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EMTICS Collaborative Group., Genetic predisposition, autoimmunity and environmental factors [e.g. pre- and perinatal difficulties, Group A Streptococcal (GAS) and other infections, stress-inducing events] might interact to create a neurobiological vulnerability to the development of tics and associated behaviours. However, the existing evidence for this relies primarily on small prospective or larger retrospective population-based studies, and is therefore still inconclusive. This article describes the design and methodology of the EMTICS study, a longitudinal observational European multicentre study involving 16 clinical centres, with the following objectives: (1) to investigate the association of environmental factors (GAS exposure and psychosocial stress, primarily) with the onset and course of tics and/or obsessive–compulsive symptoms through the prospective observation of at-risk individuals (ONSET cohort: 260 children aged 3–10 years who are tic-free at study entry and have a first-degree relative with a chronic tic disorder) and affected individuals (COURSE cohort: 715 youth aged 3–16 years with a tic disorder); (2) to characterise the immune response to microbial antigens and the host’s immune response regulation in association with onset and exacerbations of tics; (3) to increase knowledge of the human gene pathways influencing the pathogenesis of tic disorders; and (4) to develop prediction models for the risk of onset and exacerbations of tic disorders. The EMTICS study is, to our knowledge, the largest prospective cohort assessment of the contribution of different genetic and environmental factors to the risk of developing tics in putatively predisposed individuals and to the risk of exacerbating tics in young individuals with chronic tic disorders., This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under Grant agreement no. 278367. Schrag was supported by the National Institute for Health Research UCLH Biomedical Research Centre, and Müller, Burger, Schnell and Weidinger by Stiftung Immunität und Seele. This research was supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London (Heyman); partially sponsored by GSK Vaccines (Margarit, Bartolini); and Deutsche Forschungsgemeinschaft (DFG): projects 1692/3-1, 4-1 (Münchau).

OBJECTIVE: To evaluate the effect of fetal sex on singleton pregnancy growth charts customized for parental characteristics, race, and parity Methods: In a multicentric cross-sectional study, 8070 ultrasonographic examinations from low-risk singleton pregnancies between 16 and 40 weeks of gestation were considered. The fetal measurements obtained were biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), and femur length (FL). Quantile regression was used to examine the impact of fetal sex across the biometric percentiles of the fetal measurements considered together with parents' height, weight, parity, and race. RESULTS: Fetal gender resulted to be a significant covariate for BDP, HC, and AC with higher values for male fetuses (p ≤ 0.0009). Minimal differences were found among sexes for FL. Parity, maternal race, paternal height and maternal height, and weight resulted significantly related to the fetal biometric parameters considered independently from fetal gender. CONCLUSION: In this study, we constructed customized biometric growth charts for fetal sex, parental, and obstetrical characteristics using quantile regression. The use of gender-specific charts offers the advantage to define individualized normal ranges of fetal biometric parameters at each specific centile. This approach may improve the antenatal identification of abnormal fetal growth.

Objective\ud \ud We aimed to characterize the demographics of adults with dissociative (nonepileptic) seizures, placing emphasis on distribution of age at onset, male:female ratio, levels of deprivation, and dissociative seizure semiology.\ud Methods\ud \ud We collected demographic and clinical data from 698 adults with dissociative seizures recruited to the screening phase of the CODES (Cognitive Behavioural Therapy vs Standardised Medical Care for Adults With Dissociative Non‐Epileptic Seizures) trial from 27 neurology/specialist epilepsy clinics in the UK. We described the cohort in terms of age, age at onset of dissociative seizures, duration of seizure disorder, level of socioeconomic deprivation, and other social and clinical demographic characteristics and their associations.\ud Results\ud \ud In what is, to date, the largest study of adults with dissociative seizures, the overall modal age at dissociative seizure onset was 19 years; median age at onset was 28 years. Although 74% of the sample was female, importantly the male:female ratio varied with age at onset, with 77% of female but only 59% of male participants developing dissociative seizures by the age of 40 years. The frequency of self‐reported previous epilepsy was 27%; nearly half of these epilepsy diagnoses were retrospectively considered erroneous by clinicians. Patients with predominantly hyperkinetic dissociative seizures had a shorter disorder duration prior to diagnosis in this study than patients with hypokinetic seizures (P < .001); dissociative seizure type was not associated with gender. Predominantly hyperkinetic seizures were most commonly seen in patients with symptom onset in their late teens. Thirty percent of the sample reported taking antiepileptic drugs; this was more common in men. More than 50% of the sample lived in areas characterized by the highest levels of deprivation, and more than two‐thirds were unemployed.\ud Significance\ud \ud Females with dissociative seizures were more common at all ages, whereas the proportion of males increased with age at onset. This disorder was associated with socioeconomic deprivation. Those with hypokinetic dissociative seizures may be at risk for delayed diagnosis and treatment.

OBJECTIVES: The purpose of this study was to construct fetal biometric charts between 16 and 40 weeks' gestation that were customized for parental characteristics, race, and parity, using quantile regression analysis. METHODS: In a multicenter cross-sectional study, 8070 sonographic examinations from low-risk pregnancies between 16 and 40 weeks' gestation were analyzed. The fetal measurements obtained were biparietal diameter, head circumference, abdominal circumference, and femur diaphysis length. Quantile regression was used to examine the impact of parental height and weight, parity, and race across biometric percentiles for the fetal measurements considered. RESULTS: Paternal and maternal height were significant covariates for all of the measurements considered (P < .05). Maternal weight significantly influenced head circumference, abdominal circumference, and femur diaphysis length. Parity was significantly associated with biparietal diameter and head circumference. Central African race was associated with head circumference and femur diaphysis length, whereas North African race was only associated with femur diaphysis length. CONCLUSIONS: In this study we constructed customized biometric growth charts using quantile regression in a large cohort of low-risk pregnancies. These charts offer the advantage of defining individualized normal ranges of fetal biometric parameters at each specific percentile corrected for parental height and weight, parity, and race. This study supports the importance of including these variables in routine sonographic screening for fetal growth abnormalities.

International audience; A working group of the European Society for the Study of Tourette Syndrome (ESSTS) has developed the first European assessment guidelines of Tourette Syndrome (TS). The available literature including national guidelines was thoroughly screened and extensively discussed in the expert group of ESSTS members. Detailed clinical assessment guidelines of tic disorders and their comorbidities in both children and adults are presented. Screening methods that might be helpful and necessary for specialists' differential diagnosis process are suggested in order to further analyse cognitive abilities, emotional functions and motor skills. Besides clinical interviews and physical examination, additional specific tools (questionnaires, checklists and neuropsychological tests) are recommended.

International audience; To develop a European guideline on pharmacologic treatment of Tourette syndrome (TS) the available literature was thoroughly screened and extensively discussed by a working group of the European Society for the Study of Tourette syndrome (ESSTS). Although there are many more studies on pharmacotherapy of TS than on behavioral treatment options, only a limited number of studies meets rigorous quality criteria. Therefore, we have devised a two-stage approach. First, we present the highest level of evidence by reporting the findings of existing Cochrane reviews in this field. Subsequently, we provide the first comprehensive overview of all reports on pharmacological treatment options for TS through a MEDLINE, PubMed, and EMBASE search for all studies that document the effect of pharmacological treatment of TS and other tic disorders between 1970 and November 2010. We present a summary of the current consensus on pharmacological treatment options for TS in Europe to guide the clinician in daily practice. This summary is, however, rather a status quo of a clinically helpful but merely low evidence guideline, mainly driven by expert experience and opinion, since rigorous experimental studies are scarce.

Objective The current criteria for conversion disorder in the Diagnostic and Statistical Manual of Mental Disorders rely on the assumption that neurological disorders can be distinguished from conversion disorders through clinical assessment. This study aims to assess inter-rater agreement among clinicians with experience in the diagnosis of various hyperkinetic jerky movements, including psychogenic jerks.Methods 60 patients with psychogenic jerks, myoclonus or tics were rated by international experts using a standardised survey resembling daily clinical practice. The survey included the following diagnostic steps: a short video offering a visual impression of the patients and their jerky movements, medical history, neurological examination (on video), additional investigations and the findings of a standardised psychiatric interview. The diagnosis and diagnostic certainty were scored after each step.Results After all clinical information was given, moderate inter-rater agreement was reached (kappa=0.56 +/- 0.1) with absolute agreement (100%) of experts on the diagnosis in 12 (20%) patients and reasonable agreement (>75%) in 43 (72%) patients. Psychiatric evaluation did not contribute to inter-rater agreement or diagnostic certainty.Conclusions Our findings illustrate the fact that experienced movement disorder specialists moderately agree on the clinical diagnosis of jerky movements. Clinical assessment, especially by a team of clinicians in challenging individual cases, might improve diagnostic agreement.

International audience; This clinical guideline provides recommendations for the behavioural and psychosocial interventions (BPI) of children and adolescents with tic disorders prepared by a working group of the European Society for the Study of Tourette Syndrome (ESSTS). A systematic literature search was conducted to obtain an update on the efficacy of BPI for tics. Relevant studies were identified using computerised searches of the Medline and PsycINFO databases and the Cochrane Library for the years 1950-2010. The search identified no meta-analyses, yet twelve (systematic) reviews and eight randomised controlled trials provided evidence for the current review. Most evidence was found for habit reversal training (HRT) and the available but smaller evidence also supports the efficacy of exposure with response prevention (ERP). Both interventions are considered first line behavioural treatments for tics for both children and adults and should be offered to a patient, taking into account his preference. Treatments that are considered second line or add-on behavioural treatments are contingency management, function based interventions and relaxation training. Neurofeedback is still experimental. Almost no research was identified that examined the efficacy of psychosocial interventions, e.g., psychoeducation and group work. Based on clinical practice, this guideline recommends behavioural treatment as first line offer to patients in most cases. It should be embedded within a psychoeducational and supportive context and can be combined with drug treatment.

Family studies have consistently shown that Tourette syndrome (TS) is a familial disorder and twin studies have clearly indicated a genetic contribution in the etiology of TS. Whereas early segregation studies of TS suggested a single-gene autosomal dominant disorder, later studies have pointed to more complex models including additive and multifactorial inheritance and likely interaction with genetic factors. While the exact cellular and molecular base of TS is as yet elusive, neuroanatomical and neurophysiological studies have pointed to the involvement of cortico-striato-thalamocortical circuits and abnormalities in dopamine, glutamate, gamma-aminobutyric acid, and serotonin neurotransmitter systems, with the most consistent evidence being available for involvement of dopamine-related abnormalities, that is, a reduction in tonic extracellular dopamine levels along with hyperresponsive spike-dependent dopamine release, following stimulation. Genetic and gene expression findings are very much supportive of involvement of these neurotransmitter systems. Moreover, intriguingly, genetic work on a two-generation pedigree has opened new research pointing to a role for histamine, a so far rather neglected neurotransmitter, with the potential of the development of new treatment options. Future studies should be aimed at directly linking neurotransmitter-related genetic and gene expression findings to imaging studies (imaging genetics), which enables a better understanding of the pathways and mechanisms through which the dynamic interplay of genes, brain, and environment shapes the TS phenotype.

International audience; Ten years ago deep brain stimulation (DBS) has been introduced as an alternative and promising treatment option for patients suffering from severe Tourette syndrome (TS). It seemed timely to develop a European guideline on DBS by a working group of the European Society for the Study of Tourette Syndrome (ESSTS). For a narrative review a systematic literature search was conducted and expert opinions of the guidelines group contributed also to the suggestions. Of 63 patients reported so far in the literature 59 had a beneficial outcome following DBS with moderate to marked tic improvement. However, randomized controlled studies including a larger number of patients are still lacking. Although persistent serious adverse effects (AEs) have hardly been reported, surgery-related (e.g., bleeding, infection) as well as stimulation-related AEs (e.g., sedation, anxiety, altered mood, changes in sexual function) may occur. At present time, DBS in TS is still in its infancy. Due to both different legality and practical facilities in different European countries these guidelines, therefore, have to be understood as recommendations of experts. However, among the ESSTS working group on DBS in TS there is general agreement that, at present time, DBS should only be used in adult, treatment resistant, and severely affected patients. It is highly recommended to perform DBS in the context of controlled trials.

OBJECTIVE: A prospective multicenter randomized trial was designed to evaluate the clinical efficacy of postoperative protein-sparing therapy. SUMMARY BACKGROUND DATA: The metabolic effect of postoperative protein-sparing therapy has been shown by several studies, but the clinical utility of this treatment has not been investigated by large prospective trials. METHODS: Six hundred seventy-eight patients undergoing major elective abdominal surgery were randomly assigned to receive either protein-sparing therapy after surgery (protein-sparing therapy group) or conventional therapy (control group). The patients were monitored for postoperative complications and mortality. RESULTS: The rate of major postoperative complications was similar in both groups (protein-sparing therapy group, 19.5%; control group, 20.9%; p=0.66) as were the overall postoperative mortality rates (4.7% and 3.5%, respectively; p=0.43). CONCLUSIONS: The present study indicates that routine protein-sparing therapy for patients normonourished or mildly malnourished undergoing major abdominal surgery is not clinically justified.

Despite growing information, questions still surround various aspects of post-stroke depression (PSD). The Italian multicenter observational study Destro was designed to help clarify in a large sample the frequency and clinical impact of PSD. A total of 53 centers consecutively admitted 1064 patients with ischemic or hemorrhagic stroke, assessing them periodically in the first 9 months after the event. Patients with depression were followed for two years. Depression was diagnosed on clinical examination, verbal (Beck Depression Inventory) and non-verbal rating systems (Visual Analog Mood Scale), identifying the nosographic condition attributable to the mental state. The patient's clinical history, residual independence, and post-ictus quality of life were also taken into account. PSD was detected in 383 patients (36 %), most of whom had minor depression (80.17 %), with dysthymia, rather than major depression and adaptation disorder. About 80% developed depression within three months of the stroke. Cases with later onset tended to have less severe symptoms. Risk factors were a history of depression, severe disability, previous stroke and female sex, but not the type and site of the vascular lesion. PSD was not correlated with any increase in mortality or cerebrovascular recurrences, but these patients had lower autonomy and quality of life ratings. In conclusion, patients should be close observed in the first few weeks after a stroke in order to check for depression,which is more likely in those with clear risk factors and may spoil their quality of life.

Objective: The Italian multicenter observational study depression in stroke (DESTRO) aimed to identify risk factors for poststroke depression (PSD) and quantify the likelihood of it arising in various categories of patients. Method: Mood evaluation was performed in 1064 consecutive stroke patients by means of Beck Depression Inventory and Visual Analog Mood Scale. Depressive symptoms were classified using the DSM-IV and revised WHO criteria for depression in the course of a neurological disorder. Results: Poststroke depression was seen in 36% of the survivors, with dysthymia by far the predominant form (80.7%). Female sex, disability, previous cerebrovascular or depressive episodes were significantly associated with an increased risk of depression. Combinations of these factors raised the risk of PSD exponentially, from 24.3 to 89.1%. The site of the stroke did not come into the uni- or multivariate analysis. Conclusion.: At admission, it is possible to predict the likelihood of PSD and quantify the relative risk.

Purpose: To compare the performance of the algorithms proposed by the Fetal Medicine Foundation in 2012 and BCNatal in 2013 in an Italian population. Methods: A multicentric prospective study was carried out which included pregnancies at 11–13weeks’ gestation from Jan 2014 through May 2017. Two previously published algorithms were used for the calculation of the “a priori” risk of preeclampsia (based on risk factors from medical history) in each individual. Results: In a study population of 11,632 cases, 67 (0.6%) developed early preeclampsia and 211 (1.8%) developed late preeclampsia. The detection rates (95% CI) for early and late preeclampsia were 58.2% (45.5–70.2) vs. 41.8% (29.6–54.5) (p value < 0.05) and 44.1% (37.3–51.1) vs. 38% (31.3–44.8) (p value < 0.05) for the Fetal Medicine Foundation and BCNatal, respectively (at a 10% false positive rate). The associated risk was 1:226 and 1:198 (p value ns) for early PE, and 1:17 and 1:24 (p value ns) for late PE for the Fetal Medicine Foundation and BCNatal, respectively. Conclusions: The Fetal Medicine Foundation screening for preeclampsia at 11–13weeks’ gestation scored the highest detection rate for both early and late PE. At a fixed 10% false positive rate, the estimated “a priori” risks of both the Fetal Medicine Foundation and the BCNatal algorithms in an Italian population were quite similar, and both were reliable and consistent.

Recent imaging studies have associated Developmental dyscalculia (DD) to structural and functional alterations corresponding Parietal and the Prefrontal cortex (PFC). Since these areas were shown also to be involved in timing abilities, we hypothesized that time processing is abnormal in DD. We compared time processing abilities between 10 children with pure DD (8 years old) and 11 age-matched healthy children. Results show that the DD group underestimated duration of a sub-second scale when asked to perform a time comparison task. The timing abnormality observed in our DD participants is consistent with evidence of a shared fronto-parietal neural network for representing time and quantity. © 2012 Copyright Taylor and Francis Group, LLC.

Methods: Using a validated questionnaire, we screened eye symptoms (burning sensation, grittiness, dry eye) in 333 first-degree relatives of 140 probands with different forms of primary adult-onset dystonia, 208 healthy subjects, and 293 patients with primary blepharospasm. Results: The rate of eye symptoms was similar in the relatives of focal dystonia patients and in healthy subjects (adjusted HR, 1.1; 95% CI, 0.7–1.7; P = .69), thus suggesting a common origin of eye symptoms in both groups. A higher rate was observed in blepharospasm patients (adjusted HR, 2; 95% CI, 1.4–2.9; P < .0001). Relatives of focal dystonia patients who developed blepharospasm were more likely to have preceding eye symptoms than were relatives who developed focal dystonia other than blepharospasm (BSP) or relatives who did not develop dystonia. Conclusions: Eye symptoms reported by relatives of patients with focal dystonia probably result from eye diseases and are not part of the clinical spectrum of blepharospasm. © 2011 Movement Disorder Society

Background: Although environmental and genetic factors may contribute to the etiology of blepharospasm, their relative contribution in causing familial and sporadic blepharospasm is unknown. Methods: First-degree relatives of 122 patients with primary blepharospasm were examined with a validated 2-step diagnostic procedure, including a screening questionnaire and examination of some relatives. Examiners were blinded to the questionnaire data for family history of probands. Data for demographic and clinical features, prior ophthalmologic complaints, and nondecaffeinated coffee intake were collected from probands before family investigation. Results: Dystonia was diagnosed in 27 relatives from 23 families (20% rate of family history for dystonia). No significant differences were found between familial and sporadic cases in the frequency of coffee drinking and eye diseases or in sex, age at onset, or tendency to spread. Multivariable conditional logistic analysis testing of 67 case patients and 127 family-matched unaffected siblings yielded a significant positive association between blepharospasm and prior eye diseases (adjusted odds ratio [OR] 2.5; 95% confidence interval [CI] 1.1–6.1; p = 0.03) and a significant inverse association between case status and ever coffee drinking (adjusted OR 0.23; 95% CI 0.1–0.8; p = 0.02). Conclusions: The new information from this large family-based study on primary blepharospasm strongly supports eye diseases and coffee as risk factors for blepharospasm. The finding that the 2 environmental exposures exerted a similar influence on familial and sporadic blepharospasm, together with the convergent phenotypic expression in familial and sporadic cases, implies that familial and sporadic blepharospasm probably share a common etiologic background.

This study investigated whether vitamin D is associated with the presence or severity of chronic tic disorders and their psychiatric comorbidities. This cross-sectional study compared serum 25-hydroxyvitamin D [25(OH)D] (ng/ml) levels among three groups: children and adolescents (3–16 years) with CTD (n = 327); first-degree relatives (3–10 years) of individuals with CTD who were assessed for a period of up to 7 years for possible onset of tics and developed tics within this period (n = 31); and first-degree relatives who did not develop tics and were ≥ 10 years old at their last assessment (n = 93). The relationship between 25(OH)D and the presence and severity of tics, as well as comorbid obsessive–compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD), were analysed controlling for age, sex, season, centre, latitude, family relatedness, and comorbidities. When comparing the CTD cohort to the unaffected cohort, the observed result was contrary to the one expected: a 10 ng/ml increase in 25(OH)D was associated with higher odds of having CTD (OR 2.08, 95% CI 1.27–3.42, p p = 0.01) and was inversely associated with ADHD symptom severity (β = − 2.52, 95% CI − 4.16–0.88, p

Background There is clear evidence that tic disorders (TDs) are associated with psychosocial stress as well as emotional and behavioral problems. Studies have shown that individuals with TDs have higher acute physiological stress responses to external, single stressors (as reflected by saliva cortisol). The aim of the present study was to examine a physiological marker of longer-term stress (as reflected by hair cortisol concentration) in children and adolescents with TDs and unaffected siblings of individuals with TDs. Methods Two samples of a European cohort were included in this study. In the COURSE sample, 412 children and adolescents aged 3–16 years with a chronic TD including Tourette syndrome according to DSM IV-TR criteria were included. The ONSET sample included 131 3–10 years old siblings of individuals with TDs, who themselves had no tics. Differences in hair cortisol concentration (HCC) between the two samples were examined. Within the COURSE sample, relations of HCC with tic severity and perceived psychosocial stress as well as potential effects and interaction effects of comorbid emotional and behavioral problems and psychotropic medication on HCC were investigated. Results There were no differences in HCC between the two samples. In participants with TDs, there were no associations between HCC and tic severity or perceived psychosocial stress. No main effects of sex, psychotropic medication status and comorbid emotional and behavioral problems on HCC were found in participants with TDs. Conclusion A link between HCC and TDs is not supported by the present results.

Objective: To validate the performance of a first-trimester simple risk score based on the ASPRE trial algorithm for pre-eclampsia. Design: Multicentre retrospective cohort analysis. Setting: Four Italian hospitals. Population: Unselected nulliparous women at 11–13weeks of gestation from January 2014 through to January 2018. Methods: Model performance was evaluated based on discrimination and calibration. Main outcome measures: Delivery before 37weeks of gestation with a diagnosis of pre-eclampsia. Results: Based on 73 preterm pre-eclampsia cases and 7546 controls (including 101 cases of late pre-eclampsia), the area under the receiver operating characteristics curve was 0.659 (95% CI 0.579–0.726). The sensitivity was 32.9% (95% CI 22.1–43.7) at a false-positive rate of 8.8%. The positive likelihood ratio was 3.74 (95% CI 2.67–5.23), the positive predictive value was 3.49% (95% CI 2.12–4.86%) and the negative predictive value was 99.3% (95% CI 99.1–99.5%). The sensitivity and positive likelihood ratio were approximately 40% lower than in the original study. The calibration analysis showed a good agreement between observed and expected risks (P=0.037). Comparison with the Fetal Medicine Foundation (FMF) algorithm yielded a difference in the area under the curve of 0.084 (P=0.007). Conclusions: In our Italian population, the simple risk score had a lower performance than expected for the prediction of preterm pre-eclampsia in nulliparous women. The FMF algorithm applied to the same data set resulted in a better prediction. Tweetable abstract: Simple risk score predicts preterm pre-eclampsia in Italy.

Introduction Delirium and sarcopenia are common, although underdiagnosed, geriatric syndromes. Several pathological mechanisms can link delirium and low skeletal muscle mass, but few studies have investigated their association. We aimed to investigate (1) the association between delirium and low skeletal muscle mass and (2) the possible role of calf circumference mass in finding cases with delirium. Methods The analyses were conducted employing the cross-sectional “Delirium Day” initiative, on patient 65 years and older admitted to acute hospital medical wards, emergency departments, rehabilitation wards, nursing homes and hospices in Italy in 2017. Delirium was diagnosed as a 4 + score at the 4-AT scale. Low skeletal muscle mass was operationally defined as calf circumference ≤ 34 cm in males and ≤ 33 cm in females. Logistic regression models were used to investigate the association between low skeletal muscle mass and delirium. The discriminative ability of calf circumference was evaluated using non-parametric ROC analyses. Results A sample of 1675 patients was analyzed. In total, 73.6% of participants had low skeletal muscle mass and 24.1% exhibited delirium. Low skeletal muscle mass and delirium showed an independent association (OR: 1.50; 95% CI 1.09–2.08). In the subsample of patients without a diagnosis of dementia, the inclusion of calf circumference in a model based on age and sex significantly improved its discriminative accuracy [area under the curve (AUC) 0.69 vs 0.57, p Discussion and conclusion Low muscle mass is independently associated with delirium. In patients without a previous diagnosis of dementia, calf circumference may help to better identify those who develop delirium.

The recently reported CXCR4 antagonist 3 (Ac-Arg-Ala-[DCys-Arg-2Nal-His-Pen]-CO2H) was investigated as a molecular scaffold for a CXCR4-targeted positron emission tomography (PET) tracer. Toward this end, 3 was functionalized with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 1,4,7-triazacyclononanetriacetic acid (NOTA). On the basis of convincing affinity data, both tracers, [68Ga]NOTA analogue ([68Ga]-5) and [68Ga]DOTA analogue ([68Ga]-4), were evaluated for PET imaging in "in vivo" models of CHO-hCXCR4 and Daudi lymphoma cells. PET imaging and biodistribution studies revealed higher CXCR4-specific tumor uptake and high tumor/background ratios for the [68Ga]NOTA analogue ([68Ga]-5) than for the [68Ga]DOTA analogue ([68Ga]-4) in both in vivo models. Moreover, [68Ga]-4 and [68Ga]-5 displayed rapid clearance and very low levels of accumulation in all nontarget tissues but the kidney. Although the high tumor/background ratios observed in the mouse xenograft model could partially derive from the hCXCR4 selectivity of [68Ga]-5, our results encourage its translation into a clinical context as a novel peptide-based tracer for imaging of CXCR4-overexpressing tumors.

Objective: Sensory deficits are important risk factors for delirium but have been investigated in single-center studies and single clinical settings. This multicenter study aims to evaluate the association between hearing and visual impairment or bi-sensory impairment (visual and hearing impairment) and delirium. Design: Cross-sectional study nested in the 2017 "Delirium Day" project. Setting and participants: Patients 65 years and older admitted to acute hospital medical wards, emergency departments, rehabilitation wards, nursing homes, and hospices in Italy. Methods: Delirium was assessed with the 4AT (a short tool for delirium assessment) and sensory deficits with a clinical evaluation. We assessed the association between delirium, hearing and visual impairment in multivariable logistic regression models, adjusting for: Model 1, we included predisposing factors for delirium (ie, dementia, weight loss and autonomy in the activities of daily living); Model 2, we added to Model 1 variables, which could be considered precipitating factors for delirium (ie, psychoactive drugs and urinary catheters). Results: A total of 3038 patients were included; delirium prevalence was 25%. Patients with delirium had a higher prevalence of hearing impairment (30.5% vs 18%; P < .001), visual impairment (24.2% vs 15.7%; P < .01) and bi-sensory impairment (16.2% vs 7.5%) compared with those without delirium. In the multivariable logistic regression analysis, the presence of bi-sensory impairment was associated with delirium in Model 1 [odds ratio (OR) 1.5, confidence interval (CI) 1.2-2.1; P = .00] and in Model 2 (OR 1.4; CI 1.1-1.9; P = .02), whereas the presence of visual and hearing impairment alone was not associated with delirium either in Model 1 (OR 0.8; CI 0.6-1.2, P = .36; OR 1.1; CI 0.8-1.4; P = .42) or in Model 2 (OR 0.8, CI 0.6-1.2, P = .27; OR 1.1, CI 0.8-1.4, P = .63). Conclusions and implications: Our findings support the importance of routine screening and specific interventions by a multidisciplinary team to implement optimal management of sensory impairments and hence prevention and the management of the patients with delirium.

The Yale Global Tic Severity Scale (YGTSS) is a clinician-rated instrument considered as the gold standard for assessing tics in patients with Tourette's Syndrome and other tic disorders. Previous psychometric investigations of the YGTSS exhibit different limitations such as small sample sizes and insufficient methods. To overcome these shortcomings, we used a subsample of the large-scale “European Multicentre Tics in Children Study” (EMTICS) including 706 children and adolescents with a chronic tic disorder and investigated convergent, discriminant and factorial validity, as well as internal consistency of the YGTSS. Our results confirm acceptable convergent and good to very good discriminant validity, respectively, indicated by a sufficiently high correlation of the YGTSS total tic score with the Clinical Global Impression Scale for tics (rs = 0.65) and only low to medium correlations with clinical severity ratings of attention deficit/hyperactivity symptoms (rs = 0.24), obsessive–compulsive symptoms (rs = 27) as well as internalizing symptoms (rs = 0.27). Internal consistency was found to be acceptable (Ω = 0.58 for YGTSS total tic score). A confirmatory factor analysis supports the concept of the two factors “motor tics” and “phonic tics,” but still demonstrated just a marginal model fit (root mean square error of approximation = 0.09 [0.08; 0.10], comparative fit index = 0.90, and Tucker Lewis index = 0.87). A subsequent analysis of local misspecifications revealed correlated measurement errors, suggesting opportunities for improvement regarding the item wording. In conclusion, our results indicate acceptable psychometric quality of the YGTSS. However, taking the wide use and importance of the YGTSS into account, our results suggest the need for further investigations and improvements of the YGTSS. In addition, our results show limitations of the global severity score as a sum score indicating that the separate use of the total tic score and the impairment rating is more beneficial.

Introduction: Trophoblastic invasion and placental growth are critical for pregnancy outcome. The placental volume can be assessed by 3 D ultrasound using Virtual Organ Computer-aided Analysis (VOCAL). Epidemiological and clinical data suggest that there are two different clinical phenotypes of hypertensive disorders of pregnancy (HDP) that coexist at any gestational age: HDP associated to fetal growth impairment and HDP associated to appropriate for gestational age fetal growth. The aim of this study was to determine whether placental volume in the first trimester of pregnancy differs between women with HDP associated or not to fetal growth impairment and uncomplicated pregnancies. Methods: This is a retrospective cross-sectional study of prospectively recruited data in which maternal characteristics, Doppler velocimetry of uterine arteries, and three-dimensional (3 D) volume of the placenta were collected at 11 + 1 − 13 + 6 gestational weeks. The placental quotient (PQ) was calculated as placental volume/crown rump length. Results: In a 2-year period, we prospectively collected first trimester data of 1322 women. For the purposes of this cross-sectional study, 57 women that delivered a SGA fetus, 34 that developed HDP-AGA, and six that developed HDP-SGA, respectively, were included in the study as cases. The control group was made of 117 uncomplicated pregnancies. The PQ was higher in women with uncomplicated pregnancies (PQ median 16.36 cm3/cm) than in all other study groups (PQ in SGA: 13.02 cm3/cm, p

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global health emergency [1, 2], with Lombardy being the epicenter of this outbreak in Italy [3].

Introduction: Converging evidence from both clinical and experimental studies has shown that Tourette syndrome (TS) is not a unitary condition, but a cluster of multiple phenotypes, which encompass both tics and specific behavioural and cognitive symptoms (mainly attention-deficit and hyperactivity disorder and obsessive-compulsive disorder). Methods: We conducted a narrative review of the recent literature on the cognitive neuropsychiatry of TS. Results: Although clinical research has shown that TS is not associated with cognitive deficits per se, the findings of recent studies have suggested the presence of subtle alterations in specific cognitive functions. A promising line of research on imitative behaviour could provide a common background for the alterations in executive control and social cognition observed in TS. Two different (but not mutually exclusive) neurocognitive theories have recently suggested that TS could originate from altered perception-action binding and social decision-making dysfunction, respectively. Conclusions: Since the presence of behavioural comorbidities influences individualised treatment approaches, it is likely that a more precise characterisation of TS phenotypes, including cognitive aspects, will result in improved levels of care for patients with tic disorders.

Background: Several clinician, informant, and self-report instruments for tics and associated phenomena have been developed that differ in construct, comprehensiveness, and ease of administration. Objective: A Movement Disorders Society subcommittee aimed to rate psychometric quality of severity and screening instruments for tics and related sensory phenomena. Methods: Following the methodology adopted by previous Movement Disorders Society subcommittee papers, a review of severity and screening instruments for tics was completed, applying a classification as “recommended,” “suggested,” or “listed” to each instrument. Results: A total of 5 severity scales (Yale Global Tic Severity Scale, Tourette Syndrome Clinical Global Impression, Tourette's Disorder Scale, Shapiro Tourette syndrome Severity Scale, Premonitory Urges for Tics Scale) were “recommended,” and 6 (Rush Video-Based Tic Rating Scale, Motor tic, Obsessions and compulsions, Vocal tic Evaluation Survey, Tourette Syndrome Global Scale, Global Tic Rating Scale, Parent Tic Questionnaire, Tourette Syndrome Symptom List) were “suggested.” A total of 2 screening instruments (Motor tic, Obsession and compulsions, Vocal tic Evaluation Survey and Autism-Tics, Attention Deficit/Hyperactivity Disorder and Other Comorbidities Inventory) were “recommended,” whereas 2 others (Apter 4-questions screening and Proxy Report Questionnaire for Parents and Teachers) were “suggested.” Conclusions: Our review does not support the need for developing new tic severity or screening instruments. Potential objectives of future research include developing a rating instrument targeting the full spectrum of tic-related abnormal behaviors, assessing/screening malignant forms of tic disorders, and developing patient-reported outcome measures. © 2017 International Parkinson and Movement Disorder Society.

Objective: To assess the influence of maternal age on the incidence of early-onset preeclampsia requiring delivery before 34weeks of gestation in pregnancies obtained after oocyte donation. Methods: We carried out a prospective cohort analysis of 431 single and twin pregnancies, admitted to 3 Tertiary Referral Hospital in Northern Italy between 2008 and 2017. The rate of early-onset PE was calculated and stratified according to maternal age (from 30 to 49years). A reference population of 11,197 single pregnancies collected prospectively at the first trimester of pregnancy in the same geographic area of Italy and in same hospitals was used to calculate the expected incidence of early-onset PE. Results: In women who delivered after 24weeks of gestation, the rate of early-onset PE was much higher in oocyte-donation pregnancies, reaching 6.7% (29/431), than the expected rate of 0.5% of the cohort of reference. The mean early PE rate was 4.1% (10/242) in singletons and 10.1% (19/189) in twin pregnancies. According to maternal age, the rate of early PE was 1.16% and 3.12% at 30years, and 4.98% and 13.14% at 49years in single and twin pregnancies obtained after oocyte donation, respectively. Conclusion: Pregnancies obtained after oocyte donation delivering after 24weeks had a higher risk of early-onset PE requiring delivery before 34weeks of gestation, than the general population. The risk is directly correlated with the increase of maternal age and is also higher in twin pregnancies.

Gilles de la Tourette syndrome (GTS) is a neurological condition characterized by motor and vocal tics. Previous studies suggested that this syndrome is associated with abnormal sensorimotor cortex activity at rest, as well as during the execution of voluntary movements. It has been hypothesized that this abnormality might be interpreted as a form of increased tonic inhibition, probably to suppress tics; however, this hypothesis has not been tested so far. The present study was designed to formally test how voluntary tic suppression in GTS influences the activity of the sensorimotor cortex during the execution of a motor task. We used EEG to record neural activity over the contralateral sensorimotor cortex during a finger movement task in adult GTS patients, in both free ticcing and tic suppression conditions; these data were then compared with those collected during the same task in age-matched healthy subjects. We focused on the levels of activity in the beta frequency band, which is typically associated with the activation of the motor system, during three different phases: a pre-movement, a movement, and a post-movement phase. GTS patients showed decreased levels of beta modulation with respect to the healthy controls, during the execution of the task; however, this abnormal pattern returned to be normal when they were explicitly asked to suppress their tics while moving. This is the first demonstration that voluntary tic suppression in GTS operates through the normalization of the EEG rhythm in the beta frequency range during the execution of a voluntary finger movement.

ObjectiveTo make recommendations on the assessment and management of tics in people with Tourette syndrome and chronic tic disorders.MethodsA multidisciplinary panel consisting of 9 physicians, 2 psychologists, and 2 patient representatives developed practice recommendations, integrating findings from a systematic review and following an Institute of Medicine–compliant process to ensure transparency and patient engagement. Recommendations were supported by structured rationales, integrating evidence from the systematic review, related evidence, principles of care, and inferences from evidence.ResultsForty-six recommendations were made regarding the assessment and management of tics in individuals with Tourette syndrome and chronic tic disorders. These include counseling recommendations on the natural history of tic disorders, psychoeducation for teachers and peers, assessment for comorbid disorders, and periodic reassessment of the need for ongoing therapy. Treatment options should be individualized, and the choice should be the result of a collaborative decision among patient, caregiver, and clinician, during which the benefits and harms of individual treatments as well as the presence of comorbid disorders are considered. Treatment options include watchful waiting, the Comprehensive Behavioral Intervention for Tics, and medication; recommendations are provided on how to offer and monitor these therapies. Recommendations on the assessment for and use of deep brain stimulation in adults with severe, treatment-refractory tics are provided as well as suggestions for future research.

ObjectiveTo systematically evaluate the efficacy of treatments for tics and the risks associated with their use.MethodsThis project followed the methodologies outlined in the 2011 edition of the American Academy of Neurology's guideline development process manual. We included systematic reviews and randomized controlled trials on the treatment of tics that included at least 20 participants (10 participants if a crossover trial), except for neurostimulation trials, for which no minimum sample size was required. To obtain additional information on drug safety, we included cohort studies or case series that specifically evaluated adverse drug effects in individuals with tics.ResultsThere was high confidence that the Comprehensive Behavioral Intervention for Tics was more likely than psychoeducation and supportive therapy to reduce tics. There was moderate confidence that haloperidol, risperidone, aripiprazole, tiapride, clonidine, onabotulinumtoxinA injections, 5-ling granule, Ningdong granule, and deep brain stimulation of the globus pallidus were probably more likely than placebo to reduce tics. There was low confidence that pimozide, ziprasidone, metoclopramide, guanfacine, topiramate, and tetrahydrocannabinol were possibly more likely than placebo to reduce tics. Evidence of harm associated with various treatments was also demonstrated, including weight gain, drug-induced movement disorders, elevated prolactin levels, sedation, and effects on heart rate, blood pressure, and ECGs.ConclusionsThere is evidence to support the efficacy of various medical, behavioral, and neurostimulation interventions for the treatment of tics. Both the efficacy and harms associated with interventions must be considered in making treatment recommendations.

Objective To explore maternal cardiac deceleration capacity (DC), a marker of autonomic function derived from electrocardiographic (ECG) signals, in pregnancies complicated by intrauterine growth restriction (IUGR) and hypertensive disorders of pregnancy (HDP) associated to IUGR (HDP-IUGR) or to appropriate for gestational age fetal growth (HDP-AGAf). Methods Prospective single center case-control study conducted at Buzzi Children's Hospital, Milan. Maternal ECGs were analyzed by Phase Rectified Signal Averaging (PRSA) method to obtain cardiac DC in women with: HDP-IUGR, HDP-AGAf, severe-IUGR, mild-IUGR and uncomplicated pregnancies. IUGR was defined as abdominal circumference 2 standard deviations. Non-parametric tests were adopted. Results 269 women were recruited. Women with HDP-IUGR (n = 35) showed significantly higher cardiac DC compared both to controls (n = 141) (p = 0.003) and women with HDP-AGAf (n = 18) (p = 0.01). Women with severe-IUGR (n = 14) showed significantly higher DC than controls (p = 0.01). Women with mild-IUGR (n = 61) as well as women with HDP-AGAf showed no differences in DC compared to controls (both p = 0.3). Conclusions Women with pregnancy complicated by severe placental failure, such as HDP-IUGR and severe IUGR, show significant autonomic alterations, as indicated by elevated cardiac DC. On the contrary, pregnancy complications such as HDP-AGAf and mild IUGR show no impact on maternal autonomic balance. We present a new approach to explore maternal autonomic cardiovascular regulation that might reflect the severity of placental vascular insufficiency.

Objective: To evaluate the diagnostic accuracy of clinical diagnosis of Parkinson disease (PD) reported in the last 25 years by a systematic review and meta-analysis. Methods: We searched for articles published between 1988 and August 2014. Studies were included if reporting diagnostic parameters regarding clinical diagnosis of PD or crude data. The selected studies were subclassified based on different study setting, type of test diagnosis, and gold standard. Bayesian meta-analyses of available data were performed. Results: We selected 20 studies, including 11 using pathologic examination as gold standard. Considering only these 11 studies, the pooled diagnostic accuracy was 80.6% (95% credible interval [CrI] 75.2%–85.3%). Accuracy was 73.8% (95% CrI 67.8%–79.6%) for clinical diagnosis performed mainly by nonexperts. Accuracy of clinical diagnosis performed by movement disorders experts rose from 79.6% (95% CrI 46%–95.1%) of initial assessment to 83.9% (95% CrI 69.7%–92.6%) of refined diagnosis after follow-up. Using UK Parkinson9s Disease Society Brain Bank Research Center criteria, the pooled diagnostic accuracy was 82.7% (95% CrI 62.6%–93%). Conclusion: The overall validity of clinical diagnosis of PD is not satisfying. The accuracy did not significantly improve in the last 25 years, particularly in the early stages of disease, where response to dopaminergic treatment is less defined and hallmarks of alternative diagnoses such as atypical parkinsonism may not have emerged. Misclassification rate should be considered to calculate the sample size both in observational studies and randomized controlled trials. Imaging and biomarkers are urgently needed to improve the accuracy of clinical diagnosis in vivo.

Purpose To assess disease-related patterns of in vivo pathology in 11 patients with Corticobasal Syndrome (CBS) compared to 20 healthy controls and 33 mild cognitive impairment (MCI) patients due to Alzheimer’s disease. Methods We assessed tau aggregates with [18F]AV1451 PET, amyloid-β depositions with [18F]AV45 PET, and volumetric microstructural changes with MRI. We validated for [18F]AV1451 standardised uptake value ratio (SUVRs) against input functions from arterial metabolites and found that SUVRs and arterial-derived distribution volume ratio (DVRs) provide equally robust measures of [18F]AV1451 binding. Results CBS patients showed increases in [18F]AV1451 SUVRs in parietal (P

Tourette syndrome (TS) frequently involves complex tics with social significance, including imitation or socially inappropriate behaviour. This study explored every-day perspective taking and empathic tendencies in 95 patients with TS and 60 healthy controls. Analyses indicated that both males and females with TS exhibited a different interpersonal reactivity profile to controls, characterised by a reduced tendency to take other people's perspectives, and elevated personal distress in response to intense emotional situations (e.g. people experiencing crises).

BACKGROUND: Nutrients malabsorption frequently occurs in human immunodeficiency virus (HIV)-infected patients, but very few studies have investigated exocrine pancreatic digestive capacity in these patients. We therefore evaluated the frequency of exocrine pancreatic impairment and its eventual relation with fat malabsorption in HIV-infected patients. METHODS: Thirty-five HIV-infected patients (30 male, 5 female: mean age +/- standard deviation, 33.6 +/- 7.2 years) and 51 sex- and age-matched controls without gastroenterologic diseases were studied. In all subjects fecal elastase 1 (EL-1) was assayed, and fecal fat excretion was evaluated with the steatocrit test. RESULTS: Nineteen of 35 (54%) HIV-infected patients showed subnormal EL-1 values, whereas all the controls had normal values; furthermore, EL-1 values were significantly lower in patients than in controls: mean (95% confidence intervals), 207 ( 164-251 ) microg/g versus 312 (291-332) microg/g (P < 0.0001). Increased fecal fat excretion was observed in almost all (25 of 35) HIV-infected patients, and an inverse but not significant correlation was found between fecal EL-1 and steatocrit values. No association was found between reduced fecal EL-1 and the severity of HIV disease or nutritional and immunologic status. Opportunistic infections and drug administration had no influence on EL-1 concentrations in stools. CONCLUSIONS: Reduced exopancreatic function is frequent in HIV-infected patients but does not seem to be a major factor contributing to fat malabsorption.

Tourette syndrome (TS) is the primary tic disorder that reaches most commonly medical attention and monitoring, with an estimated prevalence close to 1% between 5 and 18 years of age. Motor and phonic tics are the core features of TS. In addition to their well-characterized phenomenology, tics display a peculiar variability over time, which is strongly influenced by a variety of contextual factors. The sensory phenomena of TS are increasingly recognized as another crucial symptom of TS and consist of premonitory urges and somatic hypersensitivity. A relevant proportion of patients with TS display complex, tic-like, repetitive behaviors that include echophenomena, coprophenomena, and nonobscene socially inappropriate behaviors (NOSIBs). The burden of behavioral comorbidities is very important in determining the degree of disability of TS patients. Only a small minority of TS patients presents exclusively with a tic disorder. Obsessive-compulsive symptoms and related disorder (OCD) are common in TS, and the clinical distinction between compulsions and complex tics may be difficult in some cases. Probably, the presence of comorbid attention deficit hyperactivity disorder (ADHD) is the main determinant of cognitive dysfunction in TS patients and influences heavily also the risk of developing disruptive behaviors. Affective disorders, impulse control disorders, autism spectrum disorders, and personality disorders complete the wide psychopathological spectrum of this condition, but have been less investigated than OCD and ADHD. The complexity of the Tourette spectrum has been confirmed by cluster and factor analytical approaches, and is likely to inform the study of the genetic basis of this disorder, as well as future reappraisal of its nosography, with the development of novel clinical subtypes.

Dipyridamole is a widely prescribed drug in ischemic disorders, and it is here investigated for potential clinical use as a new treatment for breast cancer. Xenograft mice bearing triple-negative breast cancer 4T1-Luc or MDA-MB-231T cells were generated. In these in vivo models, dipyridamole effects were investigated for primary tumor growth, metastasis formation, cell cycle, apoptosis, signaling pathways, immune cell infiltration, and serum inflammatory cytokines levels. Dipyridamole significantly reduced primary tumor growth and metastasis formation by intraperitoneal administration. Treatment with 15 mg/kg/day dipyridamole reduced mean primary tumor size by 67.5 % (p = 0.0433), while treatment with 30 mg/kg/day dipyridamole resulted in an almost a total reduction in primary tumors (p = 0.0182). Experimental metastasis assays show dipyridamole reduces metastasis formation by 47.5 % in the MDA-MB-231T xenograft model (p = 0.0122), and by 50.26 % in the 4T1-Luc xenograft model (p = 0.0292). In vivo dipyridamole decreased activated beta-catenin by 38.64 % (p < 0.0001), phospho-ERK1/2 by 25.05 % (p = 0.0129), phospho-p65 by 67.82 % (p < 0.0001) and doubled the expression of IkB alpha (p = 0.0019), thus revealing significant effects on Wnt, ERK1/2-MAPK and NF-kB pathways in both animal models. Moreover dipyridamole significantly decreased the infiltration of tumor-associated macrophages and myeloid-derived suppressor cells in primary tumors (p < 0.005), and the inflammatory cytokines levels in the sera of the treated mice. We suggest that when used at appropriate doses and with the correct mode of administration, dipyridamole is a promising agent for breast-cancer treatment, thus also implying its potential use in other cancers that show those highly activated pathways.

The complex motor and behavioral phenotype of Tourette syndrome presents a unique challenge to measurement and clinical observations. This chapter offers a systematic overview of the different clinician-, informant-, and self-report rating instruments for tics and associated phenomena that are available for use in clinical practice and/or research settings. Each of the scales available to measure tics has strengths and limitations; among the latter, the difficulty of capturing all the different dimensions of tic symptoms, such as frequency, intensity, interference, and impairment, is one of the most common and is an object of future research. Moreover, the visible and audible nature of core Tourette syndrome symptoms allows direct observation of these symptoms using specific video protocols. A wide range of psychometrically validated clinician- and self-rated measures for obsessive-compulsive behavior, attention-deficit/hyperactivity disorder, and depressive and anxiety symptoms are also available for use in clinical practice and/or research settings. The use of behavioral measures with adequate psychometric indices is recommended. Clinicians and researchers ideally should combine information from professionals and patients (as well as informants if possible) to ensure that the information gathered is comprehensive and accurate.

The human (h)-prune protein is a member of the DHH protein superfamily and it has a cAMP phosphodiesterase activity. Its overexpression in breast, colorectal and gastric cancers correlates with depth of invasion and a high degree of lymph-node metastasis. One mechanism by which h-prune stimulates cell motility and metastasis processes is through its phosphodiesterase activity, which can be suppressed by dipyridamole, a pyrimido[5,4-d]pyrimidine analogue. To obtain new and more potent agents that have high specificity towards inhibition of this h-prune activity, we followed structure activity-relationship methodologies starting from dipyridamole and synthesised eight new pyrimido pyrimidine derivatives. We analysed these newly generated compounds for specificity towards h-prune activities in vitro in cellular models using scintillation proximity assay for cAMP-PDE activity, cell index in cell proliferation assays and transwell methodology for two-dimensional cell migration in a top-down strategy of selection. Our findings show that two pyrimido[5,4-d]pyrimidine compounds are more effective than dipyridamole in two highly metastatic cellular models of breast cancer in vitro. Future studies will assess their therapeutic effectiveness against breast and other cancers where there is over-expression of h-prune, and in ad-hoc, proof of concept, animal models. (C) 2012 Elsevier Masson SAS. All rights reserved.

Prostate and breast cancer are major causes of death worldwide, mainly due to patient relapse upon disease recurrence through formation of metastases. Chemokines are small proteins with crucial roles in the immune system, and their regulation is finely tuned in early inflammatory responses. They are key molecules during inflammatory processes, and many studies are focusing on their regulatory functions in tumor growth and angiogenesis during metastatic cell seeding and spreading. Bindarit is an anti-inflammatory indazolic derivative that can inhibit the synthesis of MCP-1/CCL2, with a potential inhibitory function in tumor progression and metastasis formation. We show here that in vitro, bindarit can modulate cancer-cell proliferation and migration, mainly through negative regulation of TGF-beta and AKT signaling, and it can impair the NF-kappa B signaling pathway through enhancing the expression of the NF-kappa B inhibitor IkB-alpha. In vivo administration of bindarit results in impaired metastatic disease in prostate cancer xenograft mice (PC-3M-Luc2 cells injected intra-cardially) and impairment of local tumorigenesis in syngeneic Balb/c mice injected under the mammary gland with murine breast cancer cells (4T1-Luc cells). In addition, bindarit treatment significantly decreases the infiltration of tumor-associated macrophages and myeloid-derived suppressor cells in 4T1-Luc primary tumors. Overall, our data indicate that bindarit is a good candidate for new therapies against prostate and breast tumorigenesis, with an action through impairment of inflammatory cell responses during formation of the tumor-stroma niche microenvironment.

Eye tics seem to be common in Gilles de la Tourette syndrome (GTS). We analyzed the frequency and clinical characteristics of eye tics in 212 GTS patients. Of the 212 patients, 201 (94.8 %) reported eye tics in their life-time; 166 (78.3 %) reported eye movement tics (rolling eyes up/down, eyes looking sideways, staring), and 194 (91.5 %) eyelid/eyebrow movement tics (frowning, raising eyebrows, blinking or winking). Patients with eye movement tics were younger at age of GTS onset (7.1 ± 4 years) than those without (8.9 ± 6.8; p = 0.024). Tic severity positively correlated to lifetime history of eye and/ or eyelid/eyebrow movement tics. Our data confirm that eye and eyelid/eyebrow movement tics are very common in GTS, and most patients have several types of eye tics over time. Eye tic phenomenology was similar in patients with or without co-morbidity. Eye tics are therefore likely to be a core feature of GTS and should be routinely evaluated in order to strengthen the clinician's confidence in diagnosing GTS.

Summary Aim To report an outbreak of extensively drug-resistant (XDR) Acinetobacter baumannii in the neonatal intensive care unit (NICU) of an Italian university hospital. Patient risk profiles for acquisition of A. baumannii and measures used to control the outbreak are described. Methods Antibiotic susceptibility of strains was evaluated by microdilution. Genotyping was performed by pulsed-field gel electrophoresis (PFGE) and multi-locus sequence typing. Carbapenemase genes were analysed by polymerase chain reaction and DNA sequencing. A case–control study was designed to identify risk factors for acquisition of A. baumannii . Findings A. baumannii was isolated from 22 neonates, six of whom were infected. One major PFGE type was identified, assigned to sequence type (ST) 2, corresponding to International Clone II; this was indistinguishable from isolates from the adult ICU in the same hospital. A. baumannii isolates were resistant to aminoglycosides, quinolones and classes of β-lactam antibiotics, but were susceptible to tigecycline and colistin. Carbapenem resistance was associated with the presence of transposon Tn 2006 carrying the bla OxA-23 gene. Length of NICU stay, length of exposure to A. baumannii , gestational age, use of invasive devices and length of exposure to invasive devices were significantly associated with acquisition of A. baumannii on univariate analysis, while length of exposure to central venous catheters and assisted ventilation were the only independent risk factors after multi-variate analysis. Conclusions This XDR A. baumannii outbreak in an NICU was probably caused by intrahospital transfer of bacteria via a colonized neonate whose mother was admitted to the adult ICU. Strengthened infection control measures were necessary to control the outbreak.

Through microarray analyses, we identified the Mpped2 gene as differentially expressed in two neuroblastoma cell lines induced to differentiation with all-trans retinoic acid. Mpped2 codes for a new metallophosphodiesterase protein, the expression of which inhibits cell proliferation and soft agar colony formation in SH -SY5Y cells. This inhibition is concomitant to an increased proportion of the cells in G0/G1 phase and enhanced caspase 3 activation, effects not seen for the other phosphodiesterases. A Mpped2-null mutation (H67R) abrogates these functions, which indicates that the biochemical activity of Mpped2 is advantageous for cancer suppression. Expression analyses in the "Los Angeles" and "Essen" neuroblastoma gene-array data sets show that increased expression of Mpped2 is associated with good patient prognosis according to Kaplan-Meier analyses. Tumorigenic assays in mice show that overexpression of Mpped2 improves survival rate, substantially impairs tumor growth and induces neuronal differentiation. Altogether, these data show that Mpped2 expression impairs neuroblastoma tumorigenesis, and they establish a basis for future therapeutic applications.

Tourette syndrome is a childhood-onset neuropsychiatric disorder with a high prevalence of attention deficit hyperactivity and obsessive-compulsive disorder co-morbidities. Structural changes have been found in frontal cortex and striatum in children and adolescents. A limited number of morphometric studies in Tourette syndrome persisting into adulthood suggest ongoing structural alterations affecting frontostriatal circuits. Using cortical thickness estimation and voxel-based analysis of T1- and diffusion-weighted structural magnetic resonance images, we examined 40 adults with Tourette syndrome in comparison with 40 age- and gender-matched healthy controls. Patients with Tourette syndrome showed relative grey matter volume reduction in orbitofrontal, anterior cingulate and ventrolateral prefrontal cortices bilaterally. Cortical thinning extended into the limbic mesial temporal lobe. The grey matter changes were modulated additionally by the presence of co-morbidities and symptom severity. Prefrontal cortical thickness reduction correlated negatively with tic severity, while volume increase in primary somatosensory cortex depended on the intensity of premonitory sensations. Orbitofrontal cortex volume changes were further associated with abnormal water diffusivity within grey matter. White matter analysis revealed changes in fibre coherence in patients with Tourette syndrome within anterior parts of the corpus callosum. The severity of motor tics and premonitory urges had an impact on the integrity of tracts corresponding to cortico-cortical and cortico-subcortical connections. Our results provide empirical support for a patho-aetiological model of Tourette syndrome based on developmental abnormalities, with perturbation of compensatory systems marking persistence of symptoms into adulthood. We interpret the symptom severity related grey matter volume increase in distinct functional brain areas as evidence of ongoing structural plasticity. The convergence of evidence from volume and water diffusivity imaging strengthens the validity of our findings and attests to the value of a novel multimodal combination of volume and cortical thickness estimations that provides unique and complementary information by exploiting their differential sensitivity to structural change. © (2010) The Author.

Background: Tourette syndrome (TS) is characterized by dysfunctional connectivity between prefrontal cortex and sub-cortical structures, and altered meso-cortical and/or meso-striatal dopamine release. Since time processing is also regulated by fronto-striatal circuits and modulated by dopaminergic transmission, we hypothesized that time processing is abnormal in TS. Methods: We compared time processing abilities between nine children with TS-only (i.e. without major psychiatric comorbidities) and 10 age-matched healthy children, employing a time reproduction task in which subjects actively reproduce different temporal intervals, and a time comparison task in which subjects judge whether a test interval is longer or shorter than a reference interval. IQ sustained and divided attention, and working memory were assessed in both groups using the Leiter International Performance Scale-Revised, and the Digit Span sub-test of the WISC-R. Results: Children with TS-only reproduced in an overestimated fashion over-second, but not sub-second, time intervals. The precision of over-second intervals reproduction correlated with tic severity, in that the lower the tic severity, the closer the reproduction of over-second time intervals to their real duration. Time reproduction performance did not significantly correlate with IQ attention and working memory measures in both groups. No differences between groups were documented in the time comparison task. Conclusions: The improvement of time processing in children with TS-only seems specific for the over-second range of intervals, consistent with an enhancement in the 'cognitively controlled' timing system, which mainly processes longer duration intervals, and depends upon dysfunctional connectivity between the basal ganglia and the dorso-lateral prefrontal cortex. The absence of between-group differences on time comparison, moreover, suggests that TS patients manifest a selective improvement of 'motor' timing abilities, rather than of perceptual time abilities. Our data also support an enhancement of cognitive control processes in TS children, probably facilitated by effortful tic suppression. (C) 2010 Elsevier Inc. All rights reserved.