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Arteriovenous malformation of the brain (bAVM) is a vascular phenotype related to brain defective angiogenesis. Involved vessels show impaired expression of vascular differentiation markers resulting in the arteriolar to venule direct shunt. In order to clarify aberrant gene expression occurring in bAVM, here we describe results obtained by methylome analysis performed on endothelial cells (ECs) isolated from bAVM specimens, compared to human cerebral microvascular ECs. Results were validated by quantitative methylation-specific PCR and quantitative realtime-PCR. Differential methylation events occur in genes already linked to bAVM onset, as RBPJ and KRAS. However, among differentially methylated genes, we identified EPHB1 and several other loci involved in EC adhesion as well as in EC/vascular smooth muscle cell (VSMC) crosstalk, suggesting that only endothelial dysfunction might not be sufficient to trigger the bAVM phenotype. Moreover, aberrant methylation pattern was reported for many lncRNA genes targeting transcription factors expressed during neurovascular development. Among these, the YBX1 that was recently shown to target the arteridin coding gene. Finally, in addition to the conventional CpG methylation, we further considered the role of impaired CHG methylation, mainly occurring in brain at embryo stage. We showed as differentially CHG methylated genes are clustered in pathways related to EC homeostasis, as well as to VSMC-EC crosstalk, suggesting as impairment of this interaction plays a prominent role in loss of vascular differentiation, in bAVM phenotype.

Background: Vaccination protects against severe COVID-19 manifestations. For those with post-COVID-19 conditions (PCC) or long COVID, the impact of COVID-19 vaccination on the evolution of symptoms, immune responses, and viral persistence is unclear. Methods: In this prospective observational cohort study, we evaluated the number of PCC symptoms, affected organ systems, and psychological well-being scores before and after patients with PCC received COVID-19 vaccination. We simultaneously evaluated biomarkers of systemic inflammation and levels of plasma cytokines/chemokines. We measured plasma and intracellular levels of SARS-CoV-2 antigens, and immunoreactivity to SARS-CoV-2 antigens in blood. Results: COVID-19 vaccination was associated with decreases in number of PCC symptoms (pre-vaccination: 6.56 ± 3.1 vs post-vaccination: 3.92 ± 4.02; P

Introduction: Residual tumor cellularity (RTC) and pathologic complete response (pCR) after neo-adjuvant chemotherapy (NAC) are prognostic factors associated with improved outcomes in breast cancer (BC). However, the majority of patients achieve partial pathologic response (pPR) and no clear correlation between RTC patterns and outcomes was described. Our aims were to define predictive factors for pCR and compare different outcomes of patients with pCR or pPR and with different RTC patterns. Materials and methods: Baseline and post-NAC demographics, clinicopathological characteristics, post-operative data, survival and recurrence status were recorded from our institutional database. A multivariable analysis was performed using a logistic regression model to identify independent predictors of pCR. Disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) analyses were performed using the Kaplan-Meier method. Results: Overall, of the 495 patients analyzed, 148 (29.9%) achieved pCR, 347 (70.1%) had pPR, and the median RTC was 40%. Multivariable analysis identified 3 independent factors predictive of pCR: tumor stage before NAC (cT1-2 84.5% versus cT3-4 15.5%), BC sub-type (HER2-positive 54.7% versus triple-negative 29.8% versus luminal-like 15.5%), and vascular invasion (absence 98.0% versus presence 2.0%). We found statistically significant longer DFS, DDFS, and OS in patients with pCR and with RTC

Pseudoaneurysm rarely develops after orthognathic surgery, and can cause symptoms such as facial swelling, delayed bleeding, and development of a pulsatile soft mass. The aim of this report is to highlight a case of a masseteric artery pseudoaneurysm following orthognatic surgery, describing the possible while rare occurrence and its treatment. At the ninth postoperative day, persistent facial swelling and bleeding from the intraoral surgical wounds and nose occurred, followed by a syncope. Support therapy was administered, and an Angio-CT was requested. The results of the scans raised suspicion of the presence of a pseudoaneurysm. After the stabilization of the clinical picture a therapeutic angiography was performed. A pseudoaneurysmatic dilatation was documented in the distal portion of the left masseteric artery and was promptly excluded from the main circle. This artery derived, as an anatomical variant, from a common branch originating from the internal maxillary artery. While this complication is more commonly reported in traumatology, in cases of suspicious intraoperative bleeding, persistent facial swelling, and late-onset nasal-oral hemorrhage, pseudoaneurysms of the maxillofacial district should be considered as a possible complication of orthognatic surgery.

This work investigated the response of an illuminated polysilicon PV cell under AM radio waves. Using a 3 D analysis, the equations which describe the movement of excess electrons and their space and time behavior were solved in order to first find the density of the excess electrons and to subsequently derive the current density and the voltage. The effect of the amplitude of the electromagnetic field (EMF) on the current density and the voltage were studied by varying the distance between the PV cell and an AM radio antenna. The combination of the two characteristics, i.e. current density–voltage and Power–Voltageallowed the computation of the efficiency, the fill factor and the parasitic resistances (Rs, Rsh) of the electrical equivalent circuit of the PV cell. The study showed that from infinite distance to 50 m, corresponding to the Fraunhofer zone, the conversion efficiency increases slightly by about 1% and the fill factor decreases within the same order of magnitude. On the other hand, the series and shunt resistances fall considerably down by about 14% and 13% respectively.The power output curves versus the junction dynamic velocity which allow the computation of the shunt resistance, are used to highlight the impact of the electromagnetic field (EMF) on the operation of the cell. Between an infinite distance and 50 m, the results indicate a very high drop of the shunt resistance (from 64,280 Ω cm 2 to 11 Ω cm 2). Overall, one can conclude that the presence of EMF adversely affects the operation of polysilicon PV cell considering the high drop of the shunt resistance.

Background: Military service puts service members at risk for moral injury. Moral injury is an array of symptoms (e.g., guilt, shame, anger) that develop from events that violate or transgress one's moral code. Objective: We describe adaption of in-person mindfulness training program, Mindfulness to Manage Chronic Pain (MMCP), to address symptoms of moral injury to be delivered live via the web. We discuss how we will assess benchmarks (i.e., recruitment, credibility and acceptability, completion rates, and adherence) of the Mindfulness to Manage Moral Injury (MMMI) program. Methods: Aim 1: To develop and then adapt the MMCP program based on feedback from experts and veterans who took part in Study 1. Aim 2: To develop an equally intensive facilitator-led online Educational Support (ES) program to serve as a comparison intervention and conduct a run-through of each program with 20 veterans (10 MMMI; 10 ES). Aim 3: To conduct a small-scale randomized controlled trial (N = 42 veterans; 21 MMMI; 21 ES) in which we will collect pre-post-test and weekly benchmark data for both refined intervention arms. Results: Study 1 and 2 are completed. Data collection for Study 3 will be completed in 2022. Conclusion: MMMI is designed to provide a live facilitated mindfulness program to address symptoms of moral injury. If Study 3 demonstrates good benchmarks, with additional large-scale testing, MMMI may be a promising treatment that can reach veterans who may not seek traditional VAMC care and/or who prefer a web-based program.

Background and purpose: Endovascular treatment (EVT) is a time-dependent procedure that aims to remove the arterial blood flow obstruction in brain vessels in acute ischemic stroke. In our center, the MRI patient selection protocol in acute ischemic stroke is performed with DWI, FLAIR, MR angiography (MRA) and MR cisternography (MRC) sequences. MRA and MRC are promptly and automatically fused in order to have a clear detection of vessel anatomy, before and during EVT.Our study aim is to evaluate if the fusion process between MRA and MRC could be considered time-safe and could influence EVT duration or outcome. Materials and methods: 45 patients were retrospectively selected for the study and divided into 2 groups according to the presence of MRC sequence fused with MRA (Group 1) or not (Group 2 - controls). Results: MRA and MRC fusion was able to depict vessel anatomy in all subjects of Group 1 (22 patients, 12 females; age 75.59 years ± 10.87). Group 1 presented EVT time reduction (p < 0.05; p = 0.040) (51.59 min ± 30.94) when compared to Group 2 (23 patients, 13 females; age 75.04 years ± 12.12) (71.96 min ± 34.55) of 20.37 min average. No differences between groups were detected evaluating: NIHSS at admission (p = 0.49) and discharge (p = 0.67), pre-stroke mRS (p = 0.89), mRS at 90 days (p = 0.62), ASPECT (p = 0.98) and ASPECT-DWI scores (p = 0.93), time from symptom onset to groin puncture (p = 0.80), thromboaspiration vs combined technique (p = 0.67), EVT success (p = 0.63). Conclusion: Fusion of MRA and MRC is a safe and promising technique in promptly revealing vascular anatomy beyond vessel obstruction, and can play a role in EVT duration reduction.

Eagle Syndrome (ES) is an often misdiagnosed syndrome due to its wide spectrum of signs and symptoms. Recent works have pointed out the relation between ES and some types of craniofacial pain often misdiagnosed with migraine or temporomandibular disorders. Moreover, the presence of Vascular ES as a cause of Carotid Artery Dissection in same cases of stroke as well as cause of intracranial venous hypertension resulting in migraine and other pains has been recently discussed. A multidisciplinary approach is mandatory to allow clinicians to better understand the pathophysiology and clinical main patterns of ES. The aim of the work is to perform a comprehensive review all the clinical patterns and available diagnostic tools to guide clinicians through lights and shadows of such an underestimated syndrome. Finally, a novel flow-chart for comprehensive diagnosis of ES is proposed, including “dynamic” imaging investigating the relationship between stiloyd processes and the neurovascular structures of the neck during head movements.

Introdução: A quantificação confiável de Meropenem (MER) e Piperacilina (PIP) é recomendável para se atingir a Concentração Inibitória Mínima (CIM) para isolados das culturas, de forma a justificar a alteração de conduta clínica em pacientes sépticos queimados em terapia intensiva (UTI). Objetivo: Desenvolver e validar método para análise simultânea de MER e PIP por LC-MS/MS e aplicar na avaliação de efetividade antimicrobiana pela abordagem farmacocinética-farmacodinâmica (PK/PD). Método: Aprovação CAEE 07525118.3.0000.0068. Vinte e oito pacientes adultos grandes queimados de UTI foram incluídos. Na terapia do choque séptico utilizou-se infusão de 3 horas para Piperacilina-Tazobactana, 4,5 g q6h (G1:16 pacientes), ou para Meropenem, 1 g qh8h (G2:12 pacientes). Decorridas 48 horas do inicio da terapia, duas amostras de sangue foram coletadas (4 mL /cada) na 3ª h e 5ª h do início da infusão na fase precoce do choque séptico. A quantificação dos fármacos no soro foi realizada usando sistema de UHPLC-MS/MS triplo quadrupolo. Os estudos de validação foram realizados com base nas normas internacionais vigentes no país. A abordagem PK/PD foi realizada com base na dosagem sérica de cada antimicrobiano e na concentração inibitória mínima do patógeno isolado, para avaliar se o alvo terapêutico de 100%fdeltaT>CIM foi atingido, a partir da estimativa do índice preditivo (%fdeltaT>CIM) da eficácia. Resultados: Método bioanalítico mostrou-se linear na faixa de 1.0-250 µg/mL (r2 > 0.99) com Limite Mínimo de Detecção de 0.27 µg/mL (MER) e 0.024 µg/mL (PIP). Dados de precisão e exatidão foram satisfatórios em conformidade com normas internacionais. Evidenciou-se através da abordagem PK/PD, a cura clínica pela piperacilina nos pacientes G1/19 isolados sensíveis até CIM 16 mg/L. No G2, a cura clínica e microbiológica foi obtida pela erradicação dos 8 patógenos sensíveis até MIC 2 mg/L, bem como dois isolados de sensibilidade intermediária CIM 4 - 8 mg/L de P. aeruginosa e K. pneumoniae. Conclusão: O método desenvolvido e validado mostrou-se satisfatório com tempo de corrida de 5 minutos. Os antimicrobianos administrados através da infusão estendida evidenciaram cura clínica e microbiológica pela negativação das culturas de 29 isolados de Gram-negativos. A abordagem PK/PD é uma importante ferramenta que permite a alteração de conduta clínica em tempo real pela avaliação de efetividade da terapia, principalmente nos estágios iniciais de choque séptico.

Introdução/Objetivo: Pacientes com grandes queimados apresentam alterações farmacocinéticas que podem impactar a cobertura antimicrobiana da vancomicina nas doses empíricas contra patógenos Gram-positivos com concentração inibitória mínima (CIM) ≥ 1 mg/L. O objetivo do estudo foi comparar a dose empírica de vancomicina com a dose ajustada a partir da abordagem farmacocinética-farmacodinâmica (PK/PD) em pacientes sépticos com grandes queimados. Métodos: Pacientes adultos, com função renal preservada, recebendo vancomicina intravenosa foram investigados após o início da posologia empírica e após ajuste da dose. A terapia foi iniciada com 1000 mg 12/12h com infusão de 1 hora. A dose foi ajustada, quando necessário, com base no alvo PK/PD: área sob a curva/concentração inibitória mínima (ASC/CIM ≥ 400). Duas coletas de sangue foram realizadas (2 mL/cada) no estado de equilíbrio após 3 e 11 horas do início da infusão para quantificação sérica da vancomicina por cromatografia líquida. O modelo aberto de um compartimento com cinética de primeira ordem foi aplicado para estimar os parâmetros farmacocinéticos. Resultados: Foram incluídos no estudo 14 pacientes sépticos com grandes queimados. Os pacientes apresentaram (medianas): 27 anos, 74,5 kg, 30% da área de superfície corporal queimada, SAPS3 63. Os parâmetros farmacocinéticos estavam alterados no período inicial de choque séptico com aumentos na depuração de vancomicina e redução da meia-vida biológica. Com o regime empírico, todos os pacientes atingiram o alvo terapêutico contra patógenos Gram-positivos com CIM 1 mg/L. Após o ajuste da dose (750-1000 mg 8/8h), a cobertura antimicrobiana foi estendida para Staphylococcus spp. com CIM 2 mg/L em 57% dos pacientes. Nenhum óbito foi registrado durante o estudo. Conclusão: Pacientes sépticos com grandes queimados apresentam alterações farmacocinéticas que impactam no alcance do alvo terapêutica da vancomicina. Ajustes individualizados na posologia devem ser feitos em tempo real para garantir a erradicação de patógenos Gram-positivos, incluindo aquelas com valores mais altos de CIM.

Introduction and objectives: Endurance exercise (EXE) has emerged as a potent inducer of autophagy essential in maintaining cellular homeostasis in various tissues; however, the functional significance and molecular mechanisms of EXE-induced autophagy in the liver remain unclear. Thus, the aim of this study is to examine the signaling nexus of hepatic autophagy pathways occurring during acute EXE and a potential crosstalk between autophagy and apoptosis. Materials and methods: C57BL/6 male mice were randomly assigned to sedentary control group (CON, n = 9) and endurance exercise (EXE, n = 9). Mice assigned to EXE were gradually acclimated to treadmill running and ran for 60 min per day for five consecutive days. Results: Our data showed that EXE promoted hepatic autophagy via activation of canonical autophagy signaling pathways via mediating microtubule-associated protein B-light chain 3 II (LC3-II), autophagy protein 7 (ATG7), phosphorylated adenosine mono phosphate-activated protein kinase (p-AMPK), CATHEPSIN L, lysosome-associated membrane protein 2 (LAMP2), and a reduction in p62. Interestingly, this autophagy promotion concurred with enhanced anabolic activation via AKT-mammalian target of rapamycin (mTOR)-p70S6K signaling cascade and enhanced antioxidant capacity such as copper zinc superoxide dismutase (CuZnSOD), glutathione peroxidase (GPX), and peroxiredoxin 3 (PRX3), known to be as antagonists of autophagy. Moreover, exercise-induced autophagy was inversely related to apoptosis in the liver. Conclusions: Our findings indicate that improved autophagy and antioxidant capacity, and potentiated anabolic signaling may be a potent non-pharmacological therapeutic strategy against diverse liver diseases.

Oxyacetylene torch testing was performed at a range of angles of attack on Cf/ZrB2-SiC-Y2O3 composites, from 10° to 90°. The ablation behaviour was studied in-situ with thermography, and the post-ablation morphologies investigated optically and with elemental analysis. Significantly lower surface temperatures were observed at oblique angles of attack leading to less damage in terms of both oxidation extent and material removal. Rudimentary modelling of a gas stream impinging on a perfect surface showed that the angular variation also led to a significant drop in pressure at more oblique angles of attack, with a commensurate increase in shear stress. The surface oxide formed during testing seemed mainly to correspond to the temperature distribution and was apparently more susceptible to damage from higher impinging pressure than shear stress. This study elucidated some interesting aspects of a modified ablation test and showed some new parameter ranges which may be useful in targeted material screening.

Background: Vascular intracranial stenosis (IS) is a significant cause of acute ischemic stroke (AIS). This single-center study aims to show that symptomatic IS treatment by using the Neuroform Atlas stent (Stryker neurovascular, Kalamazoo, MI, USA) could be effective in reducing vessel stenosis. Methods: Ten patients affected by AIS or TIA, in the vascular territory of high-grade intracranial atherosclerotic lesions (>70% of vessel stenosis), older than 18-year-old, were treated by implanting a Neuroform Atlas stent (diameter of 4.5mm in 80% and 4mm in 20%). 70% of the patients underwent pre-stenting intracranial angioplasty. Results: Patients were between 54.8 and 83 years old (mean 68.46y ± 8.44y), 70% males and 30% females. At admission, 50% of all patients had an AIS and 50% a TIA. Restoration of the stenotic lumen was obtained after the endovascular procedure. The percentage mean of vascular stenosis was 83.7% ± 6.09% before treatment (t0), 52.2% ± 10.42% at the end of treatment (t1) and 46.2% ± 8.28% at the follow-up (t2). The IS percentage mean reduction between t0 and t1 was 31.5% ± 7.31%, and between t1 and t2 was 6% ± 5.47%, t0 and t2 of 37.5% ± 7.38%. Percentage reduction of IS was highly significant between time t0 and t1 (p = 0.005), and t0 and t2 (p = 0.005), also with a significant reduction between t1 and t2 (p = 0.012). No patient had experienced an increase of the ischemic area in the vascular territory of the target vessel at 3 months from the initial assessment. 10% of patients experienced a 3-months negative outcome (mRS = 5), 90% experienced a favorable outcome (mRS ≤2). Conclusions: Intracranial stenosis endovascular treatment with Neuroform Atlas stent provides encouraging results, with a statistically significant association between the vascular caliber improvement and the endovascular treatment.

Investigating a body found in water, without eyewitnesses, to determine the cause and manner of death is often difficult. Video recorded by a surveillance camera can document events and provide useful data for case assessment. The authors report the case of a 26-year-old man found dead in a swimming pool. The images taken by the surveillance camera are useful for reconstructing what happened: to confirm the autopsy by attributing the cause of death by drowning, without the interference of extrinsic factors. The sequence of events related to the submergence of the body, as seen from the video surveillance recording, does not seem to differ much from that described in the experiments reported in the literature even if it presents some discrepancies on the times of death, having been able to precisely control the times of death by acquiring the video surveillance. Reporting this drowning in a swimming pool has yet to be considered an isolated important case study for the study of the drowning process in humans.

Background & aims: Obeticholic acid (OCA) is the second-line treatment approved for patients with primary biliary cholangitis (PBC) and an inadequate response or intolerance to ursodeoxycholic acid. We aimed to evaluate the effectiveness and safety of OCA under real-world conditions. Methods: Patients were recruited into the Italian PBC Registry, a multicentre, observational cohort study that monitors patients with PBC at national level. The primary endpoint was the biochemical response according to Poise criteria; the secondary endpoint was the biochemical response according to normal range criteria, defined as normal levels of bilirubin, alkaline phosphatase (ALP), and alanine aminotransferase (ALT) at 12 months. Safety and tolerability were also assessed. Results: We analysed 191 patients until at least 12 months of follow-up. Median age was 57 years, 94% female, 61 (32%) had cirrhosis, 28 (15%) had histologically proven overlap with autoimmune hepatitis (PBC-AIH). At 12 months, significant median reductions of ALP (-32.3%), ALT (-31.4%), and bilirubin (-11.2%) were observed. Response rates were 42.9% according to Poise criteria, and 11% by normal range criteria. Patients with cirrhosis had lower response than patients without cirrhosis (29.5% vs. 49.2%, p = 0.01), owing to a higher rate of OCA discontinuation (30% vs. 12%, p = 0.004), although with similar ALP reduction (29.4% vs. 34%, p = 0.53). Overlap PBC-AIH had a similar response to pure PBC (46.4% vs. 42.3%, p = 0.68), with higher ALT reduction at 6 months (-38% vs. -29%, p = 0.04). Thirty-three patients (17%) prematurely discontinued OCA because of adverse events, of whom 11 experienced serious adverse events. Treatment-induced pruritus was the leading cause of OCA discontinuation (67%). Conclusions: Effectiveness and safety of OCA under real-world conditions mirror those in the Poise trial. Patients with cirrhosis had lower tolerability. Overlap PBC-AIH showed higher ALT reduction at 6 months compared with patients with pure PBC. Lay summary: Obeticholic acid (OCA) was shown to be effective in more than one-third of patients not responding to ursodeoxycholic acid in a real-world context in Italy. Patients with cirrhosis had more side effects with OCA, and this led to suspension of the drug in one-third of patients. OCA was also effective in patients who had overlap between autoimmune hepatitis and primary biliary cholangitis.

One-hundred four persons aged ≥ 18 years (62 males and 42 females) who were admitted for traumatic brain injury (TBI) underwent brain computed tomography (CT) scan and assay of serum cortisol, insulin-like growth factor 1 (IGF-1), thyrotropin (TSH) and free thyroxine (FT4). The main purpose was to assess any gender difference and the rate of empty sella (ES).Women were more likely to have empty sella (19/42 [45.2%] vs 19/62 [30.6%], P = 0.15, OR = 1.9), which was more frequently total ES or TES (16/19 [84.2%] vs 3/19 [15.8%], P = 0.0025, OR = 11.6). Neuroradiology was normal in the remaining 65 patients. Patients with TES were approximately 20–30 years older than both patients with partial ES (PES) and normal sella, but only the comparison with normal sella was significant (P = 0.001 all patients, P = 0.005 males). Presumed deficiency of IGF-1, cortisol or TSH occurred in 33 persons (31.7%; 20 Males [32.2%], 13 Females [30.9%]), 14 (13.5%; 10 M [16.2%], 4F [9.5%]) or 8 (7.7%; 1 M [1.7%], 7F [16.7%]), with only TSH deficiency having significant intergender difference (P = 0.007). The highest or lowest rates of IGF-1 deficiency occurred in men with PES (41.7%) or men with TES (14.3%), of cortisol deficiency in men with PES (33.3%) or women with PES (zero), and TSH deficiency in women with TES (18.7%) or both men and women with PES (zero) and men with normal sella (zero). Within ES, males with no deficiency were older compared to males with at least one hormone deficiency (75.7 ± 17.4 vs 55.6 ± 18.9, P = 0.022); in turn, the former males were also older compared with normal sella males having no hormone deficiency (54.1 ± 25.2, P = 0.023).In conclusion, ES is detectable in almost 40% of persons who undergo CT within 24 h from TBI. A number of intergender differences concerning ES and the hormones evaluated are apparent. Keywords: Traumatic brain injury, Post-traumatic hypopituitarism, Empty sella, Computed tomography

CHRNA7, encoding the neuronal alpha7 nicotinic acetylcholine receptor (a7nAChR), is highly expressed in the brain, particularly in the hippocampus. It is situated in the 15q13.3 chromosome region, frequently associated with a Copy Number Variation (CNV), which causes its duplication or deletion. The clinical significance of CHRNA7 duplications is unknown so far, but there are several research data suggesting that they may be pathogenic, with reduced penetrance. We have produced an iPS cell line from a single healthy donor's fibroblasts carrying a 15q13.3 CNV, including CHRNA7 in order to study the exact role of this CNV during the neurodevelopment.

Letter production relies on a tight coupling between motor movements and visual feedback—each stroke of the letter is visually experienced as it is produced. Experience with letter production leads to increases in functional connectivity, a measure of neural communication, among visual and motor brain systems and leads to gains in letter recognition in preliterate children. We hypothesized that the contingency between the motor and visual experiences of the written form during production would result in both effects. Twenty literate adults were trained on four sets of novel symbols over the course of one week. Each symbol set was trained through one of four training conditions: drawing with ink, drawing without ink, watching a handwritten symbol unfold as if being drawn, and watching a static handwritten symbol. Contingency of motor and visual experiences occurred in the drawing with ink condition. The motor and visual experiences were rendered non-contingent in each of the other three conditions by controlling for visual or motor experience. Participants were presented with the trained symbols during fMRI scanning at three time points: one pre-training, one post-training, and one after a week-long no-training delay. Recognition was tested after each training session and after the third scan. We found that the contingency between visual and motor experiences during production changed the pattern of functional connectivity among visual, motor, and auditory neural communities and resulted in better recognition performance at post-training than at pre-training. Recognition gains were maintained after the no-training delay, but the functional connections observed immediately after training returned to their pre-training baselines. Our results suggest that behaviors that couple sensory and motor systems result in temporary changes in neural communication during perception that may not directly support changes in recognition.

Smith-Magenis syndrome (SMS) is a complex genetic disorder characterized by developmental delay, behavioural problems and circadian rhythm dysregulation. About 90% of SMS cases are due to a 17p11.2 deletion containing retinoic acid induced1 (RAI1) gene, 10% are due to heterozygous mutations affecting RAI1 coding region. Little is known about RAI1 role.

Vascular endothelial growth factor A (VEGF-A) is considered one of the most important factors in tumor angiogenesis, and consequently, a number of therapeutics have been developed to inhibit VEGF signaling. Therapeutic strategies to target brain malignancies, both primary brain tumors, particularly in pediatric patients, and metastases, are lacking, but targeting angiogenesis may be a promising approach. Multiparametric MRI was used to investigate the response of orthotopic SF188luc pediatric glioblastoma xenografts to small molecule pan-VEGFR inhibitor cediranib and the effects of both cediranib and cross-reactive human/mouse anti-VEGF-A antibody B20-4.1.1 in intracranial MDA-MB-231 LM2–4 breast cancer xenografts over 48 hours. All therapeutic regimens resulted in significant tumor growth delay. In cediranib-treated SF188luc tumors, this was associated with lower Ktrans (compound biomarker of perfusion and vascular permeability) than in vehicle-treated controls. Cediranib also induced significant reductions in both Ktrans and apparent diffusion coefficient (ADC) in MDA-MB-231 LM2–4 tumors associated with decreased histologically assessed perfusion. B20-4.1.1 treatment resulted in decreased Ktrans, but in the absence of a change in perfusion; a non-significant reduction in vascular permeability, assessed by Evans blue extravasation, was observed in treated tumors. The imaging responses of intracranial MDA-MB-231 LM2–4 tumors to VEGF/VEGFR pathway inhibitors with differing mechanisms of action are subtly different. We show that VEGF pathway blockade resulted in tumor growth retardation and inhibition of tumor vasculature in preclinical models of pediatric glioblastoma and breast cancer brain metastases, suggesting that multiparametric MRI can provide a powerful adjunct to accelerate the development of antiangiogenic therapies for use in these patient populations.

Background & aims: Arachidonic (AA) and eicosapentaenoic (EPA) polyunsaturated fatty acids can play respectively a pro- and an anti-inflammatory role. We hypothesized that, at the end of 5-week experimental bed rest, baseline AA/EPA in red blood cells (RBC) membranes, considered the result of dietary fat intake over the previous month, could influence lean body mass wasting in twenty-six healthy volunteers (age: 23.5 ± 0.5 years; body mass index: 22.9 ± 0.5 kg/m2). Methods: We measured AA and EPA content in RBC membranes at baseline ambulatory conditions and at the end of the study protocol, to verify the PUFA concentrations stability. We assessed changes, between beginning and end of bed, in lean body mass (bioimpedance), insulin resistance (homeostasis model assessment), systemic inflammation (C-reactive protein) and oxidative stress (thiobarbituric acid reactive substances). Volunteers were divided in two groups according to the AA/EPA ratio median value (i.e. AA/EPA = 44): High AA/EPA group (60 ± 3; n = 13) and Low AA/EPA group (37 ± 1; n = 13). Results: At baseline, all analyzed anthropometrical and biochemical indices were similar in the two groups. Bed rest induced a major decrease in lean body mass in High AA/EPA group (−5.2 ± 0.5%), when compared to Low AA/EPA group (−3.7 ± 0.5%; p = 0.03; ANOVA). Bed rest mediated-changes of insulin resistance, fat mass, systemic inflammation and oxidative stress, failed to show significant interaction with baseline AA/EPA (ANOVA). In pooled data, baseline AA/EPA ratio and percent lean body mass delta changes showed a significant inverse correlation (n = 26; R = −0.50; p

Changes in liver mitochondrial function with more oxidized redox state and enhanced inflammation may contribute to the onset of obesity- and insulin resistance-associated hepatic complications, including non-alcoholic fatty liver disease and steato-hepatitis. Unacylated ghrelin (UnAG) is a gastric hormone reported to be associated with lower oxidative stress in different cell types, but its potential effects on liver mitochondrial function, redox state and inflammation in vivo remains undetermined. We investigated the impact of chronic UnAG overexpression (Tg Myh6/Ghrl) leading to systemic upregulation of circulating hormone on mitochondrial ATP production, redox state (oxidized-to-total glutathione) and inflammation markers in lean mice. Compared to wild-type animals (wt), Tg Myh6/Ghrl had superimposable liver weight, triglyceride content and plasma lipid profile. Liver mitochondrial enzyme activities and ATP production as well as oxidized-to-total glutathione were also similar in the two groups. In addition, no differences were observed in tissue inflammation marker TNF-alpha between wild-type and Tg Myh6/Ghrl animals. Thus, chronic systemic UnAG upregulation does not alter liver triglyceride content, mitochondrial function, redox state and inflammation markers in lean mice. These findings do not support a major role of UnAG as a physiological modulator of in vivo liver oxidative-lipid metabolism and inflammation.

The retroperitoneal location of the duodenum and the small volume of the peritoneal cavity in pediatric patients make the laparoscopic repair of congenital duodenal anomalies challenging. As a result, robotic-assisted repair of duodenal atresia in a pediatric patient has been reported only once in the literature. This report describes the robotic-assisted laparoscopic repair of a congenital duodenal diaphragm in a 2-year-old, 8 kg patient who presented with vomiting and failure to thrive. An upper gastrointestinal series revealed partial obstruction at the second part of the duodenum with proximal dilatation. These findings are consistent with a duodenal diaphragm. Traditional laparoscopy was utilized to kocherize the first and second parts of the duodenum and to identify a loop of proximal jejunum for the proposed anastomosis. A duodeno-jejunal anastomosis was then performed using intra-corporeal suturing with a daVinci SI robotic system. The patient had a quick and uneventful post-operative course. At 6 month follow-up, she was asymptomatic and the surgical incisions had healed with excellent cosmetic appearance. A combination of laparoscopic and robotic techniques offers a promising alternative to open or purely laparoscopic repair of congenital duodenal anomalies.

Background and Aims: Muscle inactivity leads to muscle atrophy and insulin resistance. The branched-chain amino acid (BCAA) leucine interacts with the insulin signaling pathway to modulate glucose metabolism. We have tested the ability of a high-protein BCAA-enriched diet to prevent insulin resistance during long-term bed rest (BR)., Methods: Stable isotopes were infused to determine glucose and protein kinetics in the postabsorptive state and during a hyperinsulinemic-euglycemic clamp in combination with amino acid infusion (Clamp + AA) before and at the end of 60 days of BR in two groups of healthy, young women receiving eucaloric diets containing 1 g of protein/kg per day (n = 8) or 1.45 g of protein/kg per day enriched with 0.15 g/kg per day of BCAAs (leucine/valine/isoleucine = 2/1/1) (n = 8). Body composition was determined by Dual X-ray Absorptiometry., Results: BR decreased lean body mass by 7.6 ± 0.3 % and 7.2 ± 0.8 % in the groups receiving conventional or high protein-BCAA diets, respectively. Fat mass was unchanged in both groups. At the end of BR, percent changes of insulin-mediated glucose uptake significantly (p = 0.01) decreased in the conventional diet group from 155 ± 23 % to 84 ± 10 % while did not change significantly in the high protein-BCAA diet group from 126 ± 20 % to 141 ± 27 % (BR effect, p = 0.32; BR/diet interaction, p = 0.01; Repeated Measures ANCOVA). In contrast, there were no BR/diet interactions on proteolysis and protein synthesis Clamp + AA changes in the conventional diet and the high protein-BCAA diet groups., Conclusion: A high protein-BCAA enriched diet prevented inactivity-induced insulin resistance in healthy women., Competing Interests: Conflict of interest The authors have declared that no conflict of interest exists., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Waist circumference (WC) is the currently recommended marker of central fat for cardiometabolic risk screening. Alternative surrogate markers have been recently proposed to better reflect the metabolic impact of central fat accumulation per se, based on WC normalization by height (Weight-to-Height Ratio - WtoH; Body Roundness Index - BRI) or body mass index (BMI) without (A Body Shape Index - ABSI) or with inclusion of plasma triglyceride and HDL-cholesterol concentrations (Visceral Adiposity Index - VAI)., Methods: We investigated associations between WtoH, BRI, ABSI or VAI and insulin resistance (HOMA-index) or metabolic syndrome (MetS) in a general population cohort from the North-East Italy Mo.Ma. study (n = 1965, age = 49 ± 13 years, BMI = 26.7 ± 5.2 kg/m 2 ). Baseline values were also evaluated as predictors of future insulin resistance and MetS in overweight-obese individuals undergoing 5-year follow-up (Ow-Ob) (n = 263; age = 54 ± 9, BMI = 30,7 ± 4,1)., Results: Compared to WC or BMI, basal WtoH and BRI were similarly associated with baseline HOMA and MetS prevalence after multiple adjustments (P < 0.001) and all markers similarly predicted 5-year HOMA and MetS (P < 0.001). Under basal conditions, superimposable results were observed for VAI whereas ABSI was less accurate or unable to identify baseline HOMA and MetS (p < 0.05 vs WtoH-BRI-VAI-WC-BMI). VAI had highest 5-year risk predictive value in Ow-Ob [ROC Area Under the Curve (AUC) VAI > WtoH-BRI-WC-BMI; p < 0.05] while no predictive value was in contrast observed for ABSI (ROC AUC ABSI < WtoH-BRI-WC-BMI; p < 0.05). Using alternate formulae with plasma lipid inclusion in ABSI and removal from VAI calculations completely reversed their 5-year predictive value and AUC., Conclusions: The current findings do not support replacement of WC with height-normalized anthropometric central fat surrogate markers to predict cardiometabolic risk in the general and overweight-obese population. BMI-normalization impairs risk assessment unless plasma lipid concentrations are available and included in calculations., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background & Aims: Physical inactivity is associated with lean body mass wasting, oxidative stress and pro-inflammatory changes of cell membrane lipids. Alkalinization may potentially counteract these alterations. We evaluated the effects of potassium bicarbonate supplementation on protein kinetics, glutathione status and pro- and anti-inflammatory polyunsaturated fatty acids (PUFA) in erythrocyte membranes in humans, during experimental bed rest., Methods: Healthy, young, male volunteers were investigated at the end of two 21-day bed rest periods, one with, and the other without, daily potassium bicarbonate supplementation (90 mmol × d -1 ), according to a cross-over design. Oxidative stress in erythrocytes was evaluated by determining the ratio between reduced (GSH) and oxidized glutathione (GSSG). Glutathione turnover and phenylalanine kinetics, a marker of whole body protein metabolism, were determined by stable isotope infusions. Erythrocyte membranes PUFA composition was analyzed by gas-chromatography., Results: At the end of the two study periods, urinary pH was 10 ± 3% greater in subjects receiving potassium bicarbonate supplementation (7.23 ± 0.15 vs. 6.68 ± 0.11, p < 0.001). Alkalinization increased total glutathione concentrations by 5 ± 2% (p < 0.05) and decreased its rate of clearance by 38 ± 13% (p < 0.05), without significantly changing GSH-to-GSSG ratio. After alkalinization, net protein balance in the postabsorptive state improved significantly by 17 ± 5% (p < 0.05) as well as the sum of n-3 PUFA and the n-3-to-n-6 PUFA ratio in erythrocyte membranes (p < 0.05)., Conclusions: Alkalinization during long-term inactivity is associated with improved glutathione status, anti-inflammatory lipid pattern in cell membranes and reduction in protein catabolism at whole body level. This study suggests that, in clinical conditions characterized by inactivity, oxidative stress and inflammation, alkalinization could be a useful adjuvant therapeutic strategy., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Competing Interests: Conflict-of-interest disclosure: A.M.H. has performed consulting for Ziopharm and Nexus Global Group. P.V. declares no competing financial interests.

Background & Aims: Ghrelin is a gastric orexigenic hormone whose activating acylation plays a relevant role in the regulation of energy balance. Nutritional modulators of ghrelin acylation and plasma acylated ghrelin (AG) concentration remain however largely undefined. We aimed at investigating whether circulating free fatty acids (FFA) contribute to regulate plasma AG and its ratio (AG/TG) to total hormone (TG)., Methods: Plasma FFA, TG, AG and AG/TG were measured in a primary outpatient care setting in a community-based population cohort of 850 individuals (age 54 ± 10 years, M/F: 408/442) from the North-East Italy MoMa study. 150-min intravenous lipid infusions in rodents (10% lipids, 600 μl/h) were used to investigate the potential causal role of FFA in the regulation of plasma ghrelin profile., Results: Plasma FFA were associated positively with AG and AG/TG while negatively with TG (P < 0.01). Associations between FFA, AG and AG/TG remained statistically significant (P < 0.02) in multiple regression analysis including HOMA insulin resistance and metabolic confounders, and both AG and AG/TG but not TG increased through plasma FFA quartiles (P < 0.01). Consistent with these findings, intravenous lipid infusion with plasma FFA elevation caused elevations of AG and AG/TG (P < 0.05) with no TG modifications., Conclusions: The current findings demonstrate a novel role for circulating FFA availability to up-regulate plasma AG, which could involve FFA-induced stimulation of ghrelin acylation., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Mesenchymal stromal cells (MSCs) are multipotent cells characterized by broad immunomodulatory properties exploited for the treatment of inflammatory disorders. However, the efficacy of MSC-based therapy is highly variable and tightly linked to MSC culture conditions and treatment schedule. Thus, the identification of novel key molecules regulating MSC immunomodulatory activities in vivo might constitute a crucial step toward the optimization of currently available clinical protocols. In this regard, herein, we sought to determine whether the newly identified chemotactic protein, chemerin, plays a role in MSC-mediated regulation of inflammation., Methods: Chemerin production by human MSCs was investigated under different culture conditions using enzyme-linked immunosorbent assay (ELISA). After purification, MSC-secreted chemerin was identified using mass spectrometry analysis and the biological activity of secreted isoforms was evaluated using migration assay., Results: Bone marrow-derived MSCs secrete chemerin and express its receptors ChemR23 and CCRL2. Chemerin production is dependent on culture conditions and increases upon stimulation with inflammatory cytokines. In particular, platelet lysate (PL)-MSCs produce higher levels of chemerin compared with fetal bovine serum (FBS)-MSCs. Furthermore, chemerin is secreted by MSCs as an inactive precursor, which can be converted into its active form by exogenous chemerin-activating serine and cysteine proteases., Discussion: Our data indicate that, in response to various inflammatory stimuli, MSCs secrete high amounts of inactive chemerin, which can then be activated by inflammation-induced tissue proteases. In light of these initial findings, we propose that further analysis of chemerin functions in vivo might constitute a crucial step toward optimizing MSC-based therapy for inflammatory diseases., (Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Ghrelin is a gastric hormone circulating in acylated (AG) and unacylated (UG) forms, and higher plasma total ghrelin (TG) and UG may be cross-sectionally associated with lower insulin resistance in metabolic syndrome patients. The potential value of ghrelin forms in predicting insulin resistance and its time-related changes in community-based population cohorts remains unknown., Methods: We measured TG, AG and calculated UG (TG-AG) in 716 individuals from the North-East-Italy MoMa study (age: 55 ± 9 years, BMI: 29 ± 5 kg/m(2), M/F:349/367) to test the hypothesis that circulating TG and UG, but not AG are negatively associated with insulin resistance (HOMA). We further hypothesized that baseline TG and UG negatively predict 5-year HOMA changes in a 350-individual subgroup., Results: Baseline TG and UG were associated negatively with HOMA after adjusting for gender and body mass index (BMI). Baseline gender- and BMI-adjusted TG and UG were also negatively associated with HOMA at 5-year follow-up (n = 350), and changes in TG and UG were negatively associated with changes in HOMA (P < 0.05) after adjustment for anthropometric and metabolic confounders. No statistically significant correlations were observed between AG and baseline or 5-year HOMA., Conclusions: In a North-East Italy community-based population cohort, plasma TG and UG but not AG are negatively associated with HOMA. TG and UG and their changes also independently predict 5-year HOMA changes. TG and UG are therefore novel potential modulators of insulin resistance and may contribute to predict its time-related changes in humans., (Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Systemic inflammation contributes to obesity-associated complications. The short pentraxin C-reactive protein (CRP) is a validated inflammatory marker, whereas long pentraxin-3 (PTX3) limits inflammation and is adaptively stimulated by proinflammatory cytokines in vitro. Severely obese (SO) patients (body mass index [BMI]>40] have the highest obesity-associated complications and increasingly undergo surgical treatment. SO-associated changes in plasma PTX3 and their interactions with systemic inflammation are, however, unknown., Objective: We sought to determine potential alterations in plasma PTX3 and their associations with changes in inflammatory markers before and after weight loss induced by laparoscopic Roux-en-Y gastric bypass (LRYGB)., Setting: University hospital in Trieste, Italy., Methods: Plasma PTX3, CRP, and cytokines, including tumor necrosis factor α and interleukin 6 were measured in (1) 24 individuals with severe, class III obesity (SO; age = 42 ± 1 yr, female/male = 18/6, BMI = 45 ± 1 kg/m(2)) before and 3, 6, and 12 months after LRYGB; and (2) age- and sex-matched normal-weight (N; n = 56, BMI = 22 ± .2 kg/m(2)) or class I obese individuals (O; n = 44, BMI = 31.2 ± .3 kg/m(2))., Results: SO, but not O, had higher plasma PTX3 compared with N, associated with highest proinflammatory cytokines and CRP (P<.05 versus N-O). In all patients, plasma interleukin 6 and tumor necrosis factor α were associated positively with PTX3 (P<.05). Plasma CRP and proinflammatory cytokines declined during LRYGB-induced weight loss. In contrast, high PTX3 further increased and remained elevated (P<.05 versus basal)., Conclusions: Obesity level and energy balance modulate interactions between PTX3 and systemic inflammation. Elevated PTX3 is a novel, potentially adaptive alteration associated with proinflammatory cytokines in SO. Their differential changes conversely suggest circulating PTX3 as a novel negative inflammatory marker in SO undergoing LRYGB-induced weight loss., (Copyright © 2016 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Sarcopenic obesity may be defined by a high fat to fat-free mass (FM/FFM) ratio. Skeletal muscle may be negatively influenced by the pro-inflammatory milieu associated with visceral fat, while the loading effect induced by a heavier body mass index (BMI) may enhance muscle anabolism. Recently, a new anthropometric measure based on waist circumference (A Body Shape Index, ABSI) was developed. In this study we have assessed the predictive power of ABSI on the FFM index (FFMI), a surrogate marker of lean mass., Methods: Standard anthropometric parameters and ABSI as well as body composition data (fat and fat-free mass determined by bioelectrical impedance analysis) were assessed in 111 female and 89 male overweight/obese subjects, with no clinically significant co-morbidities. Groups with higher- or lower-ABSI were identified according to median values of this index., Results: In women and men, ABSI did not correlate with BMI, while multiple linear regression indicated that BMI (β-coefficients: 0.62 and 0.77, respectively) and ABSI (β-coefficients: -0.26 and -0.22, respectively) independently predicted FFMI (multiple R: 0.72 and 0.83, respectively, P < 0.001). Men and women with lower-ABSI exhibited significantly greater FFMI than the higher-ABSI groups for comparable values of BMI. In men, ABSI was correlated positively with C-reactive protein (CRP) (R = 0.30; P < 0.05) and negatively with the reciprocal of insulin (R = 0.28; P < 0.05), an index of insulin sensitivity. FM/FFM ratio significantly (P < 0.01) correlated with CRP (R = 0.31) in women only., Conclusions: ABSI, a recently introduced marker of abdominal adiposity, may contribute to define the risk of sarcopenia in overweight/obese individuals., (Copyright © 2014. Published by Elsevier Ltd.)

Background & Aims: Involvement of insulin in diabetes-associated liver triglyceride deposition and its potential pathways remain incompletely defined. SIRT1 may negatively modulate lipogenesis and liver triglyceride accumulation, involving AMP-activated protein kinase (AMPK) activation. In streptozotocin-diabetic rats, we hypothesized that insulin negatively modulates liver SIRT1 and activates AMPK-inhibited lipogenic mediators leading to triglyceride accumulation. The impact of insulin deprivation (INS-) and replacement (INS+) on liver inflammation and mitochondrial oxidative capacity (also potentially regulating triglyceride deposition) was also measured., Methods: Streptozotocin-diabetic rats under chronic (8-week) INS- and INS+., Results: Compared to INS- (P < 0.05), INS+ had low liver SIRT1 with low AMPK activating phosphorylation, low inactivating phosphorylation of its lipogenic target acetyl-CoA carboxylase and high tissue triglycerides. INS- (P < 0.05 vs Control) had liver inflammation and high mitochondrial oxidative capacity, but neither was modulated by INS+. Pair-feeding showed no influence of spontaneous overeating on insulin-induced changes., Conclusions: Insulin replacement downregulates SIRT1 and AMPK activation in vivo in streptozotocin-diabetic rat liver, likely contributing to insulin-induced liver triglyceride accumulation. Under the current experimental conditions, insulin-deprived diabetes is associated with liver inflammation and high mitochondrial oxidative capacity, that are not affected by insulin replacement and are therefore unlikely to contribute to tissue triglyceride changes in this model., (Copyright © 2010 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)