole laced cocaine. Given recent publications in the news media and medical journals, this is a pertinent issue for primary care providers. CASE: A 57-year-old female presented with painful bowel movements and difficulty eating. Physical examination revealed two exquisitely tender ulcerated lesions on her lower lip and anus. Laboratory data revealed an ANC of 0 and urine drug screen positive for cocaine. She was prophylaxed with acyclovir, diflucan, and ciprofloxacin, and was started on granulocyte colony stimulating factor for four days. Her ANC normalized, but the cause of her severe neutropenia remained unclear. DISCUSSION: Levamisole is a veterinary antihelminthic used for treatment of rheumatoid arthritis and colorectal cancer in humans. 88% of regional cocaine samples are testing positive for levamisole, which is thought to potentiate cocaine's effects but can also cause agranulocytosis. CONCLUSIONS: Our patient did not fit the clinical picture for malignancy, viral infection, or bone marrow pathology. Given the high rate of levamisole adulterated cocaine and an otherwise negative work-up, this is the most likely explanation for her agranulocytosis.
22764461 Latest update on the clinical features and management of Merkel cell carcinoma. 2012 Mar Merkel cell carcinoma (MCC), is a rare, highly malignant skin tumour, with a poor prognosis. Though the aetiology of MCC is not known, but there are several features that it shares with melanoma. These include the natural history, clinical features and behaviour, e.g. an early spread to nodal sites, high local recurrence rate and early metastasis. Incidence of MCC is seen to be increased in immunosuppressed transplant patients, in patients with rheumatoid arthritis and in B cell malignancies, with a strong male predominance. Despite the ongoing research and advancement, MCC yet poses a challenge to the clinicians because of its rarity. The purpose of this paper is to review the most salient and clinically relevant updates of MCC since its first publication in July 2007 in JPMA. In order to expedite an improved understanding of the new diagnostic modalities, treatment and preventive measures, along with the new staging system established in 2009 after an extensive literature review, and an analysis of over 5,000 patients using the National Cancer Database has all been included in our article.
22436638 Atherogenic effects of TNF-α and IL-6 via up-regulation of scavenger receptors. 2012 Jun Patients with chronic inflammatory disorders such as rheumatoid arthritis (RA) have a high risk of developing cardiovascular disease. We evaluated the effects of TNF-α and IL-6 on foam cell formation, a pivotal process in atherogenesis. Accumulation of intracellular oxidized LDL (oxLDL) was induced when THP-1/macrophages were stimulated with TNF-α or IL-6. TNF-α induced the expressions of scavenger receptors SR-A and LOX-1, and IL-6 induced SR-A expression. Inhibition of the NF-κB signaling markedly decreased TNF-α-induced foam cell formation and SR-A expression. Serum from RA patients, but not healthy subjects, induced foam cell formation, which was partially reversed by either IL-6 or TNF-α blockade in conjunction with inhibiting the induction of scavenger receptors. The present study clearly showed that in patients with chronic inflammation mediated by TNF-α and IL-6, these cytokines are directly implicated in atherosclerotic plaque formation.
22338992 Mast cell activation syndrome masquerading as agranulocytosis. 2012 Jan Acquired agranulocytosis is a rare, life-threatening disorder. The few known causes/associations usually are readily identifiable (e.g., drug reaction, Felty syndrome, megaloblastosis, large granular lymphocytic leukemia, etc.). We report a novel association with mast cell disease. A 61-year-old morbidly obese man developed rheumatoid arthritis unresponsive to several medications. Agranulocytosis developed shortly after sulfasalazine was started but did not improve when the drug was soon stopped. Other symptoms across many systems developed including hives and presyncope. Marrow aspiration and biopsy showed only neutropenia. Serum tryptase was mildly elevated; urinary prostaglandin D2 was markedly elevated. Other causes were not found. Mast cell activation syndrome (MCAS) was diagnosed. Oral antihistamines, montelukast, and cromolyn were unhelpful; aspirin was initially felt contraindicated. Imatinib immediately increased neutrophils from 0% to 25% but did not help symptoms; subsequent addition of aspirin increased neutrophils further and abated symptoms. Different presentations of different MCAS patients reflect elaboration of different mediators likely consequent to different Kit mutations. Mast cells (MCs) help regulate adipocytes, and adipocytes can inhibit granulopoiesis; thus, a Kit-mutated MC clone may have directly and/or indirectly driven agranulocytosis. MCAS should be considered in otherwise idiopathic agranulocytosis presenting with comorbidities best explained by MC mediator release.
22241644 Physicochemical studies on glycation-induced structural changes in human IgG. 2012 Feb Glycation of biomolecules leads to the formation of advanced glycation end products (AGEs). Glycation of immunoglobulin G (IgG) has been implicated in autoimmune diseases such as rheumatoid arthritis (RA). In this study, human IgG was glycated with physiological concentration of glucose. The changes induced in IgG were analyzed by UV, fluorescence, circular dichroism, and Fourier transform infrared (FTIR) spectroscopy; thermal denaturation studies, native, and Sodium dodecyl sulphate (SDS)-polyacrylamide gel electrophoresis. The ketoamine moieties and carbonyl content were also quantitated in glycated IgG. We report structural perturbations, increased carbonyl content, and ketoamine moieties in the glycated IgG. This may interfere with the normal function of IgG and may contribute to initiation of arthritic complications. AGEs damaged IgG may be used as a biomarker for early detection of RA and the associated secondary complications.
22234148 Development of low blood glucose readings in nine non-diabetic patients treated with tumor 2012 Jan 10 INTRODUCTION: Treatment with various biological agents in disease states such as rheumatoid arthritis has been associated with multiple side effects. Whereas many of these are frequently reported in the literature, hypoglycemia, a possible side effect of tumor necrosis factor-alpha inhibitors, may be underpublicized. CASE PRESENTATION: We report nine cases of non-diabetic Caucasian women who were between 29 and 68 years of age and who developed low glucose readings after treatment with tumor necrosis factor-alpha inhibitors. We provide a more detailed discussion of existing evidence of the role of tumor necrosis factor-alpha in the pathogenesis of inflammation and its impact on glycemic equilibrium. CONCLUSIONS: Physicians using tumor necrosis factor-alpha inhibitors in the treatment of various rheumatic and other autoimmune diseases should be aware of the potential for the development of glycemic disturbance in these patients. A further role of tumor necrosis factor-alpha inhibitors in the glycemic equilibrium warrants larger controlled trials in patients with and those without a history of diabetes.