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We summarize clinical, laboratory and pathologic details regarding a patient who presented with extrahepatic disease manifestations of hepatitis C virus (HCV) infection, including cryoglobulinemic leg ulcers due to cutaneous vasculitis, peripheral sensorimotor neuropathy, and recurrent pulmonary infiltrates. The patient had evidence for B-cell lymphoproliferation, diagnosed as extranodal lymphoma on initial (though not subsequent) bone marrow examination, retroperitoneal lymphadenopathy, and the presence of a Type II IgM6 monoclonal rheumatoid factor which became cryoprecipitable on complexing to IgG. Chronic hepatitis was mild on liver biopsy, though fibrotic changes developed over a three-year period of follow-up. She had consistently normal liver function tests, except for a brief rebound effect on discontinuing interferon-alpha, and preterminally. Symptoms were only partially responsive to trials of corticosteroids, cytotoxic agents, plasmapheresis and interferon, and the patient ultimately died at The Mount Sinai Hospital of sepsis. We review current information regarding the spectrum of extrahepatic HCV infection, including pathogenic factors relevant to its overlapping autoimmune, rheumatic and lymphoproliferative disease manifestations. The exact prevalence of these HCV-related syndromes among the 1% of the world population estimated to be infected by this virus remains to be delineated. Chronicity of infection, and lack of efficacy of currently available therapy in effecting sustained clearance of the virus from the host, have made this an important public health problem that is likely to increase in significance. Possible relationships to non-Hodgkin's lymphoma may present novel opportunities to delineate the basis for oncogenesis in HCV infection.
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PMID:Hepatitis C virus, autoimmunity and lymphoproliferation. 1074 67

The measurement of cardiac troponins (cTn) is of considerable usefulness in the diagnosis of acute coronary syndrome. Abnormal levels of serum cTn are occasionally found in patients who are not suffering a myocardial infarction. This may be observed in several well-known situations including pulmonary embolism, pericarditis, myocarditis, coronary vasospasm, sepsis, congestive heart failure, supraventricular tachycardia with hemodynamic compromise, re-nal insufficiency, and prolonged strenuous endurance exercise. Endogenous antibodies such as heterophile antibodies, rheumatoid factor, and other autoantibodies are known to interfere with the immunoassay measurements of many different analytes, including the widely used Abbot AxSYM cTnI analyzer. Other sources of circulating antibodies include immunotherapies, vaccinations, or blood transfusions that may interfere with these immunoassays as well. We examine the case of a 48-year-old man with a history of hypercholesterolemia and obesity who presented with chest pain and was found to have elevated Tn I levels on two separate occasions. Further work-up revealed that the Tn I levels were spuriously elevated because the patient's blood revealed a normal cTnI level when mixed with polyethylene glycol to inactivate any antibodies interfering with the cTnI assay.
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PMID:Falsely elevated cardiac troponin I levels. 1732 64

"Macromolecules to PDMS transfer" technique relying on the direct entrapment of macromolecules spots during PDMS polymerisation is proposed as an alternative for the easy and simple PDMS surface modification. In the present work, the development of three different applications based on this procedure is presented as proof of the method potentialities. First, C-reactive protein (CRP) sandwich immunoassay using immobilised monoclonal anti-CRP antibodies was developed for sepsis diagnosis. The preserved integrity of the immobilised monoclonal immunoglobulin permitted the sensitive detection of free CRP in human sera (LOD=12.5 microg/L, detection ranging over two decades). Then, rheumatoid arthritis diagnosis through the rheumatoid factor (RF) detection based on rabbit immunoglobulins immobilisation allowed the detection of specific antibodies in human sera samples down to low RF levels (detection range 5.3-485 IU/mL). Finally, the "Macromolecules to PDMS transfer" procedure was used to easily and rapidly produce fibronectin-based cell culture arrays. The successful attachment of HeLa and BALB/3T3 cells was demonstrated with optical microscopy and specific staining of actin and vinculin.
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PMID:"Macromolecules to PDMS transfer" as a general route for PDMS biochips. 1867 39

Recurrence of glomerulonephritis (GN) is one of the major risk factors of long-surviving renal graft dysfunction. Cryoglobulinemic glomerulonephritis of hepatitis-C virus (HCV)-negative patient is a rare cause of end-stage renal disease. There is little case report of recurrent cryoglobulinemic glomerulonephritis in negative HCV recipients after renal transplantation. We represent a renal allograft recipient of an interesting recurrent cryoglobulinemic glomerulonephritis. The patient was diagnosed with mixed cryoglobulinemic glomerulonephritis by kidney biopsy at the age of 32 . He had no HCV, HBV nor liver dysfunction. He received immunosuppressive therapy, however, was introduced to hemodialysis treatment after 13 yr. He received a cadaveric renal transplantation at the age of 50, and immunosuppressive treatment was started with ciclosporin, prednisolone and mycophenolate mofetil (MMF). Four yr after transplantation, he developed fever and purpura of lower limbs. His serum creatinine level did not increase, however, proteinuria, hematuria, hypocomplementemia, positive rheumatoid factor and mixed cryoglobulinemia were noted. Detailed analysis failed to reveal the composition of mixed cryoglobulinemia. The renal allograft biopsy showed membranoproliferative-type GN with monocyte and polynuclear leukocyte accumulation of capillary loops and small cellular crescent. Immunofluorescent study showed C3, IgG and IgM deposition of mesangial and capillary pattern. Regardless of steroid pulse therapy, hypocomplementemia and positive rheumatoid factor did not improve. Ten yr after transplantation, he was affected by cellulitis and sepsis. Afterward, rising of serum creatinine and nephrotic range proteinuria developed. The allograft biopsy revealed advanced cryoglobulinemic glomerulonephritis with characteristic vascular lesions. Electron microscopy showed organized subendothelial deposits compatible with cryoglobulinemic glomerulonephritis and proteinaceous thrombus in arteriole.
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PMID:A case report of recurrence of mixed cryoglobulinemic glomerulonephritis in a renal transplant recipient. 2059 Jun 94

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease leading to inflammatory tissue damage in multiple organs (e.g., lupus nephritis). Current treatments including steroids, antimalarials, and immunosuppressive drugs have significant side effects. Activated protein C is a natural protein with anticoagulant and immunomodulatory effects, and its recombinant version has been approved by the U.S. Food and Drug Administration to treat severe sepsis. Given the similarities between overshooting immune activation in sepsis and autoimmunity, we hypothesized that recombinant activated protein C would also suppress SLE and lupus nephritis. To test this concept, autoimmune female MRL-Fas(lpr) mice were injected with either vehicle or recombinant human activated protein C from week 14-18 of age. Activated protein C treatment significantly suppressed lupus nephritis as evidenced by decrease in activity index, glomerular IgG and complement C3 deposits, macrophage counts, as well as intrarenal IL-12 expression. Further, activated protein C attenuated cutaneous lupus and lung disease as compared with vehicle-treated MRL-Fas(lpr) mice. In addition, parameters of systemic autoimmunity, such as plasma cytokine levels of IL-12p40, IL-6, and CCL2/MCP-1, and numbers of B cells and plasma cells in spleen were suppressed by activated protein C. The latter was associated with lower total plasma IgM and IgG levels as well as lower titers of anti-dsDNA IgG and rheumatoid factor. Together, recombinant activated protein C suppresses the abnormal systemic immune activation in SLE of MRL-Fas(lpr) mice, which prevents subsequent kidney, lung, and skin disease. These results implicate that recombinant activated protein C might be useful for the treatment of human SLE.
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PMID:Activated protein C attenuates systemic lupus erythematosus and lupus nephritis in MRL-Fas(lpr) mice. 2184 82

Dear Editor, Subcutaneous granuloma annulare (SGA) is considered a rare clinical variant of granuloma annulare, a common self-healing chronic inflammatory disorder that may appear in childhood as well as in adult age (1-3). A 29-year-old female patient reported the onset of several small subcutaneous nodules on the dorsal aspect of the second interphalangeal joint of the left medius finger and the left elbow, accompanied by vague joint pain, had occurred 13 years ago. Specific markers for rheumatoid arthritis were negative, leading to a diagnosis of sero-negative rheumatoid arthritis, for which treatment with methotrexate was initiated. No clinical benefit was obtained and the treatment was abandoned. New nodules continued to appear on several distal joints of the fingers of both hands and, in the last 6 months, on the second right toe. The course of the disease included spontaneous remission of some of the nodules. Personal medical history was significant for a thyroid nodule, surgically removed at the age of 22. A general physical exam did not reveal pathological changes. A clinical dermatological exam at the time of presentation revealed several round to oval, deep subcutaneous, indurated, asymptomatic, discreetly pigmented lesions with a diameter of 4-6 mm, located on the dorsal aspect of the interphalangeal joints of the fingers of both hands (Figure 1) and the second right toe. Hematologic and biochemical tests were within normal limits, as well as the serological tests for rheumatoid factor, ANCA, ANA, and anti-CCP antibody. Hand radiographs did not show geodes, marginal erosions, or narrow joint spaces. A pathological exam of a subcutaneous nodule showed focally altered collagen surrounded by fibroblasts, phagocytes, rare lymphocytes, and neutrophils, as well as small capillaries (Figures 2-5), compatible with the diagnosis of a pseudorheumatoid nodule or benign rheumatoid nodule in the clinical and paraclinical context. SGA is considered a rare clinical and histological variant of granuloma annulare that predominantly affects children and occasionally young adults (1-6). In 1941, Ziegler first described a case of subcutaneous nodules that appeared concomitantly with classical cutaneous lesions of granuloma annulare, as well as the histological aspect of these nodules similar to that of rheumatoid nodules (RN) (7). Since then, several case reports in the literature refer to the subcutaneous lesions of GA as "pseudorheumatoid nodules", "deep granuloma annulare" or "palisading granuloma" (3,4,8). Most reported cases of SGA occur in the first three decades of life: 98% according to Muhlemann, 79% according to Andersen and Verdich, 62% according to Studer; most cases occur in children between 2 and 6 years of age (9). Lesions often regress spontaneously, but recurrences are common in 19%-75% of the patients, often on the same anatomical areas (9,10). Reported SGA cases in adult patients predominantly affected women, and typically involved multiple lesions located on the hands, feet, ankles, and inferior pretibial area (4-6). The etiology and pathogenesis of SGA are not completely understood. Precipitating factors such as insect bites, infections with Borellia spp., herpetic virus, EBV, Streptococcus spp., PUVA-therapy, several drugs, physical trauma, acute phlebitis, and post-surgery sepsis have been considered (8). There is evidence for the pathogenic involvement of an immunological mechanism, possibly a delayed type hypersensitivity reaction mediated by T-cells that triggers a panniculitis-type inflammatory response (8,10). Correlations between SGA and systemic diseases such as diabetes mellitus, sarcoidosis, HIV infection, or autoimmune diseases have not been found (8). A positive diagnosis of pseudorheumatoid nodules relies on clinical and anamnestic data. Differential diagnosis includes rheumatoid nodules, benign rheumatoid nodules, foreign body reactions, hematomas, abscesses, and infectious granulomas (3,5). Pseudorheumatoid nodules and SGA have a low risk of progression to a systemic connective tissue disorder. In the presence of subcutaneous nodular lesions with an uncertain clinical diagnosis, cutaneous biopsy, hematological and immunological tests, and imaging may be performed to establish a positive diagnosis. Skin biopsy is the most useful test for the diagnostic approach because, even though it is sometimes difficult to interpret, a pathological exam may offer important data to distinguish between rheumatoid and pseudorheumatoid nodules. Necrobiosis may be identified in the deep dermis and subcutaneous tissue, and rarely in the deep soft tissues. Necrobiosis is less important and less deep than in rheumatoid nodules, as well as less extensive and less diffuse than in lipoidic necrobiosis (6). Anomalies in the morphology of the deep cutaneous structures may coexist with typical changes in classical granuloma annulare. Immunohistochemical studies using specific histiocyte markers such as CD68/PGM1 proved to be occasionally useful in differentiating SGA from other granulomatous conditions (11). Several tests are necessary to exclude an association with a systemic disease: hemoleucogram (absence of leucocytosis), ESR (normal values), acute phase reactants (negative fibrinogen, RCP), autoantibodies (negative ANA), and rheumatoid factor (negative). SGA is a benign disorder with esthetic implications and sometimes functional impairment. Surgical excision is only required for juxta-articular nodules causing functional impairment. Partial therapeutic benefit was reported after the administration of dapsone, clorambucil, isotretinoin, potassium iodide, or intralesional/topical steroids. Even though the risk of systemic involvement is low, periodical follow-up of these patients is required given the reported cases of associated systemic connective tissue disorders (8,12).
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PMID:Subcutaneous Granuloma Annulare. 3006 2

Internal jugular vein thrombosis is a rare critical cardiovascular emergency, which has potential catastrophic clinical outcomes by resulting in stroke and pulmonary embolism. Several etiologies have been reported; however, there are limited data on Lemierre's and Trousseau's syndromes, which are both rare conditions with advanced disease progression and poor clinical outcomes. Lemierre's syndrome may present with typical progressively infectious symptoms and signs, including sore throat, neck mass, and fever, whereas Trousseau's syndrome may present with thrombophlebitis and painful edema. Without antibiotic agents controlling the infection, the condition of patients with Lemierre's syndrome may progress to sepsis or septic shock. The infection pattern plays an important role for differential diagnosis. Herein, we describe the case of a 46-year-old woman presenting with atypical symptoms of Trousseau's syndrome mimicking Lemierre's syndrome. Laboratory analysis including protein C, protein S, rheumatoid factor, and antinuclear antibody ruled out hypercoagulopathy and autoimmune vasculitis. Abdominal computed tomography and panendoscopy revealed ulcerative tumor at the antrum. Pathological examination confirmed the presence of signet-ring cell adenocarcinoma. We highlight the clinical features and etiologies of internal jugular vein thrombosis, especially in Lemierre's syndrome and Trousseau's syndrome, to aid physicians in making an early diagnosis and providing timely management.
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PMID:Case of internal jugular vein thrombosis and fever: Lemierre's syndrome or Trousseau's syndrome? 3211 May 28


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