Electrical activity has been shown to regulate development in a variety of species and in various structures, including the retina, spinal cord and cortex. Within the mammalian cortex specifically, ...the development of dendrites and commissural axons in pyramidal cells is activity-dependent. However, little is known about the developmental role of activity in the other major cortical population of neurons, the GABA-producing interneurons. These neurons are morphologically and functionally heterogeneous and efforts over the past decade have focused on determining the mechanisms that contribute to this diversity. It was recently discovered that 30% of all cortical interneurons arise from a relatively novel source within the ventral telencephalon, the caudal ganglionic eminence (CGE). Owing to their late birth date, these interneurons populate the cortex only after the majority of other interneurons and pyramidal cells are already in place and have started to functionally integrate. Here we demonstrate in mice that for CGE-derived reelin (Re)-positive and calretinin (Cr)-positive (but not vasoactive intestinal peptide (VIP)-positive) interneurons, activity is essential before postnatal day 3 for correct migration, and that after postnatal day 3, glutamate-mediated activity controls the development of their axons and dendrites. Furthermore, we show that the engulfment and cell motility 1 gene (Elmo1), a target of the transcription factor distal-less homeobox 1 (Dlx1), is selectively expressed in Re(+) and Cr(+) interneurons and is both necessary and sufficient for activity-dependent interneuron migration. Our findings reveal a selective requirement for activity in shaping the cortical integration of specific neuronal subtypes.
During neonatal development, sensory cortices generate spontaneous activity patterns shaped by both sensory experience and intrinsic influences. How these patterns contribute to the assembly of ...neuronal circuits is not clearly understood. Using longitudinal in vivo calcium imaging in un-anesthetized mouse pups, we show that spatially segregated functional assemblies composed of interneurons and pyramidal cells are prominent in the somatosensory cortex by postnatal day (P) 7. Both reduction of GABA release and synaptic inputs onto pyramidal cells erode the emergence of functional topography, leading to increased network synchrony. This aberrant pattern effectively blocks interneuron apoptosis, causing increased survival of parvalbumin and somatostatin interneurons. Furthermore, the effect of GABA on apoptosis is mediated by inputs from medial ganglionic eminence (MGE)-derived but not caudal ganglionic eminence (CGE)-derived interneurons. These findings indicate that immature MGE interneurons are fundamental for shaping GABA-driven activity patterns that balance the number of interneurons integrating into maturing cortical networks.
Display omitted
•GABA limits MGE-cIN participation in synchronous network events during development•Synaptic GABA regulates the emergence of interneuron-pyramidal cell assemblies•GABAergic restriction of pyramidal cell activity is required for MGE-cIN apoptosis•GABAAγ2-containing GABAA receptors are essential for interneuron apoptosis
Duan, Che, Chu et al. use genetic tools and in vivo imaging to show that cortical GABAergic signaling restricts functional assemblies and enables developmental apoptosis of MGE interneurons, balancing the number of interneurons integrating into maturing cortical networks.
Purpose
We assessed feasibility and safety of extracorporeal carbon dioxide removal (ECCO
2
R) to facilitate ultra-protective ventilation (
V
T
4 mL/kg and
P
PLAT
≤ 25 cmH
2
O) in patients with ...moderate acute respiratory distress syndrome (ARDS).
Methods
Prospective multicenter international phase 2 study. Primary endpoint was the proportion of patients achieving ultra-protective ventilation with PaCO
2
not increasing more than 20% from baseline, and arterial pH > 7.30. Severe adverse events (SAE) and ECCO
2
R-related adverse events (ECCO
2
R-AE) were reported to an independent data and safety monitoring board. We used lower CO
2
extraction and higher CO
2
extraction devices (membrane lung cross-sectional area 0.59 vs. 1.30 m
2
; flow 300–500 mL/min vs. 800–1000 mL/min, respectively).
Results
Ninety-five patients were enrolled. The proportion of patients who achieved ultra-protective settings by 8 h and 24 h was 78% (74 out of 95 patients; 95% confidence interval 68–89%) and 82% (78 out of 95 patients; 95% confidence interval 76–88%), respectively. ECCO
2
R was maintained for 5 3–8 days. Six SAEs were reported; two of them were attributed to ECCO
2
R (brain hemorrhage and pneumothorax). ECCO
2
R-AEs were reported in 39% of the patients. A total of 69 patients (73%) were alive at day 28. Fifty-nine patients (62%) were alive at hospital discharge.
Conclusions
Use of ECCO
2
R to facilitate ultra-protective ventilation was feasible. A randomized clinical trial is required to assess the overall benefits and harms.
Clinicaltrials.gov
NCT02282657
The developmental journey of cortical interneurons encounters several activity-dependent milestones. During the early postnatal period in developing mice, GABAergic neurons are transient preferential ...recipients of thalamic inputs and undergo activity-dependent migration arrest, wiring, and programmed cell-death. Despite their importance for the emergence of sensory experience and the role of activity in their integration into cortical networks, the collective dynamics of GABAergic neurons during that neonatal period remain unknown. Here, we study coordinated activity in GABAergic cells of the mouse barrel cortex using in vivo calcium imaging. We uncover a transient structure in GABAergic population dynamics that disappears in a sensory-dependent process. Its building blocks are anatomically clustered GABAergic assemblies mostly composed by prospective parvalbumin-expressing cells. These progressively widen their territories until forming a uniform perisomatic GABAergic network. Such transient patterning of GABAergic activity is a functional scaffold that links the cortex to the external world prior to active exploration.
Display omitted
•In the developing barrel cortex, GABAergic neurons form functional assemblies•Prospective parvalbumin interneurons segregate into spatially clustered assemblies•Somatostatin interneurons display broadly correlated firing•GABA assemblies are regulated by sensory inputs
Using in vivo imaging in the barrel cortex, Modol et al. show that prospective parvalbumin interneurons form patches of correlated activity that merge during postnatal development. These assemblies are regulated by whisker inputs and altered by sensory deprivation.
Neuronal microcircuits in the superficial layers of the mammalian cortex provide the substrate for associative cortical computation. Inhibitory interneurons constitute an essential component of the ...circuitry and are fundamental to the integration of local and long-range information. Here we report that, during early development, superficially positioned Reelin-expressing neurogliaform interneurons in the mouse somatosensory cortex receive afferent innervation from both cortical and thalamic excitatory sources. Attenuation of ascending sensory, but not intracortical, excitation leads to axo-dendritic morphological defects in these interneurons. Moreover, abrogation of the NMDA receptors through which the thalamic inputs signal results in a similar phenotype, as well as in the selective loss of thalamic and a concomitant increase in intracortical connectivity. These results suggest that thalamic inputs are critical in determining the balance between local and long-range connectivity and are fundamental to the proper integration of Reelin-expressing interneurons into nascent cortical circuits.
The neonatal mammal faces an array of sensory stimuli when diverse neuronal types have yet to form sensory maps. How these inputs interact with intrinsic neuronal activity to facilitate circuit ...assembly is not well understood. By using longitudinal calcium imaging in unanesthetized mouse pups, we show that layer I (LI) interneurons, delineated by co-expression of the 5HT3a serotonin receptor (5HT3aR) and reelin (Re), display spontaneous calcium transients with the highest degree of synchrony among cell types present in the superficial barrel cortex at postnatal day 6 (P6). 5HT3aR Re interneurons are activated by whisker stimulation during this period, and sensory deprivation induces decorrelation of their activity. Moreover, attenuation of thalamic inputs through knockdown of NMDA receptors (NMDARs) in these interneurons results in expansion of whisker responses, aberrant barrel map formation, and deficits in whisker-dependent behavior. These results indicate that recruitment of specific interneuron types during development is critical for adult somatosensory function.
Display omitted
Display omitted
•5HT3aR Re interneurons in LI barrel cortex desynchronize by the second postnatal week•Whisker stimulation recruits 5HT3aR Re interneurons in the first postnatal week•Sensory deprivation and NMDAR knockdown in 5HT3aR Re interneurons disrupt synchrony•5HT3aR Re interneurons constrain pyramidal cell activation and barrel size
Che et al. combine genetic tools and longitudinal in vivo calcium imaging in young mouse pups to show that superficial interneurons participate in a transient thalamocortical circuit. Their recruitment is critical for the emergence of sensory maps and sensory discrimination.
One of the major evolutionary transitions that led to DNA replacing RNA as the primary informational molecule in biological systems is still the subject of an intense debate in the scientific ...community. DNA polymerases are currently split into various families. Families A, B, and C are the most significant. In bacteria and some types of viruses, enzymes from families A and C predominate, whereas family B enzymes are more common in Archaea, Eukarya, and some types of viruses. A phylogenetic analysis of these three families of DNA polymerase was carried out. We assumed that reverse transcriptase was the ancestor of DNA polymerases. Our findings suggest that families A and C emerged and organized themselves when the earliest bacterial lineages had diverged, and that these earliest lineages had RNA genomes that were in transition-that is, the information was temporally stored in DNA molecules that were continuously being produced by reverse transcription. The origin of DNA and the apparatus for its replication in the mitochondrial ancestors may have occurred independently of DNA and the replication machinery of other bacterial lineages, according to these two alternate modes of genetic material replication. The family C enzymes emerged in a particular bacterial lineage before being passed to viral lineages, which must have functioned by disseminating this machinery to the other lineages of bacteria. Bacterial DNA viruses must have evolved at least twice independently, in addition to the requirement that DNA have arisen twice in bacterial lineages. We offer two possible scenarios based on what we know about bacterial DNA polymerases. One hypothesis contends that family A was initially produced and spread to the other lineages through viral lineages before being supplanted by the emergence of family C and acquisition at that position of the principal replicative polymerase. The evidence points to the independence of these events and suggests that the viral lineage's acquisition of cellular replicative machinery was crucial for the establishment of a DNA genome in the other bacterial lineages, since these viral lineages may have served as a conduit for the machinery's delivery to other bacterial lineages that diverged with the RNA genome. Our data suggest that family B initially established itself in viral lineages and was transferred to ancestral Archaea lineages before the group diversified; thus, the DNA genome must have emerged first in this cellular lineage. Our data point to multiple evolutionary steps in the origins of DNA polymerase, having started off at least twice in the bacterial lineage and once in the archaeal lineage. Given that viral lineages are implicated in a significant portion of the distribution of DNA replication equipment in both bacterial (families A and C) and Archaeal lineages (family A), our data point to a complex scenario.
Summary
Background
The accuracy of available non‐invasive tools for staging severe fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) is still limited.
Aim
To assess the diagnostic ...performance of paired or serial combination of non‐invasive tools in NAFLD patients.
Methods
We analysed data from 741 patients with a histological diagnosis of NAFLD. The GGT/PLT, APRI, AST/ALT, BARD, FIB‐4, and NAFLD Fibrosis Score (NFS) scores were calculated according to published algorithms. Liver stiffness measurement (LSM) was performed by FibroScan.
Results
LSM, NFS and FIB‐4 were the best non‐invasive tools for staging F3‐F4 fibrosis (AUC 0.863, 0.774, and 0.792, respectively), with LSM having the highest sensitivity (90%), and the highest NPV (94%), and NFS and FIB‐4 the highest specificity (97% and 93%, respectively), and the highest PPV (73% and 79%, respectively). The paired combination of LSM or NFS with FIB‐4 strongly reduced the likelihood of wrongly classified patients (ranging from 2.7% to 2.6%), at the price of a high uncertainty area (ranging from 54.1% to 58.2%), and of a low overall accuracy (ranging from 43% to 39.1%). The serial combination with the second test used in patients in the grey area of the first test and in those with high LSM values (>9.6 KPa) or low NFS or FIB‐4 values (<−1.455 and <1.30, respectively) overall increased the diagnostic performance generating an accuracy ranging from 69.8% to 70.1%, an uncertainty area ranging from 18.9% to 20.4% and a rate of wrong classification ranging from 9.2% to 11.3%.
Conclusion
The serial combination of LSM with FIB‐4/NFS has a good diagnostic accuracy for the non‐invasive diagnosis of severe fibrosis in NAFLD.
Linked ContentThis article is linked to Khan paper. To view this article visit https://doi.org/10.1111/apt.14267.
The aim of these guidelines is to update the 2017 clinical practice guideline (CPG) of the European Society of Intensive Care Medicine (ESICM). The scope of this CPG is limited to adult patients and ...to non-pharmacological respiratory support strategies across different aspects of acute respiratory distress syndrome (ARDS), including ARDS due to coronavirus disease 2019 (COVID-19). These guidelines were formulated by an international panel of clinical experts, one methodologist and patients’ representatives on behalf of the ESICM. The review was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement recommendations. We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence and grade recommendations and the quality of reporting of each study based on the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) network guidelines. The CPG addressed 21 questions and formulates 21 recommendations on the following domains: (1) definition; (2) phenotyping, and respiratory support strategies including (3) high-flow nasal cannula oxygen (HFNO); (4) non-invasive ventilation (NIV); (5) tidal volume setting; (6) positive end-expiratory pressure (PEEP) and recruitment maneuvers (RM); (7) prone positioning; (8) neuromuscular blockade, and (9) extracorporeal life support (ECLS). In addition, the CPG includes expert opinion on clinical practice and identifies the areas of future research.
Noninvasive respiratory support (NIRS) has been diffusely employed outside the intensive care unit (ICU) to face the high request of ventilatory support due to the massive influx of patients with ...acute respiratory failure (ARF) caused by coronavirus-19 disease (COVID-19). We sought to summarize the evidence on clinically relevant outcomes in COVID-19 patients supported by NIV outside the ICU.
We searched PUBMED®, EMBASE®, and the Cochrane Controlled Clinical trials register, along with medRxiv and bioRxiv repositories for pre-prints, for observational studies and randomized controlled trials, from inception to the end of February 2021. Two authors independently selected the investigations according to the following criteria: (1) observational study or randomized clinical trials enrolling ≥ 50 hospitalized patients undergoing NIRS outside the ICU, (2) laboratory-confirmed COVID-19, and (3) at least the intra-hospital mortality reported. Preferred Reporting Items for Systematic reviews and Meta-analysis guidelines were followed. Data extraction was independently performed by two authors to assess: investigation features, demographics and clinical characteristics, treatments employed, NIRS regulations, and clinical outcomes. Methodological index for nonrandomized studies tool was applied to determine the quality of the enrolled studies. The primary outcome was to assess the overall intra-hospital mortality of patients under NIRS outside the ICU. The secondary outcomes included the proportions intra-hospital mortalities of patients who underwent invasive mechanical ventilation following NIRS failure and of those with 'do-not-intubate' (DNI) orders.
Seventeen investigations (14 peer-reviewed and 3 pre-prints) were included with a low risk of bias and a high heterogeneity, for a total of 3377 patients. The overall intra-hospital mortality of patients receiving NIRS outside the ICU was 36% 30-41%. 26% 21-30% of the patients failed NIRS and required intubation, with an intra-hospital mortality rising to 45% 36-54%. 23% 15-32% of the patients received DNI orders with an intra-hospital mortality of 72% 65-78%. Oxygenation on admission was the main source of between-study heterogeneity.
During COVID-19 outbreak, delivering NIRS outside the ICU revealed as a feasible strategy to cope with the massive demand of ventilatory assistance.
PROSPERO, https://www.crd.york.ac.uk/prospero/ , CRD42020224788, December 11, 2020.
PDF
