Expanding the clinical spectrum of biglycan-related Meester-Loeys syndrome.

Pathogenic loss-of-function variants in BGN, an X-linked gene encoding biglycan, are associated with Meester-Loeys syndrome (MRLS), a thoracic aortic aneurysm/dissection syndrome. Since the initial publication of five probands in 2017, we have considerably expanded our MRLS cohort to a total of 18 probands (16 males and 2 females). Segregation analyses identified 36 additional BGN variant-harboring family members (9 males and 27 females). The identified BGN variants were shown to lead to loss-of-function by cDNA and Western Blot analyses of skin fibroblasts or were strongly predicted to lead to loss-of-function based on the nature of the variant. No (likely) pathogenic missense variants without additional (predicted) splice effects were identified. Interestingly, a male proband with a deletion spanning the coding sequence of BGN and the 5' untranslated region of the downstream gene (ATP2B3) presented with a more severe skeletal phenotype. This may possibly be explained by expressional activation of the downstream ATPase ATP2B3 (normally repressed in skin fibroblasts) driven by the remnant BGN promotor. This study highlights that aneurysms and dissections in MRLS extend beyond the thoracic aorta, affecting the entire arterial tree, and cardiovascular symptoms may coincide with non-specific connective tissue features. Furthermore, the clinical presentation is more severe and penetrant in males compared to females. Extensive analysis at RNA, cDNA, and/or protein level is recommended to prove a loss-of-function effect before determining the pathogenicity of identified BGN missense and non-canonical splice variants. In conclusion, distinct mechanisms may underlie the wide phenotypic spectrum of MRLS patients carrying loss-of-function variants in BGN.

Assessment of Iron Biosorption Potential by Live and Dead Biomass of Bacillus subtilis (MN093305) from Aqueous Solution.

Heavy metals polluted aquatic ecosystems and become a global environmental issue due to their toxic effect on all forms of ecosystems and further on all forms of life. Heavy metals are non- degradable and accumulated in different life forms by accumulating in the food chain; this increases the need for the development of a sustainable method for the removal of these metals. Biosorption is an eco-friendly and cost-effective convenient technique of heavy metal bioremediation from the contaminated aquatic ecosystem. The current investigation involves biosorption of iron using Bacillus subtilis strain (MN093305) isolated from Ganga river at different physical parameters with the highest rate of biosorption was 96.64%, 98.91%, 97.88%, and 99.44% at pH 5, 60 min incubation period, 35 °C temperature and 2.5 mg/ml of biomass respectively for dead biomass. Living biomass biosorption rate was 87.32%, 96.74%, 96.94% and 95.02% at pH 7, 72 h, 35 °C and 2.5 mg/ml respectively. Functional groups involved in the biosorption of iron by Bacillus subtilis were fitted to a second-order kinetic model. Langmuir and Freundlich's isotherm are used to evaluate data; both isotherms indicate iron absorption as a favorable process.

Atrioventricular Conduction Abnormalities in Multisystem Inflammatory Syndrome in Children.

Cardiac manifestations in multisystem inflammatory syndrome in children (MIS-C) can include coronary artery aneurysms, left ventricular systolic dysfunction, and electrocardiographic disturbances. We report the clinical course of three children with MIS-C while focusing on the unique considerations for managing atrioventricular conduction abnormalities. All initially had normal electrocardiograms but developed bradycardia followed by either PR prolongation or QTc elongation. Two had mild left ventricular ejection fraction dysfunction prior to developing third-degree heart block and/or a junctional escape rhythm; one had moderate left ventricular systolic dysfunction that normalized before developing a prolonged QTc. On average, our patients presented to the hospital 4 days after onset of illness. Common presenting symptoms included fevers, abdominal pain, nausea, and vomiting. Inflammatory and coagulation factors were their highest early on, and troponin peaked the highest within the first two days; meanwhile, peak brain-natriuretic peptide occurred at hospital days 3-4. The patient's lowest left ventricular ejection fraction occurred at days 5-6 of illness. Initial electrocardiograms were benign with PR intervals below 200 milliseconds (ms); however, collectively the length of time from initial symptom presentation till when electrocardiographic abnormalities began was approximately days 8-9. When comparing the timing of electrocardiogram changes with trends in c-reactive protein and brain-natriuretic peptide, it appeared that the PR and QTc elongation patterns occurred after the initial hyperinflammatory response. This goes in line with the proposed mechanism that such conduction abnormalities occur secondary to inflammation and edema of the conduction tissue as part of a widespread global myocardial injury process. Based on this syndrome being a hyperinflammatory response likely affecting conduction tissue, our group was treated with different regimens of intravenous immunoglobulin, steroids, anakinra, and/or tocilizumab. These medications were successful in treating third-degree heart block, prolonged QTc, and a junctional ectopic rhythm.

What have we learned in the last 20 years? A comparison of a modern era pediatric and congenital catheter ablation registry to previous pediatric ablation registries.

BACKGROUND: Since the onset of pediatric catheter ablation, the pediatric electrophysiology community has reported outcomes via various registries (PAPCA [Prospective Assessment After Pediatric Cardiac Ablation], PCAR [Pediatric Catheter Ablation Registry]). Most recently, a modern era pediatric and congenital ablation registry (MAP-IT [Multicenter Pediatric and Congenital EP Quality Initiative]) was developed for eventual incorporation into the National Cardiovascular Data Registry (NCDR) IMPACT (Improving Pediatric and Adult Congenital Treatment) registry. OBJECTIVE: The purpose of this study was to describe initial findings from the MAP-IT pilot registry and to compare these findings to earlier registries. METHODS: Before entering the NCDR IMPACT registry, MAP-IT was active at 12 centers (11 in the United States) between October 2014 and April 2016. All electrophysiological studies for patients younger than 21 years and for patients of all ages with structural congenital heart disease were included. We compared the acute success, fluoroscopy and procedural times, and frequency of complications between MAP-IT and the earlier registries. RESULTS: Acute success rates have improved from the initial PCAR registry for both accessory and slow pathway substrates. Both fluoroscopy and procedural times have significantly decreased across the time periods (fluoroscopy time 47.6 ± 40 minutes to 7.0 ± 9.2 minutes; P <.001; procedural time 257 ± 157 minutes to 166 ± 84 minutes; P <.001). CONCLUSION: Acute success rates and fluoroscopy and procedural times in pediatric ablation all have improved over the last 25 years.

Nonfluoroscopic Ablation in the Setting of Congenital Heart Disease.

In this case series, we demonstrate the performance of nonfluoroscopic ablation in the congenital heart disease population. Techniques for procedural safety and the benefits of three-dimensional mapping in the setting of structural heart disease are reviewed.

Fluoroless Rapid Mapping and Catheter Ablation of Intra-atrial Reentry Tachycardia in a Patient with Mustard Operation Using the Ensite™ Precision™ Electroanatomic Mapping System.

Catheter ablation of atrial arrhythmias in patients with atrial baffle palliation for dextro-transposition of the great arteries (requiring the Mustard or Senning procedures) can be challenging cases to complete, with long procedure times and high degrees of associated radiation exposure. Many ablation procedures can now be done using the fluoroless technique. The new EnSite™ Precision™ cardiac mapping system (Abbott Laboratories, Chicago, IL, USA) allows for the rapid mapping of arrhythmias and the performance of non-fluoroscopic procedures. This case report describes the use of this system in an adult patient undergoing Mustard operation, to rapidly map and successfully ablate intra-atrial reentry tachycardia with fluoroless technique.

Congenital long QT 3 in the pediatric population.

There is insufficient knowledge concerning long-QT (LQT) 3 in the pediatric population to determine whether recommendations for more aggressive therapy in these patients are appropriate. An international multicenter review of 43 children with cardiac sodium channel (SCN5A) mutations and clinical manifestations of LQT syndrome without overlap of other SCN5A syndromes was undertaken to describe the clinical characteristics of LQT3 in children. Patients were aged 7.6 ± 5.9 years at presentation and were followed for 4.7 ± 3.9 years. There was significant intrasubject corrected QT interval (QTc) variability on serial electrocardiography. Forty-two percent presented with severe symptoms or arrhythmia and exhibited longer QTc intervals compared to asymptomatic patients. None of the 14 patients who underwent primary prevention implantable cardioverter-defibrillator (ICD) implantation received appropriate shocks in 41 patient-years of follow-up, while 2 of 6 patients who underwent secondary prevention ICD implantation received appropriate shocks in 30 patient-years of follow-up. Half of patients who underwent ICD implantation experienced inappropriate shocks or ICD-related complications. Mexiletine significantly shortened the QTc interval, and QTc shortening was greater in patients with longer pretreated QTc intervals. Two ICD patients with frequent appropriate ICD shocks showed immediate clinical improvement, with elimination of appropriate ICD shocks after mexiletine loading. In conclusion, severe symptoms are common in children with LQT3 and are associated with longer QTc intervals. ICD implantation is associated with significant morbidity. Mexiletine shortens the QTc interval, and it may be beneficial.

Arrhythmias in patients with hypoplastic left heart syndrome.

BACKGROUND: Mortality between stage I and II palliation for hypoplastic left heart syndrome (HLHS) has been associated with arrhythmias. The stage-related proportion, associations, and clinical impact of arrhythmias in patients with HLHS have not been evaluated. In addition, arrhythmia subtypes have not been described in this patient group. METHODS: We performed a retrospective analysis of all patients at Duke University Medical Center who received one or more palliative stages for HLHS from September 2000 to October 2008. RESULTS: Overall, 49 (57%) of 86 patients had 63 arrhythmias. The majority of arrhythmias occurred between stage I and II, with 44 (51%) of 86 patients manifesting a new arrhythmia. Arrhythmias occurring in this interval tended to be associated with a higher mortality compared with arrhythmias occurring after stage II (odds ratio = 3.2 [95% CI 0.84-12.0], P = .09). Overall mortality was similar in patients with and without arrhythmias (P = .99). Supraventricular tachycardia was the most common arrhythmia (16/63; 25%), but persistent bradycardias (sinus node dysfunction or high-grade atrioventricular block) had the worst clinical outcome with 73% mortality (8/11). There was no association between arrhythmia occurrence and degree of tricuspid regurgitation, left ventricular hypertension, genetic syndrome, type of stage I operation, or need for extracorporeal membrane oxygenation. CONCLUSIONS: A large proportion of patients with HLHS experience serious arrhythmias requiring therapy, especially between stage I and II. Persistent bradycardia following stage I is associated with a high mortality rate. Considering all arrhythmia patients, overall mortality was not different compared with the arrhythmia-free group.

Patch cramming reveals the mechanism of long-term suppression of cyclic nucleotides in intact neurons.

To understand cyclic nucleotide dynamics in intact cells, we used the patch-cramming method with cyclic nucleotide-gated channels as real-time biosensors for cGMP. In neuroblastoma and sympathetic neurons, both muscarinic agonists and nitric oxide (NO) rapidly elevate cGMP. However, muscarinic agonists also elicit a long-term (2 hr) suppression (LTS) of subsequent cGMP responses. Muscarinic agonists elevate cGMP by triggering Ca2+ mobilization, which activates NO synthase to produce NO, leading to the activation of soluble guanylate cyclase (sGC). Here we examine the mechanism of LTS. Experiments using direct intracellular cGMP injection demonstrate that enhancement of phosphodiesterase (PDE) activity, rather than depression of sGC activity, is responsible for LTS. Biochemical measurements show that both cGMP and cAMP content is suppressed, consistent with the involvement of a nonselective PDE. Application of pharmacological agents that alter Ca2+ mobilization from intracellular stores and experiments involving injection of the Ca2+ chelator BAPTA show that Ca2+ mobilization is necessary and sufficient for LTS induction but also show that LTS maintenance is Ca2+-independent. Protein phosphatase injection reverses LTS, and specific inhibitors of Ca2+/calmodulin kinase II (CaMKII) prevent induction and inhibit maintenance. The switch between the Ca2+ dependence of LTS induction to the Ca2+ independence of LTS maintenance is consistent with CaMKII autophosphorylation, similar to proposed mechanisms of hippocampal long-term potentiation. Because the molecular machinery underlying LTS is common to many cells, LTS may be a widespread mechanism for long-term silencing of cyclic nucleotide signaling.