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International audience; PURPOSE: Severely ill patients affected by coronavirus disease 2019 (COVID-19) develop circulatory failure. We aimed to report patterns of left and right ventricular dysfunction in the first echocardiography following admission to intensive care unit (ICU). METHODS: Retrospective, descriptive study that collected echocardiographic and clinical information from severely ill COVID-19 patients admitted to 14 ICUs in 8 countries. Patients admitted to ICU who received at least one echocardiography between 1st February 2020 and 30th June 2021 were included. Clinical and echocardiographic data were uploaded using a secured web-based electronic database (REDCap). RESULTS: Six hundred and seventy-seven patients were included and the first echo was performed 2 [1, 4] days after ICU admission. The median age was 65 [56, 73] years, and 71% were male. Left ventricle (LV) and/or right ventricle (RV) systolic dysfunction were found in 234 (34.5%) patients. 149 (22%) patients had LV systolic dysfunction (with or without RV dysfunction) without LV dilatation and no elevation in filling pressure. 152 (22.5%) had RV systolic dysfunction. In 517 patients with information on both paradoxical septal motion and quantitative RV size, 90 (17.4%) had acute cor pulmonale (ACP). ACP was associated with mechanical ventilation (OR\,>\,4), pulmonary embolism (OR\,>\,5) and increased PaCO(2). Exploratory analyses showed that patients with ACP and older age were more likely to die in hospital (including ICU). CONCLUSION: Almost one-third of this cohort of critically ill COVID-19 patients exhibited abnormal LV and/or RV systolic function in their first echocardiography assessment. While LV systolic dysfunction appears similar to septic cardiomyopathy, RV systolic dysfunction was related to pressure overload due to positive pressure ventilation, hypercapnia and pulmonary embolism. ACP and age seemed to be associated with mortality in this cohort.

Stress represents a major risk factor for psychiatric disorders, including post-traumatic stress disorder (PTSD). Recently, we dissected the destabilizing effects of acute stress on the excitatory glutamate system in the prefrontal cortex (PFC). Here, we assessed the effects of single subanesthetic administration of ketamine (10 mg/kg) on glutamate transmission and dendritic arborization in the PFC of footshock (FS)-stressed rats, along with changes in depressive, anxious, and fear extinction behaviors. We found that ketamine, while inducing a mild increase of glutamate release in the PFC of naïve rats, blocked the acute stress-induced enhancement of glutamate release when administered 24 or 72 h before or 6 h after FS. Accordingly, the treatment with ketamine 6 h after FS also reduced the stress-dependent increase of spontaneous excitatory postsynaptic current (sEPSC) amplitude in prelimbic (PL)-PFC. At the same time, ketamine injection 6 h after FS was found to rescue apical dendritic retraction of pyramidal neurons induced by acute stress in PL-PFC and facilitated contextual fear extinction. These results show rapid effects of ketamine in animals subjected to acute FS, in line with previous studies suggesting a therapeutic action of the drug in PTSD models. Our data are consistent with a mechanism of ketamine involving re-establishment of synaptic homeostasis, through restoration of glutamate release, and structural remodeling of dendrites.

L’ernia lombare di Grynfeltt, dall’ autore che per primo l’ha descritta nel 1866, fra tutte le ernie della parete addominale è la più rara, rappresenta infatti secondo i dati della letteratura più recente solo il 2% di tutte le ernie. Di queste circa il 20% è congenita, secondaria principalmente a difetti di sviluppo embrionale mentre l’80% sono difetti acquisiti. Gli interventi chirurgici, le ferite penetranti e le infezioni rappresentano fattori di rischio per lo sviluppo di ernie lombari secondarie e pertanto iatrogene. In letteratura è riportata una prevalenza dell’ernia a sinistra mentre eccezionale è l’osservazione di una ernia di Grynfeltt bilaterale. La recente osservazione di una voluminosa ernia di Grynfeltt ci ha indotti a rivedere l’argomento e ad eseguire una revisione della letteratura e della nostra casistica. Sulla base della nostra esperienza personale, in accordo con la letteratura più recente, riteniamo che nel caso di ernie lombari di Grynfeltt, l’approccio laparotomico con utilizzo di materiali protesici sia il più appropriato, rendendo così la procedura rapida, facile e sicura, in controtendenza al trattamento di tutti gli altri difetti della parete per i quali preferiamo sempre un approccio laparoscopico. A conferma di ciò si percepisce che la tecnica open attualmente sia più diffusa, infatti una piccola lombotomia risulta di facile esecuzione, rapida e può essere eseguita anche in anestesia loco-regionale o epidurale. Grynfeltt's lumbar hernia, from the author who first described it in 1866, is the rarest among all hernias of the abdominal wall and it represents, according to the most recent literature, only 2% of all hernias. Of these, about 20% are congenital, secondary mainly to defects of embryonic development, while 80% are acquired defects. Surgeries, penetrating wounds, and infections are risk factors for the development of secondary and therefore iatrogenic lumbar hernias. In the literature, there is a predominance of the left Grynfeltt hernia while a bilateral presentation is exceptional. Our recent observation of a massive Grynfeltt hernia brought us to perform a revision of the literature and of our case studies. Based on our personal experience, with the most recent literature, we believe that in the case of Grynfeltt's lumbar hernias, the laparotomy approach with the use of prosthetic materials is the most appropriate, thus making the procedure fast, easy, and safe, compared to the treatment of all other wall defects that often require a laparoscopic approach. To confirm this, it is perceived that the open technique is currently more widespread; in fact, a small lumbotomy is easy to perform, fast, and can also be performed under loco-regional or epidural anaesthesia. KEY WORDS: Lumbar hernioplasty, Grynfeltt hernia, Hernia repair.

Endotracheal intubation (ETI) in the pediatric setting is a complex skill and performing ETI during pediatric cardiopulmonary resuscitation is even more challenging. Simulation studies have investigated the performances of several devices for ETI. We undertook a systematic review and meta-analysis to evaluate the performances of devices for ETI during simulated pediatric on-going chest compressions. Devices were divided in four groups: direct laryngoscopy (DL) with Macintosh or Miller blade, or video-laryngoscopy with screen-on-device (VLS-SoD) or with distant monitor (VLS-DM). Primary outcomes were overall success rate (SR) and time-to-intubation (TTI). Results are expressed as Risk Ratio (RR) or Mean Difference (MD) with 95% confidence interval. We included 12 studies comparing at least two devices. The SR was greater for VLS as compared to DL-Miller (RR: 0.83 (0.78; 0.89), p < 0.00001) or DL-Macintosh (RR: 0.81 (0.77; 0.85), p < 0.00001). Subgroup analyses confirmed that both types of VLS were superior to DL-Miller (VLS-DM: p = 0.03; VLS-SoD: p < 0.00001) or DL-Macintosh (both VLSs: p < 0.00001). As compared with VLS, TTI was longer with both DL blades: Miller (MD: 8.26 seconds (5.30; 11.21), p < 0.00001) or Macintosh blade (MD: 7.63 seconds (4.14; 11.12), p < 0.00001). In the subgroup analyses, VLS-SoD was superior to DL-Miller or DL-Macintosh (both p < 0.00001), while VLS-DM was superior to DL-Macintosh (p < 0.00001), possibly not to DL-Miller (p = 0.06). Under simulated conditions of ongoing pediatric resuscitation, use of VLS guarantees higher overall SR and shorter TTI as compared to DL performed with Miller or Macintosh blade. Among VLSs, those with screen-on-device may have better performances that those with distant monitor.

The fragile X syndrome (FXS), the most common form of inherited intellectual disability, is due to the absence of FMRP, a protein regulating RNA metabolism. Recently, an unexpected function of FMRP in modulating the activity of Adenosine Deaminase Acting on RNA (ADAR) enzymes has been reported both in Drosophila and Zebrafish. ADARs are RNA-binding proteins that increase transcriptional complexity through a post-transcriptional mechanism called RNA editing. To evaluate the ADAR2-FMRP interaction in mammals we analyzed several RNA editing re-coding sites in the fmr1 knockout (KO) mice. Ex vivo and in vitro analysis revealed that absence of FMRP leads to an increase in the editing levels of brain specific mRNAs, indicating that FMRP might act as an inhibitor of editing activity. Proximity Ligation Assay (PLA) in mouse primary cortical neurons and in non-neuronal cells revealed that ADAR2 and FMRP co-localize in the nucleus. The ADAR2-FMRP co-localization was further observed by double-immunogold Electron Microscopy (EM) in the hippocampus. Moreover, ADAR2-FMRP interaction appeared to be RNA independent. Because changes in the editing pattern are associated with neuropsychiatric and neurodevelopmental disorders, we propose that the increased editing observed in the fmr1-KO mice might contribute to the FXS molecular phenotypes.

Stress is a primary risk factor for psychiatric disorders such as Major Depressive Disorder (MDD) and Post Traumatic Stress Disorder (PTSD). The response to stress involves the regulation of transcriptional programs, which is supposed to play a role in coping with stress. To evaluate transcriptional processes implemented after exposure to unavoidable traumatic stress, we applied microarray expression analysis to the PFC of rats exposed to acute footshock (FS) stress that were sacrificed immediately after the 40 min session or 2 h or 24 h after. While no substantial changes were observed at the single gene level immediately after the stress session, gene set enrichment analysis showed alterations in neuronal pathways associated with glia development, glia–neuron networking, and synaptic function. Furthermore, we found alterations in the expression of gene sets regulated by specific transcription factors that could represent master regulators of the acute stress response. Of note, these pathways and transcriptional programs are activated during the early stress response (immediately after FS) and are already turned off after 2 h—while at 24 h, the transcriptional profile is largely unaffected. Overall, our analysis provided a transcriptional landscape of the early changes triggered by acute unavoidable FS stress in the PFC of rats, suggesting that the transcriptional wave is fast and mild, but probably enough to activate a cellular response to acute stress.

Traumatic stress is the main environmental risk factor for the development of psychiatric disorders. We have previously shown that acute footshock (FS) stress in male rats induces rapid and long-lasting functional and structural changes in the prefrontal cortex (PFC), which are partly reversed by acute subanesthetic ketamine. Here, we asked if acute FS may also induce any changes in glutamatergic synaptic plasticity in the PFC 24 h after stress exposure and whether ketamine administration 6 h after stress may have any effect. We found that the induction of long-term potentiation (LTP) in PFC slices of both control and FS animals is dependent on dopamine and that dopamine-dependent LTP is reduced by ketamine. We also found selective changes in ionotropic glutamate receptor subunit expression, phosphorylation, and localization at synaptic membranes induced by both acute stress and ketamine. Although more studies are needed to understand the effects of acute stress and ketamine on PFC glutamatergic plasticity, this first report suggests a restoring effect of acute ketamine, supporting the potential benefit of ketamine in limiting the impact of acute traumatic stress.

Stress is a key risk factor in the onset of neuropsychiatric disorders. The study of the mechanisms underlying stress response is important to understand the etiopathogenetic mechanisms and identify new putative therapeutic targets. In this context, microRNAs (miRNAs) have emerged as key regulators of the complex patterns of gene/protein expression changes in the brain, where they have a crucial role in the regulation of neuroplasticity, neurogenesis, and neuronal differentiation. Among them, miR-135a-5p has been associated with stress response, synaptic plasticity, and the antidepressant effect in different brain areas. Here, we used acute unavoidable foot-shock stress (FS) and chronic mild stress (CMS) on male rats to study whether miR-135a-5p was involved in stress-induced changes in the prefrontal cortex (PFC). Both acute and chronic stress decreased miR-135a-5p levels in the PFC, although after CMS the reduction was induced only in animals vulnerable to CMS, according to a sucrose preference test. MiR-135a-5p downregulation in the primary neurons reduced dendritic spine density, while its overexpression exerted the opposite effect. Two bioinformatically predicted target genes, Kif5c and Cplx1/2, were increased in FS rats 24 h after stress. Altogether, we found that miR-135a-5p might play a role in stress response in PFC involving synaptic mechanisms.

Converging clinical and preclinical evidence demonstrates that depressive phenotypes are associated with synaptic dysfunction and dendritic simplification in cortico-limbic glutamatergic areas. On the other hand, the rapid antidepressant effect of acute ketamine is consistently reported to occur together with the rescue of dendritic atrophy and reduction of spine number induced by chronic stress in the hippocampus and prefrontal cortex of animal models of depression. Nevertheless, the molecular mechanisms underlying these morphological alterations remain largely unknown. Here, we found that miR-9-5p levels were selectively reduced in the hippocampus of rats vulnerable to Chronic Mild Stress (CMS), while acute subanesthetic ketamine restored its levels to basal condition in just 24h; miR-9-5p expression inversely correlated with the anhedonic phenotype. A decrease of miR-9-5p was reproduced in an in vitro model of stress, based on primary hippocampal neurons incubated with the stress hormone corticosterone. In both CMS animals and primary neurons, decreased miR-9-5p levels were associated with dendritic simplification, while treatment with ketamine completely rescued the changes. In vitro modulation of miR-9-5p expression showed a direct role of miR-9-5p in regulating dendritic length and spine density in mature primary hippocampal neurons. Among the putative target genes tested, Rest and Sirt1 were validated as biological targets in primary neuronal cultures. Moreover, in line with miR-9-5p changes, REST protein expression levels were remarkably increased in both CMS vulnerable animals and corticosterone-treated neurons, while ketamine completely abolished this alteration. Finally, the shortening of dendritic length in corticosterone-treated neurons was shown to be partly rescued by miR-9-5p overexpression and dependent on REST protein expression. Overall, our data unveiled the functional role of miR-9-5p in the remodeling of dendritic arbor induced by stress/corticosterone in vulnerable animals and its rescue by acute antidepressant treatment with ketamine., Highlights • miR-9-5p is reduced in the hippocampus of stress-vulnerable rats. • miR-9-5p is reduced in primary neurons treated with corticosterone. • Acute ketamine restores stress-induced morphological changes and miR-9-5p levels. • miR-9-5p directly modulates dendritic length and spine number in primary neurons. • REST is a validated target of miR-9-5p.

Stress is a major risk factor in the onset of neuropsychiatric diseases including mood disorders. Stress-based animal models of depression have shown dendritic atrophy and spine remodeling in the hippocampus (HPC), suggesting that stress-induced maladaptive changes have a primary role in the psychopathology. Recent studies showed that a single sub-anesthetic dose of ketamine (KET) exerts a fast and sustained antidepressant effect, accompanied by a rapid reverse of synaptic deficits. However, the molecular mechanisms that underlie the functional and morphological changes induced by stress and KET are still largely unknown. MicroRNA (miRNAs) have emerged as regulators of complex patterns of gene/protein expression changes in the brain and recent studies showed their involvement in the pathophysiology of mood disorders and in the action of psychotropic drugs. Their peculiar ability to fine-tune the expression of hundreds of genes makes them potential candidates as fast mediators of stress-response and KET action. Here we used the Chronic Mild Stress (CMS) animal model of depression and in vitro primary HPC cultures to study whether mechanisms of stress response and KET fast antidepressant action involved changes in dendrite remodeling of HPC pyramidal neurons, together with alteration in the expression of miRNAs known to play a role in neuroplasticity and stress response. Morphological analysis of CA3 pyramidal neurons showed, selectively in animals vulnerable to CMS, a reduction in total length and branching of apical dendrites; KET completely restored these changes. At a molecular level, the expression of miR-9-5p, a brain-enriched miRNA previously associated with neuronal morphology regulation, was selectively decreased in vulnerable animals, while KET recovered the reduction. Further, treatment of primary HPC neurons with corticosterone reduced both dendritic length and miR-9-5p levels; KET fully reversed the changes. By modulating miR-9-5p expression in primary HPC neurons, we demonstrated its direct effect on dendrites and spines remodeling. Bioinformatic analysis followed by in vitro validation identified REST and SIRT1 as biological targets of miR-9-5p. Their expression was further measured in both stress-based models. Our results suggest a role for miR-9-5p in stress-induced dendritic remodeling of pyramidal neurons and in the synaptic restorative action of the antidepressant KET.

Depression is a debilitating mental disease, characterized by persistent low mood and anhedonia. Stress represents a major environmental risk factor for depression; the complex interaction of stress with genetic factors results in different individual vulnerability or resilience to the disorder. Dysfunctions of the glutamate system have a primary role in depression. Clinical neuroimaging studies have consistently reported alterations in volume and connectivity of cortico-limbic areas, where glutamate neurons and synapses predominate. This is confirmed by preclinical studies in rodents, showing that repeated stress induces morphological and functional maladaptive changes in the same brain regions altered in humans. Confirming the key role of glutamatergic transmission in depression, compelling evidence has shown that the non-competitive NMDA receptor antagonist, ketamine, induces, at sub-anesthetic dose, rapid and sustained antidepressant response in both humans and rodents.We show here that the Chronic Mild Stress model of depression induces, only in stress-vulnerable rats, depressed-like anhedonic behavior, together with impairment of glutamate/GABA presynaptic release, BDNF mRNA trafficking in dendrites and dendritic morphology in hippocampus. Moreover, we show that a single administration of ketamine restores, in 24 h, normal behavior and most of the cellular/molecular maladaptive changes in vulnerable rats. Interestingly, ketamine treatment did not restore BDNF mRNA levels reduced by chronic stress but rescued dendritic trafficking of BDNF mRNA.The present results are consistent with a mechanism of ketamine involving rapid restoration of synaptic homeostasis, through re-equilibration of glutamate/GABA release and dendritic BDNF for synaptic translation and reversal of synaptic and circuitry impairment. Keywords: Chronic stress, Ketamine, Stress vulnerability, Glutamate release, BDNF, Antidepressant

Clinical studies on patients with stress-related neuropsychiatric disorders reported functional and morphological changes in brain areas where glutamatergic transmission is predominant, including frontal and prefrontal areas. In line with this evidence, several preclinical works suggest that glutamate receptors are targets of both rapid and long-lasting effects of stress. Here we found that acute footshock- (FS-) stress, although inducing no transcriptional and RNA editing alterations of ionotropic AMPA and NMDA glutamate receptor subunits, rapidly and transiently modulates their protein expression, phosphorylation, and localization at postsynaptic spines in prefrontal and frontal cortex. In total extract, FS-stress increased the phosphorylation levels of GluA1 AMPA subunit at Ser845immediately after stress and of GluA2 Ser8802 h after start of stress. At postsynaptic spines, stress induced a rapid decrease of GluA2 expression, together with an increase of its phosphorylation at Ser880, suggesting internalization of GluA2 AMPA containing receptors. GluN1 and GluN2A NMDA receptor subunits were found markedly upregulated in postsynaptic spines, 2 h after start of stress. These results suggest selected time-dependent changes in glutamatergic receptor subunits induced by acute stress, which may suggest early and transient enhancement of AMPA-mediated currents, followed by a transient activation of NMDA receptors.

An increased load of runs of homozygosity (ROHs) is considered a risk factor for schizophrenia (SZ), suggesting a potential role of recessive genotypes in the pathogenesis of SZ. The whole exome sequencing of SZ patients with high level of ROHs allowed us to identify some rare homozygous mutations with a high probability of being related to SZ, since mapping in neurodevelopment and GABA/glutamatergic synaptic transmission genes. Among these mutations, there was a novel missense substitution (c.391A>G; p.Thr131Ala) in the glutamate acid decarboxylase 1 (GAD1) gene (NM_000817) that encodes for the enzyme (GAD67) catalyzing the production of gamma-aminobutyric acid (GABA) from L-glutamic acid. Since the GAD1 mRNA downregulation as well as reduced levels of GAD67 have been reported in post-mortem brains of SZ patients and since polymorphisms in the GAD1 promoter have been reported as risk factors for SZ, we assessed the biological effect of this mutation to corroborate its potential role in SZ. Confocal immunofluorescence analysis of transfected cells revealed that both the exogenous wild type (WT) and the mutated protein exhibit the same localization: mainly in the Golgi apparatus and in cytosolic vesicles. Biochemical assays showed that the amount of GABA produced by transfected cells expressing the mutated isoform was 30% lower than the amount produced by the cells expressing the WT isoform. These results corroborate the hypothesis that this mutation may impact on the SZ phenotype and supports the hypothesis that also rare recessive mutations are involved in the etiopathogenesis of SZ.

Background/Aims: Compelling evidence would suggest the involvement of the serotonin 2C receptor in the pathophysiology of affective disorders and in the action of antidepressants. We analyzed the time course of 5-HT2C receptor (5-HTR2C) mRNA expression during antidepressant treatment in the prefrontal/frontal cortex (P/FC) and in the hippocampus (HC) of rats chronically treated with fluoxetine (a selective serotonin reuptake inhibitor) and reboxetine (a selective noradrenaline reuptake inhibitor). We also analyzed the 5-HTR2C RNA-editing levels at the sites called A, B, C, C’ and D, which are known to modulate 5-HTR2C receptor function. Results: The expression profile of 5-HTR2C mRNA was modified during treatment with both antidepressants. In particular, we found a general down-regulation of 5-HTR2C mRNA expression in P/FC, which became significant after 3 weeks of treatment with both antidepressants and persisted after a fourth week of drug withdrawal (–46% with fluoxetine, –41% with reboxetine, p < 0.05). In HC, however, reboxetine induced significant down-regulation (–56%, p < 0.05) of 5-HTR2C mRNA after 3 weeks, while fluoxetine induced threefold up-regulation (p < 0.01) by the 2nd and 3rd week, returning to the base level after drug withdrawal of both antidepressants. Moreover, the frequency of 5-HTR2C-edited isoforms showed no significant alterations, although analysis of the RNA-editing level at the single editing sites showed small decreases in the C’ and D sites induced by reboxetine in P/FC. Conclusion: Our results suggest that chronic administration of antidepressants in rats slightly modifies the editing levels of 5-HT2C receptor but has considerable influence on its mRNA expression patterns in a way that is area- and time-specific.

Background Several reports have shown that the glutamatergic system is involved in both the pathogenesis of affective and stress-related disorders and in the action of antidepressant drugs. In particular, antidepressant treatment was shown to modulate expression and function of ionotropic glutamate receptors, to inhibit glutamate release and to restore synaptic plasticity impaired by stress. Methods We analyzed the mRNA expression and RNA editing of α-amino-propionic-acid (AMPA) and kainate (KA) receptor subunits, in the pre-frontal/frontal cortex (P/FC) and hippocampus (HI) of rats chronically treated with three different drugs: the selective serotonin (5-HT) reuptake inhibitor fluoxetine, the selective noradrenaline (NA) reuptake inhibitor reboxetine and the tricyclic antidepressant desipramine. Results Our data showed that fluoxetine and desipramine exerted moderate but selective effects on glutamate receptor expression and editing, while reboxetine appeared to be the drug that affects glutamate receptors (GluR) most. The most consistent effect, observed with pronoradrenergic drugs (desipramine and reboxetine), was a decrease of GluR3 expression both in P/FC and HI. Interestingly, in HI, the same drugs also decreased the editing levels of either the flip (desipramine) or flop (reboxetine) form of GluR3. Conclusions Overall, these results point to specific and regionally discrete changes in the expression and editing level of glutamate receptors and, in particular, to a selective reduction of conductance for GluR3-containing receptors following treatment with antidepressant drugs. These data support the hypothesis that changes in glutamate neurotransmission are involved in the therapeutic effects induced by these drugs.

Stress-based animal models of depression have shown dendritic remodelling in the hippocampus (HPC), suggesting a primary role of stress-induced maladaptive changes in etiopathogenesis. Antidepressant treatment with ketamine was shown to rapidly reverse the dendritic simplification induced by stress. Using the Chronic Mild Stress (CMS) animal model of depression, we have shown a reduction of CA3 pyramidal neurons apical dendritic length and complexity selectively in vulnerable animals, which was completely rescued by acute ketamine (Tornese et al, 2019). Here we aimed at studying putative molecular mechanisms underlying the morphological alterations induced by stress and ketamine. We found that dendritic simplification in CMS vulnerable rats was accompanied by changes in microRNAs known to play a role in neuroplasticity and stress response. In particular, miR-9-5p was selectively reduced in the HPC of vulnerable animals, while KET restored its levels to basal condition. To assess whether miR-9-5p was able to directly induce neuronal tree remodelling, we used in vitro expression modulation studies on primary HPC cultures and found that miR-9-5p downregulation significantly decreased total dendritic length and spine number, while miR-9-5p overexpression exerted the opposite effect. Bioinformatic analysis highlighted a number of putative target genes, and the top-hit ones (Gsk-3β, REST, Sirt1) were validated with Luciferase assay. Changes in protein expression levels of validated targets were measured in the HPC of CMS animals by Western-blot. Our results suggest that alterations in miR-9-5p levels may be involved both in mechanisms of stress resilience/vulnerability and in the fast antidepressant effect.