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In healthy women, the cervicovaginal microbiota is characterized by the predominance of

Cyclic GMP–phosphodiesterase type 5 (PDE5) inhibition has been shown to counteract maladaptive cardiac changes triggered by diabetes in some but not all studies. We performed a single-center, 20-week, double-blind, randomized, placebo-controlled trial (NCT01803828) to assess sex differences in cardiac remodeling after PDE5 inhibition in patients with diabetic cardiomyopathy. A total of 122 men and women (45 to 80 years) with long-duration (>3 years) and well-controlled type 2 diabetes mellitus (T2DM; HbA1c < 86 mmol/mol) were selected according to echocardiographic signs of cardiac remodeling. Patients were randomly assigned (1:1) to placebo or oral tadalafil (20 mg, once daily). The primary outcome was to evaluate sex differences in cardiac torsion change. Secondary outcomes were changes in cardiovascular, metabolic, immune, and renal function. At 20 weeks, the treatment-by-sex interaction documented an improvement in cardiac torsion (−3.40°, −5.96; −0.84, P = 0.011) and fiber shortening (−1.19%, −2.24; −0.14, P = 0.027) in men but not women. The primary outcome could not be explained by differences in cGMP concentrations or tadalafil pharmacodynamics. In both sexes, tadalafil improved hsa-miR-199-5p expression, biomarkers of cardiovascular remodeling, albuminuria, renal artery resistive index, and circulating Klotho concentrations. Immune cell profiling revealed an improvement in low-grade chronic inflammation: Classic CD14 ++ CD16 − monocytes reduced, and Tie2 + monocytes increased. Nine patients (14.5%) had minor adverse reactions after tadalafil administration. Continuous PDE5 inhibition could offer a strategy to target cardiorenal complications of T2DM, with sex- and tissue-specific responses. Further studies are needed to confirm Klotho and hsa-miR-199-5p as markers for T2DM complications.

In healthy women, the cervicovaginal microbiota is characterized by the predominance of Lactobacillus spp., whereas the overgrowth of anaerobic bacteria leads to dysbiosis, known to increase the risk of acquiring genital infections like Chlamydia trachomatis. In the last decade, a growing body of research has investigated the composition of the cervicovaginal microbiota associated with chlamydial infection via 16s rDNA sequencing, with contrasting results. A systematic review and a meta-analysis, performed on the alpha-diversity indices, were conducted to summarize the scientific evidence on the cervicovaginal microbiota composition in C. trachomatis infection. Databases PubMed, Scopus and Web of Science were searched with the following strategy: “Chlamydia trachomatis” AND “micro*”. The diversity indices considered for the meta-analysis were Operational Taxonomic Unit (OTU) number, Chao1, phylogenetic diversity whole tree, Shannon’s, Pielou’s and Simpson’s diversity indexes. The search yielded 425 abstracts for initial review, of which 16 met the inclusion criteria. The results suggested that the cervicovaginal microbiota in C. trachomatis-positive women was characterized by Lactobacillus iners dominance, or by a diverse mix of facultative or strict anaerobes. The meta-analysis, instead, did not show any difference in the microbial biodiversity between Chlamydia-positive and healthy women. Additional research is clearly required to deepen our knowledge on the interplay between the resident microflora and C. trachomatis in the genital microenvironment.

Parent-mediated intervention is widely used for pre-schoolers with autism spectrum disorder (ASD). Previous studies indicate small-to-moderate effects on social communication skills, but with a wide heterogeneity that requires further research. In this randomized controlled trial (RCT), cooperative parent-mediated therapy (CPMT) an individual parent coaching program for young children with ASD was administered to preschool children with ASD. All children received the same low-intensity psychosocial intervention (LPI) delivered in community settings, to evaluate the potential additional benefit of CPMT. Thirty-four participants with ASD (7 females; 27 males; aged 2, 6, 11 years) and their parents were included in the trial. The primary blinded outcome was social communication skills, assessed using the ADOS-G social communication algorithm score (ADOS-G SC). Secondary outcomes included ASD symptom severity, parent-rated language abilities and emotional/behavioral problems, and self-reported caregiver stress. Evaluations were made at baseline and post-treatment (at 6 months) by an independent multidisciplinary team. Results documented that CPMT showed an additional benefit on LPI with significant improvements of the primary blinded outcome, socio-communication skills, and of some secondary outcomes such as ASD symptom severity, emotional problems and parental stress related to parent–child dysfunctional interaction. No additional benefit was found for language abilities. Findings of our RCT show that CPMT provide an additional significant short-term treatment benefit on ASD core symptoms, when compared with active control group receiving only LPI.

Aims: Several drug classes are now available to achieve a satisfactory metabolic control in patients with type 2 diabetes (T2DM), but patients’ preferences may differ. Methods: In a discrete-choice experiment, we tested T2DM patients’ preferences for recent antidiabetic drugs, in the event that their treatment might require intensification. The following attributes were considered: (a) route of administration; (b) type of delivery; (c) timing; (d) risk of adverse events; (e) effects on body weight. Twenty-two possible scenarios were built, transferred into 192 paired choices and proposed to 491 cases naïve to injectable treatments and 171 treated by GLP-1 receptor agonists (GLP-1RAs). Analyses were performed by descriptive statistics and random effects logit regression model. Results: Preferences according to dosing frequency, risk of nausea and urinary tract infections (UTls) were similar across groups, age, sex and BMI. Administration route and delivery type accounted for 1/3 of relative importance; the risk of UTIs, nausea and dosing frequency for ≈ 20% each, and weight loss for only 6%. Two significant interactions emerged (p < 0.01): type of delivery × group, and weight change × BMI class. Irrespective of previous treatment, the three preferred choices were injectable, coupled with weekly dosing and a ready-to-use device (first two choices). In a regression model, being naïve or non-naïve changed the ranking of preferences (p < 0.001), and the order was systematically shifted towards injectable medications in non-naïve subjects. Conclusion: Easy-to-deliver, injectable treatment is preferred in T2DM, independently of treatment history, and previous experience with GLP-1RAs strengthens patients’ willingness to accept injectable drugs.

Introduction Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, skeletal and haematological/lymphatic defects, distinctive facies, cryptorchidism, and a wide spectrum of congenital heart defects. Recurrent features also include variable cognitive deficits and behavioural problems. Recent research has been focused on the assessment of prevalence, age of onset and characterization of psychiatric features in this disorder. Herein, we evaluated the prevalence of attention deficit and hyperactivity disorder (ADHD), anxiety and depressive symptoms and syndromes in a cohort of individuals with clinical and molecular diagnosis of NS. Methods The Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children Present and Lifetime version (K-SADS PL) has been used for the assessment of psychiatric disorders according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Multidimensional Anxiety Scale for Children (MASC) and the Children's Depression Inventory (CDI) have been assessed for the evaluation of anxiety and depressive symptoms and syndromes, whereas Conners Teacher and Parent Rating Scales-long version (CRS-R) have been used to evaluate ADHD. Results The study included 27 individuals (67% males) with an average age of 10.4 years (range 6–18 years) receiving molecular diagnosis of NS or a clinically related condition, evaluated and treated at the Neuropsychiatric Unit of Children's Hospital Bambino Gesu and at the Center for Rare Diseases of Fondazione Policlinico Universitario Agostino Gemelli, in Rome. Twenty individuals showed mutations in PTPN11, five in SOS1 and two in SHOC2. The mean IQ was 94 (Standard Deviation = 17, min = 56, max = 130). Seventy percent of the individuals (n = 19; 95% Confidence Interval = 52–85%) showed ADHD features, with six individuals reaching DSM-IV-TR criteria for ADHD disorder, and thirteen showing subsyndromal traits. Symptoms or syndrome of anxiety were present in 37% of the cohort (n = 10; 95% Confidence Interval = 19–56%), with two individuals showing anxiety disorder and eight cases exhibiting subsyndromal traits. Conclusion Our results show individuals with NS do present a very high risk to develop psychiatric disorders or symptoms during paediatric age. Based on these findings, preschool assessment of inattentive, hyperactivity/impulsivity and anxiety/depressive symptoms is recommended in order to plan a personalized treatment for psychological/psychiatric issues in affected individuals. Dedicated prospective studies are required to confirm the present data and better characterize the psychopathological profile in NS.

Social and occupational impairments are present in the schizophrenia prodrome, and poor social functioning predicts transition to psychosis in Ultra-High Risk (UHR) individuals. We aimed to: 1) validate the Italian version of the Global Functioning: Social (GF: S) and Global Functioning: Role (GF: S) scales; 2) evaluate their association with UHR criteria. Participants were 12-21-years-old (age, mean=15.2, standard deviation=2.1, male/female ratio=117/120) nonpsychotic help-seekers, meeting (N=39) or not (N=198) UHR criteria. Inter-rater reliability was excellent for both scales, which also showed good to excellent concurrent validity, as measured by correlation with Global Assessment of Functioning (GAF) scores. Furthermore, GF:S and GF: R were able to discriminate between UHRs and non-UHRs, with UHRs having lower current scores. After adjusting for current GAF scores, only current GF:S scores independently differentiated UHR from non-UHR (OR=1.33, 95%CI: 1.02-1.75, p=0.033). Finally, UHR participants showed a steeper decrease from highest GF:S and GF: R scores in the past year to their respective current scores, but not from highest past year GAF scores to current scores. GF:S/GS: R scores were not affected by age or sex. GF:S/GF: R are useful functional level and outcome measures, having the advantage over the GAF to not confound functioning with symptom severity. Additionally, the GF:S may be helpful in identifying UHR individuals.

Background: White matter hyperintensities (WMH) are a common finding in aged individuals affected by carotid artery disease and are a risk factor for first-ever and recurrent stroke. We investigated if white matter damage increases the risk of brain microembolism during carotid artery stenting (CAS), as evaluated by the appearance of new areas of restricted diffusion on diffusion-weighted images (DWI). Methods: We evaluated 47 patients with severe internal carotid artery (ICA) stenosis undergoing CAS, comparing preprocedural clinical, ultrasound and radiological characteristics. WMH volume was computed on FLAIR images before CAS. After CAS, the DWI scan was looked over for areas of restricted diffusion (DWI lesions). A first univariate analysis was adopted to compare groups according to the occurrence of DWI lesions. Then, the variable DWI lesion was modelled by means of a logistic regression model. Results: Seventeen patients developed at least 1 DWI lesion after CAS. Compared with non-DWI, DWI patients were more commonly treated in the left ICA (p = 0.007) and had a more severe WMH damage (p = 0.027). Indeed, the risk of a DWI lesion was higher in left versus right stenosis (OR = 9.0, 95% CI 1.9-42.7, p = 0.005) and increased for each log-unit of WMH lesion load (OR = 7.05, 95% CI 1.07-46.49, p = 0.042). A WMH lesion load of at least 5.25 cm3 had a 50% probability of occurrence of a new DWI lesion. Conclusions: Treated side and preexisting white matter damage are risk conditions for brain microembolism during CAS. This should be taken into account to optimize severe carotid artery disease management.

Cognitive dysfunction affects 40–65% of multiple sclerosis (MS) patients and can occur in the early stages of the disease. This study aimed to explore cognitive functions by means of the Italian version of the minimal assessment of cognitive function in MS (MACFIMS) in relapsing-remitting MS (RRMS) patients with very mild clinical disability to identify the primarily involved cognitive functions. Ninety-two consecutive RRMS patients with Expanded Disability Status Scale (EDSS) scores ≤ 2.5 and forty-two healthy controls (HC) were investigated. Our results show that 51.1% of MS patients have cognitive dysfunction compared to HC. An impairment of verbal and visual memory, working memory, and executive functions was found in the RRMS group. After subgrouping RRMS by EDSS, group 1 (EDSS ≤ 1.5) showed involvement of verbal memory and executive functions; moreover, group 2 (2 ≤ EDSS ≤ 2.5) patients were also impaired in information processing speed and visual memory. Our results show that utilizing a comprehensive neuropsychological assessment, approximately half of MS patients with very mild physical disability exhibit cognitive impairment with a primary involvement of prefrontal cognitive functions. Detecting impairment of executive functions at an early clinical stage of disease could be useful to promptly enroll MS patients in targeted rehabilitation.

OBJECTIVE To clarify whether the clinical response after the first 2 cycles with Onabotulinumtoxin A can accurately predict the long-term response. BACKGROUND Onabotulinumtoxin-A (OBT-A) is an approved preventive treatment option for chronic migraine (CM). Nowadays, it remains to be clarified if the treatment has to be prolonged for at least an entire year (4 injections every 3 months - ie, quarterly, as proposed in the PREEMPT trials) or it can be halted after the second or third injection if not clinically effective. DESIGN AND METHODS We conducted a multicenter observational cohort study based on real-life data on the usage of OBT-A in CM patients from 2 Italian headache centers, Roma Campus Bio-Medico and Milano Besta, adopting the whole 4-injections protocol. We performed a retrospective analysis of medical records of consecutive patients treated in the 2 centers. The main statistical analysis aimed to evaluate longitudinal measures related to headache (monthly headache frequency, monthly number of analgesic drugs, MIDAS). We hypothesized from our clinical practice with OBT-A that only 2 cycles of treatment were not enough to actually define the non-responder status to botulinum toxin A and that probably a longer time of treatment is needed to get the condition of long-term (delayed) responder. RESULTS We considered 115 patients from the 2 centers: 53 in Roma and 62 in Milano. Regarding the main analysis, a clear improvement in each measure was obtained at the 6 months assessment and maintained up to 12 months. Comparing patients with

One of the most popular and widely used parent report instruments for assessing early language acquisition is the MacArthur-Bates Communicative Development Inventories (MB-CDI). This study compares normative data of the Italian Words and Sentences complete form (WS-CF) and short form (WS-SF). The samples included 752 children for the WS-CF and 816 children for the WS-SF designed for children aged 18–36 months. The concordance between WS-SF and WS-CF is analyzed in a subgroup of 65 children. The results revealed strong correlations between WS-CF and WS-SF in both lexical and grammar skills as well as strong relationship between lexical and grammar skills. There was a high percentage agreement (97%) between the two forms for scores below the 10th percentile, suggesting that the two forms may be used interchangeably in order to describe vocabulary and grammatical development.

Strokes causing similar lesions and clinical states can be followed by diverse regains of neurological functions, indicating that the clinical recovery can depend on individual modulating factors. A promising line to disclose these factors, to finally open new therapeutic strategies, is to search for individual indices of recovery prognosis. Here, we pursued on strengthening the value of acute phase electrophysiological biomarkers for poststroke functional recovery in a wide group of patients. We enrolled 120 patients affected by a monohemispheric stroke within the middle cerebral artery territory (70 left and 50 right damages) and collected the NIH stroke scale (NIHSS) score in the acute phase (T0, median 4 days) and chronic follow-up (T1, median 6 months). At T0, we executed electrophysiological noninvasive assessment (19-channel electroencephalography (EEG) or 28 channels per side magnetoencephalography (MEG)) of brain activity at rest by means of band powers in the contra- and ipsilesional hemispheres (CLH, ILH) or the homologous area symmetry (HArS). Low-band (2-6 Hz) HArS entered the regression model for predicting the stabilized clinical state (p<0.001), with bilateral impairment correlated with a poor outcome. Present data strengthen the fact that low-band impairment of homologous ipsi- and contralesional hemispheric regions in the acute stroke indicate a negative prognosis of clinical recovery.

Aims In 2017 the Italian Drug Agency (Agenzia Italiana del Farmaco, AIFA) revised the criteria for access to therapy for patients with chronic hepatitis C as part of a three-year plan to eradicate HCV. We conducted a Delphi study to determine strategies to identify and treat patients with HCV and to develop through a shared pathway, a model to manage patient referral and optimize prescription center capacity with the overall aim of increasing access to therapy. Methods The process took place in two phases – Phase I (January 2017), before the criteria for treatment of HCV were revised and Phase II (May 2017) when AIFA developed a framework for the eradication of HCV infection in Italy. Two questionnaires were devised with Q1 administered in Phase I and Q2 in Phase II. Results Q1 was sent to 823 hepatitis specialists working in 235 Italian HCV centers authorized to prescribe direct-acting antiviral drugs (DAAs). Overall, 167 centers (71%) participated with a good geographical representativeness (North 69%, Centre 74%; South and islands 70%). 548 prescribers (68.8%) provided responses to Q1 and 443 (80%) specialists who responded to Q1 completed Q2. Over 70% considered that to meet the new therapy targets local/regional networks need to be consolidated and reinforced with GPs providing the ‘missing link’ in current regional networks. Adherence to therapy was considered important by 75% of clinicians with reduction in follow-up intervals/length considered important by 65% – to free up staff/resources to manage increasing numbers of new patients. About 80% of respondents stated that medical personnel were principally involved in follow-up with follow-up having a significant impact on center capacity. Conclusion Enhancing patient referral, the need for an increased role of GPs, increasing center capacity in particular medical personnel in outpatient centers and greater liaison between Hub centers and healthcare professionals currently managing high-risk groups as yet untreated, were factors that need to be streamlined in order to meet treatment targets for eradication of HCV.

Objectives. It has been already confirmed that retinal neurodegeneration has a predictive value in the development of microvascular alterations in diabetic retinopathy. However, no data are available on the association between neuroretinal dysfunction and peripheral motor unit loss. Our study, therefore, was aimed at investigating the hypothesis that retinal neurodegeneration could be considered an early marker of diabetic peripheral neuropathy (DPN). Methods. 20 T1DM patients with no symptoms/signs of peripheral polyneuropathy, without DR or with very mild nonproliferative DR, and 14 healthy controls (C) age- and gender-matched were enrolled. The following electrophysiological tests were performed: standard nerve conduction studies (NCS) and incremental motor unit number estimation (MUNE) from the abductor hallux (AH) and abductor digiti minimi (ADM). Neuroretinal function was studied by multifocal electroretinogram (MfERG) recordings, measuring response amplitude density (RAD) and implicit time (IT) from rings and sectors of superior (S)/inferior (I)/temporal (T)/nasal (N) macular sectors up to 10 degrees of foveal eccentricity. Results. MfERG RADs from rings and sectors were significantly reduced in T1DM (p<0.05) vs. C. ADM MUNE and AH MUNE were significantly decreased in T1DM (p=0.039 and p<0.0001, respectively) vs. C. A positive correlation between mean MfERG RADs from the central 5 degrees of the four (S, I, T, and N) macular sectors and lower limb motor unit number (r=0.50, p=0.041; r=0.64, p=0.005; r=0.64, p=0.006; and r=0.61, p=0.010, respectively) was observed in T1DM patients. No abnormalities of NCS were found in any subject. Conclusions. The motor unit loss on the one hand and neuroretinal dysfunction on the other hand are already present in T1DM patients without DPN. The relationship between neuroretinal dysfunction and motor unit decline supports the hypothesis that neuroretina may represent a potential “window” to track the early neurogenic damage in diabetes.

Background In the early phases of relapsing-remitting multiple sclerosis (RR-MS), a clear correlation between brain lesion load and clinical disability is often lacking, originating the so-called clinico-radiological paradox. Different factors may contribute to such discrepancy. In particular, synaptic plasticity may reduce the clinical expression of brain damage producing enduring enhancement of synaptic strength largely dependent on neurotrophin-induced protein synthesis. Cytokines released by the immune cells during acute inflammation can alter synaptic transmission and plasticity possibly influencing the clinical course of MS. In addition, immune cells may promote brain repair during the post-acute phases, by secreting different growth factors involved in neuronal and oligodendroglial cell survival. Platelet-derived growth factor (PDGF) is a neurotrophic factor that could be particularly involved in clinical recovery. Indeed, PDGF promotes long-term potentiation of synaptic activity in vitro and in MS and could therefore represent a key factor improving the clinical compensation of new brain lesions. The aim of the present study is to explore whether cerebrospinal fluid (CSF) PDGF concentrations at the time of diagnosis may influence the clinical course of RR-MS. Methods At the time of diagnosis, we measured in 100 consecutive early MS patients the CSF concentrations of PDGF, of the main pro- and anti-inflammatory cytokines, and of reliable markers of neuronal damage. Clinical and radiological parameters of disease activity were prospectively collected during follow-up. Results CSF PDGF levels were positively correlated with prolonged relapse-free survival. Radiological markers of disease activity, biochemical markers of neuronal damage, and clinical parameters of disease progression were instead not influenced by PDGF concentrations. Higher CSF PDGF levels were associated with an anti-inflammatory milieu within the central nervous system. Conclusions Our results suggest that PDGF could promote a more prolonged relapse-free period during the course of RR-MS, without influencing inflammation reactivation and inflammation-driven neuronal damage and likely enhancing adaptive plasticity.

The population of industrialized nations is progressively aging, with Italy having one of the most elderly populations in the world. Natural aging may be associated with physical and cognitive impairments, often straining public resources. The present study aims to investigate the influence of gender on wellness of the nonagenarians. We evaluated quality of life among nonagenarians living in the Mugello area, an Italian location with a large population of individuals > 90 years, using the Health Survey Scoring SF-12. The 15-item Geriatric Depression Scale and Basic and Instrumental Activity of Daily Living scales were also assessed. The Mini-Mental State Examination was used to evaluate the cognitive status. In the current survey, women outnumbered men 2.7:1 confirming their higher longevity. However, on the basis of SF-12 scores, nonagenarian women felt worse than men, both physically (mean: women = 41.8 vs men = 44.4, p = 0.004) and mentally (mean: women = 46.7 vs men =48.5, p = 0.034), and their depression rates were higher: considering a General Depression Scale score ≥ 5 as a possible depression status; 37.5% of men reported depression vs. 48.5% of women (p = 0.021). Significant differences were observed also in daily activities, both basic (median: woman = 3 vs men = 5, p

The aim of this study was to identify the impact of comorbidities on outcomes of patients with vegetative state (VS) or minimally conscious state (MCS). All patients in VS or MCS consecutively admitted to two postacute care units within a 1-year period were evaluated at baseline and at 6 months through the Coma Recovery Scale-Revised Version and the Disability Rating Scale (DRS). Comorbidities were also recorded for each patient along the same period. Six-month outcomes included death, full recovery of consciousness, and functional improvement. One hundred and thirty-nine patients (88 male and 51 female; median age, 59 years) were included. Ninety-seven patients were in VS (70%) and 42 in MCS (30%). At 6 months, 33 patients were dead (24%), 39 had a full recovery of consciousness (28%), and 67 remained in VS or MCS (48%). According to DRS scores, 40% of patients (n=55) showed a functional improvement in the level of disability. One hundred and thirty patients (94%) showed at least one comorbidity. Severity of comorbidities (hazard ratio [HR]=2.8; 95% confidence interval [CI], 1.71-4.68; p0.001) and the presence of ischemic or organic heart diseases (HR=2.6; 95% CI, 1.21-5.43; p=0.014) were the strongest predictors of death, together with increasing age (HR=1.0; 95% CI, 1.0-1.06; p=0.033). Respiratory diseases and arrhythmias without organic heart diseases were negative predictors of full recovery of consciousness (odds ratio [OR]=0.3; 95% CI, 0.12-0.7; p=0.006; OR=0.2; 95% CI, 0.07-0.43; p0.001) and functional improvement (OR=0.4; 95% CI, 0.15-0.85, p=0.020; OR=0.2; 95% CI, 0.08-0.45; p0.001). Our data show that comorbidities are common in these patients and some of them influence recovery of consciousness and outcomes.

Objective Verifying the validity and feasibility of the WOQ-19 as a useful tool in routine clinical practice and in management of patients. Methods 532 consecutive Parkinson's disease (PD) patients were recruited from 6 different neurological outpatient units, specialized in movement disorders, of central Italy. Inclusion criteria were diagnosis of PD and any current pharmacological treatment of PD while exclusion criteria were evident cognitive or depressive impairment, infusion with dopamine agonists or Duodopa, or Deep Brain Stimulation therapy. Patients were asked to complete the Italian version of WOQ-19 before the neurological visit. A medical form for the collection of demographic and clinical data of patients and for the evaluation of comprehensibility and usability the WOQ-19 was filled by the neurologist during the visit. Results Our data confirmed that WOQ-19 was able to identify WO in 69% of patients, a percentage similar to the recently reported in the Italian WOQ-19 validation study. Motor symptoms were more frequent than non-motor symptoms (80% vs. 20%). Patients who experienced WO had a higher age of PD onset, more severe disease, longer disease duration and were more likely to be female. Conclusions The WOQ-19 was understandable for the patient, easily administered and suitable for routine outpatient use. It could be also particularly useful in clinical practice in the early identification of non-motor symptoms, often under reported by patients and revealed only with clinical support.

Management of medication overuse headache (MOH) requires abrupt suspension of overused drugs either alone or in association with a detoxification protocol to prevent withdrawal. However, there is no consensus about which suspension strategy is the most effective. Moreover, reliable data about the possible mid-term effect of detoxification are not available. The objective of this study was to evaluate whether a bridge therapy consisting of a 5-day i.v. infusion of methylprednisolone and diazepam determines a significant reduction in headache frequency and drug assumption during the detoxification protocol (day 5) and in the first 3 months in patients with MOH. We conducted a retrospective non-randomized before-and-after study comparing patients with MOH undergoing a bridge therapy protocol (5-day infusion of methylprednisolone, diazepam) with those who refused the treatment and were only recommended to suspend overused painkillers. Both groups started a prophylactic treatment and were followed-up for 3 months. At day 5, 82% of our patients were headache-free; moreover, 48% of the patients did not take any painkiller during the 5-day treatment. Three months after, the intervention group showed a greater reduction of monthly headache days (9.4 vs 3.0) and drugs (19.7 vs 6.5), a greater rate of patients with a ≥ 50% reduction of monthly headaches (p = 0.019) and symptomatic drug consumption (p = 0.000), than the control group. The methylprednisolone and diazepam detoxification protocol reduced headache attacks and drug assumption immediately and in the first 3 months after the intervention, concurring to improve the effect of a new prophylactic therapy.

Cerebral vasomotor reactivity (CVR) is reduced in patients with diabetes mellitus (DM), and glucose variability (GV) might be responsible for cerebrovascular damage.Studying patients with insulin resistance without DM, we explored the role of GV in impairing CVR.We studied 18 metabolic syndrome (MS) patients without DM, 9 controls (C), and 26 patients with DM.Groups were compared in terms of CVR, GV, and 24-hour blood pressure. To evaluate the impact of acute hyperglycemia on CVR, a hyperglycemic clamp was performed in MS patients and controls.Baseline CVR was reduced in DM vs C and MS (C vs DM = 20.2, 95% CI = 3.5-36.9, P = .014; and MS vs DM = 22.2, 95% CI = 8.6-35.8, P = .001), but similar between MS and C (MS vs C = 2.0, 95% CI = -14.7 to 18.7, P = .643). During acute hyperglycemia, CVR fell in MS and C to values comparable to DM. GV progressively increased from C to MS to DM. In MS, CVR at 120 minutes and GV displayed a negative correlation (r = -0.48, P = .043), which did not change after controlling for mean 24-hour systolic and diastolic blood pressure. In MS, the CVR reduction was significantly correlated to GV (r = 0.55, P = .02).GV is increased in patients with MS but without DM and is the major predictor of CVR reduction induced by acute hyperglycemia, possibly representing the earliest cause of cerebrovascular damage in DM.

Background Current efforts to improve clinical effectiveness and utility of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depression (MD) include theta burst stimulation (TBS), a patterned form of rTMS. Here, we investigated the efficacy of bilateral TBS to the dorsolateral prefrontal cortex (dlPFC) in patients with MD in additon to ongoing medication and psychotherapy. Methods In this randomized-controlled trial, thirty-two patients with MD were treated for six weeks (thirty sessions) with either successively intermittent, activity enhancing TBS (iTBS) to the left and continuous, inhibiting TBS (cTBS) to the right dlPFC or with bilateral sham stimulation. Primary outcome measure was the proportion of treatment response defined as a Montgomery–Asberg Depression Rating Scale (MADRS)≤50% compared to baseline. Secondary outcomes comprised response and remission rates of the Hamilton Depression Rating Scale (HAMD) and the Beck Depression Inventory (BDI). Results A larger number of responders were found in the cTBS (n=9) compared to the sham-stimulation (n=4) group (odds ratio: 3.86; Wald χ2=3.9, p=0.048). On secondary endpoint analysis, patient-reported outcome as assessed by the BDI, pointed towards a higher rate of remitters in the cTBS (n=6) than in the sham (n=1) group (odds ratio: 9; Wald χ2=3.5, p=0.061). Limitations With regard to the pilot character of the study and the small sample size, the results have to be considered as preliminary. Conclusions These findings provide first evidence that six weeks treatment of MDD with iTBS to the left and cTBS to the right dlPFC for six weeks is safe, feasible and superior to sham stimulation applied add-on to pharmacological and psychotherapeutic treatment.

Background: Neuromodulation techniques, i.e. repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), can modify cerebral hemodynamics. High frequency rTMS appeared to decrease cerebral vasomotor reactivity (VMR), while there is still poor evidence about the effect of low frequency (LF) rTMS on cerebral blood flow (CBF) and VMR. Hypothesis: The present study aimed to test if LF rTMS decreases CBF and increases cerebral VMR. Monolateral or bilateral hemispheric involvement and duration of the effect were considered. A possible role of autonomic nervous system in CBF and VMR modulation was also investigated. Methods: Twenty-four right-handed healthy subjects underwent randomly real (12) or sham (12) 20-min 1-Hz rTMS on left primary motor cortex. Mean flow velocity and VMR of middle cerebral arteries were evaluated by means of transcranial Doppler before (T0), after 10 min (T1) and after 2 (T2), 5 (T3) and 24 h (T4) from rTMS. Heart rate variability (HRV) was studied within the same timing interval, assessing low frequency/high frequency (LF/HF) ratio as index of autonomic balance. Results: After real rTMS compared with sham stimulation, MFV decreased bilaterally at T1 (F = 3.240, P = .030) while VMR increased bilaterally (F = 5.116, P = .002) for at least 5 h (T3). LF/HF ratio decreased early after real rTMS (F = 2.881, P = .040). Conclusion: 1-Hz rTMS may induce a bilateral long-lasting increase of VMR, while its effect on MFV is short-lasting. Moreover, HRV changes induced by rTMS suggest a possible autonomic nervous system modulation.

Aims Recent studies have identified neuroretinal abnormalities in persons affected by diabetes mellitus, before the onset of microvascular alterations. However, the role of glycemic variability (GV) on early retinal neurodegeneration is still not clarified. Methods To explore the relationship between glycemic control and neuroretinal characteristics, 37 persons with Type 1 diabetes mellitus (Type 1 DM) divided into two groups with no signs (noRD) and with mild non-proliferative diabetic retinopathy (NPDR) compared to 13 healthy control participants (C) were recruited. All persons underwent an optical coherence tomography with automatic segmentation of all neuroretinal layers. Measurements of mean of nasal (N)/temporal (T)/superior (S)/inferior (I) macular quadrants for individual layer were also calculated. Metabolic control was evaluated by glycated hemoglobin (HbA1c), and indexes of GV were calculated from continuous glucose monitoring. Results The difference among the three groups in terms of RNFL thickness was significantly dependent on quadrant (F(6;132) = 2.315; p = 0.037). This interaction was due to a specific difference in RNFL-N thickness, where both Type 1 DM groups showed a similar reduction versus C (−3.9 for noDR and −4.9 for NPDR), without any relevant difference between them (−1.0). Inner nuclear layer (INL) was increased in all quadrants in the two Type 1 DM groups compared to C (mean difference = 7.73; 95% CI: 0.32–15.14, p = 0.043; mean difference = 7.74; 95% CI: 0.33–15.15, p = 0.043, respectively). A negative correlation between RNFL-N and low blood glucose index (r = −0.382, p = 0.034) and positive correlation between INL and continuous overall net glycemic action −1, −2, −4 h (r = 0.40, p = 0.025; r = 0.39, p = 0.031; r = 0.41, p = 0.021, respectively) were observed in Type 1 DM patients. The triglycerides were positively and significantly correlated to INL (r = 0.48, p = 0.011), in Type 1 DM subjects. GV and triglycerides resulted both independent predictors of increased INL thickness. No correlation was found with HbA1c. Conclusions Early structural damage of neuroretina in persons with Type 1 DM patients is related to glucose fluctuations. GV should be addressed, even in the presence of a good metabolic control.

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The effect of carotid artery stenting (CAS) on cognitive function is still debated. Cerebral microembolism, detectable by post-procedural diffusion-weighted imaging (DWI) lesions, has been suggested to predispose to cognitive decline. Our study aimed at evaluating the effect of CAS on cognitive profile focusing on the potential role of cerebral microembolic lesions, taking into consideration the impact of factors potentially influencing cognitive status (demographic features, vascular risk profile, neuropsychological evaluation at baseline and magnetic resonance (MR) markers of brain structural damage). Thirty-seven patients with severe carotid artery stenosis were enrolled. Neurological assessment, neuropsychological evaluation and brain MR were performed the day before CAS (E0). Brain MR with DWI was repeated the day after CAS (E1), while neuropsychological evaluation was done after a 14-month median period (E2). Volumes of both white matter hyperintensities and whole brain were estimated at E0 on axial MR FLAIR and T1w-SE sequences, respectively. Unadjusted ANOVA analysis showed a significant CAS*DWI interaction for MMSE (F=7.154(32), p=.012). After adjusting for factors potentially influencing cognitive status CAS*DWI interaction was confirmed for MMSE (F=7.092(13), p=.020). Patients with DWI lesions showed a mean E2-E0 MMSE reduction of -3.1, while group without DWI lesions showed a mean E2-E0 MMSE of +1.1. Our study showed that peri-procedural brain microembolic load impacts negatively on cognitive functions, independently from the influence of patients-related variables.

Six-hundred twenty-one subjects with unilateral asymptomatic severe internal carotid artery (ICA) stenosis were prospectively evaluated with a median follow-up of 27 months (min = 6, max = 68). Vascular risk profile, plaque characteristic, stenosis progression, and common carotid artery intima-media thickness (IMT) were investigated in all patients. Outcome measures were occurrence of ischemic stroke ipsilateral to ICA stenosis and vascular death, while myocardial infarction, contralateral strokes, and transient ischemic attack were considered as competing events. A total of 99 subjects (15.9%) suffered from a vascular event. Among them, 39 were strokes ipsilateral to the stenosis (6.3%). Degree of stenosis, stenosis progression, and common carotid artery IMT resulted as independent predictive factors of ipsilateral stroke. Considering a stenosis of 60% to 70% as reference, a degree between 71% and 90% increased the risk by 2.45, while a degree between 91% and 99% increased the risk by 3.26. The progression of stenosis was a strong risk factor (hazard ratio = 4.32). Finally, the role of carotid IMT was confirmed as crucial additional measure, with an increased risk by 25% for each 0.1 mm IMT increase. Our data suggest that IMT, stenosis progression and severity should be considered as risk factors for cerebrovascular events in asymptomatic subjects with severe ICA stenosis.

Meta-analyses demonstrate copper involvement in Alzheimer's disease (AD), and the systemic ceruloplasmin status in relation to copper is an emerging issue. To deepen this matter, we evaluated levels of ceruloplasmin concentration, ceruloplasmin activity, ceruloplasmin specific activity (eCp/iCp), copper, non-ceruloplasmin copper iron, transferrin, the ceruloplasmin/transferrin ratio, and the APOE genotype in a sample of 84 AD patients and 58 healthy volunteers. From the univariate logistic analyses we found that ceruloplasmin concentration, eCp/iCp, copper, transferrin, the ceruloplas- min/transferrin ratio, and the APOE genotype were significantly associated with the probability of AD. In the multivariable logistic regression analysis, we selected the best subset of biological predictors by the forward stepwise procedure. The anal- ysis showed a decrease of the risk of having AD for eCp/iCp (p = 0.001) and an increase of this risk for non-ceruloplasmin copper (p = 0.008), age (p = 0.001), and APOE-4 allele (p < 0.001). The estimated model showed a good power in discrimi- nating AD patients from healthy controls (area under curve: 88%; sensitivity: 66%; specificity 93%). These data strength the breakdown of copper homeostasis and propose eCp/iCp as a reliable marker of ceruloplasmin status.

Several studies have shown that, in spite of the fact that motor symptoms manifest late in the course of Alzheimer's disease (AD), neuropathological progression in the motor cortex parallels that in other brain areas generally considered more specific targets of the neurodegenerative process. It has been suggested that motor cortex excitability is enhanced in AD from the early stages, and that this is related to disease's severity and progression. To investigate the neurophysiological hallmarks of motor cortex functionality in early AD we combined transcranial magnetic stimulation (TMS) with electroencephalography (EEG). We demonstrated that in mild AD the sensorimotor system is hyperexcitable, despite the lack of clinically evident motor manifestations. This phenomenon causes a stronger response to stimulation in a specific time window, possibly due to locally acting reinforcing circuits, while network activity and connectivity is reduced. These changes could be interpreted as a compensatory mechanism allowing for the preservation of sensorimotor programming and execution over a long period of time, regardless of the disease's progression. Hum Brain Mapp 37:2083–2096, 2016. © 2016 Wiley Periodicals, Inc.

The present study examined whether full access to sign language as a medium for instruction could influence performance in Theory of Mind (ToM) tasks. Three groups of Italian participants (age range: 6-14 years) participated in the study: Two groups of deaf signing children and one group of hearing-speaking children. The two groups of deaf children differed only in their school environment: One group attended a school with a teaching assistant (TA; Sign Language is offered only by the TA to a single deaf child), and the other group attended a bilingual program (Italian Sign Language and Italian). Linguistic abilities and understanding of false belief were assessed using similar materials and procedures in spoken Italian with hearing children and in Italian Sign Language with deaf children. Deaf children attending the bilingual school performed significantly better than deaf children attending school with the TA in tasks assessing lexical comprehension and ToM, whereas the performance of hearing children was in between that of the two deaf groups. As for lexical production, deaf children attending the bilingual school performed significantly better than the two other groups. No significant differences were found between early and late signers or between children with deaf and hearing parents.

Objective Intracortical inhibition (SICI) and facilitation (ICF) in the human motor cortex can be measured using a paired pulse transcranial magnetic stimulation (ppTMS) protocol. Recently, a technical device has been introduced, which allows recording electroencephalographic (EEG) responses to TMS of a given scalp site. The latency, amplitude and scalp topography of such responses are considered a reflection of cortico-cortical connectivity and functional state. The aim of the present study is to better characterize the neuronal circuits underlying motor cortex connectivity as well as the mechanisms regulating its balance between inhibition and facilitation by means of EEG navigated-ppTMS coregistration. Methods Sub-threshold and supra-threshold single and ppTMS of the left primary motor cortex were carried out during a multi-channel EEG recording on 8 healthy volunteers; the between-pulse intervals used in the paired pulse trials were 3 (for SICI) and 11 ms (for ICF). Motor evoked potentials (MEPs) from the opposite hand were simultaneously recorded. Results Single and ppTMS induced EEG responses characterized by a sequence of negative deflections peaking at approximately 7, 18, 44, 100 and 280 ms alternated with positive peaks at approximately 13, 30, 60 and 190 ms post-TMS. Moreover, ppTMS modulated both EEG evoked activity and MEPs. Amplitude variability of EEG responses was correlated with – and therefore might partially explain – amplitude variability of MEPs. Interpretation EEG-ppTMS is a promising tool to better characterize the neuronal circuits underlying cortical effective connectivity as well as the mechanisms regulating the balance between inhibition and facilitation within the human cortices and the corticospinal pathway.

Objective Aim of this study was to investigate if the risk of stroke and other vascular diseases can be predicted in subjects with severe asymptomatic carotid artery stenosis on the basis of carotid wall thickness evaluation. Methods We included 162 consecutive subjects with asymptomatic internal carotid artery stenosis of 60% or greater reduction in diameter. Demographic characteristics, vascular risk factors, therapy, degree of carotid stenosis and carotid intima–media thickness (IMT) were detailed for all subjects. Subjects were prospectively evaluated for a median period of 35 months (min = 10, max = 47). Outcome measures were: the occurrence of ischemic stroke ipsilateral to carotid stenosis and any other vascular event. Results Thirty subjects (18.5%) suffered a vascular event: 16 (53%) myocardial infarctions and 14 (47%) strokes. Older age and higher IMT values were the only factors significantly associated with the risk of vascular events. The hazard ratio (adjusted for age, sex and other risk factors) for each 0.1 mm of IMT increase resulted 1.30 (95% CI: 1.14, 1.18) for combined vascular events, 1.47 for cerebrovascular events (95% CI: 1.16, 1.87) and 1.24 (95% CI: 1.09, 1.42) for cardiovascular events. Values of IMT above 1.15 mm increased the risk of having a stroke 19 times and the risk of having a myocardial infarction two times. Conclusions An increased carotid wall thickness can be considered as a marker of an increased risk of vascular events in asymptomatic subjects with internal carotid artery stenosis >60%. Highest IMT values are able to identify subjects with specific stroke risk. This information could be of interest to recognize subjects who might benefit most from surgical or revascularization procedures.

Background Transcranial Doppler (TCD) studies demonstrated that cerebral vasomotor reactivity (VMR) can predict the outcome of carotid artery occlusion (CAO). Near-infrared spectroscopy (NIRS) is a non-invasive optical method for assessing hemoglobin (Hb) oxygenation parameters. The purpose of this study was to evaluate the role of NIRS parameters as prognostic markers of stroke occurrence in patients with CAO. Methods Sixty-five patients (46 men, mean age 68.8 years) with CAO were enrolled. Forty-two patients had previous cerebrovascular events (15 TIA, 27 minor stroke), the remaining 23 were asymptomatic. All subjects underwent simultaneous TCD and NIRS examination at rest and after hypercapnia. All patients completed follow-up (median, 36 months). Results During follow-up, 11 strokes occurred. Cerebral VMR measured by TCD had a prognostic role in stroke occurrence (p = 0.042). The increase in Hb oxygen saturation detected by NIRS during hypercapnia predicted the occurrence of new cerebrovascular events, although without an overt significance (p = 0.058). Hb oxygen saturation at rest, however, failed to be of prognostic value (p = 0.65). Conclusions NIRS is potentially useful in monitoring cerebral oxygenation; however, at present NIRS does not effectively predict the outcomes of stroke or vascular death in patients with CAO. This study does confirm the primary role of TCD VMR in the outcome of carotid disease.

Background and Purpose: Aim of our study was to evaluate cerebral hemodynamic changes during performance of attention tasks and to correlate them with reaction time (RT) and percentage of right answers. Methods: Mean flow velocity (MFV) in middle cerebral arteries was monitored in 30 subjects by transcranial Doppler during tonic alertness, phasic alertness, focused and divided attention tasks. Results: Mean flow velocity increase was significantly higher during divided attention with respect to other tasks (P

Objective Changes in cerebral cortex excitability have been demonstrated after a stroke and are considered relevant for recovery. Repetitive transcranial magnetic stimulation (rTMS) of the brain can modulate cerebral cortex excitability and, when rTMS is given as theta burst stimulation (TBS), LTP- or LTD-like changes can be induced. The aim of present study was to evaluate the effects of TBS on cortical excitability in acute stroke. Methods In 12 acute stroke patients, we explored the effects of facilitatory TBS of the affected hemisphere and of inhibitory TBS of the unaffected hemisphere on cortical excitability to single-pulse transcranial magnetic stimulation (TMS) on both sides. The effects produced by TBS in patients were compared with those observed in a control group of age-matched healthy individuals. Results In patients, both the facilitatory TBS of the affected motor cortex and the inhibitory TBS of the unaffected motor cortex produced a significant increase of the amplitude of MEPs evoked by stimulation of the affected hemisphere. The effects observed in patients were comparable to those observed in controls. Conclusions Facilitatory TBS over the stroke hemisphere and inhibitory TBS over the intact hemisphere in acute phase enhance the excitability of the lesioned motor cortex. Significance TBS might be useful to promote cortical plasticity in stroke patients.

Objective The increase of elderly population prompted growing research for the understanding of cerebral phenomena sustaining learning abilities, with inclusion of long-term potentiation (LTP)-like plasticity phenomena. Aim of the present study was to characterize LTP-like plasticity dependence on age and gender. Methods A LTP-like primary motor cortex plasticity inducing a potentiation of the motor evoked potential (MEP) to focal transcranial magnetic stimulation as a consequence of a paired associative stimulation (PAS) was induced in a 50 healthy subject cohort, equally distributed for gender and age groups (25 young subjects, mean age ± SD = 29.8 ± 4.5 years; elderly 61.1 ± 4.1 years). Results Resting motor thresholds’ excitability level increased in the elderly group, the basal MEP did not depend on gender or age. The PAS-induced primary motor cortex (M1) plastic excitability modulation was similar in young females and males, while it decreased with age in females only. Conclusions A reduction of the PAS-induced M1 plasticity in females after menopause was documented, possibly due to an impairment of intracortical excitatory network activity. Significance A LTP-like plasticity dependence on age was found in female only, suggesting caution in interpreting behavioural studies on learning abilities in dependence on age.

Production of reactive oxygen species after cerebral blood flow disruption may enhance tissue damage through multiple molecular pathways. Changes in nitric oxide (NO) metabolism and oxidative stress status were investigated in 47 patients with ischemic stroke by measuring plasma nitric oxide (NO) and peroxynitrite (ONOO(-)) levels.A correlation was sought between these two parameters and i) baseline stroke severity based on the National Institute of Health stroke scale (NIHSS) and ii) neurological outcome in terms of NIHSS changes from entry (T(0)) to 30 days after symptom onset (T(1)). The control group consisted of 30 age- and sex-matched healthy subjects. Mean plasma levels of ONOO(-) (arbitrary fluorescence number +/- SD) were significantly higher in patients (7.70 +/- 1.71 vs 5.35 +/- 0.69, p0.001), whereas mean NO levels (nmol/mg protein) were significantly higher in controls (115.40 +/- 12.40 vs. 51.10 +/- 12.50, p0.001). Plasma ONOO(-) was significantly higher among patients with non-lacunar stroke (8.48 +/- 1.50 vs. 6.95 +/- 1.58 in those with lacunar stroke; p = 0.001), whereas NO levels were significantly higher among lacunar stroke patients (60.00 +/- 7.86, vs. 41.77 +/- 9.29 in patients with nonlacunar stroke; p0.001). Nitric oxide plasma levels were also associated with an unfavorable evolution in non-lacunar stroke, since a 10 unit increase in NO predicted a 1 point reduction in the NIHSS score at T1. Findings show that changes in NO metabolism may be considered as markers of brain injury in patients with ischemic stroke. Further work is needed to establish whether the amount of biochemical changes related to oxidative stress may influence outcome in these patients.

Sixteen rigid-akinetic idiopathic Parkinson's disease patients (PD) and 13 healthy control subjects (controls) were included in this study.Gait analysis was performed using an optoelectronic system. The experimental design involved double evaluation of PD patients (before and after motor rehabilitation program) and a single evaluation of controls. ANOVA was performed in both groups for each gait variable (kinetic and kinematic) and for clinical conditions.Analysis of kinetic data highlighted a statistically significant difference for all gait variables studied between controls and PD patients either before, or in the same PD patients before and after the motor rehabilitation program. After the rehabilitation program, natural walking speed increased (p.000). The stance percentage was significantly decreased in the single support (p.000). After the rehabilitation program, the double support limb phase did not show a reduction in statistical significance. Kinematic data showed statistical differences between controls and PD patients in hip, knee and ankle joint angles, both before and after the motor rehabilitation program.Our results confirm that gait analysis is a valid tool for evaluating changes in PD patients' ability to walk and for quantifying the improvements gained through a motor rehabilitation program.

Objective: ERCC1 (excision repair cross-complementation group 1) expression predicts survival in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated with chemoradiation. In order to evaluate the predictive role in the adjuvant setting, we investigated ERCC1 expression in radically resected HNSCC patients who underwent surgery and cisplatin chemoradiation. Methods: ERCC1 expression levels were determined by immunohistochemistry in primary tumor tissues from 48 patients with stage III-IV cancers. The median follow-up was 38.5 months (range: 5-121). Results: High ERCC1 expression was observed in 36 (75%) patients. Univariate analysis showed that patients with high levels of ERCC1 had significantly worse disease-free survival and overall survival (OS) than patients with low levels (HR = 7.15; 95% CI, 1.68-30.35; p = 0.008 and HR = 9.90; 95% CI, 1.33-73.96; p = 0.025, respectively). In the multivariate analysis, high ERCC1 expression (HR = 7.36; 95% CI, 1.72-31.4; p = 0.007) together with high-risk category (HR = 2.69; 95% CI, 1.01-7.18; p = 0.048) were the best predictors for relapse. High ERCC1 expression was the only unfavorable independent determinant for OS (HR = 9.53; 95% CI, 1.27-71.35; p = 0.028). Conclusions: This investigation suggests that ERCC1 expression might be useful to predict prognosis in radically resected HNSCC patients treated with surgery and chemoradiation.

Background: Over time, exposure to cerebrovascular risk factors and carotid artery disease may cause multiple asymptomatic brain cortical and subcortical microinfarcts, which are commonly found at brain autopsy. So far, lack of convenient neuroimaging tools limited the investigation of grey matter ischemic damage in vivo. We applied the Double Inversion Recovery (DIR) sequence to explore the impact of carotid artery disease on intracortical ischemic lesion load in vivo, taking into account the impact of demographic characteristics and vascular risk factors. Methods: DIR was acquired in 62 patients with common cerebrovascular risk factors stratified in three groups according to carotid artery disease severity. Intracortical lesions scored on DIR (DIRlns) were classified by vascular territory, lobe and hemisphere. White matter hyperintensities (WMHs) volume was also quantified on Fluid Attenuated Inversion Recovery sequence (FLAIR). Results: Among demographic characteristics and cerebrovascular risk variables explored, General Linear Model indicated that age and carotid artery disease were significantly associated to DIRlns. After correcting for age, DIRlns load was found to be significantly dependent on carotid artery stenosis severity (F(2, 58) = 5.56, p = 0.006). A linear positive correlation between DIRlns and WMHs was found after correcting for age (p = 0.003). Conclusions: Carotid disease severity is associated with DIRlns accrual. Microembolism and impaired cerebral hemodynamics may act as physiopathological mechanisms underlying cortical ischemic damage. The role of other factors, such as small vessel disease and the possible interaction with carotid disease, remains to be further explored.

Background A globally harmonized protocol (HarP) for manual hippocampal segmentation based on magnetic resonance has been recently developed by a task force from European Alzheimer's Disease Consortium (EADC) and Alzheimer's Disease Neuroimaging Initiative (ADNI). Our aim was to produce benchmark labels based on the HarP for manual segmentation. Methods Five experts of manual hippocampal segmentation underwent specific training on the HarP and segmented 40 right and left hippocampi from 10 ADNI subjects on both 1.5 T and 3 T scans. An independent expert visually checked segmentations for compliance with the HarP. Descriptive measures of agreement between tracers were intraclass correlation coefficients (ICCs) of crude volumes and similarity coefficients of three-dimensional volumes. Results Two hundred labels have been provided for the 20 magnetic resonance images. Intra- and interrater ICCs were >0.94, and mean similarity coefficients were 1.5 T, 0.73 (95% confidence interval [CI], 0.71–0.75); 3 T, 0.75 (95% CI, 0.74–0.76). Conclusion Certified benchmark labels have been produced based on the HarP to be used for tracers' training and qualification.

Purpose: Transcranial electric stimulations (tES) with amplitude-modulated currents are promising tools to enhance neuromodulation effects. It is essential to select the correct cortical targets and inhibitory/excitatory protocols to reverse changes in specific networks. We aimed at assessing the dependence of cortical excitability changes on the current amplitude of 20 Hz transcranial alternating current stimulation (tACS) over the bilateral primary motor cortex. Methods: We chose two amplitude ranges of the stimulations, around 25 ?A/cm2 and 63 ?A/cm2 from peak to peak, with three values (at steps of about 2.5%) around each, to generate, respectively, inhibitory and excitatory effects of the primary motor cortex. We checked such changes online through transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs). Results: Cortical excitability changes depended upon current density (p = 0.001). Low current densities decreased MEP amplitudes (inhibition) while high current densities increased them (excitation). Conclusions: tACS targeting bilateral homologous cortical areas can induce online inhibition or excitation as a function of the current density.

Childhood disruptive behaviors can be precursors to later deviance. To verify the efficacy of karate, a complex psychomotor activity that enhances self-regulation and executive skills, as an intervention for externalizing behaviors, 16 children, ranging in age from 8 to 10 years, and meeting diagnostic criteria for oppositional defiant disorder were studied. Eight were randomly assigned to a 10-month Wa Do Ryu karate program, whereas 8 children received no intervention. The children were assigned to a larger karate class, composed of typically developing youngsters. Three domains of temperament—intensity, adaptability, and mood regulation—were measured at the beginning and the end of the training period in all 16 participants. A significant improvement in temperament scale scores was measured in the karate group for all tested items compared to controls. Karate, when properly taught, can be a useful adjunct in multimodal programs aimed at externalizing behavior reduction.

To assess whether serum copper in Alzheimer disease (AD) correlates with cognitive scores, beta-amyloid, and other CSF markers of neurodegeneration.The authors studied copper, ceruloplasmin, total peroxide, and antioxidants levels (TRAP) in serum; beta-amyloid in plasma; and copper, beta-amyloid, h-tau, and P-tau in the CSF of 28 patients with AD and 25 healthy controls, in relation to clinical status.Serum copper (p < 0.0001), peroxides (p = 0.002), a copper fraction unexplained by ceruloplasmin (p < 0.0001), and CSF h-tau (p = 0.001) were increased in AD, whereas serum TRAP (p = 0.03) and CSF beta-amyloid were decreased (p < 0.0001). Plasma beta-amyloid increased with age in healthy controls (r = 0.6; p = 0.05). CSF markers of AD correlated with serum copper variables. CSF copper was partially dependent on the serum copper fraction unexplained by ceruloplasmin (t = 2.2, p = 0.04). CSF beta-amyloid seemed to be related to serum copper (r = -0.46; p = 0.002). Mini-Mental Status Examination scores correlated positively with beta-amyloid (r = 0.46, p = 0.002) and inversely with copper unexplained by ceruloplasmin (r = -0.45, p = 0.003).The authors' results confirm the existence of changes in copper component distribution, particularly the copper fraction unexplained by ceruloplasmin and support the hypothesis of a beta-amyloid and copper connection in Alzheimer disease.

Objective To evaluate the prognostic impact of elevated total vascular resistance (TVR) on the outcome of pregnancy in early mild gestational hypertension (EMGH). Design Prospective observational study. Setting Data collected from women with EMGH referred to the obstetrics outpatient clinic of Tor Vergata University from June 2003 to June 2005. Population A total of 268 women with EMGH (systolic and diastolic blood pressure [BP] 140–150 mmHg and 90–99 mmHg, respectively, without significant proteinuria). Methods Women had a maternal echocardiographic examination and BP examination within 24 hours of diagnosis. From this, the TVR was calculated and the geometric pattern of the left ventricle assessed. Main outcome measures Fetal/maternal adverse outcomes (pre-eclampsia, preterm delivery, placental abruption, other maternal medical problems, fetal distress, neonatal low birthweight, admittance to neonatal intensive care unit and perinatal death). Results Ninety-two out of the 268 pregnancies showed adverse outcomes (34.3%). The best independent predictor for the composite of maternal and fetal complications was TVR (OR 64.4, 95% CI 25.9–160.1). The cutoff value was 1340 dyn seconds/cm5 with a sensitivity and a specificity of 90 and 91%, respectively. Concentric geometry of the left ventricle was also an independent predictor (OR 4.72, 95% CI 1.85–12.04). Conclusions Echocardiography could help in identifying women with EMGH who subsequently develop maternal and fetal complications, allowing a classification in high-risk (TVR > 1340 dyn seconds/cm5, concentric geometry of the left ventricle) and low-risk women (TVR < 1340 dyn seconds/cm5, nonconcentric geometry of the left ventricle) for adverse outcomes of pregnancy.

Performance on an emotional labeling task in response to schematic facial patterns representing five basic emotions without the concurrent presentation of a verbal category was investigated in 40 parents of children with autism and 40 matched controls. ‘Autism fathers’ performed worse than ‘autism mothers’, who performed worse than controls in decoding displays representing sadness or disgust.This indicates the need to include facial expression decoding tasks in genetic research of autism. In addition, emotional expression interactions between parents and their children with autism, particularly through play, where affect and prosody are ‘physiologically’ exaggerated, may stimulate development of social competence. Future studies could benefit from a combination of stimuli including photographs and schematic drawings, with and without associated verbal categories. This may allow the subdivision of patients and relatives on the basis of the amount of information needed to understand and process social-emotionally relevant information.

Cerebral hemodynamics play a pivotal role in stroke pathogenesis. Transcranial Doppler (TCD) studies demonstrated the importance of cerebral vasomotor reactivity (VMR) on the outcome of carotid artery occlusion (CAO). So far, positron emission tomography represents the best technique for detecting both hemodynamic and metabolic aspects of cerebral perfusion adaptive processes in cerebrovascular patients. Near-infrared spectroscopy (NIRS) is a new method allowing for a non-invasive assessment of cerebral blood flow and hemoglobin (Hb) oxygenation parameters. A recent TCD and NIRS study demonstrated that patients with symptomatic CAO had lower VMR values measured by TCD and lower oxygen saturation (oxygen%) increases detected by NIRS than asymptomatic ones. The parameters were obtained simultaneously after CO2 inhalation. The present study aims to investigate if Hb oxygen % could represent also at rest a marker of hemodynamic status in carotid disease. Thirty-five symptomatic and 17 asymptomatic patients with CAO underwent a simultaneous examination by means of TCD and NIRS at rest condition and during CO2 reactivity test. Symptomatic patients presented with oxygen% values at rest higher (p = 0.001) and VMR values lower (p

Background and Purpose— The aim of this study was to explore the possible contribution of alterations in cerebral hemodynamics to the evolution of cognitive impairment in patients with Alzheimer disease (AD). Method— Fifty-three patients with AD were investigated. The evolution of cognitive decline over 12 months was evaluated by means of changes in Mini Mental State Examination (MMSE) and AD Assessment Scale for Cognition (ADAS-Cog) scores. Demographic characteristics, vascular risk profile, pharmacological treatment, and presence of white matter lesions were assessed at entry. Further, a basal evaluation of cerebrovascular reactivity to hypercapnia was measured with transcranial Doppler ultrasonography using the breath-holding index (BHI). Results— Of all the variables considered, both MMSE and ADAS-Cog changes had the highest correlation with BHI, followed by age and diabetes. After subdividing both cognitive measures reductions into bigger and smaller-than-average decline (2 points for MMSE; 5 points for ADAS-Cog), multiple logistic regression indicated BHI as the sole significant predictor of cognitive decline. Conclusions— These results show an association between impaired cerebral microvessels functionality and unfavorable evolution of cognitive function in patients with AD. Further research is needed to fully establish whether altered cerebral hemodynamics may be considered an independent factor in sustaining cognitive decline progression or an effect of pathological processes involved in AD.

Objectives Validation of an Italian version of the Telephone Interview for Cognitive Status (I-TICS). Methods Telephone administration of the I-TICS within 6 weeks of face-to-face testing with the Mini Mental State Examination (MMSE), in Probable Alzheimer's disease (AD) patients and healthy controls. Two hundred and seven consecutive outpatients with cognitive impairment were recruited from Dementia Clinic of University Campus BioMedico. Of these, 45 probable AD patients with complete data were analyzed. Other dementias, Mild Cognitive Impairment (MCI), and patients with incomplete data were excluded. The control sample consisted of 64 age- and sex-matched healthy subjects. For diagnosis, an extensive clinical evaluation, laboratory testing, brain imaging, EEG, neuropsychological battery and a depression scale were used. For I-TICS validation, telephone I-TICS and face-to-face MMSE were administered. Results The I-TICS correlated highly and linearly with the MMSE (Pearson's r = 0.904). Conversion equations are provided. Sensitivity and specificity were similar between tests (area under curve = 0.894 for the I-TICS; 0.966 for the MMSE). I-TICS sensitivity was 84% and specificity 86% at a cut-off score of 28. No significant difference in accuracy with the MMSE was present. Total agreement between I-TICS and MMSE was ‘substantial’ at 86% (Cohen's K = 0.717). Repeated testing in a subset of patients showed a disease progression related decrease of 4.2 points/year (t = 2.664; p = 0.018) in I-TICS scores. Conclusion The I-TICS is a valid instrument in clinical and research screening and monitoring of AD. Potential applications in other dementias and MCI are worth further studies. Copyright © 2006 John Wiley & Sons, Ltd.

A semantic battery comprising items from living and nonliving categories was administered to a sample of subjects suffering from probable Alzheimer's type dementia (n=20). The results were analyzed to test the role of semantic distance in predicting group accuracy and its possible causal link with the phenomenon of a category-specific deficit for living things in the experimental population. Our findings confirm a category effect favoring nonliving items (over and above the role of confounding variables) in patients with Alzheimer's disease and support the major role of an imbalance of semantic distance in the testing material in the genesis of this phenomenon.

In this paper, we describe a patient (LI) suffering from semantic dementia who showed a category-specific naming impairment for living things over and above the effects of several nonsemantic confounding variables. We investigated the characteristics of LI's impairment to address the following three issues raised in three different accounts of category-specific impairments: (i) the role of an imbalance in the loss of sensory compared to nonsensory features (assumed by the Sensory Functional Theory [Warrington, E. K., & Shallice, T. (1984). Category-specific semantic impairments. Brain, 107, 829-859]); (ii) the role of cross domain differences in Feature Correlation (assumed by the Conceptual Structure Account [Moss, H., Tyler, L. K., & Devlin, J. T. (2002). The emergence of category-specific deficits in a distributed semantic system. In: E. M. E. Forde & G. W. Humphreys (Eds.), Category Specificity in Brain and Mind (pp. 115-147). New York: Psychology Press]); (iii) the role of semantic distance (proposed by Cree and McRae [Cree, G. S., & McRae, K. (2003). Analyzing the factors underlying the structure and computation of the meaning of chipmunk, cherry, chisel, cheese, and cello (and many other such concrete nouns). Journal of Experimental Psychology: General, 132, 163-201]). We found that semantic distance was the only factor causally linked to LI's poorer performance on living things. In fact, her naming performance was less accurate on items that had many semantic neighbours, which is typical of living things. On the contrary, a feature listing task revealed that the features available to LI were not predicted by their level of correlation, as expected by the Conceptual Structure Account. Finally, at variance with the Sensory Functional Theory, although LI quoted sensory features less accurately than nonsensory ones, this did not give rise to a disproportionate loss of semantic features in the living domain.