Biomedical subjects

F Schmidt

Publications and source records attributed to F Schmidt.

At least 55 records · Page 3Linked to original sources

PubMed2001

The three-dimensional structure of cystathionine beta-lyase from Arabidopsis and its substrate specificity.

The pyridoxal 5'-phosphate-dependent enzyme cystathionine beta-lyase (CBL) catalyzes the penultimate step in the de novo biosynthesis of Met in microbes and plants. Absence of CBL in higher organisms makes it an important target for the development of antibiotics and herbicides. The three-dimensional structure of cystathionine beta-lyase from Arabidopsis was determined by Patterson search techniques, using the structure of tobacco (Nicotiana tabacum) cystathionine gamma-synthase as starting point. At a resolution of 2.3 A, the model was refined to a final crystallographic R-factor of 24.9%. The overall structure is very similar to other pyridoxal 5'-phosphate-dependent enzymes of the gamma-family. Exchange of a few critical residues within the active site causes the different substrate preferences between Escherichia coli and Arabidopsis CBL. Loss of interactions at the alpha-carboxyl site is the reason for the poorer substrate binding of Arabidopsis CBL. In addition, the binding pocket of Arabidopsis CBL is larger than that of E. coli CBL, explaining the similar binding of L-cystathionine and L-djenkolate in Arabidopsis CBL in contrast to E. coli CBL, where the substrate binding site is optimized for the natural substrate cystathionine.

Amino Acid Sequence↗

PubMed2001

Hematologic and immunophenotypic characterization of human umbilical cord blood.

In this work, cord blood cells from 30 healthy term newborns were analyzed for complete blood counts with an automated cytometer and, in part of the sample, for surface molecules in cord blood monocytes, lymphocytes and CD34+ cells by two-color flow cytometry. Hematological parameters were as follows: WBC = 12.85 (5.24-15.10) x10(9)/l; platelets = 304.33 (156.00-469.00) x 10(9)/l; Hb = 14.45 (11.90-17.82) g/dl; RBC = 3.99 (3.14-5.12) x 10(12)/l; MCV 107.25 (99.60-115.00) fl; reticulocytes = 157.80 (101.00-124.00) x 10(9)/l or 3.99 (2.45-6.01)%; erythroblasts = 0.88 (0.15-2.58) x 10(9)/l or 6.63 (2.86-16.80) per 100 WBC [corrected]. The mononuclear population, as evaluated by flow cytometry, was composed of 22.9 +/- 7.2% monocytes and 77.05 +/- 7.24% lymphocytes, among which 46.59 +/- 15.62% were T lymphocytes (43.94 +/- 16.94% CD3+/CD4+ and 13.45 +/- 7.46% CD3+/CD8+). CD34+ cells were on average 0.54 +/- 0.24% of the mononuclear fraction. CD11c, CD49e and HLA-DR were found mainly on monocytes, and CD31 and CD62L occurred in similar levels on monocytes and lymphocytes. CD117+ cells were less than 5% of these populations. Among CD34+ cells, CD31 and HLA-DR were the molecules with higher frequencies (79.7 +/- 19.9 and 65.7 +/- 23.0%, respectively), followed by CD62L (41.8 +/- 31.9%) and CD117 (20.1 +/- 15.8%). The presence of CD11c and CD49e on CD34+ cells was low (below 10%). The results stress the phenotypic heterogeneity of cord blood CD34+ cells, and the different behavior of the cells when manipulated in vitro in different degrees of isolation.

Antigens, CD34↗

PubMed2001

Unilateral thalamic edema in internal cerebral venous thrombosis: is it mostly left?

Thrombotic occlusion of the internal cerebral veins is a particularly dangerous form of cerebral venous thrombosis (CVT) as it causes venous infarction of the thalami. Because both thalami drain into the vein of Galen and straight sinus, bilateral thalamic involvement is frequently encountered in internal CVT. However, unilateral thalamic edema may also occur, even if all internal cerebral veins are occluded. This suggests collateral venous drainage of the thalami, which is commonly insufficient in internal CVT. Patients with unilateral congestion of the thalamus, including 3 patients reported here, had mostly left-sided involvement, indicating that right-sided unilateral thalamic involvement in CVT may be clinically silent.

Adult↗

PubMed2001

Mineralocorticoid receptor affects AP-1 and nuclear factor-kappab activation in angiotensin II-induced cardiac injury.

Aldosterone is implicated in cardiac hypertrophy and fibrosis. We tested the role of the mineralocorticoid receptor in a model of angiotensin II-induced cardiac injury. We administered spironolactone (SPIRO; 20 mg. kg(-1). d(-1)), valsartan (VAL; 10 mg. kg(-1). d(-1)), or vehicle to rats double transgenic for the human renin and angiotensinogen genes (dTGR). We investigated basic fibroblast growth factor (bFGF), platelet-derived growth factor, transforming growth factor-beta(1), and the transcription factors AP-1 and nuclear factor (NF)-kappaB. We used immunohistochemistry, electrophoretic mobility shift assays, and TaqMan RT-PCR. Untreated dTGR developed hypertension, cardiac hypertrophy, vasculopathy, and fibrosis with a 50% mortality rates at 7 weeks. SPIRO and VAL prevented death and reversed cardiac hypertrophy, while only VAL normalized blood pressure. Both drugs prevented vasculopathy. bFGF was markedly upregulated in dTGR, whereas platelet-derived growth factor-B and transforming growth factor-beta(1) were little changed. VAL and SPIRO suppressed this upregulation. Both AP-1 and NF-kappaB were activated in dTGR compared with controls. VAL and SPIRO reduced both transcription factors and reduced bFGF, collagen I, fibronectin, and laminin in the interstitium. These findings show that aldosterone promotes hypertrophy, cardiac remodeling, and fibrosis, independent of blood pressure. The effects involve AP-1, NF-kappaB, and bFGF. Mineralocorticoid receptor blockade downregulates these effectors and reduces angiotensin II-induced cardiac damage.

Aldosterone↗

PubMed2001

Gross-total surgery of supratentorial low-grade gliomas under intraoperative MR guidance.

BACKGROUND AND PURPOSE: Length of survival of patients with low-grade glioma correlates with the extent of tumor resection. These tumors, however, are difficult to distinguish intraoperatively from normal brain tissue, often leading to incomplete resection. Our goal was to evaluate the effectiveness of intraoperative MR guidance in achieving gross-total resection. METHODS: We studied 12 patients with low-grade glioma who underwent surgery within a vertically open 0.5-T MR system. During surgery, localization of residual tumor tissue was guided by interactive, near real-time imaging. The amount of residual tumor tissue on MR images was evaluated at the point of the operation at which the neurosurgeon would have terminated the procedure under conventional conditions (first control) and again before closing the craniotomy. RESULTS: Significant residual tumor (more than 10% of original tumor volume) was shown in eight patients at the first control condition. The percentage of resection varied from 26% to 100% (mean, 68%) at this time. Twelve tissue samples from seven patients were obtained in areas identified as residual tumor on MR images. In 10 cases, the neuropathologic investigation confirmed the presence of residual low-grade glioma; in two cases, the borderzone of tumor was identified. In evaluating the final sets of images, we found total resection in six cases, over 90% resection in five cases, and 85% resection in one case (mean, 96%). CONCLUSION: Surgical treatment of low-grade gliomas under intraoperative MR guidance provides improved resection results with maximal patient safety.

Adult↗

PubMed2001

Intra-individual variability in nighttime urine production and functional bladder capacity estimated by home recordings in patients with nocturnal enuresis.

PURPOSE: We evaluated the intra-individual variability and reproducibility of nighttime urine production on wet nights and functional bladder capacity estimated by long-term home recordings of monosymptomatic nocturnal enuresis. In particular, the intention was to evaluate the validity of 1 versus 2 weeks of recording when estimating urine volume on wet nights and 1 versus 2 weekends of recording when estimating functional bladder capacity. MATERIALS AND METHODS: We analyzed 120, 2-week home recordings of nighttime urine volume from patients with monosymptomatic nocturnal enuresis 6 to 16 years old (mean age 9.1) with at least 3 wet nights per week. Most patients were nonresponders or partial responders to desmopressin. Nighttime urine volume was estimated by weighing diapers before and after sleep, and measuring morning urine volume. Of the home recordings 62 included frequency volume charts for 2 weekends, which were evaluated for functional bladder capacity defined as the largest voided volume observed. RESULTS: No significant overall week-to-week differences were observed in average urine volume on wet nights and functional bladder capacity. There was a large intra-individual variability in all measured variables, which was most pronounced for functional bladder capacity and least pronounced for urine volume on wet nights. With regard to repeatability, the limits of agreement of urine volume on wet nights were -32% and 36% (95% confidence interval) as opposed to -54% and 48% for functional bladder capacity. CONCLUSIONS: In this study intra-individual week-to-week estimates of average urine volume on wet nights demonstrated acceptable variability and repeatability in contrast to functional bladder capacity. A reliable estimate of urine volume on wet nights could be obtained by 7 nights of home recording, whereas 4 days of daytime recording were necessary when estimating functional bladder capacity. Similar studies of patients who respond to desmopressin are needed.

Adolescent↗

PubMed2000

A placebo-controlled crossover trial of creatine in mitochondrial diseases.

To test the efficacy and safety of creatine (Cr) monohydrate in mitochondrial diseases, 16 patients with chronic progressive external ophthalmoplegia or mitochondrial myopathy were randomized in a crossover design to receive double-blind placebo or 20 g Cr/day for 4 weeks. Cr was well tolerated, but there were no significant effects with regard to exercise performance, eye movements, or activities of daily life. The power of this pilot study was limited and future multicenter trials are needed.

Adult↗

PubMed2000

Role of the MEN1 tumour suppressor gene in human ductal pancreatic cancer.

MEN1 is a novel tumour suppressor gene involved in the etiology of sporadic endocrine pancreatic tumours. Based on common ontogenetic features of both tissues, we analyzed the role of MEN1 in ductal pancreatic cancer. Wild type MEN1 mRNA expression, but no mutations within the MEN1 coding sequence or MEN1 promoter region were detected in human pancreatic adenocarcinoma tissues and carcinoma cell lines, using sensitive single-strand conformational polymorphism-heteroduplex and sequencing analyses. Thus, human pancreatic cancer does not seem to require inactivation of the MEN1 tumour suppressor pathway.

Carcinoma, Ductal, Breast↗

PubMed2000

Detection of BRCA1 and BRCA2 mutations in breast cancer families by a comprehensive two-stage screening procedure.

We have developed a 2-stage protocol for BRCA1 and BRCA2 mutation screening from blood spot paper. Stage 1 screening was aimed to analyze patients at highest risk for the most common disease-associated sequence variants listed in the BIC database. Accordingly, stage1 testing implied detection of 18 disease- associated BRCA1 and 9 BRCA2 mutations by adapting the 5' nuclease assay to heterozygote screening. For stage 2 screening, we applied the conformation sensitive gel electrophoresis (CSGE) method by adapting this technique to automated heteroduplex analysis of BRCA1 and BRCA2 using fragment scanning on an ABI 377 sequencing device. Of the 120 patients with a family history of breast and ovarian cancer who took part in this study so far, 45 entered stage 1 testing. Disease-associated mutations were detected in 6 patients by stage 1 testing (13%). For these patients, the final result was available within 10 days. Mutation 300T-->G was found in 2 patients. One patient with mutation 3036delACAA in BRCA2 reported only 1 sister with a multifocal bilateral breast cancer. New disease-associated mutations were detected in 2 of the 114 patients who entered the stage 2 test (1.7%). Of particular interest was 1 patient who was diagnosed with a medullary breast carcinoma at age 39 and who had no family history of breast cancer. We conclude that pre-screening by 5' nuclease assay for the mutations most frequently seen in a given population represents a relatively effective first line of analysis. Subsequent detailed analysis by fluorescence conformation sensitive gel electrophoresis (F-CSGE) and fragment sequencing is a sensitive alternative to full nucleotide sequencing.

Adult↗

PubMed2000

Photodynamic therapy for advanced bile duct cancer: evidence for improved palliation and extended survival.

Median survival time of nonresectable hilar bile duct cancer is only 4 to 6 months owing to tumor spread in the biliary tree, refractory cholestasis, and sepsis or liver failure. We explored whether local photodynamic therapy of nonresectable bile duct cancer could improve survival. A sample size of 23 patients is required to detect an increase in 6-month survival rate from less than 50% to greater than 70% in a single-arm phase-II trial with a statistical power of 80% (Fleming's single step procedure; alpha = 0.05). Twenty-three consecutive patients (8 women, 15 men; 67 +/- 14 years) with nonresectable bile duct cancer (Bismuth type III n = 2, type IV n = 21) were treated with photodynamic therapy and biliary endoprosthesis. Photofrin (QLT Pharmaceuticals, Vancouver, Canada) (2 mg/kg body weight intravenously) was photoactivated after 1 to 4 days with laser light (630 nm; 242 J/cm(2)) via endoscopic retrograde access. The 6-month survival rate was 91% after diagnosis and 74% after start of photodynamic therapy (30-day mortality rate was 4%) at a median follow-up time of 10.3 months after diagnosis. Causes of death were tumor progression (n = 9) and bacterial infections (n = 4). The median rate of local tumor response was 74%, 54%, 29%, and 67% after the first, second, third, fourth, and fifth photodynamic therapy. Time to progression ranged from 3 to 8 months. All patients, except 1 with diffuse liver metastases, improved in cholestasis, performance, and quality of life. Photodynamic therapy can prevent tumor occlusion of hilar bile ducts. The apparent benefit in survival time should be confirmed in a controlled trial versus palliation by endoprosthesis only.

Adenocarcinoma↗

PubMed2000

[Raeder- and Collet-Siccard-Syndrome. Acute pareses of cranial nerves symptomatic of a dissection of internal carotid artery].

Acute cerebral nerve paresis can be caused in many different ways. One of the more rare causes of paresis of one or more neural pathways is dissection of the internal carotid artery. Early diagnosis is important, even with atypical symptoms, since prompt anticoagulative therapy can hinder stroke from embolism due to the dissection. We report on two patients with Raeder's syndrome and Collet-Sicard syndrome resulting from dissection of the internal carotid artery. Besides the cranial and caudal nerves involved in our study, loss of function has also been reported with the sixth to eighth cranial nerves, so that any painful, sudden cranial nerve deficiency can indicate possible carotid dissection.

Acute Disease↗

PubMed2000

[The radiological and surgical management of nonpalpable breast lesions].

In this retrospective study the results of surgical biopsy of suspected breast cancer in 319 outpatients are reported. In 113 cases (35.4%) the lesion was palpable, in 206 cases (64.6%) it was not. Concerning the nonpalpable lesions, mammography was performed in 98 patients (47.6%) for work-up of fibrocystic changes, in 41 patients (19.9%) for initial participation in a breast cancer prevention program, and in 33 patients (16.0%) for surveillance after breast conservation therapy. Prior to operation, 84.0% (n = 173) of the nonpalpable lesions were detected by mammography, 11.2% (n = 23) by sonography, and 4.8% (n = 10) by magnetic resonance imaging. Intra-operative specimen mammography was carried out in every case detected by mammography. In 19.4% (n = 40) of 206 nonpalpable lesions a malignant tumor was found. Twenty-five percent (n = 10) of all marked tumors were diagnosed and treated as in-situ stage tumors, while 65% (n = 26) were diagnosed and treated as tumors in the pT1 stage. As regards the nodal stage, 85% (n = 34) of the tumors were diagnosed and treated as pNO tumors, and 100% (n = 40) were found to be free from any distant metastases. Consequently, for improving prognosis and, at the same time, for reducing the rate of breast amputations as a means of curative therapy of breast cancer, regular screening in defined risk groups is necessary. Surgical treatment of patients with small and nonpalpable findings should be reserved for departments with marking and quick-freezing facilities.

Adolescent↗

PubMed2000

Open MRI-guided microsurgery of intracranial tumours. Preliminary experience using a vertical open MRI-scanner.

OBJECTIVES: A number of different image-guided surgical techniques have been developed during the past decade. None of these methods can provide the surgeon with information about the dynamic changes that occur intra-operatively. The development of open configurated MRI-scanners leads to new perspectives in the intra-operative management and resection control of intracranial tumours. MATERIAL AND METHOD: Using a vertical open 0.5 T MRI-scanner for intra-operative MR image guided neurosurgery, forty-four patients (20 female/24 male) with different intracranial tumours have been operated on since August 1997. The patients ranged in age from 20 to 70 years (mean +/- standard deviation = 47.2 +/- 15.9 ys). RESULTS: In 36 (82%) of 44 patients the tumours were completely removed with the aid of MR image-guidance. In 8 cases (18%) complete removal was not achieved. Postoperatively 6 (14%) of 44 patients developed neurological deficits which were transient in 5 cases (paresis, dysphasia). In these patients the tumours were located in or near eloquent brain areas (sensorimotor cortex/speech center). CONCLUSION: Intra-operative MRI is helpful for navigation as well as determining of tumour margins to achieve a complete and safe resection of intracranial lesions. Complications related to the surgical procedure are reduced and the risk of neurological deterioration due to tumour removal and postoperative complications is minimized. It can be concluded that the intra-operative application of interventional MRI technology may represent a major step foreward in the field of neurosurgery.

Adult↗

PubMed2000

Angiotensin II (AT(1)) receptor blockade reduces vascular tissue factor in angiotensin II-induced cardiac vasculopathy.

Tissue factor (TF), a main initiator of clotting, is up-regulated in vasculopathy. We tested the hypothesis that chronic in vivo angiotensin (ANG) II receptor AT(1) receptor blockade inhibits TF expression in a model of ANG II-induced cardiac vasculopathy. Furthermore, we explored the mechanisms by examining transcription factor activation and analyzing the TF promoter. Untreated transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR) feature hypertension and severe left ventricular hypertrophy with focal areas of necrosis, and die at age 7 weeks. Plasma and cardiac ANG II was three- to fivefold increased compared to Sprague-Dawley rats. Chronic treatment with valsartan normalized blood pressure and coronary resistance completely, and ameliorated cardiac hypertrophy (P < 0.001). Valsartan prevented monocyte/macrophage infiltration, nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) activation, and c-fos expression in dTGR hearts. NF-kappaB subunit p65 and TF expression was increased in the endothelium and media of cardiac vessels and markedly reduced by valsartan treatment. To analyze the mechanism of TF transcription, we then transfected human coronary artery smooth muscle cells and Chinese hamster ovary cells overexpressing the AT(1) receptor with plasmids containing the human TF promoter and the luciferase reporter gene. ANG II induced the full-length TF promoter in both transfected cell lines. TF transcription was abolished by AT(1) receptor blockade. Deletion of both AP-1 and NF-kappaB sites reduced ANG II-induced TF gene transcription completely, whereas the deletion of AP-1 sites reduced transcription. Thus, the present study clearly shows an aberrant TF expression in the endothelium and media in rats with ANG II-induced vasculopathy. The beneficial effects of AT(1) receptor blockade in this model are mediated via the inhibition of NF-kappaB and AP-1 activation, thereby preventing TF expression, cardiac vasculopathy, and microinfarctions.

Angiotensin II↗

PubMed2000

Bone-muscle strength indices for the human lower leg.

This cross-sectional study is based on images from the lower leg as assessed by peripheral quantitative computer tomography (pQCT). Measurements were performed in 39 female and 38 male control subjects and 15 female professional volleyball players, all between 18 and 30 years of age. The images were obtained at shank levels of 4%, 14%, 33%, and 66% from the distal end. Bone and muscle cross-sectional areas, and the bones' density-weighted area moment of resistance and of inertia were assessed. From these, muscle-bone strength indices (MBSIs) were developed for compression (CI = 100. bone area/muscle area) and bending (BI = 100. bone area moment of resistance/muscle area/tibia length). Significant correlations between muscle cross-sectional area and bone were found at all section levels investigated. The strongest correlation for compression was observed in the sections at 14% (correlation coefficient r = 0.74), where 4.10 +/- 0.46 cm(2) bone, on average, was related to 100 cm(2) muscle. The compression index (CI) at the 14% level was independent of the tibia length. Interestingly, the 15 athletes had significantly greater CIs than the control subjects. This is most probably due to the greater tension development in the athletes. The highest correlation for bending was for anteroposterior bending at 33% of tibia length (r = 0.81), where the area moment of resistance, R, was on, average, 4.21 +/- 0.54 cm(3)/100 cm(2) muscle/m tibia length. Analysis of the bones' area moment of inertia showed that buckling is a possible cause of bending at the 33% and 66% levels, but not at the 14% level. No gender differences in MBSI were found. Likewise, age was without significant effect. The data show that bone architecture depends critically on muscle cross section and tension development. Moreover, bone geometry (e.g., the tibia length) influences the geometrical distribution of bone mineral, as it was found that long bones adapted to the same compressive strength are wider than short ones. We conclude that MBSIs offer a powerful diagnostic tool for bone disorders and may contribute to improving the treatment of bone metabolic and other diseases.

Absorptiometry, Photon↗

PubMed2000

Treosulfan chemotherapy for recurrent malignant glioma.

Treosulfan is a bifunctional alkylating prodrug with activity against various solid tumors. To improve the outcome for patients with recurrent malignant glioma, we assessed the efficacy of intravenous treosulfan (6-10 g/m2 4-weekly) as salvage therapy for patients with recurrent or progressive glioblastoma (GB, n = 14) or anaplastic astrocytoma (AA, n = 2). All patients had prior involved-field radiotherapy and adjuvant nitrosourea-based chemotherapy. A total of 56 cycles were administered. Tumor responses were assessed radiologically and clinically prior to each cycle. All patients were assessable for toxicity, response and survival. There were no complete or partial responses (CR, PR). Two patients progressed after the first cycle, 14 patients had initially stable disease (SD). Median progression-free survival was 3.25 months for the GB patients. Five patients were progression-free at 6 months (30%), including the 2 AA patients. The 2 AA patients are stable at 22 months. Myelosuppression was the dose-limiting toxicity in this cohort of nitrosourea-pretreated patients. Treosulfan has modest activity in patients with recurrent malignant glioma. Further evaluation of treosulfan in chemonaive malignant glioma patients is warranted.

Adult↗

PubMed2000

Localization and quantification of hydrophobicity: the molecular free energy density (MolFESD) concept and its application to sweetness recognition.

A method for the localization, the quantification, and the analysis of hydrophobicity of a molecule or a molecular fragment is presented. It is shown that the free energy of solvation for a molecule or the transfer free energy from one solvent to another can be represented by a surface integral of a scalar quantity, the molecular free energy surface density (MolFESD), over the solvent accessible surface of that molecule. This MolFESD concept is based on a model approach where the solvent molecules are considered to be small in comparison to the solute molecule, and the solvent can be represented by a continuous medium with a given dielectric constant. The transfer energy surface density for a 1-octanol/water system is empirically determined employing a set of atomic increment contributions and distance dependent membership functions measuring the contribution of the increments to the surface value of the MolFESD. The MolFESD concept can be well used for the quantification of the purely hydrophobic contribution to the binding constants of molecule-receptor complexes. This is demonstrated with the sweeteners sucrose and sucralose and various halogen derivatives. Therein the relative sweetness, which is assumed to be proportional to the binding constant, nicely correlates to the surface integral over the positive, hydrophobic part of the MolFESD, indicating that the sweetness receptor can be characterized by a highly flexible hydrophobic pocket instead of a localized binding site.

Models, Molecular↗

PubMed2000

A phase II study of pegylated liposomal doxorubicin for treatment of advanced hepatocellular carcinoma.

BACKGROUND: Pegylated liposomal doxorubicin has an enhanced efficacy and reduced toxicity compared with free doxorubicin. The efficacy and toxicity of pegylated liposomal doxorubicin was investigated in patients with hepatocellular carcinoma. PATIENTS AND METHODS: Patients with histologically confirmed, locally advanced or metastatic hepatocellular carcinoma and a Karnofsky index > 60% were included in this prospective single-arm study. Exclusion criteria were liver cirrhosis stage Child-Pugh C, previous chemotherapy, or chemoembolization. Pegylated liposomal doxorubicin was given in a dose of 30 mg/m2 every three weeks until progression of disease. After inclusion of five patients the dose could be escalated to 40 mg/m2 in absence of toxicity grade 3 and 4. RESULTS: Sixteen patients were evaluable for response. No objective response was achieved. The median survival time was 140 days (95% confidence interval: 126-154 days). Treatment toxicities grade > or = 3 comprised increased liver enzymes in patients with preexisting grade 1 or 2 elevation (n = 6), hematologic toxicity (n = 5), and hypersensitivity (n = 2). CONCLUSIONS: Pegylated liposomal doxorubicin is not effective for treatment of advanced hepatocellular carcinoma. The favorable toxicity profile was confirmed even in patients with underlying liver disease.

Adult↗