The chemokine CXCL16 modulates neurotransmitter release in hippocampal CA1 area.

Chemokines have several physio-pathological roles in the brain. Among them, the modulation of synaptic contacts and neurotransmission recently emerged as crucial activities during brain development, in adulthood, upon neuroinflammation and neurodegenerative diseases. CXCL16 is a chemokine normally expressed in the brain, where it exerts neuroprotective activity against glutamate-induced damages through cross communication with astrocytes and the involvement of the adenosine receptor type 3 (A3R) and the chemokine CCL2. Here we demonstrated for the first time that CXCL16 exerts a modulatory activity on inhibitory and excitatory synaptic transmission in CA1 area. We found that CXCL16 increases the frequency of the miniature inhibitory synaptic currents (mIPSCs) and the paired-pulse ratio (PPR) of evoked IPSCs(eIPSCs), suggesting a presynaptic modulation of the probability of GABA release. In addition, CXCL16 increases the frequency of the miniature excitatory synaptic currents (mEPSCs) and reduces the PPR of evoked excitatory transmission, indicating that the chemokine also modulates and enhances the release of glutamate. These effects were not present in the A3RKO mice and in WT slices treated with minocycline, confirming the involvement of A3 receptors and introducing microglial cells as key mediators of the modulatory activity of CXCL16 on neurons

Electrophysiological Properties of CA1 Pyramidal Neurons along the Longitudinal Axis of the Mouse Hippocampus

Evidence for different physiological properties along the hippocampal longitudinal axis is emerging. Here, we examined the electrophysiological features of neurons at different dorso-ventral sites of the mouse CA1 hippocampal region. Cell position was defined with respect to longitudinal coordinates of each slice. We measured variations in neuronal excitability, subthreshold membrane properties and neurotransmitter responses along the longitudinal axis. We found that (i) pyramidal cells of the dorsal hippocampus (DH) were less excitable than those of the ventral hippocampus (VH). Resting Membrane Potential (RMP) was more hyperpolarized and somatic Input Resistance (Ri) was lower in DH compared to VH. (ii) The Paired-pulse ratio (PPR) of focally induced synaptic responses was systematically reduced from the DH to the VH; (iii) Long-term-potentiation was most pronounced in the DH and fell gradually in the intermediate hippocampus and in the VH; (iv) the frequency of miniature GABAergic events was higher in the VH than in the DH; (v) the PPR of evoked inhibitory post-synaptic current (IPSC) was higher in the DH than in the VH. These findings indicate an increased probability of both GABA and glutamate release and a reduced plasticity in the ventral compared to more dorsal regions of the hippocampus

Structured reporting for fibrosing lung disease: a model shared by radiologist and pulmonologist

Objectives: To apply the Delphi exercise with iterative involvement of radiologists and pulmonologists with the aim of defining a structured reporting template for high-resolution computed tomography (HRCT) of patients with fibrosing lung disease (FLD). Methods: The writing committee selected the HRCT criteria\ue2\u80\u94the Delphi items\ue2\u80\u94for rating from both radiology panelists (RP) and pulmonology panelists (PP). The Delphi items were first rated by RPs as \ue2\u80\u9cessential\ue2\u80\u9d, \ue2\u80\u9coptional\ue2\u80\u9d, or \ue2\u80\u9cnot relevant\ue2\u80\u9d. The items rated \ue2\u80\u9cessential\ue2\u80\u9d by < 80% of the RP were selected for the PP rating. The format of reporting was rated by both RP and PP. Results: A total of 42 RPs and 12 PPs participated to the survey. In both Delphi round 1 and 2, 10/27 (37.7%) items were rated \ue2\u80\u9cessential\ue2\u80\u9d by more than 80% of RP. The remaining 17/27 (63.3%) items were rated by the PP in round 3, with 2/17 items (11.7%) rated \ue2\u80\u9cessential\ue2\u80\u9d by the PP. PP proposed additional items for conclusion domain, which were rated by RPs in the fourth round. Poor consensus was observed for the format of reporting. Conclusions: This study provides a template for structured report of FLD that features essential items as agreed by expert thoracic radiologists and pulmonologists

Evolving trends in the management of acute appendicitis during COVID-19 waves. The ACIE appy II study

Background: In 2020, ACIE Appy study showed that COVID-19 pandemic heavily affected the management of patients with acute appendicitis (AA) worldwide, with an increased rate of non-operative management (NOM) strategies and a trend toward open surgery due to concern of virus transmission by laparoscopy and controversial recommendations on this issue. The aim of this study was to survey again the same group of surgeons to assess if any difference in management attitudes of AA had occurred in the later stages of the outbreak. Methods: From August 15 to September 30, 2021, an online questionnaire was sent to all 709 participants of the ACIE Appy study. The questionnaire included questions on personal protective equipment (PPE), local policies and screening for SARS-CoV-2 infection, NOM, surgical approach and disease presentations in 2021. The results were compared with the results from the previous study. Results: A total of 476 answers were collected (response rate 67.1%). Screening policies were significatively improved with most patients screened regardless of symptoms (89.5% vs. 37.4%) with PCR and antigenic test as the preferred test (74.1% vs. 26.3%). More patients tested positive before surgery and commercial systems were the preferred ones to filter smoke plumes during laparoscopy. Laparoscopic appendicectomy was the first option in the treatment of AA, with a declined use of NOM. Conclusion: Management of AA has improved in the last waves of pandemic. Increased evidence regarding SARS-COV-2 infection along with a timely healthcare systems response has been translated into tailored attitudes and a better care for patients with AA worldwide

Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment

It has been hypothesized that selective serotonin reuptake inhibitors (SSRIs), the most common treatment for major depression, affect mood through changes in immune function. However, the effects of SSRIs on inflammatory response are contradictory since these act either as anti- or pro-inflammatory drugs. Previous experimental and clinical studies showed that the quality of the living environment moderates the outcome of antidepressant treatment. Therefore, we hypothesized that the interplay between SSRIs and the environment may, at least partially, explain the apparent incongruence regarding the effects of SSRI treatment on the inflammatory response. In order to investigate such interplay, we exposed C57BL/6 mice to chronic stress to induce a depression-like phenotype and, subsequently, to fluoxetine treatment or vehicle (21days) while being exposed to either an enriched or a stressful condition. At the end of treatment, we measured the expression levels of several anti- and pro-inflammatory cytokines and inflammatory mediators in the whole hippocampus and in isolated microglia. We also determined microglial density, distribution, and morphology to investigate their surveillance state. Results show that the effects of fluoxetine treatment on inflammation and microglial function, as compared to vehicle, were dependent on the quality of the living environment. In particular, fluoxetine administered in the enriched condition increased the expression of pro-inflammatory markers compared to vehicle, while treatment in a stressful condition produced anti-inflammatory effects. These findings provide new insights regarding the effects of SSRIs on inflammation, which may be crucial to devise pharmacological strategies aimed at enhancing antidepressant efficacy by means of controlling environmental conditions

Fractalkine receptor deficiency impairs microglial and neuronal responsiveness to chronic stress

Chronic stress is one of the most relevant triggering factors for major depression. Microglial cells are highly sensitive to stress and, more generally, to environmental challenges. However, the role of these brain immune cells in mediating the effects of stress is still unclear. Fractalkine signaling - which comprises the chemokine CX3CL1, mainly expressed by neurons, and its receptor CX3CR1, almost exclusively present on microglia in the healthy brain - has been reported to critically regulate microglial activity. Here, we investigated whether interfering with microglial function by deleting the Cx3cr1 gene affects the brain's response to chronic stress. To this purpose, we housed Cx3cr1 knockout and wild-type adult mice in either control or stressful environments for 2weeks, and investigated the consequences on microglial phenotype and interactions with synapses, synaptic transmission, behavioral response and corticosterone levels. Our results show that hampering neuron-microglia communication via the CX3CR1-CX3CL1 pathway prevents the effects of chronic unpredictable stress on microglial function, short- and long-term neuronal plasticity and depressive-like behavior. Overall, the present findings suggest that microglia-regulated mechanisms may underlie the differential susceptibility to stress and consequently the vulnerability to diseases triggered by the experience of stressful events, such as major depression

Combined Fluoxetine and Metformin Treatment Potentiates Antidepressant Efficacy Increasing IGF2 Expression in the Dorsal Hippocampus

An increasing number of studies show that selective serotonin reuptake inhibitors (SSRIs) exert their therapeutic action, at least in part, by amplifying the influence of the living environment on mood. As a consequence, when administered in a favorable environment, SSRIs lead to a reduction of symptoms, but in stressful conditions, they show limited efficacy. Therefore, novel therapeutic approaches able to neutralize the influence of the stressful environment on treatment are needed. The aim of our study was to test whether, in a mouse model of depression, the combined administration of SSRI fluoxetine and metformin, a drug able to improve the metabolic profile, counteracts the limited efficacy of fluoxetine alone when administered in stressful conditions. Indeed, metabolic alterations are associated to both the onset of major depression and the antidepressant efficacy. To this goal, adult C57BL/6 male mice were exposed to stress for 6 weeks; the first two weeks was aimed at generating a mouse model of depression. During the remaining 4 weeks, mice received one of the following treatments: vehicle, fluoxetine, metformin, or a combination of fluoxetine and metformin. We measured liking- and wanting-type anhedonia as behavioral phenotypes of depression and assessed the expression levels of selected genes involved in major depressive disorder and antidepressant response in the dorsal and ventral hippocampus, which are differently involved in the depressive symptomatology. The combined treatment was more effective than fluoxetine alone in ameliorating the depressive phenotype after one week of treatment. This was associated to an increase in IGF2 mRNA expression and enhanced long-term potentiation, specifically in the dorsal hippocampus, at the end of treatment. Overall, the present results show that, when administered in stressful conditions, the combined fluoxetine and metformin treatment may represent a more effective approach than fluoxetine alone in a short term. Finally, our findings highlight the relevance of polypharmacological strategy as effective interventions to increase the efficacy of the antidepressant drugs currently available

Dark microglia: A new phenotype predominantly associated with pathological states

The past decade has witnessed a revolution in our understanding of microglia. These immune cells were shown to actively remodel neuronal circuits, leading to propose new pathogenic mechanisms. To study microglial implication in the loss of synapses, the best pathological correlate of cognitive decline across chronic stress, aging, and diseases, we recently conducted ultrastructural analyses. Our work uncovered the existence of a new microglial phenotype that is rarely present under steady state conditions, in hippocampus, cerebral cortex, amygdala, and hypothalamus, but becomes abundant during chronic stress, aging, fractalkine signaling deficiency (CX3CR1 knockout mice), and Alzheimer's disease pathology (APP‐PS1 mice). Even though these cells display ultrastructural features of microglia, they are strikingly distinct from the other phenotypes described so far at the ultrastructural level. They exhibit several signs of oxidative stress, including a condensed, electron‐dense cytoplasm and nucleoplasm making them as “dark” as mitochondria, accompanied by a pronounced remodeling of their nuclear chromatin. Dark microglia appear to be much more active than the normal microglia, reaching for synaptic clefts, while extensively encircling axon terminals and dendritic spines with their highly ramified and thin processes. They stain for the myeloid cell markers IBA1 and GFP (in CX3CR1‐GFP mice), and strongly express CD11b and microglia‐specific 4D4 in their processes encircling synaptic elements, and TREM2 when they associate with amyloid plaques. Overall, these findings suggest that dark microglia, a new phenotype that we identified based on their unique properties, could play a significant role in the pathological remodeling of neuronal circuits, especially at synapses. GLIA 2016;64:826–83