Hybrid therapy for hypoplastic left heart syndrome: Myth, alternative, or standard?

OBJECTIVE: This retrospective study presents our operative results, mortality, and morbidity with regard to pulmonary artery growth and reinterventions on the pulmonary artery and aortic arch, including key features of our institutional standards for the 3-stage hybrid palliation of patients with hypoplastic left heart syndrome. METHODS: Between June 1998 and February 2015, 182 patients with hypoplastic left heart structures underwent the Giessen hybrid stage I procedure. Among these, 126 patients with hypoplastic left heart syndrome who received a univentricular palliation or heart transplantation were included in the main analysis. Median age and body weight of patients at hybrid stage I were 6 days (0-237) and 3.2 kg (1.2-7), respectively. Comprehensive stage II operation was performed at 4.5 months (2.9-39.5), and Fontan completion was established at 33.7 months (21.1-108.2). Operative and interstage mortality, morbidity, growth and reinterventions on the pulmonary arteries, and long-term operative results of the aortic arch reconstruction were assessed. RESULTS: Median follow-up time after Giessen hybrid stage I palliation was 4.6 years (0-16.8). Operative mortality at hybrid stage I, comprehensive stage II, and Fontan completion was 2.5%, 4.9%, and 0%, respectively. Cumulative interstage mortality was 14.2%. At 10 years, the probability of survival is 77.8%. Body weight (<2.5 kg) and aortic atresia had no significant impact on survival. McGoon ratio did not differ at comprehensive stage II and Fontan completion (P = .991). Freedom from pulmonary artery intervention was estimated to be 32.2% at 10 years. Aortic arch reinterventions were needed in 16.7% of patients; 2 reoperations on the aortic arch were necessary. CONCLUSIONS: In view of the early results and long-term outcome, the hybrid approach has become an alternative to the conventional strategy to treat neonates with hypoplastic left heart syndrome and variants. Further refinements are warranted to decrease patient morbidity.

Investigation on the hermeticity of an implantable package with 32 feedthroughs for neural prosthetic applications.

This paper presents an implantable package aimed at hosting a bidirectional neural interface for neural prosthetic applications. The package has been conceived to minimize the invasivity for the patient, for this reason a cylindrical container with an outer diameter of 7 mm and a length of 21 mm has been designed. The package, realized in alumina (Al2O3), presents 32 hermetic feedthroughs located at the top and bottom base of the cylinder. The hermetic housing has been assembled using a low-temperature soldering method based on a previous platinum/gold (Pt/Au) metallization of the ceramic parts. The package's hermeticity has been successfully proved by means of in-vitro tests, exhibiting an increase in the inner relative humidity of 20 %RH over 75 days of observation.

High-Throughput Screening Using iPSC-Derived Neuronal Progenitors to Identify Compounds Counteracting Epigenetic Gene Silencing in Fragile X Syndrome.

Fragile X syndrome (FXS) is the most common form of inherited mental retardation, and it is caused in most of cases by epigenetic silencing of the Fmr1 gene. Today, no specific therapy exists for FXS, and current treatments are only directed to improve behavioral symptoms. Neuronal progenitors derived from FXS patient induced pluripotent stem cells (iPSCs) represent a unique model to study the disease and develop assays for large-scale drug discovery screens since they conserve the Fmr1 gene silenced within the disease context. We have established a high-content imaging assay to run a large-scale phenotypic screen aimed to identify compounds that reactivate the silenced Fmr1 gene. A set of 50,000 compounds was tested, including modulators of several epigenetic targets. We describe an integrated drug discovery model comprising iPSC generation, culture scale-up, and quality control and screening with a very sensitive high-content imaging assay assisted by single-cell image analysis and multiparametric data analysis based on machine learning algorithms. The screening identified several compounds that induced a weak expression of fragile X mental retardation protein (FMRP) and thus sets the basis for further large-scale screens to find candidate drugs or targets tackling the underlying mechanism of FXS with potential for therapeutic intervention.

The tyrosine kinase BMX is an essential mediator of inflammatory arthritis in a kinase-independent manner.

Inflammatory cytokines like TNF play a central role in autoimmune disorders such as rheumatoid arthritis. We identified the tyrosine kinase bone marrow kinase on chromosome X (BMX) as an essential component of a shared inflammatory signaling pathway. Transient depletion of BMX strongly reduced secretion of IL-8 in cell lines and primary human cells stimulated by TNF, IL-1ß, or TLR agonists. BMX was required for phosphorylation of p38 MAPK and JNK, as well as activation of NF-κB. The following epistasis analysis indicated that BMX acts downstream of or at the same level as the complex TGF-ß activated kinase 1 (TAK1)-TAK1 binding protein. At the cellular level, regulation of the IL-8 promoter required the pleckstrin homology domain of BMX, which could be replaced by an ectopic myristylation signal, indicating a requirement for BMX membrane association. In addition, activation of the IL-8 promoter by in vitro BMX overexpression required its catalytic activity. Genetic ablation of BMX conferred protection in the mouse arthritis model of passive K/BxN serum transfer, confirming that BMX is an essential mediator of inflammation in vivo. However, genetic replacement with a catalytically inactive BMX allele was not protective in the same arthritis animal model. We conclude that BMX is an essential component of inflammatory cytokine signaling and that catalytic, as well as noncatalytic functions of BMX are involved.