Serum soluble CD25 as a risk factor of renal impairment in systemic lupus erythematosus - a prospective cohort study.

Objective Serum soluble CD25 (sCD25) could be used as a biomarker for disease activity in conditions associated with T-cell activation including various autoimmune diseases. This study aimed to explore the role of sCD25 as an indicator of disease activity and organ involvement in patients with systemic lupus erythematosus (SLE). Methods Serum samples were collected from 107 SLE patients and 92 age-matched healthy controls (HCs). All patients were followed up for 24 weeks, and sCD25 was measured by enzyme-linked immunosorbent assay. Clinical and laboratory data were recorded at baseline and then every two weeks until week 24. The Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI)-2K was adopted for assessing disease activity at all visits. Results Serum sCD25 levels were significantly increased in SLE patients compared to those in HCs ( p < 0.001). More patients in the high-sCD25 group had lupus nephritis, arthritis and vasculitis ( p = 0.010, p = 0.023 and p = 0.042, respectively). SLEDAI-2K, erythrocyte sedimentation rate, C-reactive protein and 24-hour urinary protein excretion were all associated with high levels of sCD25 ( p < 0.001, p = 0.002, p = 0.038 and p = 0.029, respectively). During the 24-week follow-up, more patients in the high-sCD25 group developed renal impairment (48% vs 6.2%, p = 0.005), and higher levels of sCD25 ( p = 0.033) were found at the time of onset of renal disease. Conclusions Serum sCD25 is a hallmark of disease activity and a predictor of renal disease in patients with SLE.

P2Y2 R deletion ameliorates sialadenitis in IL-14α-transgenic mice.

OBJECTIVE: Interleukin-14α-transgenic (IL-14αTG) mice develop an autoimmune exocrinopathy with characteristics similar to Sjögren's syndrome, including sialadenitis and hyposalivation. The P2Y2 receptor (P2Y2 R) for extracellular ATP and UTP is upregulated during salivary gland inflammation (i.e., sialadenitis) where it regulates numerous inflammatory responses. This study investigated the role of P2Y2 Rs in autoimmune sialadenitis in the IL-14αTG mouse model of Sjögren's syndrome. MATERIALS AND METHODS: IL-14αTG mice were bred with P2Y2 R-/- mice to generate IL-14αTG × P2Y2 R-/- mice. P2Y2 R expression, lymphocytic focus scores, B- and T-cell accumulation, and lymphotoxin-α expression were evaluated in the submandibular glands (SMG) along with carbachol-stimulated saliva secretion in IL-14αTG, IL-14αTG × P2Y2 R-/- , and C57BL/6 control mice at 9 and 12 months of age. RESULTS: Genetic ablation of P2Y2 Rs in IL-14αTG mice significantly reduced B and T lymphocyte infiltration of SMGs. However, reduced sialadenitis did not restore saliva secretion in IL-14αTG × P2Y2 R-/- mice. Decreased sialadenitis in IL-14αTG × P2Y2 R-/- mice correlated with decreased lymphotoxin-α levels, a critical proinflammatory cytokine associated with autoimmune pathology in IL-14αTG mice. CONCLUSIONS: The results of this study suggest that P2Y2 Rs contribute to the development of salivary gland inflammation in IL-14αTG mice and may also contribute to autoimmune sialadenitis in humans.

Multimodal imaging in systemic lupus erythematosus patients with diffuse neuropsychiatric involvement.

OBJECTIVES: The objective of this paper is to investigate conventional and nonconventional brain magnetic resonance imaging (MRI) findings in systemic lupus erythematosus (SLE) patients with diffuse neuropsychiatric involvement (dNPSLE) compared to healthy controls (HCs). METHODS: Twenty-six (26) SLE patients with one or more diffuse NP syndromes related to the central nervous system (CNS) (dNPSLE) and 36 age- and sex-matched HCs were scanned on a 3T MRI using a multimodal imaging approach. Univariate and multivariate analyses were used to determine MRI-specific measure differences between dNPSLE and HCs for lesion burden, tissue-specific atrophy, magnetization transfer ratio (MTR) and diffusion-tensor imaging (DTI) outcomes. RESULTS: In univariate analyses, dNPSLE patients showed significantly increased T1 lesion number (p = .001) and T1-lesion volume (LV, p = .008) compared to HCs. dNPSLE patients showed decreased whole brain volume (p < .0001), gray matter volume (p < .0001), cortical volume (p < .0001) and increased lateral ventricle volume (p = .004) compared to HCs. dNPSLE patients had increased axial diffusivity (AD) of NAWM (p = .008) and NA brain tissue (p = .017) compared to HCs. In the multivariate regression analysis, decreased cortical volume was associated with SLE (R (2) = 0.59, p < .0001). CONCLUSIONS: This study shows that cortical and central atrophy are associated with SLE patients with diffuse CNS syndromes. Microscopic tissue injury in the NAWM on AD DTI measures in SLE patients indicates a predominant reduction of axonal density.

Multiple medical problems following agent orange exposure.

A patient exposed to agent orange and a gunshot wound during the Vietnam War has developed multiple medical problems including nocardiosis, onychomycosis (Trichophyton rubrum), multiple thromboembolic episodes, hemochromatosis, diabetes mellitus type 2, diabetic neuropathy, activated protein C resistance (without Leyden V 1st mutation), degree A-V block, lung cancer (metastatic adenocarcinoma), carpal tunnel syndrome and arthritis.

Evaluation of chronic urticaria in patients with Hashimoto thyroiditis.

The coincidence of Hashimoto thyroiditis (HT) and chronic idiopathic urticaria (CIU) is a commonly observed phenomenon in western New York. Previous literature suggested that there may be a direct relationship between them. We undertook these studies to determine whether humoral or cell-mediated mechanisms might link HT and CIU. Skin biopsies from patients with CIU, with or without HT, were indistinguishable by light microscopy. No immune complex deposition was observed, although only the skin from patients with CIU and HT contained perivascular fibrin deposits. Similarly, immunohistochemical studies evaluating cellular expression of CD3, CD4, CD8, CD20, and CD68 failed to differentiate between CIU with or without HT. Analysis of Vbeta restriction in thyroid tissue of patients with HT and the skin of patients with CIU and HT by in situ polymerase chain reaction failed to reveal any oligoclonal T-lymphocyte subpopulations. In contrast, only patients with CIU and HT had anti-FcepsilonRI antibodies in their sera that could induce degranulation of normal basophils. Some sera from patients with CIU and HT caused degranulation of normal basophils in the absence of anti-FceRI. The factor causing basophil degranulation in these sera was not determined. Patients with CIU and HT failed to improve clinically with thyroid replacement therapy. All CIU patients were equally well managed with symptomatic therapies. In conclusion, HT likely represents a marker of other autoimmunity, rather than being a direct causative agent in CIU. Management of CIU, with or without HT and with or without anti-FceRI antibodies, should be the same. Future studies will have to examine whether cell-mediated responses participate in CIU, especially in association with HT.

Treatment of lead poisoning with an immobilized chelator comparison with conventional therapy.

Lead poisoning is a global public health problem. In pregnant women it may result in developmental delays of the fetus, in children it my produce learning disability. Available chelators are nephrotoxic when eliminated as lead-chelator complexes. For safe removal of lead from the body we developed a "Lead-Hemopurifier" (L-HP), a device with an immobilized chelator. In vitro, applied to lead solutions, this device reduced the lead concentration. Applied to dogs with lead intoxication, Lead-HP-s removed lead from the blood; this was continuously replaced by lead from the bones until the skeleton was cleared from lead deposit. Treatment of lead poisoning in dogs with Lead-HP-s compared favorably with Versenate treatment of children with lead toxicity. This report demonstrates the in vivo efficiency and safety of this new detoxfication method. Methods to induce lead poisoning in dogs and procedures to identify lead released from skeletal deposits are described.

Microscopic polyangiitis in a pediatric patient.

Microscopic polyangiitis (MPA), previously called hypersensitivity angiitis, is a systemic necrotizing vasculitis that involves many organ systems including the skin, joints, kidneys, and lungs. Microscopic polyangiitis most commonly affects adults in the fourth and fifth decades of life, with only a few cases reported in children. We describe a pediatric patient with microscopic polyangiitis. Arch Fam Med. 2000;9:1189-1192

Mild hyperthermia modulates biological activities of interferons.

A significant enhancement of antiviral activity of human IFN-alpha, -beta and -gamma and murine IFN-gamma is observed when cells are treated with mild hyperthermia (39 degrees C) during antiviral assays. Treatment of primary human fibroblast cells with mild hyperthermia for 4 and 24 hours prior to interferon antiviral assays (pre-assay hyperthermia) further enhances interferon antiviral activity. An enhancement of interferon induced enzyme, 2,5-oligoadenylate synthetase, is also observed in cells treated with interferon and mild hyperthermia. This increase in enzyme activity is, in part, responsible for the observed increase in interferon antiviral activity with hyperthermia. Besides antiviral activity, mild hyperthermia also increases interferon antiproliferative activity on different tumour cells beyond its effect at normal physiological temperatures. On the other hand, mild hyperthermia decreases human interferon production in both human and murine cells when challenged with a viral or non-viral inducer. Also, mild hyperthermia suppresses interferon-mediated enhancement of natural killer (NK) cell activity in human and murine cells. The findings demonstrate that, although mild hyperthermia has suppressive effects upon interferon production and NK cell activity, it significantly increases both antiviral and antiproliferative activities of all three human interferons. These observations have direct bearing upon clinical utilization of exogenously administered interferons to late stage cancer patients who for the most part have a weaker immune system. In these patients, the antiviral and antiproliferative efficacies of administered interferon can be enhanced by combining interferon and hyperthermia.

CD8 expression on B cells in chronic lymphocytic leukemia: a case report and review of the literature.

The expression of CD8, a restricted T-cell antigen, on B cells in B chronic lymphocytic leukemia is rare, and its significance, if any, remains unknown. We report herein a patient with B chronic lymphocytic leukemia in whom CD8 was strongly expressed on all B cells, both in the bone marrow and peripheral blood. The patient required no therapy for 6 years after being diagnosed as having B chronic lymphocytic leukemia. Then, when the disease progressed, he was treated with conventional doses of fludarabine phosphate (25 mg/m(2) daily for 5 days), but unlike other patients with B chronic lymphocytic leukemia he tolerated this therapy poorly. He received a total of only 4 series of fludarabine therapy, and following each course of treatment, he developed considerable myelosuppression. After the fourth course of therapy, his bone marrow failed to show any evidence of regeneration, and he died as a result of intercurrent respiratory tract infection 1 month after his last dose of fludarabine was given.

Study of antiangiogenic agents with possible therapeutic applications in neoplastic disorders and macular degeneration.

Using a previously developed method (Ambrus, et al., 1991), we found that pentoxifylline and thalidomide potentiate each others antiangiogenic effect induced by human malignant melanoma cells in the cornea of Macaca arctoides monkeys.

Desmoid tumour: a pleomorphic lesion.

BACKGROUND: Desmoid tumour (DT) is an uncommon locally invasive non-metastasizing neoplastic lesion. The aetiology of this tumour is unknown and its treatment is controversial. Twelve cases of DT are presented and the literature is reviewed. METHODS: Twelve cases of DT treated at our institution during a 3.5-year period are analysed and the literature reviewed. Ten patients were referred with a primary tumour, one with local recurrence and one patient with a second primary desmoid tumour. One patient had multiple mesenteric DT (familial adenomatous polyposis coli-FAP), and in the remaining 11 patients the tumour was located in the abdominal wall in four, at an extremity in three, in the upper back in two patients, in the pelvis in one and retroperitoneally in one. RESULTS: The largest mesenteric DT was marginally excised en bloc with total jejunectomy. In the remaining 11 DT, complete excision to microscopically tumour-free margins was possible in nine cases and to microscopically involved margins in two cases. At a mean follow-up of 22 months (range 7-38 months), one patient was alive with stable disease (Gardner's syndrome), 10 patients were alive and free of recurrence and one patient (9%) developed local recurrence which was re-excised-she is disease-free 10 months later. CONCLUSIONS: Complete excision is the main modality of treatment for primary and recurrent DT. This is feasible in most cases except for tumours involving the base of the bowel mesentery. Surgical resection alone achieved local control of the tumour in most of the patients in this series (92%).

Thromboembolic disease susceptibility related to red cell membrane fluidity in patients with polycythemia vera and effect of phlebotomies.

Thromboembolic disorders are frequent complications in polycythemia vera. In addition to thrombocytosis with hyperaggregability, leukocytosis, and high hematocrit, hyperviscosity syndrome, a new component, is described in the pathophysiology of this phenomenon. There is decreased red cell membrane fluidity with decreased deformability which increases the susceptibility to microvascular occlusion and also increases the chance of disseminated intravascular coagulation (DIC). Periodic phlebotomies improved the hematologic picture in these patients and results in the removal of the "stiff" red cells with an increased production of young red cells, greater membrane fluidity, deformability and less chance of microvascular occlusion.

Myocardial release of non-transferrin-bound iron during cardio-pulmonary bypass surgery.

Myocardium reperfusion following coronary artery bypass grafting (CABG) may result in "reperfusion injury" by free radical generations. Since desferrioxamine administration attenuates this syndrome, non-transferrin-bound-iron (NTBI) released into the perfusing medium during CABG was implicated as a catalyst for oxygen radical formation. From 13 patients with "redo" CABG, specimens were collected from the coronary sinus (influx) and the aortic vent (efflux) after each distal coronary anastomosis. Specimens were subjected to sieving chromatography, and fractions were analyzed for total iron and NTBI using atomic absorption spectrometry (AAS). A statistically significant increase in NTBI was measured in influx (p = 0.002) and efflux samples (p = 0.023) collected after each graft. The combined amount of NTBI measured in these specimen was proportional to the CK-MB increase measured in the patients' sera on the day of surgery and the subsequent day. NTBI which accumulated in the circulatory bypass fluid during CABG may catalyze the generation of free radicals in the myocardium when body temperature is restored. This may aggravate myocardial damage as reflected by a post-surgical increase in CK-MB concentrations. Studies are in progress to develop new methods for the removal of NTBI during cardiac surgery. Tissue injury occurs with reperfusion during ischemia. This has been attributed to oxygen-derived free radicals that are generated by substances released from hypoxic areas (Kloner, Przyklenk et al., 1989; McCord, 1998). Reperfusion injury, i.e. the "reperfusion syndrome," occurs after coronary artery bypass grafting (CABG) when the ischemic myocardium is again provided with a supply of blood. Its most serious manifestations are arrhythmia and myocardial stunning (Ar"Rajab, Dawidson et al., 1996; Ferrari, Ceconi et al, 1996). The role of iron in reperfusion injury has been implicated by indirect evidence: during the reperfusion syndrome, the binding of iron with the chelator desferrioxamine (Ambrosio, Zweier et al., 1987; Bel, Martinod et al., 1996), or the administration of exogenous apo-transferrin, improved cardiac contractility and delayed manifestations of cardiac injury (Tiede, Sareen et al., 1990). Iron, as a transition metal, is able to catalyze free radical formation when released into the circulation from endogenous stores as non-transferrin-bound-iron (NTBI). This iron may be bound to small proteins or inorganic ligands (Halliwell and Gutteridge, 1984; Pollock and Campana, 1980; Zweier, 1992). A method for the measurement of NTBI was recently developed (Ambrus, Stadler et al., 1999). The purpose of this study was to explore whether a correlation exists among (a) the amount of NTBI released during CABG surgery, (b) the length of time of myocardial ischemia, and (c) the myocardial damage that occurs during cardiopulmonary bypass.

Removal of non-transferrin-bound iron from blood with iron overload using a device with immobilized desferrioxamine.

An extracorporeal hollow-fiber device with immobilized desferrioxamine (DFO) was developed for the removal of nontransferrin-bound iron (NTBI) from blood, without the toxicity of parenteral chelation. When blood circulates through the fibers having pores with 30 kD cut-off, non-transferrin-bound-iron (NTBI) crosses the fiber pores and is chelated by the immobilized desferrioxamine. Removal of circulating iron stimulates iron release from larger proteins and tissue stores, establishing continuous iron flow to the immobilized chelator. During in vitro circulation through a device, iron removed from blood of hemodialysis or sickle cell patients was proportional to, but always in less than 50% of the initial iron level. We attribute the inability to remove more serum iron to irreversible iron binding by transferrin. To investigate where removable and fixed iron was bound, iron binding proteins were analyzed in sera from six patients with genetic anemias and iron overload. Sera separated by sieving chromatography contained 1-14% of the iron in the < 30 kD protein pool, 26-48% was in the combined non-transferrin pools. Sera from hemochromatosis patients without iron overload did not contain NTBI. Circulation of hemochromatosis blood through the device removed one third of the iron, this came from all molecular weight fractions. Iron removal by the device from the < 30 kD pool appears to establish a disequilibrium, that stimulates continuous iron release from ligands with low iron affinity, renewing the pool in the < 30 kD range, which includes potentially toxic NTBI. Therapy with the chelator device having immobilized desferrioxamine should be beneficial for treatment of patients with iron overload.