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Detection of alpha II-spectrin breakdown products in the serum of neonates with congenital heart disease*.

ABSTRACT: To determine if alpha II-spectrin breakdown products can be detected in the serum of neonates with congenital heart disease in the perioperative period.Prospective observational cohort study.Pediatric cardiac ICU in an urban tertiary care academic center.Neonates with congenital heart disease undergoing surgical repair or palliation.Serial blood sampling for measurement of 120 and 150 kDa spectrin breakdown products.Fourteen neonates with congenital heart disease undergoing cardiac surgery were evaluated. Nine infants underwent open-heart surgery and five underwent closed-heart surgery. Serum spectrin breakdown products were measured with sandwich enzyme-linked immunosorbent assay preoperatively and then 6, 24, 48, 72, and 96 hours following surgery. Brain imaging was obtained as part of routine clinical care in 12 patients preoperatively and six patients postoperatively. Six patients had normal preoperative imaging (three closed-heart surgery and three open-heart surgery), whereas six had evidence of neurologic injury prior to surgery (one closed-heart surgery and five open-heart surgery). Only one patient had a postoperative imaging study that lacked injury. All others demonstrated infarction or hemorrhage. Spectrin breakdown product 120 kDa significantly increased 24 hours after open-heart surgery compared to preoperative values and time-matched closed-heart surgery levels. Spectrin breakdown product 150 kDa significantly increased 6 hours after open-heart surgery compared to preoperative values. There was no significant change in spectrin breakdown products following closed-heart surgery. Peak spectrin breakdown products significantly increased following open-heart surgery compared to closed-heart surgery.Spectrin breakdown products can be detected in the serum of neonates with congenital heart disease in the perioperative period and levels increased to a greater degree in infants following open-heart surgery. These findings suggest that, in future work, serum spectrin breakdown products may potentially be developed as biomarkers for brain necrosis and apoptosis in infants with congenital heart disease.

SUBMITTER: Jain P

PROVIDER: S-EPMC4059536 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Detection of alpha II-spectrin breakdown products in the serum of neonates with congenital heart disease*.

Jain Parag P Spaeder Michael C MC Donofrio Mary T MT Sinha Pranava P Jonas Richard A RA Levy Richard J RJ

Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies 20140301 3

<h4>Objectives</h4>To determine if alpha II-spectrin breakdown products can be detected in the serum of neonates with congenital heart disease in the perioperative period.<h4>Design</h4>Prospective observational cohort study.<h4>Setting</h4>Pediatric cardiac ICU in an urban tertiary care academic center.<h4>Patients</h4>Neonates with congenital heart disease undergoing surgical repair or palliation.<h4>Interventions</h4>Serial blood sampling for measurement of 120 and 150 kDa spectrin breakdown ...[more]

PMID: 24395002

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Project description:Spectrin is a large, flexible protein that stabilizes membranes and organizes proteins and lipids into microdomains in intracellular organelles and at the plasma membrane. Alternative splicing occurs in spectrins, but it is not yet clear if these small variations in structure alter spectrin's functions. Three alternative splice sites have been identified previously for alpha II-spectrin. Here we describe a new alternative splice site, a 21-amino acid sequence in the 21st spectrin repeat that is only expressed in significant amounts in cardiac muscle (GenBank GQ502182). The insert, which we term alpha II-cardi+, results in an insertion within the high affinity nucleation site for binding of alpha-spectrins to beta-spectrins. To assess the developmental regulation of the alpha II-cardi+ isoform, we used qRT-PCR and quantitative immunoblotting methods to measure the levels of this form and the alpha II-cardi- form in the cardiac muscles of rats, from embryonic day 16 (E16) through adulthood. The alpha II-cardi+ isoform constituted approximately 26% of the total alpha II-spectrin in E16 hearts but decreased to approximately 6% of the total after 3 weeks of age. We used long-range RT-PCR and Southern blot hybridization to examine possible linkage of the alpha II-cardi+ alternatively spliced sequence with alternatively spliced sequences of alpha II-spectrin that had been previously reported. We identified two new isoforms of alpha II-spectrin containing the cardi+ insert. These were named alpha II Sigma 9 and alpha II Sigma 10 in accordance with the spectrin naming conventions. In vitro studies of recombinant alpha II-spectrin polypeptides representing the two splice variants of alpha II-spectrin, alpha II-cardi+ and alpha II-cardi-, revealed that the alpha II-cardi+ subunit has lower affinity for the complementary site in repeats 1-4 of betaII-spectrin, with a K(D) value of approximately 1 nM, as measured by surface plasmon resonance (SPR). In addition, the alpha II-cardi+ form showed 1.8-fold lower levels of binding to its site on beta II-spectrin than the alpha II-cardi- form, both by SPR and blot overlay. This suggests that the 21-amino acid insert prevented some of the alpha II-cardi+ form from interacting with beta II-spectrin. Fusion proteins expressing the alpha II-cardi+ sequence within the two terminal spectrin repeats of alpha II-spectrin were insoluble in solution and aggregated in neonatal myocytes, consistent with the possibility that this insert removes a significant portion of the protein from the population that can bind beta subunits. Neonatal rat cardiomyocytes infected with adenovirus encoding GFP-fusion proteins of repeats 18-21 of alpha II-spectrin with the cardi+ insert formed many new processes. These processes were only rarely seen in myocytes expressing the fusion protein lacking the insert or in controls expressing only GFP. Our results suggest that the embryonic mammalian heart expresses a significant amount of alpha II-spectrin with a reduced avidity for beta-spectrin and the ability to promote myocyte growth.

Project description:ObjectivesTo develop a population pharmacokinetic model for IV phenobarbital in neonates following cardiac surgery and perform simulations to identify optimal dosing regimens.DesignRetrospective single-center pharmacokinetic study.SettingCardiac ICU at Children's Hospital of Philadelphia.PatientsConsecutive neonates who received greater than or equal to one dose of IV phenobarbital and had greater than or equal to one phenobarbital concentration drawn per standard of care from June 15, 2012, to October 15, 2018.InterventionsNone.Measurements and main resultsA population pharmacokinetic model was developed using nonlinear mixed-effects modeling. Simulations were performed using the final model variables. Optimal phenobarbital loading doses were determined based on attainment of peak and maintenance concentrations between 20 and 40 mg/L. A total of 37 neonates contributed 159 pharmacokinetic samples. The median (range) weight, postmenstrual age, and postnatal age were 3.2 kg (1.3-3.8), 39 2/7 weeks (28 2/7 to 42 6/7), and 5 days (0-26 d), respectively. Twelve patients (32%) were on extracorporeal membrane oxygenation. An one-compartment model best described the data. The final population pharmacokinetic model included (1) weight and postnatal age for clearance and (2) weight, extracorporeal membrane oxygenation, and albumin for volume of distribution. In neonates not on extracorporeal membrane oxygenation, loading doses of 30 and 20 mg/kg reached goal concentration with albumin values less than or equal to 3 and 3.5 mg/dL, respectively. Loading doses of 30 mg/kg reached goal concentration on extracorporeal membrane oxygenation regardless of albumin values. Maintenance doses of 4-5 mg/kg/d reached goal concentration in all neonates.ConclusionsIn neonates following cardiac surgery, phenobarbital clearance increased with postnatal age. Volume of distribution increased with extracorporeal membrane oxygenation and lower albumin values. Loading doses of 30 mg/kg on extracorporeal membrane oxygenation and 20-30 mg/kg without extracorporeal membrane oxygenation were needed to reach goal concentration based on simulations.

Project description:Vocal fold motion impairment (VFMI) is a known risk factor following congenital heart surgery (CHS). The impact of this diagnosis on utilization and outcomes is unknown.To evaluate the cost, postprocedure length of stay (PPLOS), and outcomes for neonates with VFMI after CHS.A cross-sectional analysis of the 2012 Kids' Inpatient Database (KID) of neonates who underwent CHS was carried out. The KID is an administrative data set of patients, aged 20 years or younger, and contains data on more than 10 million hospitalizations from 44 states. The KID is limited to inpatient hospitalization and contains discharge summary level of data. Patients were limited to those who were born during the hospitalization and those who were aged 28 days or younger at the time of admission for CHS. A weighted total of 4139 neonates who underwent CHS were identified, of which 3725 survived. The proportion of neonates diagnosed with VFMI was 264 (6.92%) of 3725.Congenital heart surgery.Cost of inpatient hospital stay, postprocedure length of stay, odds of pneumonia, gastrostomy tube placement, and tracheostomy tube placement. Risk-adjusted generalized linear models examined differences in cost and PPLOS between neonates who underwent CHS and were diagnosed with VFMI and those who were not. Risk-adjusted logistic regression compared the odds of selected outcomes (gastrostomy, tracheostomy, pneumonia). Models were weighted to provide national estimates.Of 3725 neonates (aged 0-28 days), 2203 (59.1%) were male and 1517 (40.7%) were female. Neonates diagnosed with VFMI had significantly higher total cost by $34 000 (95% CI, 2200-65 000) and PPLOS by 9.1 days (95% CI, 4.6-13.7) compared with those who did not. When PPLOS was included as a covariate in the model for cost, presence of VFMI was no longer significant. There were no differences in odds of pneumonia, gastrostomy, or tracheostomy.Vocal fold motion impairment after CHS was associated with significant increases in cost owing to increased PPLOS. These findings provide a foundation to further investigate standardized screening for VFMI following CHS; early identification and treatment may decrease cost and PPLOS.

Dataset Information

Detection of alpha II-spectrin breakdown products in the serum of neonates with congenital heart disease*.

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Detection of alpha II-spectrin breakdown products in the serum of neonates with congenital heart disease*.

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