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The embryonic extracellular matrix (ECM) undergoes transition to mature ECM as development progresses, yet specific transition mechanisms ensuring ECM proteostasis and their regulatory impact are poorly defined. Fibrillin microfibrils are macromolecular ECM complexes serving structural and regulatory roles. In mice, Fbn1 and Fbn2, encoding major microfibrillar components, are strongly expressed during embryogenesis, but fibrillin-1 is the major component observed in adult tissue microfibrils. Here, analysis of mouse Adamts6 and Adamts10 mutant embryos, lacking these homologous secreted metalloproteases individually and in combination, along with in vitro analysis of microfibrils, measurement of ADAMTS6-fibrillin affinities and N-terminomics identification of ADAMTS6-cleaved sites, demonstrates a transcriptionally adapted system for fibrillin-2 proteolysis that contributes to postnatal fibrillin-1 dominance. The lack of ADAMTS6, alone and in combination with ADAMTS10 led to excess fibrillin-2 in perichondrium, with impaired skeletal development resulting from a drastic reduction of aggrecan, cartilage link protein and impaired BMP, but not TGFβ signaling in cartilage. Although ADAMTS6 cleaves fibrillin-1 and fibrillin-2 as well as fibronectin, which provides the initial scaffold for microfibril assembly, primacy of the protease-substrate relationship between ADAMTS6 and fibrillin-2 was unequivocally established by reversal of these defects in Adamts6-/- embryos by genetic reduction of Fbn2, but not Fbn1.

Motivated by problems in comparative genomics and paleogenomics, we study the computational complexity of the Gapped Consecutive-Ones Property ((k,δ)-C1P) Problem: given a binary matrix M and two integers k and δ, decide if the columns of M can be permuted such that each row contains at most k blocks of ones and no two neighboring blocks of ones are separated by a gap of more than δ zeros. The classical C1P decision problem, which is known to be polynomial-time solvable is equivalent to the (1,0)-C1P problem. We extend our earlier results on this problem [C. Chauve, J. Mauch, M. Patterson, On the gapped consecutive-ones property, in: Proceedings of the European Conference on Combinatorics, Graphs Theory and Applications (EuroComb), in: Electronic Notes in Discrete Mathematics, vol. 34, 2009, pp. 121-125] to show that for every k

Systemic local anesthetic (LA) toxicity resulting from inadvertent intravascular injection of LA is a rare but potentially fatal event. Early recognition of intravascular injection and approaches to improve therapeutic safety are required. This study investigated the influence of intravascular injection dose rate of bupivacaine on bupivacaine plasma levels and timing of LA-induced cardiovascular compromise. Forty-five piglets, anesthetized with sevoflurane, were randomized into three groups. Bupivacaine was intravenously infused at a rate of 1, 4, or 16 mg/kg/min (groups A, B, and C, respectively) until mean arterial pressure (MAP) dropped to 50% of initial value. Thereafter, bupivacaine infusion was stopped and spontaneous hemodynamic course was observed. Time to MAP 50%, amount of bupivacaine infused, bupivacaine plasma level at infusion stop, spontaneous survivors, or time from bupivacaine stop to circulatory arrest were recorded. Median time to MAP 50% was 297, 119, and 65 s, respectively, in groups A, B, and C (P

Background Origin of electrocardiographic (ECG) alterations during intravascular injection of local anaesthetic solutions is controversial. The aim of this study was to elucidate whether epinephrine, bupivacaine or their combination is responsible for ECG alteration. Methods Forty-five piglets were randomized into three groups. After induction of general anaesthesia using sevoflurane and peripheral venous cannulation, the trachea was intubated, the lungs were artificially ventilated, and anaesthesia was maintained by sevoflurane. Under steady state 0.2 ml kg −1 and after 10 min 0.4 ml kg −1 of one of the following three test solutions was administered i.v.: bupivacaine 0.125% (Group 1), bupivacaine 0.125%+epinephrine 1:200 000 (Group 2), and plain epinephrine 1:200 000 (Group 3). The ECG was analysed for alterations in heart rate and T-elevation. Results After injection of 0.2 or 0.4 ml kg −1 test solution, an increase in heart rate of at least 10% was found in none of Group 1 and in all of Groups 2 and 3. After application of 0.2 ml kg −1 test solution, T-elevation was found in 7% of Group 1 and in 93% of Groups 2 and 3. The injection of 0.4 ml kg −1 revealed a T-elevation in 27%, 100%, and 100%, respectively, in Groups 1, 2, and 3. Conclusions This animal model demonstrated that increases in heart rate and T-elevation in the ECG during i.v. application of a common test dose (0.2 ml kg −1 ) of bupivacaine are caused by epinephrine addition. Whether higher doses of bupivacaine alone can cause similar ECG changes or not requires further studies.

Background It is controversial as to whether T-wave elevation is caused by local anaesthetics, epinephrine, or their combination. It has been shown that T-elevation after intravascular injection of a small bupivacaine test dose is caused by epinephrine and not by bupivacaine. The aim of this study was to investigate ECG changes with higher doses of i.v. bupivacaine. Methods Thirty neonatal pigs were anaesthetized with sevoflurane and their tracheas intubated and artificially ventilated. Under steady-state conditions, bupivacaine was continuously infused (flow rate 3.2 ml kg−1 min−1) by a syringe infusion pump through a central venous catheter. Group 1 received bupivacaine 0.125%, Group 2 bupivacaine 0.5%. The ECG was continuously printed and subsequently analysed for alterations in heart rate, ventricular de- and repolarization, and arrhythmias at 1.25, 2.5, and 5 mg kg−1 bupivacaine infused. Results Sinus rhythm persisted in all pigs. Heart rate decreased progressively in both groups, but this was significantly more pronounced in Group 1. T-wave elevation occurred in 40% and 0% (Groups 1 and 2) at 1.25 mg kg−1, in 80% and 0% at 2.5 mg kg−1, and in 93% and 80% at 5 mg kg−1 bupivacaine infused. There were significant differences between the two groups at 1.25 and 2.5 mg kg−1 infused. Conclusions Higher doses of i.v. infused bupivacaine can cause T-elevation. With slower injection technique, T-elevation can already be detected at lower bupivacaine doses administered.