Biomedical subjects

Gert Baumann

Publications and source records attributed to Gert Baumann.

At least 37 records · Page 2Linked to original sources

PubMed2005

NT-ProBNP in acute heart failure: correlation with invasively measured hemodynamic parameters during recompensation.

BACKGROUND: N-terminal brain natriuretic peptide (NT-proBNP) level is elevated in patients with acute and chronic heart failure. This study addresses whether NT-proBNP correlates with invasively measured hemodynamic parameters and whether a decrease of NT-proBNP over time correlates with invasively monitored hemodynamic improvement. METHODS AND RESULTS: Twenty consecutive patients with acute exacerbation of chronic heart failure (New York Heart Association class III-IV) were included in this prospective study. NT-proBNP and hemodynamic measurements by balloon-tipped pulmonary artery catheter were performed simultaneously. Recompensation strategies included vasodilators, diuretics, and inotropes. The patients were divided in 2 subgroups. Group A, by definition, had a hemodynamic improvement over 24 hours with an increase of cardiac index of >30% and a decrease of pulmonary capillary wedge pressure of >30%. Group B did not show a hemodynamic improvement. Group A had a decline of NT-proBNP levels to 42% of the baseline value over 32 hours. In group B, the NT-pro BNP levels did not change significantly over 32 hours. CONCLUSION: The decrease of NT-proBNP correlates with hemodynamic improvement in patients with decompensated heart failure. The relative changes of NT-proBNP seem to be a reliable diagnostic tool in monitoring these patients. There results have been confirmed in a larger patient group.

Biomarkers↗

PubMed2005

The flavonoid phloretin suppresses stimulated expression of endothelial adhesion molecules and reduces activation of human platelets.

Atherosclerosis is a chronic inflammatory disease accompanied by the expression of endothelial adhesion molecules. Phloretin is a plant-derived phytochemical that is mainly present in apples. Because phloretin is reported to promote antioxidative activities, we investigated the effects of phloretin on cytokine-induced expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin) in human umbilical vein endothelial cells (HUVECs). Phloretin prevented TNF-alpha-stimulated upregulation of VCAM-1, ICAM-1, and E-selectin expression in a concentration-dependent manner. To the same extent as for TNF-alpha, phloretin also inhibited IL-1beta-induced upregulation in expression of all 3 adhesion molecules. Inhibition of cytokine-induced adhesion molecule expression for VCAM-1, ICAM-1, and E-selectin was detected already at the level of mRNA. Preincubation with phloretin dose-dependently attenuated TNF-alpha-stimulated adhesion of monocytic THP-1 cells to HUVECs and human aortic endothelial cells. Phloretin did not affect TNF-alpha-stimulated activation of nuclear factor kappaB (NF-kappaB) but inhibited activation of interferon regulatory factor 1, a transcription factor involved in the regulation of endothelial cell adhesion molecule expression. In human platelets, phloretin diminished adenosine diphosphate (ADP) and thrombin receptor-activating peptide-stimulated expression of the activated form of the GPIIb/IIIa complex and reduced platelet aggregation stimulated by ADP. Thus phloretin may have beneficial effects in the onset and progression of cardiovascular diseases.

Blood Platelets↗

PubMed2005

Hemodynamic effects of alpha1-adrenoceptor antagonist, doxazosin, in patients with chronic congestive heart failure.

PURPOSE: Non-selective alpha-adrenoceptor antagonists have not demonstrated significant beneficial effects in chronic heart failure. Previous studies with the selective alpha1-adrenoceptor antagonist, doxazosin, led to conflicting results. We assessed the hypothesis that treatment with doxazosin adjuvant to standard oral therapy results in significant increase in cardiac index in patients with chronic heart failure. METHODS: A double-blind, randomized study was conducted on 30 patients with chronic congestive heart failure (NYHA III-IV), with cardiac index<2.5 l/minxm, and/or with pulmonary capillary wedge pressure>16 mm Hg. Of the 30 patients, 15 were treated with doxazosin and 15 with placebo, both adjuvant to stable oral therapy, which included a minimum of an ACE inhibitor and a diuretic. Hemodynamic measurements were performed on days 1 and 2, and after 12 weeks on study medication. On day 1, patients were treated with 4 mg doxazosin or placebo. On day 2 and throughout the following 12 weeks, the patients were treated with 4 mg or 8 mg doxazosin/d (the latter, if 4 mg/d did not induce an increase >0.75 l/minxm in cardiac index), or with placebo. RESULTS: Six patients were treated with 4 mg doxazosin/d (group A), 9 patients with 8 mg doxazosin/d (group B), and 15 with placebo. Baseline values for the cardiac index on day 1, day 2, and after 12 weeks failed to disclose significant differences between patient groups and between the days of study. On day 1, the increase in cardiac index compared with baseline was significantly higher in group A than in the placebo group (P=0.004) and group B (P=0.001). On day 2, the increase in cardiac index compared with baseline on day 1 was significantly higher in group A than in group B (P=0.003) (with reference to alpha/3=0.0167 according to Bonferroni). This was no longer observed after 12 weeks. In the placebo group, following significant changes occurred in baseline values, heart rate was lower (P=0.023) and stroke volume index was higher after 12 weeks in comparison to day 1 (P=0.032). CONCLUSIONS: In conclusion, oral application of doxazosin supplementary to standard oral medication did not induce sustained hemodynamic benefit. Significant acute increase in cardiac index was observed in a minority (40%) of patients, whereas favorable changes in baseline hemodynamic parameters after 12 weeks occurred in the placebo group.

Adrenergic alpha-Antagonists↗

PubMed2005

Chronotropic incompetence in patients with an implantable cardioverter defibrillator: prevalence and predicting factors.

Chronotropic incompetence (CI), which has not been systematically examined in the ICD patient population, may have implications for device programming. A total of 123 ICD patients were classified into three groups: single-chamber ICD with sinus rhythm, dual-chamber ICD with sinus rhythm, and single-chamber ICD with permanent atrial fibrillation. Heart rate response, maximum oxygen uptake, and oxygen uptake at the anaerobic threshold were measured during treadmill exercise testing. In addition, clinical variables such as antiarrhythmic drug therapy, underlying heart disease, and left-ventricular (LV) ejection fraction were recorded. Of the patients studied, 38% were chronotropically incompetent (47/123). Significant predictors of CI were as follows: presence of a coronary disease (P = 0.036), prior cardiac surgery (P = 0.037), chronic drug therapy with beta-blockers (P = 0.032), administration of amiodarone (P = 0.025), and a combination of these two forms of treatment (P = 0.01). Spiroergometry revealed reduced exercise capacity (P = 0.041) and lessened VO2max (P = 0.034) among chronotropically incompetent patients. A large percentage of ICD patients demonstrates CI with subsequently reduced physical stress tolerance. In light of the DAVID study, we believe that a closer examination of rate-adaptive modes for ICD patients is warranted under enhanced conditions: (1) optimized AV interval programming; (2) utilization of new algorithms to reduce ventricular pacing in combination with rate-adaptive atrial pacing, with the goal of addressing CI while minimizing ventricular pacing; and (3) an optimized upper heart-rate limit.

Arrhythmias, Cardiac↗

PubMed2005

Reduction of right ventricular pacing in patients with sinus node dysfunction using an enhanced search AV algorithm.

BACKGROUND: Dual chamber pacing typically results in a high percentage of ventricular pacing. A number of studies have been conducted suggesting detrimental effects of ventricular desynchronization produced by long-term RV pacing. Pacemaker algorithms that extend the AV interval to uncover intrinsic AV conduction have been utilized to reduce ventricular pacing. These algorithms are often limited to AV intervals below 250 ms limiting the ventricular pacing reduction. We hypothesized that by allowing AV intervals to extend beyond 300 ms, a marked reduction in RV pacing can be achieved. METHODS: A total of 30 patients (17 men, mean age 71 +/- 9) with standard Brady indications, and implanted with a Medtronic Kappa 700 pacemaker, were randomized to 2-week treatments with default Search AV (KSAV) parameters or Enhanced Search AV (ESAV) parameters. The Enhanced Search AV algorithm included the capability for continuous adjustment of AV delays and the ability to auto disable in patients with persistent AV block. RESULTS: Among patients with intact AV conduction, percent VP was greater in KSAV versus ESAV (70 +/- 40% vs 19 +/- 28%, P < 0.001). In patients with persistent AV block, the algorithm suspended appropriately and there was no significant change in the percent VP between both arms of the study. In 18/22 patients, percent VP was reduced below 40%. CONCLUSIONS: Substantial reduction in ventricular pacing can be achieved by allowing the AV interval parameters to extend beyond 300 ms using the ESAV algorithm. In patients with AV block, ESAV suspended and patients were paced at their nominal settings.

Aged↗

PubMed2005

The pregnancy hormone relaxin binds to and activates the human glucocorticoid receptor.

The insulin-like peptide relaxin is a central hormone of pregnancy, but it also produces antifibrotic, myocardial, renal, central nervous, and vascular effects. Recently, two G-protein-coupled receptors, LGR7 and LGR8, were identified as relaxin receptors. Prompted by reports on the immunoregulatory effects of relaxin, we investigated possible interactions with the human glucocorticoid receptor (GR). Relaxin blunted the endotoxin-induced production of inflammatory cytokines (interleukin 1 [IL-1], IL-6, and tumor necrosis factor- alpha) by human macrophages, an effect that was suppressed by the GR antagonist RU-486. In three different cell lines, relaxin induced GR activation, nuclear translocation, and DNA binding as assessed in glucocorticoid response element (GRE)-luciferase assays. Coimmunoprecipitation experiments revealed physical interaction of endogenous and exogenous relaxin with cytoplasmic and nuclear GR. Relaxin competed with GR agonists for GR binding both in vivo, in whole-cell assays, and in vitro, in fluorescence polarization assays. In LGR7- and LGR8-free cells, the relaxin-mediated activation of GR was preserved. In conclusion, relaxin acts as a GR agonist, a pathway pivotal to relaxin's effects on cytokine secretion by human macrophages. These findings may deepen our understanding of relaxin's many physiologic actions as well as our insights into general principles of hormone signaling.

Cell Line↗

PubMed2005

Myocardial relaxin counteracts hypertrophy in hypertensive rats.

Current findings in male relaxin knockout mice indicate antifibrotic and positive lusitropic actions of relaxin on the myocardium. We investigated in 12-month-old male spontaneously hypertensive rats (SHR) and age-matched male Wistar-Kyoto rats (WKY) whether RLX shows antihypertrophic actions as well. SHR showed left heart hypertrophy and a selective elevation of left atrial and ventricular relaxin peptide which inversely correlated with the degree of hypertrophy. In adult rat cardiomyocytes, relaxin blunted phenylephrine-induced hypertrophy by inhibiting activated ERK-1/2 kinases. In conclusion, endogenous myocardial relaxin, upregulated in left heart hypertrophy, exerts antihypertrophic effects by inhibition of activated ERK-1/2 kinases.

Animals↗

PubMed2005

High concordance of invasive and echocardiographic mean pressure gradients in patients with a mechanical aortic valve prosthesis.

BACKGROUND AND AIM OF THE STUDY: Conflicting data exist regarding the accuracy of echocardiographic Doppler gradients compared to invasive pressure gradients in the hemodynamic assessment of patients with prosthetic aortic valves. The study aim was to determine the correlation between these measurements for mechanical single- and double-leaflet aortic valve prostheses in vivo. METHODS: Forty-four patients with an aortic valve prosthesis were included in this prospective study. Transthoracic echocardiography was performed immediately before the invasive measurements. Left ventricular pressure measurements were achieved by either atrial transseptal puncture and antegrade, transmitral left ventricular catheterization or--in the case of mitral valve replacement--direct left ventricular puncture. RESULTS: Comparison of echocardiographic and invasive mean pressure gradients of all examined aortic prosthetic valves revealed a Pearson correlation r = 0.59 (p < 0.001). The mean pressure gradient was overestimated by 7.4 mmHg with echocardiography. Classifying patients into clinically relevant categories (mild, moderate, severely increased pressure gradient) resulted in a kappa value of 0.72 and an agreement of 86.4%. There was no relevant difference between single- and double-leaflet valves. CONCLUSION: A high concordance was found between echocardiographic and invasive mean pressure gradients in vivo. Invasive measurements of the prosthetic valve gradients therefore seem to be indicated only in patients with contradictory echocardiographic and clinical findings.

Adult↗

PubMed2004

Tissue Doppler echocardiography and biventricular pacing in heart failure: patient selection, procedural guidance, follow-up, quantification of success.

Asynchronous myocardial contraction in heart failure is associated with poor prognosis. Resynchronization can be achieved by biventricular pacing (BVP), which leads to clinical improvement and reverse remodeling. However, there is a substantial subset of patients with wide QRS complexes in the electrocardiogram that does not improve despite BVP. QRS width does not predict benefit of BVP and only correlates weakly with echocardiographically determined myocardial asynchrony. Determination of asynchrony by Tissue Doppler echocardiography seems to be the best predictor for improvement after BVP, although no consensus on the optimal method to assess asynchrony has been achieved yet. Our own preliminary results show the usefulness of Tissue Doppler Imaging and Tissue Synchronization Imaging to document acute and sustained improvement after BVP. To date, all studies evaluating Tissue Doppler in BVP were performed retrospectively and no prospective studies with patient selection for BVP according to echocardiographic criteria of asynchrony were published yet. We believe that these new echocardiographic tools will help to prospectively select patients for BVP, help to guide implantation and to optimize device programming.

Cardiac Pacing, Artificial↗

PubMed2004

Downregulation of matrix metalloproteinases and collagens and suppression of cardiac fibrosis by inhibition of the proteasome.

Myocardial remodeling is an adaptive response of the myocardium to several forms of stress culminating in cardiac fibrosis, left ventricular dilation, and loss of contractility. The remodeling processes of the extracellular matrix are controlled by matrix metalloproteinases, which are in turn regulated by growth factors and inflammatory cytokines. The inflammatory transcription factor nuclear factor kappaB has been implicated in the transcriptional regulation of several matrix metalloproteinases. Because activation of nuclear factor kappaB in turn is essentially controlled by the ubiquitin-proteasome system, we investigated the hypothesis that inhibition of the proteasome may prevent activation of matrix metalloproteinases. We demonstrate here that inhibition of the proteasome in rat cardiac fibroblasts suppressed not only expression of matrix metalloproteinases 2 and 9, but also expression of collagen Ialpha1, Ialpha2, and IIIalpha1 as determined by in-gel zymography and real-time reverse transcription-polymerase chain reaction. Moreover, myocardial expression of matrix metalloproteinases and collagens was effectively suppressed by systemic treatment of spontaneously hypertensive rats over 12 weeks with the proteasome inhibitor MG132, which resulted in a marked reduction of cardiac fibrosis (-38%) compared with control animals. We conclude that inhibition of the ubiquitin-proteasome system may provide a new and attractive tool to interfere with collagen and matrix metalloproteinase expression, and therefore might be of possible use in the therapy of myocardial remodeling.

Animals↗

PubMed2004

Potential role of humoral immunity in cardiac dysfunction of patients suffering from dilated cardiomyopathy.

OBJECTIVES: This research was conducted to evaluate the role played by the humoral immune system in cardiac dysfunction among dilated cardiomyopathy (DCM) patients, as enabled by immunoadsorption therapy (IA) that effectively removes functionally active cardiac autoantibodies from plasma. BACKGROUND: Various circulating autoantibodies have been detected among patients suffering from DCM. METHODS: Before IA, antibodies were purified from plasma of 45 DCM patients (left ventricular ejection fraction [LVEF] <30%). We analyzed the functional effects of antibodies (300 mg/l) on calcium transients and on systolic cell shortening in adult rat cardiomyocytes. After this in vitro analysis, IA was performed in four courses at one-month intervals until month 3. RESULTS: Antibodies from 29 patients induced a reduction (>10%) in calcium transients (mean reduction: -16.5 +/- 1.9%) and a simultaneous reduction (>10%) of cell shortening (mean reduction: -21.2 +/- 1.8%) on cardiomyocytes (p < 0.001) (cardiodepressant group). Antibodies from 16 patients did not significantly influence calcium transients and cell shortening (<10%) (non-cardiodepressant group). During the first IA course, the cardiodepressant group demonstrated an acute increase in cardiac index (CI) from 2.2 +/- 0.1 l/min/m(2) to 2.9 +/- 0.1 l/min/m(2) (p < 0.001). In the non-cardiodepressant group, hemodynamics did not significantly change throughout three months. After three months before the final IA course (prolonged effects), the CI was 2.1 +/- 0.1 l/min/m(2) in the non-cardiodepressant group and 2.9 +/- 0.1 l/min/m(2) in the cardiodepressant group (p < 0.001). After three months LVEF increased only in the cardiodepressant group: from 20.8 +/- 1% to 30.5 +/- 1% (p < 0.01). CONCLUSIONS: In the majority of DCM patients, disturbances of humoral immunity with production of cardiodepressant antibodies may play a functional role in cardiac dysfunction. Evidence of cardiodepressant antibodies predicts hemodynamic benefits during IA.

Animals↗

PubMed2004

Atypical vessels as an early sign of intracardiac myxoma?

We report on a woman with previously unknown left atrial myxoma, who underwent percutaneous coronary intervention. 45 months after the initial coronary angiography, echocardiography demonstrated a large atrial myxoma, which was not seen echocardiographically before. The retrospective analysis of the pre-intervention coronary angiography revealed atypical vessels in the atrial septum, which are interpreted as early signs of myxoma.

Chest Pain↗

PubMed2004

Identification of the pregnancy hormone relaxin as glucocorticoid receptor agonist.

The insulin-like peptide relaxin is a central hormone of pregnancy, but it also produces anti-fibrotic, myocardial, renal, central-nervous, and vascular effects. Recently, two G protein-coupled receptors, LGR7 and LGR8, have been identified as relaxin receptors. Prompted by reports on immunoregulatory effects of relaxin, we investigated possible interactions with the human glucocorticoid receptor (GR). Relaxin blunted the endotoxin-induced production of inflammatory cytokines (IL-1, IL-6, TNF-alpha) by human macrophages--an effect that was suppressed by the GR antagonist RU-486. In three different cell lines, relaxin induced GR activation, nuclear translocation, and DNA binding as assessed in GRE-luciferase assays. Co-immunoprecipitation experiments revealed physical interaction of endogenous and exogenous relaxin with cytoplasmic and nuclear GR. Relaxin competed with GR agonists for GR binding, both in vivo in whole-cell assays, and in vitro in fluorescence polarization assays. Relaxin was shown to up-regulate GR protein expression as well as the number of functionally active GR sites. In LGR7/8-free cells, the relaxin-mediated activation of GR was preserved. In conclusion, relaxin acts as GR agonist--a pathway pivotal to its effects on cytokine secretion by human macrophages. These findings may deepen our understanding of relaxin's abundant physiological actions, as well as our insights into general principles of hormone signaling.

Active Transport, Cell Nucleus↗

PubMed2004

Percutaneous closure of interatrial communications in adults - prospective embolism prevention study with two- and three-dimensional echocardiography.

BACKGROUND: Patients with interatrial communications after paradoxical embolic events are at risk for recurrent thromboembolism. We hypothesized that transcatheter closure of the defects would result in long-term prevention of systemic embolism and performed clinical and echocardiographic follow-up. METHODS: We included 161 patients (mean age 46.8 +/- 11 years, 83 females) with patent foramen ovale or atrial septal defect and at least one documented paradoxical systemic thrombembolic event and/or a large atrial shunting. RESULTS: The implantation procedure was successfully performed without major complications in all patients and minor complications in 2.5%. Two and / or three dimensional echocardiography was performed before and after 4 weeks and 12 months using a multiplane transoesophageal probe. After 4 weeks and 6 months two patients had minimal shunting. These residual defects were closed with a second device implantation without shunting after further 4 weeks. During a follow-up of 324.3 patient years (range, 13 to 19 months), recurrent embolic events occurred in only 1 patient (0.6%). CONCLUSION: After primary paradoxical systemic embolism, results of transcatheter occlusion of the interatrial communications are dependent on the closure device system and can prevent further secondary embolic events for up to 1 year after the percutaneous closure. Three dimensional echocardiography provides dynamic features of the defects and the post closure status and may lead to an improved understanding and diagnosis of the interatrial defect.

Balloon Occlusion↗

PubMed2004

The tea flavonoid epigallocatechin-3-gallate reduces cytokine-induced VCAM-1 expression and monocyte adhesion to endothelial cells.

Attachment of leukocytes to the vascular endothelium and the subsequent migration of cells into the vessel wall are early events in atherogenesis. This process requires the expression of endothelial adhesion molecules. Since tea catechins are reputed to promote antiatherogenic activities, we investigated the effects of various tea catechins-i.e., epicatechin (EC), epicatechin gallate (ECG), epigallocatechin (EGC), and epigallocatechin-3-gallate (EGCG)-on cytokine-induced expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin) in HUVECs by ELISA. EGCG and to a lesser extent ECG prevented the induction of VCAM-1 expression in a concentration-dependent manner after stimulation with TNF-alpha, whereas EC and EGC were without effect. EGCG also inhibited the IL-1beta-induced induction of VCAM-1 expression. Inhibition of cytokine-induced VCAM-1 expression was manifested already on the transcriptional level. Furthermore, EGCG reduced the TNF-alpha-induced adhesion of THP-1 cells to HUVECs. EGCG did not influence TNF-alpha-stimulated NF-kappaB activation.

Catechin↗

PubMed2004

Fibrinolysis of acute peripheral arterial occlusion with tenecteplase--a new weight-optimized treatment regimen.

Peripheral arterial occlusions are associated with high morbidity. Thrombolysis has become established as effective treatment in clinical practice. Tenecteplase is a new thrombolytic agent that offers advantages over existing drugs with respect to mechanism of action and adverse effects. This case report describes successful thrombolysis of an acute thromboembolic brachial artery subtotal occlusion in a 76-year-old woman. In contrast to previously published data, tenecteplase was administered in a weight-adapted dose regimen over six hours, with application of one-fourth of the dose usually given in patients with myocardial infarction. Tenecteplase was immediately effective, and proved safe and well tolerated.

Aged↗

PubMed2004

Tenecteplase for the treatment of massive and submassive pulmonary embolism.

BACKGROUND: Data on thrombolytic therapy disclose benefits from thrombolytic therapy in patients with massive and submassive pulmonary embolism (PE). Previously published case reports have described the successful use of tenecteplase under these conditions. METHODS: Four patients with massive and submassive PE received a weight-optimized dosing regimen of tenecteplase, administered as an intravenous bolus. RESULTS: All patients experienced clinically relevant improvement of dyspnea following thrombus regression. Regression of right ventricular enlargement was documented in three cases. Tenecteplase was well tolerated and did not cause bleeding complications. Thirty-day mortality was zero. CONCLUSIONS: These data support the use of this new thrombolytic agent in patients with massive and submassive PE; however, sufficiently powered, randomized trials have not yet taken place for these indications.

Aged↗

PubMed2004

Diagnostic accuracy of new handheld echocardiography with Doppler and harmonic imaging properties.

BACKGROUND: The first generation of handheld echocardiography devices was evaluated with divergent results because of inherent technical limitations. New handheld devices with continuous/pulsed wave Doppler and tissue harmonic imaging were introduced recently. In this study, comparisons were drawn among standard echocardiography, invasively measured systolic pulmonary artery pressure, and these new devices. OBJECTIVE: We sought to evaluate new handheld echocardiography and its diagnostic accuracy compared with standard echocardiography. METHODS: Two consecutive echocardiographic examinations were performed by experienced and independent examiners using handheld and standard echocardiography. Systolic pulmonary artery pressure was measured by Swan-Ganz catheter. RESULTS: In all, 177 (56.2%) patients had normal cardiac function; 138 (43.8%) had underlying cardiac pathology. Handheld echocardiography had an overall agreement of 94.8% and kappa of 0.89 to detect the main echocardiographic finding. Handheld echocardiography detected valve disease with an agreement of 96.7% and kappa of 0.93; global left ventricular function was assessed correctly in 85.6% of cases. Pericardial effusion was diagnosed with an agreement of 91.2%. Dyssynergy was found by handheld echocardiography with an agreement of 95.4% and kappa value of 0.88. Systolic pulmonary artery pressure measured by handheld echocardiography and Swan-Ganz catheter had a correlation of 0.97. CONCLUSION: This study demonstrates the high diagnostic accuracy of handheld devices with continuous/pulsed wave Doppler and harmonic imaging, and that these devices broaden the diagnostic spectrum while allowing for enhanced mobility in everyday clinical applications.

Adult↗