Chronic hyperammonemia induces neuroinflammation which mediates cognitive impairment. How hyperammonemia induces neuroinflammation remains unclear. We aimed to assess whether: chronic hyperammonemia ...induces peripheral inflammation, and whether this then contributes to neuroinflammation, altered neurotransmission and impaired spatial learning — before assessing whether this neuroinflammation and impairment is reversible following hyperammonemia elimination or treatment of peripheral inflammation with anti-TNF-α.
Chronic hyperammonemia was induced by feeding rats an ammonia-containing diet. Peripheral inflammation was analyzed by measuring PGE2, TNF-α, IL-6 and IL-10. We tested whether chronic anti-TNF-α treatment improves peripheral inflammation, neuroinflammation, membrane expression of glutamate receptors in the hippocampus and spatial learning.
Hyperammonemic rats show a rapid and reversible induction of peripheral inflammation, with increased pro-inflammatory PGE2, TNF-α and IL-6, followed at around 10 days by reduced anti-inflammatory IL-10. Peripheral anti-TNF-α treatment prevents peripheral inflammation induction and the increase in IL-1b and TNF-α and microglia activation in hippocampus of the rats, which remain hyperammonemic. This is associated with prevention of the altered membrane expression of glutamate receptors and of the impairment of spatial memory assessed in the radial and Morris water mazes.
This report unveils a new mechanism by which chronic hyperammonemia induces neurological alterations: induction of peripheral inflammation. This suggests that reducing peripheral inflammation by safe procedures would improve cognitive function in patients with minimal hepatic encephalopathy.
This article unveils a new mechanism by which chronic hyperammonemia induces cognitive impairment in rats: chronic hyperammonemia per se induces peripheral inflammation, which mediates many of its effects on the brain, including induction of neuroinflammation, which alters neurotransmission, leading to cognitive impairment. It is also shown that reducing peripheral inflammation by treating rats with anti-TNF-α, which does not cross the blood-brain barrier, prevents hyperammonemia-induced neuroinflammation, alterations in neurotransmission and cognitive impairment.
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•Chronic hyperammonemia per se induces peripheral inflammation in rats.•Peripheral inflammation mediates induction of neuroinflammation by hyperammonemia.•Peripheral inflammation also mediates changes in membrane expression of glutamate receptors and spatial learning.•Hyperammonemia-induced inflammation and neuroinflammation are reversible.•Peripheral treatment with anti-TNFa prevents the effects of hyperammonemia on brain.
Patients with non-alcoholic fatty liver disease (NAFLD) may show mild cognitive impairment. Neuroinflammation in the hippocampus mediates cognitive impairment in rat models of minimal hepatic ...encephalopathy (MHE). Treatment with rifaximin reverses cognitive impairment in a large proportion of cirrhotic patients with MHE. However, the underlying mechanisms remain unclear. The aims of this work were to assess if rats with mild liver damage, as a model of NAFLD, show neuroinflammation in the hippocampus and impaired cognitive function, if treatment with rifaximin reverses it, and to study the underlying mechanisms. Mild liver damage was induced with carbon-tetrachloride. Infiltration of immune cells, glial activation, and cytokine expression, as well as glutamate receptors expression in the hippocampus and cognitive function were assessed. We assessed the effects of daily treatment with rifaximin on the alterations showed by these rats. Rats with mild liver damage showed hippocampal neuroinflammation, reduced membrane expression of glutamate N-methyl-D-aspartate (NMDA) receptor subunits, and impaired spatial memory. Increased C-C Motif Chemokine Ligand 2 (CCL2), infiltration of monocytes, microglia activation, and increased tumor necrosis factor α (TNFα) were reversed by rifaximin, that normalized NMDA receptor expression and improved spatial memory. Thus, rifaximin reduces neuroinflammation and improves cognitive function in rats with mild liver damage, being a promising therapy for patients with NAFLD showing mild cognitive impairment.
Purpose: To retrospectively report a large single-center experience of visceral artery aneurysms (VAAs) and pseudoaneurysms (VAPAs) treated with covered stenting (CS) as the first therapeutic option ...vs transcatheter embolization (TE). Methods: One hundred patients (mean age 59±14 years; 58 men) underwent 59 elective and 41 emergent endovascular procedures to treat 51 VAAs and 49 VAPAs. Seventy patients had TE and 30 received CS (27 Viabahn and 3 coronary stent grafts). Both TE and CS were performed in 10 cases. Results: Technical success was 96% (97% CS, 96% TE), and 30-day clinical success was 83% (87% CS, 81.4% TE). Four major complications occurred; 30-day mortality was 7%, mainly due to septic shock following pancreatic surgery. The midterm follow-up was 20.8 months in the total population and 32.8 months in the CS group. More than 6 months after CS all aneurysms remained excluded; stent patency was achieved in 88%. Twelve CS patients with >3 years’ follow-up had maintained stent patency. Conclusion: In endovascular treatment of visceral aneurysms, covered stenting was feasible in 30%. CS showed a slightly better efficacy than TE and good midterm patency. The Viabahn covered stent seems to be suitable for endovascular repair of tortuous visceral arteries affected by true or false aneurysms.
•Hyperammonemic rats show neuroinflammation and motor in-coordination.•Extracellular cGMP was administered intra-cerebrally to rats with chronic hyperammonemia.•This reduced microglia and astrocytes ...activation and TNFa receptor in membrane in cerebellum.•This was associated with reduced glutaminase expression and extracellular glutamate.•This reduced extracellular GABA in cerebellum and restored motor coordination.
Hyperammonemia is a main contributor to cognitive impairment and motor in-coordination in patients with hepatic encephalopathy. Hyperammonemia-induced neuroinflammation mediates the neurological alterations in hepatic encephalopathy. Intracerebral administration of extracellular cGMP restores some but not all types of cognitive impairment. Motor in-coordination, is mainly due to increased GABAergic tone in cerebellum. We hypothesized that extracellular cGMP would restore motor coordination in hyperammonemic rats by normalizing GABAergic tone in cerebellum and that this would be mediated by reduction of neuroinflammation.
The aims of this work were to assess whether chronic intracerebral administration of cGMP to hyperammonemic rats: 1) restores motor coordination; 2) reduces neuroinflammation in cerebellum; 3) reduces extracellular GABA levels and GABAergic tone in cerebellum; and also 4) to provide some advance in the understanding on the molecular mechanisms involved.
The results reported show that rats with chronic hyperammonemia show neuroinflammation in cerebellum, including microglia and astrocytes activation and increased levels of IL-1b and TNFa and increased membrane expression of the TNFa receptor. This is associated with increased glutaminase expression and extracellular glutamate, increased amount of the GABA transporter GAT-3 in activated astrocytes, increased extracellular GABA in cerebellum and motor in-coordination. Chronic intracerebral administration of extracellular cGMP to rats with chronic hyperammonemia reduces neuroinflammation, including microglia and astrocytes activation and membrane expression of the TNFa receptor. This is associated with reduced nuclear NF-κB, glutaminase expression and extracellular glutamate, reduced amount of the GABA transporter GAT-3 in activated astrocytes and reduced extracellular GABA in cerebellum and restoration of motor coordination.
The data support that extracellular cGMP restores motor coordination in hyperammonemic rats by reducing microglia activation and neuroinflammation, leading to normalization of extracellular glutamate and GABA levels in cerebellum and of motor coordination.
The rate of patients with pancreatic ductal adenocarcinoma (PDAC) receiving neoadjuvant chemotherapy is increasing, but upfront resection is still offered to most patients with resectable or ...borderline resectable disease. Encouraging data reported in adjuvant chemotherapy trials prompts surgeons towards upfront surgery, but such trials are subject to a significant selection bias. This systematic review aims to summarize available high-quality evidence regarding survival of patients treated with upfront surgery for PDAC.
Pubmed, Cochrane, and Web of Science Databases were interrogated for prospective studies published between 2000 and 2021 that included at least a cohort of patients treated with upfront surgery for resectable or borderline resectable PDAC. The Cochrane Collaboration's risk-of-bias tool for randomized trials (RoB-2) was used to assess risk of bias in all randomized studies. Patient weighted median overall survival (OS) and disease-free survival (DFS) were calculated.
Overall, 8,341 abstracts were screened, 17 reports were reviewed in full text, and finally 5 articles and 1 conference abstract underwent data extraction. Included studies were published between 2014 and 2021. All studies were RCTs comparing different neoadjuvant treatment strategies to upfront surgery. Three studies included only resectable PDAC patients, two studies recruited patients with resectable and borderline resectable disease, and one study selected only borderline resectable patients. A total of 439 patients were included in the upfront resection cohorts of the 6 studies, ranging between 20 to 180 patients per study. The weighted median OS after upfront surgery was 18.8 (95% CI 12.4 - 20.6) months. Median DFS was 9 (95% CI 1.6 - 12.5) months. Resection rate was 74.5% (range 65-90%). Adjuvant treatment was initiated in 68% (range 43-77%) of resected patients.
High-quality data for PDAC patients undergoing upfront surgery is scarce. Meta-analysis from the included studies showed a significantly shorter OS and DFS compared to recently published studies focusing on adjuvant combination chemotherapy, suggesting that the latter may overestimate survival due to the exclusion of most patients scheduled for upfront surgery.
We report the analysis of 1 year of data from the first cohort of 15 patients enrolled in an open-label, first-in-human, dose-escalation phase I study (ClinicalTrials.gov: NCT03282760, ...EudraCT2015-004855-37) to determine the feasibility, safety, and tolerability of the transplantation of allogeneic human neural stem/progenitor cells (hNSCs) for the treatment of secondary progressive multiple sclerosis. Participants were treated with hNSCs delivered via intracerebroventricular injection in combination with an immunosuppressive regimen. No treatment-related deaths nor serious adverse events (AEs) were observed. All participants displayed stability of clinical and laboratory outcomes, as well as lesion load and brain activity (MRI), compared with the study entry. Longitudinal metabolomics and lipidomics of biological fluids identified time- and dose-dependent responses with increased levels of acyl-carnitines and fatty acids in the cerebrospinal fluid (CSF). The absence of AEs and the stability of functional and structural outcomes are reassuring and represent a milestone for the safe translation of stem cells into regenerative medicines.
Previous studies show encouraging oncologic outcomes for neoadjuvant chemotherapy (NACT) in the setting of pancreatic ductal adenocarcinoma (PDAC). However, recent literature reported an increased ...clinical burden in patients undergoing pancreaticoduodenectomy (PD) following NACT. Therefore, the aim of our study was to assess the impact of NACT on postoperative outcomes and recovery after PD.
A retrospective propensity score-matched study was performed including all patients who underwent PD for PDAC in a single center between 2015 and 2018. Patients treated with NACT for resectable, borderline resectable or locally advanced PDAC were matched based on nearest neighbor propensity scores in a 1:1 ratio to patients who underwent upfront resection. Propensity scores were calculated using 7 perioperative variables, including gender, age, BMI, ASA score, Charlson-Deyo comorbidity score, fistula risk score (FRS), vascular resection. Primary outcome was the number and severity of complications at 90-days after surgery measured by the comprehensive complication index (CCI). Data are reported as median (IQR) or number of patients (%).
Of 283 resected patients, 95 (34%) were treated with NACT. Before matching, NACT patients were younger, had less comorbidities (Charlson-Deyo score 0 vs. 1,
= 0.04), similar FRS 2 (0-3) for both groups, and more vascular resections performed
= 28 (30%) vs.
= 26 (14%),
< 0.01. After propensity-score matching, preoperative and intraoperative characteristics were comparable. Postoperatively, CCI was similar between groups 8.7 (0-29.6) for both groups,
= 0.59. NACT patients had a non-statistically significant increase in superficial incisional surgical site infections
= 12 (13%) vs. 6 (6%),
= 0.14, while no difference was found for overall infectious complications and organ-space SSI. The occurrence of clinically-relevant pancreatic fistula was similar between groups 10 (11%) vs. 13 (14%),
= 0.51. No difference was found between groups for length of hospital stay 8 (7-15) vs. 8 (7-14) days,
= 0.62, and functional recovery outcomes.
After propensity score adjustment for perioperative risk factors, NACT did not worsen postoperative outcomes and functional recovery following PD for PDAC compared to upfront resection.
Adequate criteria for pancreatic surgery centralization are debated. This retrospective study aimed to define a reproducible method for complex care centralization, accounting for hospital ...performance and access to care.
The method consisted in: 1. Analysis of overall outcome and mortality-related factors. 2. Assessment of volume and adjusted mortality of each hospital. 3. Definition of different centralization models. 4. Final adjustments to guarantee access to care, evaluating travel times and waiting lists. This method was tested on Lombardy, the most populous Italian region (about 10 million inhabitants, 24 000 km2).
According to Ministry of Health data, 79 hospitals performed 3037 resections in 2014–2016. Mean overall mortality was 5.0%, increasing from 2.3%, of seven high-volume facilities (>30 resections/year) to 10.7% of 56 low-volume facilities (<10 resections/year). Five centralization models were tested (range: 7–23 hospitals): the best performing model included seven high-volume facilities, providing both low mortality (<2%), and easy access to care, namely reasonable travel time (≤60 min for >90% of the population), and limited impact on waiting list (1.1 extra-resection/hospital/week).
The four-step method appears as a flexible tool to centralize pancreatic surgery, allowing regulatory institutions to estimate the effect of different models.
Patients with liver cirrhosis may develop minimal hepatic encephalopathy (MHE) with mild cognitive impairment. Hyperammonemia is a main contributor to cognitive impairment in MHE, which is mediated ...by neuroinflammation. GABAergic neurotransmission is altered in hyperammonemic rats. We hypothesized that, in hyperammonemic rats, (a) enhanced GABAergic tone would contribute to induce neuroinflammation, which would be improved by reducing GABAergic tone by chronic bicuculline treatment; (b) this would improve spatial learning and memory impairment; and (c) modulation of glutamatergic neurotransmission would mediate this cognitive improvement. The aim of this work was to assess the above hypotheses. Bicuculline was administrated intraperitoneally once a day for 4 weeks to control and hyperammonemic rats. The effects of bicuculline on microglia and astrocyte activation, IL-1β content, on membrane expression of AMPA and NMDA glutamate receptors subunits in the hippocampus and on spatial learning and memory as well as anxiety were assessed. Treatment with bicuculline reduces astrocyte activation and IL-1β but not microglia activation in the hippocampus of hyperammonemic rats. Bicuculline reverses the changes in membrane expression of AMPA receptor subunits GluA1 and GluA2 and of the NR2B (but not NR1 and NR2A) subunit of NMDA receptors. Bicuculline improves spatial learning and working memory and decreases anxiety in hyperammonemic rats. In hyperammonemia, enhanced activation of GABA
receptors in the hippocampus contributes to some but not all aspects of neuroinflammation, to altered glutamatergic neurotransmission and to impairment of spatial learning and memory as well as anxiety, all of which are reversed by reducing activation of GABA
receptors with bicuculline.
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