Inhibition of leukotriene receptors boosts neural progenitor proliferation.

Neural stem and progenitor cells serve as a reservoir for new neurons in the adult brain throughout lifetime. One of the critical steps determining the net production of new neurons is neural progenitor proliferation, which needs to be tightly controlled. Since inflammation has detrimental effects on neurogenesis and the 5-lipoxygenase/leukotriene pathway is involved in inflammatory processes, we investigated the effects of leukotrienes and montelukast, a small molecule inhibitor of the leukotriene receptors CysLT(1)R and GPR17, on neural stem and progenitor cell proliferation. We demonstrate expression of the leukotriene receptor GPR17 by neural progenitors and by neural stem cells. Stimulation with excess amounts of leukotrienes did not affect progenitor proliferation, whereas blockade of GPR17 with montelukast strongly elevated neural stem and progenitor proliferation, while maintaining their differentiation fate and potential. This effect was associated with increased ERK1/2 phosphorylation suggesting an involvement of the EGF signaling cascade. Based on our results, montelukast and the inhibition of the 5-LOX pathway might be potent candidates for future therapies employing neurogenesis to promote structural and functional improvement in neurodegeneration, neuropsychiatric disease and ageing.

Oligodendrogenesis of adult neural progenitors: differential effects of ciliary neurotrophic factor and mesenchymal stem cell derived factors.

The oligodendrogenic program of progenitor cells in the adult CNS follows a sequential process of progenitor proliferation, fate choice, determination, differentiation, maturation and survival. Previously, we described a soluble activity derived from mesenchymal stem cells that induces oligodendrogenesis in adult neural progenitor cells. Here, we hypothesized that ciliary neurotrophic factor might be a candidate for this activity, since (i) it is expressed by mesenchymal stem cells and (ii) it can promote oligodendrogenesis during development. Along the course of the study, we found differential effects by ciliary neurotrophic factor and by the mesenchymal stem cells-derived activity on neural progenitors. While the mesenchymal stem cells-derived activity induced oligodendrogenesis at the expense of astrogenesis and promoted oligodendroglial differentiation/maturation, the effect of ciliary neurotrophic factor was restricted to the latter one. This was reflected at the levels of the cell fate determinants Olig1, Olig2, Id2, and the oligodendroglia-maturation transcription factor GTX/Nkx6.2. Finally, experiments using blocking antibodies excluded ciliary neurotrophic factor to be the mesenchymal stem cell-derived oligodendroglial activity. In summary, this work provides evidence for differential effects of ciliary neurotrophic factor and mesenchymal stem cells-derived activity on oligodendrogenesis of adult neural progenitor cells.

HeartMate 3 in Lowest INTERMACS Profile Cohort: The Swiss Experience.

New generation devices for long-term mechanical circulatory support are centrifugal pumps having fully magnetically levitated rotors to reduce blood trauma. Recently, the novel HeartMate 3 was cleared for clinical application in Switzerland. In two Swiss University Hospitals part of the "Lausanne-Geneva Transplantation Network," 10 consecutive patients in end-stage heart failure received the HeartMate 3 (Thoratec Corporation, Pleasanton, CA). Device implantation criteria were persistent low output syndrome despite optimal medical treatment. The primary end-point of the study was survival or transplantation to 90 days on the device. Five patients (50%) were in Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) class 1 and 2 (two were under venoarterial extracorporeal membrane oxygenation [VA-ECMO]), and five were in class 3 and 4. The indication was bridge-to-transplant in seven patients, and destination therapy in three. Two patients (20%) received concomitant aortic valve surgery. Four patients (40%) required temporary right ventricle support (tRVAD) for a mean of 8 ± 1.5 days. Bleeding requiring surgical revision occurred in five (50%) patients, two during the tRVAD support. At the 90 day end-point, survival was 90%, one (10%) died due to respiratory failure. Three (30%) experienced critical illness polyneuropathy. Two had body temperature over 38.5°C for more than 7 days after implant, without infections. Two (20%) had late driveline infection. The pump allowed rapid improvement of patients' clinical conditions even in severely compromised patients. Postoperative bleeding occurred in the setting of anticoagulation. No hemolysis or pump thrombosis occurred. Fever occurred frequently but was not associated with mortality. Hemodynamic support was consistent over time without significant adverse events.

[Tetralogy of Fallot: after the successful surgical correction...]. / Tétralogie de Fallot: les suites d'un succès....

Tetralogy of Fallot is the most frequent cyanotic congenital heart disease (1/10000 births). The first complete corrections have been done in the fifties, and we now have long-term follow-up studies, revealing the most frequent arrhythmias and anatomic substrates compromising the long-term survival of these patients. The purpose of this article is to review some of the long-term complications of these patients, who, even if they have been completely corrected, will never be cured.

Self-expandable valved stent of large size: off-bypass implantation in pulmonary position.

OBJECTIVE: To evaluate the feasibility of the off-bypass implantation of a self-expandable valved stent of large size in pulmonary position. MATERIALS AND METHODS: A glutaraldehyde preserved valved bovine jugular xenograft with internal diameter = 22 mm, mounted in two rings of nitinol 'Z' stent, expandable from 7 to 24 mm of internal diameter, was acutely evaluated in 6 adult pigs, mean body weight 55.6 kg (range 47-67 kg). Through a stent-graft delivery system (24 French) the self expandable valved stent was implanted off-bypass in pulmonary valve position by trans-ventricular approach through median sternotomy. RESULTS: The mean diameter of the main pulmonary artery measured was 21.7 +/- 1.6 mm. The mean length of the self expandable valved stent was 23.1 +/- 0.7 mm, the mean internal diameter 21.6 +/- 0.7 mm and the mean external diameter 26.3 +/- 0.7 mm. The mean peak pressure gradient recorded across the valve was 6.33 +/- 2.8 mmHg (range 4.5-9.6 mmHg) at Doppler echocardiography, and 4.5 +/- 3.1 mmHg (range 0-7 mmHg) at invasive measurement, with a pulmonary blood flow of 3.03 +/- 0.05 l/min. Intra-vascular ultrasound showed complete opening and closure of the valve (mean area reduction from 315.08 +/- 54.13 to 0 mm2). CONCLUSIONS: (a) Off-bypass implantation of self-expandable valved stent is feasible in pulmonary position; (b) off-bypass surgical approach allows for valved stent implantation of adult size with adequate hemodynamic functioning; and (c) intra-vascular ultrasound makes implantation and evaluation easy and reproducible.