Assessment of Intraoperative Scoring Systems for Predicting Cytoreduction Outcome in Peritoneal Metastatic Disease: A Systematic Review and Meta-analysis.

BACKGROUND: Cytoreductive surgery (CRS) is a widely acknowledged treatment approach for peritoneal metastasis, showing favorable prognosis and long-term survival. Intraoperative scoring systems quantify tumoral burden before CRS and may predict complete cytoreduction (CC). This study reviews the intraoperative scoring systems for predicting CC and optimal cytoreduction (OC) and evaluates the predictive performance of the Peritoneal Cancer Index (PCI) and Predictive Index Value (PIV). METHODS: Systematic searches were conducted in Embase, MEDLINE, and Web of Science. Meta-analyses of extracted data were performed to compare the absolute predictive performances of PCI and PIV. RESULTS: Thirty-eight studies (5834 patients) focusing on gynecological (n = 34; 89.5%), gastrointestinal (n = 2; 5.3%) malignancies, and on tumors of various origins (n = 2; 5.3%) were identified. Seventy-seven models assessing the predictive performance of scoring systems (54 for CC and 23 for OC) were identified with PCI (n = 39/77) and PIV (n = 16/77) being the most common. Twenty models (26.0%) reinterpreted previous scoring systems of which ten (13%) used a modified version of PIV (reclassification). Meta-analyses of models predicting CC based on PCI (n = 21) and PIV (n = 8) provided an AUC estimate of 0.83 (95% confidence interval [CI] 0.79-0.86; Q = 119.6, p = 0.0001; I2 = 74.1%) and 0.74 (95% CI 0.68-0.81; Q = 7.2, p = 0.41; I2 = 11.0%), respectively. CONCLUSIONS: Peritoneal Cancer Index models demonstrate an excellent estimate of CC, while PIV shows an acceptable performance. There is a need for high-quality studies to address management differences, establish standardized cutoff values, and focus on non-gynecological malignancies.

Microglial large extracellular vesicles propagate early synaptic dysfunction in Alzheimer's disease.

Synaptic dysfunction is an early mechanism in Alzheimer's disease that involves progressively larger areas of the brain over time. However, how it starts and propagates is unknown. Here we show that amyloid-ß released by microglia in association with large extracellular vesicles (Aß-EVs) alters dendritic spine morphology in vitro, at the site of neuron interaction, and impairs synaptic plasticity both in vitro and in vivo in the entorhinal cortex-dentate gyrus circuitry. One hour after Aß-EV injection into the mouse entorhinal cortex, long-term potentiation was impaired in the entorhinal cortex but not in the dentate gyrus, its main target region, while 24 h later it was also impaired in the dentate gyrus, revealing a spreading of long-term potentiation deficit between the two regions. Similar results were obtained upon injection of extracellular vesicles carrying Aß naturally secreted by CHO7PA2 cells, while neither Aß42 alone nor inflammatory extracellular vesicles devoid of Aß were able to propagate long-term potentiation impairment. Using optical tweezers combined to time-lapse imaging to study Aß-EV-neuron interaction, we show that Aß-EVs move anterogradely at the axon surface and that their motion can be blocked through annexin-V coating. Importantly, when Aß-EV motility was inhibited, no propagation of long-term potentiation deficit occurred along the entorhinal-hippocampal circuit, implicating large extracellular vesicle motion at the neuron surface in the spreading of long-term potentiation impairment. Our data indicate the involvement of large microglial extracellular vesicles in the rise and propagation of early synaptic dysfunction in Alzheimer's disease and suggest a new mechanism controlling the diffusion of large extracellular vesicles and their pathogenic signals in the brain parenchyma, paving the way for novel therapeutic strategies to delay the disease.

T1AM-TAAR1 signalling protects against OGD-induced synaptic dysfunction in the entorhinal cortex.

Abnormalities in thyroid hormones (TH) availability and/or metabolism have been hypothesized to contribute to Alzheimer's disease (AD) and to be a risk factor for stroke. Recently, 3-iodothyronamine (T1AM), an endogenous amine putatively derived from TH metabolism, gained interest for its ability to promote learning and memory in the mouse. Moreover, T1AM has been demonstrated to rescue the ß-Amyloid dependent LTP impairment in the entorhinal cortex (EC), a brain area crucially involved in learning and memory and early affected during AD. In the present work, we have investigated the effect of T1AM on ischemia-induced EC synaptic dysfunction. In EC brain slices exposed to oxygen-glucose deprivation (OGD), we demonstrated that the acute perfusion of T1AM (5 µM) was capable of preventing ischemia-induced synaptic depression and that this protective effect was mediated by the trace amine-associated receptor 1 (TAAR1). Moreover, we demonstrated that activation of the BDNF-TrkB signalling is required for T1AM action during ischemia. The protective effect of T1AM was more evident when using EC slices from transgenic mutant human APP (mhAPP mice) that are more vulnerable to the effect of OGD. Our results confirm that the TH derivative T1AM can rescue synaptic function after transient ischemia, an effect that was also observed in a Aß-enriched environment.

The safety profile of hydroxychloroquine: major cutaneous and extracutaneous adverse events.

Hydroxychloroquine is an established therapy for several rheumatological disorders, and very recently it has been proposed as a possible treatment for the new coronavirus disease 2019 even if recent randomised trials did not prove any benefit. Notably, hydroxychloroquine has been associated with a heterogeneous range of cutaneous and extra-cutaneous adverse events. We carried out a narrative review of the literature up to November 1st, 2020, related to the safety of hydroxychloroquine. In particular, cutaneous and extra-cutaneous adverse events associated with hydroxychloroquine were reviewed. The following databases were consulted: PubMed, Embase, Google Scholar and ResearchGate. The research of articles was conducted by using the following search terms: ''hydroxychloroquine," ''adverse event/effect,'' "cutaneous", "skin", "cardiotoxicity", "retinopathy", gastrointestinal and neurological toxicity". The main indication for which hydroxychloroquine was used in the reports was an immune mediated disorder. Adverse events were described mostly in females over 50 years of age. The most common cutaneous adverse effect was maculopapular and erythematous rash occurring within 4 weeks of initiating hydroxychloroquine and disappearing within few weeks of discontinuation. Gastrointestinal symptoms and headache were the most frequent extracutaneous manifestations. Rarer cutaneous manifestations include hyperpigmentation, psoriasiform dermatitis, photodermatitis, stomatitis, melanonychia and hair loss. More severe conditions were acute generalised exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome/toxic epidermal necrolysis, and among extra-cutaneous adverse events cardiotoxicity and retinopathy. Since hydroxychloroquine is widely prescribed in rheumatology, it is important for rheumatologists to be familiar with its safety profile.

Productivity and nutritional and nutraceutical value of strawberry fruits (Fragaria x ananassa Duch.) cultivated under irrigation with treated wastewaters.

BACKGROUND: Agriculture represents a productive sector typically characterized by a high water demand, whereas freshwater (FW) availability is a problem of increasing concern in the world and FW resources are becoming insufficient for sustaining agricultural irrigation. The reuse of treated wastewaters (TWWs) for crop irrigation could be an efficient tool for reducing water shortage. Hence, the present study evaluated the food quality of Fragaria x ananassa (cultivar Camarosa) fruits irrigated with four types of treated wastewaters (TWWs). Strawberries were analysed for yield, sucrose, fructose, glucose, total soluble polyphenols (TSP), total monomeric anthocyanins (TMA), and antiradical and antioxidant capacity. In addition, a targeted quantification of the most representative phenolic compounds of strawberry was performed. RESULTS: TWWs complied the Italian ministerial decree 185/2003 for wastewater reuse, with very few exceptions, mainly represented by chloride concentrations (258-643 mg L-1 versus a legal threshold of 250 mg L-1 ). The reuse of TWWs reduced fruit yield (10-26%) compared to irrigation with tap water as a control. Irrigation with TWWs gave also rise to the decrease of total sugars (14-26%), TSP (2-10%) and TMA (29-49%). Individual phenolic acids, flavonols and flavanols were quite stable in response to the irrigation with TWWs, whereas anthocyanidins decreased significantly. CONCLUSION: Although TWWs negatively affected fruit quality, the nutritional and nutraceutical parameters determined in the present study were in line with data previously reported for strawberries purchased in the market or cultivated in research orchards, thus suggesting that the use of TWWs does not prevent the fruit marketability. © 2020 Society of Chemical Industry.

Involvement of p38 MAPK in Synaptic Function and Dysfunction.

Many studies have revealed a central role of p38 MAPK in neuronal plasticity and the regulation of long-term changes in synaptic efficacy, such as long-term potentiation (LTP) and long-term depression (LTD). However, p38 MAPK is classically known as a responsive element to stress stimuli, including neuroinflammation. Specific to the pathophysiology of Alzheimer's disease (AD), several studies have shown that the p38 MAPK cascade is activated either in response to the Aß peptide or in the presence of tauopathies. Here, we describe the role of p38 MAPK in the regulation of synaptic plasticity and its implication in an animal model of neurodegeneration. In particular, recent evidence suggests the p38 MAPK α isoform as a potential neurotherapeutic target, and specific inhibitors have been developed and have proven to be effective in ameliorating synaptic and memory deficits in AD mouse models.

Laparoscopic Liver Surgery Training Course on Thiel-Embalmed Human Cadavers: Program Evaluation, Trainer's Long-Term Feedback and Steps Forward.

OBJECTIVES: The purpose of this study was to evaluate the feedback of participants upon laparoscopic liver surgery (LLS) course on Thiel-embalmed human bodies. METHODS: From 2010 to 2017, ten LLS masterclasses have been organized by the Department of Hepatobiliary Surgery at Ghent University Hospital. A 23-question anonymous survey was electronically sent to 119 participants between November 2017 and January 2018, exploring their characteristics and asking for evaluation of the course. The obstacles for implementing LLS in their centers have been assessed. RESULTS: Sixty-four surgeons (53.8%) responded to the survey; 42 (65.6%) were employed at a university hospital; and 39 (60.9%) were in the first decade of their practice as a consultant surgeon. Forty-three (67.2%) surgeons reported an increased percentage of LLS cases afterward. Training on Thiel cadavers was considered superior (49.2%) to other training options including proctoring in the operating room (34.9%), virtual reality (6.3%), video training (4.8%) and practicing on pigs (4.8%). Obstacles identified contained inadequate training, patient's referral pattern, financial issues, lack of dedicated surgical team and time constrains. CONCLUSIONS: This survey revealed that a structured short-time program incorporating interactive discussion, live operations and hands-on training on human bodies under proctorship may enhance efficient training in laparoscopic liver surgery. In a step forward for upcoming courses, the importance of team building has to be addressed.

Remediated marine sediment as growing medium for lettuce production: assessment of agronomic performance and food safety in a pilot experiment.

BACKGROUND: The use of reclaimed dredged sediments as growing media may offer a profitable alternative to their disposal as a waste and at the same time meets the need of peat-substitute substrates in horticulture. When sediments are reused to cultivate food crops, issues related to human health rise due to potential accumulation of contaminants in the product. This pilot study aimed at verifying the suitability of a reclaimed dredged port sediment, used pure or mixed with peat, as a growing medium for lettuce cultivation. RESULTS: The pure sediment caused a reduction in crop yield, probably due to its unsuitable physical properties, whereas the mixture sediment-peat and pure peat resulted in the same yield. Although the sediment contained potentially phytotoxic heavy metals and some organic pollutants, no symptoms of plant toxicity were noted. Besides, no organic contaminants were detected in lettuce heads, and heavy metals amounts were not hazardous for consumers. Conversely, plants grown in the sediment were particularly rich in minerals like Ca, Mg and Fe, and showed higher concentrations of organic acids and antioxidants. CONCLUSION: The use of the sediment as a growing medium for lettuce was shown to be safe for both inorganic and organic contaminants. Nevertheless, considering crop yield results, the mixture of the sediment with other materials is recommended in order to produce a substrate with more suitable physicochemical properties for vegetable cultivation. © 2019 Society of Chemical Industry.

Laparoscopic Versus Open Approach for Formal Right and Left Hepatectomy: A Propensity Score Matching Analysis.

BACKGROUND: Laparoscopic liver surgery is expanding worldwide, but further evidence is needed to assess safety and efficacy of laparoscopic major hepatectomy. The study analyzes perioperative outcomes of pure laparoscopic versus open major hepatectomies matched by the propensity score method. METHODS: From 2005 to 2017, 268 major hepatectomies were performed of which 73 were laparoscopic. After a 1:1 propensity score matching, 59 laparoscopic right and left hepatectomies were compared to 59 open. The matching was based on age, gender, year of procedure, BMI, ASA score, underlying liver disease, previous abdominal surgery, type of hepatectomy, preoperative chemotherapy, number, dimension and nature of lesions. An intention-to-treat analysis and a per-protocol analysis were carried out. RESULTS: Mean surgical time was 315 min in the laparoscopic group and 292.5 min in the open group (p = 0.039); conversion rate in laparoscopy was 20.3%; blood loss was 480 ml (50-3000) versus 550 ml (50-2600), respectively, for laparoscopic and open (p = 0.577). Lengths of postoperative analgesia and hospital stay were shorter in the laparoscopic group (p = 0.0001 and 0.024, respectively). Postoperative complications occurred in 11.9% of laparoscopic cases and in 25.4% of open cases (p = 0.098). Median Comprehensive Complication Index was 26.2 (8.7-54.2) in the open group versus 20.9 (8.7-66.2) in open (p = 0.368). Per-protocol analysis showed a better trend in favor of laparoscopy concerning surgical time. CONCLUSIONS: Laparoscopic major hepatectomies are safe and feasible procedures allowing a similar complication rate with a shorter hospital stay and diminished postoperative pain with respect to the standard approach.

Systematic review of surgical training on reperfused human cadavers.

BACKGROUND: The role of reperfused human cadavers in surgical training has not been established. METHODS: Reports describing reperfused human cadaver models in terms of simulated surgeries, the use of tools to assess technical competency and skills transfer to patients, cadaver status and reperfusion techniques were included. RESULTS: Thirty-five reports were included. Most participants practised vascular (n = 27), flap (n = 6) and trauma (n = 4) procedures. Training progression was evaluated objectively in only two studies. In two publications, flap techniques were practised on cadavers and repeated successfully in patients. Eighteen studies employed whole bodies. Fresh and embalmed cadavers were both used in 17 publications. Most embalmed cadavers were formalin-fixed (n = 10), resulting in stiffness. Few trainings were offered on soft Thiel-embalmed cadavers (n = 5). Only arteries were reperfused in 20 studies, while in 13 publications, the arteries and veins were filled. Arteries and/or veins were mostly pressurized (n = 21) and arterial flow was generated in 14 studies. CONCLUSIONS: Various reperfused human cadaver models exist, enabling practise of mainly vascular procedures. Preservation method determines the level of simulation fidelity. Thorough evaluation of these models as surgical training tools and transfer effectiveness is still lacking.

Lifelike Vascular Reperfusion of a Thiel-Embalmed Pig Model and Evaluation as a Surgical Training Tool.

BACKGROUND: Vascular reperfusion of Thiel cadavers can aid surgical and anatomical instruction. This study investigated whether ideal embalming circumstances provide lifelike vascular flow, enabling surgical practice and enhancing anatomical reality. METHODS: Pressure-controlled pump-driven administration of blue embalming solution was assessed directly postmortem in a pig model (n = 4). Investigation of subsequent pump-driven vascular injection of red paraffinum perliquidum (PP) included assessment of flow parameters, intracorporeal distribution, anatomical alterations, and feasibility for surgical training. The microscopic distribution of PP was analyzed in pump-embalmed pig and gravity-embalmed human small intestines. RESULTS: Embalming lasted 50-105 min, and maximum arterial pressure was 65 mm Hg. During embalming, the following consecutive alterations were observed: arterial filling, organ coloration, venous perfusion, and further tissue coloration during the next weeks. Most organs were adequately preserved. PP generated low arterial pressures (<30 mm Hg) and drained through the venous cannula. Generally, realistic reperfusion and preservation of original anatomy were observed, but leakage in the pleural, abdominal, and retroperitoneal cavities occurred, and computed tomography showed edematous spleen and liver. Reduction of arterial flow rates after venous drainage is a prerequisite to prevent anatomical deformation, allowing simulation of various surgeries. In pump-embalmed pig small intestines, PP flowed from artery to vein through the capillaries without extravasation. In contrast, arterioles were blocked in gravity-embalmed human tissues. CONCLUSIONS: In a pig model, immediate postmortem pressure-controlled pump embalming generates ideal circumstances for (micro)vascular reperfusion with PP, permitting lifelike anatomy instruction and surgical training.

Proton magnetic resonance spectroscopy of N-acetyl aspartate in first depressive episode and chronic major depressive disorder: A systematic review and meta-analysis.

N-acetyl aspartate (NAA) is a marker of neuronal integrity and metabolism. Deficiency in neuronal plasticity and hypometabolism are implicated in Major Depressive Disorder (MDD) pathophysiology. To test if cerebral NAA concentrations decrease progressively over the MDD course, we conducted a pre-registered meta-analysis of Proton Magnetic Resonance Spectroscopy (1H-MRS) studies comparing NAA concentrations in chronic MDD (n = 1308) and first episode of depression (n = 242) patients to healthy controls (HC, n = 1242). Sixty-two studies were meta-analyzed using a random-effect model for each brain region. NAA concentrations were significantly reduced in chronic MDD compared to HC within the frontal lobe (Hedges' g = -0.330; p = 0.018), the occipital lobe (Hedges' g = -0.677; p = 0.007), thalamus (Hedges' g = -0.673; p = 0.016), and frontal (Hedges' g = -0.471; p = 0.034) and periventricular white matter (Hedges' g = -0.478; p = 0.047). We highlighted a gap of knowledge regarding NAA levels in first episode of depression patients. Sensitivity analyses indicated that antidepressant treatment may reverse NAA alterations in the frontal lobe. We highlighted field strength and correction for voxel grey matter as moderators of NAA levels detection. Future studies should assess NAA alterations in the early stages of the illness and their longitudinal progression.

Standardizing eligibility and patient selection for Pressurized Intraperitoneal Aerosol Chemotherapy: A Delphi consensus statement.

INTRODUCTION: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is a procedure for minimally invasive drug administration in patients with peritoneal metastasis. Previous studies have emphasized the importance of uniformity in treatment protocols and standardization of this practice. This study aimed to reach a consensus on eligibility, patient selection, and choice of chemotherapy for PIPAC. METHODS: A three-round modified Delphi study was conducted. A steering group formulated a list of baseline statements, addressing the objectives. The steering group consisted of seven expert surgical and medical oncologists. Available evidence and published key opinions were critically reviewed. An international expert panel scored those statements on a 4-point Likert scale. The statements were submitted electronically and anonymously. Consensus was reached if the agreement rate was ≥75%. A minimum Cronbach's alpha of >0.8 was set. RESULTS: Forty-five (45/58; 77.6%) experts participated and completed all rounds. Experts were digestive surgeons (n = 28), surgical oncologists (n = 7), gynecologists (n = 5), medical oncologists (n = 4), and one clinical researcher. Their assessment of 81 preliminary statements in the first round resulted in 41 consolidated statements. In round two, consensus was reached on 40 statements (40/41; 97.6%) with a consensus of ≥80% for each individual statement. In the third round, 40 statements were unanimously approved as definitive. The choice of first- and second-line chemotherapy remained controversial and could not reach consensus. CONCLUSIONS: This International Delphi study provides practical guidance on eligibility and patient selection for PIPAC. Ongoing trial data and long-term results that could contribute to the further standardization of PIPAC are eagerly awaited.

Machine learning improves prediction of postoperative outcomes after gastrointestinal surgery: a systematic review and meta-analysis.

BACKGROUND: Machine learning (ML) approaches have become increasingly popular in predicting surgical outcomes. However, it is unknown whether they are superior to traditional statistical methods such as logistic regression (LR). This study aimed to perform a systematic review and meta-analysis to compare the performance of ML vs LR models in predicting postoperative outcomes for patients undergoing gastrointestinal (GI) surgery. METHODS: A systematic search of Embase, MEDLINE, Cochrane, Web of Science, and Google Scholar was performed through December 2022. The primary outcome was the discriminatory performance of ML vs LR models as measured by the area under the receiver operating characteristic curve (AUC). A meta-analysis was then performed using a random effects model. RESULTS: A total of 62 LR models and 143 ML models were included across 38 studies. On average, the best-performing ML models had a significantly higher AUC than the LR models (ΔAUC, 0.07; 95% CI, 0.04-0.09; P < .001). Similarly, on average, the best-performing ML models had a significantly higher logit (AUC) than the LR models (Δlogit [AUC], 0.41; 95% CI, 0.23-0.58; P < .001). Approximately half of studies (44%) were found to have a low risk of bias. Upon a subset analysis of only low-risk studies, the difference in logit (AUC) remained significant (ML vs LR, Δlogit [AUC], 0.40; 95% CI, 0.14-0.66; P = .009). CONCLUSION: We found a significant improvement in discriminatory ability when using ML over LR algorithms in predicting postoperative outcomes for patients undergoing GI surgery. Subsequent efforts should establish standardized protocols for both developing and reporting studies using ML models and explore the practical implementation of these models.

National practice patterns in the use of endoscopic ultrasound biopsy for resectable Pancreatic Neuroendocrine Tumors: Insights into the role of DOTATATE PET/CT in diagnosis.

INTRODUCTION: Pancreatic neuroendocrine tumors (PNETs) are typically diagnosed using endoscopic ultrasound-guided (EUS) biopsy, which can be associated with complications. Since 2016, DOTATATE PET/CT has emerged as an effective tool to localize and stage PNETs. METHODS: Patients with PNETs who underwent R0 resections were identified from the 2004-2019 National Cancer Database PUF. Joinpoint regression and multivariable logistic regression were used to analyze trends in the use of biopsy. RESULTS: Of 16,746 R0 resected PNET patients, 44 â€‹% underwent diagnostic biopsy. Joinpoint regression showed a significant increase in the use of biopsy from 2004 to 2019 (APC 1.80, p â€‹< â€‹0.001). A higher percentage of patients diagnosed after DOTATATE approval underwent biopsy compared to those diagnosed before (48 â€‹% vs. 42 â€‹%, p â€‹< â€‹0.001). Adjusted analysis showed diagnosis after 2016 was associated with increased odds of biopsy (OR â€‹= â€‹1.67, p â€‹< â€‹0.001). CONCLUSIONS: Despite technologic advancement with DOTATATE PET/CT, there has been a significant increase in the proportion of resectable PNETs undergoing preoperative biopsy.

Systematic study on nail plate assessment: differences in nail plate shape, thickness, power Doppler signal and scanning approach.

Ultrasonography (US) of the nail is raising interest in the last years and its feasibility, quickness and amount of descriptive data may provide valuable information. Different authors presented several scanning approaches to nail complex in different pathological conditions, such as psoriasis, but no scanning protocol was ever proposed using healthy subjects as population of reference. The aim of the study was to establish a protocol for the US of nail plate and to assess whether the measurement of the nail plate is influenced by longitudinal vs transverse scan, sex, digit and hand dominance. Using high frequency probe and a Canon Aplio i800 machine, ultrasonographers took scans of nail plates of the hands from healthy subjects. Nail plate shape, thickness and power Doppler signal (PDUS) were evaluated and scans were taken both on longitudinal and transverse axis, at distal, middle and proximal portion of the nail plate or at a fixed angles of - 45°, 0° or + 45°. All the images were then revised and scored using a DICOM software, in order to allow good standards of accuracy and reproducibility. A total of 27 subjects (14 females and 13 males) were assessed. The measures did not result to differ in different portions or angles. Furthermore, no difference appears in sex or dominant vs not dominant hand. A decreasing and significant trend for nail plate thickness was found from the first to the fifth finger. Doppler signal was found in all but one subjects, with a range from almost absent to very evident. No difference was found between groups regarding PDUS. The data provided suggest that a proper scan protocol should include all the nails and evaluation should be done both on longitudinal and transverse axis. Since Doppler signal is highly variable in healthy subjects, its presence should be carefully considered as pathological finding. Observations provided by this study clarify important points of the scanning technique and solve doubts related to which nails should be scanned and where to evaluate quantitative parameters.

Microglial extracellular vesicles induce Alzheimer's disease-related cortico-hippocampal network dysfunction.

ß-Amyloid is one of the main pathological hallmarks of Alzheimer's disease and plays a major role in synaptic dysfunction. It has been demonstrated that ß-amyloid can elicit aberrant excitatory activity in cortical-hippocampal networks, which is associated with behavioural abnormalities. However, the mechanism of the spreading of ß-amyloid action within a specific circuitry has not been elucidated yet. We have previously demonstrated that the motion of microglia-derived large extracellular vesicles carrying ß-amyloid, at the neuronal surface, is crucial for the initiation and propagation of synaptic dysfunction along the entorhinal-hippocampal circuit. Here, using chronic EEG recordings, we show that a single injection of extracellular vesicles carrying ß-amyloid into the mouse entorhinal cortex could trigger alterations in the cortical and hippocampal activity that are reminiscent of those found in Alzheimer's disease mouse models and human patients. The development of EEG abnormalities was associated with progressive memory impairment as assessed by an associative (object-place context recognition) and non-associative (object recognition) task. Importantly, when the motility of extracellular vesicles, carrying ß-amyloid, was inhibited, the effect on network stability and memory function was significantly reduced. Our model proposes a new biological mechanism based on the extracellular vesicles-mediated progression of ß-amyloid pathology and offers the opportunity to test pharmacological treatments targeting the early stages of Alzheimer's disease.

A comprehensive atlas of perineuronal net distribution and colocalization with parvalbumin in the adult mouse brain.

Perineuronal nets (PNNs) surround specific neurons in the brain and are involved in various forms of plasticity and clinical conditions. However, our understanding of the PNN role in these phenomena is limited by the lack of highly quantitative maps of PNN distribution and association with specific cell types. Here, we present a comprehensive atlas of Wisteria floribunda agglutinin (WFA)-positive PNNs and colocalization with parvalbumin (PV) cells for over 600 regions of the adult mouse brain. Data analysis shows that PV expression is a good predictor of PNN aggregation. In the cortex, PNNs are dramatically enriched in layer 4 of all primary sensory areas in correlation with thalamocortical input density, and their distribution mirrors intracortical connectivity patterns. Gene expression analysis identifies many PNN-correlated genes. Strikingly, PNN-anticorrelated transcripts are enriched in synaptic plasticity genes, generalizing PNNs' role as circuit stability factors.

Emerging Roles of Extracellular Vesicles in Alzheimer's Disease: Focus on Synaptic Dysfunction and Vesicle-Neuron Interaction.

Alzheimer's disease (AD) is considered by many to be a synaptic failure. Synaptic function is in fact deeply affected in the very early disease phases and recognized as the main cause of AD-related cognitive impairment. While the reciprocal involvement of amyloid beta (Aß) and tau peptides in these processes is under intense investigation, the crucial role of extracellular vesicles (EVs) released by different brain cells as vehicles for these molecules and as mediators of early synaptic alterations is gaining more and more ground in the field. In this review, we will summarize the current literature on the contribution of EVs derived from distinct brain cells to neuronal alterations and build a working model for EV-mediated propagation of synaptic dysfunction in early AD. A deeper understanding of EV-neuron interaction will provide useful targets for the development of novel therapeutic approaches aimed at hampering AD progression.

Intensified Total Neoadjuvant Therapy Versus Intensified Concurrent Chemoradiotherapy in Locally Advanced Rectal Cancer: A Propensity Score Matching Analysis.

BACKGROUND/AIM: To compare clinical outcomes following intensified total neoadjuvant therapy (TNT) and intensified neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC). PATIENTS AND METHODS: Of the 79 patients with LARC admitted to our department, 51 received intensified neoadjuvant CRT (CRT group) and 28 received intensified TNT (TNT group). Intensified TNT was defined as multi-agent chemotherapy, including FOLFOXIRI regimen plus bevacizumab (mutated Ras-BRAF) or panitumumab/cetuximab (wild-type Ras-BRAF) followed by oxaliplatin-5-fluorouracil-based CRT and surgery. Kaplan-Meier and Log rank test were used for survival analysis. Survival rates of the two groups were compared using propensity score matching. RESULTS: Data from 28 TNT patients and 28 CRT patients were analyzed after a 1:1 propensity matching with replacement. Kaplan-Meier curve showed that overall survival (OS), disease-free survival (DFS) and distant metastasis-free survival (DMFS) rates with TNT were comparable to those with CRT. The 5-year DMFS rates for TNT and CRT were 61.5% versus 63.0% (p=0.82), respectively. In the TNT group, 32.1% patients (n=9) achieved pathological complete response (pCR), whereas 21.4% patients (n=6) achieved pCR with CRT (p=0.37). CONCLUSION: Intensified TNT and CRT resulted in similar survival outcomes, while intensified TNT led to higher pCR, albeit not statistically significant.