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Background & Aims: Multiple colorectal adenomas (MCRAs) can result from APC (AFAP) or biallelic MUTYH (MAP) mutations, but most patients are wild type and referred to as non-APC/MUTYH polyposis (NAMP). We aim to examine the risk of colorectal cancer (CRC) and the role of endoscopy in managing patients with MCRAs, with a specific focus on clinical features and genotype., Methods: Records of MRCAs between 2000 and 2022 were retrospectively analysed. Patients were divided according to the genotype (MAP vs. NAMP) and the number of categorised polyps' burden (group 1: 10-24, group 2: 25-49, and group 3: 50-99 adenomas). Predictors of outcome were CRC-free survival (CRC-FS) and Surgery free-survival (S-FS)., Results: 220 patients were enrolled (NAMP n = 178(80.0%)). CRC at diagnosis was more frequent in group 3 (p = 0.01), without significant differences between the genotypes (p = 0.20). At a follow-up of 83(41-164) months, 15(7%) patients developed CRC during surveillance. CRC-FS was not correlated to genotype (p = 0.07) or polyps' number (p = 0.33), while S-FS was similar in MAP and NAMP (p = 0.22) and lower in groups 2 and 3 (p = 0.0001)., Conclusions: MAP and NAMP have the same CRC risk and no difference in treatment. Endoscopic surveillance compared favorably with surgery in avoiding CRC risk, even in patients with more severe colorectal polyposis., Competing Interests: Conflict of interest Matteo Fassan received research funding from Astellas Pharma, Macrophage Pharma, and QED Therapeutics and had roles as consultant or advisor for Astellas Pharma, GSK-Tesaro, MSD, Roche, and Astra Zeneca. The other authors have no conflicts of interest to declare regarding the present manuscript., (Copyright © 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objective: Epilepsy patients with mesial temporal sclerosis (MTS) on imaging who are drug-resistant usually undergo epilepsy surgery without previous invasive evaluation. However, up to one-third of patients are not seizure-free after surgery. Prior studies have identified risk factors for surgical failure, but it is unclear if they are associated with bilateral or discordant seizure onset., Methods: In this retrospective case series, we identified 17 epilepsy patients who had MRI-confirmed MTS but received invasive stereo-EEG (SEEG) evaluation before definitive intervention. We analyzed their presurgical risk factors in relation to SEEG seizure onset localization and MRI/SEEG concordance., Results: SEEG ictal onset was concordant with MTS localization (i.e. seizures started only from the hippocampus with MTS) in 5 out of 13 patients with unilateral MTS (UMTS) and in 3 out of 4 patients with bilateral MTS.No statistically significant association regarding concordance of SEEG ictal onset and MTS location was found in patients with such risk factors as a history of non-mesial temporal aura, frequent focal to bilateral tonic-clonic seizures, prior viral brain infection, or family history of epilepsy. Nine out of 13 UMTS patients had resective surgery only, 5 out of 9 (56 %) have Engel class I outcome at most recent follow-up (median 46.5 months, range 22-91 months). In Engel class I cohort, the SEEG ictal onset was concordant with MTS location in 3 out of 5 patients, and 2 patients had ipsilateral temporal neocortical ictal onset., Conclusions: Our findings suggest that patients with MTS might have discordant SEEG ictal onset (in 61.5% patients with UMTS in presented cohort), which may explain poor surgical outcome after destructive surgery in these cases., Significance: Although no statistically significant association was found in this under-powered study, these findings could be potentially valuable for future meta -analyses., (© 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.)

Pancreatic cancer is likely to become one of the leading causes of cancer-related death in many countries within the next decade. Surgery is the potentially curative treatment for pancreatic ductal adenocarcinoma (PDAC), although only 10%-20% of patients have a resectable disease after diagnosis. Despite recent advances in curative surgery the current prognosis ranges from 6% to 10% globally. One of the main issues at the pre-clinical level is the lacking of model which simultaneously reflects the tumour microenvironment (TME) at both structural and cellular levels. Here we describe an innovative tissue engineering approach applied to PDAC starting from decellularized human biopsies in order to generate an organotypic 3D in vitro model. This in vitro 3D system recapitulates the ultrastructural environment of native tissue as demonstrated by histology, immunohistochemistry, immunofluorescence, mechanical analysis, and scanning electron microscopy. Mass spectrometry confirmed a different extracellular matrix (ECM) composition between decellularized healthy pancreas and PDAC by identifying a total of 110 non-redundant differently expressed proteins. Immunofluorescence analyses after 7 days of scaffold recellularization with PANC-1 and AsPC-1 pancreatic cell lines, were performed to assess the biocompatibility of 3D matrices to sustain engraftment, localization and infiltration. Finally, both PANC-1 and AsPC-1 cells cultured in 3D matrices showed a reduced response to treatment with FOLFIRINOX if compared to conventional bi-dimensional culture. Our 3D culture system with patient-derived tissue-specific decellularized ECM better recapitulates the pancreatic cancer microenvironment compared to conventional 2D culture conditions and represents a relevant approach for the study of pancreatic cancer response to chemotherapy agents., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Crises like the COVID-19 pandemic can trigger concerns about loss of employment and changes in work conditions, and thereby increase job insecurity. Yet, little is known about how perceived job insecurity subsequently unfolds over time and how individual differences in habitual coping moderate such a trajectory. Using longitudinal data from 899 US-based participants across 5 waves (March to June 2020), we investigated the trajectory of job insecurity during the COVID-19 pandemic and how this trajectory depended on habitual coping strategies such as planning, reappraisal, and distraction. Results from latent growth curve analysis indicated that, on average, job insecurity initially increased and then decreased after signing of the coronavirus stimulus bill, suggesting a pattern of shock followed by adjustment. During the shock phase, habitual use of distraction was related to less increases in job insecurity. Later during the adjustment phase, decreases in job insecurity were more pronounced for individuals with higher habitual use of planning, but were not affected by reappraisal or distraction. Hence, different coping strategies appear beneficial in different phases of adjustment, and the beneficial effect of planning may take time to manifest. Altogether, our study highlights how in the context of extraordinary and uncontrollable events, coping strategies can impact the trajectory of a stressor., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) has received tremendous attention as a potential neuromodulator of cognitive and affective functions, which likely exerts its effects via activation of the locus coeruleus-noradrenaline (LC-NA) system. Reliable effects of taVNS on markers of LC-NA system activity, however, have not been demonstrated yet., Methods: The aim of the present study was to overcome previous limitations by pooling raw data from a large sample of ten taVNS studies (371 healthy participants) that collected salivary alpha-amylase (sAA) as a potential marker of central NA release., Results: While a meta-analytic approach using summary statistics did not yield any significant effects, linear mixed model analyses showed that afferent stimulation of the vagus nerve via taVNS increased sAA levels compared to sham stimulation (b = 0.16, SE = 0.05, p = 0.001). When considering potential confounders of sAA, we further replicated previous findings on the diurnal trajectory of sAA activity., Conclusion(s): Vagal activation via taVNS increases sAA release compared to sham stimulation, which likely substantiates the assumption that taVNS triggers NA release. Moreover, our results highlight the benefits of data pooling and data sharing in order to allow stronger conclusions in research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

This study sought to investigate whether slow deep breathing (SDB) facilitates reversal learning. We also explored whether SDB modulates the renewal effect. After learning a series of cue-outcome associations (early acquisition phase) in a predictive learning task, 37 participants paced their breathing according to a normal (NPB group; 0.2 Hz) or a slow (SDB group; 0.1 Hz) pattern while completing the reversal and renewal phases. Response correctness, heart rate variability (HRV, i.e., Root mean square of successive differences), and respiratory rate were assessed. Findings indicated that both groups adopted the targeted breathing pattern. As expected, the SDB (vs. NPB) group displayed a steeper rise in HRV from early acquisition to the later phases of the task during which the breathing manipulation took place. However, the performance of the NPB and SDB groups did not significantly differ in any phase of the predictive learning task. Despite the inconclusive findings on the effect of SDB on reversal and renewal, these results confirm that SDB can be performed while performing a learning task., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: The objective of this study was to evaluate the immunoexpression profiles of breast cancer 1 (BRCA1) and acetyl-histone H3 (AcH3) in squamous cell carcinoma of the mobile tongue (SCC-MT) and their correlation with epidemiologic data and the histopathological grade of tumors., Study Design: Incisional biopsies of 43 SCC-MT were submitted to immunohistochemistry for AcH3 and BRCA1. Samples were microscopically graded as well differentiated (n = 21) or poorly differentiated (n = 22). Both groups were submitted to statistical analysis (P < .05) regarding the percentage of positive cells., Results: Thirty-nine cases were positive for AcH3 (91%), but no difference was observed for the histologic grading (P = .27). Positivity for BRCA1 was observed in all samples regardless of their cellular locations. Most cases in the poorly differentiated group presented with less than 10% nuclear staining (P < .01) and a predominance of cytoplasmic staining (P = .034). The well-differentiated group showed nuclear staining in most of the cases, with more than 50% of cells staining positive (P < .01)., Conclusion: AcH3 and BRCA1 were expressed in all samples. There was a significant decrease in cytoplasmic BRCA1 expression in the poorly differentiated group, suggesting BRCA1 as a possible prognostic marker for SCC-MT., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to report the clinicopathologic features of 62 cases of central odontogenic fibroma (COdF)., Study Design: Clinical and radiographic data were collected from the records of 13 oral pathology laboratories. All cases were microscopically reviewed, considering the current World Health Organization classification of tumors and were classified according to histopathologic features., Results: There were 43 females and 19 males (average age 33.9 years; range 8-63 years). Clinically, COdF lesions appeared as asymptomatic swellings, occurring similarly in the maxilla (n = 33) and the mandible (n = 29); 9 cases exhibited palatal depression. Imaging revealed well-defined, interradicular unilocular (n = 27), and multilocular (n = 12) radiolucencies, with displacement of contiguous teeth (55%) and root resorption (46.4%). Microscopically, classic features of epithelial-rich (n = 33), amyloid (n = 10), associated giant cell lesion (n = 7), ossifying (n = 6), epithelial-poor (n = 3), and granular cell (n = 3) variants were seen. Langerhans cells were highlighted by CD1a staining in 17 cases. Most patients underwent conservative surgical treatments, with 1 patient experiencing recurrence., Conclusions: To the best of our knowledge, this study represents the largest clinicopathologic study of COdF. Most cases appeared as locally aggressive lesions located in tooth-bearing areas in middle-aged women. Inactive-appearing odontogenic epithelium is usually observed within a fibrous/fibromyxoid stroma, occasionally exhibiting amyloid deposits, multinucleated giant cells, or granular cells., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Recovery of hand function after stroke represents the hardest target for clinicians. Robot-assisted therapy has been proved to be effective for hand recovery. Nevertheless, studies aimed to refer patients to the best therapy are missing., Methods: With the aim to identify which clinical features are predictive for referring to robot-assisted hand therapy, 174 stroke patients were assessed with: Fugl-Meyer Assessment (FMA), Functional Independence Measure (FIM), Reaching Performance Scale (RPS), Box and Block Test (BBT), Modified Ashworth Scale (MAS), Nine Hole Pegboard Test (NHPT). Moreover, patients ability to control the robot with residual force and surface EMG (sEMG) independently, was checked. ROC curves were calculated to determine which of the measures were the predictors of the event., Results: sEMG control (AUC = 0.925) was significantly determined by FMA upper extremity (FMUE) (>24/66) and sensation (>23/24) sections, MAS at Flexor Carpi (<3/4) and total MAS (>4/20). Force control (AUC = 0.928) was correlated only with FMUE (>24/66)., Conclusions: FMUE and MAS were the best predictors of preserved ability to control the device by two different modalities. This finding opens the possibility to plan specific therapies aimed at maximizing the highest functional outcome achievable after stroke., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: The objective of this study was to describe the clinicopathological, molecular, and prognostic features of oral/oropharyngeal diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma., Study Design: All cases were retrieved from 7 Brazilian institutions. Immunohistochemical reactions were performed to confirm the diagnoses and to categorize the tumors. In situ hybridization was used to detect Epstein-Barr virus (EBV) and fluorescence in situ hybridization was used to identify gene rearrangements., Results: Most cases involved the oral cavity (76.8%). Males and females, with a mean age of 60 years, were evenly affected. Tumors mostly presented as painful swellings. Forty cases represented germinal center B-cell type (58%). Five cases presented double-hit translocation and 3 harbored rearrangement for MYC/BCL2/BCL6. EBV was detected in 3 cases (4.3%). The 5-year overall survival was 44.4%. Female sex, presence of pain and ulcer, microscopic "starry sky pattern" and necrosis, co-expression of c-Myc/Bcl2, and translocation of MYC were associated with a lower survival in univariate analysis (P = .05, P = .01, P = .01, P = .03, P = .05, P = .006, P = .05, respectively)., Conclusion: Patients affected by oral/oropharyngeal DLBCL have a low survival rate. High-grade B-cell lymphoma (17.7%) and EBV-positive DLBCL, not otherwise specified (4.3%) account for a small number of cases., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to report on clinical experience in Brazil in the dental treatment and the oral conditions of a group of patients with hereditary angioedema (HAE)., Study Design: The study analyzed demographic data, type of HAE, intensity of attacks, long-term and short-term prophylaxis, dental procedures, and occurrence of crises after the procedures were performed. Radiographic evaluation of the number of teeth and bone loss was also performed., Results: Data from 12 patients were collected; most were women, presenting with C1-INH-HAE type I and a history of severe attacks. All patients reported use of regular medications (long-term prophylaxis), mostly attenuated androgens, to prevent/attenuate HAE attacks. These patients had several missing teeth and alveolar bone loss. Tooth extraction was the most common procedure. In half the patients, the procedures had been performed without modification in long-term prophylaxis. The others were treated with an additional prophylaxis protocol (short-term prophylaxis), particularly those who underwent tooth extraction. None of the study patients developed HAE attacks after dental procedures., Conclusion: The occurrence and intensity of a possible HAE attack after dental procedures are unpredictable, but with careful preliminary screening by dental and immunology teams and the use of therapeutic prophylaxis, the risk could be minimized., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to describe the clinicopathologic features of a series of gnathic epithelioid osteoblastomas. As high levels of Proto-oncogene c-Fos proteins resulting from FOS-FOSB translocation were recently demonstrated in osteoblastomas, we also evaluated the immunoexpression of these proteins., Study Design: Records of all cases of epithelioid osteoblastoma of the jaws were retrieved from oral pathology services, and their clinicopathologic and immunohistochemical data were collected. Immunohistochemistry was also performed by using anti-FOS and anti-FOSB antibodies., Results: Six cases of epithelioid osteoblastomas were obtained, 4 in men and 2 in women, and they were mainly located in the posterior body of the mandible (n = 4). Radiographically, the tumors showed mixed radiolucent and radiopaque images, most with poorly defined margins. Microscopically, large epithelioid cells with eccentrically located nuclei predominated among osteoid and immature bone trabeculae. Sharp delineation from adjacent normal bone was observed in all cases. FOS immunostaining was diffuse and strong in the cytoplasm and nucleus of neoplastic cells in all cases, whereas FOSB was only focally positive, with few epithelioid osteoblasts showing nuclear staining., Conclusions: Although epithelioid osteoblastomas of the jaws are locally aggressive, widespread metastasis does not occur, and, as with conventional osteoblastomas, there is wide expression of the FOS protein., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Objectives: Amongst social contextual influences on pain, the manner in which pain and painful procedures are communicated to patients is considered an important contributor to the subjective experience of pain. Threatening information, e.g., by the use of technical language, is suggested to increase pain reports. Validation, or communicating understanding towards another person reporting personal experiences, is suggested to reduce pain. The current study examines effects of both information language (technical vs. plain language) and validation (validation vs. invalidation) on the subjective experience of experimentally induced pain., Methods: Pain-free participants (N = 132) were randomly assigned to one of four groups as formed by manipulations of validation and information language. After reading a description concerning the upcoming thermal stimulus formulated in technical or plain language, participants engaged in a computer controlled simulation (CCS; based on virtual reality technology). Participants received three thermal stimuli while interacting with an avatar who either validated or invalidated their experience during the CCS. Pain intensity and pain unpleasantness were assessed after each stimulus., Results: The validation manipulation showed to be effective, but the information language manipulation did not induce differential threat expectancies. Results show no effect of validation or information language on subjective pain reports., Limitations: Suboptimality of the information language manipulation and shortcomings of the CCS procedure might account for current findings., Conclusions: The study offers an interesting model for the further experimental study of isolated and combined effects of (social) contextual factors on pain. Diverse future research avenues are discussed., (Copyright © 2019. Published by Elsevier Ltd.)

Introduction: Despite many devices are helpful for motion analysis, there is still no established standard technique for the assessment of cervical spine mobility., Objective: To compare differences in using immersive or non-immersive virtual reality (VR) for the assessment of the sensorimotor movement of the cervical spine in healthy subjects., Methods: Thirty-five healthy adults were asked to perform head rotation, flexion, extension, lateral flexion, reaching and repositioning tasks with the head. The same tasks were performed interacting with both non-immersive and immersive virtual reality. Random sequence determined which of the environments was used as first assessment. Range of motion and kinematics i.e. number of completed targets, time of execution (seconds), spatial length (cm), angle distance (°), jerk of the cervical spine, were automatically computed by a 6D electromagnetic motion tracking system., Results: The following variables were significantly larger in immersive than non-immersive VR: head right rotation (p = 0.027), extension (p = 0.047), flexion (p = 0.000), time (p = 0.001), spatial length (p = 0.004), jerk target (p = 0.032), trajectory repositioning (p = 0.003), jerk target repositioning (p = 0.007). A regression model showed that assessment in both VR environments can be influenced by dependent and independent variables., Conclusions: Immersive VR provided more accurate measurement of cervical spine than non-immersive VR in healthy adults., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Cystinosis is a rare lysosomal storage disorder caused by loss-of-function mutations of the CTNS gene, encoding cystinosin, a symporter that mediates cystine efflux from lysosomes. Approximately 95% of patients with cystinosis display renal Fanconi syndrome, short stature, osteopenia, and rickets. In this study, we investigated whether the absence of cystinosin primarily affects bone remodeling activity, apart from the influences of the Fanconi syndrome on bone mineral metabolism. Using micro-computed tomography and histomorphometric and bone serum biomarker analysis, we evaluated the bone phenotype of 1-month-old Ctns -/- knockout (KO) male mice without tubulopathy. An in vitro study was performed to characterize the effects of cystinosin deficiency on osteoblasts and osteoclasts. Micro-computed tomography analysis showed a reduction of trabecular bone volume, bone mineral density, and number and thickness in KO mice compared with wild-type animals; histomorphometric analysis revealed a reduction of osteoblast and osteoclast parameters in tibiae of cystinotic mice. Decreased levels of serum procollagen type 1 amino-terminal propeptide and tartrate-resistant acid phosphatase in KO mice confirmed reduced bone remodeling activity. In vitro experiments showed an impairment of Ctns -/- osteoblasts and osteoclasts. In conclusion, cystinosin deficiency primarily affects bone cells, leading to a bone loss phenotype of KO mice, independent from renal failure., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Oral and maxillofacial metastatic tumors are uncommon, with the breast, prostate, lung, and kidney representing the most common primary sites. Less than 1% of all breast cancers occur in male patients, and to date, only 8 cases of metastatic breast adenocarcinoma to the oral and maxillofacial region in a male patient have been reported in the literature. An 88-year-old male with previous history of a successfully treated primary breast adenocarcinoma 12 years earlier was referred for evaluation of an oral swelling lasting 6 months. Intraoral examination revealed a 2-cm reddish, pedunculated nodule with a smooth surface located in the left retromolar region. Imaging revealed maxillary sinus involvement. The patient underwent incisional biopsy, and microscopic evaluation revealed invasive tumor islands compounded by malignant epithelial cells, sometimes exhibiting ductal arrangement, which were positive for the estrogen receptor and gross cystic disease fluid protein 15. The final diagnosis was metastatic breast adenocarcinoma. Breast metastases are exceedingly rare in the oral and maxillofacial region of male patients; however, clinicians should consider breast metastasis when evaluating reddish oral nodules in older patients, including men, especially those with a history of malignancy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Insulin-resistance and hyperinsulinemia could have a role in the growing incidence of esophageal adenocarcinoma (EAC) and its pre-cancerous lesion Barrett's Esophagus (BE). HER2 activation has also a pivotal role in EAC carcinogenesis but no data correlate these two phenomena in this disease context., Aims: To investigate the role of hyperinsulinemia in BE-dysplasia-adenocarcinoma sequence and the possible relationship between insulin-mediated and HER2 signaling in EAC development., Methods: Serum insulin, C-peptide, IGF1, glucagon, IL-6, TNF-alpha, leptin, adiponectin and Insulin-Resistance-index were analyzed in 19 patients with gastro-esophageal reflux disease, 51 with BE, 24 with dysplastic-BE and 14 with EAC. Insulin/IGF1/HER2 pathways were analyzed in esophageal biopsies using Luminex ® Technology. Insulin effect was also evaluated in EAC-derived OE19 cells. Data were analyzed by Fisher's exact test, Kruskal-Wallis test, Mann-Whitney U-test, Cuzick's test and Spearman correlation coefficient calculation., Results: Insulin-Resistance-index, insulin and C-peptide levels increased along with disease progression (p=0.019, p=0.002, p<0.0001, respectively) and correlated with HER2 expression and with downstream mediators phospho-Akt and phospho-mTOR in esophageal tissue. In vitro, insulin was also able to induce cell proliferation through HER2 activation., Conclusions: Our data pinpoint a possible role of hyperinsulinemia in the Barrett's Esophagus metaplasia-dysplasia-adenocarcinoma sequence through HER2 activation in esophageal epithelial cells., (Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Alterations of brain network activity are observable in Alzheimer's disease (AD) together with the occurrence of mild cognitive impairment, before overt pathology. However, in humans as well in AD mouse models, identification of early biomarkers of network dysfunction is still at its beginning. We performed in vivo recordings of local field potential activity in the dentate gyrus of PS2APP mice expressing the human amyloid precursor protein (APP) Swedish mutation and the presenilin-2 (PS2) N141I. From a frequency-domain analysis, we uncovered network hyper-synchronicity as early as 3 months, when intracellular accumulation of amyloid beta was also observable. In addition, at 6 months of age, we identified network hyperactivity in the beta/gamma frequency bands, along with increased theta-beta and theta-gamma phase-amplitude cross-frequency coupling, in coincidence with the histopathological traits of the disease. Although hyperactivity and hypersynchronicity were respectively detected in mice expressing the PS2-N141I or the APP Swedish mutant alone, the increase in cross-frequency coupling specifically characterized the 6-month-old PS2APP mice, just before the surge of the cognitive decline., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Evidence from animal studies suggests maternal caffeine intake during pregnancy has detrimental effects on subsequent brain development in offspring. However, human data in this area are limited. The aim of this study was to assess whether caffeine intake by women during pregnancy is associated with impaired cognitive development in offspring at age 5.5 years., Methods: Multivariate modeling was conducted using data of 1083 mother-child pairs from a population-based birth cohort in France followed from pregnancy to age 5.5 years of the children. Measures included an estimate of maternal caffeine intake during pregnancy, children's IQ at age 5.5, and individual and family characteristics., Results: Prenatal caffeine exposure was common in the sample (91%) with 12% displaying an intake ≥200 mg/day (high). Multivariable modeling showed a significant negative relationship between caffeine intake and children's IQ at 5.5 years (-.94 [95% confidence interval = -1.70, -.17] full IQ unit per 100 mg daily caffeine intake). In particular, children of mothers consuming ≥200 mg/day were more likely to have borderline or lower IQ compared with children of mothers consuming <100 mg/day (13.5% vs. 7.3%; odds ratio = 2.30, 95% confidence interval = 1.13, 4.69)., Conclusions: We found an association between caffeine intake during pregnancy and impaired cognitive development in offspring, a result in line with animal data. More epidemiologic and biologically grounded research is needed to determine whether this association is causal. This finding suggests that conservative guidelines regarding the maximum caffeine intake recommended in pregnancy (i.e., 200 mg/day) should be maintained., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD), since its characterization as a precise form of dementia with its own pathological hallmarks, has captured scientists' attention because of its complexity. The last 30 years have been filled with discoveries regarding the elusive aetiology of this disease and, thanks to advances in molecular biology and live imaging techniques, we now know that an important role is played by calcium (Ca 2+ ). Ca 2+ , as ubiquitous second messenger, regulates a vast variety of cellular processes, from neuronal excitation and communication, to muscle fibre contraction and hormone secretion, with its action spanning a temporal scale that goes from microseconds to hours. It is therefore very challenging to conceive a single hypothesis that can integrate the numerous findings on this issue with those coming from the classical fields of AD research such as amyloid-beta (Aβ) and tau pathology. In this contribution, we will focus our attention on the Ca 2+ hypothesis of AD, dissecting it, as much as possible, in its subcellular localization, where the Ca 2+ signal meets its specificity. We will also follow the temporal evolution of the Ca 2+ hypothesis, providing some of the most updated discoveries. Whenever possible, we will link the findings regarding Ca 2+ dysfunction to the other players involved in AD pathogenesis, hoping to provide a crossover body of evidence, useful to amplify the knowledge that will lead towards the discovery of an effective therapy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Computational approaches for modelling the central nervous system (CNS) aim to develop theories on processes occurring in the brain that allow the transformation of all information needed for the execution of motor acts. Computational models have been proposed in several fields, to interpret not only the CNS functioning, but also its efferent behaviour. Computational model theories can provide insights into neuromuscular and brain function allowing us to reach a deeper understanding of neuroplasticity. Neuroplasticity is the process occurring in the CNS that is able to permanently change both structure and function due to interaction with the external environment. To understand such a complex process several paradigms related to motor learning and computational modeling have been put forward. These paradigms have been explained through several internal model concepts, and supported by neurophysiological and neuroimaging studies. Therefore, it has been possible to make theories about the basis of different learning paradigms according to known computational models. Here we review the computational models and motor learning paradigms used to describe the CNS and neuromuscular functions, as well as their role in the recovery process. These theories have the potential to provide a way to rigorously explain all the potential of CNS learning, providing a basis for future clinical studies., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Familial adenomatous polyposis (FAP) is one of the most important clinical forms of inherited susceptibility to colorectal cancer. So far, no accepted prognostic markers are present to monitor patients with FAP. Consequently, the major problem in managing patients with FAP is the difficulty to predict when the switch between adenoma and malignant carcinoma occurs, leading to the necessity of preventive surgery. Proteomics is one of the most suitable approaches to identify biomarkers, and it is widely used in cancer research. In this investigation, we studied the circulating plasma peptides in samples collected from patients with FAP and compared the obtained results with adenoma, colorectal cancer, and control samples to discover peptides able to distinguish different phenotypes., Materials and Methods: The peptide fingerprint was obtained by matrix-assisted laser desorption/ionization coupled to time-of-flight mass spectrometry. After statistical analysis, a subset of 45 ionic species was found differently expressed in the 4 groups considered, 12 of them peculiar to patients with FAP. Moreover, 4 ionic species were found significantly changed in the switch between adenoma and malignant carcinoma., Results: Potentially prognostic peptides identified by this study derive mainly from circulating proteins, some of which are involved in the inflammatory response, such as complement C3 and C4 subjected to an exoprotease activity that seemed pathology related., Conclusions: In this study, we defined for the first time a specific panel of peptides for monitoring patients with FAP that could be profitably used to monitor and predict the pathologic evolution in adenocarcinoma malignancy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Malignant peripheral nerve sheath tumor (MPNST) is an uncommon soft tissue sarcoma with a predilection for the extremities and trunk of adults, rarely occurring in the oral cavity. To date, 10 cases of MPNSTs affecting the lower labial mucosa have been reported in the English language literature. We describe an additional case of MPNST in the lower labial mucosa of a 67-year-old male patient, who exhibited a painful swelling with a history of 4 months of evolution. Microscopic examination showed dense plexiform fascicles of spindle cells with wavy atypical nuclei. Mitotic figures and nuclear pleomorphism were evident. Immunohistochemical analysis of tumor cells revealed positivity for S-100 protein, CD56, CD34, and neuron-specific enolase but was negative for neurofilament protein, glut-1, claudin-1, desmin, and smooth muscle actin. Ki-67 labeling was 20%. The final diagnosis was MPNST. The lesion was surgically removed with wide margins, with no signs of recurrence after 4 years of follow-up., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To describe the clinicopathologic and immunohistochemical features of five cases of oral solitary fibrous tumor., Study Design: Clinical data were collected from charts of two oral pathology laboratories of Latin America. All cases were evaluated by conventional hematoxylin and eosin staining and an extended immunohistochemical panel comprising vimentin, CD34, CD99, bcl-2, HHF-35, smooth muscle actin, calponin, S-100 protein, h-caldesmon, and Ki-67., Results: The study included 1 male (20%) and 4 female (80%) patients, with a median age of 43 years. The most common affected site was the buccal mucosa (40%). Tumors were characterized by proliferation of spindled and ovoid cells in a variably vascular and collagenized stroma. All tumors were positive for vimentin, CD34, bcl-2, and CD99. Recurrence was not observed after complete surgical enucleation., Conclusions: Oral solitary fibrous tumors usually appear as well-delimited submucous nodules with a firm-rubbery consistency and covered by intact mucosa. Immunoreactivity for CD34, bcl-2, and CD-99 is helpful to confirm the diagnosis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Analyze clinical and electrographic characteristics of patients with autoimmune epilepsy, and evaluate the effect of early diagnosis and treatment on reduction of seizure frequency., Methods: Observational retrospective case series, conducted using electronic medical data from two teaching hospitals. Clinical data was collected from 2008 to 2013. Cases of new onset seizures were selected based on the presence of laboratory evidence of autoimmunity., Results: 34 hospitalized patients who presented predominantly due to seizures with concern for autoimmune etiology were identified. Mean age of patients was 44.94 years and 64.7% were males. Autoimmune antibodies were detected in 76.5% (26) of patients as follows: VGKc (8); NMDA-R (7); anti-thyroid (5); GAD (4); GABAB (2). 22 patients had unilateral temporal lobe onset and 4 had bilateral temporal lobe onset, while 8 had extra-temporal onset/multiple ictal foci. Median number of seizures during initial prolonged vEEG monitoring was 8 (range 0-48); median number of anti-seizure medications used was 2 (range 1-5). 9 patients had an underlying malignancy. 94.1% (32) patients received immunomodulation, as follows: high dose corticosteroids (96.8%), plasmapheresis (62.5%), IVIG (34.4%), rituximab (21.8%), mycophenolate (15.6%), cyclophosphamide (12.5%). 63.3% (19) participants achieved ≥ 50% seizure reduction (Responder Rate) at first clinic visit. Patients without malignancy had better seizure control (p < 0.05). Time from symptom onset to diagnosis (p < 0.005) and symptom onset to immunomodulation (p < 0.005) was significantly lower among patients who achieved responder rate (RR)., Conclusion: This study highlights certain important clinical and electrographic aspects of autoimmune epilepsy, and the significance of early diagnosis and initiation of immunomodulatory therapy., (Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Accumulation of amyloid-β (Aβ) peptides correlates with aging and progression of Alzheimer's disease (AD). Aβ peptides, which cause early synaptic dysfunctions, spine loss, and memory deficits, also disturb intracellular Ca(2+) homeostasis. By cytosolic and endoplasmic reticulum Ca(2+) measurements, we here define the short-term effects of synthetic Aβ42 on neuronal Ca(2+) dynamics. When applied acutely at submicromolar concentration, as either oligomers or monomers, Aβ42 did not cause Ca(2+) release or Ca(2+) influx. Similarly, 1-hour treatment with Aβ42 modified neither the resting cytosolic Ca(2+) level nor the long-lasting Ca(2+) influx caused by KCl-induced depolarization. In contrast, Aβ42 oligomers, but not monomers, significantly altered Ca(2+) release from stores with opposite effects on inositol 1,4,5-trisphosphate (IP3)- and caffeine-induced Ca(2+) mobilization without alteration of the total store Ca(2+) content. Ca(2+) dysregulation by Aβ42 oligomers involves metabotropic glutamate receptor 5 and requires network activity and the intact exo-endocytotic machinery, being prevented by tetrodotoxin and tetanus toxin. These findings support the idea that Ca(2+) store dysfunction is directly involved in Aβ42 neurotoxicity and represents a potential therapeutic target in AD-like dementia., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Long-chain polyunsaturated fatty acids (LC-PUFAs) of the n6 (ω6) and n3 series are essential for the development of a child's brain. Fetal LC-PUFA exposure as well as infant exposure via breast milk depend on the maternal intake of these LC-PUFAs and of their respective dietary precursors (PUFAs). We aimed to investigate the associations between maternal LC-PUFA and PUFA [(LC)PUFA] dietary intake during pregnancy and child neurodevelopment at ages 2 and 3 y. In 1335 mother-child pairs from the EDEN cohort, we evaluated associations between daily maternal (LC)PUFA intake during the last 3 months of pregnancy with the child's language at age 2 y and with different assessments of development at age 3 y. Associations were investigated separately in breastfed and never-breastfed children. We examined interactions between the ratios of n6 and n3 (LC)PUFA intakes (n6:n3 fatty acid ratio) and duration of breastfeeding. Breastfeeding mothers had a lower n6:n3 fatty acid ratio (8.4 vs. 8.8; P = 0.02). Among never-breastfed children (n = 338), we found negative associations between maternal dietary n6:n3 fatty acid ratios and neurodevelopment, as reflected by the child's language at age 2 y (β ± SE = -2.1 ± 0.7; P = 0.001) and development assessed with the Ages and Stages Questionnaire at age 3 y (-1.5 ± 0.8; P = 0.05). Among mothers with a high n6:n3 fatty acid ratio only, breastfeeding duration was positively associated with language at age 2 y (P-interaction < 0.05). This suggests that the ratio between maternal dietary n6 and n3 (LC)PUFA intake possibly influences the child's brain development during fetal life but not during or by breastfeeding. However, breastfeeding might compensate for prenatal imbalance in maternal dietary n6:n3 fatty acid ratio.

Background: Currently there is no reliable technique for predicting clinical or pathologic complete tumor response after radiochemotherapy (RCT) in patients with rectal cancer. We applied reverse phase protein microarray (RPMA) technology to find a signal pathway that may predict the response to preoperative treatment., Patients and Methods: Fifteen rectal cancer samples were collected during preoperative RCT. Seven patients had a good response to preoperative therapy (Mandard grade I-II) and 8 patients had a poor response (Mandard grade III-V). Using laser capture microdissection (LCM) and RPMA analysis, we measured the phosphorylation level of nearly 80 end points and analyzed the signaling pathways., Results: We identified 4 signaling proteins whose phosphorylation levels were significantly different (P < .05) between the good vs. poor responders; CHK2 and β-catenin were more highly phosphorylated in poor responders, whereas PDK1 and glycogen synthase kinase (GSK)-3α/β had lower phosphorylation levels in poor responders. Interestingly GSK-3α/β, β-catenin, and PDK1 are all present in the phosphatidylinositol-3-kinase (PI3K)-AKT signaling pathway., Conclusions: Based on our results, we hypothesize that the activating state of the PI3K-AKT pathway can stratify patients who could benefit most from neoadjuvant treatment. Moreover, identification of theranostic targets has the potential to pinpoint new therapeutic strategies for the nonresponsive population., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We report the case of a 16-month-old boy who presented an exuberant erythematous gingival swelling and severe tooth mobility. Radiographic examination confirmed alveolar bone loss, and gingival biopsy showed epithelium containing numerous dyskeratotic cells. Because of feeding difficulties, the enlarged gingival tissue and involved teeth were removed. One year later, similar problems were encountered during the eruption of the deciduous second molars. The patient also exhibited papular skin lesions. Histopathologic features on biopsies of the skin and oral lesions were similar. The oral and cutaneous lesions presented by this patient were similar to those described by From et al. in 1978 in a father and son, reported as dyskeratosis benigna intraepithelialis mucosae et cutis hereditaria--the sole report in the English language. To avoid confusion with hereditary benign intraepithelial dyskeratosis (Witkop-von Sallmann syndrome) we have renamed the condition as mucocutaneous dyskeratosis with periodontal destruction and tooth loss., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Apoptosis, a genetically regulated form of cell death with distinct biochemical and morphological features, plays a relevant physiological and pathological role in the organism, being pivotal in the maintenance of tissue development and homeostasis in the adult as well as in the regulation of immune responses. Deregulation of this process causes several human disorders including cancer, autoimmune and neurodegenerative diseases. Thus, modulation of the apoptotic process and of cell death in general, is a potential therapeutic approach for the treatment of several human pathologies., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Increasing evidence has demonstrated that the senescence of vascular endothelial cells has critical roles in the pathogenesis of vascular dysfunction such as atherosclerosis and thrombosis. MicroRNA (miR) are small non-coding RNAs that inhibit gene expression by binding to complementary sequences in the 3'UTR of their target mRNAs. MiRs modulate a variety of biological functions such as cell development, cell differentiation, and apoptosis. Moreover, several miRs involved in endothelial cell function have been identified., Methods and Results: Through a microarray approach, we have identified a miR-146a that is progressively modulated in endothelial cells with aging. In young human umbilical vein endothelial cells, this miR is involved in a premature senescence-like phenotype through direct targeting of the NOX4 protein, implicated in cell senescence and aging., Conclusions and General Significance: Finding important factors that regulate endothelial cell senescence, like miR-146a, will help provide novel therapeutic strategies for vascular disorders., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Lynch syndrome is a genetic disease that predisposes to colorectal tumors, caused by mutation in mismatch repair genes. The use of genetic tests to identify mutation carriers does not always give perfectly clear results, as happens when an unclassified variant is found. This study aimed to define the pathogenic role of 35 variants present in MSH2, MLH1, MSH6, and PMS2 genes identified in our 15-year case study., Methods: We collected clinical and molecular data of all carriers, and then we analyzed the variants pathogenic role with web tools and molecular analyses. Using a Bayesian approach, we derived a posterior probability of pathogenicity and classified each variant according to a standardized five-class system., Results: The MSH2 p.Pro349Arg, p.Met688Arg, the MLH1 p.Gly67Arg, p.Thr82Ala, p.Lys618Ala, the MSH6 p.Ala1236Pro, and the PMS2 p.Arg20Gln were classified as pathogenic, and the MSH2 p.Cys697Arg and the PMS2 p.Ser46Ile were classified as likely pathogenic. Seven variants were likely nonpathogenic, 3 were nonpathogenic, and 16 remained uncertain., Conclusion: Quantitative assessment of several parameters and their integration in a multifactorial likelihood model is the method of choice for classifying the variants. As such classifications can be associated with surveillance and testing recommendations, the results and the method developed in our study can be useful for helping laboratory geneticists in evaluation of genetic tests and clinicians in the management of carriers.

p73, a member of the p53 family, is a transcription factor that plays a key role in many biological processes. In the present study, we show that TAp73 is expressed in neural stem cells (NSC) and its expression increases following their differentiation. NSC from p73 null mice have a reduced proliferative potential, together with reduced expression of members of the Sox-2 and Notch gene families known to be important for NSC proliferation. In parallel with this in vitro data, the width of the neurogenic areas was reduced in the brains of embryonic and adult p73-/- mice. These data suggest that p73, and in particular TAp73, is important for maintenance of the NSC pool., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Numerous miRNAs are deregulated in human cancers and experimental evidence indicates that they can play roles as oncogenes or tumor suppressor genes. Colorectal cancer represents a wide and exciting area of research for molecular biology, due to the growing need of a molecular classification as well as prognostic and predictive molecular factors that may guide oncologists in the clinical management of patients. The aim of this review is to analyze the state of art of the miRNA expression profiles in colorectal cancer to explore some perspectives in this research field., (Copyright 2010. Published by Elsevier B.V.)

Silymarin, a mixture of bioactive flavonolignans isolated from Silybum marianum, exhibits anti-carcinogenic, anti-inflammatory and cytoprotective effects. In this study, the in vitro immunomodulatory activity of silymarin was investigated using CD4+ splenocytes from C57/Bl6 mice. Proliferation assay revealed that silymarin, at 50 microM concentration, significantly inhibited CD4+ cells proliferation. ELISA analyses indicated that silymarin significantly inhibited IL-2 and IFN-gamma production. Immunofluorescence staining performed on the mouse hybridoma T cell line (3DO) revealed a block of nuclear translocation of transcription factor kappaB (NF-kappaB), which is known to be responsible for IL-2 transcriptional activation. Moreover, silymarin inhibited p65/NF-kappaB phosphorylation in CD4+ T cell. These results suggest that silymarin is able to inhibit T cell activation and proliferation, notably acting on pathways of NF-kappaB activation/translocation., ((c) 2010 Elsevier Ltd. All rights reserved.)

The mammalian nervous system exerts essential control on many physiological processes in the organism and is itself controlled extensively by a variety of genetic regulatory mechanisms. microRNA (miR), an abundant class of small non-coding RNA, are emerging as important post-transcriptional regulators of gene expression in the brain. Increasing evidence indicates that miR regulate both the development and function of the nervous system. Moreover, deficiency in miR function has also been implicated in a number of neurological disorders. Expression profile analysis of miR is necessary to understand their complex role in the regulation of gene expression during the development and differentiation of cells. Here we present a comparative study of miR expression profiles in neuroblastoma, in cortical development, and in neuronal differentiation of embryonic stem (ES) cells. By microarray profiling in combination with real time PCR we show that miR-7 and miR-214 are modulated in neuronal differentiation (as compared to miR-1, -16 and -133a), and control neurite outgrowth in vitro. These findings provide an important step toward further elucidation of miR function and miR-related gene regulatory networks in the mammalian central nervous system., (2010 Elsevier Inc. All rights reserved.)

Serum prostate-specific antigen screening has led to earlier detection and surgical treatment of prostate cancer, favoring an increasing incidence-to-mortality ratio. However, about one third of tumors that are diagnosed when still confined to the prostate can relapse within 10 years from the first treatment. The challenge is therefore to identify prognostic markers of aggressive versus indolent tumors. Although several preclinical models of advanced prostate tumors are available, a model that recapitulates the genetic and growth behavior of primary tumors is still lacking. Here, we report a complete histopathological and genomic characterization of xenografts derived from primary localized low- and high-grade human prostate tumors that were implanted under the renal capsule of immunodeficient mice. We obtained a tumor take of 56% and show that these xenografts maintained the histological as well as most genomic features of the parental tumors. Serum prostate-specific antigen levels were measurable only in tumor xenograft-bearing mice, but not in those implanted with either normal prostate tissue or in tumors that likely regressed. Finally, we show that a high proliferation rate, but not the pathological stage or the Gleason grade of the original tumor, was a fundamental prerequisite for tumor take in mice. This mouse xenograft model represents a useful preclinical model of primary prostate tumors for their biological characterization, biomarker discovery, and drug testing.

The glucocorticoid-induced TNFR-related (GITR) protein is a member of the tumor necrosis factor receptor superfamily influencing natural and acquired immune response. GITR is activated by its ligand, GITRL, mainly expressed on antigen presenting cells. Previously, we demonstrated that GITR plays a role in regulating immune response to Candida albicans. Here we analyzed whether GITRL-GITR interaction influences the recognition of C. albicans by regulating the expression of pattern recognition receptors on splenic dendritic cells. Our report demonstrates that under physiological conditions and during candidiasis the GITRL-GITR system affects TLR-2 and TLR-4 expression on DC. These changes correlate with decrease in: MyD88 activation; CD80 and CD40 expression on DC; T cell activation response, including CD28 expression, IL-2 and IFN-gamma production. Our results point out that, during fungal infection, GITRL-GITR interaction modulates TLR-4 and TLR-2 expression, thereby altering the antigen presentation process, and suggesting a role of GITRL-GITR interaction in resistance against infectious diseases.

Malignant solitary fibrous tumor (MSFT) of the pleura is a rare neoplasm, with unpredictable biologic behavior and a low sensitivity to chemotherapy. To the authors' knowledge, no other effective medical treatment is available for this disease. Imatinib mesylate is a tyrosine kinase inhibitor targeting the platelet-derived growth factor (PDGFR-alpha and PDGFR-beta), the BCR-ABL, and c-KIT receptors. We report the first evidence of the activity of imatinib in a symptomatic patient with a chemo- and radio-resistant advanced MSFT, who obtained a 21-months lasting major clinical benefit with a consistent reduction in tumor metabolism. Immunostaining of tumor cells demonstrated the positivity for PDGFR-alpha and PDGFR-beta and the absence of c-KIT over-expression, in the absence of c-KIT and PDGRFR mutations; all the cells strongly and diffusely expressed the ligand PDGF A in the cytoplasm. This profile suggests that the observed tumor response was mediated through the inhibition of the tyrosine kinase activity of PDGFR. Treatment with imatinib should be considered for patients with recurrent or unresectable MSFTs with PDGFR expression.

Background: Pregnant women are at increased risk of influenza-related complications, but research to examine barriers to maternal influenza vaccination has been limited and no studies have assessed the barriers to vaccinating pregnant women in Canada., Objectives: The objectives of the study were to assess (1) how the knowledge, attitudes, and beliefs of Canadian maternity care providers influence their discussion and recommendation patterns, and (2) how the knowledge, attitudes, and beliefs of Canadian women, along with care providers' recommendations, influence their acceptance of influenza vaccine during pregnancy., Methods: Two cross-sectional surveys, one of maternity care providers and one of postpartum women, were carried out between December 1, 2003, and March 31, 2004., Results: Multivariate logistic analysis demonstrated that high levels of provider knowledge about maternal vaccination (OR = 2.64; 95% CI 1.56-4.46), positive attitudes towards influenza vaccination (OR = 2.29; 95% CI 1.43-3.68), and increased age (OR = 1.03; 95% CI 1.02-1.06) were associated with recommending influenza vaccine to pregnant women. Similarly, women who had higher levels of knowledge about maternal vaccination (OR = 3.46; 95% CI 1.31-9.17), positive attitudes towards influenza vaccination (OR = 4.69; 95% CI 1.63-13.5), and a recommendation from their maternity care provider (OR = 32.3; 95% CI 10.4-100) were more likely to be vaccinated during pregnancy. One of the most striking provider barriers identified was uncertainty about who bears responsibility for discussion, recommendation, and vaccination., Conclusion: Maternity care provider recommendation was found to be an important element in increasing influenza vaccination rates during pregnancy. Clarity about responsibility for providing vaccine is needed.