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Nephrogenic systemic fibrosis after gadopentetate dimeglumine exposure: case series of 36 patients

Mon, 05/04/2015 - 4:16pm

PURPOSE: To retrospectively assess the association between gadopentetate dimeglumine exposure at magnetic resonance imaging and the development of nephrogenic systemic fibrosis (NSF).

MATERIALS AND METHODS: This HIPAA-compliant study had institutional review board approval. Informed consent was waived. A search of medical and pathologic records was performed to identify patients with NSF that was diagnosed between January 1998 and December 2007. Patients with known exposure to gadolinium-based contrast agents other than gadopentetate dimeglumine were excluded. Medical records were then reviewed for gadopentetate dimeglumine exposure, renal status, concomitant diseases, timing of NSF symptom onset, date of NSF diagnosis, and clinical outcome. Skin gadolinium deposition was assessed for those patients with adequate available tissue. Spearman rank correlations were estimated to assess the relationship between the dose of gadopentetate dimeglumine and the time to onset of NSF.

RESULTS: Thirty-six patients (mean age, 62.6 years; range, 30-83 years) had been exposed to gadopentetate dimeglumine prior to NSF onset. All had stage 5 chronic kidney disease and all but one were undergoing dialysis at the time of exposure. NSF developed within 3 months after the last gadopentetate dimeglumine exposure (range, 1-59 months) in 21 (66%) of 32 patients. The patients had been exposed to median cumulative gadopentetate dimeglumine volumes of 35, 40, 85, and 117.5 mL over the 3, 12, and 24 months and up to 11 years preceding the onset of NSF, respectively. Patients who received higher cumulative and total gadopentetate dimeglumine doses had a higher risk of developing NSF than did those who received lower doses (odds ratio = 1.2). Twenty (56%) of 36 patients died, with a median interval of 18 months between NSF symptom onset and death.

CONCLUSION: NSF develops in patients with renal impairment after exposure to gadopentetate dimeglumine in a dose- and time-dependent manner.


E-selectin, interleukin 18, serum amyloid a, and matrix metalloproteinase 9 are associated with clinical response to golimumab plus methotrexate in patients with active rheumatoid arthritis despite methotrexate therapy

Mon, 05/04/2015 - 4:16pm

OBJECTIVE: To assess the effect of golimumab (human monoclonal antibody to tumor necrosis factor-alpha) plus methotrexate (MTX) on selected inflammatory biomarkers, and to determine if these effects predict clinical response in rheumatoid arthritis (RA).

METHODS: Sera from adults with active RA despite MTX therapy, who received subcutaneous injections of placebo + MTX (MTX alone, n = 34) or golimumab 50 or 100 mg every 2 or 4 weeks + MTX (n = 137), were analyzed for levels of C-reactive protein (CRP), serum amyloid A (SAA), interleukin 18 (IL-18), E-selectin, matrix metalloproteinase 9 (MMP-9), and tissue inhibitor of matrix metalloproteinase 1 (TIMP-1).

RESULTS: Golimumab + MTX treatment significantly decreased serum CRP, SAA, IL-18, E-selectin, TIMP-1, and MMP-9 levels (median percent changes of -4.1% to -74.3% across treatment groups) versus MTX alone (-5.8% to 9.7%) when first measured at Week 4; decreases were sustained through Week 16. Larger magnitudes of decrease in all biomarkers were observed for clinical responders versus nonresponders. For golimumab + MTX, regression analyses including all biomarkers and select clinical measures showed that reductions in levels of several markers (SAA, E-selectin, MMP-9) as early as Week 4 correlated significantly with improvement in swollen joint count (SJC) at Week 16, as did reductions in E-selectin with improvement in tender joint count at Week 16. After accounting for the biomarkers, however, treatment group was no longer significant for SJC.

CONCLUSION: Significant decreases in several inflammatory biomarkers were associated with golimumab + MTX therapy. Decreases in serum levels of SAA, E-selectin, and MMP-9 at Week 4 may be useful in predicting clinical response at Week 16.

Physician ability to assess rheumatoid arthritis disease activity using an electronic medical record-based disease activity calculator

Mon, 05/04/2015 - 4:16pm

OBJECTIVE: To assess physicians' concordance with Disease Activity Score in 28 joints (DAS28) categories calculated by an electronic medical record (EMR)-embedded disease activity calculator, as well as attitudes toward this application.

METHODS: Fifteen rheumatologists used the EMR-embedded disease activity calculator to predict a rheumatoid arthritis (RA) DAS28 disease activity category at the time of each clinical encounter.

RESULTS: Physician-predicted DAS28 disease activity categories ranged from high ( > 5.1, 15% of cohort, 66 of 429 patient visits) to moderate ( > 3.2-5.1, 21% of cohort, 90 of 429 patient visits) to low (2.6-3.2, 29% of cohort, 123 of 429 patient visits) to remission ( < 2.6, 35% of cohort, 150 of 429 patient visits). Overall concordance between calculated DAS28 results and physician-predicted RA disease activity was 64%. Using either the physician-predicted or the calculated DAS28 category as the gold standard, accuracy was greatest for patients in remission (75% and 88% accuracy, respectively) and those with high disease activity (68% and 79% accuracy, respectively), and less for patients with moderate (48% and 62% accuracy, respectively) or low disease activity (62% and 31% accuracy, respectively).

CONCLUSION: Accurate physician prediction of DAS28 remission and high disease activity categories, even without immediate availability of the erythrocyte sedimentation rate or the C-reactive protein level at the time of the visit, may be used to guide quantitatively driven outpatient RA management.

A rheumatology-specific informatics-based application with a disease activity calculator

Mon, 05/04/2015 - 4:16pm

OBJECTIVE: To design a rheumatology-specific tool with a disease activity calculator integrated into the electronic medical records (EMRs) at our institution and assess physicians' attitudes toward the use of this tool.

METHODS: The Rheumatology OnCall (ROC) application culls rheumatology-pertinent data from our institution's laboratory, microbiology, pathology, radiology, and pharmacy information systems. Attending rheumatologists and rheumatology fellows accessed the ROC and disease activity calculator during outpatient visits at the time of the clinical encounter.

RESULTS: During the 12-week study period, 15 physicians used the ROC application and the disease activity calculator during 474 and 429 outpatient clinic visits, respectively. In weekly survey responses, physicians reported that use of the ROC interface improved patient care in 140 (78%) of 179 visits, and that the Disease Activity Score in 28 joints (DAS28) results at the time of the visit would not have changed patient management in 157 (88%) of these, although seeing a trend in DAS28 was useful in 149 (96%) of 156 visits. At the study's conclusion, most physicians reported that the ROC application was useful (11 of 12 physicians) and that seeing a trend in DAS28 improved daily patient care (12 of 13 physicians).

CONCLUSION: The ROC application is useful in daily rheumatologic care, and the disease activity calculator facilitates management of patients with rheumatoid arthritis. However, widespread acceptance and use of such tools depend upon the general acceptance of and access to EMRs in the clinical setting. The utility of the disease activity calculator may be limited by the lack of available acute-phase reactant results at the time of the clinical encounter.

Imatinib mesylate treatment of nephrogenic systemic fibrosis

Mon, 05/04/2015 - 4:16pm

OBJECTIVE: To examine the effectiveness of imatinib mesylate in the treatment of nephrogenic systemic fibrosis (NSF).

METHODS: Two patients with stage 5 chronic kidney disease and NSF were treated with oral imatinib mesylate at a dosage of 400 mg/day. Skin thickening and tethering were assessed using the modified Rodnan skin thickness score (MRSS), and knee joint flexion contractures were measured with a goniometer.

RESULTS: Each patient displayed progressive reduction of skin thickening and tethering, with a steady decrease in the MRSS, following the initiation of imatinib mesylate treatment. The patient who had knee joint contractures achieved increased knee extension with passive range-of-motion exercises once his skin thickening and tethering had begun to decrease. Within weeks of stopping imatinib mesylate, the skin changes recurred in each patient. Recurrent skin thickening and tethering again improved in the patient who resumed taking imatinib mesylate for longer than 2 weeks. Skin biopsies performed both before and after initial dosing of that patient revealed less fibrosis and less staining for type I procollagen after imatinib mesylate treatment, but essentially unchanged tissue gadolinium content.

CONCLUSION: Imatinib mesylate treatment decreases fibrosis and results in the relatively rapid and steady improvement of skin changes and knee joint contractures in patients with stage 5 chronic kidney disease and NSF, despite the persistence of gadolinium in the tissues. Because skin changes recurred after discontinuation of imatinib mesylate, the duration for which treatment may be required is undetermined.

Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate: a randomized, double-blind, placebo-controlled, dose-ranging study

Mon, 05/04/2015 - 4:16pm

OBJECTIVE: To assess the efficacy, safety, and pharmacology of subcutaneous administration of golimumab in patients with active rheumatoid arthritis (RA) despite treatment with methotrexate (MTX).

METHODS: Patients were randomly assigned in a double-blinded manner to receive injections of placebo plus MTX or 50 mg or 100 mg golimumab every 2 or 4 weeks plus MTX through week 48. Patients originally assigned to receive injections every 2 weeks had the interval increased to every 4 weeks starting at week 20. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 16. The study was powered to detect a difference in the primary end point when the combined golimumab groups and at least 1 of the individual dose groups were compared with placebo.

RESULTS: The primary end point was attained. Sixty-one percent of patients in the combined golimumab plus MTX dose groups achieved an ACR20 response at week 16 compared with 37% of patients in the placebo plus MTX group (P=0.010). In addition, 79% of patients in the group receiving 100 mg golimumab every 2 weeks achieved an ACR20 response (P < 0.001 versus placebo). Through week 20 (after which patients receiving placebo were switched to active infliximab therapy), serious adverse events were reported in 9% of patients in the combined golimumab groups and in 6% of patients in the placebo group.

CONCLUSION: Golimumab plus MTX effectively reduces the signs and symptoms of RA and is generally well tolerated in patients with an inadequate response to MTX.

Cutaneous changes of nephrogenic systemic fibrosis: predictor of early mortality and association with gadolinium exposure

Mon, 05/04/2015 - 4:16pm

OBJECTIVE: Nephrogenic systemic fibrosis (NSF) is a rapidly progressive, debilitating condition that causes cutaneous and visceral fibrosis in patients with renal failure. Little is known about its prevalence or etiology. The aim of this study was to establish the prevalence of NSF and associated risk factors

METHODS: Two cohorts of patients were recruited from 6 outpatient hemodialysis centers and examined for cutaneous changes of NSF, which were defined using a scoring system based on hyperpigmentation, hardening, and tethering of skin on the extremities. Demographic data were gathered, mortality was followed up prospectively for 24 months, and gadolinium exposure was ascertained for a subgroup of patients in the second cohort.

RESULTS: Examination reproducibility was 97% in cohort 1. In cohort 2, 25 (13%) of 186 patients demonstrated cutaneous changes of NSF. Twenty-four-month mortality following examination was 48% and 20% in patients with and those without cutaneous changes of NSF, respectively (adjusted hazard ratio 2.9, 95% confidence interval [95% CI] 1.4-5.9). Cutaneous changes of NSF were observed in 16 (30%) of 54 patients with prior exposure to gadopentetate dimeglumine contrast during imaging studies. Exposure to gadolinium-containing contrast was associated with an increased risk of developing cutaneous changes of NSF (odds ratio 14.7, 95% CI 1.9-117.0) compared with nonexposed patients.

CONCLUSION: In patients receiving hemodialysis, NSF is an underrecognized disorder that is associated with increased mortality. Exposure to gadolinium-containing contrast material appears to be a significant risk factor for the development of NSF.

beta(2)-Microglobulin modified with advanced glycation end products delays monocyte apoptosis

Mon, 05/04/2015 - 4:16pm

BACKGROUND: A local inflammatory reaction to beta(2)-microglobulin (beta(2)m) amyloid deposits by monocytes/macrophages is a characteristic histologic feature of dialysis-related amyloidosis (DRA). Since beta(2)m modified with advanced glycation end products (AGE-beta(2)m) is a major constituent of amyloid in DRA, we tested the hypothesis that AGE-beta(2)m affects apoptosis and phenotype of human monocytes.

METHODS: Human peripheral blood monocytes were incubated with or without in vitro-derived AGE-beta(2)m, and their viability, extent of apoptosis, morphology, and function examined over the subsequent four days.

RESULTS: AGE-modified but not unmodified beta(2)m significantly delayed spontaneous apoptosis of human peripheral blood monocytes in adherent and nonadherent cultures. The effect of AGE-beta(2)m on monocytes apoptosis was time- and dose-dependent and was attenuated by a blocking antibody directed against the human AGE receptor (RAGE). There was no difference in effect between AGE-beta(2)m and that of AGE-modified human serum albumin. Culture of monocytes with AGE-beta(2)m did not alter membrane expression of Fas or Fas ligand. Monocytes cultured with AGE-beta(2)m underwent substantial changes in morphology similar to those observed when monocytes differentiate into macrophages. The cultured cells increased in size and vacuolization, and their content of beta-glucuronidase and acid phosphatase increased by 5- to 10-fold at day 4. Expression of the monocyte--macrophage membrane antigens HLA-DR, CD11b, and CD11c also increased at day 4. Although exhibiting phenotypic characteristics of macrophages, monocytes cultured with AGE-beta(2)m functioned differently than macrophages cultured with serum. Superoxide production in response to phorbol myristic acetate was maintained in monocytes cultured with AGE-beta(2)m, but declined with time in cells cultured with serum. Constitutive synthesis of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and prostaglandin E2 (PGE2) increased in monocytes cultured for four to six days with AGE-beta(2)m.

CONCLUSIONS: These findings support a novel role for AGE-modified proteins such as AGE-beta(2)m that may contribute to the development of a local inflammatory response, with predominant accumulation of monocytes/macrophages, in DRA.

Beta 2-microglobulin modified with advanced glycation end products modulates collagen synthesis by human fibroblasts

Mon, 05/04/2015 - 4:16pm

Beta 2-microglobulin amyloidosis (A beta 2m) is a serious complication for patients undergoing long-term dialysis. beta 2-microglobulin modified with advanced glycation end products (beta 2m-AGE) is a major component of the amyloid in A beta 2m. It is not completely understood whether beta 2m-AGE plays an active role in the pathogenesis of A beta 2m, or if its presence is a secondary event of the disease. beta 2-microglobulin amyloid is mainly located in tendon and osteo-articular structures that are rich in collagen, and local fibroblasts constitute the principal cell population in the synthesis and metabolism of collagen. Recent identification of AGE binding proteins on human fibroblasts lead to the hypothesis that the fibroblast may be a target for the biological action of beta 2m-AGE. The present study demonstrated that two human fibroblast cell lines exhibited a decrease in procollagen type I mRNA and type I collagen synthesis after exposure to beta 2m-AGE for 72 hours. Similar results were observed using AGE-modified albumin. Antibody against the RAGE, the receptor for AGE, attenuated this decrease in synthesis, indicating that the response was partially mediated by RAGE. In addition, antibody against epidermal growth factor (EGF) attenuated the decrease in type I procollagen mRNA and type I collagen induced by beta 2m-AGE, suggesting that EGF acts as an intermediate factor. These findings support the hypothesis that beta 2m-AGE actively participates in connective tissue and bone remodeling via a pathway involving fibroblast RAGE, and at least one interposed mediator, the growth factor EGF.

Aminoguanidine inhibits advanced glycation end products formation on beta2-microglobulin

Mon, 05/04/2015 - 4:16pm

Because advanced glycation end products (AGE)-modified beta2-microglobulin (AGE-beta2M) is a dominant constituent of amyloid in dialysis-related amyloidosis (DRA), AGE-beta2M may be directly involved in the pathobiology of DRA. In experimental diabetes mellitus, blocking the formation of AGE prevents AGE-mediated tissue damage. In this study, it is postulated that similar pharmacologic intervention may be beneficial in DRA. Aminoguanidine, a nucleophilic hydrazine compound that prevents AGE formation on collagen, may have a similar effect on the advanced glycation of beta2M. To test this hypothesis, beta2M was incubated in vitro with 50 or 100 mM D-glucose for 3 wk in the presence and absence of incremental concentrations of aminoguanidine. On the basis of enzyme-linked immunosorbent assay and immunoblots using anti-AGE-keyhole limpet hemocyanin antibody, aminoguanidine inhibited glucose-induced N(epsilon)-(carboxymethyl)lysine formation on beta2M. At aminoguanidine-glucose molar ratios of 1:8 to 1:1, 26 to 53% inhibition occurred. Fluorospectrometry examination showed that aminoguanidine also inhibited the formation of fluorescent AGE on beta2M in a dose-dependent manner. At aminoguanidine-glucose molar ratios of 1:8 to 1:1, fluorescent product generation was inhibited by 30 to 70%. Furthermore, aminoguanidine suppressed the AGE formation on beta2M bound to AGE-modified collagen. If aminoguanidine is similarly active in vivo, this compound may be of clinical utility for treating DRA in patients on maintenance dialysis.

Interaction between beta 2-microglobulin and advanced glycation end products in the development of dialysis related-amyloidosis

Mon, 05/04/2015 - 4:16pm

Dialysis related amyloidosis (DRA) is a progressive debilitating complication of long-term dialysis. beta 2-microglobulin (beta 2m) amyloid deposition occurs preferentially in older patients and initially is located in collagen-rich osteo-articular tissues. Since an age-dependent increase in the formation of advanced glycation end products (AGE) has been observed in collagen-containing structures, we hypothesized that AGE-modified beta 2m in the amyloid of DRA may be formed locally in osteo-articular structures as a subsequent event of its binding to collagen-AGE. Based on this hypothesis, we investigated the binding between beta 2m and AGE-modified collagen (collagen-AGE) in vitro. Significantly larger amounts of human beta 2m were bound to types I to IV of immobilized collagen-AGE than to unmodified collagens (P < 0.0001). The quantity of beta 2m bound to collagen-AGE was dependent on the concentrations of both beta 2m and of AGE contained in collagen (P < 0.01). Unmodified beta 2m was more avidly bound to collagen-AGE or collagen in comparison to AGE-modified beta 2m (P < 0.0001). beta 2m bound to collagen-AGE could be modified further by nonenzymatic glycosylation during three weeks of incubation with physiologic concentrations of glucose. Similar processes in vivo may be important in the pathobiology of DRA.

Performance characteristics of a dialysis-related amyloidosis questionnaire

Mon, 05/04/2015 - 4:16pm

To evaluate the effects of beta-2 microglobulin amyloidosis on functional status, a 19-item self-administered questionnaire exploring two major domains-symptoms and disability-was developed as part of this study. Fifteen patients with dialysis-related amyloidosis (DRA) were identified and compared with 15 age-matched control subjects who had been on hemodialysis for less than 24 months. Demographic data, Charlson comorbidity scores, and other clinical and laboratory variables were recorded. Total dialysis-related amyloidosis questionnaire (DRAQ) score (52.1 +/- 16.3 versus 24.4 +/- 6.2, P < 0.0001) and the scores of the symptom (24.5 +/- 7.0 versus 11.5 +/- 2.3, P < 0.0001) and disability (27.5 +/- 10.8 versus 12.9 +/- 4.0, P < 0.0001) subscales were markedly increased among patients with DRA. Baseline characteristics among case and control subjects were similar, except for serum creatinine concentration, which tended to be lower among patients with DRA (8.9 +/- 2.6 versus 11.5 +/- 2.3 mg/dL, P = 0.07). Instrument reliability and internal consistency were high. With a total DRAQ score of 30 or more, the sensitivity and specificity of the instrument were 93% and 80%, respectively. The DRAQ is a reliable, internally consistent, and valid instrument that may be suitable for population screening and clinical practice.

Enhancement of human monocyte beta-glucan receptors by glucocorticoids

Mon, 05/04/2015 - 4:16pm

Glucocorticoids are potent and diverse in their effects on mononuclear phagocytes, ranging from suppression to stimulation. To determine whether glucocorticoids affected functions mediated by monocyte beta-glucan receptors, human mononuclear cells (MNC) were incubated for 20 hr at 37 degrees with 20-2000 nM dexamethasone or hydrocortisone, and the monocytes were subsequently assayed for their ingestion of purified yeast glucan particles. Prior treatment with dexamethasone or hydrocortisone enhanced monocyte phagocytosis of glucan particles in a dose-dependent manner and both steroids effected a twofold increase at 200 nM. Monocytes from three different donors were assessed for secretion of beta-N-acetylglucosaminidase, and all were increased by exposure to 200 nM dexamethasone for 20 hr and subsequent stimulation with glucan particles for 2 hr; the average percentage net release was 16.2%. The enhancement in monocyte phagocytosis of glucan particles did not result by culture of MNC with beta-oestradiol, progesterone, testosterone or spironolactone, indicating a specificity for corticosteroids with glucocorticoid activity. The increases in phagocytic activity by monocytes that had been exposed during culture to either 200 nM dexamethasone or 200 nM hydrocortisone were both reduced by 40-50% by pretreatment of monocytes with the anti-idiotype (anti-Id) that recognizes beta-glucan receptors. Exposure of cells to 200 nM dexamethasone for 2 hr and washing before continued incubation for 18 hr in steroid-free media resulted in stimulation of monocyte beta-glucan receptors, whereas similar exposure without subsequent culture or with the addition of cycloheximide for the final 18 hr did not. Thus, glucocorticoids enhance monocyte functions mediated by beta-glucan receptors, and this stimulation is dependent on proteins that are newly synthesized during culture.

Utility of high-resolution ultrasound for the diagnosis of dialysis-related amyloidosis

Mon, 05/04/2015 - 4:16pm

OBJECTIVE: To evaluate the utility of real-time, high-resolution ultrasound of the shoulder in the diagnosis of dialysis-related amyloidosis.

METHODS: We performed a case series study of 2 groups of patients seen at a referral-based clinic in a tertiary care hospital. The shoulders of 13 patients with normal renal function and of 38 patients receiving long-term hemodialysis were studied by real-time, high-resolution ultrasound. All hemodialysis patients were evaluated clinically for the presence of dialysis-related amyloidosis. Surgical specimens of joints were available for all 13 patients with normal renal function and for 17 of the 38 hemodialysis patients. These specimens were evaluated for the presence of beta 2-microglobulin (beta 2m) amyloid by Congo red and immunohistochemical staining.

RESULTS: Two ultrasonographic findings were selectively observed in the dialysis patients with clinical and histologic evidence of beta 2m amyloid in comparison with patients with normal renal function and no evidence of amyloid: rotator cuffs greater than 8 mm in thickness and echogenic pads between muscle groups of the rotator cuff. The presence of at least 1 of these 2 findings corresponded to the presence of clinically and histologically evident beta 2m amyloid with a sensitivity of 79% and a specificity of 100%. When additional patients without surgical specimens for histologic confirmation of amyloidosis were included, the sensitivity of these 2 sonographic findings was 72% and the specificity was 97%.

CONCLUSION: Real-time, high-resolution ultrasound is a relatively sensitive and highly specific noninvasive adjunct to the clinical diagnosis of beta 2m amyloidosis in patients receiving long-term hemodialysis.

Isolation and characterization of beta-glucan receptors on human mononuclear phagocytes

Mon, 05/04/2015 - 4:16pm

beta-glucan receptors, with ligand specificity for yeast and fungal carbohydrate polymers, have been studied as phagocytic receptors of human monocytes. To characterize their structure, binding studies were carried out with human U937 cells and a rabbit IgG anti-Id that recognizes epitopes on monocyte beta-glucan receptors. Unstimulated U937 cells specifically bound large amounts of the anti-Id, but almost none of the control anti-isotype. At saturation, the number of anti-Id molecules bound per U937 cell was 2.6 x 10(6) with an apparent Ka of 1.9 x 10(7) M-1. Immunoprecipitates from detergent lysates of surface-radioiodinated U937 cells contained only two membrane proteins with antigenic specificity for the anti-Id, one having a mol wt of 180 kD and the other 160 kD. Both proteins were disulfide-linked and presented, after reduction, as five polypeptides of 95, 88, 60, 27, and 20 kD. Detergent lysates of unlabeled U937 cells, purified by affinity chromatography on anti-Id-Sepharose, yielded the same two nonreduced proteins and five reduction products in slab gels stained with Coomassie blue. In Western blots probed with the anti-Id, the most immunoreactive nonreduced and reduced affinity-purified products were the 160 and 20 kD molecules, respectively. Immunoblots of two-dimensional gels showed the 180 and 160 kD proteins to express a common epitope through disulfide linkage to the 20 kD polypeptide. By immunoblot analysis, U937 cell glucan-binding proteins from detergent lysates contained two cell proteins antigenic for the anti-Id that were indistinguishable from affinity-purified molecules in size and subunit composition. Studies of affinity-purified proteins from detergent lysed human monocytes were characterized by immunoblot analysis and found to be identical to U937 cell beta-glucan receptors. They consisted of two disulfide-linked proteins, with mol wt of 180 and 160 kD, and had in common a 20 kD polypeptide with the anti-Id epitope.

Identification and characterization of opsonic fibronectin in synovial fluids of patients with active rheumatoid arthritis

Mon, 05/04/2015 - 4:16pm

A cofactor that selectively opsonizes particulate activators of the human alternative complement pathway and enhances their phagocytosis by human monocytes was identified in synovial fluids of patients with rheumatoid arthritis. The active material was present in fluids treated with protease inhibitors, was heat stable, and was unaffected by incubation with hyaluronidase. Chromatographic isolation of synovial fluid fibronectin by gelatin affinity and by immunoaffinity on antifibronectin monoclonal antibody BD4 yielded similar quantities of protein for each of 3 fluids. Synovial fluid proteins with the BD4 fibronectin epitope accounted for essentially all of the phagocytosis-enhancing activity and expressed this activity by opsonizing target activators. Additional chromatographic analyses of synovial fluid fibronectin with the BD4 epitope were carried out using Sepharose-bearing gelatin and 4 additional antifibronectin monoclonal antibodies. The opsonic materials were characterized as having 2 distinct fibronectin epitopes, which always mapped from the cell adhesive domain to the carboxyl-terminus of plasma fibronectin, but only rarely contained the gelatin binding domain.

Activation of CD4 cells by fibronectin and anti-CD3 antibody. A synergistic effect mediated by the VLA-5 fibronectin receptor complex

Mon, 05/04/2015 - 4:16pm

In this study, fibronectin synergized with anti-CD3 antibody to promote CD4 cell proliferation in a serum-free culture system. The cell-adhesive domain plus additional regions of the fibronectin molecule are involved in this synergy. Anti4B4(CDw29) antibody blocked the activation of CD4 cells in this system. Furthermore, it is the VLA-5 protein within the set of molecules recognized by anti-4B4 that serves as a fibronectin receptor on the CD4 lymphocytes. The VLA-5 fibronectin receptor was mainly expressed on CD4+ CD45R-CDw29+ cells and may in part contribute to the unique function of these cells.

Synovial fluid eosinophilia in Lyme disease

Mon, 05/04/2015 - 4:16pm

We describe three 14-year-old boys who developed synovial fluid eosinophilia associated with Lyme disease. One patient, with arthritis that began in 1975, had the first documented case of Lyme disease in New Jersey. Lyme disease should be considered when eosinophilia is noted on analysis of synovial fluid from patients with undiagnosed arthritis.

Separation of functionally distinct subpopulations of Corynebacterium parvum-activated macrophages with predominantly stimulatory or suppressive effect on the cell-mediated cytotoxic T cell response

Mon, 05/04/2015 - 4:16pm

Peritoneal cells (PEC) from mice injected ip with Corynebacterium parvum (CP) showed greatly enhanced suppressive activity on the growth of syngeneic tumor cells and on the generation of alloreactive cytotoxic T lymphocytes (CTL) in vitro. On the other hand, CP-activated PEC exhibited increased immunostimulatory (accessory or A cell) activity as measured by the restoration of the CTL response of nonadherent spleen cells. After fractionation of the CP-activated PEC according to cell size by velocity sedimentation, the mutually antagonistic A cell and immunosuppressive activities were clearly separated and found to be associated with functionally distinct subpopulations of macrophages. Thus A cell function was detected in fractions rich in small and medium sized macrophages which were probably derived from recently arrived monocytes. Immunosuppressive (and anti-tumor) activity was associated with the largest macrophages which were almost devoid of A cell function and probably represented a highly activated and differentiated macrophage subpopulation.

Location of All-cause 30-day Readmission Following Total Joint Replacement: Surgical Hospital Versus Outside Hospital

Fri, 05/01/2015 - 11:35am

Background: Evaluating posthospital complications and hospital readmissions in the United States is limited under the current system. This is due to an inability to quantify posthospital care delivered to patients at locations other than the surgical hospital. In order to circumvent this issue, information can be sought directly from patients about posthospital health care utilization. This approach provides a more complete record in comparison with methods that evaluate complications treated only at the surgical hospital.

Methods: Participants undergoing total joint replacement (TJR) between 5/10/11 and 5/17/11 were identified from the Function and Outcomes Research in Comparative Effectiveness Registry (FORCE-TJR) cohort. The cohort is a nationally representative sample of TJR patients undergoing total knee replacement and total hip replacement. Patients are asked to self-report complications on the six-month follow-up questionnaire. The questionnaire specifically inquires about any emergency department visit, outpatient surgery, or hospital admission that occurred within six months of the total joint replacement surgery. For each positive report of postoperative complication, the pertinent medical records are retrieved and reviewed and discharge diagnoses are used to identify whether the complication is a surgical site symptom or a medical complication. The location of the care is identified as the surgical hospital or an outside hospital. We report on the location of all readmissions within 30 days of discharge from the initial TJR surgery.

Results: In total, our sample yielded 112 validated patient-reported readmissions following TJR. Of these readmissions, 75% were treated at the surgical hospital and 25% were treated at an outside hospital. Patients receiving care at the surgical hospital were similar in terms of demographics compared with those seeking care at an outside hospital in terms of mean age (66.7 years vs. 66.9 years, p=0.92), and gender (67.9% male vs. 63.1% male, p=0.65). Additionally, the mean number of days since discharge was similar (16.7 days vs. 15.1 days, p = 0.45) among patients treated at the surgical hospital compared with those treated at an outside hospital. Discharge diagnoses varied by the location of care. At the surgical hospital, discharge diagnoses identified surgical site symptoms as the cause of 36.9% of admissions and medical conditions as the cause of 63.1% of admissions. When compared with discharge diagnoses at outside hospitals, surgical site symptoms accounted for 17.9% of admissions and medical conditions for 82.1% (p=0.067).

Conclusion: Public reporting of all post-TJR discharge complications is currently used to compare quality of care between hospitals. However, our study demonstrates that hospitals and surgeons may underestimate their complication rates by 25%. This suggests that novel approaches, such as direct to patient contact, are needed to minimize missing post-hospital event data.