Early Appearance of Dendritic Alterations in Neocortical Pyramidal Neurons of the Ts65Dn Model of Down Syndrome.

Down syndrome (DS), which is due to triplication of chromosome 21, is constantly associated with intellectual disability (ID). ID can be ascribed to both neurogenesis impairment and dendritic pathology. These defects are replicated in the Ts65Dn mouse, a widely used model of DS. While neurogenesis impairment in DS is a fetal event, dendritic pathology occurs after the first postnatal months. Neurogenesis alterations across the life span have been extensively studied in the Ts65Dn mouse. In contrast, there is scarce information regarding dendritic alterations at early life stages in this and other models, although there is evidence for dendritic alterations in adult mouse models. Thus, the goal of the current study was to establish whether dendritic alterations are already present in the neonatal period in Ts65Dn mice. In Golgi-stained brains, we quantified the dendritic arbors of layer II/III pyramidal neurons in the frontal cortex of Ts65Dn mice aged 2 (P2) and 8 (P8) days and their euploid littermates. In P2 Ts65Dn mice, we found a moderate hypotrophy of the apical and collateral dendrites but a patent hypotrophy of the basal dendrites. In P8 Ts65Dn mice, the distalmost apical branches were missing or reduced in number, but there were no alterations in the collateral and basal dendrites. No genotype effects were detected on either somatic or dendritic spine density. This study shows dendritic branching defects that mainly involve the basal domain in P2 Ts65Dn mice and the apical but not the other domains in P8 Ts65Dn mice. This suggests that dendritic defects may be related to dendritic compartment and age. The lack of a severe dendritic pathology in Ts65Dn pups is reminiscent of the delayed appearance of patent dendritic alterations in newborns with DS. This similarly highlights the usefulness of the Ts65Dn model for the study of the mechanisms underlying dendritic alterations in DS and the design of possible therapeutic interventions.

Treatment with the flavonoid 7,8-Dihydroxyflavone: a promising strategy for a constellation of body and brain disorders.

Flavonoids have long been known to exert benefits in various health problems. Among them, the BDNF mimetic 7,8-Dihydroxyflavone (7,8-DHF) is emerging as a potential treatment for a constellation of brain and body pathologies. During the past 10 years, more than 180 preclinical studies have explored the efficacy of 7,8-DHF in animal models of different pathologies. The current review intends to be an exhaustive survey of these studies. By providing detailed information on the rationale of the experimental design and outcome of treatment, we will give the reader tools to critically interpret the achievement obtained so far. If we put together each individual piece of this complex mosaic, a picture emerges that is full of promise regarding the potential usefulness of 7,8-DHF for human treatment. Much has been done so far and we believe that the time is now ripe to move from the bench to the bedside, in order to establish whether supplementation with 7,8-DHF may serve as therapy or, at least, as adjuvant for the treatment of pathologies affecting brain and body functioning.

Early appearance of developmental alterations in the dendritic tree of the hippocampal granule cells in the Ts65Dn model of Down syndrome.

Down syndrome (DS), a genetic condition caused by triplication of chromosome 21, is characterized by alterations in various cognitive domains, including hippocampus-dependent memory functions, starting from early life stages. The major causes of intellectual disability in DS are prenatal neurogenesis alterations followed by impairment of dendritic development in early infancy. While there is evidence that the Ts65Dn mouse, the most widely used model of DS, exhibits dendritic alterations in adulthood, no studies are available regarding the onset of dendritic pathology. The goal of the current study was to establish whether this model exhibits early dendritic alterations in the hippocampus, a region whose function is severely damaged in DS. To this purpose, in Golgi-stained brains, we evaluated the dendritic arborization and dendritic spines of the granule cells of the hippocampal dentate gyrus in Ts65Dn mice aged 8 (P8) and 15 (P15) days. While P15 Ts65Dn mice exhibited a notably hypotrophic dendritic arbor and a reduced spine density, P8 mice exhibited a moderate reduction in the number of dendritic ramifications and no differences in spine density in comparison with their euploid counterparts. Both in P8 and P15 mice, spines were longer and had a longer neck, suggesting possible alterations in synaptic function. Moreover, P8 and P15 Ts65Dn mice had more thin spines and fewer stubby spines in comparison with euploid mice. Our study provides novel evidence on the onset of dendritic pathology, one of the causes of intellectual disability in DS, showing that it is already detectable in the dentate gyrus of Ts65Dn pups. This evidence strengthens the suitability of this model of DS as a tool to study dendritic pathology in DS and to test the efficacy of early therapeutic interventions aimed at ameliorating hippocampal development and, therefore, memory functions in children with DS.

Complicated postoperative course in isolated tricuspid valve surgery: Looking for predictors.

BACKGROUND: This study aims at better defining the profile of patients with a complicated versus noncomplicated postoperative course following isolated tricuspid valve (TV) surgery to identify predictors of a favorable/unfavorable hospital outcome. METHODS: All patients treated with isolated tricuspid surgery from March 1997 to January 2020 at our institution were retrospectively reviewed. Considering the complexity of most of these patients, a regular postoperative course was arbitrarily defined as a length-of-stay in intensive care unit less than 4 days and/or postoperative length-of-stay less than 10days. Patients were therefore divided accordingly in two groups. RESULTS: One hundred and seventy-two patients were considered, among whom 97 (56.3%) had a regular (REG) and 75 (43.6%) a non-regular (NEG) postoperative course. The latter had worse baseline clinical and echocardiographic characteristics, with higher rate of renal insufficiency, previous heart failure hospitalizations, cardiac operations, and right ventricular dysfunction. NEG patients more frequently needed tricuspid replacement and experienced a greater number of complications (p < .001) and higher in-hospital mortality (13% vs. 0%, p < .001). The majority of these complications were related to more advanced stage of the tricuspid disease. Among most important predictors of a negative outcome univariate analysis identified chronic kidney disease, ascites, previous right heart failure hospitalizations, right ventricular dysfunction, previous cardiac surgeries, TV replacement and higher MELD scores. At multivariate analysis, liver enzymes and diuretics' dose were predictors of complicated postoperative course. CONCLUSION: In isolated TV surgery a complicated postoperative course is observed in patients with more advanced right heart failure and organ damage. Earlier surgical referral is associated to excellent outcomes and should be recommended.

Neonatal therapy with clenbuterol and salmeterol restores spinogenesis and dendritic complexity in the dentate gyrus of the Ts65Dn model of Down syndrome.

Down syndrome (DS), a neurodevelopmental disorder caused by triplication of chromosome 21, is characterized by intellectual disability. In DS, defective neurogenesis causes an overall reduction in the number of neurons populating the brain and defective neuron maturation causes dendritic hypotrophy and reduction in the density of dendritic spines. No effective therapy currently exists for the improvement of brain development in individuals with DS. Drug repurposing is a strategy for identifying new medical use for approved drugs. A drug screening campaign showed that the ß2-adrenergic receptor (ß2-AR) agonists clenbuterol hydrochloride (CLEN) and salmeterol xinafoate (SALM) increase the proliferation rate of neural progenitor cells from the Ts65Dn model of DS. The goal of the current study was to establish their efficacy in vivo, in the Ts65Dn model. We found that, at variance with the in vitro experiments, treatment with CLEN or SALM did not restore neurogenesis in the hippocampus of Ts65Dn mice treated during the postnatal (P) period P3-P15. In Ts65Dn mice treated with CLEN or SALM, however, dendritic spine density and dendritic arborization of the hippocampal granule cells were restored and the lowest dose tested here (0.01 mg/kg/day) was sufficient to elicit these effects. CLEN and SALM are used in children as therapy for asthma and, importantly, they pass the blood-brain barrier. Our study suggests that treatment with these ß2-AR agonists may be a therapy of choice in order to correct dendritic development in DS but is not suitable to rescue neurogenesis.

Neonatal treatment with cyclosporine A restores neurogenesis and spinogenesis in the Ts65Dn model of Down syndrome.

Down syndrome (DS), a genetic condition due to triplication of chromosome 21, is characterized by reduced proliferation of neural progenitor cells (NPCs) starting from early life stages. This defect is worsened by a reduction of neuronogenesis (accompanied by an increase in astrogliogenesis) and dendritic spine atrophy. Since this triad of defects underlies intellectual disability, it seems important to establish whether it is possible to pharmacologically correct these alterations. In this study, we exploited the Ts65Dn mouse model of DS in order to obtain an answer to this question. In the framework of an in vitro drug-screening campaign of FDA/EMA-approved drugs, we found that the immunosuppressant cyclosporine A (CSA) restored proliferation, acquisition of a neuronal phenotype, and maturation of neural progenitor cells (NPCs) from the subventricular zone (SVZ) of the lateral ventricle of Ts65Dn mice. Based on these findings, we treated Ts65Dn mice with CSA in the postnatal period P3-P15. We found that treatment fully restored NPC proliferation in the SVZ and in the subgranular zone of the hippocampal dentate gyrus, and total number of hippocampal granule cells. Moreover, CSA enhanced development of dendritic spines on the dendritic arbor of the granule cells whose density even surpassed that of euploid mice. In hippocampal homogenates from Ts65Dn mice, we found that CSA normalized the excessive levels of p21, a key determinant of proliferation impairment. Results show that neonatal treatment with CSA restores the whole triad of defects of the trisomic brain. In DS CSA treatment may pose caveats because it is an immunosuppressant that may cause adverse effects. However, CSA analogues that mimic its effect without eliciting immunosuppression may represent practicable tools for ameliorating brain development in individuals with DS.

Neuroanatomical alterations and synaptic plasticity impairment in the perirhinal cortex of the Ts65Dn mouse model of Down syndrome.

Down syndrome (DS), a genetic condition due to triplication of Chromosome 21, is characterized by numerous neurodevelopmental alterations and intellectual disability. Individuals with DS and DS mouse models are impaired in several memory domains, including hippocampus-dependent declarative (spatial, in rodents) memory and visual recognition memory, a form of memory in which the perirhinal cortex (PRC) plays a fundamental role. The anatomo-functional substrates of hippocampus-dependent memory impairment have been largely elucidated in the Ts65Dn mouse model of DS. In contrast, there is a lack of corresponding information regarding visual recognition memory. Therefore, we deemed it of interest to examine at both an anatomical and functional level the PRC of Ts65Dn mice. We found that the PRC of adult (1.5-3.5month-old) Ts65Dn mice exhibited diffused hypocellularity and neurons with a reduced spine density. No difference between Ts65Dn and euploid mice was detected in the abundance of glutamatergic and GABAergic terminals. We examined brain slices for long-term potentiation (LTP), a form of synaptic plasticity involved in long-term memory. Theta burst stimulation of intracortical fibers was used in order to elicit LTP in the superficial layers of the PRC. We found that in trisomic slices LTP had a similar time-course but a reduced magnitude in comparison with euploid slices. While exposure to the GABAA receptor antagonist picrotoxin had no effect on LTP magnitude, exposure to the GABAB receptor antagonist CGP55845 caused an increase in LTP magnitude that became even larger than in euploid slices. Western blot analysis showed increased levels of the G-protein-activated inwardly rectifying K+ channel 2 (GIRK2) in the PRC of Ts65Dn mice, consistent with triplication of the gene coding for GIRK2. This suggests that the reduced magnitude of LTP may be caused by GIRK2-dependent exaggerated GABAB receptor-mediated inhibition. Results provide novel evidence for anatomo-functional alterations in the PRC of Ts65Dn mice. These alterations may underlie trisomy-due impairment in visual recognition memory.

Long-term effect of neonatal inhibition of APP gamma-secretase on hippocampal development in the Ts65Dn mouse model of Down syndrome.

Neurogenesis impairment is considered a major determinant of the intellectual disability that characterizes Down syndrome (DS), a genetic condition caused by triplication of chromosome 21. Previous evidence obtained in the Ts65Dn mouse model of DS showed that the triplicated gene APP (amyloid precursor protein) is critically involved in neurogenesis alterations. In particular, excessive levels of AICD (amyloid precursor protein intracellular domain) resulting from APP cleavage by gamma-secretase increase the transcription of Ptch1, a Sonic Hedgehog (Shh) receptor that keeps the mitogenic Shh pathway repressed. Previous evidence showed that neonatal treatment with ELND006, an inhibitor of gamma-secretase, reinstates the Shh pathway and fully restores neurogenesis in Ts65Dn pups. In the framework of potential therapies for DS, it is extremely important to establish whether the positive effects of early intervention are retained after treatment cessation. Therefore, the goal of the current study was to establish whether early treatment with ELND006 leaves an enduring trace in the brain of Ts65Dn mice. Ts65Dn and euploid pups were treated with ELND006 in the postnatal period P3-P15 and the outcome of treatment was examined at ~one month after treatment cessation. We found that in treated Ts65Dn mice the pool of proliferating cells in the hippocampal dentate gyrus (DG) and total number of granule neurons were still restored as was the number of pre- and postsynaptic terminals in the stratum lucidum of CA3, the site of termination of the mossy fibers from the DG. Accordingly, patch-clamp recording from field CA3 showed functional normalization of the input to CA3. Unlike in field CA3, the number of pre- and postsynaptic terminals in the DG of treated Ts65Dn mice was no longer fully restored. The finding that many of the positive effects of neonatal treatment were retained after treatment cessation provides proof of principle demonstration of the efficacy of early inhibition of gamma-secretase for the improvement of brain development in DS.

SNX27, a protein involved in down syndrome, regulates GPR17 trafficking and oligodendrocyte differentiation.

The G protein-coupled receptor 17 (GPR17) plays crucial roles in myelination. It is highly expressed during transition of oligodendrocyte progenitor cells to immature oligodendrocytes, but, after this stage, it must be down-regulated to allow generation of mature myelinating cells. After endocytosis, GPR17 is sorted into lysosomes for degradation or recycled to the plasma membrane. Balance between degradation and recycling is important for modulation of receptor levels at the cell surface and thus for the silencing/activation of GPR17-signaling pathways that, in turn, affect oligodendrocyte differentiation. The molecular mechanisms at the basis of these processes are still partially unknown and their characterization will allow a better understanding of myelination and provide cues to interpret the consequences of GPR17 dysfunction in diseases. Here, we demonstrate that the endocytic trafficking of GPR17 is mediated by the interaction of a type I PDZ-binding motif located at the C-terminus of the receptor and SNX27, a recently identified protein of the endosome-associated retromer complex and whose functions in oligodendrocytes have never been studied. SNX27 knock-down significantly reduces GPR17 plasma membrane recycling in differentiating oligodendrocytes while accelerating cells' terminal maturation. Interestingly, trisomy-linked down-regulation of SNX27 expression in the brain of Ts65Dn mice, a model of Down syndrome, correlates with a decrease in GPR17(+) cells and an increase in mature oligodendrocytes, which, however, fail in reaching full maturation, eventually leading to hypomyelination. Our data demonstrate that SNX27 modulates GPR17 plasma membrane recycling and stability, and that disruption of the SNX27/GPR17 interaction might contribute to pathological oligodendrocyte differentiation defects. GLIA 2016. GLIA 2016;64:1437-1460.

Inhibition of APP gamma-secretase restores Sonic Hedgehog signaling and neurogenesis in the Ts65Dn mouse model of Down syndrome.

Neurogenesis impairment starting from early developmental stages is a key determinant of intellectual disability in Down syndrome (DS). Previous evidence provided a causal relationship between neurogenesis impairment and malfunctioning of the mitogenic Sonic Hedgehog (Shh) pathway. In particular, excessive levels of AICD (amyloid precursor protein intracellular domain), a cleavage product of the trisomic gene APP (amyloid precursor protein) up-regulate transcription of Ptch1 (Patched1), the Shh receptor that keeps the pathway repressed. Since AICD results from APP cleavage by γ-secretase, the goal of the current study was to establish whether treatment with a γ-secretase inhibitor normalizes AICD levels and restores neurogenesis in trisomic neural precursor cells. We found that treatment with a selective γ-secretase inhibitor (ELND006; ELN) restores proliferation in neurospheres derived from the subventricular zone (SVZ) of the Ts65Dn mouse model of DS. This effect was accompanied by reduction of AICD and Ptch1 levels and was prevented by inhibition of the Shh pathway with cyclopamine. Treatment of Ts65Dn mice with ELN in the postnatal period P3-P15 restored neurogenesis in the SVZ and hippocampus, hippocampal granule cell number and synapse development, indicating a positive impact of treatment on brain development. In addition, in the hippocampus of treated Ts65Dn mice there was a reduction in the expression levels of various genes that are transcriptionally regulated by AICD, including APP, its origin substrate. Inhibitors of γ-secretase are currently envisaged as tools for the cure of Alzheimer's disease because they lower ßamyloid levels. Current results provide novel evidence that γ-secretase inhibitors may represent a strategy for the rescue of neurogenesis defects in DS.

Long-term effects of neonatal treatment with fluoxetine on cognitive performance in Ts65Dn mice.

Individuals with Down syndrome (DS), a genetic condition caused by triplication of chromosome 21, are characterized by intellectual disability and are prone to develop Alzheimer's disease (AD), due to triplication of the amyloid precursor protein (APP) gene. Recent evidence in the Ts65Dn mouse model of DS shows that enhancement of serotonergic transmission with fluoxetine during the perinatal period rescues neurogenesis, dendritic pathology and behavior, indicating that cognitive impairment can be pharmacologically restored. A crucial question is whether the short-term effects of early treatments with fluoxetine disappear at adult life stages. In the current study we found that hippocampal neurogenesis, dendritic pathology and hippocampus/amygdala-dependent memory remained in their restored state when Ts65Dn mice, which had been neonatally treated with fluoxetine, reached adulthood. Additionally, we found that the increased levels of the APP-derived ßCTF peptide in adult Ts65Dn mice were normalized following neonatal treatment with fluoxetine. This effect was accompanied by restoration of endosomal abnormalities, a ßCTF-dependent feature of DS and AD. While untreated adult Ts65Dn mice had reduced hippocampal levels of the 5-HT1A receptor (5-HT1A-R) and methyl-CpG-binding protein (MeCP2), a protein that promotes 5-HT1A-R transcription, in neonatally-treated mice both 5-HT1A-R and MeCP2 were normalized. In view of the crucial role of serotonin in brain development, these findings suggest that the enduring outcome of neonatal treatment with fluoxetine may be due to MeCP2-dependent restoration of the 5-HT1A-R. Taken together, results provide new hope for the therapy of DS, showing that early treatment with fluoxetine enduringly restores cognitive impairment and prevents early signs of AD-like pathology.

Edge-to-edge surgical mitral valve repair in the era of MitraClip: what if the annuloplasty ring is missed?

PURPOSE OF REVIEW: The purpose of this review is to define the role of annuloplasty in the surgical edge-to-edge repair, an issue that seems particularly relevant in the current MitraClip era, when more than 15 000 patients have been submitted to a percutaneous transcatheter edge-to-edge repair without concomitant annuloplasty. RECENT FINDINGS: Only a few studies have reported the clinical and echocardiographic outcomes of the ringless edge-to-edge mitral repair. In all of them, however, only mid-term data were provided. Recently, the long-term results of the surgical edge-to-edge procedure performed without a concomitant annuloplasty in a selected group of patients with degenerative mitral regurgitation have been published. SUMMARY: The surgical edge-to-edge technique should always be combined with prosthetic ring annuloplasty in order to provide excellent long-term outcomes in patients with degenerative mitral regurgitation. The overall long-term results of the surgical edge-to-edge technique without annuloplasty are not satisfactory. The ringless edge-to-edge technique is not effective in the challenging setting of extensively calcified annulus. In patients without annular calcification, in whom annuloplasty was intentionally avoided, the ringless edge-to-edge repair provides acceptable results in the mid term but is associated with a high failure rate in the long term. In the MitraClip perspective, these findings emphasize the need for a reliable annuloplasty to improve the long-term outcomes of the currently available transcatheter edge-to-edge procedure.

Prenatal pharmacotherapy rescues brain development in a Down's syndrome mouse model.

Intellectual impairment is a strongly disabling feature of Down's syndrome, a genetic disorder of high prevalence (1 in 700-1000 live births) caused by trisomy of chromosome 21. Accumulating evidence shows that widespread neurogenesis impairment is a major determinant of abnormal brain development and, hence, of intellectual disability in Down's syndrome. This defect is worsened by dendritic hypotrophy and connectivity alterations. Most of the pharmacotherapies designed to improve cognitive performance in Down's syndrome have been attempted in Down's syndrome mouse models during adult life stages. Yet, as neurogenesis is mainly a prenatal event, treatments aimed at correcting neurogenesis failure in Down's syndrome should be administered during pregnancy. Correction of neurogenesis during the very first stages of brain formation may, in turn, rescue improper brain wiring. The aim of our study was to establish whether it is possible to rescue the neurodevelopmental alterations that characterize the trisomic brain with a prenatal pharmacotherapy with fluoxetine, a drug that is able to restore post-natal hippocampal neurogenesis in the Ts65Dn mouse model of Down's syndrome. Pregnant Ts65Dn females were treated with fluoxetine from embryonic Day 10 until delivery. On post-natal Day 2 the pups received an injection of 5-bromo-2-deoxyuridine and were sacrificed after either 2 h or after 43 days (at the age of 45 days). Untreated 2-day-old Ts65Dn mice exhibited a severe neurogenesis reduction and hypocellularity throughout the forebrain (subventricular zone, subgranular zone, neocortex, striatum, thalamus and hypothalamus), midbrain (mesencephalon) and hindbrain (cerebellum and pons). In embryonically treated 2-day-old Ts65Dn mice, precursor proliferation and cellularity were fully restored throughout all brain regions. The recovery of proliferation potency and cellularity was still present in treated Ts65Dn 45-day-old mice. Moreover, embryonic treatment restored dendritic development, cortical and hippocampal synapse development and brain volume. Importantly, these effects were accompanied by recovery of behavioural performance. The cognitive deficits caused by Down's syndrome have long been considered irreversible. The current study provides novel evidence that a pharmacotherapy with fluoxetine during embryonic development is able to fully rescue the abnormal brain development and behavioural deficits that are typical of Down's syndrome. If the positive effects of fluoxetine on the brain of a mouse model are replicated in foetuses with Down's syndrome, fluoxetine, a drug usable in humans, may represent a breakthrough for the therapy of intellectual disability in Down's syndrome.

Transcatheter vs surgical aortic valve replacement in intermediate-surgical-risk patients with aortic stenosis: a propensity score-matched case-control study.

BACKGROUND: Limited real-world data comparing outcomes after transcatheter (TAVR) and surgical aortic valve replacement (SAVR) in intermediate-surgical-risk patients with aortic stenosis are available. METHODS: We identified 182 consecutive patients who underwent TAVR via the transfemoral (TF) route (November 2007-February 2011) and 111 moderate-to-high-risk historical case controls undergoing SAVR (August 2003-July 2008). Using propensity score matching based on clinical characteristics and surgical risk scores, we compared clinical outcomes in 111 matched patients. Valve Academic Research Consortium definitions were applied for end point adjudication. RESULTS: Baseline clinical characteristics, in particular Logistic European System for Cardiac Operative Risk Evaluation (23.2 ± 15.1 vs 24.4 ± 13.4) and Society of Thoracic Surgeons score (4.6 ± 2.3 vs 4.6 ± 2.6), were well matched between groups. Transfemoral TAVR was associated with more vascular complications (33.3% vs 0.9%, P < .001). On the other hand, acute kidney injury was more frequent after SAVR (8.1% vs 26.1%, P < .001). The rates of all-cause mortality in both TF-TAVR and SAVR groups was1.8% at 30 days (P = 1.00) and 6.4% and 8.1%, respectively, at 1 year (P = .80). At 1 year, the rate of cerebrovascular events was similar in the 2 groups (4.6% vs 9.1%, P = .19). CONCLUSIONS: In this real-world cohort of intermediate-surgical-risk patients with aortic stenosis, TF-TAVR and SAVR were associated with similar mortality rates during follow-up but with a different spectrum of periprocedural complications. Furthermore, the survival rate after TF-TAVR in this group of elderly patients with intermediate Society of Thoracic Surgeons score was encouraging.

Percutaneous mitral valve repair with the MitraClip system: acute results from a real world setting.

AIMS: This study sought to evaluate the feasibility and early outcomes of a percutaneous edge-to-edge repair approach for mitral valve regurgitation with the MitraClip system (Evalve, Inc., Menlo Park, CA, USA). METHODS AND RESULTS PATIENTS: were selected for the procedure based on the consensus of a multidisciplinary team. The primary efficacy endpoint was acute device success defined as clip placement with reduction of mitral regurgitation to < or =2+. The primary acute safety endpoint was 30-day freedom from major adverse events, defined as the composite of death, myocardial infarction, non-elective cardiac surgery for adverse events, renal failure, transfusion of >2 units of blood, ventilation for >48 h, deep wound infection, septicaemia, and new onset of atrial fibrillation. Thirty-one patients (median age 71, male 81%) were treated between August 2008 and July 2009. Eighteen patients (58%) presented with functional disease and 13 patients (42%) presented with organic degenerative disease. A clip was successfully implanted in 19 patients (61%) and two clips in 12 patients (39%). The median device implantation time was 80 min. At 30 days, there was an intra-procedural cardiac tamponade and a non-cardiac death, resulting in a primary safety endpoint of 93.6% [95% confidence interval (CI) 77.2-98.9]. Acute device success was observed in 96.8% of patients (95% CI 81.5-99.8). Compared with baseline, left ventricular diameters, diastolic left ventricular volume, diastolic annular septal-lateral dimension, and mitral valve area significantly diminished at 30 days. CONCLUSION: Our initial results with the MitraClip device in a very small number of patients indicate that percutaneous edge-to-edge mitral valve repair is feasible and may be accomplished with favourable short-term safety and efficacy results.

The flavonoid 7,8-DHF fosters prenatal brain proliferation potency in a mouse model of Down syndrome.

Neurogenesis impairment is a key determinant of intellectual disability in Down syndrome (DS), a genetic pathology due to triplication of chromosome 21. Since neurogenesis ceases after birth, apart in the hippocampus and olfactory bulb, the only means to tackle the problem of neurogenesis impairment in DS at its root is to intervene during gestation. A few studies in DS mouse models show that this is possible, although the drugs used may raise caveats in terms of safety. We previously found that neonatal treatment with 7,8-dihydroxyflavone (7,8-DHF), a flavonoid present in plants, restores hippocampal neurogenesis in the Ts65Dn model of DS. The goal of the current study was to establish whether prenatal treatment with 7,8-DHF improves/restores overall brain proliferation potency. Pregnant Ts65Dn females received 7,8-DHF from embryonic day 10 until delivery. On postnatal day 2 (P2) the pups were injected with BrdU and were killed after either 2 h or 52-60 days (P52-60). Evaluation of the number of proliferating (BrdU+) cells in various forebrain neurogenic niches of P2 mice showed that in treated Ts65Dn mice proliferation potency was improved or even restored in most of the examined regions, including the hippocampus. Quantification of the surviving BrdU+ cells in the dentate gyrus of P52-60 mice showed no difference between treated and untreated Ts65Dn mice. At P52-60, however, treated Ts65Dn mice exhibited a larger number of granule cells in comparison with their untreated counterparts, although their number did not reach that of euploid mice. Results show that 7,8-DHF has a widespread impact on prenatal proliferation potency in Ts65Dn mice and exerts mild long-term effects. It remains to be established whether treatment extending into the neonatal period can lead to an improvement in brain development that is retained in adulthood.

Transcatheter aortic valve implantation through the left subclavian artery with a patent LIMA graft.

We report the case of an 80-year-old male with severe aortic valve stenosis previously submitted to surgical myocardial revascularization with patent mammary graft treated by TAVI through left-transaxillary approach because of unsuitable transfemoral and transapical approaches.

A new technique for vascular access management in transcatheter aortic valve implantation.

OBJECTIVES: To describe results from a novel percutaneous technique designed to minimize the risk of hemorrhage in the event of a major complication during transcatheter aortic valve implantation. BACKGROUND: Vascular access management is a major challenge in transfemoral TAVI due to the large introducer sheathes required. METHODS: Fifty-two pts underwent TAVI between November 2007 and March 2009. Of these, 37 received an Edwards-Sapien Valve (23 mm valve: 17/37; 26 mm valve: 20/37) whilst 15 patients received a CoreValve (26 mm valve: 6/15; 29 mm valve: 9/15). Using a crossover technique, the opposing femoral artery was cannulated with a 7Fr long sheath. This allowed contralateral passage of a balloon and inflation in the proximal iliac. The sheath was then removed and Prostar sutures tied in a dry field. Balloon optimization of the puncture site was performed as required. RESULTS: In three subjects, elective surgical repair was undertaken due to excessive femoral arterial calcification. In the remaining 49, the crossover technique was employed and closed with two Prostar devices (Edwards-Sapien) or one (CoreValve). There were serious "on-table" complications in seven patients, six due to the large introducer sheathes used in the TAVI procedure-iliac avulsion, two iliac dissections, iliac perforation, common femoral perforation and scrotal hematoma. All were repaired safely by combined surgical and endovascular techniques, using the crossover technique to ensure patient stability. All made a good recovery and were independently ambulant at discharge. CONCLUSION: Using crossover balloon inflation as an adjunct to Prostar closure may be helpful for managing TAVI vascular access sites.

Neuroanatomical alterations in higher-order thalamic nuclei of fetuses with Down syndrome.

OBJECTIVES: Down syndrome (DS) is a genetic condition characterized by cognitive disability starting from infancy. Children with DS exhibit deficits in several cognitive domains, including executive function, i.e., a set of cognitive processes that heavily depend on higher-order thalamic nuclei. The goal of this study was to establish whether executive function-related thalamic nuclei of fetuses with DS exhibit neuroanatomical alterations that may contribute to the defects in higher-order control processes seen in children with DS. PATIENTS AND METHODS: In brain sections from fetuses with DS and control fetuses (gestational week 17-22), we evaluated the cellularity in the mediodorsal nucleus (MD), the centromedian nucleus (CM), and the parafascicular nucleus (PF) of the thalamus and the density of proliferating cells in the third ventricle. RESULTS: We found that all three nuclei had a notably reduced cell density. This defect was associated with a reduced density of proliferating cells in the third ventricle, suggesting that the reduced cellularity in the MD, CM, and PF of fetuses with DS was due to neurogenesis impairment. The separate evaluation of projection neurons and interneurons in the MD, CM, and PF showed that in fetuses with DS the density of projection neurons was reduced, with no changes in interneuron density. CONCLUSION: This study provides novel evidence for DS-linked cellularity alterations in the MD, CM, and PF and suggests that altered signal processing in these nuclei may be involved in the impairment in higher-order control processes observed in individuals with DS starting from infancy.

Excellent long-term results with minimally invasive edge-to-edge repair in myxomatous degenerative mitral valve regurgitation.

OBJECTIVES: Previous series of minimally invasive mitral valve repairs showed excellent results at up to 10 years of follow-up. The goal of this study was to assess the long-term durability beyond 10 years of the edge-to-edge repair for myxomatous degeneration performed through a minimally invasive approach. METHODS: Ninety-seven consecutive patients (mean age 35 ± 9 years; left ventricular ejection fraction 63 ± 6%) with severe myxomatous mitral regurgitation (MR) underwent mitral valve repair through a right minithoracotomy between 1999 and 2006. MR was due to lesions involving the posterior leaflet (7.2% of patients), anterior leaflet (12.4%) and both leaflets (80.4%). RESULTS: No hospital deaths occurred. At hospital discharge all patients had no or trivial MR. Follow-up was 100% complete (median 15.5 years; interquartile range 13.6-17.0, max 19.3 years). The 16-year overall survival rate was 95.9 ± 2.02% [95% confidence interval (CI) 89.39-98.43]. At 16 years, the cumulative incidence function of cardiac death, with non-cardiac death as a competing risk, was 3.1 ± 1.75 (95% CI 0.83-8.02). Only 3 patients (4.1%) had redo operations for recurrent severe MR. At 16 years, the cumulative incidence functions of reoperation for and recurrence of MR ≥3+, with death as a competing risk, were 3.1 ± 1.76% (95% CI 0.83-8.02) and 5.6 ± 2.47% (95% CI 2.06-11.83), respectively. No predictors of recurrence of MR ≥3+ were identified. At the last follow-up, moderate MR (2+/4+) was detected in 17 patients (17.5%); most of the patients were in New York Heart Association functional class I-II (97%) and in sinus rhythm (90%). CONCLUSIONS: Minimally invasive mitral valve edge-to-edge repair through a right minithoracotomy for myxomatous degeneration appears to be an effective and durable approach even in the long-term follow-up (up to 19 years).