SEARCH · PubMed Health

Results for “rejection”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 145 records · Page 8Linked to original sources

PubMed1999

Features of acute rejection that increase risk for chronic rejection.

BACKGROUND: Acute rejection (AR) has been shown to be a significant risk factor for chronic rejection (CR) in kidney transplant recipients, yet many recipients with AR do not progress to CR. The purpose of this study was to determine if certain AR episodes are associated with a worse prognosis. METHODS: The study group consisted of 279 kidney transplant recipients, all treated for a single episode of biopsy-proven AR. All AR episodes were initially treated with steroids; steroid-resistant rejection was managed with an antibody preparation. RESULTS: First, by univariate techniques, we determined the clinical impact of severity of AR (as estimated by delta creatinine [dCr], defined as the change in baseline serum creatinine level 6 weeks after AR treatment) on two different endpoints--biopsy-proven CR and graft survival. Irrespective of 6-week dCr, all recipients with AR had a significantly increased risk of CR vs. those with no AR (P<0.01). Recipients with dCr between 0.5 and 1.0 mg/dl had a significantly higher incidence of CR vs. those with dCr <0.5 mg/dl (P<0.05), but a significantly lower incidence vs. those with dCr >1.0 mg/dl (P<0.05). We then performed multivariate analysis. We used severity of AR in addition to other variables (e.g., timing of AR, donor age) to determine which factors were most associated with risk for CR and graft loss. Risk for CR increased with AR episodes occurring >6 months after transplant (relative risk [RR] = 3.8, P = 0.005); with moderate or severe (vs. mild) AR episodes (RR = 2.7, P = 0.05); and with dCr >0.5 mg(dl (vs. <0.5 mg/dl) at 6 weeks after AR treatment (RR = 2.3, P = 0.1). Findings were similar when graft survival (death-censored) was the endpoint instead of CR. CONCLUSIONS: All AR episodes are associated with some increase in the risk for CR. But AR episodes occurring >6 months after transplant and those of increased severity (as assessed qualitatively by histologic grading and quantitatively by dCr) confer the greatest risk. Recipients with these risk factors could be targeted with measures to decrease their risk for CR, including trials of novel immunosuppressive regimens.

Acute Disease↗

PubMed2000

Sialyl Lewis(x) (CD15s) monitoring as a means to select antirejection therapy in patients with rejection after renal transplantation: CD15s monitoring for treatment and diagnosis in patients with acute rejection after renal transplantation.

BACKGROUND: Sialyl Lewis(x) (CD15s), which is known to serve as a ligand for the cell adhesion molecules E-selectin and P-selectin, is expressed on peripheral lymphocytes in renal transplant patients with rejection. In this study, we examined whether CD15s monitoring could differentiate the patients with rejection in whom steroids were effective from those in whom steroids were not effective. METHODS: To investigate CD15s expression on peripheral lymphocytes, flow cytometry was performed before and after steroid pulse therapy in 20 recipients with rejection after renal transplantation, including 5 recipients resistant to steroid therapy. We also compared CD15s expression with pathological findings before and after steroid pulse therapy. RESULTS: CD15s expression was stronger before steroid pulse therapy in the 5 patients resistant to steroids than in the 15 patients responsive to steroid treatment. In addition, CD15s expression remained high without any pathological improvement in the 5 patients resistant to steroids after steroid treatment, although CD15s recovered to normal levels with remarkable improvement of pathological findings in the other 15 patients. Five patients in whom steroids were not effective, had full recovery of serum creatinine levels as well as CD15s expression after muromonab (OKT3) therapy. CONCLUSIONS: CD15s monitoring might help clinicians to select antirejection therapy.

Adult↗

PubMed2005

Humoral heart rejection (severe allograft dysfunction with no signs of cellular rejection or ischemia): incidence, management, and the value of C4d for diagnosis.

Severe allograft dysfunction after heart transplant (HT), without ischemia or evidence of cellular rejection upon endomyocardial biopsy (EMB), is a rare but potentially fatal condition that suggests humoral rejection (HR). Its incidence, and the methods of choice for its diagnosis and management, remain uncertain. We retrospectively studied 445 HT patients (April 1991-December 2003) to determine incidence of HR diagnosed by clinical and conventional histopathological criteria. We used immunofluorescence (IF) techniques to test archived frozen EMB issue for IgM, IgG, C1q, C3, fibrin and C4d. Twelve patients (2.7%) fulfilled the criteria for HR after a mean time post-HT of 21.3 +/- 24.7 months (range: 2-72 months). Patients were treated with high doses of steroids and plasmapheresis, with successful recovery in 11 cases. IF studies using classical markers were mainly negative for the six patients with enough EMB tissue for testing. All six patients showed positivity for C4d during the HR episode but not before or after. Humoral rejection was observed in less than 3% of HT patients. Plasmapheresis treatment was highly effective. Classical IF tests were not useful for diagnosis, but C4d appears to be useful both for confirmation of diagnosis and for monitoring response to treatment.

Adult↗

PubMed2004

The role of TNF-related activation-induced cytokine-receptor activating NF-kappa B interaction in acute allograft rejection and CD40L-independent chronic allograft rejection.

We analyzed the role of TNF-related activation-induced cytokine (TRANCE), a member of the TNF family expressed on activated T cells that shares functional properties with CD40L, and its receptor-activating NF-kappaB (RANK) which is mostly expressed on mature dendritic cells, during allogenic responses in vivo using a rodent heart allograft model. TRANCE mRNA was strongly up-regulated in acutely rejected allografts on days 4 and 5 posttransplantation whereas RANK was detected as early as day 1 but did not show further up-regulation during the first week. Immunofluoresence analyses of heart allografts showed that 80 and 100% of TRANCE and RANK-expressing cells were T cells and APCs, respectively. We show for the first time that short-term TRANCE blockade using a mouse RANKIg fusion molecule can significantly prolong heart allograft survival in both rat and mouse models. Similarly, rat heart allografts transduced with a RANKIg encoding recombinant adenovirus exhibited a significant prolongation of survival (14.3 vs 7.6 days, p < 0.0001). However, TRANCE blockade using RANKIg did not appear to inhibit allogeneic T and B cell priming humoral responses against RANKIg. Interestingly, TRANCE blockade induced strong up-regulation of CD40 ligand (CD40L) mRNA in allografts. Combined CD40L and TRANCE blockade resulted in significantly decreased chronic allograft rejection lesions as well as allogeneic humoral responses compared with CD40L blockade alone. We conclude that TRANCE-RANK interactions play an important role during acute allograft rejection and that CD40L-independent allogeneic immune responses can be, at least in part, dependent on the TRANCE pathway of costimulation.

Acute Disease↗

PubMed1988

Telemetric detection of cardiac allograft rejection. Correlation of electrophysiological, histological, and biochemical changes during unmodified rejection.

Intra-abdominal mismatched heterotopic cardiac allograft transplantation without immunosuppression was performed in eight pigs. Postoperatively, daily electrophysiological studies were carried out either with exteriorized temporary epicardial pacing wires (n = 4) or by a telemetrically controlled implanted pacemaker connected to permanent epicardial pacing leads (n = 4). Electrophysiological studies data were correlated with histopathologic and biochemical findings from daily myocardial biopsies. Electrophysiological studies revealed no significant alteration of sinus or atrioventricular node function, refractoriness, or ventricular pacing threshold. However, ventricular voltage amplitude, measured through the electrodes, decreased steadily with time in all donor hearts and was significantly correlated with histopathologic rejection grade (p less than 0.001) and with adenosine 5'-triphosphate (ATP) depletion (p less than 0.001). Ventricular voltage amplitude less than 75% of baseline occurred 4.5 +/- 1.5 days after transplantation, and this decreased voltage amplitude coincided with a moderate to severe (Grade 2 or 3) histological rejection pattern with a sensitivity of 89% (17 of 19) and a specificity of 77% (17 of 22). Similar changes in voltage amplitude were not found in control hearts. Myocardial tissue ATP values fell significantly from control values with early (Grade 1) rejection (p less than 0.05). Evidence for oxygen free radical injury was indicated by a rise in conjugated dienes of free fatty acids; this increase in diene level occurred 4.3 +/- 1.2 days postoperatively and then regressed during the terminal stages.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMed1994

Leflunomide in experimental transplantation. Control of rejection and alloantibody production, reversal of acute rejection, and interaction with cyclosporine.

Leflunomide is a compound recently shown to reduce T and B cell-mediated responses in a number of experimental rat, mouse, and human systems. To explore its potential as an immunosuppressant, we studied leflunomide in 128 Brown-Norway/Lewis cardiac transplants and in 48 unoperated Lewis rats. At doses ranging from 0.63 mg/kg to 10 mg/kg given for 7 days, leflunomide significantly prolonged graft survival compared with controls. When cyclosporine or leflunomide was given for 21 days at a dose of 5 mg/kg, indefinite graft survival occurred in 3/6 animals receiving leflunomide but in none of the 21-day cyclosporine-treated animals. When acute rejection was allowed to develop for four days in untreated rats, leflunomide but not cyclosporine reversed the rejection, returning histology to a normal appearance by seven days. Alloantibody responses measured in microcytoxicity assays as well as total allospecific IgG and IgM in the rejecting animals also were returned to baseline levels by leflunomide but not cyclosporine. When both drugs were used together, a synergistic effect was observed at low doses of both drugs. Pharmacokinetics studies showed that their combined use for up to 28 days did not affect the trough levels of cyclosporine or cyclosporine elimination, suggesting that the synergistic effect was not caused by reduced elimination. The toxicity of each drug was negligible in a group of 32 rats receiving the drugs alone or in combination as measured by serial observation of general appearance, testing of serum ALT, AST, bilirubin, creatinine, white blood cell counts, hemoglobin, and gross necropsy appearance. Weight gain was slightly reduced by both drugs but combined drug use did not alter the pattern. The results of these experiments show leflunomide to be a potent, well-tolerated immunosuppressant, synergistic in its activity with cyclosporine, and would seem to encourage a closer look at this drug for potential use in man.

Abdomen↗

PubMed2004

Contribution of CD4+ and CD8+ T cells and interferon-gamma to the progress of chronic rejection of kidney allografts: the Th1 response mediates both acute and chronic rejection.

T cells mediating chronic rejection (CR) of human kidney allografts were characterized by comparing them with those mediating acute rejection (AR). Two lines of analysis were performed using biopsy specimens (23 CR and 8 AR). First, the extent of infiltration of CD4+ and CD8+ T cells into allografts was assessed from mRNA expression of CD4 and CD8. The group of CR specimens was not significantly different from the group of AR specimens in terms of the extent of CD4+ and CD8+ T cell infiltration, underlining the importance of the immunological contribution to the progress of CR. Second, Th1/Th2 polarization in infiltrating T cells was investigated by measuring mRNA expression of interferon gamma (IFN-gamma; a Th1 cytokine) and interleukin 4 (IL-4; a Th2 cytokine). IFN-gamma expression was detected in most CR specimens, and was not significantly different between the group of CR specimens and the group of AR specimens. On the other hand, IL-4 expression was detected in only two CR specimens and one AR specimen; from its pathological features, the AR in this last case was concomitant with CR. These results suggest that most cases of CR and of AR are mediated by Th1 mechanisms, although some cases of CR show features of both Th1 and Th2.

Acute Disease↗

PubMed1987

Spontaneous tumor rejection is not always due to a complete cellular rejection.

In this paper we have studied whether there is a correlation between efficacy of hosts to reject tumor cells spontaneously and the induction of cytotoxic macrophages in these recipients due to injection (immunization) with tumor cells. Results show that there is no cause-effect relationship between macrophage cytotoxicity and tumor rejection in vivo. This lack of cause-effect relationship is greatly influenced by differences in immunogenicity between the various tumor cell lines as well as by the release of tumor-factors by some of these tumors.

Animals↗

PubMed2002

Acute xenograft rejection, late xenograft rejection and long term survival xenografts in the hamster-to-rat heart transplantation model: histological characterisation under low-dose of FK506.

BACKGROUND: Long-term survival studies have been conducted in hamster-to-rat cardiac models with a range of immunosuppressive treatments, but the histological pattern of Late Xenograft Rejection (LXR) has not been outlined. This study offers a detailed description of the histological changes in cardiac xenografts under three different immunological responses. MATERIALS AND METHODS: Heterotopic hamster-to-Lewis rat cardiac transplant. Recipients were administered an antiproliferative drug (MMF, 25 mg/kg, or CyP, 10 mg/kg, from day -7 to +7 or from day 0 to +7, according to group) and FK506 (0.2 mg/kg; from day 0 to +30 or continuously). Unmodified recipients were used as controls. Conventional histology and indirect immunofluorescence of IgM, IgG and C3 deposits were performed. RESULTS: In our study, xenografted rats that did not receive treatment developed a pattern of Acute Xenograft Rejection (AXR), with substantial tissue breakdown. Pretreated and treated animals until day 30 post-transplant developed LXR that may present two different histological patterns: one with vascular damage and predominant interstitial haemorrhage, and the other with extensive myocardial fibrosis. Long-term surviving rats (LTS) showed a morphology that was almost normal, with mild fibrosis and vascular endothelium preserved. CONCLUSIONS: AXR, LXR and LTS in the hamster-to-rat heart transplantation model present a common humoral mechanism although their histopathological patterns are different depending on the length of immunosuppressive treatment but not on the type of antiproliferative drug administered. Pretreatment exerts an effect on fibrosis formation.

Acute Disease↗

PubMed1978

The cellular basis of allograft rejection in vivo. II. The nature of memory cells mediating second set heart graft rejection.

An adoptive transfer system was used to study the cellular basis of memory in animals immunized by grafting with major histocompatibility complex incompatible tissue. Memory was characterised by a large (greater than 100 fold) increase in the potency of lymphocytes to precure graft rejection. This increase in potency endured for at least 1 yr after sensitization. The memory cells were shown to be Ig-- small lymphocytes which were long lived and which did not recirculate from blood to lymph in normal recipients although they did home to lymphoid tissue from which they could be recovered several months later. The thymus was not required either for the generation of memory cells or their maintenance. Cells carrying memory for alloantibody synthesis did recirculate normally but alloantibody synthesis was shown not to be required for rejection.

Animals↗

PubMed1982

Graft rejection in sponges. Genetic structure of accepting and rejecting populations.

Graft rejection frequencies in a population of the sponge Ectyoplasia ferox are reported in relation to the complexity of the histocompatibility system in this species. The frequency of graft acceptance is high but we show that, despite assumptions in the literature to the contrary, this does not imply that sponges accepting each other's grafts are genetically identical. This paper reports that graft-accepting pairs of sponges can have dissimilar plasmalemmal proteins. In addition, a theoretical analysis is presented of the types of histocompatibility systems that would account for the present results and those of others. We concluded that there is no evidence that sponges have highly polymorphic histocompatibility systems. The paper also reports on the histology of graft rejection and discusses some of the ecological relevance of the findings.

Alleles↗

PubMed1996

CD40-gp39 interactions play a critical role during allograft rejection. Suppression of allograft rejection by blockade of the CD40-gp39 pathway.

Studies in vivo have documented the importance of CD40-gp39 interactions in the development of T-dependent antibody responses to foreign and auto-antigens. In this report, we demonstrate that allograft rejection is also associated with strong induction of CD40 and gp39 transcripts. When treatment was initiated at the time of transplant, MR1, a mAb specific for gp39, induced markedly prolonged survival of fully disparate murine cardiac allografts in both naive and sensitized hosts. However, when therapy was delayed until postoperative day 5, anti-gp39 failed to prolong graft survival. Allografts from recipients treated with MR1 from the time of transplantation showed decreased expression of transcripts for the macrophage effector molecule, inducible nitric oxide synthase, but essentially unaltered expression of B7 molecules and T cell cytokine transcripts (interleukin [IL]-2, interferon-gamma, IL-10, and IL-4) relative to control allografts. In addition, alloantibody responses in the MR1-treated mice were profoundly inhibited. However, our studies using B cell-deficient mice indicated that the ability of MR1 to prolong allograft survival was not dependent on B cells. These data suggest that blockade of CD40-gp39 interactions may inhibit allograft rejection primarily by interfering with T cell help for effector functions, rather than by interference with T cell activation.

Animals↗

PubMed1996

Allograft and xenograft rejection in C3H/SCID mice. A new model for the study of non-T cell graft rejection mechanisms.

Comparative cell transfer experiments have revealed that, despite their equal immune deficiency, C3H/SCID mice were markedly inferior compared with C.B-17/SCID mice in their ability to accept allogeneic and xenogeneic grafts. Allogeneic C.B-17/SCID bone marrow cells were engrafted poorly compared with syngeneic C3H/SCID when transplanted into C3H/SCID recipients, whereas cells of both strains were equally well engrafted into C.B-17/SCID mice. C.B-17/SCID mice were much more permissive for outgrowth of human Burkitt lymphoma (Raji), as well as for Epstein-Barr virus lymphoma development after transplantation of human peripheral blood lymphocytes. Human skin grafts were accepted by the C.B-17/SCID mice but were promptly rejected by the C3H/SCID mice. The resistance to human RaJi cells could be adoptively transferred by infusion of C3H/SCID splenocytes into C.B-17/SCID mice. Because the C.B-17/SCID and C3H/SCID mice equally lack both T and B lymphocytes, the latter may provide a relevant model for studies of non-T mechanisms of allograft or xenograft rejection.

Animals↗

PubMed1998

Mouse parvovirus infection potentiates allogeneic skin graft rejection and induces syngeneic graft rejection.

BACKGROUND: The recently identified autonomous mouse parvovirus designated mouse parvovirus-1 (MPV-1) persists in adult BALB/c mice for at least 9 weeks, infects lymphoid tissues, interferes with the ability of cloned T cells to proliferate, and exhibits immunomodulatory properties. As a consequence of these findings, the present studies were undertaken to characterize further the inmunomodulatory effects of MPV-1 on T cell-mediated immune responses in vivo and in vitro. METHODS: To evaluate the effect of MPV-1 infection on CD8+ T cell-mediated responses, BALB/c-H2dm2 mice were infected after transplantation of allogeneic BALB/c skin. RESULTS: MPV-1 potentiated the rejection of allogeneic skin grafts. This potentiation was not a result of virus infecting the cellular or vascular component of the graft as determined by in situ hybridization, but was mediated by T cells. However, the proliferative capacity of alloantigen-reactive lymphocytes from graft-sensitized infected mice was diminished. MPV-1 also induced the rejection of syngeneic skin grafts, and T cells from these infected graft-sensitized mice lysed syngeneic P815 target cells. CONCLUSIONS: These results suggest that MPV-1 infection of skin-grafted mice may disrupt normal mechanisms of peripheral tolerance and provide a unique model to study virus-induced autoimmunity.

Animals↗

PubMed2002

The significance of parenchymal changes of acute cellular rejection in predicting chronic liver graft rejection.

BACKGROUND: Chronic rejection (CR) in liver allografts shows a rapid onset and progressive course, leading to graft failure within the first year after transplantation. Most cases are preceded by episodes of acute cellular rejection (AR), but histological features predictive for the transition toward CR are not well documented. METHODS: We assessed the predictive value of centrilobular necrosis, central vein endothelialitis (CVE), central vein fibrosis, and lobular inflammation in the development of CR. One-week and one-month biopsy specimens of 12 patients with CR were compared with those of a control group consisting of 17 patients, who experienced AR without developing CR. The progress of the histological changes was further evaluated in follow-up biopsy specimens of the CR group taken at 2 months and beyond 3 months after transplantation. RESULTS: Centrilobular necrosis, CVE, central vein fibrosis, and lobular inflammation were common features in both groups at 1 week. At 1 month, the incidence declined in the control group. The CR group showed an increased incidence and persistence of these features in the follow-up biopsy specimens. The incidence and median grade of severity of CVE was significantly higher in the CR group (P=0.04 and P<0.001). The severity of portal and lobular inflammation was also more pronounced in the CR group (P=0.01 and 0.068). Conversely, in the control group, the incidence of the lobular features decreased and the severity of CVE declined significantly (P=0.03). CONCLUSION: The shift from a predominantly portal-based process toward lobular graft damage represents the early transition of AR to CR, for which a modification of immunosuppression might be necessary to prevent graft loss.

Acute Disease↗

PubMed2005

High CXCL10 expression in rejected kidneys and predictive role of pretransplant serum CXCL10 for acute rejection and chronic allograft nephropathy.

BACKGROUND: Several experimental models have shown that CXCL10 is required for initiation and development of graft failure caused by both acute and chronic rejection. METHODS: CXCL10 expression and distribution was investigated in tissue specimens obtained from 22 patients suffering from acute rejection (AR) or chronic allograft nephropathy (CAN) by using in situ hybridization. Furthermore, pretransplantation sera of 316 cadaveric kidney-graft recipients were tested retrospectively for serum CXCL10 levels by a quantitative sandwich immunoassay. RESULTS: Bioptic specimens obtained from patients with CAN were characterized by wide CXCL10 expression not only at level of infiltrating inflammatory cells but also of vascular, tubular, and glomerular structures. In addition, assessment of pretransplant serum CXCL10 levels in 316 graft recipients and stratification of patients in three groups according to serum CXCL10 levels (<100 pg/mL, n=163; 100-150 pg/mL, n=69; >150 pg/mL, n=84) showed highly significant differences in 5-year survival rates for the two extreme groups (95.7% vs. 79.7%, P=0.0002). Accordingly, patients who developed severe, early AR (277.14+/-65.08 p=0.004) and those who developed CAN also showed increased pretransplant serum CXCL10 levels (193.2+/-36.9, P=0.03). Multivariate analysis demonstrated that among the analyzed variables, CXCL10 (relative risk [RR] 2.801) and delayed graft function (RR 3.728) had the highest predictive power of graft loss. CONCLUSIONS: These results suggest that pretransplant serum CXCL10 levels greater than 150 pg/mL confer an increased risk of early, severe, AR and subsequent CAN, finally resulting in renal-allograft failure. This finding might be used for the individualization of immunosuppressive therapies.

Biomarkers↗

PubMed2005

Mycophenolate mofetil vs. azathioprine is associated with decreased acute rejection, late acute rejection, and risk for cardiovascular death in renal transplant recipients with pre-transplant diabetes.

Outcomes specifically in mycophenolate mofetil (MMF)-treated diabetic renal transplant patients have not been previously reported. This study compared acute rejection (AR), late acute rejection (LAR), patient survival [and specifically death from cardiovascular (CV), infectious and malignant causes], incidence of post-transplant malignancies, and graft loss in MMF- or azathioprine (AZA)-treated renal transplant patients with pre-transplant diabetes. Outcomes were compared between MMF- (n = 14 144) and AZA- (n = 3001) treated diabetic patients using the Scientific Registry of Transplant Recipients data on all U.S. adult renal transplants performed between 1995 and 2002. Statistical analyses included Kaplan-Meier survival analysis, Cox multivariable regression and chi-square tests. MMF patients had less AR compared with AZA-treated patients (23.5% vs. 28.3%, p < 0.001) and less risk for LAR over 4 yr [hazard ratio (HR): 0.64, 95% CI 0.44, 0.92; p = 0.02]. While time to any-cause death did not differ between the groups, MMF treatment was associated with a 20% decreased risk of CV death (HR: 0.80, 95% CI 0.67, 0.97; p = 0.020) compared with AZA treatment. MMF patients also had a lower incidence of malignancies than AZA patients (2.2% vs. 3.7%, p < 0.001). These results suggest treatment with MMF compared with treatment with AZA in diabetic transplant patients is associated with less AR, less risk of LAR, a decreased risk of CV death, and a lower incidence of malignancies.

Adolescent↗

PubMed2005

Acute cellular rejection predominated by monocytes is a severe form of rejection in human renal recipients with or without Campath-1H (alemtuzumab) induction therapy.

Campath-1H has been used successfully for induction and has resulted in a low rate of acute cellular rejection (ACR) in renal transplantation in combination with various postoperative immunosuppression regimens. This study was undertaken to investigate the extent of monocyte involvement in ACR, with or without Campath-1H induction. We found that monocytes represented the majority of inflammatory cells in grades Ib or higher ACR, but not with Ia type of ACR, regardless of the status of Campath-1H induction. Cases of ACR, following Campath-1H induction, appear to demonstrate a 'pure form' of monocytic ACR, whereas monocytes were mixed with many other types of inflammatory cells in the cases of ACR in the absence of Campath-1H induction. In addition with Campath-1H induction, the cases of monocyte-predominant ACR were found to uniformly exhibit a good response to corticosteroid treatment. We conclude that monocyte-predominate ACR may represent a severe form of rejection, with or without Campath-1H treatment.

Adolescent↗