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Biomedical subjects

R J Falk

Publications and source records attributed to R J Falk.

At least 37 records · Page 2Linked to original sources
PubMed2000

Antineutrophil cytoplasmic antibodies and associated diseases: a review of the clinical and laboratory features.

There have been a number of recent advances in this field. First, the "International Consensus Statement on Testing and Reporting of Antineutrophil Cytoplasmic Antibodies (ANCA)" has been developed to optimize ANCA testing. It requires that all sera are tested by indirect immunofluorescent (IIF) examination of normal peripheral blood neutrophils and, where there is positive fluorescence, in enzyme-linked immunosorbent assays (ELISAs) for antibodies against both proteinase 3 (PR3) and myeloperoxidase (MPO). Testing will be further improved when international standards and common ELISA units are available. Second, new diagnostic criteria for the small vessel vasculitides that take into account ANCA-positivity and target antigen specificity as well as histologic features are currently being produced. Third, we understand that the complications associated with treatment of the ANCA-associated vasculitides are often more hazardous than the underlying disease, and regimens that use effective but less toxic agents are being evaluated. The factors associated with increased risk of relapse, however, remain incompletely understood. Finally, ANCA with specificities other than PR3 and MPO are present in many nonvasculitic autoimmune diseases. Their clinical significance is still largely unclear, and some of the target antigens are present in other cells as well as neutrophils and thus are not strictly "ANCA."

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2000

The life readiness program: a physical rehabilitation program for patients on hemodialysis.

Patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD) are typically sedentary and functionally limited as a consequence of their condition. The purpose of this study is to test the effect of a lifestyle physical rehabilitation program (The Life Readiness Program) on physical function in patients with ESRD undergoing HD. Physical function was measured by the Kidney Disease Quality of Life Short Form (KDQOL-SF) physical function score (range, 0 to 100). Eighty-two patients were randomly assigned to a 6-month rehabilitation program (intervention; n = 39) or to standard clinical management alone (control; n = 43). The groups were frequency matched by age, sex, ethnicity, and diabetes as the cause of ESRD. General linear modeling of the change in physical function score was used for multivariate analysis. Physical function scores were not different between groups at baseline. Change in physical function score increased significantly in the intervention group compared with the control group when data were adjusted for the matching variables and adequacy of dialysis (3.2, -3.6; P = 0.04). Additionally, the control group reported more problems with work or daily functions because of emotional problems (P: </= 0.05). In this brief 6-month intervention, The Life Readiness Program showed the therapeutic benefit of a lifestyle rehabilitation program on functional outcomes and health-related quality of life for patients with ESRD undergoing hemodialysis.

Adolescent↗
PubMed2000

Future molecular approaches to the diagnosis and treatment of glomerular disease.

Current diagnoses and treatment decisions for renal disease are made based upon a combination of clinical and pathological determinations. With the advances in both biochemical and molecular biological techniques, identifying the underlying biochemical and genetic changes that may have initiated and/or contributed to the disease is possible. We describe here technologies that may lead to significant changes in renal disease diagnosis, characterization, treatment, and potentially prevention. For example, differential display techniques and DNA gene chip arrays show the changes in mRNA expression patterns and can potentially identify previously unknown genes and reveal new roles for previously known genes in renal disease. The generation of the single nucleotide polymorphisms (SNP) genomic map will facilitate genetic screening that may identify a gene or combination of genes that produce enhanced disease susceptibility. Combining genomic analysis with epidemiological studies may identify environmental factors that contribute to renal disease onset in genetically susceptible individuals. A number of novel therapies are already on the horizon. These include reagents that abrogate the function of specific cytokines, chemokines, and effector cells. With the list of renal disease genes in hand, their role in renal physiology and pathophysiology can be determined, which should lead to the discovery of pharmacological intervention directed at those genes and their products that play a role in the pathogenesis of renal disease.

Biotechnology↗
PubMed2000

ANCA glomerulonephritis and vasculitis: a Chapel Hill perspective.

Microscopic polyangiitis, Wegener's granulomatosis, Churg-Strauss syndrome, and pauci-immune necrotizing glomerulonephritis share pathogenic, pathological, and clinical features. They all involve capillaries, venules, arterioles, and small arteries. Approximately 90% of patients have autoantibodies either to myeloperoxidase (MPO-ANCA) or to proteinase 3 (PR3-ANCA). The clinical manifestations of ANCA-small vessel vasculitis are protean. These can be limited to the kidney alone, or may involve the upper respiratory tract, the lungs, the skin, or a number of other organs in various combinations. The characteristic feature of the glomerular lesion is a focal necrotizing glomerulonephritis associated with crescent formation and little or no glomerular staining for immunoglobulin by immunofluorescence microscopy. The renal manifestations can present as a rapidly progressive glomerulonephritis or that of a more indolent, remitting, and relapsing course that leads to substantial glomerulosclerosis. The two main prognostic markers of the long-term outcome are the presence of pulmonary hemorrhage (which accounts for at least half of all deaths) and the entry serum creatinine. The higher the entry serum creatinine, the higher the risk of developing end-stage renal disease. The treatment of ANCA-small vessel vasculitis and glomerulonephritis rests primarily on the use of induction high-dose corticosteroids and cyclophosphamide. Patients with pulmonary hemorrhage also benefit from plasmapheresis. With the use of an alkylating agent, the rate of remission is of the order of 75%, but relapses occur in about 30% of patients who achieve a remission, and in about 17% of patients after renal transplantation. Despite the improved outcome of patients with ANCA vasculitis in the recent decade, their long-term prognosis continues to be primarily determined by a rapid diagnosis, and the prompt institution of therapy.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1999

Diagnostic usefulness of antineutrophil cytoplasmic autoantibody serology. Comparative evaluation of commercial indirect fluorescent antibody kits and enzyme immunoassay kits.

Antineutrophil cytoplasmic autoantibodies (ANCAs) are increasingly used as serologic markers for pauci-immune crescentic glomerulonephritis and small vessel vasculitis. Many hospital laboratories and referral laboratories use commercial assay kits to detect ANCAs, despite inadequate documentation in the medical literature of kit performance. We evaluated the diagnostic sensitivity, specificity, and predictive value of 3 commercial indirect immunofluorescence assay (IFA) kits and 7 commercial enzyme immunoassay (EIA) kits for several ANCA subtypes. Serum samples from 396 patients with a variety of renal diseases were analyzed, including 146 patients with pauci-immune crescentic glomerulo-nephritis with or without systemic vasculitis. With 1 exception, the kits had more than 90% agreement with the reference standard and gave results similar to those of research laboratories. IFA diagnostic sensitivity ranged from 81% to 91% and EIA sensitivity from 75% to 84%. Maximum specificity was obtained with combined IFA and EIA. Diagnostic specificity was more than 70% for 2 of 3 IFA kits and at least 90% for 5 of 7 EIA kits. Predictive values varied with clinical manifestations. Most commercial IFA and EIA kits that were evaluated provide acceptably accurate analytic results.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1999

International Consensus Statement on Testing and Reporting of Antineutrophil Cytoplasmic Antibodies (ANCA)

Antineutrophil cytoplasmic antibody (ANCA) tests are used to diagnose and monitor inflammatory activity in the primary systemic small vessel vasculitides. ANCA is best demonstrated in these diseases by using a combination of indirect immunofluorescence (IIF) of normal peripheral blood neutrophils and enzyme-linked immunosorbent assays (ELISAs) that detect ANCA specific for proteinase 3 (PR3) or myeloperoxidase (MPO). For ANCA testing in "new" patients, IIF must be performed on all serum samples. Serum samples containing ANCA, any other cytoplasmic fluorescence, or an antinuclear antibody (ANA) that results in homogeneous or peripheral nuclear fluorescence then should be tested in ELISAs for PR3-ANCA and MPO-ANCA. Optimally, ELISAs for PR3-ANCA and MPO-ANCA should be performed on all serum samples. Inclusion of the most recent positive sample in the IIF or ELISA may help demonstrate a change in antibody level. Reports should use recommended terms. Any report of positive neutrophil fluorescence issued before the ELISA results are available should indicate that positive fluorescence alone is not specific for the diagnosis of Wegener granulomatosis or microscopic polyangiitis and that decisions about treatment should not be based solely on the ANCA results.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1999

Mycophenolate mofetil therapy in lupus nephritis: clinical observations.

Controlled clinical trials in renal transplantation have demonstrated that mycophenolate mofetil is well tolerated and has lower renal transplant rejection rates than azathioprine regimens. This study reports on the clinical experiences at two institutions with mycophenolate mofetil (MMF) for severe lupus nephritis. Twelve patients with relapsing or resistant nephritis previously treated with cyclophosphamide therapy and one patient who refused cyclophosphamide as initial therapy for diffuse proliferative nephritis but accepted MMF were included. During combined MMF/prednisone therapy, serum creatinine values remained normal or declined from elevated values: mean change in serum creatinine was -0.26+/-0.46 microM/L, P = 0.039. Proteinuria significantly decreased: mean change in urine protein-to-creatinine ratios was -2.53+/-3.76, P = 0.039. Decreased serum complement component C3 and elevated anti-double-stranded DNA antibody levels at baseline improved in some, but not all, patients. The mean initial dose of MMF was 0.92 g/d (range, 0.5 to 2 g/d). The mean duration of therapy was 12.9 mo (range, 3 to 24 mo). Adverse events included herpes simplex stomatitis associated with severe leukopenia (n = 1), asymptomatic leukopenia (n = 2), nausea/ diarrhea (n = 2), thinning of scalp hair (n = 1), pancreatitis (n = 1), and pneumonia without leukopenia (n = 1). Recurrence of the pancreatitis led to discontinuation of MMF in this patient; all other adverse events resolved with dose reduction. It is concluded that MMF is well tolerated and has possible efficacy in controlling major renal manifestations of systemic lupus erythematosus. Controlled clinical trials are needed to define the role of MMF in the management of lupus nephritis.

Adolescent↗
PubMed1998

Efficacy of treatment for unexplained infertility.

OBJECTIVE: To analyze the efficacy and cost-effectiveness of alternative treatments for unexplained infertility. DESIGN: Retrospective analysis of 45 published reports. SETTING: Clinical practices. PATIENT(S): Couples who met criteria for unexplained infertility. Women with Stage I or Stage II endometriosis were included. INTERVENTION(S): Observation; clomiphene citrate (CC); gonadotropins (hMG); IUI; and GIFT and IVF. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate. RESULT(S): Combined pregnancy rates per initiated cycle, adjusted for study quality, were as follows: no treatment = 1.3%-4.1%; IUI = 3.8%; CC = 5.6%; CC + IUI = 8.3%; hMG = 7.7%; hMG + IUI = 17.1%; IVF = 20.7%; GIFT = 27.0%. The estimated cost per pregnancy was $10,000 for CC + IUI, $17,000 for hMG + IUI, and $50,000 for IVF. CONCLUSION(S): Clomiphene citrate + IUI is a cost-effective treatment for unexplained infertility. If this treatment fails, hMG + IUI and assisted reproduction are efficacious therapeutic options.

Cost-Benefit Analysis↗
PubMed1998

Interleukin-8 delays spontaneous and tumor necrosis factor-alpha-mediated apoptosis of human neutrophils.

During inflammation, polymorphonuclear neutrophils (PMN) are exposed to and influenced by various cytokines, including the chemoattractant interleukin-8 (IL-8). We tested the hypothesis that IL-8 affects apoptosis in PMN. We investigated which IL-8 receptor (RI or RII) might be involved, as well as the role of Bcl-2. Human PMN were isolated and cultured up to 30 hours. Apoptosis was detected by UV and light microscopy, as well as by DNA-fragmentation assay, and quantitated by flow cytometry. Interleukin-8 significantly delayed spontaneous apoptosis at 10, 20, and 30 hours in a dose-dependent fashion. Polymorphonuclear neutrophil treatment with the highest concentration of IL-8 (100 nM) decreased the percentage of apoptotic cells from 2.1 +/- 1.5 to 0.8 +/- 0.2 after 10 hours, from 31 +/- 14 to 8 +/- 5 after 20 hours, and from 47 +/- 15 to 18 +/- 8 after 30 hours of incubation (P < 0.05 for all time points, N = 6). Interleukin-8 also inhibited TNF alpha-mediated PMN apoptosis. Incubation with 20 ng/ml TNF alpha resulted in 23 +/- 6% apoptotic cells at four hours, whereas pretreatment with IL-8 (50 nM) decreased this percentage to 11 +/- 3 (N = 5, P < 0.05). We next studied the role of both types of IL-8 receptors, RI and RII, by comparing the effect of IL-8 and the product of growth-related oncogene alpha (Gro alpha) on PMN cultured for 20 hours. Both IL-8 and Gro alpha attenuated apoptosis, although IL-8 was more effective than Gro alpha. Bcl-2 was detected by intracellular fluorescent antibody cell sorter analysis, Western blot, and reverse transcription-polymerase chain reaction (RT-PCR). Neither resting PMN nor IL-8-treated neutrophils expressed BCL-2 protein, which was readily detected in control cells. Furthermore, we could not detect BCL-2 gene expression by RT-PCR. We conclude that IL-8 prolongs the lifespan of human neutrophils in vitro by delaying apoptosis. This effect may be important for a controlled and effective inflammatory response. The delay in apoptosis can be mediated by the IL-8 RII, while RI may provide an added effect. The actions of IL-8 on apoptosis are Bcl-2 independent.

Antigens, CD↗
PubMed1998

Immunosuppressive therapy of lupus nephritis.

Aggressive immunosuppressive therapy should be considered for patients with proliferative lupus nephritis as the risk for progression to end stage renal disease is high. Intermittent intravenous cyclophosphamide therapy improves renal survival; longer duration of therapy is associated with fewer relapse of nephritis and decreased risk of diminished renal function. While azathioprine therapy does not differ statistically from steroids alone in prolonging renal survival, this therapy may be considered in patients with few risk factors for progression to renal insufficiency. Methylprednisolone as a single therapy does not prolong renal survival compared with regimens including cyclophosphamide. Plasmapheresis remains under study but has not shown additional benefit in treatment of severe lupus nephritis. The potential roles for cyclosporin A and mycophenylate mofetil in the therapy of proliferative lupus nephritis remain to be defined. Supportive care including rigorous control of hypertension, consideration of angiotensin receptor inhibition or blockade to reduce proteinuria and prolong renal function, control of hyperlipidemia, prevention of osteoporosis, and prevention of pregnancy remain important clinical goals. Current research efforts focus on genetic and socioeconomic factors involved in racial differences in expression of lupus nephritis, hormonal manipulation to preserve gonadal function during cyclophosphamide therapy, and the potential impact on lupus activity of estrogen-containing oral contraceptives or postmenopausal hormone replacement therapy.

Animals↗
PubMed1997

Diagnosis and management of glomerular diseases.

Glomerular diseases are a diagnostic challenge. Early recognition and timely institution of appropriate treatment are critical to optimum outcome in many patients, especially those with rapidly progressive glomerulonephritis. The clinical presentations and laboratory data provide adequate presumptive diagnoses in some patients; however, renal biopsy evaluation is often required for a definitive diagnosis.

Glomerulonephritis, Membranous↗
PubMed1997

Crosslinking of ANCA-antigens stimulates superoxide release by human neutrophils.

Anti-neutrophil cytoplasmic antibodies (ANCA) activate primed human polymorphonuclear neutrophils (PMN) in vitro, resulting in a respiratory burst and degranulation. In this study, the hypotheses that the initiation of this process requires engagement of the F(ab')2 portion of ANCA, and that crosslinking of ANCA target antigens is necessary to trigger superoxide (O2-) release, were explored. It is speculated that Fc gamma receptor engagement is a modulator of ANCA-mediated activation. Flow cytometry demonstrated that intact human ANCA immunoglobulin (Ig), their corresponding F(ab')2 and Fab fragments, as well as a murine monoclonal to human PR3 and its F(ab')2 fragment, bind to ANCA antigens on the surface of PMN primed with tumor necrosis factor (TNF) alpha. Intact Ig of patients with PR3-ANCA or with MPO-ANCA stimulate O2- release from TNF alpha-primed normal PMN (2.6 +/- 3.57 to 15.3 +/- 7.39 nmol O2-/2.5 x 10(6) PMN/30 min). Corresponding F(ab')2 fragments result in similar O2- production (10.2 +/- 4.34 to 36.9 nmol) in a dose-dependent manner. ANCA Fab fragments do not stimulate O2- generation until these fragments are crosslinked with F(ab')2 of goat anti-human Ig F(ab')2, or when fragments are biotinylated and crosslinked with avidin. In contrast with these human autoantibody data, a mouse monoclonal anti-human PR3 antibody (25.7 +/- 8.55 nmol O2-), but not its corresponding F(ab')2 fragment, activates TNF alpha-treated human PMN. When the Fc gamma IIa receptors were blocked, superoxide production was reduced by 33% using human PR3-ANCA Ig (P < 0.05). In conclusion, PMN activation by ANCA occurs when intact ANCA or ANCA F(ab')2 fragments crosslink target antigens on the neutrophil cell surface. ANCA F(ab') fragments result in PMN activation when crosslinked by secondary reagents.

Animals↗
PubMed1997

Neutrophil superoxide release is required for spontaneous and FMLP-mediated but not for TNF alpha-mediated apoptosis.

Polymorphonuclear leukocyte (PMN) lifespan is characterized by both rapid production and apoptotic cell death. The mechanisms triggering apoptosis in PMN are not completely understood. In this study, the relationship of neutrophil activation and apoptosis as related to released superoxide was investigated. PMN apoptosis was detected by DNA fragmentation, and ultraviolet and light microscopy, and was quantified by flow cytometry; superoxide release was measured by superoxide dismutase-inhibitable reduction of ferricytochrome C. Incubation of PMN with 20 ng/ml tumor necrosis factor (TNF)alpha induced superoxide release (8.8 +/- 7.5 nmol O2-/30 min, n = 7) in normal PMN and also resulted in apoptosis within 2 h, whereas a subactivating dose of 2 ng/ml TNF alpha, which did not trigger superoxide release (3.1 +/- 1.7 nmol O2-, n = 10), did facilitate apoptosis, although to a lesser degree. PMN cultured under nonstimulating conditions underwent apoptotic cell death after 8 h. Exogenous superoxide dismutase did not inhibit apoptosis induced by 20 ng/ml TNF alpha. No upregulation of endogenous manganese superoxide dismutase mRNA expression was observed in response to TNF alpha as measured by reverse transcription PCR. Formyl-methionyl-leucyl-phenylalanine (FMLP) stimulation (10(-7) M) resulting in superoxide release of 31.7 +/- 6.1 nmol O2-/30 min (n = 10) also significantly increased the percentage of apoptosis, but at 24 h (P < 0.05). Exogenous superoxide dismutase did inhibit FMLP-induced apoptosis, as well as apoptosis due to aging in culture. In conclusion, aging and FMLP-stimulated PMN undergo apoptosis by a superoxide release-dependent pathway, whereas TNF alpha-facilitated apoptosis appears to be unrelated to respiratory burst oxidase activity.

Apoptosis↗