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Biomedical subjects

F C Breedveld

Publications and source records attributed to F C Breedveld.

At least 109 records · Page 6Linked to original sources
PubMed2001

Intensive immunosuppression and autologous stem cell transplantation for patients with severe rheumatoid arthritis: the Leiden experience.

Ten patients with active, destructive rheumatoid arthritis refractory to antirheumatic therapy enrolled in a study to evaluate the effects of intensive immunosuppression followed by autologous stem cell transplantation. Intensive immunosuppression was achieved with high dose cyclophosphamide as part of the mobilization (4 g/m2) and conditioning (200 mg/kg) regimen. The autologous stem cell products were enriched for CD34+ cells to minimize the chance of reinfusing autoreactive lymphocytes. Eight patients completed all consecutive treatment steps, one patient withdrew after mobilization because of improvement, one patient was taken off study because of pulmonary embolism. The treatment appeared feasible and safe, and marked sustained clinical improvement was observed in 6 patients, 2 of whom were previously unresponsive to tumor necrosis factor blocking therapy. In 5 patients disease modifying antirheumatic drugs were successfully withdrawn after transplantation. The treatment induced significant lymphopenia, with low levels of naive CD4+ T cells in particular, without clinical sequelae. Titers of rheumatoid factor dropped but did not normalize.

Adult↗
PubMed2000

Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group.

BACKGROUND: Neutralization of tumor necrosis factor a (TNF-alpha) for three to six months reduces the symptoms and signs of rheumatoid arthritis. However, the capacity of this approach to effect a more sustained benefit and its effect on joint damage are not known. METHODS: We treated 428 patients who had active rheumatoid arthritis despite methotrexate therapy with placebo or infliximab, a chimeric monoclonal antibody against TNF-alpha, in intravenous doses of 3 or 10 mg per kilogram of body weight every 4 or 8 weeks in combination with oral methotrexate for 54 weeks. We assessed clinical responses with use of the criteria of the American College of Rheumatology, the quality of life with a health-status questionnaire, and the effect on joint damage radiographically. RESULTS: The combination of infliximab and methotrexate was well tolerated and resulted in a sustained reduction in the symptoms and signs of rheumatoid arthritis that was significantly greater than the reduction associated with methotrexate therapy alone (clinical response, 51.8 percent vs. 17.0 percent; P<0.001). The quality of life was also significantly better with infliximab plus methotrexate than with methotrexate alone. Radiographic evidence of joint damage increased in the group given methotrexate, but not in the groups given infliximab and methotrexate (mean change in radiographic score, 7.0 vs. 0.6, P<0.001). Radiographic evidence of progression of joint damage was absent in infliximab-treated patients whether or not they had a clinical response. CONCLUSIONS: In patients with persistently active rheumatoid arthritis despite methotrexate therapy, repeated doses of infliximab in combination with methotrexate provided clinical benefit and halted the progression of joint damage.

Antibodies, Monoclonal↗
PubMed2000

The development of clinical signs of rheumatoid synovial inflammation is associated with increased synthesis of the chemokine CXCL8 (interleukin-8).

Paired synovial tissue samples were obtained from both clinically uninvolved (CU) and clinically involved (CI) knee joints of eight rheumatoid arthritis (RA) patients. In addition, biopsies were taken from five control subjects. We observed the expression of the chemokines CXCL8, CXCL9, CXCL10, CCL2 and CCL4 in CI and CU joints of RA patients. In particular, CXCL8 protein levels were specifically increased in CI joints compared with CU joints, which was confirmed by immunohistochemistry and in situ hybridization.

Arthritis, Rheumatoid↗
PubMed2000

Therapeutic monoclonal antibodies.

The therapeutic potential of monoclonal antibodies (mAb) was quickly realised after the hybridoma technique allowed their development in the mid 1970s. Chimeric humanised and fully humanised mAb can now be made by recombinant engineering. About a quarter of all biotech drugs in development are mAb, and around 30 products are in use or being investigated. Licensed products are available for inhibition of alloimmune and autoimmune reactivity, and for antitumour, antiplatelet, or antiviral therapy. Short-term side-effects are tolerable and as expected, although long-term safety remains to be elucidated. The cost-effectiveness and quality-of-life benefits of the use of mAb in patients who are usually seriously and chronically ill also needs studying. The therapeutic use of mAb is now established, and is perhaps the first example of how the "new biology" and the understanding of underlying molecular mechanisms has benefited patients.

Animals↗
PubMed2000

Displacement of linker for activation of T cells from the plasma membrane due to redox balance alterations results in hyporesponsiveness of synovial fluid T lymphocytes in rheumatoid arthritis.

The T lymphocytes that reside in the synovium of the inflamed joints in patients with rheumatoid arthritis display severe hyporesponsiveness upon antigenic stimulation, which is probably due to their constant subjection to high levels of oxidative stress. Here we report that the synovial fluid T lymphocytes exert severely impaired phosphorylation of the adaptor protein linker for activation of T cells (LAT), a crucial component of the TCR-mediated signaling pathways. In healthy T lymphocytes, LAT is a membrane-bound protein and becomes phosphorylated by zeta-associated protein of 70 kDa (ZAP-70) upon TCR engagement. The molecular basis underlying the deficient phosphorylation of LAT and consequently the hyporesponsiveness of the synovial fluid T lymphocytes lies in the membrane displacement of LAT. We demonstrate that the subcellular localization of LAT is sensitive to changes in the intracellular levels of the antioxidant glutathione. The membrane anchorage of LAT, and consequently the phosphorylation of LAT and the cellular activation of the synovial fluid T lymphocytes upon TCR engagement, is restored in synovial fluid T lymphocytes after supplementation of the intracellular glutathione levels with N-acetyl-l -cysteine. These data suggest a role for the membrane displacement of LAT in the hyporesponsiveness of the synovial fluid T lymphocytes as a consequence of oxidative stress.

Adaptor Proteins, Signal Transducing↗
PubMed2000

TNF-308A and HLA-DR3 alleles contribute independently to susceptibility to systemic lupus erythematosus.

OBJECTIVE: To evaluate the respective contributions of tumor necrosis factor (TNF) promoter polymorphisms and HLA-DR alleles to susceptibility to systemic lupus erythematosus (SLE). METHODS: TNF-238G/A and 308G/A promoter polymorphisms and HLA-DRB1 alleles were determined in 99 consecutive Caucasian SLE patients and 177 Caucasian controls. Standard and Mantel-Haenszel odds ratios were calculated to assess the magnitude of the susceptibility factors. The presence or absence of the SLE classification criteria was determined and correlated with the TNF promoter and HLA-DRB1 genotypes. RESULTS: The frequency of the TNF-308A/A and 308G/A genotypes was significantly higher in SLE patients (odds ratio 5.0). Conversely, TNF-238G/A and 238A/A genotypes were equally prevalent in SLE patients and controls. The HLA-DR3 specificity (DRBI*0301 allele) was significantly more prevalent in the SLE population (odds ratio 4.4). Stratification to correct for interdependence of the 2 loci confirmed the association of both TNF-308A and HLA-DR3 with SLE (Mantel-Haenszel odds ratio 3.2 and 2.4, respectively). No correlation was found between TNF promoter and HLA-DRB1 genotypes and any SLE classification criterion or disease manifestation. CONCLUSION: TNF-308A and HLA-DR3 alleles are independent susceptibility factors for SLE.

Adult↗
PubMed2000

The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide.

OBJECTIVE: Since modern treatment of rheumatoid arthritis (RA) is shifting toward aggressive antirheumatic therapy in an early phase of the disease, diagnostic tests with high specificity are desirable. A new serologic test (anti-cyclic citrullinated peptide [anti-CCP] enzyme-linked immunosorbent assay [ELISA]) was developed to determine the presence of antibodies directed toward citrullinated peptides, using a synthetic peptide designed for this purpose. METHODS: A cyclic peptide variant that contains deiminated arginine (citrulline) was designed and used as antigenic substrate in ELISA. Test parameters and diagnostic characteristics of the test were studied in patients with and without RA, in patients with various infectious diseases, and in a group of patients from an early arthritis clinic (EAC). RESULTS: Using prevalent RA and non-RA sera, the anti-CCP ELISA proved to be extremely specific (98%), with a reasonable sensitivity (68%). Also, in the EAC study group, the anti-CCP ELISA appeared to be highly specific for RA (96%). In comparison with the IgM rheumatoid factor (IgM-RF) ELISA, the anti-CCP ELISA had a significantly higher specificity (96% for CCP versus 91% for IgM-RF; P = 0.016) at optimal cut-off values. The sensitivity of both tests for RA was moderate: 48% and 54% for the anti-CCP ELISA and the IgM-RF ELISA, respectively (P = 0.36). Combination of the anti-CCP and the IgM-RF ELISAs resulted in a significantly higher positive predictive value of 91% (P = 0.013) and a slightly lower negative predictive value of 78% (P = 0.35) as compared with the use of the IgM-RF ELISA alone. The ability of the 2 tests performed at the first visit to predict erosive disease at 2 years of followup in RA patients was comparable (positive predictive value 91%). CONCLUSION: The anti-CCP ELISA might be very useful for diagnostic and therapeutic strategies in RA of recent onset.

Adolescent↗
PubMed2000

The effects of interferon-beta treatment of synovial inflammation and expression of metalloproteinases in patients with rheumatoid arthritis.

OBJECTIVE: Interferon-beta (IFNbeta) treatment is emerging as a potentially effective form of therapy in various immune-mediated conditions. This study evaluated the effects of IFNbeta therapy on the cell infiltrate, cytokine profile, and expression of metalloproteinase 1 (MMP-1) in synovial tissue from patients with rheumatoid arthritis (RA). To further assess the mechanism of action, in vitro experiments were conducted to determine the effects of IFNbeta on the production of MMP-1, MMP-3, tissue inhibitor of metalloproteinases 1 (TIMP-1), and prostaglandin E2 (PGE2) by human fibroblast-like synoviocytes (FLS). METHODS: Eleven patients were treated for 12 weeks with purified natural fibroblast IFNbeta (Frone; Ares-Serono, Geneva, Switzerland) subcutaneously 3 times weekly with the following dosages: 6 million IU (n = 4), 12 million IU (n = 3), and 18 million IU (n = 4). Synovial biopsy specimens were obtained by needle arthroscopy at 3 time points: directly before and at 1 month and 3 months after initiation of treatment. Immunohistologic analysis was performed using monoclonal antibodies specific for the following phenotypic markers and mediators of joint inflammation and destruction: CD3, CD38, CD68, CD55, tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), IL-6, MMP-1, and TIMP-1. In addition, we measured the production of MMP-1, MMP-3, TIMP-1, and PGE2 by RA FLS and dermal fibroblasts in the presence and absence of IFNbeta. RESULTS: A statistically significant reduction in the mean immunohistologic scores for CD3+ T cells and the expression of MMP-1 and TIMP-1 at 1 month, CD38+ plasma cells and the expression of IL-6 at 3 months, and the expression of IL-1beta at both 1 and 3 months was observed in synovial tissue after IFNbeta treatment. The scores for CD68+ macrophages and TNFalpha expression also tended to decrease, but the differences did not reach statistical significance. The in vitro experiments revealed inhibition of MMP-1, MMP-3, and PGE2 production by RA FLS, whereas TIMP-1 production was only slightly decreased. These effects were more consistent in RA FLS than in dermal fibroblasts. CONCLUSION: The changes in synovial tissue after IFNbeta treatment and the in vitro data support the view that IFNbeta therapy has immunomodulating effects on rheumatoid synovium and might help to diminish both joint inflammation and destruction. Larger well-controlled studies are warranted to show the efficacy of IFNbeta treatment for RA.

Adjuvants, Immunologic↗
PubMed2000

Presence of bacterial DNA and bacterial peptidoglycans in joints of patients with rheumatoid arthritis and other arthritides.

OBJECTIVE: The continuous presence of bacteria or their degraded antigens in the synovium may be involved in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to determine the presence of bacterial nucleic acids and bacterial cell wall constituents in the joints of patients with RA and other forms of arthritis. METHODS: Joint samples were obtained from patients with RA (n = 26), septic arthritis (n = 2), inflammatory osteoarthritis (n = 5), and gout (n = 6), and joint trauma (n = 1). Universal 16S-ribosomal RNA primers were used to detect the presence of bacterial DNA in these samples, using stringent regimens for sample collection and molecular microbiologic analysis. Automated sequencing and comparative data analysis were performed to identify the species. The presence of bacterial peptidoglycan-polysaccharide complexes in synovial tissue was detected by immunohistologic analysis with a specific antibody. RESULTS: The bacterial species cultured from the synovium could be identified in both of the patients with septic arthritis. DNA amplicons were also detected in the synovial fluid and/or tissue samples from 5 patients with RA and 2 patients with crystal-induced arthritis; these originated from multiple bacterial species. Staining for peptidoglycan-polysaccharide complexes was positive in the synovial tissue of both patients with septic arthritis, 16 with RA, 4 with inflammatory osteoarthritis, 4 with crystal-induced arthropathy, and 1 with joint trauma. The staining was mainly found in cells in the synovial sublining, including macrophages. CONCLUSION: The results indicate that bacterial DNA and bacterial cell wall constituents are retained in the joints of some patients with arthritis, where they might enhance synovial inflammation.

Adult↗
PubMed2000

Regulation of synovial B cell survival in rheumatoid arthritis by vascular cell adhesion molecule 1 (CD106) expressed on fibroblast-like synoviocytes.

OBJECTIVE: B lymphocytes accumulate in the inflamed joints of patients with rheumatoid arthritis (RA) and are responsible for production of high amounts of (auto)-antibodies. The aim of this study was to determine the capacity of fibroblast-like synoviocytes (FLS) to contribute to the accumulation of synovial fluid (SF) B cells by extending their life span. METHODS: Highly purified SF B cells were cultured with FLS in the presence or absence of blocking antibodies directed against cell adhesion molecules, and cell viability was determined after various time intervals by trypan blue, annexin V, propidium iodide, or Hoechst staining. Phenotypic characterization of peripheral blood and SF B cells and FLS was carried out by flow cytometry. RESULTS: Synovial B cells, which consist predominantly of memory B cells and plasma cells (PC), undergo spontaneous cell death by apoptosis upon removal from their in vivo environment, despite expression of Bcl-2. Coculture with FLS rescued synovial B cells from apoptosis in a cell contact-dependent manner. Blocking studies using monoclonal antibodies demonstrated a role for the molecular interaction of SF B cells with vascular cell adhesion molecule 1 (VCAM-1; CD106) in FLS-induced survival. The ability of FLS to induce SF B cell survival was not related to the rheumatoid origin since FLS from non-RA patients had similar properties. CONCLUSION: These findings indicate a crucial role for FLS in the survival of synovial B cells at the site of inflammation in RA through the interaction with VCAM-1 expressed on FLS. Consequently, memory B cells and PC accumulation arise and persist not only as a result of maturation and recruitment of these cells, but also by active prevention from cell death by the microenvironment.

Antibodies, Blocking↗
PubMed2000

A comparison of three radiologic scoring systems for the long-term assessment of rheumatoid arthritis: findings of an ongoing prospective inception cohort study of 132 women followed up for a median of twelve years.

OBJECTIVE: To compare the sensitivity and efficiency of 3 different radiologic scoring systems in measuring radiologic progression of rheumatoid arthritis (RA) over a 12-year period. METHODS: Radiographs of the hands and feet of 112 RA patients were assessed at 0, 3, 6, and 12 years of disease duration using the Sharp score as modified by van der Heijde (SHS), the Sharp score with increased maximum scores (Sharp Max), and the Kellgren score. The sensitivity to change was tested using the standardized response mean (SRM); the efficiency was determined by calculating the number of patients needed to detect 50% difference in progression between 2 patient groups. RESULTS: Radiologic abnormalities were steadily progressive irrespective of the scoring method used. In early disease, the SRM was significantly larger for the SHS and Kellgren scores compared with the Sharp Max score. In late disease, the Kellgren score was slightly more sensitive to change compared with the SHS and Sharp Max scores; the difference, however, did not reach significance. In erosive disease, the SRM was significantly larger for the Kellgren compared with the SHS and Sharp Max scores. The numbers of patients needed to detect a 50% difference during the 0-3-year followup period were 129, 138, and 124 for the SHS, the Sharp Max, and the Kellgren, respectively. The numbers of patients needed to detect a 50% difference during the 6-12-year followup period were 117, 121, and 104, respectively. The numbers of patients needed to detect a 50% difference during the 6-12-year followup in patients with erosive disease were 74, 78, and 68, respectively, for the 3 scores. The Kellgren required 33 minutes to score 10 sets of radiographs of the hands and feet; the SHS score took 55 minutes. CONCLUSION: The Kellgren scoring system is the most efficient method for monitoring the radiologic progression of RA. The Kellgren and the SHS are equally sensitive to change early in the disease, whereas the Kellgren score becomes more sensitive to change late in the disease in patients with erosions.

Adult↗
PubMed2000

Inhibition of neutrophil migration soon after initiation of treatment with leflunomide or methotrexate in patients with rheumatoid arthritis: findings in a prospective, randomized, double-blind clinical trial in fifteen patients.

OBJECTIVE: Leflunomide is a novel immunomodulating drug that has recently been approved as a disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA). The aim of this study was to determine the relationship between the clinical effects of leflunomide and neutrophil migration. METHODS: The effects of leflunomide and methotrexate on neutrophil chemotaxis were studied in 15 RA patients who participated in a prospective, randomized, double-blind clinical trial. When possible, neutrophil numbers were counted in synovial fluid (SF) samples at baseline and after 14 days, 4 months, and 1 year of treatment. The chemotactic properties of peripheral blood neutrophils from RA patients treated with either leflunomide or methotrexate were studied by the Boyden chamber technique, using the activators formyl-methionyl-leucyl-phenylalanine (fMLP) and interleukin-8 (IL-8). The in vitro effects of A77 1726, the active metabolite of leflunomide, and methotrexate on peripheral blood neutrophils from 7 healthy control subjects were also investigated. RESULTS: Both therapy groups exhibited clinical improvement, including rapid reductions in SF neutrophil counts and reduced joint swelling and tenderness. On day 14, 3 of 7 patients who received leflunomide showed no detectable effusions. There was a significant effect on neutrophil chemotaxis (P < 0.001), which was similar for leflunomide and methotrexate. The direct effects on the neutrophils diminished over time. Incubation of peripheral blood neutrophils from healthy controls with A77 1726 confirmed the inhibitory effect on chemotaxis. CONCLUSION: Leflunomide treatment is beneficial in RA patients. Different mechanisms are operative in various phases of treatment, leading to decreased recruitment of inflammatory cells in the joints.

Aged↗
PubMed2000

Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of a cell surface-targeted plasmin inhibitor.

OBJECTIVE: Joint destruction in rheumatoid arthritis (RA) is a result of degradation and invasion of the articular cartilage by the pannus tissue. The present study was undertaken to examine the role of the plasminogen activation system in cartilage degradation and invasion by synovial fibroblasts and investigate a novel gene therapeutic approach using a cell surface-targeted plasmin inhibitor (ATF.BPTI). METHODS: Adenoviral vectors were used for gene transfer. The effects of ATF.BPTI gene transfer on RA synovial fibroblast-dependent cartilage degradation were studied in vitro, and cartilage invasion was studied in vivo in the SCID mouse coimplantation model. RESULTS: The results indicate that cartilage matrix degradation by rheumatoid synovial fibroblasts is plasmin mediated and depends on urokinase-type plasminogen activator for activation. Targeting plasmin inhibition to the cell surface of the fibroblasts by gene transfer of a cell surface-binding plasmin inhibitor resulted in a significant reduction of cartilage matrix degradation in vitro and of cartilage invasion in vivo. Compared with uninfected rheumatoid synovial fibroblasts, the mean +/-SEM cartilage degradation in vitro was reduced to 87.9+/-0.9% after LacZ gene transfer versus a reduction to 24.0+/-1.6% after ATF.BPTI gene transfer (P<0.0001). The mean +/- SEM in vivo cartilage invasion score was 3.1+/-0.4 in the control-transduced fibroblasts and 1.8+/-0.4 in the ATF.BPTI-transduced fibroblasts (P<0.05). CONCLUSION: These results indicate a role of the plasminogen activation system in synovial fibroblast-dependent cartilage degradation and invasion in RA, and demonstrate an effective way to inhibit this by gene transfer of a cell surface-targeted plasmin inhibitor.

Activating Transcription Factors↗
PubMed2000

Modulation of inflammation and metalloproteinase expression in synovial tissue by leflunomide and methotrexate in patients with active rheumatoid arthritis. Findings in a prospective, randomized, double-blind, parallel-design clinical trial in thirty-nine patients at two centers.

OBJECTIVE: Leflunomide and methotrexate have proven to be efficacious in reducing joint inflammation and slowing destruction in clinical trials of patients with rheumatoid arthritis (RA). This study was conducted to provide more insight into the mechanism of action of these agents in synovial tissue. METHODS: In a 2-center, prospective, randomized, double-blind clinical trial, we compared leflunomide (20 mg/day, after a 3-day 100 mg/day loading dose) and methotrexate (increased stepwise to 15 mg/week) treatment in patients with active RA. Paired synovial tissue biopsy samples were obtained by knee arthroscopy at baseline and after 4 months of treatment. Frozen synovial tissue sections were stained for macrophages (CD68), T cells (CD3), adhesion molecules (intercellular adhesion molecule 1 [ICAM-1], vascular cell adhesion molecule 1 [VCAM-1]), cytokines (tumor necrosis factor alpha, interleukin-1beta [IL-1beta]), matrix metalloproteinase 1 (MMP-1), and tissue inhibitor of metalloproteinases 1 (TIMP-1). RESULTS: Paired synovial tissue sections were available in 35 patients (16 taking leflunomide, 19 taking methotrexate). Both drugs displayed equal clinical efficacy, with 8 leflunomide-treated patients (50%) and 10 methotrexate-treated patients (53%) fulfilling the American College of Rheumatology 20% response criteria. Both compounds showed similar effects on synovial tissue: reduced numbers of macrophages and reduced ICAM-1 and VCAM-1 expression were noted after 4 months of treatment. Both leflunomide- and methotrexate-treated patients exhibited a decreased MMP-1:TIMP-1 ratio in the synovial tissue. In the subset of patients fulfilling the 20% response criteria of the American College of Rheumatology, a more pronounced reduction in the expression of ICAM-1, VCAM-1, IL-1beta, and MMP-1 was found compared with the nonresponders. CONCLUSION: Leflunomide and methotrexate are clinically efficacious drugs that interfere with mechanisms involved in joint inflammation and destruction of joint integrity.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Are magnetic resonance flexion views useful in evaluating the cervical spine of patients with rheumatoid arthritis?

OBJECTIVE: To determine whether MR imaging in flexion adds value relative to imaging in the neutral position with respect to displaying involvement of the subarachnoid space, brainstem and spinal cord. DESIGN AND PATIENTS: T1-weighted MR images of the cervical spine in 42 rheumatoid arthritis patients with cervical spine involvement were obtained and analyzed prospectively. We assessed changes between images obtained in the neutral position and following active flexion, especially horizontal atlantoaxial and subaxial motion, presence or absence of brainstem compression, subarachnoid space involvement at the atlantoaxial and subaxial level and the cervicomedullary angle. Vertical atlantoaxial subluxation and the amount of pannus were correlated with motion and change in subarachnoid space. RESULTS: The flexion images showed horizontal atlantoaxial motion in 21 patients and subaxial motion in one patient. The flexion view displayed brainstem compression in only one patient. Involvement of the subarachnoid space increased at the atlantoaxial level in eight (19%) patients (P=0.004) and at the level below C2 in five (12%) patients (P=0.03). There were no patients with a normal subarachnoid space in neutral position and compression in the flexed position. The cervicomedullary angle changed significantly with flexion. Vertical atlantoaxial subluxation and the amount of pannus did not show a significant correlation with motion or subarachnoid space involvement. CONCLUSION: MR imaging in the flexed position shows a statistically significant narrowing of the subarachnoid space at the atlantoaxial level and below C2. Cord compression is only observed on flexion views if the subarachnoid space in neutral position is already decreased. MR imaging in the flexed position might be useful, since subarachnoid space involvement may be an indicator for the development of neurologic dysfunction.

Adult↗