Hemodynamic nature of black-blood enhancement in long-term coiled cerebral aneurysms.

PURPOSE: Vessel wall imaging (VWI) with black-blood (BB) technique can demonstrate aneurysmal enhancement preluding to growth/rupture in treatment-naive cerebral aneurysms. Interestingly, recent works showed that BB enhancement may also occur in endovascularly treated aneurysms, though its meaning is controversial. Hypothesizing a flow-related mechanism of BB enhancement, we explored its relationship with incomplete occlusion status and coil packing density at DSA. METHODS: We analyzed the subjects undergoing 3T MRI between January 2017 and October 2020 for a previous aneurysmal coiling. All the MRI studies included pre- and post-contrast 3D BB sequences. The presence of intra-aneurysmal pre-contrast BB signal was assessed. BB enhancement (when present) was classified as follows: (1) enhancement at the neck, (2) intrasaccular/intra-coil enhancement, and (3) peripheral enhancement. Coil packing density and aneurysmal occlusion status (according to the modified Raymond-Roy classification, MRRC) were determined on post-treatment DSA and compared with BB findings using generalized linear mixed-effect model and ANOVA. Significant p values were <0.05. RESULTS: Forty-eight aneurysms from 44 patients were eligible for analysis. Pre-contrast BB signal was observed in 50% of the aneurysms and showed a relationship with baseline aneurysmal size. BB enhancement was detectable in 31 aneurysms (65%), being significantly associated with incomplete aneurysmal occlusion and reduced coil packing density at DSA. CONCLUSION: BB enhancement of coiled aneurysms is related with increasing degrees of post-coiling aneurysmal remnants and with loose coil packing density at DSA. This supports a hemodynamic interpretation of BB enhancement in long-term coiled aneurysms.

Insights into the Porretta Terme (northern Apennines, Italy) hydrothermal system revealed by geochemical data on presently discharging thermal waters and paleofluids.

This study focuses on the geochemical features of the presently discharging thermal and cold springs and on paleofluids from the upstream portion of the Reno river basin (Alto Reno; central-northern Italy). The aim is investigating the primary sources of the modern and fossil fluids and the interactions between deep and shallow aquifers. Paleofluids are from fluid inclusions hosted within euhedral and hopper quartz crystals and consist of a two-phase, liquid-vapor aqueous fluid and a unary CH4 fluid. The aqueous inclusions have constant phase ratios and a calculated salinity of ~ 1.5 wt% NaCleq. They homogenize by bubble disappearance at 100-200 °C, whereas the estimated entrapment depth is ~ 3-5.5 km. The paleofluids likely represent the vestiges of the deep and hot, CH4-rich, Na+-Cl- fluids produced by the interaction between meteoric waters and Triassic and Miocene formations. The modern Na+-Cl-(HCO3-) thermal waters originate from meteoric waters infiltrating SW of the study area, at elevation > 800 m a.s.l., circulating within both the Triassic evaporites and the overlying Miocene turbiditic formations, where salt dissolution/precipitation, sulfate reduction, and production of thermogenic CH4 occur. The equilibrium temperature of the deep fluid source is ~ 170 °C, corresponding to > 5 km depth. Cold springs are Ca2+-HCO3- type and show low amounts of biogenic CO2 and CH4 with no inputs of deep-originated fluids excepting in the immediate surroundings of the thermal area, confirming the lack of significant hydraulic connection between shallow and deep aquifers. We propose a genetic link between the quartz-hosted paleofluid and the thermal waters present in the area.

Carotid artery stenosis and brain connectivity: the role of white matter hyperintensities.

PURPOSE: It is under debate how white matter hyperintensities (WMH) affects the brain connectivity. The objective of this research study is to validate the hypothesis, if and how the WMH influences brain connectivity in a population with carotid artery stenosis (CAS), which are eligible for carotid endarterectomy (CEA). We used resting state functional connectivity (rs-fc) magnetic resonance (MR) to validate our hypothesis, focusing on the effects of the total number of WMH (TNWMH) and of the WMH Burden (WMHB). METHODS: Twenty-three patients (sixteen males and seven females, mean age 74.34 years) with mono or bilateral carotid stenosis eligible for carotid endarterectomy (CEA), underwent an MR examination on a 1.5-T scanner. The protocol included a morphologic T1-3D isotropic, an EPI functional sequence for rs-fc MR analysis, and a 3D isotropic FLAIR sequence. For each patient, the TNWMH and the WMHB were obtained using two online tools-volBrain and lesionBrain. The rs-fc region-of-interest to region-of-interest (ROI-to-ROI) analysis was performed with the CONN toolbox v18a: two different multiple regression analyses including both WMHB and TNWMH as second-level covariates evaluated the individual effects of WMHB (Analysis A) and TNWMH (Analysis B), adopting a p value corrected for false discovery rate (p-FDR) < 0.05 to identify statistically significant values. RESULTS: Both analyses A and B identified several statistically significant positive and negative correlations associated with WMHB and TNWMH. CONCLUSION: WMH influence functional connectivity in patients with carotid artery stenosis eligible for CEA; further, WMHB and TNWMH influence differently functional connectivity.

Discovery, synthesis, selectivity modulation and DMPK characterization of 5-azaspiro[2.4]heptanes as potent orexin receptor antagonists.

Starting from a orexin 1 receptor selective antagonist 4,4-disubstituted piperidine series a novel potent 5-azaspiro[2.4]heptane dual orexin 1 and orexin 2 receptor antagonist class has been discovered. SAR and Pharmacokinetic optimization of this series is herein disclosed. Lead compound 15 exhibits potent activity against orexin 1 and orexin 2 receptors along with low cytochrome P450 inhibition potential, good brain penetration and oral bioavailability in rats.

Imaging characterization of an adult H3 K27M-altered diffuse midline glioma of the medulla oblongata with a confounding steroid response.

We report an uncommon, infratentorial localization of adult H3 K27M-altered diffuse midline glioma arising in a particularly rare site (medulla oblongata). In addition to this unusual presentation, the lesion exhibited a substantial contrast enhancement and size decrease after dexamethasone, generating diagnostic dilemmas. Histology, molecular details, advanced Magnetic Resonance imaging features and differential diagnoses are here described and discussed, as well as common misconceptions about steroid-sensitive mass lesions, and practical difficulties for clinicians involved in the process of making diagnosis.

Antipsychotic-like effects of the N-methyl-D-aspartate receptor modulator neboglamine: an immunohistochemical and behavioural study in the rat.

Neboglamine is a functional modulator of the glycine site on the N-methyl-d-aspartate (NMDA) receptor. Dysfunction of this receptor has been associated with negative and cognitive symptoms in schizophrenia. Thus, we tested the hypothesis that neboglamine behaves as a potential antipsychotic. We compared the effects of neboglamine, D-serine, clozapine, and haloperidol on the expression of Fos-like immunoreactivity (FLI), a marker of neuronal activation, in rat forebrain. We also studied the effects of these agents on phencyclidine (PCP)-induced behaviour in rats, a model predictive of potential antipsychotic activity. Neboglamine, like haloperidol and clozapine, significantly increased the number of FLI-positive cells in the prefrontal cortex, nucleus accumbens, and lateral septal nucleus (3.2-, 4.8-, and 4.5-fold over control, respectively). Haloperidol dramatically increased FLI (390-fold over control) in the dorsolateral striatum, a brain region in which neboglamine and clozapine had no effect. The pattern of FLI induced by neboglamine closely matched that of d-serine, an endogenous agonist at the glycine site of NMDA receptors. Consistent with this finding, neboglamine restored NMDA-mediated neurotransmitter release in frontal cortex punches exposed to the NMDA antagonist PCP. In the behavioural model, all test compounds significantly inhibited PCP-induced hyperlocomotion. Unlike haloperidol and clozapine, neither neboglamine nor D-serine affected the basal levels of locomotor activity. Moreover, oral neboglamine dose-dependently inhibited both the hyperlocomotion and the frequency of rearing behaviour induced by PCP. These results, while confirming that the NMDA glycine site is a feasible target for activating the frontostriatal system, support the clinical evaluation of neboglamine as a treatment for schizophrenia.

Effects of White Matter Hyperintensities on Brain Connectivity and Hippocampal Volume in Healthy Subjects According to Their Localization.

Purpose: To investigate the relationships between white matter hyperintensities (WMH) and hippocampal volume and their influence on brain networks by using resting-state functional connectivity (rs-fc) magnetic resonance (MR) according to their localization. Methods: In this exploratory cross-sectional study, 38 subjects from the public "Leipzig Study for Mind/Body/Emotion Interactions" (LEMON) data set were selected. Morphometric analyses of both WMH burden and the total hippocampal relative volume (tHRV) were performed for each subject with two automated software. The WMH were then categorized as total (tWMH), periventricular (pvWMH), deep (dWMH), and juxtacortical (jcWMH). Spearman's correlation analyses were performed to evaluate the relationships between the following variables: age, tWMH, pvWMH, dWMH, jcWMH, and tHRV. Subsequently, three different rs-fc MR group analyses were performed using a multiple regression model that included age, pvWMH, dWMH, and jcWMH as second-level covariates. The graph theoretical analysis was applied to evaluate the effects of pvWMH (analysis 1), jcWMH (analysis 2), and dWMH (analysis 3). Results: Spearman's correlation analysis revealed several statistically significant (p < 0.05) positive and negative correlations, in particular positive between age and tWMH, and negative between dWMH and tHRV. rs-fc MR analysis 1 and 2 did not reveal statistically significant results; analysis 3 revealed that dWMH influenced network properties of several cerebral regions, in particular global and local efficiency of both the hippocampi. Conclusion: The localization of WMH influences brain activity in healthy subjects. In particular, dWMH are inversely correlated with tHRV and influence several properties of different cerebral areas, included both the hippocampi. Impact statement In this exploratory research we evidenced how both the load and the localization of white matter hyperintensities influence brain activity; in particular, we evidenced an inverse correlation between the volume of the deep white matter hyperintensities and hippocampal volume, as well as a direct influence on the connectivity properties of this important cerebral region. This finding represent a new element for understanding the effects of white matter hyperintensities on brain networking, and a cue that could be taken into account for possible future studies investigating brain connectivity and cognitive functions in healthy and pathological conditions.

Connectometry evaluation in patients undergoing carotid endarterectomy: an exploratory study.

This research investigated local brain connectivity changes following Carotid Endarterectomy (CEA) by connectometry. Seventeen subjects (15 males and 2 females, mean age 74.1 years), all eligible for CEA, were prospectively recruited in this exploratory study. On the same day within the week before the CEA, each patient underwent a cognitive evaluation with a Mini Mental State Examination (MMSE) and a Magnetic Resonance Imaging (MRI) exam that included a DTI sequence for the connectometry analysis. A second MMSE and the same MRI protocol were performed on follow-up, 3-6 months after CEA. The MMSE scores were analyzed using T-Student tests. The connectometry analysis was performed using a multiple regression model to consider the effect of CEA, choosing three different T-score threshold (T-threshold) values (1, 2 and 3). Results were considered statistically valid for p value adjusted for False Discovery Rate (p-FDR) < 0.05. Comparison of pre-CEA and post-CEA MMSE scores showed improvement of MMSE scores after CEA. Connectometry analysis revealed no areas of statistically significant increased connectivity related to CEA for T-threshold value = 1 and 2, but showed statistically significant increase of connectivity after CEA in both cerebellar hemispheres and corpus callosum for T-threshold value = 3 (p-FDR = 0.0106667). The network property analysis showed improved small worldness (2.14%), clustering coefficient (1.64%), local (1.94%) and global efficiency (0.56%), and reduced characteristic path length (-0.52%) after CEA. These results suggest that CEA is associated both with cognitive performance improvement and changes in interhemispheric local connectivity in the corpus callosum and cerebellum.

Reorganization of brain networks following carotid endarterectomy: an exploratory study using resting state functional connectivity with a focus on the changes in Default Mode Network connectivity.

OBJECTIVES: To assess whether there is mid-term reorganization in brain networks connectivity after Carotid Endarterectomy (CEA) using resting state functional connectivity Magnetic Resonance (fc-rsMR), with a special focus on the Default Mode Network (DMN). MATERIALS AND METHODS: In this prospective exploratory study, 14 asymptomatic consecutive patients (10 males and 4 females, mean age 73.5) with unilateral, significant ICA stenosis eligible for CEA according to European Society for Vascular Surgery guidelines were prospectively recruited. The week before CEA procedure, each patient underwent both neurocognitive and rs-fcMR evaluations on the same day; the neurocognitive test consisted on a Mini Mental State Examination (MMSE). The same neurocognitive test and rs-fcMR examination were repeated on follow-up between 3-6 months after CEA. MMSE scores were compared using paired T-Student Test. Rs-fcMR Region Of Interest (ROI-to-ROI) and Seed-to-voxel group analysis were conducted using the CONN toolbox v18 and the SPM 12 software. RESULTS: Patients showed improvements in MMSE scores from before to after CEA (p-value = 0.0001). ROI-to-ROI analysis revealed several statistically significant connectivity changes following CEA, both in terms of positive and negative correlations; Seed-to-Voxel focusing on DMN revealed increased connectivity between medial prefrontal cortex (mPFC) and three different clusters of voxels. CONCLUSIONS: CEA procedure is associated with an improvement in neurocognitive performance (according to MMSE testing) and reorganization of functional connectivity, including the DMN. These results represent a starting point in order to design further studies for a better understanding of the reorganization of brain networks following CEA, and to investigate the potential role of CEA as a therapeutic procedure for cognitive impairments in selected patients with critical ICA stenosis.

Wound healing properties of hyaluronan derivatives bearing ferulate residues.

HAFA macromolecules were designed as graft copolymers combining ferulic acid (FA) structure and the hyaluronic acid (HA) backbone linked through an ester bond. These materials were prepared by feruloylation of HA with bisimidazolide 3 [i.e. (E)-4-(3-(1H-imidazol-1-yl)-3-oxoprop-1-enyl)-2-methoxyphenyl 1H-imidazole-1-carboxylate] and obtained with different grafting degree (GD) values, which could be tuned by applying suitable reaction conditions. Among the numerous applications envisioned for HAFA graft copolymers on the basis of the physico-chemical, biological, and pharmacological properties of the starting natural products and the grafting-derived features such as physical cross-linking, potential wound healing properties have been evaluated in vitro and in vivo in preclinical models. In human keratinocyte (HaCaT) cells, our data showed the ability of HAFA-17 (GD = 7%) to ameliorate the in vitro scratch wound significantly with respect to the control HA and FA alone, and this effect was associated with the ability of HAFA-17 to also induce keratinocyte proliferation as determined by BrdU assay. In addition, experiments on wound healing in SKH1 mice confirmed the ability of HAFA-17 to improve the wound closure rate also in vivo. Overall, the data presented herein suggest HAFA-17 as a possible future drug for the therapeutic treatment of acute and chronic wounds.

Correction: Wound healing properties of hyaluronan derivatives bearing ferulate residues.

Correction for 'Wound healing properties of hyaluronan derivatives bearing ferulate residues' by Giuseppe Valacchi et al., J. Mater. Chem. B, 2015, DOI: .

Analgesic efficacy of CR4056, a novel imidazoline-2 receptor ligand, in rat models of inflammatory and neuropathic pain.

Two decades of investigations have failed to unequivocally clarify the functions and the molecular nature of imidazoline-2 receptors (I2R). However, there is robust pharmacological evidence for the functional modulation of monoamino oxidase (MAO) and other important enzyme activities by I2 site ligands. Some compounds of this class proved to be active experimental tools in preventing both experimental pain and opioid tolerance and dependence. Unfortunately, even though these compounds bind with high potency to central I2 sites, they fail to represent a valid clinical opportunity due to their pharmacokinetic, selectivity or side-effects profile. This paper presents the preclinical profile of a novel I2 ligand (2-phenyl-6-(1H-imidazol-1yl) quinazoline; [CR4056]) that selectively inhibits the activity of human recombinant MAO-A in a concentration-dependent manner. A sub-chronic four day oral treatment of CR4056 increased norepinephrine (NE) tissue levels both in the rat cerebral cortex (63.1% ±4.2%; P < 0.05) and lumbar spinal cord (51.3% ± 6.7%; P < 0.05). In the complete Freund's adjuvant (CFA) rat model of inflammatory pain, CR4056 was found to be orally active (ED50 = 5.8 mg/kg, by mouth [p.o.]). In the acute capsaicin model, CR4056 completely blocked mechanical hyperalgesia in the injured hind paw (ED50 = 4.1 mg/kg, p.o.; ED100 = 17.9 mg/kg, p.o.). This effect was dose-dependently antagonized by the non-selective imidazoline I2/α2 antagonist idazoxan. In rat models of neuropathic pain, oral administration of CR4056 significantly attenuated mechanical hyperalgesia and allodynia. In summary, the present study suggests a novel pharmacological opportunity for inflammatory and/or neuropathic pain treatment based on selective interaction with central imidazoline-2 receptors.

Efficacy of CR3294, a new benzamidine derivative, in the prevention of 5-fluorouracil-induced gastrointestinal mucositis and diarrhea in mice.

PURPOSE: Gastrointestinal mucositis, commonly associated with diarrhea, is a dose-limiting toxicity of chemotherapy. The new benzamidine derivative CR3294 reduces tissue damage in animal models of intestinal inflammation. Thus, we tested whether CR3294 had the potential to prevent chemotherapy-induced mucositis. METHODS: In tests on isolated cells, reactive oxygen species (ROS) formation and cytokine release were measured by chemiluminescence and immunoassays, respectively. In studies in vivo, BDF1 mice were given oral CR3294 (2.5-20 mg/kg) for 3 days before receiving 5-fluorouracil. Intestinal crypt survival, cell apoptosis and proliferation, and diarrhea score were assessed. Additionally, nude mice bearing tumor xenografts were treated with CR3294 and/or 5-fluorouracil, and tumor growth was monitored. RESULTS: CR3294 significantly inhibited cytokine release from stimulated leukocytes at concentrations similar to the IC(50) (2.9 +/- 0.2 muM) for ROS production by these cells. Consistent with these molecular findings, CR3294 dose-dependently protected the intestinal mucosa against 5-fluorouracil-induced toxicity in a mouse model of mucositis. The number of surviving crypts per cross-section in mice receiving 20 mg/kg CR3294 was 2.8-fold that in vehicle-treated animals (18.1 +/- 1.9 vs. 6.5 +/- 0.9, P < 0.001). Moreover, CR3294 decreased the cumulative diarrhea score by 50%, reduced by nearly 70% the incidence of severe episodes, and increased by 3-fold the number of mice without diarrhea. CR3294 neither affected the growth of tumor xenografts nor protected tumors from the cytotoxic activity of 5-fluorouracil. CONCLUSIONS: This study demonstrates that CR3294 acts on key molecular targets to reduce the signs of mucositis and the occurrence of diarrhea in mice exposed to the chemotherapy drug 5-fluorouracil.