Clinical and echocardiographic results of the MEMO 4D semi-rigid annuloplasty ring.

Background: Mitral regurgitation is a frequent valvular disease, with an increasing prevalence. We analyzed the short-term outcomes of mitral valve repair procedures conducted in our clinic using a new semirigid annuloplasty ring featuring a gradual saddle shape design.

Methods: We retrospectively analyzed mitral valve repair surgeries performed at our Institution between December 2019 and November 2021 with the MEMO 4D semirigid annuloplasty ring.

Upregulation of Ca-binding proteins contributes to VTA dopamine neuron survival in the early phases of Alzheimer's disease in Tg2576 mice.

Background: Recent clinical and experimental studies have highlighted the involvement of Ventral Tegmental Area (VTA) dopamine (DA) neurons for the early pathogenesis of Alzheimer's Disease (AD). We have previously described a progressive and selective degeneration of these neurons in the Tg2576 mouse model of AD, long before amyloid-beta plaque formation. The degenerative process in DA neurons is associated with an autophagy flux impairment, whose rescue can prevent neuronal loss.

Astrocytes mediate long-lasting synaptic regulation of ventral tegmental area dopamine neurons.

The plasticity of glutamatergic transmission in the ventral tegmental area (VTA) represents a fundamental mechanism in the modulation of dopamine neuron burst firing and phasic dopamine release at target regions. These processes encode basic behavioral responses, including locomotor activity, learning and motivated behaviors. Here we describe a hitherto unidentified mechanism of long-term synaptic plasticity in mouse VTA.

Genetic deletion of α7 nicotinic acetylcholine receptors induces an age-dependent Alzheimer's disease-like pathology.

The accumulation of amyloid-beta peptide (Aβ) and the failure of cholinergic transmission are key players in Alzheimer's disease (AD). However, in the healthy brain, Aβ contributes to synaptic plasticity and memory acting through α7 subtype nicotinic acetylcholine receptors (α7nAChRs). Here, we hypothesized that the α7nAChR deletion blocks Aβ physiological function and promotes a compensatory increase in Aβ levels that, in turn, triggers an AD-like pathology.

Specific activation of GluN1-N2B NMDA receptors underlies facilitation of cortical spreading depression in a genetic mouse model of migraine with reduced astrocytic glutamate clearance.

Migraine is a common but poorly understood sensory circuit disorder. Mouse models of familial hemiplegic migraine (FHM, a rare monogenic form of migraine with aura) show increased susceptibility to cortical spreading depression (CSD, the phenomenon that underlies migraine aura and can activate migraine headache mechanisms), allowing an opportunity to investigate the mechanisms of CSD and migraine onset. In FHM type 2 (FHM2) knock-in mice with reduced expression of astrocytic Na, K-ATPases, the reduced rate of glutamate uptake into astrocytes can account for the facilitation of CSD initiation.

Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer's Disease.

What happens precociously to the brain destined to develop Alzheimer's Disease (AD) still remains to be elucidated and this is one reason why effective AD treatments are missing. Recent experimental and clinical studies indicate that the degeneration of the dopaminergic (DA) neurons in the Ventral Tegmental Area (VTA) could be one of the first events occurring in AD. However, the causes of the increased vulnerability of DA neurons in AD are missing.

Non-canonical glutamate signaling in a genetic model of migraine with aura.

Migraine with aura is a common but poorly understood sensory circuit disorder. Monogenic models allow an opportunity to investigate its mechanisms, including spreading depolarization (SD), the phenomenon underlying migraine aura. Using fluorescent glutamate imaging, we show that awake mice carrying a familial hemiplegic migraine type 2 (FHM2) mutation have slower clearance during sensory processing, as well as previously undescribed spontaneous "plumes" of glutamate.

A Reappraisal of GAT-1 Localization in Neocortex.

γ-Aminobutyric acid (GABA) transporter (GAT)-1, the major GABA transporter in the brain, plays a key role in modulating GABA signaling and is involved in the pathophysiology of several neuropsychiatric diseases, including epilepsy. The original description of GAT-1 as a neuronal transporter has guided the interpretation of the findings of all physiological, pharmacological, genetic, or clinical studies. However, evidence published in the past few years, some of which is briefly reviewed herein, does not seem to be consistent with a neurocentric view of GAT-1 function and calls for more detailed analysis of its localization.

Microglial expression of GAT-1 in the cerebral cortex.

Microglial cells are the immune cells of the brain that, by sensing the microenvironment, permit a correct brain development and function. They communicate with other glial cells and with neurons, releasing and responding to a number of molecules that exert effects on surrounding cells. Among these, neurotransmitters and, in particular, gamma-aminobutyric acid (GABA) has recently gained interest in this context.

Neuromodulatory Action of Picomolar Extracellular Aβ42 Oligomers on Presynaptic and Postsynaptic Mechanisms Underlying Synaptic Function and Memory.

Failure of anti-amyloid-β peptide (Aβ) therapies against Alzheimer's disease (AD), a neurodegenerative disorder characterized by high amounts of the peptide in the brain, raised the question of the physiological role of Aβ released at low concentrations in the healthy brain. To address this question, we studied the presynaptic and postsynaptic mechanisms underlying the neuromodulatory action of picomolar amounts of oligomeric Aβ (oAβ) on synaptic glutamatergic function in male and female mice. We found that 200 pm oAβ induces an increase of frequency of miniature EPSCs and a decrease of paired pulse facilitation, associated with an increase in docked vesicle number, indicating that it augments neurotransmitter release at presynaptic level.

Heterogeneity of Astrocytic and Neuronal GLT-1 at Cortical Excitatory Synapses, as Revealed by its Colocalization With Na+/K+-ATPase α Isoforms.

GLT-1, the major glutamate transporter, is expressed at perisynaptic astrocytic processes (PAP) and axon terminals (AxT). GLT-1 is coupled to Na+/K+-ATPase (NKA) α1-3 isoforms, whose subcellular distribution and spatial organization in relationship to GLT-1 are largely unknown. Using several microscopy techniques, we showed that at excitatory synapses α1 and α3 are exclusively neuronal (mainly in dendrites and in some AxT), while α2 is predominantly astrocytic.

Hypoalbuminemia as a predictor of acute kidney injury during colistin treatment.

This study aimed to assess the predictors of acute kidney injury (AKI) during colistin therapy in a cohort of patients with bloodstream infections (BSI) due to colistin-susceptible Gram-negative bacteria, focusing on the role of serum albumin levels. The study consisted of two parts: (1) a multicentre retrospective clinical study to assess the predictors of AKI during colistin therapy, defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria; and (2) bioinformatic and biochemical characterization of the possible interaction between human serum albumin and colistin. Among the 170 patients included in the study, 71 (42%), 35 (21%), and 11 (6%) developed KDIGO stage 1 (K1-AKI), KDIGO stage 2 (K2-AKI), and KDIGO stage 3 (K3-AKI), respectively.

The effect of amyloid-β peptide on synaptic plasticity and memory is influenced by different isoforms, concentrations, and aggregation status.

The increase of oligomeric amyloid-beta (oAβ) has been related to synaptic dysfunction, thought to be the earliest event in Alzheimer's disease pathophysiology. Conversely, the suppression of endogenous Aβ impaired synaptic plasticity and memory, suggesting that the peptide is needed in the healthy brain. However, different species, aggregation forms and concentrations of Aβ might differently influence synaptic function/dysfunction.

Interneuron-specific signaling evokes distinctive somatostatin-mediated responses in adult cortical astrocytes.

The signaling diversity of GABAergic interneurons to post-synaptic neurons is crucial to generate the functional heterogeneity that characterizes brain circuits. Whether this diversity applies to other brain cells, such as the glial cells astrocytes, remains unexplored. Using optogenetics and two-photon functional imaging in the adult mouse neocortex, we here reveal that parvalbumin- and somatostatin-expressing interneurons, two key interneuron classes in the brain, differentially signal to astrocytes inducing weak and robust GABA receptor-mediated Ca elevations, respectively.

In-vivo effects of knocking-down metabotropic glutamate receptor 5 in the SOD1 mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder due to loss of upper and lower motor neurons (MNs). The mechanisms of neuronal death are largely unknown, thus prejudicing the successful pharmacological treatment. One major cause for MN degeneration in ALS is represented by glutamate(Glu)-mediated excitotoxicity.

GAT-1 mediated GABA uptake in rat oligodendrocytes.

Stimulated by the results of a recent paper on the effects of tiagabine, a selective inhibitor of the main GABA transporter GAT-1, on oligodendrogenesis, we verified the possibility that GAT-1 may be expressed in oligodendrocytes using immunocytochemical methods and functional assays. Light microscopic analysis of the subcortical white matter of all animals revealed the presence of numerous GAT-1+ cells of different size (from 3 to 29 µm) and morphology. An electron microscope analysis revealed that, besides fibrous astrocytes and interstitial neurons, GAT-1 immunoreactivity was present in immature and mature oligodendrocytes.

Defective glutamate and K+ clearance by cortical astrocytes in familial hemiplegic migraine type 2.

Migraine is a common disabling brain disorder. A subtype of migraine with aura (familial hemiplegic migraine type 2: FHM2) is caused by loss-of-function mutations in α2 Na(+),K(+) ATPase (α2 NKA), an isoform almost exclusively expressed in astrocytes in adult brain. Cortical spreading depression (CSD), the phenomenon that underlies migraine aura and activates migraine headache mechanisms, is facilitated in heterozygous FHM2-knockin mice with reduced expression of α2 NKA The mechanisms underlying an increased susceptibility to CSD in FHM2 are unknown.

Plasma membrane transporters GAT-1 and GAT-3 contribute to heterogeneity of GABAergic synapses in neocortex.

Cortical GABAergic synapses exhibit a high degree of molecular, anatomical and functional heterogeneity of their neurons of origins, presynaptic mechanisms, receptors, and scaffolding proteins. GABA transporters (GATs) have an important role in regulating GABA levels; among them, GAT-1 and GAT-3 play a prominent role in modulating tonic and phasic GABAAR-mediated inhibition. We asked whether GAT-1 and GAT-3 contribute to generating heterogeneity by studying their ultrastructural localization at cortical symmetric synapses using pre- and post-embedding electron microcopy.

A quantitative analysis of cellular and synaptic localization of GAT-1 and GAT-3 in rat neocortex.

High-affinity plasma membrane GABA transporters GAT-1 and GAT-3 contribute to the modulation of GABA-mediated inhibition in adult mammalian cerebral cortex. How GATs regulate inhibition in neocortical circuits remains however poorly understood for the lack of information on key localizational features. In this study, we used quantitative pre- and post-embedding electron microscopy to define the distribution of GAT-1 and GAT-3 in elements contributing to synapses and to unveil their ultrastructural organization at adult cortical GABAergic synapses.