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Biomedical subjects

H Greten

Publications and source records attributed to H Greten.

At least 91 records · Page 5Linked to original sources
PubMed1994

Successful treatment of Toxoplasma gondii myocarditis in an AIDS patient.

Central nervous system disease due to Toxoplasma gondii is a common cause of morbidity and mortality in patients with the acquired immunodeficiency syndrome. Cardiac toxoplasmosis, however, has been described in only a limited number of cases. In a 45-year-old patient with symptoms suggestive of myocarditis, Toxoplasma gondii was detected in myocardial tissue obtained by biopsy. After the institution of appropriate antiprotozoal therapy, the patient recovered. This patient is believed to be the first patient to survive biopsy-proven myocarditis caused by Toxoplasma gondii. Cardiac toxoplasmosis should be ruled out in HIV-infected patients presenting with high fever and/or cardiorespiratory symptoms and exhibiting serologic evidence of prior exposure to Toxoplasma gondii as determined by a positive IgG EIA, especially if the CD4+ count is low and no systemic Pneumocystis carinii pneumonia prophylaxis has been administered. A high index of clinical suspicion and, if necessary, invasive diagnostic tests, including myocardial biopsies, are most important in making the correct diagnosis.

AIDS-Related Opportunistic Infections↗
PubMed1994

Selective uptake of high-density lipoprotein-associated cholesteryl esters and high-density lipoprotein particle uptake by human monocyte-macrophages.

High-density lipoprotein (HDL) cholesteryl esters (CE) are taken up by many cells without parallel uptake of HDL apolipoproteins. This selective uptake of HDL CE was investigated in human monocyte-derived macrophages (HMM). HDL3 (d = 1.125-1.21 g/ml) was labeled in its apolipoprotein A-I moiety with 125I and in its CE moiety with [3H]cholesteryl oleyl ether. Cultured human monocyte-macrophages were incubated in the presence of doubly labeled HDL3 followed by determination of tracer uptake. HMM took up HDL3 particles as indicated by the uptake of HDL3 apolipoproteins. Uptake of HDL3-associated CE tracer was in significant excess of that due to HDL3 particle uptake indicating selective uptake of CE. Increased cell cholesterol due to preincubation with acetylated low-density lipoprotein (LDL) down-regulated selective uptake by HMM. According to several experimental approaches, selective uptake of HDL3 CE was independent from cell-secreted products, LDL receptor-mediated endocytosis or HDL3 retroendocytosis. The intracellular catabolism of HDL3 CE was investigated with HDL3 labeled in its CE moiety with [3H]cholesteryl oleate. The lysosomal inhibitor chloroquine had no effect on CE hydrolysis indicating that CE selectively taken up is hydrolyzed independently from lysosomes. In conclusion, HMM selectively take up HDL3-associated CE. The cellular mechanism of selective uptake is independent from endocytosis or retroendocytosis. Intracellularly, HDL3 CE selectively taken up are catabolized independently from lysosomes.

Apolipoprotein A-I↗
PubMed1994

Requirements for editing in the genomic RNA of hepatitis delta virus.

Hepatitis delta virus is a satellite of the hepatitis B virus which provides the surface antigen for the viral coat. The genome of the hepatitis delta virus consists of a single-stranded, circular RNA of 1679 nucleotides which forms a rod structure due to a high extent of self homology and which replicates via synthesis of an antigenomic RNA in a rolling circle mechanism similar to plant viroids. The antigenomic RNA contains the open reading frame for the delta-antigen which exists in two isoforms, p24 and p27. The formation of these two isoforms is explained by RNA editing at nucleotide 1012 which changes the stop translation codon UAG at amino acid residue 196 into the codon UGG for tryptophan and extends the open reading frame for the synthesis of p27. In order to investigate whether the editing occurs cotranscriptionally during RNA replication or is a posttranscriptional base modification in the genomic or antigenomic RNA, replication defective deletion mutants of the HDV genome were constructed and expressed in COS-7 cells. Editing was demonstrated in non-replicating fragments of genomic HDV RNA but not in antigenomic HDV RNA fragments. The sequences from nucleotide position 337-1200 of the genomic RNA were sufficient to enable low levels of editing. Editing at position 1012 required the opposite strand of the RNA rod from nucleotide position 337-783. Replicating circular HDV RNA was much more efficiently edited than non-replicating full length genomic HDV RNA. Expression of delta-antigen in trans did not complement the low editing efficiency of replication defective genomic HDV RNA. These results demonstrate posttranscriptional U to C editing in the genomic HDV RNA and exclude misincorporation during HDV RNA replication as the editing mechanism. The minimal structural requirements for HDV RNA editing reside between nucleotide position 337-1200.

Animals↗
PubMed1994

Interleukin 1 beta, tumor necrosis factor-alpha and interleukin 6 decrease nuclear thyroid hormone receptor capacity in a liver cell line.

Many of the acute inflammatory responses in critical illness are mediated by tumor necrosis factor-alpha (TNF-alpha), interleukin 1 beta (IL-1 beta) and interleukin 6 (IL-6). Furthermore, these cytokines are involved in mediating the characteristic changes of thyroid function during acute disease known as non-thyroidal illness. In the present studies we investigated in vitro whether TNF-alpha, IL-1 beta and IL-6 modify nuclear thyroid hormone receptor (TR) capacity and/or affinity. Regulation of TR synthesis was studied in the human hepatoma cell line Hep-G2. Subconfluent cells were incubated with recombinant cytokines in serum-free medium. Nuclear extracts were prepared by high-salt extraction of cell nuclei. Binding assays were performed with [125I]-triiodothyronine; bound and free hormone were separated by filtration. Interleukin 1 beta decreased TR capacity in a dose-dependent manner. Compared with unstimulated cells, the TR capacity was reduced to 87.9 +/- 3.9% (p < 0.05), 80.1 +/- 3.9% (p < 0.01) and 72.1 +/- 5.1% (p < 0.01) after incubation with 0.1, 1.0 and 100 micrograms/l IL-1 beta, respectively. Interleukin 6 and TNF-alpha significantly reduced receptor capacity only at concentrations of 10 micrograms/l or higher and the magnitude of the reduction was lower than with IL-1 beta. The TR capacity was reduced to 81.2 +/- 2.3% (p < 0.01) and 83.2 +/- 6.6% (p < 0.05) after stimulation with 10 micrograms/l IL-6 or TNF-alpha, respectively. TR affinity was not altered significantly after stimulation with any of the cytokines.(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinoma, Hepatocellular↗
PubMed1993

Metformin increases glucose transporter protein and gene expression in human fibroblasts.

To investigate the effect of the antihyperglycemic drug metformin on glucose transporter protein and gene expression, skin fibroblasts obtained from normal and diabetic volunteers were grown in culture and incubated with metformin at various concentration for up to 16 days. Metformin caused a dose and time dependent increase in GLUT1 number with a maximum at a concentration of 10 micrograms metformin given over 4 days. This was accompanied by an increase in GLUT1 mRNA, suggesting that metformin has a stimulating effect on glucose transporter gene expression. No significant difference was observed between cells obtained from type II diabetic patients and those from controls. We conclude that in human fibroblasts GLUT1 de novo synthesis is involved in the long term effect of metformin on glucose transport.

Adult↗
PubMed1993

Selective association of lipoprotein cholesteryl esters with liver plasma membranes.

High-density lipoprotein (HDL) cholesteryl esters are taken up by hepatocytes without parallel uptake of HDL apolipoproteins. This selective uptake of HDL cholesteryl esters is mediated by a non-endocytotic mechanism. Recently, selective uptake of cholesteryl esters also from low-density lipoprotein (LDL) was demonstrated. In this study, the role of the plasma membrane in selective uptake by the liver was investigated. Plasma membranes were prepared from rat liver or from human Hep G2 hepatoma cells. Human HDL3 (d = 1.125-1.21 g/ml) was either radioiodinated or labeled with [3H]cholesteryl oleate. Human low-density lipoprotein (d = 1.019-1.05 g/ml) was labeled in its protein and in its lipid moiety as well. Labeled lipoproteins, unlabeled lipoproteins and membranes were incubated. After separation by ultracentrifugation, apparent lipoprotein particle association with membranes was determined. Plasma membranes from rat liver and Hep G2 cells bound 125I-HDL3, indicating specific HDL3 particle binding. With both types of membrane, apparent HDL3 particle association according to [3H]cholesteryl oleate-labeled HDL3 was in significant excess on that due to 125I-HDL3. This indicates selective, i.e., particle binding independent, association of cholesteryl esters with the membrane. Excess unlabeled HDL3 competed for selective association, indicating a specific process. Selective association of HDL3 cholesteryl esters was concentration-, time-, temperature-dependent; however, parameters differed from HDL3 particle binding. HDL3 was modified by nitration; this modification inhibited HDL3 particle binding in contrast to unchanged selective association. These results suggested distinct membrane sites for HDL3 particle binding and selective cholesteryl ester association. Regulation of selective association was investigated. Hep G2 cells were cholesterol-loaded or cholesterol-depleted. Cellular cholesterol-loading down-regulated selective association of HDL3 cholesteryl esters with isolated membranes prepared from these cells. In parallel, selective uptake of HDL3 cholesteryl esters by Hep G2 cells was down-regulated in cholesterol-loaded cells. This parallel regulation of selective association with membranes and selective uptake by cells suggests a functional relationship. LDL, radiolabeled in its protein and in its lipid moiety, was incubated with liver plasma membranes. Besides LDL holo-particle receptor binding, also LDL cholesteryl esters were selectively associated with membranes. These data showed that selective association with membranes is not restricted to HDL but can occur from LDL as well. It is concluded that HDL3 as well as LDL cholesteryl esters can selectively be associated with hepatic plasma membranes, i.e., independent from particle binding. Results suggest an important role of the plasma membrane in the mechanism of selective cholesteryl ester uptake by the liver.

5'-Nucleotidase↗
PubMed1993

Dissection of compartments in rat hepatocytes involved in the intracellular trafficking of high-density lipoprotein particles or their selectively internalized cholesteryl esters.

The trafficking of apolipoprotein E-deficient high-density lipoprotein particles and of their component cholesteryl esters in rat hepatocytes was studied. Human high-density lipoprotein 3, labeled with two nondegradable, intracellularly trapped tracers in their apolipoprotein A-I and their cholesteryl esters, were injected into rats, and five subcellular hepatocytic fractions were isolated at various time intervals. In control experiments with homologous lipoproteins, doubly labeled rat high-density lipoproteins depleted of apolipoprotein E were used. In endosomes and lysosomes the two labels were recovered at near unity, indicating that high-density lipoproteins are endocytosed as particles, transported to early and late endosomes and finally subjected to lysosomal degradation. No significant amounts of label were found in receptor-recycling endosomes. In contrast to label of those of low-density lipoproteins, label of component protein and cholesteryl esters of high-density lipoproteins from isolated endosomes floated at different densities in gradient ultracentrifugation, indicating early disintegration of high-density lipoprotein particles. In contrast to the endocytic organelles, in the whole liver, label of high-density lipoprotein-associated cholesteryl esters exceeded the label of high-density lipoprotein-associated apolipoprotein A-I twofold to threefold. This finding is compatible with selective uptake of high-density lipoprotein cholesteryl esters in addition to uptake of high-density lipoprotein particles. The excess cholesteryl esters accumulated in a nonendosomal fraction, whose major proteins differed from the integral proteins of endosomes. These data suggest two distinct intracellular routes of hepatocytic high-density lipoprotein trafficking in vivo. High-density lipoproteins free of apolipoprotein E are internalized intact by hepatocytes, are predominantly transported to early and late endosomes and are finally subjected to lysosomal degradation. High-density lipoprotein particles do not undergo retroendocytosis in hepatocytes. In addition, high-density lipoprotein-associated cholesteryl esters can be taken up by hepatocytes selectively. They, however, accumulate in a nonendosomal, nonlysosomal compartment.

Animals↗
PubMed1993

A novel variety of atypical Pneumocystis carinii infection after long-term prophylactic pentamidine inhalation in an AIDS patient: large lower lobe pneumocystoma.

Atypical pulmonary manifestations of Pneumocystis carinii infection and fair numbers of extrapulmonary and disseminated infections have lately been documented in patients with human immunodeficiency virus infection treated prophylactically with inhalative pentamidine. We report the case of a 32-year-old homosexual patient who was assessed for complaints of night sweats, weight loss, and progressive malaise. The patient denied any respiratory tract symptoms such as cough, sputum production, pleuritic chest pain, or shortness of breath. Chest X-ray revealed two large round noncavitating lesions in the lower lobe of the right lung. Pneumocystomas were diagnosed by fine-needle aspiration. A 3-week course of intravenous high-dose cotrimoxazole resulted in amelioration of symptoms but no change in the radiographic appearance of the pulmonary lesions. Four months later the patient is alive and stable and is being treated with pentamidine inhalation of 300 mg per 2 weeks and two tablets of pyrimethamine sulfadoxine per week.

AIDS-Related Opportunistic Infections↗
PubMed1993

Antiviral and immunological effects of escalating low doses of zidovudine in HIV-positive patients.

Twenty-eight patients with different stages of HIV infection who had not undergone antiretroviral pretreatment were treated with an escalating dose regimen of zidovudine (4 weeks 2 x 50 mg, 4 weeks 2 x 100 mg, 4 weeks 2 x 250 mg). CD4+ cell counts and p24 antigen levels were monitored every four weeks. Twenty-one patients were evaluable. p24 antigen levels showed a significant decrease after four weeks (p < 0.01, Sign test, Wilcoxon matched pairs test) that was sustained until week 12 without a further significant decrease. CD4+ cell counts increased significantly within the first four weeks (p < 0.01, Sign test, Wilcoxon matched pairs test). This increase was sustained until week 12 but no further significant increase was noted. Mean corpuscular erythrocyte volume values increased significantly after week 4 and continued to rise until week 12. These results demonstrate antiretroviral activity of a very low zidovudine dose, however low doses should not be used for treatment unless the clinical efficacy is shown to be equivalent to that of standard doses.

CD4-Positive T-Lymphocytes↗
PubMed1993

Characterization of muscarinic receptors on guinea pig gallbladder smooth muscle.

BACKGROUND: Cholinergic agonists are of major importance for the regulation of gallbladder motility. However, the gallbladder muscarinic receptors have not been localized or characterized directly using radioligands, and it has not been clearly established which subtype of muscarinic receptor mediates contraction. The aim of the present study was to characterize the gallbladder muscarinic receptors. METHODS: Binding studies to guinea pig gallbladder sections were performed using 1-[N-methyl-3H] scopolamine methyl chloride. Carbachol-induced contraction was measured using muscle strips. RESULTS: Binding of 1-[N-methyl-3H] scopolamine methyl chloride was reversible, dependent on time, temperature, and pH. Autoradiography showed binding only over the smooth muscle. Binding and carbachol-induced contractions were inhibited by muscarinic receptor antagonists with the following potencies: atropine > N-methyl-scopolamine > silahexocyclium-methylsulfate > AF-DX 384 [(+-)-5,11-dihydro-11-([(2-(2-[(dipropylamino)-methyl]-1- piperidinyl)ethyl)amino]carbonyl)-6H-pyrido (2,3b) (1,4)-benzodiazepine-6-one] > hexahydro-siladifenidol hydrochloride > AF-DX 116 [(+-)-11-([2-[(diethylamino)methyl]-1- piperidinyl]-acetyl)-5,11-dihydro-6H-pyrido (2,3b)(1,4)benzodiazepine-6-one] > pirenzepine. Carbachol inhibited binding to gallbladder sections over the same range of concentrations that caused contractions. The concentration-contraction curves for carbachol were not altered by tetrodotoxin. CONCLUSIONS: Gallbladder smooth muscle cells possess muscarinic receptors of the M3 type. These receptors mediate carbachol-induced contraction.

Animals↗
PubMed1993

Oxygen consumption and resting metabolic rate in sepsis, sepsis syndrome, and septic shock.

OBJECTIVE: To test the hypothesis that variations in oxygen consumption (VO2) and resting metabolic rate reflect the severity of bacterial infections and reflect the development of sepsis syndrome and septic shock. DESIGN: Observational study with sequential measurements of VO2 and resting metabolic rate by expiratory gas analysis. SETTING: Medical intensive care unit. PATIENTS: Thirty patients, treated primarily for presumed bacterial infection, were examined on 118 treatment days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: VO2 and resting metabolic rate were measured by expiratory gas analysis. For mechanically ventilated patients, a measurement system was developed, based on a paramagnetic oxygen sensor, an infrared CO2 sensor, and digital signal averaging. Measurements in spontaneously breathing patients were performed with a metabolic monitor. Patients were assigned by clinical criteria to the following groups: sepsis, sepsis syndrome, and septic shock. The lowest VO2 value of each patient in each stage was evaluated. Mean VO2 in 15 patients with sepsis was 180 +/- 19 (SD) mL/min/m2, in 11 patients with sepsis syndrome 156 +/- 22 mL/min/m2, and in eight patients with septic shock 120 +/- 27 mL/min/m2 (p < .001). Mean resting metabolic rate in sepsis was +55 +/- 14%, in sepsis syndrome +24 +/- 12%, and in septic shock +2 +/- 24% (p < .001). Mean oxygen delivery (DO2) was 501 +/- 116 mL/min/m2 in sepsis, 515 +/- 186 mL/min/m2 in sepsis syndrome, and 404 +/- 96 mL/min/m2 in septic shock. Oxygen extraction (VO2/DO2) was highest in sepsis (0.39 vs. 0.33 in sepsis syndrome and 0.29 in septic shock). During recovery from sepsis syndrome or septic shock, a significant increase in resting metabolic rate to +61 +/- 22% was measured in nine patients. CONCLUSIONS: In sepsis syndrome, VO2 and resting metabolic rate are enhanced by 30% compared with normal basal metabolism, but they are markedly reduced compared with uncomplicated sepsis. The higher VO2 in uncomplicated sepsis is flow independent. The noninvasive measurement of VO2 and resting metabolic rate by expiratory gas analysis therefore can be used as a quantitative staging and monitoring parameter for the development of sepsis syndrome and septic shock.

Adult↗
PubMed1993

In vivo metformin treatment ameliorates insulin resistance: evidence for potentiation of insulin-induced translocation and increased functional activity of glucose transporters in obese (fa/fa) Zucker rat adipocytes.

To examine the cellular mechanism of the antihyperglycemic action of in vivo metformin (M) we used an animal model of severe insulin resistance, the genetically obese (fa/fa) Zucker rat. The animals were treated with or without M (250 mg/kg.day) which was supplied with the drinking water. Three weeks of in vivo M-treatment had no effect on body weight and several blood lipid parameters, but markedly reduced plasma insulin levels by 45% (-M: 2932 +/- 166 vs. +M: 1614 +/- 85 pmol/liter, P < 0.01); plasma glucose was slightly but significantly decreased by 8.3% (-M: 7.2 +/- 0.2 vs. +M: 6.6 +/- 0.16 mmol/liter, P < 0.05). Adipocytes were isolated and incubated with or without insulin. In vivo M-treatment had no effect on basal 3-O-methylglucose uptake. In contrast, in vivo M-treatment increased insulin-stimulated glucose transport by 2.6 +/- 0.6-fold (P < 0.01). Measurement of cell surface insulin receptors revealed no effect of M on neither specific [125I]insulin binding nor on insulin receptor kinase activity. Insulin-mediated translocation of both GLUT1 and GLUT4 glucose transporters was enhanced by in vivo M-treatment, GLUT1 by 26.1%, GLUT4 by 30.5%. To fully account for the M-induced increment of insulin-stimulated glucose transport (2.6-fold), these data suggest that M increased the functional activity of glucose transporters. We conclude that amelioration of insulin resistance in (fa/fa) Zucker rats after 3 weeks of in vivo M-treatment is associated with 1) a marked reduction of in vivo hyperinsulinemia, 2) an increase of insulin-stimulated glucose transport in adipocytes; 3) this increase of insulin-stimulated glucose transport is accompanied with both a potentiation of insulin-induced translocation of GLUT1 and GLUT4 glucose transporters from an intracellular pool to the plasma membrane as well as increased functional activity of plasma membrane glucose transporters. 4) This M-effect seems to be independent of de novo glucose transporter synthesis, since total cellular GLUT1 and GLUT4 glucose transporter number were uneffected by M. 5) These results strongly suggest a direct action of M at the level of glucose transport, since neither tracer insulin binding nor insulin receptor kinase activity were significantly altered by M.

3-O-Methylglucose↗
PubMed1993

Rotavirus antigen detection in patients with HIV infection and diarrhea.

A wide variety of bacterial, viral, and parasitic pathogens can cause severe diarrhea in patients with advanced human immunodeficiency virus (HIV) infection. The role of enteric viruses, especially rotaviruses, in HIV-related diarrhea is still unclear. One hundred and six stool samples from 66 HIV-infected patients with otherwise unexplained diarrhea and 35 samples from 35 patients with advanced HIV infection but without diarrhea were tested for the presence of rotavirus antigen. Rotavirus was detected in 13 samples from 9 patients with diarrhea and in none of the samples from patients without diarrhea. Two patients had recurrence of rotavirus infection more than 6 months after the first episode. Rotavirus was associated with prolonged diarrhea, often accompanied by abdominal cramping. Symptoms were readily controlled with anti-diarrheal and pain-relieving measures. Illness was self-limited and did not require hospitalization. A seasonal variation, typical of infantile rotavirus infection, was not observed in this setting. While rotavirus infection has been infrequently detected in American HIV-infected patients, the prevalence in Australia and Europe appears to be considerably higher.

Adult↗
PubMed1993

[Double infection of the lung with Pneumocystis carinii and Cryptococcus neoformans in an AIDS patient].

A 25-year old HIV-1-positive hemophiliac was admitted with fever, cough, exertional dyspnea and pleuritic chest pain. Chest x-ray showed diffuse bilateral infiltrates with a left sided nodular consolidation. Pneumocystis-carinii-pneumonia was suspected and diagnosed by broncho-alveolar lavage. With therapy the diffuse infiltrates improved, but the nodule and the symptoms failed to resolve. A fine-needle aspiration of the nodule revealed concurrent cryptococcosis. Treatment with fluconazole resulted in complete resolution of symptoms. Details of the case are presented and clinical implications are discussed.

AIDS-Related Opportunistic Infections↗
PubMed1993

Apolipoprotein B mRNA editing in 12 different mammalian species: hepatic expression is reflected in low concentrations of apoB-containing plasma lipoproteins.

Two different isoproteins are encoded by the apolipoprotein (apo) B gene, apoB-48 and apoB-100. ApoB-48, core component of intestinally derived chylomicrons, has an accelerated plasma turnover as compared with the full-length protein apoB-100. A posttranscriptional modification of the apoB mRNA by conversion of cytidine into uridine at nucleotide position 6666 changes the genomically encoded glutamine codon CAA at amino acid residue 2153 into a translational stop codon UAA. This mRNA editing explains the formation of the truncated isoform apoB-48. In the present investigation editing of apoB mRNA in liver and intestine from 12 different mammalian species was measured by a quantitative primer extension analysis of reverse-transcribed and polymerase chain reaction- (PCR) amplified apoB mRNA in order to determine whether i) editing of apoB mRNA is generally restricted to the intestine or may also be found in the liver of other species than rodents, and ii) hepatic expression of apoB mRNA editing influences lipoprotein concentrations in plasma. Intestinal apoB mRNA was edited at high levels in all species, 40% in sheep, 73% in horse, 82% in pig, 84% in dog, 84% in cat, 87% in guinea pig, 88% in rat, 89% in mouse, and > 90% in human, monkey, cow, and rabbit. In liver apoB mRNA was edited to 18% in dog, to 43% in horse, to 62% in rat, and to 70% in mouse. Low levels of editing below 1% were detected in liver of rabbit and guinea pig. In contrast, hepatic apoB mRNA from human, monkey, pig, cow, sheep, and cat liver was not edited. The results of the primer extension analysis were confirmed by cloning and sequencing of the PCR products from dog, horse, cat, guinea pig, sheep, and cow for all of which the apoB cDNA sequence had not been established by previous investigations. Primer extension analysis of apoB mRNA from dog intestine and dog liver indicated C/U editing at C6655 in addition to C6666. Cloning and sequencing of apoB cDNA from dog liver and intestine confirmed additional C/U editing at C6655 which changes ACA for threonine at amino acid residue 2149 into AUA for isoleucine. Synthesis and secretion of apoB-48-containing lipoproteins from liver was demonstrated by pulse labeling of freshly isolated horse hepatocytes and immunoprecipitation with apoB-specific antibodies or density gradient ultracentrifugation. The concentrations of VLDL, LDL, and HDL in all species were determined after fractionation by density gradient ultracentrifugation.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗