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The evolution of the prominent role of the cerebellum in the development of composite tools, and cumulative culture, leading to the rise of Homo sapiens is examined. Following Stout and Hecht's (2017) detailed description of stone-tool making, eight key repetitive involvements of the cerebellum are highlighted. These key cerebellar learning involvements include the following: (1) optimization of cognitive-social control, (2) prediction (3) focus of attention, (4) automaticity of smoothness, appropriateness, and speed of movement and cognition, (5) refined movement and social cognition, (6) learns models of extended practice, (7) learns models of Theory of Mind (ToM) of teachers, (8) is predominant in acquisition of novel behavior and cognition that accrues from the blending of cerebellar models sent to conscious working memory in the cerebral cortex. Within this context, the evolution of generalization and blending of cerebellar internal models toward optimization of social-cognitive learning is described. It is concluded that (1) repetition of movement and social cognition involving the optimization of internal models in the cerebellum during stone-tool making was the key selection factor toward social-cognitive and technological advancement, (2) observational learning during stone-tool making was the basis for both technological and social-cognitive evolution and, through an optimizing positive feedback loop between the cerebellum and cerebral cortex, the development of cumulative culture occurred, and (3) the generalization and blending of cerebellar internal models related to the unconscious forward control of the optimization of imagined future states in working memory was the most important brain adaptation leading to intertwined advances in stone-tool technology, cognitive-social processes behind cumulative culture (including the emergence of language and art) and, thereby, with the rise of Homo sapiens., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Multidrug-resistant organisms (MDROs) are prevalent in patients admitted to the Emergency Department (ED) and increase the risk of inappropriate empirical antibiotic therapy. Risk stratification for MDRO infection is essential to early identify patients requiring empirical broad-spectrum antibiotic therapy, but it remains challenging for emergency physicians. This study aimed to evaluate prevalence, risk factors, and outcomes of patients admitted to the ED with a bloodstream infection (BSI) caused by MDROs. A retrospective observational study enrolling all consecutive adult patients admitted with a BSI to the ED of Niguarda Hospital, Italy, from January 2019 to December 2021 was performed. 757 patients were enrolled, 14.1% with septic shock. 156 (20%) patients had a BSI caused by MDRO: extended-spectrum beta-lactamase (ESBL) producing Enterobacterales were the most prevalent followed by methicillin-resistant Staphylococcus aureus (MRSA). Risk factors for BSI due to MDRO and specifically for ESBL were chronic renal failure (OR 2.2; 95%CI 1.4-3.6), nursing home residency (OR 4.4; 95%CI 1.9-10.2) and antibiotic therapy in the last 90-days (OR 2.6; 95%CI 1.7-4), whereas for MRSA were dialysis (OR 12.3; 95%CI 1.8-83), antibiotic therapy and/or hospital admission in the past 90-days (OR 3.6; 95%CI 1.2-10.6) and ureteral stent or nephrostomy (OR 7.8; 95%CI 1.5-40.9). Patients with BSI due to MDRO had a higher rate of inappropriate empirical antibiotic therapy (50%) and longer length of stay, but no higher in-hospital mortality. Among patients admitted to the ED with a BSI, MDROs are frequent and often associated with inappropriate empirical antibiotic therapy. Specific updated risk factors for MDRO may help clinicians to better identify patients requiring a broader antibiotic therapy in the ED, while awaiting microbiological results., (© 2024. The Author(s).)

Cerebellar syndromes are clinically and etiologically heterogeneous and can be classified as hereditary, neurodegenerative non-hereditary, or acquired. Few data are available on the frequency of each form in the clinical setting. Growing interest is emerging regarding the genetic forms caused by triplet repeat expansions. Alleles with repeat expansion lower than the pathological threshold, termed intermediate alleles (IAs), have been found to be associated with disease manifestation. In order to assess the relevance of IAs as a cause of cerebellar syndromes, we enrolled 66 unrelated Italian ataxic patients and described the distribution of the different etiology of their syndromes and the frequency of IAs. Each patient underwent complete clinical, hematological, and neurophysiological assessments, neuroimaging evaluations, and genetic tests for autosomal dominant cerebellar ataxia (SCA) and fragile X-associated tremor/ataxia syndrome (FXTAS). We identified the following diagnostic categories: 28% sporadic adult-onset ataxia, 18% cerebellar variant of multiple system atrophy, 9% acquired forms, 9% genetic forms with full-range expansion, and 12% cases with intermediate-range expansion. The IAs were six in the FMR1 gene, two in the gene responsible for SCA8, and one in the ATXN2 gene. The clinical phenotype of patients carrying the IAs resembles, in most of the cases, the one associated with full-range expansion. Our study provides an exhaustive description of the causes of cerebellar ataxia, estimating for the first time the frequency of IAs in SCAs- and FXTAS-associated genes. The high percentage of cases with IAs supports further screening among patients with cerebellar syndromes., (© 2023. The Author(s).)

Cerebellar transcranial direct current stimulation (tDCS) represents a promising therapeutic approach for both motor and cognitive symptoms in neurodegenerative ataxias. Recently, transcranial alternating current stimulation (tACS) was also demonstrated to modulate cerebellar excitability by neuronal entrainment. To compare the effectiveness of cerebellar tDCS vs. cerebellar tACS in patients with neurodegenerative ataxia, we performed a double-blind, randomized, sham controlled, triple cross-over trial with cerebellar tDCS, cerebellar tACS or sham stimulation in twenty-six participants with neurodegenerative ataxia. Before entering the study, each participant underwent motor assessment with wearable sensors considering gait cadence (steps/minute), turn velocity (degrees/second) and turn duration (seconds), and a clinical evaluation with the scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS). After each intervention, participants underwent the same clinical assessment along with cerebellar inhibition (CBI) measurement, a marker of cerebellar activity. The gait cadence, turn velocity, SARA, and ICARS significantly improved after both tDCS and tACS, compared to sham stimulation (all p<0.010). Comparable effects were observed for CBI (p<0.001). Overall, tDCS significantly outperformed tACS on clinical scales and CBI (p<0.01). A significant correlation between changes of wearable sensors parameters from baseline and changes of clinical scales and CBI scores was detected. Cerebellar tDCS and cerebellar tACS are effective in ameliorating symptoms of neurodegenerative ataxias, with the former being more beneficial than the latter. Wearable sensors may serve as rater-unbiased outcome measures in future clinical trials. ClinicalTrial.gov Identifier: NCT05621200., (© 2023. The Author(s).)

Spiritual experience can represent an important aspect of mental health. The purpose of the current study was to validate the Italian version of the Daily Spiritual Experience Scale (DSES-IT) in a population of patients with different psychiatric disorders. It involved 209 patients enrolled in four facilities within the network of IRCCS Centro San Giovanni di Dio Fatebenefratelli Research Institute in Italy. The exploratory factor analysis (EFA) indicated two domains. Internal consistency was very good (Cronbach's Alpha = .93). Scale stability across time assessed by test-retest reliability showed a good performance (Pearson's correlation r > 0.9 for all items). Convergent reliability was assessed by Pearson's correlation between the DSES-IT and the WHOQOL-SRPB scales (r = - .63, p = 0.001). Diagnostic group comparison revealed a statistically significant difference among the patient groups (ANOVA test p = 0.01). The results confirm good psychometric properties of the Italian version of the DSES scale., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To assess the impact of long-term use of different drugs commonly prescribed in Alzheimer's disease (AD) on its clinical course and to identify clinical and therapeutic factors associated with a delay in AD progression., Methods: We retrospectively enrolled 50 patients visited at the Neurology Unit, Careggi University Hospital (Florence), followed for at least 24 months. AD diagnosis was made according to clinical diagnostic criteria for probable/possible AD dementia, always supported at least by one biomarker. Clinical features, MMSE scores evaluated at diagnosis and every 6 months, and AD drugs used for at least 6 months, were recorded. Cox regression analysis was performed to estimate the hazard ratio (HR) for AD progression, assuming as the "final event," the progression to a more severe disease stage, defined as the achievement of an MMSE score less than 10., Results: At baseline, the median MMSE score was 22. During follow-up (median of 41 months), 56% of patients progressed to a more severe disease stage. The use of memantine, either alone (HR 0.24; 95% CI 0.09-0.60) or combined with acetylcholinesterase inhibitors (HR 0.35; 95% CI 0.14-0.88) and a higher MMSE score at baseline (HR 0.82; 95% CI 0.70-0.96) were associated with a significantly lower risk of AD progression., Conclusion: Nowadays, effective disease-modifying therapy for AD is missing. Nevertheless, when the diagnosis is established, our results support the advantage of long-term use of available pharmacological treatments, especially in combination, in delaying AD progression to its more severe disease stage., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The cerebellum is increasingly attracting scientists interested in basic and clinical research of neuromodulation. Here, we review available studies that used either transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) to examine the role of the posterior cerebellum in different aspects of social and affective cognition, from mood regulation to emotion discrimination, and from the ability to identify biological motion to higher-level social inferences (mentalizing). We discuss how at the functional level the role of the posterior cerebellum in these different processes may be explained by a generic prediction mechanism and how the posterior cerebellum may exert this function within different cortico-cerebellar and cerebellar limbic networks involved in social cognition. Furthermore, we suggest to deepen our understanding of the cerebro-cerebellar circuits involved in different aspects of social cognition by employing promising stimulation approaches that have so far been primarily used to study cortical functions and networks, such as paired-pulse TMS, frequency-tuned stimulation, state-dependent protocols, and chronometric TMS. The ability to modulate cerebro-cerebellar connectivity opens up possible clinical applications for improving impairments in social and affective skills associated with cerebellar abnormalities., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To assess the role of ultrasound (US) in detecting and characterizing ductal carcinoma in situ (DCIS) of the breast and to investigate the correlation between ultrasonographic and biological features of DCIS., Methods: In total, 171 patients (mean age 44; range 39-62) with 178 lesions were retrospectively evaluated by two independent radiologists searching for US mass or non-mass lesions. Immunohistochemistry analysis was performed to determine estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. The US detection rate and pattern distribution among the lesion types were evaluated. The χ 2 test was used to evaluate the correlation between the US findings and the biological factors. Statistical significance was indicated by p values < 0.05. Inter-observer agreement was calculated by Kohen's k test., Results: US detected 35% (63/178) of all lesions. Fifty-two (83%) lesions were classified as mass lesions, and 11 (17%) as non-mass lesions (p < 0.0001). Among the mass lesions, the most common shape was irregular (79%; p < 0.0001), with 45 (87%) lesions having indistinct margins. Hypoechogenicity was the most common echo pattern (49 cases, 94%; p < 0.0001). Microcalcifications were found in 23 cases (37%; p = 0.004) and were associated with mass lesions in 15 cases (65%) and with non-mass lesions in 8 cases (35%) (p = 0.21). An almost perfect inter-observer agreement (k = 0.87) was obtained between the two radiologists. A significant ER expression was found in mass lesions (83%; p < 0.0001), with no significant PR (p = 0.89) or HER2 expression (p = 0.81). Among the lesions with microcalcifications, only 7 out of 23 cases (30%) were positive for HER2 (p = 0.09)., Conclusion: DCIS represents a heterogeneous pathological process with variable US appearance (mass-like, non-mass-like, or occult). The most common US finding is represented by mass-type, hypoechogenic lesions with indistinct margins. A significant ER expression exists among mass-type lesions, while microcalcifications seem not to be associated with HER2 expression., (© 2021. Società Italiana di Ultrasonologia in Medicina e Biologia (SIUMB).)

Background: Postoperative ascites (POA) is the most common complication after liver surgery for hepatocarcinoma (HCC), but its impact on survival is not reported. The aim of the study is to investigate its impact on overall survival (OS) and disease-free survival (DFS), and secondarily to identify the factors that may predict the occurrence., Method: Data were collected from 23 centers participating in the Italian Surgical HCC Register (HE.RC.O.LE.S. Group) between 2008 and 2018. POA was defined as ≥500 ml of ascites in the drainage after surgery. Survival analysis was conducted by the Kaplan Meier method. Risk adjustment analysis was conducted by Cox regression to investigate the risk factors for mortality and recurrence., Results: Among 2144 patients resected for HCC, 1871(88.5%) patients did not experience POA while 243(11.5%) had the complication. Median OS for NO-POA group was not reached, while it was 50 months (95%CI = 41-71) for those with POA (p < 0.001). POA independently increased the risk of mortality (HR = 1.696, 95%CI = 1.352-2.129, p < 0.001). Relapse risk after surgery was not predicted by the occurrence of POA. Presence of varices (OR = 2.562, 95%CI = 0.921-1.822, p < 0.001) and bilobar disease (OR = 1.940, 95%CI = 0.921-1.822, p: 0.004) were predictors of POA, while laparoscopic surgery was protective (OR = 0.445, 95%CI = 0.295-0.668, p < 0.001). Ninety-day mortality was higher in the POA group (9.1% vs 1.9% in NO-POA group, p < 0.001)., Conclusion: The occurrence of POA after surgery for HCC strongly increases the risk of long-term mortality and its occurrence is relatively frequent. More efforts in surgical planning should be made to limit its occurrence., (© 2021. The Society for Surgery of the Alimentary Tract.)

Aim: The diagnosis, severity and extent of a sterile inflammation or a septic infection could be challenging since there is not one single test able to achieve an accurate diagnosis. The clinical use of 18F-fluorodeoxyglucose ([ 18 F]FDG) positron emission tomography/computed tomography (PET/CT) imaging in the assessment of inflammation and infection is increasing worldwide. The purpose of this paper is to achieve an Italian consensus document on [ 18 F]FDG PET/CT or PET/MRI in inflammatory and infectious diseases, such as osteomyelitis (OM), prosthetic joint infections (PJI), infective endocarditis (IE), prosthetic valve endocarditis (PVE), cardiac implantable electronic device infections (CIEDI), systemic and cardiac sarcoidosis (SS/CS), diabetic foot (DF), fungal infections (FI), tuberculosis (TBC), fever and inflammation of unknown origin (FUO/IUO), pediatric infections (PI), inflammatory bowel diseases (IBD), spine infections (SI), vascular graft infections (VGI), large vessel vasculitis (LVV), retroperitoneal fibrosis (RF) and COVID-19 infections., Methods: In September 2020, the inflammatory and infectious diseases focus group (IIFG) of the Italian Association of Nuclear Medicine (AIMN) proposed to realize a procedural paper about the clinical applications of [ 18 F]FDG PET/CT or PET/MRI in inflammatory and infectious diseases. The project was carried out thanks to the collaboration of 13 Italian nuclear medicine centers, with a consolidate experience in this field. With the endorsement of AIMN, IIFG contacted each center, and the pediatric diseases focus group (PDFC). IIFG provided for each team involved, a draft with essential information regarding the execution of [ 18 F]FDG PET/CT or PET/MRI scan (i.e., indications, patient preparation, standard or specific acquisition modalities, interpretation criteria, reporting methods, pitfalls and artifacts), by limiting the literature research to the last 20 years. Moreover, some clinical cases were required from each center, to underline the teaching points. Time for the collection of each report was from October to December 2020., Results: Overall, we summarized 291 scientific papers and guidelines published between 1998 and 2021. Papers were divided in several sub-topics and summarized in the following paragraphs: clinical indications, image interpretation criteria, future perspectivess and new trends (for each single disease), while patient preparation, image acquisition, possible pitfalls and reporting modalities were described afterwards. Moreover, a specific section was dedicated to pediatric and PET/MRI indications. A collection of images was described for each indication., Conclusions: Currently, [ 18 F]FDG PET/CT in oncology is globally accepted and standardized in main diagnostic algorithms for neoplasms. In recent years, the ever-closer collaboration among different European associations has tried to overcome the absence of a standardization also in the field of inflammation and infections. The collaboration of several nuclear medicine centers with a long experience in this field, as well as among different AIMN focus groups represents a further attempt in this direction. We hope that this document will be the basis for a "common nuclear physicians' language" throughout all the country., Supplementary Information: The online version contains supplementary material available at 10.1007/s40336-021-00445-w., Competing Interests: Conflict of interestThe authors declare no conflict of interest., (© Italian Association of Nuclear Medicine and Molecular Imaging 2021.)

Background: Few studies have focused on risk factors which may predict an intrahepatic local recurrence (LR) on the surgical edge rather than a distant recurrence (DR) in other liver segments after surgery for hepatocarcinoma (HCC). The purpose of this study was to assess the risk factors for both patterns of recurrence., Methods: An international, multicentre, retrospective study was conducted by collecting data on all consecutive patients with a first diagnosis of HCC who were treated between 2010 and 2017. The presence of macrovascular invasion was an exclusion criteria., Results: About 376 patients were enrolled, and, among them, 62 presented LR, while 90 had DR. Baseline characteristics were comparable between the two groups, but the DR group had a much higher rate of HCV infection (48.9% vs 29%, p 0.014) and a higher median nodule size (3.40 cm IQR 2.2-5.5 versus 3.0 cm IQR 2.0-5.0 in the LR group, p 0.025). A positive surgical margin (R1, HR 4.721; 95% CI 1.83-12.17; p 0.001) was the only independent risk factor for LR, while MVI (HR 1.837; 95% CI 1.03-3.77; p 0.039) and satellitosis (HR 2.440, 95% CI 1.43-3.77, p 0.001) were the only predictive factors for DR., Conclusion: MVI and satellitosis are predictive factors of intrahepatic distant recurrence, configuring a probable hallmark of advanced systemic disease, regardless of the treatment. LR has to be considered the expression of surgical failure.

The traditional view on the cerebellum is that it controls motor behavior. Although recent work has revealed that the cerebellum supports also nonmotor functions such as cognition and affect, only during the last 5 years it has become evident that the cerebellum also plays an important social role. This role is evident in social cognition based on interpreting goal-directed actions through the movements of individuals (social "mirroring") which is very close to its original role in motor learning, as well as in social understanding of other individuals' mental state, such as their intentions, beliefs, past behaviors, future aspirations, and personality traits (social "mentalizing"). Most of this mentalizing role is supported by the posterior cerebellum (e.g., Crus I and II). The most dominant hypothesis is that the cerebellum assists in learning and understanding social action sequences, and so facilitates social cognition by supporting optimal predictions about imminent or future social interaction and cooperation. This consensus paper brings together experts from different fields to discuss recent efforts in understanding the role of the cerebellum in social cognition, and the understanding of social behaviors and mental states by others, its effect on clinical impairments such as cerebellar ataxia and autism spectrum disorder, and how the cerebellum can become a potential target for noninvasive brain stimulation as a therapeutic intervention. We report on the most recent empirical findings and techniques for understanding and manipulating cerebellar circuits in humans. Cerebellar circuitry appears now as a key structure to elucidate social interactions.

Neurologically intact individuals usually show a leftward bias in spatial attention, known as pseudoneglect, likely reflecting a right-hemisphere dominance in the control of spatial attention. A leftward bias also seems to manifest when individuals are asked to provide aesthetic judgments about visual stimuli, like artworks. However, whether artwork perception affects the allocation of spatial attention has never been directly investigated. Here, we assessed whether viewing figurative paintings affects hemispheric imbalance in the control of spatial attention by asking participants to bisect a series of lines presented on a grey background, on figurative paintings or on non-artistic photographs of real-world scenes, while either simply observing or explicitly evaluating each image. In line with previous evidence, participants showed a leftward bisection bias in the baseline condition, reflecting pseudoneglect. Critically, the presence of a painting in the background (irrespective of whether an aesthetic evaluation was required or not) significantly shifted the bias further to the left compared to when lines were bisected over a grey background (baseline) or a photographed scene. This finding suggests that perception of visual art may affect the control of spatial attention, possibly tapping on right-hemisphere resources related to visuospatial exploration, regardless of reward apprehension mechanisms (at least when images do not evoke strong emotional reactions leading to polarized like/dislike judgements).

Background: Alzheimer's Disease (AD) is a multifactorial disorder driven by genetic and modifiable lifestyle risk factors. Lifestyle primary prevention initiatives may reduce the prevalence and incidence of dementia in older adults., Objectives: The E.Mu.N.I study is a randomized controlled trial investigating the effect of multilevel non-pharmacologic interventions on cognitive performances (primary outcome) and structural and vascular brain MRI markers (secondary outcome), as well as markers of brain functional connectivity change (exploratory outcome), in older adults with subjective memory decline (SMD). Here, we present the study design and the baseline features of the sample., Methods: Cognitively intact older adults with SMD, enrolled between February 2016 and June 2017, were randomly assigned to one of the 3 interventions for 1 year: Active Control Intervention (ACI), i.e., educational lessons; Partial Intervention (PI), i.e., homotaurine administration (100 mg/die) and lessons on the Mediterranean diet; Multilevel Intervention (MI), i.e., PI plus computerized cognitive training and physical exercise training., Results: One-hundred and twenty-eight eligible participants were enrolled (66% female; age: 68 ± 5 years). Eighty-two percent of the sample was composed of volunteers with SMD from the community. Participants were randomly allocated to the interventions as follows: ACI (N = 40), PI (N = 44), MI (N = 44). No significant differences among groups emerged on socio-demographic, clinical-neuropsychological variables and MRI markers at baseline., Conclusions: The outcomes obtained from the E.Mu.N.I. study will clarify the efficacy of multilevel non-pharmacologic interventions on cognitive and neuroimaging markers in SMD individuals. This is a crucial step forward for the development of cost-effective non-pharmacologic primary prevention initiatives for AD.

To validate the Italian Perceived Maternal Parenting Self-Efficacy (PMP S-E), the first questionnaire specifically developed for mothers of preterm neonates hospitalized in the Neonatal Intensive Care Unit. Two hundred mothers filled the PMP S-E, the General Self-Efficacy Scale (GSES), the Edinburgh Postnatal Depression Scale (EPDS), the Parental Distress Index (PSI-SF/Pd). The Explanatory Factor Analysis outlined four factors: care-taking procedures, evoking behaviours, reading and managing bodily cues, reading and managing emotional cues. This factor-solution demonstrated adequate goodness of fit when the Confirmatory Factor Analysis was carried out. Internal consistency was high for the overall scale (α = 0.932), and the all the factors (all α > 0.80). There was a moderate correlation with GSES (r = .438; p < .001), while the associations with EPDS (r = .295; p < .001) and PSI-SF/Pd (r = .193; p = .006) were low. Good test-retest reliability was found over 2 weeks (r = .73; p < .001). These findings support the validity and reliability of the Italian PMP S-E.

When viewing a portrait, we are often captured by its expressivity, even if the emotion depicted is not immediately identifiable. If the neural mechanisms underlying emotion processing of real faces have been largely clarified, we still know little about the neural basis of evaluation of (emotional) expressivity in portraits. In this study, we aimed at assessing-by means of transcranial magnetic stimulation (TMS)-whether the right superior temporal sulcus (STS) and the right somatosensory cortex (SC), that are important in discriminating facial emotion expressions, are also causally involved in the evaluation of expressivity of portraits. We found that interfering via TMS with activity in (the face region of) right STS significantly reduced the extent to which portraits (but not other paintings depicting human figures with faces only in the background) were perceived as expressive, without, though, affecting their liking. In turn, interfering with activity of the right SC had no impact on evaluating either expressivity or liking of either paintings' category. Our findings suggest that evaluation of emotional cues in artworks recruit (at least partially) the same neural mechanisms involved in processing genuine biological others. Moreover, they shed light on the neural basis of liking decisions in art by art-naïve people, supporting the view that aesthetic appreciation relies on a multitude of factors beyond emotional evaluation.

Converging evidence suggests that the perception of auditory pitch exhibits a characteristic spatial organization. This pitch-space association can be demonstrated experimentally by the Spatial Musical Association of Response Codes (SMARC) effect. This is characterized by faster response times when a low-positioned key is pressed in response to a low-pitched tone, and a high-positioned key is pressed in response to a high-pitched tone. To investigate whether the development of this pitch-space association is mediated by normal visual experience, we tested a group of early blind individuals on a task that required them to discriminate the timbre of different instrument sounds with varying pitch. Results revealed a comparable pattern in the SMARC effect in both blind participants and sighted controls, suggesting that the lack of prior visual experience does not prevent the development of an association between pitch height and vertical space.

Background: A low burden of disease represents an independent favorable prognostic factor of response to peptide receptor radionuclide therapy (PRRT) in patients affected by gastro-entero-pancreatic neuroendocrine tumors. However, it is not clear whether this is due to a lower diffusion of the disease or thanks to debulking surgery., Methods: From 1996 to 2013 those patients diagnosed with G1-G2 pancreatic neuroendocrine tumor (PNET) and synchronous liver metastases who were not deemed eligible for liver radical surgery but were eligible to receive upfront PRRT were prospectively included in the study. Two groups of comparison were identified: those submitted for primary tumor resection before PRRT and those who were not. The outcome was evaluated as: objective response to PRRT (OR), progression-free survival (PFS), and overall survival (OS)., Results: Of the 94 subjects, 31 were previously submitted for primary tumor resection. After propensity score adjustments, patients who underwent surgery before PRRT showed higher stabilization or objective responses after PRRT (p = .006), and this translated into a better median PFS (70 vs. 30 months; p = .002) and OS (112 vs. 65 months; p = .011), for operated versus nonoperated patients, respectively. At multivariate analysis, operated patients showed a statistically significantly improved PFS: HR, 5.11 (95 % CI 1.43-18.3); p = .012, whereas Ki-67 in continuous fashion was correlated significantly with OS: 1.13 (95 % CI 1-1.27); p = .048., Conclusions: Primary tumor resection prior to PRRT can be safely proposed in G1-G2 PNETs with diffuse liver metastases because it seems to enhance response to PRRT and to improve significantly PFS.

In our everyday social interactions we often need to deal with others' unpredictable behaviors. Integrating unexpected information in a consistent representation of another agent is a cognitively demanding process. Several neuroimaging studies point to the medial prefrontal cortex (mPFC) as a critical structure in mediating social evaluations. Our aim here was to shed light on the possible causal role of the mPFC in the dynamic process of forming and updating social impressions about others. We addressed this issue by suppressing activity in the mPFC by means of 1 Hz offline transcranial magnetic stimulation (TMS) prior to a task requiring participants to evaluate other agents' trustworthiness after reading about their social behavior. In two different experiments, we found that inhibiting activity in the mPFC increased perceived trustworthiness when inconsistent information about one agent's behavior was provided. In turn, when only negative or positive behaviors of a person were described, TMS over the mPFC did not affect judgments. Our results indicate that the mPFC is causally involved in mediating social impressions updating-at least in cases in which judgment is uncertain due to conflicting information to be processed.

Background and Aims: Ageing trends in populations are common amongst most European countries. One of the consequences of this trend is the increase of hospitalisation of elderly patients. To better manage the elderly population hospitalisation, it is crucial to obtain a better understanding of this population's clinical and functional conditions and their hospitalisation outcome predictors. The present prospective observational cohort study aimed at studying the variables considered predictive of the length of stay, of destination at discharge, of re-hospitalisation, and of mortality at 6 months of elderly (age >64 years, N = 329) admitted to ten geriatric units, having different missions (e.g., cognitive impairment and dementia; movement disorders; bone fractures and immobilisation syndrome; or stroke), of the St. John of God Order during a 4-month-long index period., Methods: The patients were monitored from the first day of hospitalisation through the discharge. Researchers filled in a "Patient Schedule" based on a comprehensive set of socio-demographic and clinical variables and standardised assessment tools. We used a standardised telephone interview to re-assess patients at the 6-month follow-up., Results: The BRASS score proved to be a better reliable predictor of length of stay (F = 3.9, p = 0.04) among all variables associated with higher risks of prolonged hospital stay and post-discharge problems. In addition, discharge destination was also predicted by the use of the Tinetti Scale score (OR = 0.95, 95 % CI 0.90-0.99), the Mini Mental State Examination (MMSE) score (OR = 0.1.07, 95 % CI 1.01-1.13) and by independence in daily activity as measured by the IADL scale (OR = 4.09, 95 % CI 1.46-11.44). Motor functioning resulted as a reliable predictor (OR = 2.67, 95 % CI 1.27-5.59) of re-hospitalisation in all the medical units. Lastly, female gender (OR = 0.28, 95 % CI 0.11-0.71) resulted as the only reliable variable associated with a lower mortality risk after discharge., Conclusion: The variables related to the clinical and functional status were reliable predictors for length of stay, for discharge destination, and for re-hospitalisation among older patients admitted to ten geriatric units in Italy. Further research is needed to establish valid and reliable predictors of mortality risk, to develop effective preventive strategies in those vulnerable populations.

According to a recent hypothesis, the prefrontal cortex has been proposed as the site of emotional memory integration, because it is sensitive to the recognition of emotional contents. In the present research, we explored the role of the dorsolateral prefrontal cortex (DLPFC) in memory recognition processes for positive versus negative emotional stimuli when old (target) and new (distractor, either semantically related or unrelated to the target) stimuli were presented. The role of the DLPFC was analysed using an rTMS (repeated transcranial magnetic stimulation) paradigm that induced increased cortical activation of the left DLPFC. The subjects were required to perform a task that consisted of two experimental phases (i.e., an encoding and a recognition phase) in which the targets and the distractors were presented and recognition performance was measured. rTMS stimulation was provided over the left DLPFC during the recognition phase. We found that the rTMS stimulation affected the memory recognition of positive emotional material. Moreover, related and unrelated distractors were discarded better when they were positively valenced, and a more significant effect (i.e., increased performance) was produced in response to related distractors. This result suggests that the activation of the left DLPFC favours the memory recognition of positive emotional information, and that such activation is able to induce a more appropriate selective process to distinguish target from distractor stimuli in the presence of more complex processes (related distractors). The valence model of emotional cue processing may explain this increased performance by demonstrating the distinct role of the left hemisphere in the retrieval of positive emotional information.

A suggestive hypothesis proposed that the lateral prefrontal cortex (LPFC) may be identified as the site of emotion-memory integration, since it was shown to be sensitive to the encoding and retrieval of emotional content. In the present research we explored the role of the dorsolateral prefrontal cortex (DLPFC) in memory retrieval of positive vs. negative emotional stimuli. This effect was analyzed by using an rTMS paradigm that induced a cortical activation of the left DLPFC. Subjects were required to perform a task consisting of two experimental phases: an encoding phase, where some lists composed by positive and negative emotional words were presented to the subjects; a retrieval phase, where the old stimuli and the new stimuli were presented for a recognition performance. The rTMS stimulation was provided during the retrieval phase over the left DLPFC. We found that the rTMS stimulation over this area affects the memory retrieval of positive emotional material, with higher memory efficiency (reduced RTs). This result suggested that left DLPFC activation promotes the memory retrieval of emotional information. Secondly, the valence model of emotional cue processing may explain decreasing of RTs, by pointing out the distinct role the left hemisphere has in positive emotional cue processing.

16S rRNA gene (rrs) clone libraries were constructed from two snow samples (May 11, 2007 and June 7, 2007) and two meltwater samples collected during the spring of 2007 in Svalbard, Norway (79 degrees N). The libraries covered 19 different microbial classes, including Betaproteobacteria (21.3%), Sphingobacteria (16.4%), Flavobacteria (9.0%), Acidobacteria (7.7%) and Alphaproteobacteria (6.5%). Significant differences were detected between the two sets of sample libraries. First, the meltwater libraries had the highest community richness (Chao1: 103.2 and 152.2) and Shannon biodiversity indices (between 3.38 and 3.59), when compared with the snow libraries (Chao1: 14.8 and 59.7; Shannon index: 1.93 and 3.01). Second, integral-LIBSHUFF analyses determined that the bacterial communities in the snow libraries were significantly different from those of the meltwater libraries. Despite these differences, our data also support the theory that a common core group of microbial populations exist within a variety of cryohabitats. Electronic supplementary material The online version of this article (doi:10.1007/s00792-009-0299-2) contains supplementary material, which is available to authorized users.

Imported malaria is the most common cause of fatal infections in returning travellers. The increased amount of both tourist movement and migration has resulted in a growing number of people at risk of infection. In the present study, 507 malaria patients admitted to Italy's National Institute for Infectious Diseases in Rome between January 1984 and December 2003 were studied. Overall, 445 cases, or 87.7%, were acquired in Africa, of which 55% were acquired in five sub-Saharan countries. Plasmodium falciparum accounted for 393 (77.5%) of the imported cases. Patients consisted of short-term travellers (n = 213, 42%), long-term visitors (n = 134, 26.4%), and immigrants from endemic areas (n = 137, 27%). Malaria chemoprophylaxis was completed in less than one-quarter of all patients, with immigrants having the lowest rate of completion: only 3.6% of immigrants fully completed chemoprophylaxis compared to 31% of short-term travellers and 29.1% of long-term visitors (p < 0.001). Upon multivariate analysis, the lack of chemoprophylaxis was independently associated with the occurrence of severe malaria (p = 0.009). Severe malaria was reported in 59 (11.6%) individuals: all 11 deaths due to severe P. falciparum infection occurred in patients from sub-Saharan countries, two of whom were immigrants from countries where malaria is endemic. Malaria poses a serious health threat to individuals visiting endemic areas. Ensuring the correct chemoprophylaxis for all travellers, including immigrants from endemic areas, and providing prompt access to healthcare providers for unhealthy returning travellers are major points still to be addressed in Italy.

Formyl-peptide receptors (FPRs) belong to the family A of the G-protein coupled receptor superfamily and include three subtypes: FPR, FPR-like-1 and FPR-like-2. They have been involved in the control of many inflammatory processes promoting the recruitment and infiltration of leukocytes in regions of inflammation through the molecular recognition of chemotactic factors. A large number of structurally diverse chemotypes modulate the activity of FPRs. Newly identified antagonists include bile acids deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA). The molecular recognition of these compounds at FPR receptor was computationally investigated using both ligand- and structure-based approaches. Our findings suggest that all antagonists bind at the first third of the seven helical bundles. A closer inspection of bile acid interaction reveals a number of unexploited anchor points in the binding site that may be used to aid the design of new potent and selective bile acids derivatives at FPR.

Background, Aims and Scope: Most existing models used to describe the fate of chemicals in surface water and sediment generally consider a 'static scenario', in which a contaminant is discharged at a constant rate and environmental input parameters do not change during the simulation time. This approach is not suitable in environmental scenarios characterized by daily or periodic changes of several input parameters. The aim of this study is to estimate approximate emissions of DDT lo Lake Maggiore using a new surface water model, (DynA Model) that describes the fate of a chemical in a dynamic scenario., Methods: The model is developed on the grounds of an existing and validated model (QWASI). A numerical solution was adopted to build the fully dynamic version of the model., Results and Discussion: The model was applied to Lake Maggiore emitting DDT at a constant rate until steady-state was reached. Emissions were stopped and later sporadic 'pulse' emissions were added. This was done to calculate the amount of DDT needed to simulate concentrations close to those measured in water and sediments. This allowed the evaluation of the order of magnitude of emissions. An uncertainty analysis for sediment resuspension was also performed, given the lack of measured resuspension rates., Conclusion: The model showed the time response of the Lake Maggiore system to varying emission scenarios and provided what are regarded as reasonable estimates of DDT emissions. The model demonstrated the importance of sediment-water exchange., Recommendation and Outlook: In order to better calculate DDT concentrations the model should be run with different discharge scenarios to clarify the time trends of concentrations, possibly with the use of different sets of measured data (such as biota and sediment deposition/resuspension rates).

Background: Laparoscopic treatment of sigmoid diverticulitis is commonly accepted in Hinchey cases I and II, whereas it is debated in the case of purulent peritonitis, and not indicated for fecal peritonitis., Methods: A single-center experience of 103 patients treated for Hinchey I-III sigmoid diverticulitis was reviewed. One-stage laparoscopic resection and primary anastomosis constituted the planned procedure. Abscesses in patients with Hinchey IIa were drained percutaneously before surgery. Patients with Hinchey III underwent surgery in emergency. A four-trocar approach with left iliac fossa minilaparotomy was used. Fistulas were treated laparoscopically with Harmonic Scalpel dissection., Results: Laparoscopic treatment was successfully completed for 100 patients. Intraoperative complications occurred in 2.9% of the cases. Postoperative procedure-related morbidity was 8%, occurring mainly in Hinchey I patients. A longer hospital stay was recorded among Hinchey IIb patients treated for colovescical fistula. No mortality was observed., Conclusions: Laparoscopic surgery for sigmoid diverticulitis in experienced hands can be a safe and effective gold standard procedure also for patients with fistula or purulent peritonitis.

In recent years because of their diagnostic importance techniques of immunohistochemistry have been increasingly employed; The use of specific cellular antibodies has allowed for the recognition of tumors of mesenchymal, epithelial, muscular, endothelial, and neuroendocrine origin, and, within these classes, for the revelation of different cellular populations. These techniques together with histochemical and ultramicroscopic studies help define not only the genesis but also the stage of differentiation and the cell function, which are important factors in the prognosis of tumors. These have proven to be particularly useful for the differential diagnosis of highly undifferentiated forms in which cellular morphology differs from that of the tissue of origin.

Established methods for definitive ablation of autonomous thyroid nodules are surgery and radioiodine. Since it has been demonstrated that percutaneous ethanol injection can inactivate parathyroid adenomas and small hepatocellular carcinomas, we started a trial of this treatment in patients with autonomous thyroid nodules. Twenty-eight patients, 22 toxic and 6 nontoxic, all with undetectable thyrotropin serum levels and suppressed extranodular tissue on scintigraphy, were treated. Treatment consisted of percutaneous intranodular ethanol injection under ultrasound guidance. The total amount of alcohol injected ranged from 0.4 to 2.2 times the estimated nodule volume, divided into 4 to 9 injections performed at 2 to 7 day intervals. Most patients were treated with a single cycle of injections, but 7 of them required 2 cycles. The signs and symptoms of hyperthyroidism disappeared in all cases. Apparently complete cure (normal serum free thyroid hormones, thyrotropin in basal conditions and after thyrotropin releasing hormone, reactivation of extranodular tissue on scintigraphy with nodule no longer visible) was obtained in 17 patients (13 after 1 cycle and 4 after 2 cycles). Partial cure (normal serum free thyroid hormone levels, detectable thyrotropin levels with normal or blunted response to thyrotropin releasing hormone and partial reactivation of extranodular tissue on scintigraphy with nodule or parts of it still visible) was obtained in 10 patients (8 after 1 cycle and 2 after 2 cycles). In 1 patient with a very large nodule thyrotropin levels remained undetectable, but thyroid hormone levels eventually became normal. No recurrences were observed after a follow-up of 12 to 32 months (mean 20 months). No serious side effects were encountered. A clinically valuable result was obtained in all patients. These data suggest that this form of treatment could constitute an alternative to surgery and radioiodine for the ablation of autonomous thyroid nodules.

A 48-year-old woman whose past history was unrevealing presented with sudden swelling of the neck with pain and dysphonia. Neck ultrasonography suggested the possibility of hemorrhage in a parathyroid adenoma. Surgical exploration revealed a hemorrhagic parathyroid adenoma of the chief cell type. This event is exceedingly rare, but should be considered in the differential diagnosis of suddenly appearing masses of the neck region.

The effect of acute oral administration of loperamide (4, 8 and 16 mg), a peripheral opiate agonist used in the treatment of diarrhoea, on several metabolic and endocrine variables has been evaluated in healthy volunteers in comparison with placebo. Plasma glucose was significantly raised by all three doses, whereas serum IRI and C-peptide were decreased and serum FFA was significantly increased only after loperamide 8 and 16 mg; serum PRL, GH, LH and FSH did not change. The data suggest that opiates may be involved in the regulation of glycaemia, probably by modifying islet hormone secretion by acting at a peripheral site, since loperamide does not cross the blood-brain barrier. Although the precise mechanism of these actions is unknown, it is suggested that the effects of loperamide are mediated either by stimulation of opiate receptors per se, or by suppression of acetylcholine release from cholinergic nerve endings. The lack of change in pituitary hormone secretion by loperamide is in agreement with previous observations indicating that opiate effects on PRL, GH and gonadotropins occur at the level of the central nervous system.

The effects of short-term treatment with either placebo or two serotonin antagonists, cyproheptadine and metergoline, on oral glucose tolerance and insulin secretion have been evaluated in normal subjects and in patients with chemical diabetes. Placebo treatment was not associated with any significant change in the parameters examined. Glucose tolerance in chemical diabetics was significantly improved both after cyproheptadine and metergoline; fasting plasma glucose was also reduced by metergoline. Treatment with the latter drug was also associated with a significant decrease in incremental glucose area in healthy subjects, which was not affected by cyproheptadine. Basal and glucose-stimulated insulin secretion were not affected by either drug in any subjects. Cyproheptadine and metergoline improve glucose metabolism in chemical diabetes probably by reducing insulin resistance. This may depend either on decreased secretion of counter-regulatory hormones or on a direct pharmacological action of the drugs on glucose utilization, possibly mediated by their common antiserotoninergic properties.

The effects of acute oral administration of the antiserotoninergic drugs methysergide (3 mg) and metergoline (4 mg) on basal, submaximal (0.6 micrograms/kg i. m.) and maximal (6 micrograms/kg) pentagastrin-stimulated gastric acid secretion, as well as on basal and food-induced gastrin release, have been evaluated in healthy volunteers. Methysergide significantly increased basal and submaximal pentagastrin-stimulated gastric acid secretion, and metergoline significantly inhibited gastric acidity in all experiments. Basal and stimulated serum gastrin concentrations were not modified by either drug. The effect of methysergide on gastric acid secretion was opposed to that of serotonin and was probably dependent on its antiserotoninergic action, but the decrease in gastric acidity caused by metergoline is not easily explained. Although the effect is similar to that of a dopamine infusion, it does not depend on dopamine infusion, it does not depend on dopamine receptor stimulation, since it was not influenced by pretreatment with metoclopramide. It is suggested that it might be due to the weak anticholinergic and/or antihistaminic properties of metergoline.

The endocrine effects of a relatively potent dopaminergic agent, dihydroergokryptine, have been studied in normal subjects, and in hyperprolactinaemic and acromegalic patients. A single 6 mg oral dose of the drug caused a marked, long lasting fall in prolactin (PRL) plasma levels in healthy subjects, in hyperprolactinaemic patients and in normoprolactinaemic acromegalics. Growth hormone (GH) levels decreased in 1-DOPA - responder, acromegalic patients, but dihydroergokryptine did not affect GH levels in normal volunteers or in 1-DOPA non-responder, acromegalic patients. The PRL- and GH- lowering activity of 6 mg dihydroergokryptine was significantly greater than that of 6 mg dihydroergocristine, and was similar to that of an oral dose of 500 mg 1-DOPA.

Few data are available on serum free thyroid hormone concentration in patients with T3-toxicosis. In this study total and free T4 and T3 and TBG were evaluated in 35 subjects with T3-toxicosis, including 12 with untreated Graves' disease, 5 Graves' patients on methimazole treatment, 13 with autonomous adenoma, 3 with multinodular goiter, and 2 with subacute thyroiditis. T4, T3, free T4 (FT4), free T3 (FT3) as well as calculated T4/TBG and T3/TBG ratios were significantly higher in patients than in 37 healthy controls. Serum FT4 levels above the normal range were found in 19 subjects with T3-toxicosis (9 with untreated and one with methimazole-treated Graves' disease, 6 with autonomous adenoma, 1 with multinodular goiter and 2 with subacute thyroiditis). These data, together with the few previous reports, indicate that high FT4 levels are present in about half of the patients with so called T3-toxicosis, and that this occurs more frequently in diffuse than nodular goiter. It is suggested that the term T3-toxicosis be used only for those subjects with normal total and free T4.

The effects of acute oral administration of the dopaminergic drug, bromocriptin (5 mg), on basal and submaximal (1 and 3 microgram per kg bw given sc) and maximal (6 mug per kg bw) pentagastrin-stimulated gastric acid secretion and on basal and meal-induced gastrin release have been evaluated in healthy volunteers. Although basal and maximal pentagastrin-stimulated acid output did not change, the response to submaximal pentagastrin doses was significantly increased. Basal and stimulated serum gastrin concentrations were not modified, nor was fasting serum gastrin during chronic bromocriptine treatment (10 mg per day for 90 days) in acromegalic patients. As dopamine infusion is known to reduce basal and pentagastrin-induced gastric acid secretion, the presently reported effect of bromocriptine is not dependent on dopamine receptor stimulation. It is suggested that it might be due to alpha-adrenergic and/or serotoninergic antagonism, both actions being properties of bromocriptine. Alternatively, since bromocriptine, at variance with iv infused dopamine, crosses the blood-brain barrier, the effect of this drug on gastric function might depend on interference by centrally mediated actions on those directly exerted at the gastric level.

The pharmacodynamic effects of FCE20700, a new PGE2 derivative, have been investigated in 6 healthy volunteers given single intragastric (i.g.) and intraduodenal (i.d.) doses of 1 and 2 mg and placebo, according to a double-blind, within-subjects design. For 30-270 min following i.g. administration the effect of FCE20700 on peptone-stimulated gastric acid secretion (AS) was assessed by i.g. titration, and serum gastrin (G) levels were also determined. For the same period after i.d. dosing the effect of the compound on pentagastrin-stimulated AS and on mucoproteins and bicarbonate content in the gastric juice was measured. Blood pressure (BP), heart rate and possible side-effects were monitored. Following i.g. administration there was a moderate, dose-related, significant inhibition of AS; significant inhibition of G levels was observed only after the highest dose. After i.d. administration there was a very modest though dose-related and significant inhibition of AS; a brief maximal increase in mucoproteins and in bicarbonate levels was apparent after the 1 mg dose. After i.d. but not after i.g. administration of 2 mg there was a modest but significant decrease in BP. No side-effects of clinical relevance were reported. The results appear to suggest a major activity of FCE20700 on cytoprotection rather than in inhibiting gastric acid secretion. The observed change in BP may indicate that after i.d. administration there will be some systemic effects of FCE20700.

The PRL response to iv cimetidine was tested in 8 healthy males and 8 females at 4 different dose levels (0.75, 1.5, 3.0 and 6.0 mg/kg bw). Serum PRL levels were significantly increased in comparison with a placebo study by the second cimetidine dose in both sexes. The PRL response was significantly higher in females than in males at all but the lowest dose tested. A significant correlation between the cimetidine dose and the PRL response was observed. There was no significant modifications in serum GH, LH, FSH, IRI and glucose. Present findings demonstrate that the stimulation of PRL release by iv cimetidine is quite specific and dose-dependent.