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Biomedical subjects

R W Seiler

Publications and source records attributed to R W Seiler.

At least 19 recordsLinked to original sources
PubMed2006

Morbidity in 201 patients with small sized meningioma treated by microsurgery.

BACKGROUND: The management of patients with small, often asymptomatic meningiomas is controversial and includes observation, microsurgery (MS) and stereotactic radiosurgery (SRS). The purpose of this retrospective study was to analyze the morbidity and the extent of removal after MS for small (< or =3 cm) intracranial meningiomas and compare these results to those of SRS reported in the literature. METHODS: All patients with an intracranial meningioma with a maximum diameter up to 3 cm operated on in our institution over a 10 year period (1992-2002) were included in the study and retrospectively analyzed. Patients were grouped into asymptomatic and symptomatic and according to tumor location as: group I (cranial vault, parasagittal, lateral sphenoid), group II (falx, frontobasal, medial sphenoid, parasellar and tentorial), group III (cavernous sinus, petroclival, petrosal, CPA and foramen magnum). FINDINGS: There were a total of 201 patients, of whom 102 were asymptomatic and 99 were symptomatic. The overall risk of permanent neurological morbidity was 4.9% in asymptomatic and 23.2% in symptomatic patients. The combined risk in asymptomatic and symptomatic patients was 5.4% in group I, 11.5% in group II, and 39.9% in group III lesions. Radical removal was achieved in all patients in group I, in 93.7% of group II, and 80% of group III lesions. There was no disease related mortality. CONCLUSIONS: MS provides excellent efficacy and morbidity results in groups I and II meningiomas, especially in asymptomatic patients and might therefore be considered the first choice of treatment for these patients. The results of MS in group III were worse than those of SRS reported in the literature.

Adult↗
PubMed2005

Effects of creatine treatment on survival and differentiation of GABA-ergic neurons in cultured striatal tissue.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder, characterized by a prominent loss of GABA-ergic medium-sized spiny neurons in the caudate putamen. There is evidence that impaired energy metabolism contributes to neuronal death in HD. Creatine is an endogenous substrate for creatine kinases and thereby supports cellular ATP levels. This study investigated the effects of creatine supplementation (5 mm) on cell survival and neuronal differentiation in striatal cultures. Chronic creatine treatment resulted in significant increased densities of GABA-immunoreactive (-ir) neurons, although total neuronal cell number and general viability were not affected. Similar effects were seen after short-term treatment, suggesting that creatine acted as a differentiation factor. Inhibitors of transcription or translation did not abolish the creatine-mediated effects, nor did omission of extracellular calcium, whereas inhibition of mitogen-activated protein kinase and phosphatidylinositol-3-kinase significantly attenuated the creatine induced increase in GABA-ir cell densities. Creatine exhibited significant neuroprotection against toxicity instigated either by glucose- and serum deprivation or addition of 3-nitropropionic acid. In sum, the neuroprotective properties in combination with promotion of neuronal differentiation suggest that creatine has potential as a therapeutic drug in the treatment of neurodegenerative diseases, like HD.

Animals↗
PubMed2005

Cerebral revascularization model in a swine.

The purpose of this study was to analyze the suitability of the cerebral vasculature of the pig regarding a revascularization procedure. In two 60 kg pigs the femoral artery was exposed and canulated for selective angiography and interventional procedures. After the angiography, the pigs were brought to the animal OR for craniotomy and analysis of the intracranial cerebral arteries and the surgical exposure of the carotid arteries under the microscope. Angiography demonstrated the presence of a true internal-, external carotid artery and vertebral arteries. Both the vertebral and internal carotid arteries are feeding a rete mirabilis both at the cranial base and the cranio-cervical junction. At these sites further advancement of the angiography catheter was not possible. Out of these rete mirabilis, an intracranial carotid artery and an intracranial vertebral artery were formed, respectively. The intracranial cerebral vessels were of the dimension of 1 mm and less. The extracranial portion of the internal carotid artery was 2.5 mm of diameter. From these findings, we conclude that a direct cerebral revascularization procedure of the intracranial vessels is not possible in the swine. However, a global revascularization procedure on the extracranial portion of the internal carotid artery is thus feasible, both using a low- and high-flow anastamosis technique.

Animals↗
PubMed2005

Effects of creatine treatment on the survival of dopaminergic neurons in cultured fetal ventral mesencephalic tissue.

Parkinson's disease is a disabling neurodegenerative disorder of unknown etiology characterized by a predominant and progressive loss of dopaminergic neurons in the substantia nigra. Recent findings suggest that impaired energy metabolism plays an important role in the pathogenesis of this disorder. The endogenously occurring guanidino compound creatine is a substrate for mitochondrial and cytosolic creatine kinases. Creatine supplementation improves the function of the creatine kinase/phosphocreatine system by increasing cellular creatine and phosphocreatine levels and the rate of ATP resynthesis. In addition, mitochondrial creatine kinase together with high cytoplasmic creatine levels inhibit mitochondrial permeability transition, a major step in early apoptosis. In the present study, we analyzed the effects of externally added creatine on the survival and morphology of dopaminergic neurons and also addressed its neuroprotective properties in primary cultures of E14 rat ventral mesencephalon. Chronic administration of creatine [5 mM] for 7 days significantly increased survival (by 1.32-fold) and soma size (by 1.12-fold) of dopaminergic neurons, while having no effect on other investigated morphological parameters. Most importantly, concurrent creatine exerted significant neuroprotection for dopaminergic neurons against neurotoxic insults induced by serum and glucose deprivation (P < 0.01), 1-methyl-4-phenyl pyridinium ion (MPP+) [15 microM] and 6-hydroxydopamine (6-OHDA) [90 microM] exposure (P < 0.01). In addition, creatine treatment significantly protected dopaminergic cells facing MPP+-induced deterioration of neuronal morphology including overall process length/neuron (by 60%), number of branching points/neuron (by 80%) and area of influence per individual neuron (by 60%). Less pronounced effects on overall process length/neuron and number of branching points/neuron were also found after 6-OHDA exposure (P < 0.05) and serum/glucose deprivation (P < 0.05). In conclusion, our findings identify creatine as a rather potent natural survival- and neuroprotective factor for developing nigral dopaminergic neurons, which is of relevance for therapeutic approaches in Parkinson's disease and for the improvement of cell replacement strategies.

1-Methyl-4-phenylpyridinium↗
PubMed2004

The impact of tumour volume and surgery on the outcome of adults with supratentorial WHO grade II astrocytomas and oligoastrocytomas.

BACKGROUND: The study was performed to elucidate the impact of tumour volume and surgical resection on the long-term outcome of patients with supratentorial, diffuse, World Health Organization (WHO) grade II astrocytomas and oligo-astrocytomas. METHOD: After analysing 79 adult patients consecutively diagnosed between 1991 and 2000, we selected a group of 42 patients treated by surgery without adjuvant therapy. The tumour volume was defined as the whole region of T2-hyperintensity and measured interactively on pre- and postoperative and follow-up Magnetic Resonance Imaging (MRI) using a dedicated imaging software. Volumetric, clinical, and histological data were analysed for correlation with tumour progression (TP), malignant transformation (MT), drop in functional status (DKPS) and overall survival (OS). FINDINGS: Pre- and postoperative tumour volumes, and the involvement of more than one lobe were strongly associated with worse outcome. Preoperative tumour volume was the strongest predictor of OS (p<0.01) and the only predictor of MT (p<0.05). The absolute and relative volumes of tumour removed by surgery were not significantly associated with outcome. CONCLUSIONS. Initial tumour volume, measured as the volume of T2-hyperintensity on MRI, and tumour extension are the strongest predictors of outcome in patients with supratentorial diffuse astrocytic WHO Grade II tumours. The potential benefit of aggressive tumour resection needs to be investigated in a prospective controlled trial.

Adult↗
PubMed2003

Effects of cerebral perfusion pressure and increased fraction of inspired oxygen on brain tissue oxygen, lactate and glucose in patients with severe head injury.

OBJECTIVE: The purpose of the study was to measure the effects of increased inspired oxygen on patients suffering severe head injury and consequent influences on the correlations between CPP and brain tissue oxygen (PtiO2) and the effects on brain microdialysate glucose and lactate. METHODS: In a prospective, observational study 20 patients suffering severe head injury (GCS< or =8) were studied between January 2000 and December 2001. Each patient received an intraparenchymal ICP device and an oxygen sensor and, in 17 patients brain microdialysis was performed at the cortical-subcortical junction. A 6 h 100% oxygen challenge (F IO2 1.0) ( Period A) was performed as early as possible in the first 24 hours after injury and compared with a similar 6 hour period following the challenge ( Period B). Statistics were performed using the linear correlation analysis, one sample t-test, as well as the Lorentzian peak correlation analysis. RESULTS: F IO2 was positively correlated with PtiO2 (p < 0.0001) over the whole study period. PtiO2 was significantly higher (p < 0.001) during Period A compared to Period B. CPP was positively correlated with PtiO2 (p < 0.001) during the whole study. PtiO2 peaked at a CPP value of 78 mmHg performing a Lorentzian peak correlation analysis of all patients over the whole study. During Period A the brain microdialysate lactate was significantly lower (p = 0.015) compared with Period B. However the brain microdialysate glucose remained unchanged. CONCLUSION: PtiO2 is significantly positively correlated with F IO2, meaning that PtiO2 can be improved by the simple manipulation of increasing F IO2 and ABGAO2. PtiO2 is positively correlated with CPP, peaking at a CPP value of 78 mmHg. Brain microdialysate lactate can be lowered by increasing PtiO2 values, as observed during the oxygen challenge, whereas microdialysate glucose is unchanged during this procedure. Extension of the oxygen challenge time and measurement of the intermediate energy metabolite pyruvate may clarify the metabolic effects of the intervention. Prospective comparative studies, including analysis of outcome on a larger multicenter basis, are necessary to assess the long term clinical benefits of this procedure.

Adolescent↗
PubMed2001

Identification and validation of P311 as a glioblastoma invasion gene using laser capture microdissection.

The mRNA expression profiles from glioblastoma cells residing at the tumor core and invasive rim of a human tumor resection were compared. From a single tumor specimen, 20,000 single cells from each region were collected by laser capture microdissection. Differential expression of 50-60 cDNA bands was detected. One of the sequences overexpressed by the invasive cells showed 99% homology to the P311 gene, the protein product of which is reported to localize at focal adhesions. Relative overexpression of P311 by invading glioblastoma cells compared with tumor core was confirmed by quantitative reverse transcription-PCR of six glioblastoma specimens after laser capture microdissection collection of rim and core cells. In vitro studies using antisense oligodeoxynucleotides and integrin activation confirmed the role of P311 in supporting migration of malignant glioma cells. Immunochemistry studies confirmed the presence of the P311 protein in tumor cells, particularly at the invasive edge of human glioblastoma specimens.

Amino Acid Sequence↗
PubMed2001

Influence of time in culture and BDNF pretreatment on survival and function of grafted embryonic rat ventral mesencephalon in the 6-OHDA rat model of Parkinson's disease.

Embryonic midbrain can be maintained as free-floating roller tube cultures prior to grafting in experimental Parkinson's disease. We examined the influence of pregrafting culture time and pretreatment with brain-derived neurotrophic factor on graft survival and function. Cultures were prepared from solid pieces of embryonic (E14) rat ventral mesencephalon and maintained 4, 8, or 12 days in vitro with or without brain-derived neurotrophic factor (100 ng/ml) and grafted into the striatum of 6-hydroxydopamine-lesioned rats. Graft survival and function were evaluated by amphetamine-induced rotation behavior, number of tyrosine hydroxylase-immunoreactive neurons, striatal reinnervation, and graft volume. Rats receiving untreated tissue cultured for 4 or 8 days displayed no differences in graft quality, while grafts from 12-day-old cultures contained significantly fewer (P < 0.05) tyrosine hydroxylase-immunoreactive neurons (340 +/- 97, 267 +/- 92, and 62 +/- 19) and displayed a lower survival rate (9.6 +/- 2.7, 7.9 +/- 2.7, and 2.6 +/- 0.8% for 4, 8, and 12 days in vitro, respectively). Only rats grafted with 4- and 8-day-old cultures recovered significantly (P < 0.05) from lesion-induced rotations (69.4 +/- 18.6, 70.3 +/- 13.9, and 23.2 +/- 12.1% for 4, 8, and 12 days in vitro, respectively). Striatal reinnervation decreased with increasing culture time (P < 0.05). Pretreatment of the cultures with brain-derived neurotrophic factor affected only graft-induced fiber reinnervation, which was reduced even after short culture times. We therefore suggest that a storage period of 8 days is well suited to maintain embryonic rat ventral mesencephalon with the free-floating roller tube culture technique prior to transplantation. BDNF pretreatment as a new strategy to improve graft survival and function, however, was not effective.

Amphetamine↗
PubMed2001

Principles of the morbidity and mortality conference.

The goals of the morbidity and mortality conference are learning from mistakes, recognising problems, and being aware of the risks of one's own procedures. Data are continuously collected, complications are classified, and the results of surgery are analyzed. By analysing and discussing the results every three months, total case mortality, mortality of specific procedures, incidence of haematomas, infection rate and incidence of thromboses and emboli are known and a continuous quality control is possible.

Humans↗
PubMed2001

Additive effect of glial cell line-derived neurotrophic factor and neurotrophin-4/5 on rat fetal nigral explant cultures.

Transplantation of embryonic dopaminergic neurons is an experimental therapy for Parkinson's disease, but limited tissue availability and suboptimal survival of grafted dopaminergic neurons impede more widespread clinical application. Glial cell line-derived neurotrophic factor (GDNF) and neurotrophin-4/5 (NT-4/5) exert neurotrophic effects on dopaminergic neurons via different receptor systems. In this study, we investigated possible additive or synergistic effects of combined GDNF and NT-4/5 treatment on rat embryonic (embryonic day 14) nigral explant cultures grown for 8 days. Contrary to cultures treated with GDNF alone, cultures exposed to NT-4/5 and GDNF+NT-4/5 were significantly larger than controls (1.6- and 2.0-fold, respectively) and contained significantly more protein (1.6-fold). Treatment with GDNF, NT-4/5 and GDNF+NT-4/5 significantly increased dopamine levels in the culture medium by 1.5-, 2.5- and 4.7-fold, respectively, compared to control levels, and the numbers of surviving tyrosine hydroxylase-immunoreactive neurons increased by 1.7-, 2.1-, and 3.4-fold, respectively. Tyrosine hydroxylase enzyme activity was moderately increased in all treatment groups compared to controls. Counts of nigral neurons containing the calcium-binding protein, calbindin-D28k, revealed a marked increase in these cells by combined GDNF and NT-4/5 treatment. Western blots for neuron-specific enolase suggested an enhanced neuronal content in cultures after combination treatment, whereas the expression of glial markers was unaffected. The release of lactate dehydrogenase into the culture medium was significantly reduced for GDNF+NT-4/5-treated cultures only. These results indicate that combined treatment with GDNF and NT4/5 may be beneficial for embryonic nigral donor tissue either prior to, or in conjunction with, intrastriatal transplantation in Parkinson's disease.

Animals↗
PubMed2001

Intratumoral arteriovenous shunting in malignant gliomas.

OBJECTIVE: Intratumoral arteriovenous shunting in glioblastomas has been suspected but neither proven nor quantified. METHODS: Using a previously described technique of selective intra-arterial intratumoral injection of 99mTc-labeled microparticles (macroaggregated albumin), we measured the amount of radioactivity, by cerebral and pulmonary scintigraphy, in seven patients with malignant gliomas (six with glioblastomas and one with an anaplastic oligodendroglioma). The pulmonary shunt index was calculated as a percentage from the pulmonary/pulmonary plus cerebral radioactivity ratio. RESULTS: The results revealed a mean pulmonary shunt index of 67% (range, 47-89%), indicating that most of the microparticles injected into the tumor via the arterial route bypassed the tumor and reached the lungs. The measured arteriovenous shunting was greater when the injection was performed in an artery exclusively perfusing the tumor. CONCLUSION: Important intratumoral arteriovenous shunting exists in glioblastomas. The potential consequences of this finding for intra-arterial treatment strategies are discussed.

Aged↗
PubMed2001

Death-associated protein 3 (Dap-3) is overexpressed in invasive glioblastoma cells in vivo and in glioma cell lines with induced motility phenotype in vitro.

PURPOSE: To discover the genetic determinants of glioma invasion in vivo, we compared the mRNA expression profiles of glioblastoma cells residing at the tumor core versus those at the invasive rim of a human tumor resection. EXPERIMENTAL DESIGN: From a single glioblastoma specimen, 20,000 individual cells from each region (core and invasive rim) were collected by laser capture microdissection and analyzed by mRNA differential display. Differential expression of gene candidates was confirmed by laser capture microdissection and quantitative reverse transcription-PCR in additional glioblastoma multiforme specimens, and the role in migration was further evaluated in glioma cell lines in vitro. RESULTS: Reproducible overexpression the death-associated Protein 3 (Dap-3) mRNA (NM 004632, GenBank; also reported as human ionizing resistance conferring protein mRNA, HSU18321, GenBank) by invasive cells was identified. Although the full-length Dap-3 protein has been described as proapoptotic, the NH(2)-terminal fragment can act in a dominant negative way resulting in protection from programmed cell death. In glioma cell lines T98G and G112 with an induced motility phenotype, Dap-3 was up-regulated at the mRNA and protein level as assessed by quantitative reverse transcription-PCR, cDNA microarray, and Western blot analysis. These cells showed an increased resistance to undergo camptothecin-induced apoptosis, which was overcome by effective Dap-3-antisense treatment. Antisense treatment also decreased the migration ability of T98G cells. CONCLUSIONS: Dap-3 is up-regulated in invasive glioblastoma multiforme cells in vivo and in glioma cells with an induced motility phenotype in vitro. When migration is activated, Dap-3 is up-regulated and cells become resistant to apoptosis. These findings suggest that Dap-3 confers apoptosis-resistance when migration behavior is engaged.

Apoptosis↗
PubMed2000

[Results and role of carotid endarterectomy].

BACKGROUND: The indications for carotid endarterectomy have been defined on the basis of several large prospective randomised trials. Today this operation is widely performed as primary and secondary stroke prevention in patients with high grade carotid artery stenosis. Permanent quality control of the surgical results is mandatory to ensure optimal stroke prevention and further reduce perioperative complications. METHODS: In this retrospective study we analyse the surgical results of 272 consecutive carotid endarterectomies performed in 260 patients with special emphasis on the prevention of intraoperative brain ischaemia. Patients were operated on in general anaesthesia and moderate hypothermia. Before clamping the arteries at the neck, a fast-acting barbiturate or propofol was administered intravenously to obtain burst suppression on the EEG. Transcranial Doppler sonography allowed continuous intraoperative monitoring of brain perfusion and detection of emboli. Intraoperative shunting was performed only when the collateral circulation was insufficient. RESULTS: The postoperative course was uneventful in 249 endarterectomies (91.5%). The internal carotid artery was sonographically recanalised at hospital discharge and at 6-week follow-up in all 249 cases. Ischaemic cerebral complications were observed in 7 patients (2.6%): minor reversible brain ischaemia in 4 (1.5%), and major brain ischaemia with infarction in 3 (1.1%). Three patients died in the perioperative period, representing a mortality rate of 1.1% in this series. The overall combined stroke and death rate was 3.7%. The combined major stroke and death rate was 2.2%. Various non cerebral complications occurred in 13 patients (4.8%). CONCLUSIONS: These results confirm that endarterectomy is a safe and efficient treatment for atherosclerotic carotid stenosis at the neck. Very low complication rates can be attained by non-invasive diagnostic methods combined with intraoperative monitoring of cerebral blood flow velocity. New upcoming endovascular therapies such as percutaneous angioplasty and stenting need to be compared with these current surgical results with regard not only to perioperative morbidity and mortality but also patency rate, restenosis, and intracerebral blood flow restoration.

Adult↗
PubMed2000

Glial cell line-derived neurotrophic factor stimulates the morphological differentiation of cultured ventral mesencephalic calbindin- and calretinin-expressing neurons.

Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor for mesencephalic dopaminergic neurons. Subpopulations of these neurons express the calcium-binding proteins calbindin (CB) and calretinin (CR). Understanding the specific effects of GDNF on these neurons is important for the development of an optimal cell replacement therapy for Parkinson's disease. To investigate the effects of GDNF on the morphological complexity of mesencephalic tyrosine hydroxylase (TH)-immunoreactive (-ir), CB-ir, and CR-ir neurons, dissociated cultures of embryonic (E14) rat ventral mesencephalon were prepared. Chronic administration of GDNF (10 ng/ml) for 7 days promoted the survival of TH-ir and CB-ir neurons but did not alter the density of CR-ir neurons. Total fiber length/neuron and number of branching points/neuron of CB-ir and CR-ir cells were significantly increased after GDNF treatment (2x for CB-ir cells and 1.4x and 1.7x, respectively, for CR-ir cells), which resulted in a significantly larger size of neurite field/neuron (2.9x and 1.5x for CB-ir and CR-ir neurons, respectively). The number of primary neurites/neuron of CB-ir neurons was found to be 1.5x larger, while no difference could be detected for CR-ir cells. Assessment of the effects of GDNF on TH-ir neurons unveiled a similar outcome with an increased total fiber length/neuron (1.5x), an increased number of primary neurites/neuron (1.6x), and a twofold larger size of neurite field/neuron. In conclusion, our findings recognize GDNF as a neurotrophic factor that stimulates the morphological differentiation of ventral mesencephalic CB-ir and CR-ir neurons.

Animals↗
PubMed2000

Dilemmas in the management of patients with arteriovenous malformations.

An arteriovenous malformation (AVM) consists of one or more arteries that drain through one or several small openings directly into one or more veins. The capillary system between arteries and veins is missing. The natural history of an unruptured AVM demonstrates a 1-2% bleeding rate and once ruptured a 2-4% annual risk of rebleeding. There is a risk of dying of AVM up to 1% per year, a 1% annual risk of developing de novo epilepsy, and a 1% chance of disability per year. Small AVMs are more likely to rupture than large AVMs. The goal of treatment is complete obliteration of the malformation. The risk of surgical treatment depends mainly on its size, location and drainage pattern. Size and angioarchitecture determine the risks of embolotherapy and radiotherapy. AVMs in Spetzler-Martin grades I-III should be treated by microneurosurgery or a combination of embolotherapy and microneurosurgery. They can be excised with low surgical mortality and morbidity. For AVMs in Spetzler-Martin grades IV and V staged treatment approaches such as embolotherapy followed by surgery or radiotherapy should be considered. Rarely is embolotherapy or radiotherapy alone indicated. There are AVMs in Spetzler-Martin grades IV and V that may be inaccessible for surgical or any other treatment, and that should be left alone. Prospective randomised trials on the optimal management of AVMs are lacking. All our knowledge on AVMs stems from open series and indirect comparisons.

Cerebral Angiography↗
PubMed2000

Central lumbar disc herniation.

UNLABELLED: A follow-up study which describes the experience of the Department of Neurosurgery in Berne in the treatment of patients with central lumbar disc herniation (CLDH). BACKGROUND DATA: The anatomical position of lumbar disc herniation, in general, does not seem to affect postoperative outcome. However, according to other studies a subgroup of patients with central lumbar disc herniations appears to have poorer results. OBJECTIVES: The aim of the present study was to assess clinical outcome in a recent cohort of patients, to investigate whether there is a difference in outcome with regard to the surgical approach (unilateral vs bilateral) and to compare the postoperative results between the subcategories of CLDH: central massprolaps (CMP) and central contained disc herniation (CCDH). METHODS: Between 1990 and 1997, 40 out of 3150 patients operated on for lumbar disc herniation were diagnosed with CLDH (1.2%). The patients were operated on through unilateral or bilateral fenestrations with microdiscectomy. Recent follow-up studies were obtained by standardized questionnaires. The retrospective investigation was performed by an unbiased observer. RESULTS: Long-term follow-up was available for 34 of the 40 patients (85%) at a mean of 3.3 years. Eight patients had an excellent result (24%), 15 patients a good result (44%), 8 patients a fair (24%) and 3 patients had a poor result (9%). Overall, the operation was considered successful in 68% of patients. There was no statistically significant difference in outcome in patients with CMP as compared with those with CCDH (75% versus 64%). There was also no significant difference for better outcome between bilateral as compared with unilateral approaches. CONCLUSIONS: Postoperative outcome of central lumbar disc herniation (CLDH) is poorer as compared with other types of lumbar disc herniation. The reason seems to be the anatomical position of the disc herniation with a peculiar derangement of the disc architecture. The surgical approach itself or the subcategories of CLDH appear to have only minor impact on postoperative outcome. Interlaminar fenestrations, in general, are appropriate for removal of the disc fragments.

Adult↗