Efficacy of prophylactic high-flow nasal cannula therapy for postoperative pulmonary complications after pediatric cardiac surgery: a prospective single-arm study.

PURPOSE: This study investigated the incidence of postoperative pulmonary complications (PPC) when high-flow nasal cannula therapy (HFNC) is used prophylactically after pediatric cardiac surgery, and evaluated its efficacy. METHODS: This was a single-arm prospective interventional study that was conducted in a tertiary teaching hospital with eight beds in the pediatric cardiac ICU after approval by the Ethics Committee. One-hundred children under the age of 48 months who were scheduled for cardiac surgery for congenital heart disease were recruited. HFNC was used for 24 h after extubation at a 2 L/kg/min flow rate. The primary outcome was the incidence of PPC within 48 h after extubation. PPC was defined as atelectasis and acute respiratory failure meeting certain criteria. We considered prophylactic HFNC as effective if the prevalence of PPC was < 10%, based on previous reports of reintubation rates of 6%-9% after pediatric cardiac surgery. RESULTS: A total of 91 patients were finally included in the analysis. The incidence of PPC within 48 h after extubation was 18.7%, whereas atelectasis was observed in 13.2%, and acute respiratory failure in 8.8%. Reintubation rate within 48 h after extubation was 0%. CONCLUSIONS: We found the incidence of PPC with prophylactic HFNC after planned extubation after pediatric cardiac surgery. However, the incidence was > 10%; therefore, we could not demonstrate its efficacy in this single-arm study. Further studies are needed to investigate whether the HFNC could be adapted as first-line oxygen therapy after pediatric cardiac surgery.

Facile Preparation of Peptides with C-Terminal N-Alkylamide via Radical-Initiated Dethiocarboxylation.

A new synthetic method has been developed to prepare peptides bearing a C-terminal N-alkylamide from peptide thioacids via a radical-initiated dethiocarboxylation process. This method enables the introduction of various alkyl groups to C-terminal amides simply by replacing the amino acid building block. Its application to the preparation of anti-cancer drug ABT-510 is also reported.

General Anesthesia With Remimazolam During Minimally Invasive Cardiac Surgery for Atrial Septal Defect: A Pediatric Case Report.

Remimazolam is a new ultrashort-acting benzodiazepine sedative, the use of which has not been reported for pediatric cardiac surgery. This case report describes the use of remimazolam in a 6-year-old girl who underwent minimally invasive cardiac surgery with right-sided thoracotomy for an atrial septal defect. Under electroencephalographic monitoring, remimazolam (2-4 mg kg-1 h-1) and remifentanil (0.05 µg kg-1 min-1) were administered with an intercostal nerve block during the procedure. The patient awoke and was extubated promptly after surgery, without any serious adverse events, including intraoperative awareness. Remimazolam may be a viable option for general anesthesia during pediatric cardiac surgery.

[Increase in serum vecuronium concentration following sugammadex administration in a pediatric patient after prolonged sedation].

It is known that blood concentration of rocuronium increases after administration of sugammadex, but this is not clear in the case of vecuronium. We report a pediatric case in which serum vecuronium concentration increased following sugammadex administration after prolonged sedation using vecuronium. A 19-month-old girl weighing 7.8 kg had a history of aortic valvuloplasty at 4 months of age due to truncus arteriosus. She presented again to our hospital due to aortic regurgitation. She underwent aortic valvuloplasty and then aortic valve replacement. The postoperative course was complicated with severe heart failure and acute kidney injury requiring peritoneal dialysis. For that reason she required long-term sedation including administration of a large amount of muscle relaxant due to severe low cardiac output syndrome after aortic valvuloplasty. A total of 615 mg (79 mg x kg(-1)) of vecuronium was administered over a period of 24 days. On weaning from mechanical ventilation, 125 mg (16 mg x kg(-1)) of sugammadex was given. Vecuronium concentration measured by high-performance liquid chromatography (HPLC) was 5.03 ng x ml(-1) before sugammadex administration and increase to 13.98 ng x ml(-1) after that. However, blood concentration of metabolic products of vecuronium did not exceed the lower limits of measurement in each sample. She was successfully weaned from mechanical ventilation without recurarizarion. Serum concentration of vecuronium increased after administration of sugammadex because extravascular vecuronium was redistributed to intravascular space according to the concentration gradient induced by binding and clathration of vecuronium. The measured values of vecuronium after sugammadex administration on HPLC represented the total amount of free vecuronium and vecuronium combined with sugammadex. Recurarization might occur after sugammadex reversal in patients after long-term administration of vecuronium, especially if relatively smaller doses of sugammadex were given. We experienced a pediatric case in which serum vecuronium concentration increased following sugammadex administration after prolonged sedation using vecuronium. There is a risk of recurarization after sugammadex reversal in patients after long-term administration of vecuronium.

Temporary hypotension and ventilation difficulty during endoscopic injection sclerotherapy for esophageal varices in a child with Fontan circulation: a case report.

BACKGROUND: Endoscopic procedures are rarely performed in children with congenital heart disease (CHD); therefore, the associated complications are unknown. We report an abrupt change in circulatory and respiratory condition during endoscopic injection sclerotherapy for esophageal varices. CASE PRESENTATION: A 9-year-old boy with a history of total anomalous pulmonary venous connection (TAPVC) repair and Fontan procedure for asplenia and a single ventricle with TAPVC underwent endoscopic injection sclerotherapy under general anesthesia for esophageal varices. Systolic blood pressure decreased from 70 to 50 mmHg following a sclerosant injection; a second injection reduced his peripheral oxygen saturation from 93 to 79% secondary to ventilation difficulty. Although we suspected anaphylaxis intraoperatively, postoperative imaging suggested that balloon dilation performed to prevent sclerosing agent leakage caused compression of the pulmonary venous chamber and trachea owing to the anomalous intrathoracic organ anatomy. CONCLUSION: Thorough understanding of the complex anatomy is important before performing endoscopic procedures in children with CHD to preoperatively anticipate possible intraoperative complications and select the optimal therapeutic approach and anesthesia management.

Intact survival from severe cardiogenic shock caused by the first attack of atrial tachycardia treated with extracorporeal membrane oxygenation and surgical left atrium appendage resection: a case report.

BACKGROUND: Atrial tachycardia (AT) is rare in children and can usually be reversed to sinus rhythm with pharmacotherapy and cardioversion. We report a rare case of severe left-sided heart failure due to refractory AT. CASE PRESENTATION: A 12-year-old boy had AT with a heart rate of 180 beats/minute, which was refractory to any medication and defibrillation despite the first attack. Due to rapid cardiorespiratory collapse shortly after arriving at our hospital, central extracorporeal membrane oxygenation (ECMO) with left arterial venting was started immediately. Although AT persisted after that, it stopped on the 3rd day after admission following surgical resection of the left atrial appendage thought to be the source of AT. He was weaned off ECMO on the 7th day and ventilator on the 14th day. CONCLUSIONS: The appropriate timing of central ECMO and surgical ablation were effective in saving this child from a life-threatening situation caused by refractory AT.

Preferential formation of (5S,6R)-thymine glycol for oligodeoxyribonucleotide synthesis and analysis of drug binding to thymine glycol-containing DNA.

We previously reported the chemical synthesis of oligonucleotides containing thymine glycol, a major form of oxidative DNA damage. In the preparation of the phosphoramidite building block, the predominant product of the osmium tetroxide oxidation of protected thymidine was (5R,6S)-thymidine glycol. To obtain the building block of the other isomer, (5S,6R)-thymidine glycol, in an amount sufficient for oligonucleotide synthesis, the Sharpless asymmetric dihydroxylation (AD) reaction was examined. Although the reaction was very slow, (5S,6R)-thymidine glycol was obtained in preference to the (5R,6S) isomer. The ratio of (5S,6R)- and (5R,6S)-thymidine glycols was 2:1, and a trans isomer was also formed. When an ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate, was used as a co-solvent, the reaction became faster, and the yield was improved without changing the preference. The phosphoramidite building block of (5S,6R)-thymidine glycol was prepared, and oligonucleotides containing 5S-thymine glycol were synthesized. One of the oligonucleotides was used to analyze the binding of distamycin A to thymine glycol-containing DNA by Circular dichroism (CD) spectroscopy and surface plasmon resonance (SPR) measurements. Distamycin A bound to a duplex containing either isomer of thymine glycol within the AATT target site, and its binding was observed even when the thymine glycol was placed opposite cytosine.

DNA alkylation by pyrrole-imidazole seco-CBI conjugates with an indole linker: sequence-specific DNA alkylation with 10-base-pair recognition through heterodimer formation.

The sequence-specific DNA alkylation by conjugates 4 and 5, which consist of N-methylpyrrole (Py)-N-methylimidazole (Im) polyamides and 1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (seco-CBI) linked with an indole linker, was investigated in the absence or presence of partner Py-Im polyamide 6. High-resolution denaturing polyacrylamide gel electrophoresis revealed that conjugate 4 alkylates DNA at the sequences 5'-(A/T)GCCTA-3' through hairpin formation, and alkylates 5'-GGAAAGAAAA-3' through an extended binding mode. However, in the presence of partner Py-Im polyamide 6, conjugate 4 alkylates DNA at a completely different sequence, 5'-AGGTTGTCCA-3'. Alkylation of 4 in the presence of 6 was effectively inhibited by a competitor 7. Surface plasmon resonance (SPR) results indicated that conjugate 4 does not bind to 5'-AGGTTGTCCA-3', whereas 6 binds tightly to this sequence. The results suggest that alkylation proceeds through heterodimer formation, indicating that this is a general way to expand the recognition sequence for DNA alkylation by Py-Im seco-CBI conjugates.

Human DNA polymerase N (POLN) is a low fidelity enzyme capable of error-free bypass of 5S-thymine glycol.

Human DNA polymerase N (POLN or pol nu) is the most recently discovered nuclear DNA polymerase in the human genome. It is an A-family DNA polymerase related to Escherichia coli pol I, human POLQ, and Drosophila Mus308. We report the first purification of the recombinant enzyme and examination of its biochemical properties, as a step toward understanding the functions of POLN. Unusual for an A-family DNA polymerase, POLN is a low fidelity enzyme incorporating T opposite template G with a frequency of 0.45 and G opposite template T with a frequency of 0.021. The frequency of misincorporation of T opposite template G is higher than any other known DNA polymerase. POLN has a processivity of DNA synthesis (1-100 nucleotides) similar to the exonuclease-deficient Klenow fragment of E. coli pol I, is inhibited by dideoxynucleotides, and resistant to aphidicolin. The strand displacement activity of POLN was higher than exonuclease-deficient Klenow fragment. Furthermore, POLN can perform translesion synthesis past thymine glycol, a common endogenous and radiation-induced product of reactive oxygen species damage to DNA. Thymine glycol blocks DNA synthesis by most DNA polymerases, but POLN was particularly adept at efficient and accurate translesion synthesis past a 5S-thymine glycol.

Sequence-specific alkylation of double-strand human telomere repeat sequence by pyrrole-imidazole polyamides with indole linkers.

We designed and synthesized pyrrole (Py)-imidazole (Im) hairpin polyamide 1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (seco-CBI) conjugates 1 and 2, which target both strands of the double-stranded region of the human telomere repeat sequences, 5'-d(TTAGGG)(n)-3'/5'-d(CCCTAA)(n)-3'. High-resolution denaturing polyacrylamide gel electrophoresis demonstrated that conjugates 1 and 2 alkylated DNA at the 3' A of 5'-ACCCTA-3' and 5'-AGGGTTA-3', respectively. Cytotoxicities of conjugates 1 and 2 were evaluated using 39 human cancer cell lines; averages of log IC(50) values for conjugates 1 and 2 were -6.96 (110 nM) and -7.24 (57.5 nM), respectively. Conjugates 1 and 2 have potential as antitumor drugs capable of targeting telomere repeat sequence.

The biological impact of sequence-specific DNA alkylation by pyrrole-imidazole polyamides.

We have developed a series of novel DNA alkylating polyamides possessing indole linkers. Investigations using high-resolution gel electrophoresis revealed that the indole linked Py-Im polyamide alkylated at A of a targeted nine base pair matching sequence. Evaluation in human cancer cell lines revealed that the indole linked Py-Im polyamides have strong cytotoxicities. Furthermore, we showed that alkylation of the template strand of the coding region by these polyamides causes effective gene silencing.

Synthesis and evaluation of sequence-specific DNA alkylating agents: effect of alkylation subunits.

We have demonstrated that hairpin pyrrole (Py)- imidazole (Im) polyamide-CBI conjugates selectively alkylate predetermined sequences. In this study, we investigated the effect of alkylation subunits, for example conjugates 1-4 with three types of DNA alkylating units, and Py-Im polyamides with indole linker. Conjugate 3 and 4 selectively alkylated the predetermined sequences as described previously, while conjugates 1 and 2 alkylate at mismatched sites.

Molecular design of DNA alkylating pyrrole-imidazole polyamides with longer recognition sequence.

The sequence-specificity, and DNA alkylating activity of the conjugate 1, which consists of N-methylpyrrole (Py)-N-methylimidazole (Im) polyamides, 1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (seco-CBI) with indole linker, were investigated in the absence or presence of partner Py-Im polyamide 2. High-resolution denaturing polyacrylamide gel electrophoresis showed that the specificity of DNA alkylation by 1 modulated in the presence of partner 2. We found that sequence-specific DNA alkylation by 1 and 2 with 10 base pair (bp) match recognition sequence through heterodimer formation. This result indicates one possibility of DNA alkylation with longer recognition sequence by different two molecules.