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Environmental enrichment may slow cognitive decay possibly acting through an improvement in vascular function. Aim of the study was to assess the effects of a 7-month cognitive, social, and physical training program on cognitive and vascular function in patients with mild cognitive impairment. In a single-center, randomized, parallel-group study, 113 patients (age, 65–89 years) were randomized to multidomain training (n=55) or usual care (n=58). All participants underwent neuropsychological tests and vascular evaluation, including brachial artery flow-mediated dilation, carotid–femoral pulse wave velocity, carotid distensibility, and assessment of circulating hematopoietic CD34+ and endothelial progenitor cells. At study entry, an age-matched control group (n=45) was also studied. Compared with controls, patients had at study entry a reduced flow-mediated dilation (2.97±2.14% versus 3.73±2.06%; P =0.03) and hyperemic stimulus (shear rate area under the curve, 19.1±15.7 versus 25.7±15.1×10 −3 ; P =0.009); only the latter remained significant after adjustment for confounders ( P =0.03). Training improved Alzheimer disease assessment scale cognitive (training, 14.0±4.8 to 13.1±5.5; nontraining, 12.1±3.9 to 13.2±4.8; P for interaction visit×training=0.02), flow-mediated dilation (2.82±2.19% to 3.40±1.81%, 3.05±2.08% to 2.24±1.59%; P =0.006; P =0.023 after adjustment for diameter and shear rate area under the curve), and circulating hematopoietic CD34 + cells and prevented the decline in carotid distensibility (18.4±5.3 to 20.0±6.6, 23.9±11.0 to 19.5±7.1 Pa −1 ; P =0.005). The only clinical predictor of improvement of cognitive function after training was established hypertension. There was no correlation between changes in measures of cognitive and vascular function. In conclusion, a multidomain training program slows cognitive decline, especially in hypertensive individuals. This effect is accompanied by improved systemic endothelial function, mobilization of progenitor CD34 + cells, and preserved carotid distensibility. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01725178.

Vitamin B12, folate, and homocysteine are implicated in pivotal neurodegenerative mechanisms and partake in elders' mental decline. Findings on the association between vitamin-related biochemistry and cognitive abilities suggest that the structural and functional properties of the brain may represent an intermediate biomarker linking vitamin concentrations to cognition. Despite this, no previous study directly investigated whether vitamin B12, folate, and homocysteine levels are sufficient to explain individual neuropsychological profiles or, alternatively, whether the activity of brain regions modulated by these compounds better predicts cognition in elders. Here, we measured the relationship between vitamin blood concentrations, scores at seventeen neuropsychological tests, and brain activity of sixty-five elders spanning from normal to Mild Cognitive Impairment. We then evaluated whether task-related brain responses represent an intermediate phenotype, providing a better prediction of subjects' neuropsychological scores, as compared to the one obtained considering blood biochemistry only. We found that the hemodynamic activity of the right dorsal anterior cingulate cortex was positively associated (p value < 0 05 cluster corrected) with vitamin B12 concentrations, suggesting that elders with higher B12 levels had a more pronounced recruitment of this salience network region. Crucially, the activity of this area significantly predicted subjects' visual search and attention abilities (p value = 0 0023), whereas B12 levels per se failed to do so. Our results demonstrate that the relationship between blood biochemistry and elders' cognitive abilities is revealed when brain activity is included into the equation, thus highlighting the role of brain imaging as intermediate phenotype. Vitamin B12, folate, and homocysteine are implicated in pivotal neurodegenerative mechanisms and partake in elders' mental decline. Findings on the association between vitamin-related biochemistry and cognitive abilities suggest that the structural and functional properties of the brain may represent an intermediate biomarker linking vitamin concentrations to cognition. Despite this, no previous study directly investigated whether vitamin B12, folate, and homocysteine levels are sufficient to explain individual neuropsychological profiles or, alternatively, whether the activity of brain regions modulated by these compounds better predicts cognition in elders. Here, we measured the relationship between vitamin blood concentrations, scores at seventeen neuropsychological tests, and brain activity of sixty-five elders spanning from normal to Mild Cognitive Impairment. We then evaluated whether task-related brain responses represent an intermediate phenotype, providing a better prediction of subjects' neuropsychological scores, as compared to the one obtained considering blood biochemistry only. We found that the hemodynamic activity of the right dorsal anterior cingulate cortex was positively associated (p value < 0 05 cluster corrected) with vitamin B12 concentrations, suggesting that elders with higher B12 levels had a more pronounced recruitment of this salience network region. Crucially, the activity of this area significantly predicted subjects' visual search and attention abilities (p value = 0 0023), whereas B12 levels per se failed to do so. Our results demonstrate that the relationship between blood biochemistry and elders' cognitive abilities is revealed when brain activity is included into the equation, thus highlighting the role of brain imaging as intermediate phenotype.

To develop and validate the Visual Function Classification System (VFCS), which was created to classify how children with cerebral palsy (CP) use visual abilities in daily life.The process of development and validation of the VFCS involved four phases: (1) drafting of the five levels from the analysis of literature and clinical experience; (2) validation of constructs and revision of the levels for concept meaningfulness, using nominal group process; (3) refinement by international Delphi survey; and(4) assessment of interrater reliability among professionals and with caregivers, and of test-retest reliability.Five nominal groups involved 29 participants; 65 people completed the first round and 51 the second round of the Delphi survey. Construct validity was demonstrated within an expert group and external validation through several stakeholders, with the involvement of patients and families to ensure meaningfulness of the concept. Discussions continued until consensus was reached about the construct and content of the five levels. Participants in the reliability study included 29 professionals, 39 parents, and a total sample of 160 children with CP (mean age [SD] 6y 6mo [3y 4mo]; median 5y 7mo, range 1-19y). Absolute interrater agreement among professionals was 86% (weighted κ=0.88; 95% confidence interval [CI] 0.83-0.93). Test-retest reliability was high (weighted κ=0.97; 95% CI 0.95-0.99). Parent-professional interrater reliability on 39 children was moderate (weighted κ=0.51; 95% CI 0.39-0.63).The VFCS has been appropriately constructed and provides a reliable system to classify visual abilities of children with CP both in clinical and in research settings.The Visual Function Classification System is a valid and reliable system. It classifies visual abilities of children with cerebral palsy in clinical and research settings. At a clinical level, it can be used to harmonize communication among professionals and identify patients' strengths and weaknesses. In research settings, it can be used to stratify patients, define natural history evolution, and interpret intervention studies.SISTEMA DE CLASIFICACIÓN DE LA FUNCIÓN VISUAL PARA NIÑOS CON PARÁLISIS CEREBRAL: DESARROLLO Y VALIDACIÓN: OBJETIVO: Desarrollar y validar el Sistema de Clasificación de la Función Visual (VFCS, siglas en inglés), que fue creado para clasificar cómo los niños con parálisis cerebral (PC) usan las habilidades visuales en la vida diaria. MÉTODO: El proceso de desarrollo y validación del VFCS involucró cuatro fases: (1) elaboración de los cinco niveles a partir del análisis de la literatura y la experiencia clínica; (2) la validación de constructos y la revisión de los niveles para el significado de los conceptos, utilizando un proceso de grupo nominal; (3) refinamiento por encuesta internacional de Delphi; (4) evaluación de la confiabilidad entre evaluadores entre profesionales y con los cuidadores, y de confiabilidad de prueba y reevaluación RESULTADOS: Cinco grupos nominales incluyeron 29 participantes; 65 personas completaron la primera ronda y 51 la segunda ronda de la encuesta de Delphi. La validez de constructo se demostró dentro de un grupo de expertos y una validación externa a través de varias partes interesadas, con la participación de los pacientes y las familias para garantizar el significado del concepto. Las discusiones continuaron hasta que se llegó a un consenso sobre el constructo y el contenido de los cinco niveles. Los participantes en el estudio de confiabilidad incluyeron 29 profesionales, 39 padres y una muestra total de 160 niños con PC (edad media [DS] 6 años 6 meses [3 años 4 meses]; mediana 5 años 7 meses, rango 1-19 años). El acuerdo de evaluador absoluto entre profesionales fue del 86% (κ ponderada = 0,88; intervalo de confianza del 95% [IC] 0,83-0,93). La fiabilidad de Test-Retest fue alta (κ ponderada = 0,97; IC del 95%: 0,95 a 0,99). La confiabilidad entre los padres y profesionales entre 39 niños fue moderada (ponderada κ = 0,51; IC del 95%: 0,39 a 0,63). INTERPRETACIÓN: El VFCS se ha construido de manera adecuada y proporciona un sistema confiable para clasificar las habilidades visuales de los niños con PC, tanto en el ámbito clínico como en el de investigación.SISTEMA DE CLASSIFICAÇÃO DA FUNÇÃO VISUAL PARA CRIANÇAS COM PARALISIA CEREBRAL: DESENVOLVIMENTO E VALIDAÇÃO: OBJETIVO: Desenvolver e validar o Sistema de Classificação da Função Visual (SCFV), que foi criado para classificar como crianças com paralisia cerebral (PC) usam capacidades visuais na vida diária. MÉTODO: O processo de desenvolvimento e validação do SCFV envolve quatro fases: (1) rascunho dos cinco níveis a partir da análise da literatura e experiência clínica; (2) validação de construtos e revisão dos níveis de significância dos conceitos, usando processo nominal de grupos; (3) refinamento por meio de levantamento Delphi internacional; (4) avaliação da confiabilidade inter-examinadores entre profissionais e cuidadores, e confiabilidade teste-reteste. RESULTADOS: Cinco grupos nominais envolveram 29 participantes; 65 pessoas completaram a primeira rodada e 51 a segunda rodada do levantamento Delphi. A validade de constructo foi demonstrada em um grupo de especialistas, e a validade externa por meio de vários interessados, com envolvimento de pacientes e famílias para assegurar a significância do conceito. As discussões continuaram até que fosse atingido consenso sobre o constructo e o conteúdo dos cinco níveis. Os participantes no estudo de confiabilidade incluíram 29 profissionais, 39 pais e uma amostra total de 160 crianças com PC (média de idade [DP] 6a 6m [3a 4m]; mediana 5a 7m, variação 1-19a). A confiabilidade inter-examinadores absoluta entre profissionais foi 86% (κ ponderado=0,88; intervalo de confiança [IC] a 95% 0,83-0,93). A confiabilidade teste-reteste foi alta (κ ponderado =0,97; IC 95% 0,95-0,99). A confiabilidade inter-examinadores pais-profissionais em 39 crianças foi moderada (κ ponderado =0,51; IC 95% 0,39-0,63). INTERPRETAÇÃO: O SCFV foi elaborado apropriadamente e é um sistema confiável para classificar as capacidades visuais de crianças com PC em ambientes clínicos e acadêmicos.

Background Movement Disorders - Childhood Rating Scale for age 4-18 (MD-CRS 4-18) is a tool aimed to evaluate movement disorders in developmental age, validated since 2008 and applied in the literature. Psychometric properties, including inter- and intra-reliability and construct validity have been evaluated over time on children and adolescents with different types of movement disorders. Aim The aim of the study is to revise the Movement Disorders - Childhood Rating Scale 4-18 (MD-CRS 4-18 R) and evaluate its psychometric properties, compared to previous version of the scale, in dyskinetic cerebral palsy. Design This is a measurement-focused study of video recorder sessions. Setting Video session carried out inpatient and outpatient. Population This measurement-focused study was carried out on a cohort of 57 participants with DCP (37 males; mean age 9 years and 6 months ±3 years and 8 months) evaluated through video-recorded sessions by experienced scorers using MD-CRS 4-18 and MR-CRS 4-18 R. Methods Inter-rater reliability, intra-rater reliability of MD-CRS 4-18 and MD-CRS 4-18 R were performed. Results This study supports the relevant contribution of MD-CRS 4-18 R to identify the severity of movement disorders in dyskinetic cerebral palsy, as indicated by the higher ICC values on Index II compared to previous MD-CRS 4-18 results. Standard Error Measurement (SEM) and Minimally Detectable Difference (MDD) of MD-CRS 4-18 R in DCP were all very low, with SEMs ranging from 0.01 to 0.02 and MDD from 0.03 to 0.06. Conclusions Data obtained with MD-CRS 4-18 R are in accordance with previous scale on individuals with movement disorders due to different etiologies, tested with MD-CRS 4-18. Clinical rehabilitation impact MD-CRS 4-18 R is able to verify natural history of the disease and represents a standardized clinical outcome measure in the evaluation and follow-up of children with DCP. Also MD-CRS 4-18 Revised form is a feasible tool, now easier to understand than the previous one, more available for incoming clinical trials.

Although the female gender is generally less represented in cardiovascular studies, observational and randomized investigations suggest that-compared with men-women may obtain different benefits from antiplatelet therapy. Multiple factors, including hormonal mechanisms and differences in platelet biology, might contribute to such apparent gender peculiarities. The thrombotic and bleeding risks, as well as outcomes after a cardiovascular event, appear to differ between genders, partly in relation to differences in age, comorbidities and body size. Equally, the benefits of antiplatelet therapy may differ in women compared with men in different vascular beds, during primary or secondary prevention and according to the type of an antiplatelet agent used. This document is an attempt to bring together current evidence, clinical practices and gaps of knowledge on gender-specific platelet function and antiplatelet therapy. On the basis of the available data, we provide suggestions on current indications of antiplatelet therapy for cardiovascular prevention in women with different clinical features; no strong recommendation may be given because the available data derive from observational studies or post hoc/subgroup analyses of randomized studies without systematic adjustments for baseline risk profiles.

Autosomal recessive spastic paraplegia with thinning of corpus callosum (ARHSP-TCC) is a complex form of HSP initially described in Japan but subsequently reported to have a worldwide distribution with a particular high frequency in multiple families from the Mediterranean basin. We recently showed that ARHSP-TCC is commonly associated with mutations in SPG11/KIAA1840 on chromosome 15q. We have now screened a collection of new patients mainly originating from Italy and Brazil, in order to further ascertain the spectrum of mutations in SPG11, enlarge the ethnic origin of SPG11 patients, determine the relative frequency at the level of single Countries (i.e., Italy), and establish whether there is one or more common mutation. In 25 index cases we identified 32 mutations; 22 are novel, including 9 nonsense, 3 small deletions, 4 insertions, 1 in/del, 1 small duplication, 1 missense, 2 splice-site, and for the first time a large genomic rearrangement. This brings the total number of SPG11 mutated patients in the SPATAX collection to 111 cases in 44 families and in 17 isolated cases, from 16 Countries, all assessed using homogeneous clinical criteria. While expanding the spectrum of mutations in SPG11, this larger series also corroborated the notion that even within apparently homogeneous population a molecular diagnosis cannot be achieved without full gene sequencing.

This study was conducted to assess the long-term effect of methylphenidate (MPH) or atomoxetine (ATX) on growth in attention-deficit/hyperactivity disorder (ADHD) drug-naïve children.The study was an observational, post-marketing, fourth phase study.Data on height and weight were collected at baseline and every 6 months up to 24 months.Both ATX and MPH lead to decreased height gain (assessed by means of z-scores); the effect was significantly higher for ATX than for MPH. At any time, height z-score decrease in the ATX group was higher than the corresponding decrease observed in the MPH group, but the difference was significantly relevant only during the first year of treatment. An increment of average weight was observed both in patients treated with MPH and in those treated with ATX. However, using Tanner's percentile, a subset of patients showed a degree of growth lower than expected. This negative effect was significantly higher for ATX than for MPH.We conclude that ADHD drugs show a negative effect on linear growth in children in middle term. Such effect appears more evident for ATX than for MPH.

Objective Magnetic resonance imaging of hepatocellular carcinomas (HCCs) was performed before and after transcatheter arterial chemoembolization (TACE). The changes of tumor signal intensity were compared to residual tumor or tumor recurrence in the follow-up period. Materials and Methods Fifteen cirrhotic patients with HCC were studied. All patients were examined with MRI both before and 3 months after TACE. Requirement for the study was that all lesions were detectable by MR before TACE. Results Magnetic resonance imaging detected 31 tumors. The changes of tumor signal intensity were compared to residual tumor or tumor recurrence in the follow-up period. On T1-weighted (T1W) images before TACE, 16 tumors were hyperintense, 11 were isointense, and 4 were hypointense; on T2W images, 26 tumors were hyperintense, 5 were isointense, and none were hypointense. On T1W images 3 months after TACE, 8 tumors were hyperintense, 18 were isointense, and 9 were hypointense; on T2W images, 11 were hyperintense, 11 were isointense, and 9 were hypointense. All the tumors that became hypointense on T2W images after TACE did not recur on follow-up. All lesions that were still hyperintense on T2W images after TACE showed residual tumor during the follow-up. Among 11 tumors that were isointense on T2W images after TACE, 7 were hyperintense on T2W images before TACE; 6 of these did not recur. Four tumors were isointense on T2W images before and after TACE; 2 of these showed residual tumor in the follow-up. On T2W images after TACE, 15 of 16 HCCs that decreased in signal intensity did not recur on follow-up. On T1W images no correlation was seen between the changes of the signal intensity of the lesion and tumor recurrence in the follow-up; however, 9 of 17 HCCs that did not recur after TACE showed decreased signal intensity. All the tumors (10 of 10) with decreased signal intensity on both T1W and T2W images after TACE did not show tumor recurrence on follow-up. Conclusion The results suggest that MRI is useful in the assessment of the therapeutic effect of TACE in HCC.

Eighteen cirrhotic patients with esophageal varices at risk for bleeding took part in a double-blind study. The variations in PFV induced by either 40 mg of propranolol or 60 mg of sustained-release isosorbide-5-mononitrate on two consecutive days were evaluated with a duplex Doppler device. Both drugs caused a significant decrease in maximum (propranolol, P = 0.002; isosorbide-5-mononitrate, P = 0.021). Four patients responded to propranolol, three to isosorbide-5-mononitrate, and eight to both drugs; three did not show any change. Duplex Doppler sonography may be of use in the selection of the right pharmacologic treatment for the individual patient for the prevention of a bleeding esophageal varix.

Brain magnetic resonance (MR) was performed in 29 liver cirrhosis patients without (N = 10) and with hepatic encephalopathy (HE) of chronic recurrent (N = 10) and of chronic persistent (N = 9) type. Sixty percent of the patients with chronic recurrent HE and 100% of the patients with chronic persistent HE showed a bilateral and symmetrical hyperintensity of the globus pallidus in the T1-weighted images while the T2-weighted images were normal, suggesting the possibility of the accumulation of a paramagnetic compound in this brain area during HE. Other findings of the study were evidence of brain atrophy of mild or moderate degree in 70% of patients with chronic recurrent HE and in 77% with chronic persistent HE and patients with liver cirrhosis without HE appeared normal on MR examination.

The aim of this study was to validate a recent classification of gait in children with the spastic diplegic form of cerebral palsy (CP) by checking the reliability of different scorers in assigning subject walking performance to one of the four specific patterns described in the classification.The gait patterns of 50 children and adolescents with CP (23 males, 27 females; age range 3-17 years) were selected among patients whose videos were stored in the archives of the Pisa and Reggio Emilia Hospitals. Only video recordings of gait with homogeneous features (duration of at least 90 s, simultaneous recordings on sagittal and frontal views, and other criteria) were taken for examination. The videos were blindly scored using an observational gait scale, at first by two of the authors of the classification system (defined as ''maximum experts''), then by ten expert observers, and finally by 206 professionals of rehabilitation after a one-day training on the classification. Cohen's kappa statistics (k) and intra class correlations (ICC) were calculated.Kappa and ICC indicate an almost perfect agreement both between the two maximum experts and among the ten expert observers. Good results were also obtained in the group of one-day trained scorers. Only a few cases were assigned to the ''unclassified'' category. The profession of the observer (doctor or therapist) and previous knowledge of the classification had no significant influence on reliability scores.The results suggest that the proposed classification can be reliably applied, even utilizing short video recordings, to arrange diplegic children into different patterns. Further studies are needed to validate the use of this classification system for clinical and research aims.

BACKGROUND AND PURPOSE: Brain creatine (Cr) deficiencies (BCr-d) are rare disorders of creatine biosynthesis and transport. We performed consecutive measures of total Cr (tCr) and of its phosphorylated fraction, phosphocreatine (PCr), in the brains of children affected by Cr synthesis defects during a long period of therapy. The aim was to identify the optimal treatment strategy for these disorders. MATERIALS AND METHODS: Two patients with guanidinoacetate methyltransferase defect (GAMT-d) were treated with different amounts of Cr and with diet restrictions aimed at reducing endogenous guanidinoacetate (GAA) synthesis. Three patients with arginine:glycine amidinotransferase defect (AGAT-d) were treated with different Cr intakes. The patients’ treatments were monitored by means of (1)H- and (31)P-MR spectroscopy. RESULTS: Cr and PCr replenishment was lower in GAMT-d than in AGAT-d even when GAMT-d therapy was carried out with a very high Cr intake. Cr and especially PCr replenishment became more efficient only when GAA blood values were reduced. Adenosine triphosphate (ATP) was increased in the baseline phosphorous spectrum of GAMT-d, and it returned to a normal value with treatment. Brain pH and brain P(i) showed no significant change in the AGAT-d syndrome and at any Cr intake. However, 1 of the 2 GAMT-d patients manifested a lower brain pH level while consuming the GAA-lowering diet. CONCLUSIONS: AGAT-d treatment needs lower Cr intake than GAMT-d. Cr supplementation in GAMT-d treatment should include diet restrictions aimed at reducing GAA concentration in body fluids. (1)H- and especially (31)P-MR spectroscopy are the ideal tools for monitoring the therapy response to these disorders.

The aim of our study was to assess whether acute variations in portal vein Doppler sonographic parameters induced by administration of a single beta-blocker agent are predictive of the long-term effects of these drugs in the prevention of a first episode of variceal bleeding. In 30 patients with liver cirrhosis at high risk for variceal bleeding, duplex Doppler sonographic parameters (maximal portal flow velocity, portal blood flow, and congestion index) were measured before and 4 h after the administration of 40 mg of propranolol. Twenty-three of these patients started chronic therapy with propanolol and were evaluated periodically (seven patients were excluded because they did not continue the therapy). The percentage of patients free from bleeding was 86.9% at the first year and 77.8% at the second year. Among a series of clinical, laboratory, and instrument-based parameters, the only one related to first bleeding, selected by the Cox regression model, was the percentage decrease in maximal portal flow velocity observed after initial administration of propranolol (P0.01). The best cutoff value for the percentage decrease in portal flow velocity (portal flow velocity test) was 12%. The prevalence of bleeding had been 25% (3 of 12) in patients with positive portal flow velocity test results (12% decrease or more), versus 64% (7 of 11) in patients with negative portal flow velocity test results. The actuarial probability of remaining free from bleeding (Kaplan-Meier analysis) was different in these two groups (log rank P0.01). The portal flow velocity test represents a safe and feasible method to predict the efficacy of beta-blockers in the prevention of a first bleeding episode in patients with cirrhosis. In patients with negative results on the portal flow velocity test, an alternative therapeutic approach should be considered.

Upper gastrointestinal bleeding is a leading cause of death in patients with liver cirrhosis. In most cases haemorrhage originates from oesophageal varices or from congestive gastropathy, and the evaluation of the bleeding risk is based on oesophagogastroduodenoscopic data. The aim of this prospective study was to determine whether the measurement of portal flow velocity by Duplex-Doppler, compared with endoscopic data, can help in detecting patients with cirrhosis at risk of bleeding. One hundred and seventy-three patients underwent endoscopy to ascertain the size of the varices and the severity of congestive gastropathy. For each patient maximal portal flow velocity measurements were obtained. No difference in portal flow velocity was observed between patients with or without oesophageal varices or congestive gastropathy. During a 2-year observation period, 27 patients (15.6%) had at least one episode of acute digestive bleeding. Stepwise multiple logistic regression analysis demonstrated a correlation between oesophageal varices and congestive gastropathy endoscopic grading and the incidence of bleeding; only the former was entered into the final regression equation (p>0.001). No relationship between the max portal flow velocity value and incidence of bleeding was found. This study shows that portal flow velocity is unrelated to the degree of the endoscopic abnormalities in patients with liver cirrhosis and that it has no value in the identification of patients with cirrhosis at risk of upper gastrointestinal bleeding.

In about 50% of patients with liver cirrhosis, upper digestive bleeding is not due to oesaphageal varices rupture, but to a group of peculiar mucosal lesions usually referred as "congestive gastropathy" and "hepatogenic ulcer". The pathogenesis of such mucosal damage is still unclear: an important causative role is commonly thought to be played by portal hypertension, but the role of peptical pathway and of the mucosal barrier impairment must not be underscored as well. Aim of this study was to evaluate the effect of roxatidine in the long-term treatment of mucosal damage in 19 patients with liver cirrhosis. Patients showed a good tolerance and no side effects. The improvement of endoscopic pattern after a three months period of roxatidine therapy was statistically significant; moreover there was no occurrence of digestive bleeding. In conclusion, H2 antagonist may be considered as the drug of choice for the treatment of mucosal damage in patients with liver cirrhosis, for both its safety and effectiveness.

Twenty-five liver cirrhosis patients with endoscopically demonstrated gastro-duodenal mucosal damage (microhemorrhages, erosions, ulcers) were treated with misoprostol (prostaglandin E1) 400 mg/die. Eleven patients (44%) had abdominal pain and diarrhea and stopped treatment. Three months later, a new endoscopy was performed in the 11 patients that completed the study (3 patients were lost at follow up). Mucosal damage was stable in 5 patients (45%) and improved in 6 patients (55%), with complete absence of mucosal lesions in 2 patients (P = 0.027, Wilcoxon Ranks test). No case of worsening was observed and no patient had digestive bleeding during treatment. Digestive bleeding is a common complication of liver cirrhosis, originating in about 50% of cases from gastro-duodenal mucosal damage. Misoprostol suggests itself as a possible alternative therapy to the drugs usually utilized in these lesions (beta-blockers, H2-inhibitors), but individual intolerance is frequent and must be preliminary excluded.

To assess the utility of Duplex-Doppler ultrasonography (DDUS) in the evaluation of portal haemodynamics we studied 52 patients with compensated liver cirrhosis (mean age 53.9 ± 9.2 years, males 32, females 20) diagnosed by laparoscopy and biopsy. All patients underwent laparoscopy and oesophageal-gastro-duodenoscopy (OGDS): we postulated that haemodynamically significant portal hypertension (PH) was present if varices were detected at OGDS and/or if collateral veins were revealed at laparoscopy. DDUS was performed with a strictly standardized method and maximum portal flow velocity (PFV) was measured in all patients. Max-PFV ranged between 3.5 and 33.4 cm/s. Overall, 36 patients (69%) had a max-PFV lower than 20.3 cm/s (normal max-PFV range in our laboratory is 20.3–33.3 cm/s), while 16 patients (31%) had normal max-PFV values. Five patients (9.6%) had no signs of PH at laparoscopy and/or OGDS and all five had normal max-PFV values. The other 47 patients (90.4%) had collateral circuli at laparoscopy and 2947 (61.7%) exhibited also varices at OGDS: max-PFV was lower than 20.3 cm/s in 3647 patients (76.6%). The measurement of max-PFV demonstrated a 76.6% sensitivity and a 100% specificity in detecting PH, with 100% positive predictive value and 31% negative predictive value. Three patients with PH and apparently normal max-PFV values exhibited a recanalization of the umbilical vein. In conclusion, in cirrhotic patients: (1) a low max-PFV can be considered a sure sign of PH; (2) a normal max-PFV is less probative and may be interpreted in different ways: either (a) portal pressure is really normal or (b) portal pressure is high but collateral circuli originate distally from the sampling volume or (c) a hyperdynamic component exists.

Sixteen patients (15 males, aged 48–70) affected by liver cirrhosis and oesophageal varices were subjected to duplex-Doppler ultrasonographic study (DDUS). Four patients (three with a portal thrombosis and one with a hepatofugal portal flow) were excluded from the subsequent pharmacological test. The twelve remaining patients took part in a double blind cross-over study that evaluated the variations of heart rate (HR), mean systemic arterial pressure (SAP), portal vein diameter (PVD), maximal and mean portal flow velocity (PFV) after the administration of either 40 mg of propranolol or placebo per os, on two consecutive days. Propranolol caused no significant variation in mean SAP and in PVD, whereas it reduced the HR from 67.7±8.0 to 58.4±7.0 beats/min (mean±s.d.; P

Portal venous flow velocity (PFV) was measured with duplex-Doppler equipment in 50 normal subjects and in 117 patients with suspected chronic liver disease who showed no evidence of decompensation such as ascites, hepatic encephalopathy, jaundice or oesophageal bleeding. All the patients underwent percutaneous liver biopsy which demonstrated non-cirrhotic liver disease in 58 cases (CH-patients: steatosis 8, persistent chronic hepatitis 8, active chronic hepatitis 42) and liver cirrhosis in the other 59 cases (LC-patients). The normal subjects and the CH-patients had similar values of max-PFV and mean-PFV (max-PFV 26.7 +/- 3.2 and 25.7 +/- 3.4 cm/s respectively; mean-PFV 22.9 +/- 2.8 and 22.4 +/- 3.8 cm/s respectively). The LC-patients' values (max-PFV 19.3 +/- 3.5; mean-PFV 16.9 +/- 2.9) were significantly lower than those of the normal subjects (P less than 0.001) and of the CH-patients (P less than 0.001). Considering the normal max-PFV to be in the range 20-33.1 cm/s (mean +/- 2 s.d. of the normal subjects, 95% confidence limits), max-PFV was reduced in 0/50 normal subjects, 1/58 CH-patients and 39/59 LC-patients (66.1% sensitivity; 98.2% specificity). In conclusion, the duplex-Doppler measurement of PFV is of great interest in the diagnostic study of patients with suspected chronic compensated liver disease and in the early diagnosis of cirrhosis. A low max-PFV is a reliable pointer to liver cirrhosis, whereas a normal max-PFV indicates a non-cirrhotic liver disease but is less probative. Each centre should standardize normal PFV values in order to establish their own threshold value for diagnosing liver cirrhosis.

In patients with liver cirrhosis, especially in the advanced stage, the coexistence of low clotting factor levels, hypofibrinogenemia, thrombocytopenia and elevated fibrin(ogen) degradation product (FDP) and D-dimer levels may suggest the presence of disseminated intravascular coagulation (DIC). In this study we evaluated, in 21 patients with decompensated liver cirrhosis and elevated FDP and D-dimer levels, the time sequence of their coagulation data during a follow-up period of 15 days after the first observation; our aim was to clarify if these patients tend to develop during this time interval a severe consumption coagulopathy as an expression of overt DIC. We evaluated serum fibrinogen, platelet count, prothrombin activity, serum FDP and plasma D-dimer levels at days 1, 3, 6, 10 and 15. The coagulation data were fairly stable during the study period in all patients, even in the two patients who had upper digestive tract bleeding during the study time. Only two patients affected by infectious diseases showed a decrease of D-dimer and FDP levels after healing. Our data suggest that in decompensated liver cirrhosis the detection of elevated FDP and D-dimer levels is seldom related to the occurrence of an overt DIC, at least during a short time interval; in this condition heparin therapy seems therefore not advisable and even potentially dangerous.

Fibrin(ogen) degradation product (FDP) and D-dimer levels were evaluated in 168 liver cirrhosis (LC) patients without evidence of bleeding. Eighty-two (48%) had FDP higher than 10 micrograms/ml; only 43 of them had a concomitant increase of D-dimer. These alterations were more frequent in older and decompensated patients and correlated to the Child-Turcotte score. In the patients with elevated FDP and/or D-dimer levels the mean values of platelets, prothrombin activity and fibrinogen were not significantly different from those of the other patients and remained fairly stable over the period of the study. Finally, an increase of FDP is frequent in LC and this may suggest a diagnosis of disseminated intravascular coagulation (DIC), but a concomitant increase of D-dimer is rarely detectable, thus excluding this diagnosis. Moreover, even in the cases with increased levels of D-dimer the presence of clinical or laboratory evidence of a consumption coagulopathy, expression of a manifest DIC, seems to be unusual.

The recent development of the duplex-Doppler technique, which combined real-time US with pulsed Doppler flowmetry, has allowed the flowmetric hemodynamic study of large abdominal vessels. As yet, however, both accuracy and possible applications of this method in the study of portal hypertension have not been fully investigated. This study was aimed at assessing whether or not the combined use of Doppler flowmetry and bidimensional US is able to detect portal hypertension in patients with liver cirrhosis (LC), and could therefore represent a valid alternative to endoscopic, angiographic, and direct pressure measurement techniques. Twenty-six patients with LC and 25 control patients were studied with a strictly standardized method; portal hypertension was detected in the patients with LC by EGDS and laparoscopy. The results demonstrated pulsed duplex-Doppler US to be able to detect portal hypertension in 92.4% of LC patients, with 2 false negatives only (7.6%). The difference in the flowmetric data of normal and LC patients was highly significant (p less than 0.001 Student's t test). In conclusion, duplex-Doppler US can be considered as a valid technique to detect portal hypertension in LC patients, and can thus be used as an alternative to more invasive techniques of general use in clinics.

Glucose intolerance often occurs in liver cirrhosis; therefore a long-term control of plasma glucose levels appears to be important. For this purpose glycated hemoglobin A (HbA1c) determination is proposed as a suitable method, while no data are available on fructosamine test. In 98 cirrhotic patients serum fructosamine and HbA1c levels were compared with those of normal controls and among cirrhotic patients grouped in non glucose-intolerant and with non insulin-dependent (NIDDM) or insulin-dependent diabetes mellitus (IDDM). The mean HbA1c values of cirrhotic patients with normal glycemic control were significantly lower than normal, and only a few IDDM and NIDDM cirrhotic patients showed high values of HbA1c, indicating that HbA1c is often underestimated in these patients. On the contrary, serum fructosamine levels were on the average higher than normal in nondiabetic patients, but they were significantly higher in IDDM and NIDDM patients than in nondiabetics, and the 72% of NIDDM and 85% of IDDM patients had fructosamine levels higher than the upper normal value. In conclusion, in diabetic patients with liver cirrhosis fructosamine seems to be a more suitable test than HbA1c for monitoring blood glucose levels.

Background Clostridium difficile (CD) is a leading cause of diarrhoea among hospitalized patients. The objective of this study was to evaluate the rate, the optimal diagnostic work-up, and outcome of CD infections (CDI) in Internal Medicine (IM) wards in Italy. Methods PRACTICE is an observational prospective study, involving 40 IM Units and evaluating all consecutive patients hospitalized during a 4-month period. CDI were defined in case of diarrhoea when both enzyme immunoassay for GDH, and test for A/B toxin were positive. Patients with CDI were followed-up for recurrences for 4 weeks after the end of therapy. Results Among the 10,780 patients observed, 103 (0.96 %) showed CDI, at admission or during hospitalization. A positive history for CD, antibiotics in the previous 4 weeks, recent hospitalization, female gender and age were significantly associated with CDI (multivariable analysis). In-hospital mortality was 16.5 % in CD group vs 6.7 % in No-CD group (p

General movements (GMs) are a distinct movement pattern carried out spontaneously without external stimulation and seen in fetuses of 9 weeks gestational age till 21 weeks postterm. GMs are helpful in the early diagnosis of an impaired central nervous system and the specific prediction of later neurological deficits. Autism spectrum disorder (ASD) is a neurodevelopmental disorder involving a life-long deficit in several aspects of the social and communicative behavior. Recently there appeared studies proving that children with ASD demonstrate disorders of motor development. To detect whether abnormalities in spontaneous motor activity can be observed already in the first months of life in infants with ASD. A retrospective study was performed by analyzing the family videos provided by parents of 20 children (male 17, female 3) later diagnosed as ASD. Home videos provided by parents of a control group of healthy children (n=20; male 10, female 10) matched for age with the ASD subjects and recorded in similar conditions were also analysed. In total 70 sequences were studied. Two independent observers, blind of the infants' outcome (ASD or normal), assessed the cases applying a global and a more detailed assessment of GMs. Hence, the age-specific GM pattern (normal or abnormal) as well as motor optimality scores were determined for each video sequence. Cohen kappa was 0.614. During the writhing movement period 70.0% sequences of infants with ASD showed poor repertoire GMs. In the control group, poor repertoire GMs were only seen in 12.5% of the sequences. In the fidgety movement period 20.8% of sequences were assessed as absent fidgety movements, 29.2% as abnormal fidgety movements. The large majority of the videos for the control cases were scored as normal (88.9%), 11.1% had no fidgety movements. According to the Mann-Whitney U test there were significant differences between the ASD and the control groups' optimality scores. The optimality scores were lower in the ASD group. The reduced optimality scores were mainly due to a lack of variable sequences, amplitude and speed of writhing GMs and an altered quality of fidgety and other spontaneous movements in the ASD group. Infants with ASD had more often poor repertoire writhing GMs as well as abnormal or absent fidgety movements than control infants. These data encourage further studies involving a larger number of family videos.

Neuroimaging literature on phonological processing during reading lacks of studies taking into account orthographic differences across languages and behavioural variability across subjects. The present study aimed at investigating brain representation of phonological processing in reading Italian, a language with regular orthography, with particular regard to inter-individual variability and brain-behavioural correlates. Ten Italian adults performed a rhyme generation and a rhyme judgment task during fMRI acquisition and were tested with behavioural measures of phonological processing. Results for both tasks showed activations of the left Inferior Frontal Gyrus and Dorsolateral Prefrontal Cortex, likely underlying output sublexical strategies, for all or most of the subjects, while a minority of subjects activated the Superior Temporal Sulcus and the Temporo-Parietal-Occipital Junction. These results suggest that phonological processing of written Italian is based on the prevalent use of frontal structures. However, it is of interest that the activation of the Superior Temporal Sulcus, involved in phonological input, was associated to better behavioural performances in tasks of phonological processing. Our findings may contribute to understand neural correlates of phonological processing of languages with regular orthography.

BACKGROUND AND PURPOSE: Proton (hydrogen-1 [(1)H]) MR spectroscopy is a useful diagnostic tool in many metabolic diseases, but only scattered and inconclusive data are available on mitochondrial diseases. We performed MR imaging and (1)H MR spectroscopy of the brain in patients with different types of primary mitochondrial diseases to investigate the role of (1)H MR spectroscopy in the clinical evaluation of these disorders. METHODS: In 15 patients (11 adults, four children) with mitochondrial diseases, localized MR spectra were obtained at short TEs in cerebellar white matter, paratrigonal white matter, and parieto-occipital cortex that appeared normal on MR images. Additional spectra of basal ganglia and cortical gray matter structural lesions were obtained in three patients. RESULTS: A significant choline reduction and N-acetylaspartate reduction were found in areas that appeared normal on MR images. Lactate was never found in areas that appeared normal on MR images, except in two children in whom MR studies were performed during episodes of symptom exacerbation and revealed elevated lactate both in areas that appeared damaged on MR images and in normal-appearing areas. An additional abnormal signal at 0.9 ppm was found in a consistent number of studies. CONCLUSION: (1)H MR spectroscopy proved to be a useful investigational tool for mitochondrial diseases, as it enabled detection of metabolic abnormalities even in areas of brain that appeared normal on MR images, especially when it was performed during episodes of clinical relapses or clinical exacerbation.

Object recognition is a complex adaptive process that can be impaired in children with neurodevelopmental disabilities. Recently, we found a significant effect of time on the development of unimodal and crossmodal recognition skills for common objects in typical children and this was a starting point for the study of visuo-haptic object recognition skills in impaired populations. In this study, we investigated unimodal visual information, unimodal haptic information and visuo-haptic information transfer in 30 children, from 4.0 to 10.11years of age, with bilateral Periventricular Leukomalacia (PVL) and bilateral cerebral palsy. Results were matched with those of 116 controls. Participants were tested using a clinical protocol, adopted in the previous study, involving visual exploration of black-and-white photographs of common objects, haptic exploration of real objects and visuo-haptic transfer of these two types of information. Results show that in the PVL group as in controls, there is an age-dependent development of object recognition abilities for visual, haptic and visuo-haptic modalities, even if PVL children perform worse in all the three conditions, in comparison with the typical group. Furthermore, PVL children have a specific deficit both in visual and haptic information processing, that improves with age, probably thanks to everyday experience, but the visual modality shows a better and more rapid maturation, remaining more salient compared to the haptic one. However, multisensory processes partially facilitate recognition of common objects also in PVL children and this finding could be useful for planning early intervention in children with brain lesion.

Transcranial Direct Current Stimulation (tDCS) is an emerging tool to improve upper limb motor functions after stroke acquired in adulthood; however, there is a paucity of reports on its efficacy for upper limb motor rehabilitation in congenital or early-acquired stroke. In this pilot study we have explored, for the first time, the immediate effects, and their short-term persistence, of a single application of anodal tDCS on chronic upper limb motor disorders in children and young individuals with Unilateral Cerebral Palsy (UCP). To this aim, in a crossover sham-controlled study, eight subjects aged 10-28 years with UCP underwent two sessions of active and sham tDCS. Anodal tDCS (1.5 mA, 20 min) was delivered over the primary motor cortex (M1) of the ipsilesional hemisphere. Results showed, only following the active stimulation, an immediate improvement in unimanual gross motor dexterity of hemiplegic, but not of nonhemiplegic, hand in Box and Block test (BBT). Such improvement remained stable for at least 90 minutes. Performance of both hands in Hand Grip Strength test was not modified by anodal tDCS. Improvement in BBT was unrelated to participants’ age or lesion size, as revealed by MRI data analysis. No serious adverse effects occurred after tDCS; some mild and transient side effects (e.g., headache, tingling, and itchiness) were reported in a limited number of cases. This study provides an innovative contribution to scientific literature on the efficacy and safety of anodal tDCS in UCP. This trial is registered with NCT03137940.

Background Children with Down Syndrome (DS) have a high prevalence of ocular disorders, and even when ophthalmological deficits (i.e. refractive errors or strabismus) are corrected, visual acuity seems to have a different developmental trend compared to typical children. Unfortunately, there is no consensus about the age at which it is fundamental to perform a first comprehensive visual assessment in this population. Aims We analyzed early visual functions in a sample of 42 Italian children with DS, in order to achieve new insights for early surveillance and intervention. Material and methods DS children were evaluated with the Early Neurovisual Assessment, including Teller Acuity Cards (at 6, 12 and 18 months of age) and the Pediatric Ophthalmological Examination (within the 36th months of age). Results Visual acuity in our sample was lower than findings reported in the literature on healthy Italian children, but the values were within the confidence interval reported in previous studies on DS children. Moderate or severe refractive errors (> 3diopters) were present in five children (four had hyperopia and one myopia). Abnormalities in ocular motility were observed in 15 children and pathological findings for fundus oculi or lens were found in another eight. Furthermore, ophthalmological findings correlated with visual acuity at 18 months of age. Conclusion According to our results, the Early Neurovisual Assessment at 18 months of life is a reliable tool for early detection of visual disorders in children with DS and it is useful for programming early intervention to promote their neurodevelopment.

OBJECTIVE: An increased cardiovascular mortality and morbidity has been widely reported in patients with atrial fibrillation (AF). In this study, a subanalysis of the AntiThrombotic Agents Atrial Fibrillation (ATA‐AF) is performed with the aim to evaluate estimated glomerular filtration rate (eGFR) as an independent prognostic marker of cardiovascular mortality and morbidity in patients with AF. METHODS AND RESULTS: The ATA‐AF study enrolled 7148 patients with AF, in 360 Italian centers. The eGFR was calculated from data reported in patient notes or hospital database. This post‐hoc analysis included 1097 AF patients with eGFR data available and 1‐year clinical follow‐up. The endpoint was assessed as cardiovascular mortality and/or hospital admission for cardiovascular causes at follow‐up. Patients were also divided in two groups according to the eGFR (

Results obtained in both animal models and hemianopic patients indicate that sound, spatially and temporally coincident with a visual stimulus, can improve visual perception in the blind hemifield, probably due to activation of ‘multisensory neurons’, mainly located in the superior colliculus. In view of this evidence, a new rehabilitation approach, based on audiovisual stimulation of visual field, has been proposed, and applied in adults with visual field reduction due to unilateral brain lesions. So far, results have been very encouraging, with improvements in visual search abilities. Based on these findings, we have investigated the possibility of inducing long-lasting amelioration also in children with a visual deficit due to acquired brain lesions. Our results suggest that, in the absence of spontaneous recovery, audiovisual training can induce activation of visual responsiveness of the oculomotor system also in children and adolescents with acquired lesions and confirm the putatively important role of the superior colliculus (SC) in this process.

Background Down syndrome is a frequent cause of intellectual disability, with severe impact on the quality of life of affected individuals and their families, and high social costs. Intervention programs should start soon after birth but no consensus exists on specific types and timing of early interventions in this population. Aim This pilot study explores the effects of an early multi-sensory intervention, based on body massage, on the development of visual function in infants with Down syndrome. Method Infants were randomly allocated to either a massage or a control group. Intervention consisted of only standard care (Control Group) or standard care plus infant massage (Massaged Group). Visual acuity was assessed by Teller Acuity Cards and stereopsis by the Frisby Stereopsis Screening Test at 5, 6, 9 and 12 months. Results Massaged Group Infants showed a significantly higher visual acuity at 6 months of age and an accelerated development up to at least 12 months; compared to Controls, stereopsis had an earlier onset in the Massaged Group followed by a faster maturation. Conclusion Environmental enrichment, in the tested form of infant massage, seems to affect maturation of visual functions in human infants, also in the presence of a genetic disability, when applied during a period of high brain plasticity.

Object recognition is a long and complex adaptive process and its full maturation requires combination of many different sensory experiences as well as cognitive abilities to manipulate previous experiences in order to develop new percepts and subsequently to learn from the environment. It is well recognized that the transfer of visual and haptic information facilitates object recognition in adults, but less is known about development of this ability. In this study, we explored the developmental course of object recognition capacity in children using unimodal visual information, unimodal haptic information, and visuo-haptic information transfer in children from 4 years to 10 years and 11 months of age. Participants were tested through a clinical protocol, involving visual exploration of black-and-white photographs of common objects, haptic exploration of real objects, and visuo-haptic transfer of these two types of information. Results show an age-dependent development of object recognition abilities for visual, haptic, and visuo-haptic modalities. A significant effect of time on development of unimodal and crossmodal recognition skills was found. Moreover, our data suggest that multisensory processes for common object recognition are active at 4 years of age. They facilitate recognition of common objects, and, although not fully mature, are significant in adaptive behavior from the first years of age. The study of typical development of visuo-haptic processes in childhood is a starting point for future studies regarding object recognition in impaired populations.

The study aimed to evaluate the development of awakenings during preterm and term age in 12 low-risk infants observed between 33 and 40 weeks of post-conceptional age. Waking was been detected through the analysis of body motility. Gross generalized body movements with prolonged startles, marked stretching and writhing was considered as waking, whereas vigorous, forceful abrupt body movements with high frequency tremor sometimes superimposed upon movements were considered as corresponding to crying. Total number of awakenings in the 24 h does not show significant changes with age, whereas the mean duration increases significantly, which is accounted for mainly by those awakenings starting with crying, in particular, during the day. These data suggest a developmental gap between the ability to sustain the waking state, which already starts to increase before term age, and the ability to maintain prolonged sleep episodes, which has been shown to develop later. Furthermore, the developmental difference between awakenings starting with crying and awakenings starting with wakefulness suggests that two kinds of awakenings might be modulated by different factors.

Background. Visual search refers to the capacity of an individual to find a target among simultaneously presented distracters and is based on visual abilities such as a fast visual processing and an accurate control of ballistic eye movements (saccades) that guide the fovea to the target location. Objective. In adults, visual field defects caused by brain damage are often associated with visual search disorders; in children, little is known about the effects of early brain lesions on visual search abilities. Methods. To test the presence of visual search defects and to investigate the role of cortical plasticity after early brain lesions, 29 children with congenital or acquired cerebral lesions, with and without visual field defects, underwent a visual search test battery. Results. The children with acquired lesions and visual field defects had longer reaction times (RTs) in the contralesional visual field compared with the ipsilesional, whereas those with congenital lesions and visual field defects did not have differences in RTs between the contralateral and ipsilateral visual fields and had a visual search pattern similar to children without a visual field defect. Conclusions. These findings support the hypothesis of more effective mechanisms of functional compensation and reorganization of the visual system in children with very early brain lesions, as opposed to those with later damage.