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Biomedical subjects

Andreas Koch

Publications and source records attributed to Andreas Koch.

At least 19 recordsLinked to original sources

Stereodynamics of 1-(methylsulfonyl)-3,5-bis(trifluoromethylsulfonyl)-1,3,5-triazinane: experimental and theoretical analysis.

Dynamic NMR of 1-(methylsulfonyl)-3,5-bis(trifluoromethylsulfonyl)-1,3,5-triazinane reveals the existence of three conformers and two dynamic processes: ring inversion and rotation about the N-S bond, both processes having DeltaG(++) = 13.5 kcal/mol. An unprecedented large reverse Perlin effect (J(CHax) > J(CHeq)) was found experimentally and calculated theoretically.

Journal Article↗

Hyperconjugation and the increasing bulk of OCOCX3 substituents in trans-1,4-disubstituted cyclohexanes destabilize the diequatorial conformer.

The trans diesters of 1,4-cyclohexanediol with a number of acetic acid analogues, CX3COOH, of varying steric hindrance and polarity (CX3 = Me, Et, iso-Pr, tert-Bu, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, CBr3) were synthesized, and the axial,axial/equatorial,equatorial conformational equilibria were studied by low-temperature 1H NMR spectroscopy in CD2Cl2. The structures and relative energies of the axial,axial and equatorial,equatorial conformers were calculated at both the MP2/6-311G* and the MP2/6-311+G* levels of theory, and it was only by including diffuse functions that a good correlation of deltaG(o)calcd vs deltaG(o)exptl could be obtained. Both the structures and the energy differences of the axial,axial and equatorial,equatorial conformers are discussed with respect to the established models of conformational analysis, viz., steric 1,3-diaxial and hyperconjugative interactions. Interestingly, the hyperconjugative interactions sigma(C-C)/sigma(C-H) --> sigma*(C-O), together with a steric effect which also destabilizes the equatorial,equatorial conformers on increasing bulk of the substituents, proved to dominate the position of the conformational equilibria. In addition, the preference of the axial,axial conformers with respect to their equatorial,equatorial analogues was greater than expected from the conformational energies of the corresponding substituents in the monosubstituted cyclohexyl esters. The reason for this very interesting and unexpected result is also discussed.

Journal Article↗

Impact of cardiac surgery on plasma levels of B-type natriuretic peptide in children with congenital heart disease.

OBJECTIVE: To examine prospectively the effect of cardiac surgery on plasma concentration of B-type natriuretic peptide (BNP) in children with congenital heart disease. SETTING: Tertiary referral center. METHODS: BNP plasma concentration was measured by sandwich immunoassay (Biosite) in 65 consecutive patients with congenital heart disease (age 4 days to 17.1 years, mean (S.D.) age 3.6 (4.7) years, median age 1.0 years) on the day before and after surgical therapy. BNP levels were compared to perioperative data and to healthy subjects. RESULTS: BNP increased significantly (p<0.001) after cardiac surgery from median 31 pg/ml (mean 189 pg/ml) to median 453 pg/ml (mean 607 pg/ml) and remained significantly elevated during the first week (p<0.001). After a first peak mean (S.D.) 1.3 (0.7) days after surgery, there was a significant decrease of plasma BNP followed by a second peak 5.1 (1.1) days after surgery. Postoperative BNP plasma concentration was correlated to BNP before surgery (r=0.58, p<0.001), to cardiopulmonary bypass duration (r=0.52, p<0.001) and to serum lactate concentration at the first day after surgery (r=0.49, p<0.001). CONCLUSIONS: In children with congenital heart defects plasma BNP increased immediately after cardiac surgery despite haemodynamic unloading. The correlation to cardiopulmonary bypass time and serum lactate concentration and the similarity between the pattern of BNP release after surgery and after myocardial ischaemia might be explained by a cytoprotective role for BNP after cardiac surgery.

Adolescent↗

Nonhypotensive dose of beta-adrenergic blocker ameliorates capillary deficits in the hearts of rats with moderate renal failure.

Renal failure causes sympathetic overactivity and inadequate capillary growth in response to cardiomyocyte hypertrophy in experimental renal failure, as well as in uremic patients. In nonuremic animals, sympathetic overactivity was shown to suppress capillary growth. The purpose of this study was to examine whether blockade with alpha- and beta-adrenoblockers ameliorates the capillary deficit that was documented in the hearts of rats with moderate renal failure. Male Sprague-Dawley rats, 3 days after surgical ablation [subtotal nephrectomy (SNX)] or sham operation (sham), were treated with phenoxybenzamine, metoprolol, or a combination of both: After 12 weeks, the hearts were investigated using morphometric and stereologic techniques. The length density of myocardial capillaries was lower (p<0.05) in untreated SNX than in sham (2,786+/-372 vs 3,397+/-602 mm/mm3); the decrease was abrogated by metoprolol (3,305+/-624 mm/mm3), but not by phenoxybenzamin (2,628+/-480 mm/mm3). The intercapillary distance increased (p<0.05) in SNX (20.5+/-1.5 microm) and tended to be lower after metoprolol treatment (19.0+/-1.9 microm). The media area of intramyocardial arterioles was significantly higher in untreated SNX (1,158+/-1,343 vs 686+/-771 microm2 in sham). Metoprolol in nonhypotensive doses prevents the capillary deficit in the hearts of rats with moderate renal failure and presents an argument for an important role of sympathetic overactivity in the genesis of the capillary deficit in moderate chronic renal insufficiency.

Adrenergic beta-Antagonists↗

Recent developments in X-ray imaging with micrometer spatial resolution.

X-ray detectors for imaging with a spatial resolution in the micrometer and submicrometer range have been developed at synchrotron radiation sources since 1996. The detectors consist of a scintillator, a light microscopy optic and a charge-coupled device (CCD). The scintillator converts part of the X-ray stopped by a material into a visible-light image which is projected onto the CCD by the light optics. A resolution of 0.5 microm FWHM has been achieved using a 1 microm-thick europium-doped Lu3Al5O12 film. The detective quantum efficiency of the detector is mainly limited by the low absorption of X-rays in the thin layer of the scintillator. To increase the absorption, and therefore reduce the exposure time, new scintillators (Lu2O3:Eu3+, Gd2O3:Eu3+, Lu2SiO5:Ce, Gd3Ga5O12:Eu3+, CdWO4) have been investigated. These were fabricated using sol-gel and liquid-phase epitaxy processes. Finally, the first fast microtomography experiment including radiation hardness of the optic is shown. This detector uses a high-intensity white beam with 60 keV effective energy and a fast CCD camera at up to 60 frames s(-1).

Journal Article↗

B-type natriuretic peptide in paediatric patients with congenital heart disease.

AIMS: To examine the diagnostic value of B-type natriuretic peptide (BNP) plasma concentration in congenital heart disease. METHODS AND RESULTS: BNP was measured in 288 consecutive patients (mean age 6.0 +/- 6.4 years) with left-to-right shunt, left or right heart obstruction, tetralogy of Fallot, functionally univentricular heart, or impaired left ventricular function and compared with age- and gender-specific normal values, and to haemodynamic and echocardiographic data. BNP increased with decreasing left ventricular shortening fraction (r = -0.80; P < 0.001). In patients with left-to-right shunt, BNP was increased (mean SDS +1.64; P < 0.001) and positively correlated (P < 0.001) to shunt volume (r = 0.66), systolic right ventricular pressure (r = 0.69), mean pressure of the pulmonary artery (r = 0.66), and pulmonary resistance (r = 0.59). There was no correlation between BNP and invasive pressure gradient or extent of ventricular hypertrophy in patients with left or right heart obstruction. In patients with tetralogy of Fallot, BNP was not significantly increased. Patients with functionally univentricular heart had elevated BNP plasma levels (mean SDS +1.39; P < 0.001) without decrease after volume unloading by cavopulmonary connection. CONCLUSION: In children with congenital heart defects, plasma BNP correlates closely to ventricular function. BNP plasma levels do not reflect directly the extent of ventricular pressure or volume work, but mirror the impairment of the loaded ventricles. Normal BNP cannot exclude pathology, but reflects a compensated status of the heart.

Blood Pressure↗

Influence of vitamin C and E supplementation on oxidative stress induced by hyperbaric oxygen in healthy men.

AIM: To investigate the effect of a 4-week vitamin C and E supplementation on oxidative stress induced by hyperbaric oxygen (HBO). METHODS: 19 healthy men were exposed to 3 sequential protocols, i.e. HBO (100% O2, 2.4 bar, 131 min) before (T1) and after 4 weeks of daily supplementation with 500 mg slow-release vitamin C and 272 IU vitamin E (T2). A normoatmospheric protocol (21% O2, 1.0 bar, 131 min) served as control treatment (nonexposed). Blood samples were taken before (B) and immediately after (A) treatment. Plasma levels of vitamin A, C, E, beta-carotene, reduced glutathione and malondialdehyde were measured by HPLC. Antioxidative capacity and lipid peroxides in plasma were analyzed by ELISA. RESULTS: HBO decreased vitamin C and antioxidative capacity (T1). At T1, Delta A - B of vitamin C and lipid peroxides was different from nonexposed. Vitamin supplementation increased plasma levels of vitamin C and E by 28 and 37%, respectively. Vitamin supplementation led to decreased concentrations of lipid peroxides and reduced glutathione. After supplementation, HBO decreased vitamin C and reduced glutathione. At T2, Delta A - B of vitamin C and lipid peroxides was significantly different from nonexposed. CONCLUSION: In humans, oxidative stress decreased plasma levels of vitamin C and antioxidative capacity and increased plasma lipid peroxides. Supplementation with vitamin C and E did not prevent these effects.

Adult↗

Renoprotective effect of a dopamine D3 receptor antagonist in experimental type II diabetes.

Diabetic nephropathy is the leading cause of end-stage renal disease. Dopamine receptors are involved in the regulation of renal hemodynamics and may play a role in diabetes-induced hyperfiltration. To test this hypothesis, we investigated the renal effect of a dopamine D3 receptor antagonist (D3-RA) in hypertensive type II diabetic SHR/N-cp rats. Lean and obese SHR/N-cp rats were randomly assigned to D3-RA, angiotensin-converting enzyme inhibitor (ACE-i), or D3-RA+ACE-i treatment or control conditions. Treated animals were given the D3-RA A-437203 (10 mg/kg/body weight (BW)/day) or the ACE-i trandolapril (0.3 mg/kg BW/day) or a combination of both. At 6 months following perfusion, fixed kidneys were analyzed by morphological and stereological methods. Indices of renal damage (glomerulosclerosis, glomerulosclerosis damage index (GSI), tubulointerstitial and vascular damage), glomerular geometry and functional variables such as urinary albumin excretion, glomerular filtration rate, blood pressure, blood chemistry and BW were determined. The GSI (score 0-4) was significantly higher (P<0.05) in untreated diabetic animals (1.62+/-0.3) compared to nondiabetic controls (0.4+/-0.2) and the treatment groups (D3-RA: 0.31+/-0.12; ACE-i: 0.29+/-0.1; combination treatment: 0.12+/-0.01). Urinary albumin excretion (mg/24 h) was higher in untreated diabetic controls (102+/-19) compared to nondiabetic controls (31+/-12) and the treatment groups (D3-RA: 44+/-15; ACE-i: 41+/-13; combination treatment: 15+/-8). Mean glomerular volume was higher in untreated diabetic animals compared to nondiabetic controls and to the treatment groups. Desmin expression, a marker of podocyte damage, was elevated in untreated diabetic controls and diminished in all treatment groups. These data suggest that in a model of type II diabetes, the dopamine D3-RA had a beneficial effect on renal morphology and albuminuria, which was comparable in magnitude to that of ACE-i treatment.

Angiotensin-Converting Enzyme Inhibitors↗

Decline of FEV1 in scuba divers.

STUDY OBJECTIVES: Obstructive changes in lung function have been reported with cumulative scuba diving exposure. The aim of this study was to investigate the decline in FEV1 in scuba divers over time. DESIGN: Prospective controlled cohort study. SETTING: German Naval Medical Institute. PATIENTS: Four hundred sixty-eight healthy, male, military scuba divers and 122 submariners (control subjects) were entered. MEASUREMENTS AND RESULTS: Pulmonary function tests were performed in all subjects on at least three occasions with a minimum interval of 1 year between first and last measurement. The decline in FEV1 was investigated fitting a general linear model to FEV1 across time with a factorial main-effects model for slopes and intercepts with respect to the factors group, smoking status, and baseline FEV1. Mean baseline age of all subjects was 32 years (SD, 9.1), and mean body mass index was 24.7 kg/m2 (SD, 2.4). Subjects were followed up for 5 years (range, 1 to 9 years) on average. Baseline FEV1 exceeded the predicted values in both divers and nondiving control subjects. There was no significant difference in the decline of FEV1 between divers and control subjects. Over time, FEV1 declined more rapidly in smokers than in nonsmokers (p = 0.0064) and declined more rapidly also in subjects with a baseline FEV1 above average compared to subjects below average (p < 0.0001). The annual decline of FEV1 peaked in smoking divers who had a high FEV1 at baseline. CONCLUSIONS: The data indicate that scuba diving is not associated with an accelerated decline in FEV1. Combined exposure to diving and smoking contributes to the fall of FEV1; therefore, smoking cessation is advised for divers.

Adult↗

Propagation of polar substituent effects in 1-(substituted phenyl)-6,7-dimethoxy-3,4-dihydro- and -1,2,3,4-tetrahydroisoquinolines as explained by resonance polarization concept.

[structures: see text] Propagation of inductive and resonance effects of phenyl substituents within 1-(substituted phenyl)-6,7-dimethoxy-3,4-dihydro- and -1,2,3,4-tetrahydroisoquinolines were studied with the aid of 13C and 15N NMR chemical shifts and ab initio calculations. The substituent-induced changes in the chemical shift (SCS) were correlated with a dual substituent parameter equation. The contributions of conjugative (rhoR) and nonconjugative effects (rhoF) were analyzed, and mapping of the substituent-induced changes is given over the entire isoquinoline moiety for both series. The experimental results can be rationalized with the aid of the resonance polarization concept. This means the consideration of the substituent-sensitive balance of different resonance structures, i.e., electron delocalization, and the effect of the aromatic ring substituents on their relative contributions. With tetrahydroisoquinolines, the delocalization of the nitrogen lone pair (stereoelectronic effect) particularly contributes. Correlation analysis of the Mulliken atomic charges for the dihydroisoquinoline derivatives was also performed. The results support the concept of the substituent-sensitive polarization of the isoquinoline moiety even if the polarization pattern achieved via the NMR approach is not quite the same as that predicted by the computational charges. Previously the concepts of localized pi-polarization and extended polarization have been used to explain polar substituent effects within aromatic side-chain derivatives. We consider that the resonance polarization model effectively contributes to the understanding of the polar substituent effects.

Journal Article↗

Global expression profiling of Bacillus subtilis cells during industrial-close fed-batch fermentations with different nitrogen sources.

A detailed gene expression analysis of industrial-close Bacillus subtilis fed-batch fermentation processes with casamino acids as the only nitrogen source and with a reduced casamino acid concentration but supplemented by ammonia was carried out. Although glutamine and arginine are supposed to be the preferred nitrogen sources of B. subtilis, we demonstrate that a combined feeding of ammonia and casamino acids supports cell growth under fed-batch fermentation conditions. The transcriptome and proteome analyses revealed that the additional feeding of ammonia in combination with a reduced amino acid concentration results in a significantly lower expression level of the glnAR or tnrA genes, coding for proteins, which are mainly involved in the nitrogen metabolism of B. subtilis. However, the mRNA levels of the genes of the ilvBHC-leuABD and hom-thrCB operons were significantly increased, indicating a valine, leucine, isoleucine, and threonine limitation under these fermentation conditions. In contrast, during the fermentation with casamino acids as the only nitrogen source, several genes, which play a crucial role in nitrogen metabolism of B. subtilis (e.g., glnAR, nasCDE, nrgAB, and ureABC), were up-regulated, indicating a nitrogen limitation under these conditions. Furthermore, increased expression of genes, which are involved in motility and chemotaxis (e.g., hag, fliT) and in acetoin metabolism (e.g., acoABCL), was determined during the fermentation with the mixed nitrogen source of casamino acids and ammonia, indicating a carbon limitation under these fermentation conditions. Under high cell density and slow growth rate conditions a weak up-regulation of autolysis genes could be observed as well as the induction of a number of genes involved in motility, chemotaxis and general stress response. Results of this study allowed the selection of marker genes, which could be used for the monitoring of B. subtilis fermentation processes. The data suggest for example acoA as a marker gene for glucose limitation or glnA as an indicator for nitrogen limitation.

Bacillus subtilis↗

Ab initio study of the substituent effects on the relative stability of the E and Z conformers of phenyl esters. Stereoelectronic effects on the reactivity of the carbonyl group.

Equilibria between the Z (tau1= 0 degrees) and E (tau1= 180 degrees) conformers of p-substituted phenyl acetates 4 and trifluoroacetates 5 (X = OMe, Me, H, Cl, CN, NO2) were studied by ab initio calculations at the HF/6-31G* and MP2/6-31G* levels of theory. The preference for the Z conformer, DeltaE(HF), was calculated to be 5.36 kcal mol(-1) and 7.50 kcal mol(-1) for phenyl acetate and phenyl trifluoroacetate (i.e., with X = H), respectively. The increasing electron-withdrawing ability of the phenyl substituent X increases the preference of the Z conformer. An excellent correlation with a negative slope was observed for both series between DeltaE of the E-Z equilibrium and the Hammett sigma constant. By using an appropriate isodesmic reaction, it was shown that electron-withdrawing substituents decrease the stability of both conformers, but the effect is higher with the E conformer. Electron-withdrawing phenyl substituents decrease the delocalization of the lone pair of the ether oxygen to the C=O antibonding orbital (nO--> pi*C=O) in both the E and Z forms and in both series studied; this effect is higher in the E conformer than in the Z conformer. The nO --> pi*C=O electron donation has a minimum value with tau1= 90 degrees and a maximum value with tau1= 0 degrees (the Z conformer), the value with tau1= 180 degrees (the E conformer) being between these two values, obviously due to steric hindrance. The effects of the phenyl substituents on the reactivity of the esters studied are discussed in terms of molecular orbital interactions. ED/EW substituents adjust the availability of the pi*C=O antibonding orbital to interact with the lone pair orbital of the attacking nucleophile and therefore affect the reactivity: EW substituents increase and ED substituents decrease it. Excellent correlations were observed between the rate coefficients of nucleophilic acyl substitutions and pi*C=O occupancies of the ester series 4 and 5.

Journal Article↗

Synthesis, characterisation and theoretical calculations of 2,6-diaminopurine etheno derivatives.

Four derivatives of 2,6-diaminopurine (1) were synthesised and characterised. When 1 was reacted with chloroacetaldehyde, 5-aminoimidazo[2,1-i]purine (2), 9-aminoimidazo[2,1-b]purine (3), 9-aminoimidazo[1,2-a]purine (4) and diimidazo[2,1-b:2',1'-i]purine (5) were formed. The purified products (3-5) were fully characterised by MS, complete NMR assignments as well as fluorescence and UV spectroscopy. The purified, isolated yields of these products (3-5) varied from 2.5 to 30%. The relative stability of different tautomers was investigated by theoretical calculations. Fluorescence characteristics are also discussed and compared to the starting material 1 and a reference molecule 2-aminopurine.

2-Aminopurine↗

TAp63alpha induces apoptosis by activating signaling via death receptors and mitochondria.

TP63, an important epithelial developmental gene, has significant homology to p53. Unlike p53, the expression of p63 is regulated by two different promoters resulting in proteins with opposite functions: the full-length transcriptionally active TAp63 and the dominant-negative DeltaNp63. We investigated the downstream mechanisms by which TAp63alpha elicits apoptosis. TAp63alpha directly transactivates the CD95 gene via the p53 binding site in the first intron resulting in upregulation of a functional CD95 death receptor. Stimulation and blocking experiments of the CD95, TNF-R and TRAIL-R death receptor systems revealed that TAp63alpha can trigger expression of each of these death receptors. Furthermore, our findings demonstrate a link between TAp63alpha and the mitochondrial apoptosis pathway. TAp63alpha upregulates expression of proapoptotic Bcl-2 family members like Bax and BCL2L11 and the expression of RAD9, DAP3 and APAF1. Of clinical relevance is the fact that TAp63alpha is induced by many chemotherapeutic drugs and that inhibiting TAp63 function leads to chemoresistance. Thus, beyond its importance in development and differentiation, we describe an important role for TAp63alpha in the induction of apoptosis and chemosensitivity.

Adaptor Proteins, Signal Transducing↗

Sarcoidosis is associated with a truncating splice site mutation in BTNL2.

Sarcoidosis is a polygenic immune disorder with predominant manifestation in the lung. Genome-wide linkage analysis previously indicated that the extended major histocompatibility locus on chromosome 6p was linked to susceptibility to sarcoidosis. Here, we carried out a systematic three-stage SNP scan of 16.4 Mb on chromosome 6p21 in as many as 947 independent cases of familial and sporadic sarcoidosis and found that a 15-kb segment of the gene butyrophilin-like 2 (BTNL2) was associated with the disease. The primary disease-associated variant (rs2076530; P(TDT) = 3 x 10(-6), P(case-control) = 1.1 x 10(-8); replication P(TDT) = 0.0018, P(case-control) = 1.8 x 10(-6)) represents a risk factor that is independent of variation in HLA-DRB1. BTNL2 is a member of the immunoglobulin superfamily and has been implicated as a costimulatory molecule involved in T-cell activation on the basis of its homology to B7-1. The G --> A transition constituting rs2076530 leads to the use of a cryptic splice site located 4 bp upstream of the affected wild-type donor site. Transcripts of the risk-associated allele have a premature stop in the spliced mRNA. The resulting protein lacks the C-terminal IgC domain and transmembrane helix, thereby disrupting the membrane localization of the protein, as shown in experiments using green fluorescent protein and V5 fusion proteins.

Bronchoalveolar Lavage↗

Interpretation of conformational effects on 2-endo-norborneol by natural chemical shielding analysis.

This paper represents an extension of our work on the (1)H and (13)C NMR chemical shifts of norbornane and 2-endo-norborneol. NCS-NBO analysis was employed to probe contributions of bond orbitals and orbitals of lone pairs to nuclear shielding in conformers of the alcohol generated by rotation of the C-O bond. Variations in (1)H and (13)C chemical shifts with the dihedral angle are discussed in terms of Lewis and non-Lewis partitioning and their respective importance is evaluated. In addition to hyperconjugation of the lone pair in a p orbital of oxygen that was previously reported, a sizable participation of the lone pair which is in an sp orbital is also observed and their combined effect dominates the carbon chemical shifts of the C(1)-C(2)-OH and C(3)-C(2)-OH fragments. Both lone pairs on oxygen also contribute to localized, though-space effects on nuclei in the vicinity, these effects answering for the largest deviations in hydrogen chemical shifts on rotation around the C-O bond. On the other hand, for conformers in which nonbonded repulsions lead to distortions in the molecular framework, variations in chemical shifts may be attributed to angular effects.

Journal Article↗

Cardiovascular anomalies in children and young adults with Ullrich-Turner syndrome the Erlangen experience.

BACKGROUND: Females with Ullrich-Turner syndrome (UTS) have typical clinical features such as short stature, ovarian failure, visible dysmorphic stigmata, and abnormalities in different organs such as kidney or heart. HYPOTHESIS: The aim of the present study was to analyze the distribution, prevalence, and relative risk of cardiovascular anomalies (CVA) in females with Ullrich-Turner syndrome (UTS) seen at one single center compared with that of the regional Bavarian population. METHODS: The associations between CVA and karyotype were determined. In all, 117 girls and women with UTS, aged between 3 and 43 years (median 17.4 years) were studied retrospectively. The detailed cardiologic status including echocardiography was available in all patients. The prevalences of each cardiovascular anomaly were determined. On the basis of published epidemiologic data of CVA in Bavarian children, we assessed the relative risks of each CVA. RESULTS: Thirty-five (29.9%) girls with UTS had at least one CVA. In all of these CVAs, coarctation of the aorta and bicuspid aortic valve occurred most often (18.5% each). The aortic malformations represented over two-thirds of all CVA (72.8%), whereas anomalies of the septum (8.6%), mitral valve (6.2%), pulmonary veins (4.9%), and other locations together accounted for the other third. Bicuspid aortic valve and partial anomalous pulmonary venous drainage were associated with the highest relative risk (RR) (3603 and 1293, respectively) compared with the Bavarian population. The overall RR of CVA was 48.7. Of the 117 girls and women examined, 64 (54.7%) had complete monosomy 45 X. CONCLUSIONS: Our data demonstrate that about every third female with UTS is affected with at least one CVA, mainly left sided and associated with aortic structures. Our results underline the necessity of thorough cardiologic evaluation.

Adolescent↗