SPECC1L regulates palate development downstream of IRF6.

SPECC1L mutations have been identified in patients with rare atypical orofacial clefts and with syndromic cleft lip and/or palate (CL/P). These mutations cluster in the second coiled-coil and calponin homology domains of SPECC1L and severely affect the ability of SPECC1L to associate with microtubules. We previously showed that gene-trap knockout of Specc1l in mouse results in early embryonic lethality. We now present a truncation mutant mouse allele, Specc1lΔC510, that results in perinatal lethality. Specc1lΔC510/ΔC510 homozygotes showed abnormal palate rugae but did not show cleft palate. However, when crossed with a gene-trap allele, Specc1lcGT/ΔC510 compound heterozygotes showed a palate elevation delay with incompletely penetrant cleft palate. Specc1lcGT/ΔC510 embryos exhibit transient oral epithelial adhesions at E13.5, which may delay shelf elevation. Consistent with oral adhesions, we show periderm layer abnormalities, including ectopic apical expression of adherens junction markers, similar to Irf6 hypomorphic mutants and Arhgap29 heterozygotes. Indeed, SPECC1L expression is drastically reduced in Irf6 mutant palatal shelves. Finally, we wanted to determine if SPECC1L deficiency also contributed to non-syndromic (ns) CL/P. We sequenced 62 Caucasian, 89 Filipino, 90 Ethiopian, 90 Nigerian and 95 Japanese patients with nsCL/P and identified three rare coding variants (p.Ala86Thr, p.Met91Iso and p.Arg546Gln) in six individuals. These variants reside outside of SPECC1L coiled-coil domains and result in milder functional defects than variants associated with syndromic clefting. Together, our data indicate that palate elevation is sensitive to deficiency of SPECC1L dosage and function and that SPECC1L cytoskeletal protein functions downstream of IRF6 in palatogenesis.

Reducing radiation exposure by lowering frame rate in children undergoing cardiac catheterization: A quality improvement study.

INTRODUCTION: Reduction of radiation dosage in the pediatric cardiac catheterization laboratory (PCL) is important to reduce the risk of its stochastic effect in children with congenital heart disease. Lowering the frame rate would reduce radiation dosage possibly at the expense of image quality, potentially resulting in higher fluoroscopic time and procedural complication rate. METHODS: The data were retrospectively analyzed in three eras: era 1 (n = 234), cineangiography 30 frames/sec (f/s) and fluoroscopy 15 pulse/sec (p/s); era 2 (n = 381), cineangiography 30 f/s and fluoroscopy 6 p/s; and era 3 (n = 328), cineangiography 15 f/s and fluoroscopy 6 p/s. Also, three operators blinded to the frame rate setting evaluated cineangiography image quality. In this study, the impact of lowering the default frame rates on radiation dosage, fluoroscopic time, contrast volume, diagnostic image quality, and complication rates in the PCL was assessed. RESULTS: Overall radiation dosage progressively declined during these eras (70.0 vs 64.1 vs 36.6 µGym2 /kg, P < .001) without a difference in significant adverse event rates. There was no significant increase in either fluoroscopy time or contrast volume. There was no difference in the diagnostic image quality between cineangiography 30 and 15 f/s. Lowering the default frame/pulse rates of both fluoroscopy and cineangiography significantly decreased the overall radiation dosage in the PCL. Importantly, fluoroscopy time, contrast volume, and complication rates did not increase while maintaining diagnostic image quality. CONCLUSION: This quality improvement project proved successful in lowering radiation dosage without compromising the efficacy and safety of catheterizations.

Cardiovascular disease in survivors of childhood cancer.

PURPOSE OF REVIEW: We review the cardiotoxic chemotherapeutic agents, the clinical and subclinical presentations and progression of their cardiotoxicity, and the management of the subsequent cardiovascular disease in survivors of childhood cancer. We discuss various preventive measures, especially the cardioprotectant, dexrazoxane, whose use with anthracycline chemotherapy, including doxorubicin, is based on strong evidence. Most treatment recommendations for this unique population are based on expert opinion, not on empirical evidence. RECENT FINDINGS: As patients with childhood cancers live longer, morbidity from the cardiac side effects of chemotherapy is increasing. Treatment-related cardiac damage is irreversible and often progressive. It is imperative that such damage be prevented with strategies such as limiting the cumulative anthracycline dose, the use of anthracycline structural analogues and the use of cardioprotective agents. SUMMARY: A deeper understanding of the mechanisms of their cardiotoxicity reveals that there is no 'safe' dose of anthracyclines. However, certain risk factors, such as higher lifetime anthracycline cumulative doses, higher anthracycline dose rates, female sex, longer follow-up, younger age at anthracycline treatment and cardiac irradiation, are associated with more severe cardiotoxicity. We advocate the use of dexrazoxane to limit the cardiotoxic effects of anthracycline chemotherapy.

Successful treatment of fulminant neonatal enteroviral myocarditis in monochorionic diamniotic twins with cardiopulmonary support, intravenous immunoglobulin and pocapavir.

Neonatal cardiogenic shock most commonly occurs due to critical congenital heart disease, sepsis, metabolic disorder or arrhythmias. In particular, enterovirus infections are common in the neonatal period, and patients can present with fulminant myocarditis. Early recognition is imperative due to its high morbidity and mortality without prompt and aggressive treatment. We present the successful treatment of fulminant neonatal enteroviral myocarditis in a pair of monochorionic diamniotic twins with cardiopulmonary support, intravenous immunoglobulin and pocapavir, an enteroviral capsid inhibitor. The twins took an almost exact parallel hospital course, including day of extracorporeal membrane oxygenation (ECMO) cannulation, day of ECMO decannulation, improvement of cardiac function, discharge and status at follow-up. While it was difficult to assess the relative contribution of each intervention, our case shows promise in the use of pocapavir for treatment of severe enteroviral infections. Remarkably, both twins demonstrated remarkable recovery within 2 weeks, underscoring that early aggressive cardiopulmonary support, and potentially pocapavir, contributed to their recovery.

Outcome of pediatric heart transplantation in blood culture positive donors in the United States.

Active donor infection at the time of organ procurement poses a potential infection risk and may increase post-transplant morbidity and mortality in recipients. Our hypothesis was that pediatric heart transplant recipients from blood culture positive donors (BCPD) would have increased morbidity and mortality compared to non-blood culture positive donors (NBCPD). A retrospective analysis of pediatric heart transplant recipients using the organ procurement and transplant network (OPTN) between 1987 and 2015 was conducted. Recipient as well as donor data were analyzed. Propensity score matching with 1:2 ratios was performed for recipient variables. Post-transplant morbidity and mortality were compared for recipients of BCPD and NBCPD. Among 9618 heart transplant recipients, 450 (4.7%) were from culture positive donors. Recipients of BCPD had longer duration of listing as Status 1; diagnosis of congenital heart disease or restrictive cardiomyopathy and required support (IV inotropes, Inhaled NO and LVAD) prior to transplant. Post-transplant survival between the 2 groups was not different. Propensity-matched recipients had similar length of stay; stroke rate; need for dialysis; pacemaker implantation and treated rejection episodes in the first year post-transplant. Careful acceptance of BCPD may have the potential to increase availability of donor hearts in the pediatric population.

NT-pro BNP-A marker for worsening respiratory status and mortality in infants and young children with pulmonary hypertension.

AIM: To evaluate predictors of morbidity and mortality in pediatric patients with pulmonary hypertension (PH), laboratory and echocardiographic measures of PH were analyzed. METHODS: A retrospective review of all infants and children < 2 years of age with PH from January 2011 to August 2016 was conducted. Correlations were determined using Spearman's rank correlation coefficients. Differences in characteristics between survivors and nonsurvivors were analyzed and Kaplan-Meier survival curves were generated. RESULTS: Of 56 patients, the majority were extremely premature; of African American ethnicity; and had bronchopulmonary dysplasia. Patients who died were more likely to have underlying congenital heart disease; have a higher increase in the concentration of carbon dioxide in the blood (pCO2 ) with a corresponding greater mean percentage decrease in pH and percentage rise in NT-pro BNP during PH exacerbations; more likely to have been on medications for pulmonary hypertension; and have a higher RVSP/SBP (%) ratio and S/D ratio. There were positive correlations between percentage rise in NT-pro BNP and pCO2 ; NT-pro BNP and RVSP/SBP (%) ratio; and RVSP/SBP (%) ratio and S/D ratio. CONCLUSIONS: Infants and young children with pulmonary hypertension have increased morbidity and mortality. NT-pro BNP is a useful biomarker for both respiratory exacerbations and mortality, and RVSP/SBP (%) ratio and S/D ratio are echocardiographic identifiers for increased mortality.

Hematuria in an Adult with Congenital Heart Disease.

BACKGROUND: Adults with congenital heart disease (CHD) in the United States now outnumber children with CHD, due in part to the improvement in surgical and medical management. This growing population may present postoperatively to the emergency department (ED) with nonspecific complaints from unforseen complications secondary to cardiac intervention. CASE REPORT: We describe a 39-year-old male who presented to the ED with hematuria and dysuria after he underwent percutaneous device ventricular septal defect (VSD) closure 10 days before. Upon initial evaluation, laboratory results confirmed a urinary tract infection and hematuria. Given persistent red discoloration of urine and easy fatigability, further investigation and re-evaluation found him to be anemic secondary to intravascular hemolysis. Cardiac catheterization showed residual shunting through the VSD device margins causing the hemolysis. Although this is a rare complication of VSD device closure, the patient's initial presentation of hematuria and dysuria presented a unique diagnostic challenge. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Patients with underlying CHD require emergency physicians to consider a multidisciplinary approach to properly diagnose and facilitate treatment.

Transcatheter therapy of anomalous systemic venous drainage.

Anomalous drainage of the right superior caval vein into the left atrium is a rare congenital anomaly that causes cyanosis and occult infection owing to right-to-left shunting. Transcatheter management of this anomaly is unique and rarely reported. We report a 32-year-old man with a history of brain abscess, who was diagnosed with an anomalous right superior caval vein draining to the left atrium; right upper pulmonary vein and right middle pulmonary vein draining into the inferior portion of the right superior caval vein; and a left superior caval vein draining into the right atrium through the coronary sinus without a bridging vein. Pre-procedural planning was guided by three-dimensional printed model. The right superior caval vein was occluded with a 16-mm Amplatzer muscular Ventricular Septal Defect occluder inferior to the azygous vein, but superior to the entries of right upper and middle pulmonary veins. This diverted the right superior caval vein flow to the inferior caval vein system through the azygos vein in a retrograde manner and allowed the right upper pulmonary vein and right middle pulmonary vein flow to drain into the left atrium normally, achieving exclusion of right-to-left shunting and allowing normal drainage of pulmonary veins into the left atrium. At the 6-month follow-up, his saturation improved from 93 to 97% with no symptoms of superior caval vein syndrome.

Utility of Echocardiography in Detecting Silent Complications After Pediatric Catheter Ablations.

Although transcatheter arrhythmia ablation (TCA) has been performed in children for over two decades, guidelines for routine use of post-ablation transthoracic echocardiography (TTE) are absent. We sought to determine the efficacy of TTE after apparently uneventful TCA procedures in detecting adverse findings and identify predisposing factors. A retrospective review of clinical and procedural data on patients who underwent TCA for supraventricular arrhythmias from 2000 to 2015 was performed. Pre- and post-ablation TTE data were reviewed. All patients were followed at 1 week, 6 and 12 months post-TCA. A repeat TTE was performed at 12 months on patients in whom post-TCA abnormalities were found. Patients were divided into two groups: those with and without adverse TTE findings and comparative analysis between variables was performed. Data on 252 patients, 52% males, mean age 14 ± 3 years were analyzed. New onset or worsening atrioventricular valve regurgitation occurred in 17 (6.7%), a small pericardial effusion in 3 (1.2%) and worsened ventricular function in 2 patients (0.8%). Patients in the complication group had higher mean number of ablations (22.6 ± 15.3 vs. 16.8 ± 9.2, p 0.001) and required longer duration of ablation (sec) (254.6 ± 256.4 vs. 180.9 ± 158.9, p < 0.001). TCA location (including coronary sinus), energy source, arrhythmia substrate, and a trans-septal approach were noncontributory to any adverse findings. Routine post-ablation TTE uncovers asymptomatic self-resolving abnormalities that typically do not require any intervention.

Molecular interaction between type 2 diabetes and Alzheimer's disease through cross-seeding of protein misfolding.

Numerous epidemiological studies have shown a significantly higher risk for development of Alzheimer's disease (AD) in patients affected by type 2 diabetes (T2D), but the molecular mechanism responsible for this association is presently unknown. Both diseases are considered protein misfolding disorders associated with the accumulation of protein aggregates; amyloid-beta (Aß) and tau in the brain during AD, and islet amyloid polypeptide (IAPP) in pancreatic islets in T2D. Formation and accumulation of these proteins follows a seeding-nucleation model, where a misfolded aggregate or 'seed' promotes the rapid misfolding and aggregation of the native protein. Our underlying hypothesis is that misfolded IAPP produced in T2D potentiates AD pathology by cross-seeding Aß, providing a molecular explanation for the link between these diseases. Here, we examined how misfolded IAPP affects Aß aggregation and AD pathology in vitro and in vivo. We observed that addition of IAPP seeds accelerates Aß aggregation in vitro in a seeding-like manner and the resulting fibrils are composed of both peptides. Transgenic animals expressing both human proteins exhibited exacerbated AD-like pathology compared with AD transgenic mice or AD transgenic animals with type 1 diabetes (T1D). Remarkably, IAPP colocalized with amyloid plaques in brain parenchymal deposits, suggesting that these peptides may directly interact and aggravate the disease. Furthermore, inoculation of pancreatic IAPP aggregates into the brains of AD transgenic mice resulted in more severe AD pathology and significantly greater memory impairments than untreated animals. These data provide a proof-of-concept for a new disease mechanism involving the interaction of misfolded proteins through cross-seeding events which may contribute to accelerate or exacerbate disease pathogenesis. Our findings could shed light on understanding the linkage between T2D and AD, two of the most prevalent protein misfolding disorders.

Molecular mechanisms of serotonergic action of the HIV-1 antiretroviral efavirenz.

Efavirenz is highly effective at suppressing HIV-1, and the WHO guidelines list it as a component of the first-line antiretroviral (ARV) therapies for treatment-naïve patients. Though the pharmacological basis is unclear, efavirenz is commonly associated with a risk for neuropsychiatric adverse events (NPAEs) when taken at the prescribed dose. In many patients these NPAEs appear to subside after several weeks of treatment, though long-term studies show that in some patients the NPAEs persist. In a recent study focusing on the abuse potential of efavirenz, its receptor psychopharmacology was reported to include interactions with a number of established molecular targets for known drugs of abuse, and it displayed a prevailing behavioral profile in rodents resembling an LSD-like activity. In this report, we discovered interactions with additional serotonergic targets that may be associated with efavirenz-induced NPAEs. The most robust interactions were with 5-HT3A and 5-HT6 receptors, with more modest interactions noted for the 5-HT2B receptor and monoamine oxidase A. From a molecular mechanistic perspective, efavirenz acts as a 5-HT6 receptor inverse agonist of Gs-signaling, 5-HT2A and 5-HT2C antagonist of Gq-signaling, and a blocker of the 5-HT3A receptor currents. Efavirenz also completely or partially blocks agonist stimulation of the M1 and M3 muscarinic receptors, respectively. Schild analysis suggests that efavirenz competes for the same site on the 5-HT2A receptor as two known hallucinogenic partial agonists (±)-DOI and LSD. Prolonged exposure to efavirenz reduces 5-HT2A receptor density and responsiveness to 5-HT. Other ARVs such as zidovudine, nevirapine and emtricitabine did not share the same complex pharmacological profile as efavirenz, though some of them weakly interact with the 5-HT6 receptor or modestly block GABAA currents.