Prophylactic effect of angiotensin receptor blockers in children with genetic aortopathies: the early bird catches the worm.

AIMS: In genetic aortopathies (GA) particular attention is paid to aortic root dilatation which has an impact on morbidity and mortality. This study focuses on the effects of therapy with angiotensin-II-receptor-blockers (ARB) or beta-blockers (BB) on aortic root growth and the question which therapy should be initiated at which dosage and at what age. METHODS: Since 1998 we diagnosed 208 patients with GA (170 FBN-1). 81 patients between 5 months and 18 years receiving either ARB or BB therapy were included. We retrospectively analyzed the progression of the dilatation of Sinus Valsalva aortae (SV) using calculated z-scores before and after therapy initiation and compared BB and ARB treatment. RESULTS: Both ARB and BB (p < 0.05) therapy showed significant improvement in aortic root growth, while the effect is significantly more pronounced in ARB (p < 0.01) independent of age and genetic cause. A detailed comparison of the two drug groups showed a more sustained effect in limiting the progression of the dilatation of the aortic root in patients treated with ARB. Progression of dilatation of the SV was significantly lower in children treated with ARBs compared to BB (delta z-score, p < 0.05). In addition, ARBs were better tolerated and had a significantly lower discontinuation rate (3%) compared to BB (50%) (p < 0.01). Independently of age at initiation all children and adolescents were able to reach the target dose under ARB. CONCLUSION: We demonstrated a significant change in both treatment options, with the effect of ARB being more pronounced while being better tolerated throughout the treatment period.

Qualification of the Low-pressure Cold Gas Spraying for the Additive Manufacturing of Copper-Nickel-Diamond Grinding Wheels.

Grinding wheels are usually manufactured by powder metallurgical processes, i.e., by molding and sintering. Since this requires the production of special molds and the sintering is typically carried out in a continuous furnace, this process is time-consuming and cost-intensive. Therefore, it is only worthwhile for medium and large batches. Another influencing factor of the powder metallurgical process route is the high thermal load during the sintering process. Due to their high thermal sensitivity, superabrasives such as diamond or cubic boron nitride are very difficult to process in this way. In this study, a novel and innovative approach is presented, in which superabrasive grinding wheels are manufactured by thermal spraying. For this purpose, flat samples as well as grinding wheel bodies were coated by low-pressure (LP) cold gas spraying with a blend of a commercial Cu-Al2O3 cold gas spraying powder and nickel-coated diamonds. The coatings were examined metallographically in terms of their composition. A well-embedded superabrasive content of 12 % was achieved. After the spraying process, the grinding wheels were conditioned and tested for the grinding application of cemented carbides and the topographies of both the grinding wheel and the cemented carbide were evaluated. Surface qualities of the ground surface that are comparable to those of other finishing processes were reached. This novel process route offers great flexibility in the combination of binder and hard material as well as a cost-effective single-part and small-batch production.

Alveolar capillary dysplasia with left heart obstruction - rare but lethal.

Alveolar capillary dysplasia (ACD) is a rare neonatal lung disease characterized anatomically by a defective and hypoplastic development of pulmonary alveoli leading to persistent pulmonary hypertension (PPHN) and finally lethal respiratory failure. It is often associated with congenital left heart obstruction. Given the fatal prognosis an early diagnosis is important. However, due to the fast onset of PPHN in neonates and lack of pathognomonic signs for its cause, safe and fast detection of ACD is challenging. Therefore, following the exclusion of cardiac and common pulmonary causes, lung biopsy becomes essential for diagnosis.We hereby report a case of ACD with atrial septal defect type one and hypoplastic aortic arch with an ante-mortem diagnosis and discuss the current state of medicine in relation to ACD.

Enhanced Ca²+ influx through cardiac L-type Ca²+ channels maintains the systolic Ca²+ transient in early cardiac atrophy induced by mechanical unloading.

Cardiac atrophy as a consequence of mechanical unloading develops following exposure to microgravity or prolonged bed rest. It also plays a central role in the reverse remodelling induced by left ventricular unloading in patients with heart failure. Surprisingly, the intracellular Ca(2+) transients which are pivotal to electromechanical coupling and to cardiac plasticity were repeatedly found to remain unaffected in early cardiac atrophy. To elucidate the mechanisms underlying the preservation of the Ca(2+) transients, we investigated Ca(2+) cycling in cardiomyocytes from mechanically unloaded (heterotopic abdominal heart transplantation) and control (orthotopic) hearts in syngeneic Lewis rats. Following 2 weeks of unloading, sarcoplasmic reticulum (SR) Ca(2+) content was reduced by ~55 %. Atrophic cardiac myocytes also showed a much lower frequency of spontaneous diastolic Ca(2+) sparks and a diminished systolic Ca(2+) release, even though the expression of ryanodine receptors was increased by ~30 %. In contrast, current clamp recordings revealed prolonged action potentials in endocardial as well as epicardial myocytes which were associated with a two to fourfold higher sarcolemmal Ca(2+) influx under action potential clamp. In addition, Cav1.2 subunits which form the pore of L-type Ca(2+) channels (LTCC) were upregulated in atrophic myocardium. These data suggest that in early cardiac atrophy induced by mechanical unloading, an augmented sarcolemmal Ca(2+) influx through LTCC fully compensates for a reduced systolic SR Ca(2+) release to preserve the Ca(2+) transient. This interplay involves an electrophysiological remodelling as well as changes in the expression of cardiac ion channels.

[Peripartum cardiomyopathy: interdisciplinary challenge]. / Peripartale Kardiomyopathie: Interdisziplinäre Herausforderung.

Peripartum cardiomyopathy (PPCM) is a rare type of heart failure which presents towards the end of pregnancy or in the first 5 months after delivery. Depending on the geographical location the incidence is reported in the literature as 1:300 up to 1:15,000. There are a number of known risk factors, such as multiparity and age of the mother over 30 years. The symptoms of PPCM correspond to those of idiopathic cardiomyopathy. The diagnosis is mainly carried out using echocardiography which shows a clear reduction of systolic left ventricular function. The therapeutic approach is the same as for idiopathic cardiomyopathy and in this context it is absolutely necessary to show caution concerning the state of pregnancy and the resulting contraindications for therapeutic drugs. The prognosis is dependent on recovery from the heart failure during the first 6 months postpartum. The lethality of the disease is high and is given in the literature as up to 28 %. Because of its complexity PPCM is an interdisciplinary challenge. In the peripartum phase a close cooperation between the disciplines of cardiology, cardiac surgery, neonatology, obstetrics and anesthesiology is indispensable. For anesthesiology the most important aspects are the mostly advanced unstable hemodynamic condition of the mother and the planning and implementation of the perioperative management. This article presents the case of a patient in advanced pregnancy with signs of acute severe heart failure and a suspected diagnosis of PPCM. The patient presented as an emergency case and delivery of the child was carried out using peridural anesthesia with a stand-by life support machine.

Multi-targeted antifolates aimed at avoiding drug resistance form covalent closed inhibitory complexes with human and Escherichia coli thymidylate synthases.

Crystal structures of four pyrrolo(2,3-d)pyrimidine-based antifolate compounds, developed as inhibitors of thymidylate synthase (TS) in a strategy to circumvent drug-resistance, have been determined in complexes with their in vivo target, human thymidylate synthase, and with the structurally best-characterized Escherichia coli enzyme, to resolutions of 2.2-3.0 A. The 2.9 A crystal structure of a complex of human TS with one of the inhibitors, the multi-targeted antifolate LY231514, demonstrates that this compound induces a "closed" enzyme conformation and leads to formation of a covalent bond between enzyme and substrate. This structure is one of the first liganded human TS structures, and its solution was aided by mutation to facilitate crystallization. Structures of three other pyrrolo(2,3-d)pyrimidine-based antifolates in complex with Escherichia coli TS confirm the orientation of this class of inhibitors in the active site. Specific interactions between the polyglutamyl moiety and a positively charged groove on the enzyme surface explain the marked increase in affinity of the pyrrolo(2,3-d)pyrimidine inhibitors once they are polyglutamylated, as mediated in vivo by the cellular enzyme folyl polyglutamate synthetase.

D221 in thymidylate synthase controls conformation change, and thereby opening of the imidazolidine.

In thymidylate synthase (TS), the invariant residue Asp-221 provides the only side chain that hydrogen bonds to the pterin ring of the cofactor, 5,10-methylene-5,6,7,8-tetrahydrofolate. All mutants of D221 except cysteine abolish activity. We have determined the crystal structures of two ternary complexes of the Escherichia coli mutant D221N. In a complex with dUMP and the antifolate 10-propargyl-5,8-dideazafolate (CB3717), dUMP is covalently bound to the active site cysteine, as usual. CB3717, which has no imidazolidine ring, is also bound in the usual productive orientation, but is less ordered than in wild-type complexes. The side chain of Asn-221 still hydrogen bonds to N3 of the quinazoline ring of CB3717, which must be in the enol form. In contrast, the structure of D221N with 5-fluoro-dUMP and 5,10-methylene-5,6,7, 8-tetrahydrofolate shows the cofactor bound in two partially occupied, nonproductive binding sites. In both binding modes, the cofactor has a closed imidazolidine ring and adopts the solution conformation of the unbound cofactor. In one of the binding sites, the pterin ring is turned around such that Asn-221 hydrogen bonds to the unprotonated N1 instead of the protonated N3 of the cofactor. This orientation blocks the conformational change required for forming covalent ternary complexes. Taken together, the two crystal structures suggest that the hydrogen bond between the side chain of Asp-221 and N3 of the cofactor is most critical during the early steps of cofactor binding, where it enforces the correct orientation of the pterin ring. Proper orientation of the cofactor appears to be a prerequisite for opening the imidazolidine ring prior to formation of the covalent steady-state intermediate in catalysis.