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ID PMID Title PublicationDate abstract
11249145 The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthr 2001 Feb RPR132331, a 2-(2-dioxanyl)imidazole, was identified as an inhibitor of tumour necrosis factor (TNF)alpha release from lipopolysaccharide (LPS)-stimulated human monocytes. An intensive programme of work exploring the biology, toxicity and physical chemistry of a novel series of inhibitors, derived from RPR132331, has led to the identification of RPR200765A, a development candidate for the treatment of rheumatoid arthritis (RA). RPR200765A is a potent and selective inhibitor of p38 MAP kinase (IC50 = 50 nM). It inhibits LPS-stimulated TNFalpha release both in vitro, from human monocytes (EC50 = 110 nM), and in vivo in Balb/c mice (ED50 = 6 mg/kg). At oral doses between 10 and 30 mg/kg/day it reduces the incidence and progression in the rat streptococcal cell wall (SCW) arthritis model when administered in either prophylactic or therapeutic dosing regimens. The compound, which is a mesylate salt and exists as a stable monohydrate, shows good oral bioavailabiltiy (F = 50% in the rat) and excellent chemical stability. The data from the SCW disease model suggests that RPR200765A could exhibit a profile of disease modifying activity in rheumatoid arthritis (RA) patients which is not observed with current drug therapies.
9415246 Hypocomplementaemic urticarial vasculitis associated with Jaccoud's syndrome. 1997 Nov We report a 33-year-old Japanese man diagnosed as having hypocomplementaemic urticarial vasculitis at the age of 21, who subsequently developed Jaccoud's syndrome. Although Jaccoud's syndrome has been most frequently seen in patients with systemic lupus erythematosus, an association with other diseases has occasionally been described. Jaccoud's syndrome clinically shows joint deformities similar to rheumatoid arthritis, and needs to be differentiated from it. Patients with hypocomplementaemic urticarial vasculitis may develop Jaccoud's syndrome.
10612913 A prospective study of Lyme arthritis in north India. 1999 Sep Twenty seven patients presenting with mono/oligoarticular disease of unknown etiology were prospectively screened for Lyme arthritis. In addition, 12 healthy blood bank donors, 25 individuals with rheumatoid arthritis (disease controls), and 20 deer handlers and veterinarians were also screened for IgG antibodies to Borrelia burgdorferi. Only one patient tested borderline positive for antibodies to B. burgdorferi (more likely false positive). None of the healthy subjects, disease controls or occupationally exposed individuals exhibited serological evidence of exposure to B. burgdorferi. Screening for Lyme disease may not be warranted while investigating mono/oligoarthritides of unknown etiology in this part of the country.
10343159 An unequal crossover between the RCCX modules of the human MHC leading to the presence of 1999 The RCCX module of the human MHC class III region is comprised of four genes arranged in tandem: RP, complement C4, steroid 21-hydroxylase (CYP21), and tenascin X (TNX). Variations in the number and genes of the RCCX modules may lead to genetic and/or autoimmune diseases. Restriction fragment length polymorphism (RFLP) analysis was utilized to determine the RCCX modular variation in patients with juvenile rheumatoid arthritis (JRA). In JRA patient L1, RFLP analysis suggested the presence of a bimodular RCCX structure containing both C4A long and C4B short genes, yet missing the markers for the CYP21A and TNXA genes usually located between the C4A and C4B genes. The 7.5-kb genomic fragment spanning the CYP21-TNX-RP2 genes was cloned and sequenced, revealing that a genetic recombination occurred between TNXA of a bimodular RCCX chromosome and TNXB of a monomodular RCCX chromosome. This recombination results in a new MHC haplotype with a CYP21B gene and a TNXB/TNXA-RP2 recombinant between the two C4 genes. Elucidation of the breakpoint region provides further evidence for the instability of the MHC class III gene region as a result of the RCCX modular variation.
9598903 Estimates of the discriminant ability of definitions of improvement for juvenile rheumatoi 1998 May OBJECTIVE: To investigate the ability of various definitions of improvement to distinguish between patients with juvenile rheumatoid arthritis (JRA) treated with active drug from those given placebo in randomized trials. METHODS: A core set of 6 response (outcome) variables for use in JRA has been reported. These core variables were combined into a number of "definitions of improvement" for the purpose of classifying individual patients as either "clinically significantly improved" or "not improved." We used a large dataset from randomized controlled trials to test the discriminant ability (sensitivity to change) of the definitions. We calculated the proportion of patients classified as "improved" by each definition in each of the treatment and control groups. RESULTS: Effect sizes were weak in 4 of the treatment regimens used (D-penicillamine, hydroxychloroquine, auranofin, and very low dose methotrexate) and no definition discriminated well between drug and placebo treated groups. Definitions that required 20 to 30% improvement in 3 to 4 of the 6 core set variables showed statistically significant differences in the proportions of patients who were classified as improved in the group treated with low dose methotrexate (10 mg/m2 body surface area/wk) compared to placebo. A definition resembling the Paulus criteria used in adult RA trials (4 of 6 core set variables improved by > or = 20%) performed well, as did the definition selected previously as the best for JRA (3 of 6 core set variables improved by > or = 30%, not more than one worsening by > 30%). CONCLUSION: Definitions that require 20 to 30% improvement in 3 to 4 core outcome variables are sensitive to change and are able to clearly distinguish between treated and control groups when an effective drug is being tested. Further testing of their validity is under way.
9145108 Structure of human IgM rheumatoid factor Fab bound to its autoantigen IgG Fc reveals a nov 1997 May Rheumatoid factors are the characteristic autoantibodies of rheumatoid arthritis, which bind to the Fc regions of IgG molecules. Here we report the crystal structure of the Fab fragment of a patient-derived IgM rheumatoid factor (RF-AN) complexed with human IgG4 Fc, at 3.2 A resolution. This is the first structure of an autoantibody-autoantigen complex. The epitope recognised in IgG Fc includes the C gamma 2/C gamma 3 cleft region, and overlaps the binding sites of bacterial Fc-binding proteins. The antibody residues involved in autorecognition are all located at the edge of the conventional combining site surface, leaving much of the latter available, potentially, for recognition of a different antigen. Since an important contact residue is somatic mutation, the structure implicates antigen-driven selection, following somatic mutation of germline genes, in the production of pathogenic rheumatoid factors.
10526583 [Antibiotic prophylaxis of hematogenous bacterial arthritis]. 1999 Sep 4 The outcome of bacterial arthritis is generally poor: the mortality is 10-15% and there is loss of joint function in 25-50% of the survivors. Adverse prognostic factors are advanced age, a pre-existent joint disease and an infection of a prosthetic joint. The incidence of bacterial arthritis is low: 2-6 per 100,000 persons per year. Risk factors are advanced age, a joint disease--especially rheumatoid arthritis--diabetes mellitus and presence of a prosthetic joint. Situations that can lead to bacterial arthritis are mainly skin infections of the feet and only rarely invasive medical or dental procedures. Because of the severity of the disease, antibiotic prophylaxis of haematogenous bacterial arthritis in patients with prosthetic joints is advocated in guidelines. However, because of the rarity of the disease it is unclear whether the advantages of prophylaxis outweigh the disadvantages of the large-scale use of antibiotics, such as side effects, costs and increased resistance of bacteria. In a decision analysis of a large group of patients with joint diseases, antibiotic treatment of skin infections appeared to be (cost-)effective in the prevention of haematogenous bacterial arthritis, mainly in high-risk patients. On the other hand, prophylaxis around medical or dental procedures was not (cost-)effective, except possibly in a small group of patients with increased risk.
9706435 Juvenile arthritis in Turner's syndrome: a multicenter study. 1998 Jul OBJECTIVE: Turner's syndrome (TS) is a disorder associated with characteristic defects in the X chromosome. Autoimmune conditions such as thyroiditis, inflammatory bowel diseases and diabetes have been described in association with TS. METHODS: We have studied the association between TS and juvenile arthritis (JA) by using a survey in which 28 pediatric rheumatology centers (15 in the USA, 10 in Europe, and 3 in Canada) participated. RESULTS: Eighteen cases of TS in a population of approximately 15,000 JRA patients have been found. Two different patterns of arthritis were present: polyarticular (7) and oligoarticular (11). Children with polyarticular disease had early onset, seronegative, progressively deforming arthritis and growth retardation. Those with oligoarticular arthritis had a benign course and were ANA+ (8/11). The oligoarticular children had varying karyotypes whereas almost all of the polyarthritic patients shared the same 45X0 karyotype (6/7). The light and electron microscopic studies of synovium performed in two patients showed chronic inflammation and hyperplasia of the synovial lining cells, vascular proliferation and infiltration with lymphocytes, plasma cells and mononuclear phagocytes. CONCLUSION: Juvenile arthritis is a new autoimmune condition association with Turner's syndrome. The prevalence seems to be at least six times greater than would be expected if the two conditions were only randomly associated. This is the first description of the synovium in Turner's syndrome; no differences from other forms of juvenile rheumatoid arthritis were found.
9518212 [The value of leukocyte scintigraphy in suspected implant infection in patients with chron 1997 Nov When infection of implants is suspected, optimal management requires accurate confirmation or exclusion of infection. However, in spite of demonstrative clinical signs cultures of smears or chemical parameters of inflammation frequently are ambiguous. Scintigraphy with indium-labeled white blood cells (WBC) has been reported to be sensitive and specific in the diagnosis of low-grade sepsis of the musculoskeletal system. Twenty-eight patients with possible infection were prospectively studied. Infection was suspected in 19 cases with total hip joint prosthesis, 14 cases with knee joint prosthesis and 1 case with shoulder joint prosthesis. All of them underwent scanning with indium-111-labeled WBC and subsequently underwent surgery. At surgery infections were determined by means of culture or histologic results. When correlated with culture and histologic results sensitivity of 111-indium-WBC imaging was 89% with a specificity of 67% and a predictive accuracy of 77%. In patients with rheumatoid arthritis, however, predictive accuracy of 111-indium-labeled WBC imaging was higher than with standard diagnostic methods. The difference was statistically significant (P < 0.05, chi(2)-test). In the patients examined as a whole, predictive accuracy of 111-indium-labeled WBC imaging does not differ from that of standard diagnostic methods. That is why expensive and time-consuming 111-indium-WBC imaging is not justified generally in diagnosis of infection of implants. 111-Indium-WBC imaging is well suited to supplement standard diagnostic methods in patients with rheumatoid arthritis.
9558185 Paleopathology in osseous remains from the 16th century. A survey of rheumatic diseases. 1998 Apr OBJECTIVE: To describe the rheumatic conditions found in skeletal remains of Amerindian ancestry disinterred from a 16th century Mexican cemetery. METHODS: A physical anthropologist and 2 rheumatologists surveyed the recovered skeletal remains. RESULTS: We examined the skeletal remains of 443 subjects. We found 19 cases of Pott's disease, 17 of osteoarthrosis in various anatomical locations, 2 spondyloarthropathies, probably ankylosing spondylitis or diffuse idiopathic skeletal hyperostosis, one probable septic arthritis in the stemoclavicular joint, and 2 compression fractures of the spine. We found no cases of gout or rheumatoid arthritis. CONCLUSION: This is the first report on the presence of rheumatic conditions in colonial Mexico. Studying the remains of these populations can provide useful information about the origin and evolution of different rheumatic conditions.
9323998 Effect of milk extract of Semecarpus anacardium nuts on glycohydrolases and lysosomal stab 1997 Sep Lysosomal acid hydrolases are thought to play an important role in inflammation associated with rheumatoid arthritis. A Siddha preparation of Semecarpus anacardium nut extract called Serankottai Nei was tested for its capacity to stabilize lysosomes obtained from liver and kidney of adjuvant-induced arthritic animals. Lysosomal membrane stability was measured by determining the release of acid hydrolases from the lysosomes. The drug was administered at a dose level of 150 mg/kg body weight for 14 days to arthritic animals after the adjuvant injection. The total and free activity of lysosomal enzymes were significantly increased in arthritic rats with concomitant increase in plasma levels of protein-bound carbohydrates. Significantly increased lysosomal membrane fragility as observed in arthritic condition was reduced in drug-treated animals. Antiarthritic activity of the drug through its stabilizing action on lysosomal membranes could be inferred from this study.
11117294 Changes in cross-sectional geometry of the distal femoral metaphysis associated with infla 2000 Sep An increased risk of fracture is a feature of rheumatoid arthritis and of animal models of inflammatory arthritis. We examined geometrical changes in the metaphyseal cortex of the distal femur in an animal model of inflammatory arthritis. Additionally, we examined the effect of a bisphosphonate in preventing these changes. Five groups of rabbits were studied: normal controls, those with inflammatory arthritis, and three groups with arthritis treated with bisphosphonate. To determine geometrical properties, image analysis was performed on digitized cross sections of the femoral metaphyseal cortices. The results demonstrated that the posterior cortical wall was significantly less thick in rabbits with arthritis than in normal rabbits and in the rabbits in the three bisphosphonate treatment groups (p < 0.05). Moment of inertia about the lateral-medial axis was reduced in rabbits with arthritis compared with normal rabbits (p < 0.05). Cross-sectional area was not significantly different between groups. The changes suggest a mechanism of weakening of bone in arthritis; when the results are coupled with results of previous porosity studies, severe directional weakness is apparent. Bisphosphonate was effective in preserving bone integrity in inflammatory arthritis.
11486809 Juvenile rheumatoid arthritis of the knee: evaluation with contrast-enhanced color Doppler 2001 Jul BACKGROUND: Contrast-enhanced color Doppler ultrasonography is a non-radiation-bearing tool that can be of value for assessment of inflammatory and vascular synovial changes in juvenile rheumatoid arthritis (JRA). OBJECTIVES: To evaluate the effect of contrast-enhanced color Doppler ultrasound (US) in the evaluation of synovial changes in the knees of children with JRA. MATERIALS AND METHODS: Sagittal color Doppler sonograms of 31 knees in 22 patients with JRA and of 10 knees in 5 control subjects were obtained before (at baseline) and after (at peak contrast phase) intravenous injection of SHU 508. Images were assessed for overall mean pixel intensity within the synovial tissue and for peak enhancement ratios [[(mean pixel intensity values at maximum contrast enhancement-unenhanced mean pixel intensity values)/unenhanced mean pixel intensity values] x 100]. The joints were classified into three groups by clinical/laboratory criteria: group A (active disease in the knee), n = 9; group B (quiescent disease with serum chemistry levels of active disease), n = 12 and group C (remission disease), n = 10. RESULTS: Mean color pixel intensity values were markedly increased by the use of US contrast agents in groups A (P = 0.004) and B (P = 0.0001), did not reach statistical significance in group C (P = 0.06) and remained essentially unchanged in the control group (P = 0.25). Enhancement ratios for the three groups of JRA patients were not different (P = 0.38) (mean +/- SD, 720% +/- 402 for group A, 731% +/- 703 for group B and 314% +/- 263 for group C). CONCLUSION: Contrast-enhanced color Doppler imaging holds promise for the detection of active synovial inflammatory disease in subclinical cases of JRA, thereby allowing earlier treatment and improved clinical outcome.
10399226 [Sandimmun-Neoral--a new quality of life for patients with severe systemic juvenile rheuma 1999 AIM: To develop an effective and safe therapeutic policy for Sandimmun-Neoral in order to prevent joint destruction, invalidation, achieve higher life quality in patients with systemic juvenile rheumatoid arthritis (SJRA). MATERIALS AND METHODS: The trial included 26 patients with SJRA aged 4-15 years. 12 of them had early SJRA, 14--late SJRA. 13 patients received Neoral for one year and the other 13 for 2-3.5 years. Markers of aggressive SJRA course in the debut were registered in all the patients. Previous treatment incorporated nonsteroid antiinflammatory drugs, intraarticular corticosteroids (all the patients), prednisolone (19 patients), methotrexate (3 patients). Before Neoral treatment 80% of the patients had structural alterations in the joints, signs of invalidation, low quality of life. SJRA activity was defined as the 3d degree. All the patients suffered from obesity, hypertrichosis, steroid spondylopathy, nanism. RESULTS: Neoral recovered joint motility in 30% of patients, 60% were capable for self-service. Quality of life was assess as high in 80%, moderately reduced--in 20%. 35% of the patients achieved clinico-laboratory remission. The disease activity dropped to degree I-II in 65% of patients. Structural changes in the joints stopped progressing in 77%, regress of the anatomic stage was seen in 20% of patients. Prednisolone was discontinued in 7 and dose-reduced in 6 patients. Exogenic hypercorticism relieved and growth resumed in all the patients. Neoral proved effective both in early and late SJRA, inhibited destruction both in patients in remission and in active disease. Side effects were: hypertrichosis in 13 patients, moderate blood hypertension in 1 case. CONCLUSION: Neoral can control the disease. It is indicated both in early and late SJRA in the presence of aggressive course markers, acute coxitis with aseptic necrosis of the head of the femur or free of it. Neoral treatment should be started as early as on the first year of the disease, before the structural changes in the joints. For safe long-term therapy it is valid to give cyclosporin A in monotherapy or in combination with voltaren in minimal doses. Corticosteroids are used on demand. The preference should be given to intraarticular or intravenous prolonged drugs but not oral prednisolone which may course such severe complications as obesity, hypertension, nanism.
9231071 Pathogenic lymphoid cells engineered to express TGF beta 1 ameliorate disease in a collage 1997 Jun Collagen-induced arthritis in DBA/1 mice is a model of rheumatoid arthritis with marked synovitis and erosions. The disease can be adoptively transferred to SCID mice with arthritogenic splenocytes from DBA/1 mice injected with bovine collagen type II. However, infection of arthritogenic splenocytes with a retrovirus expressing TGF beta 1 inhibits development of arthritis in SCID mice. When DBA/1 mice, at onset of arthritis have additional arthritogenic splenocytes transferred, exacerbation occurs, reflected in a rapid increase in the number of arthritic joints, increased paw swelling and higher levels of anti-collagen antibody. By infecting arthritogenic splenocytes ex vivo with TGF beta 1 retrovirus, this exacerbation was inhibited. TGF beta 1 was effective in lowering inflammation of joints with already established arthritis and inhibiting the spreading of the disease to other joints. Transient reduction in anti-collagen antibody levels could also be obtained using purified T cells infected with TGF beta 1 retrovirus. In addition, expression of TGF beta 1 in lymphocytes reduced the levels of gelatinase (MMP2) activity in inflamed joints.
11083261 Early predictors of poor functional outcome in systemic-onset juvenile rheumatoid arthriti 2000 Nov OBJECTIVE: To examine the ability of a previously described set of criteria to predict poor functional outcome in a large, multicenter cohort of children with systemic-onset juvenile rheumatoid arthritis (JRA). METHODS: All children who were diagnosed with systemic-onset JRA since 1980 at the Hospital for Sick Children (Toronto), since 1983 at the Isaac Walton Killam Hospital for Children (Halifax), and since 1981 at the Children's Hospital of Eastern Ontario (Ottawa) were evaluated. Patients were included in the study if they had been evaluated clinically within 6 months of diagnosis and had been followed up for at least 2 years. Patients were divided into 4 cohorts according to their length of followup: 2-4 years, 4-7 years, 7-10 years, and >10 years. Using previously described criteria for destructive arthritis in children with systemic-onset JRA, the patients were classified as either high risk or low risk for poor functional outcome based on the data from their 6-month visit. High-risk patients had active systemic disease (persistent fever or corticosteroid requirement for control of systemic disease) and a platelet count > or =600 x 10(9)/liter. Poor outcome was defined as moderate or severe disability (defined as a score of > or =0.75 on the Childhood Health Assessment Questionnaire) or disease-associated death. RESULTS: Among 122 eligible patients with systemic-onset JRA, we were able to contact 111 (91%) for outcome data. The mean followup period was 7.7 years (SD 3.7). The mean age at outcome assessment was 13.5 years (SD 5.3). There were 51 boys and 60 girls. Twenty-four patients (22%) had moderate-to-severe disability and 2 patients died; these 26 patients were considered to have had a poor outcome. We could determine risk classification for 104 patients. Twenty-four patients (23%) met the criteria for high risk at the 6-month visit. Overall, the risk of a poor functional outcome was significantly higher in the high-risk group (relative risk 3.3, 95% confidence interval [95% CI] 1.73-6.43, P = 0.0004). This risk was most marked in the cohort with > 10 years of followup (relative risk 4.3, 95% CI 1.82-10.29, P = 0.006). CONCLUSION: The presence of active systemic disease at 6 months, as characterized by fever or the need for corticosteroids, and thrombocytosis strongly predicted the development of a poor functional outcome in these patients. This was especially apparent with longterm followup. Our study validates the previously developed prognostic criteria for systemic-onset JRA.
10502576 Ocular manifestations in children and adolescents with Lyme arthritis. 1999 Oct BACKGROUND: Lyme arthritis is the most frequent late manifestation of Lyme borreliosis and has been associated with ocular inflammation. METHODS: A group of 153 children and adolescents with arthritis, 84 of whom had Lyme arthritis and 69 other causes of arthritis, were followed prospectively for 22-73 (median 44) months in the course of a national study. RESULTS: Three of 84 patients with Lyme arthritis had ocular inflammation (4%), including keratitis, anterior uveitis, and uveitis intermedia. All three had symptoms of decreased visual acuity. Whereas anterior uveitis disappeared without sequelae, a corneal scar and a permanent loss of visual acuity in the patients with keratitis and intermediate uveitis remained. Systematic examination of all patients revealed no further ocular involvement. Of 69 patients with other causes of arthritis who were followed in parallel as a control group, four of 15 patients with early onset pauciarticular juvenile rheumatoid arthritis had chronic anterior uveitis and two of 12 patients with juvenile spondyloarthropathy had acute anterior uveitis. CONCLUSIONS: Ocular involvement with keratitis, anterior uveitis, and intermediate uveitis may occur in children and adolescents with Lyme arthritis. Visual loss appears to be symptomatic, making regular ocular screening of such patients unnecessary.
11056668 Apoptosis and p53 expression in rat adjuvant arthritis. 2000 STATEMENT OF FINDINGS: The kinetics of apoptosis and the apoptosis-regulating gene p53 in adjuvant arthritis (AA) were investigated to assess the value of the AA rat model for testing apoptosis-inducing therapies. Very few terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end-labeling (TUNEL)-positive cells were detected during the early phases of AA, but on day 23 (chronic arthritis) the percentage of TUNEL-positive cells was significantly increased. Expression of p53 in synovial tissue gradually increased from days 5-23, which was markedly higher than p53 levels in rheumatoid arthritis (RA) synovium. Significant apoptosis only occurs late in rat AA and is concordant with marked p53 overexpression, making it useful model for testing proapoptotic therapies, but rat AA is not the best model for p53 gene therapy because dramatic p53 overexpression occurs in the latter stages of the disease.
9916728 Mice lacking mature T and B lymphocytes develop arthritic lesions after immunization with 1999 Jan 15 Collagen-induced arthritis in DBA/1 mice is a widely used experimental model of rheumatoid arthritis. The induction phase of the disease is thought to be dependent upon MHC-restricted T and B cell-mediated immune responses to type II collagen, but an influence of additional non-MHC-restricted mechanisms has also been proposed. In this study, we report that type II collagen immunization of DBA/1 mice lacking mature T and B lymphocytes resulted in the development of arthritic lesions, which were characterized by synovial hyperplasia with occasional inflammation as well as cartilage and bone destruction. The specificity of disease induction to type II collagen was confirmed, because arthritis could not be induced when control preparations of OVA or adjuvant alone were administered. A delay in clinical disease onset and a reduction in severity between lymphocyte-positive and -negative DBA/1 mice confirmed that lymphocytes play an important role in disease; however, similar pathologic features and normal incidence suggest that lymphocyte-independent mechanisms of disease induction also operate in the standard collagen-induced arthritis model. We conclude that adaptive immune responses are not the only arthritogenic mechanism and hypothesize that the nonantigenic properties of type II collagen can also lead to arthritis.
11060742 Small molecule alpha(v) integrin antagonists: novel anticancer agents. 2000 Jun The members of the integrin family are targets that potentially provide both therapeutic and diagnostic opportunities. Advances in the understanding of the signalling pathways, transcriptional regulation and the structure/function relationships of the adhesion molecules to extracellular matrix proteins have all contributed to these opportunities. The role of the integrins in pathological processes in both acute and chronic diseases, include ocular, cancer (solid tumours and metastasis), cardiovascular (stroke and heart failure) and inflammatory (rheumatoid arthritis) conditions. Various therapeutic candidates, including antibodies, cyclic peptides and peptidomimetics, have been identified. This review will focus on the key role of the alpha(v) integrin (alpha(v)beta(3) and alpha(v)beta(5)) in angiogenic processes in tumours, including its potential use in cancer diagnostics and therapy.