Maternal suboptimal selenium intake and low-level lead exposure affect offspring's microglial immune profile and its reactivity to a subsequent inflammatory hit.

Micronutrients such as selenium (Se) are essentials since prenatal life to support brain and cognitive development. Se deficiency, which affects up to 1 billion people worldwide, can interact with common adverse environmental challenges including (Pb), exacerbating their toxic effects. Exploiting our recently validated rat model of maternal Se restriction and developmental low Pb exposure, our aims were to investigate: (i) the early consequences of suboptimal Se intake and low-Pb exposure on neuroinflammation in neonates' whole brains; (ii) the potential priming effect of suboptimal Se and low-Pb exposure on offspring's glial reactivity to a further inflammatory hit. To these aims female rats were fed with suboptimal (0.04 mg/kg; Subopt) and optimal (0.15 mg/kg; Opt) Se dietary levels throughout pregnancy and lactation and exposed or not to environmentally relevant Pb dose in drinking water (12.5 µg/mL) since 4 weeks pre-mating. We found an overall higher basal expression of inflammatory markers in neonatal brains, as well as in purified microglia and organotypic hippocampal slice cultures, from the Subopt Se offspring. Subopt/Pb cultures were highly activated than Subopt cultures and showed a higher susceptibility to the inflammatory challenge lipopolysaccharide than cultures from the Opt groups. We demonstrate that even a mild Se deficiency and low-Pb exposure during brain development can influence the neuroinflammatory tone of microglia, exacerbate the toxic effects of Pb and prime microglial reactivity to subsequent inflammatory stimuli. These neuroinflammatory changes may be responsible, at least in part, for adverse neurodevelopmental outcomes.

A snapshot of gut microbiota data from murine models of Autism Spectrum Disorder: Still a blurred picture.

Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by deficits in social communication and interaction and repetitive/stereotyped behaviors. In recent years, the role of microbiota-gut-brain axis in ASD pathogenesis received growing attention, appearing as an attractive therapeutic target. We provide a comprehensive overview of changes in microbiota composition in ASD murine models so far identified, and summarize the therapeutic approaches targeting the microbiota on ASD-like neurobehavioral profile. Although alterations in microbiota composition have been observed in both genetic and environmental murine models of ASD, a clear microbiota profile shared by different ASD murine models has not been identified. We documented substantial discrepancies among studies (often within the same model), likely due to several confounding factors (from sex and age of animals to housing conditions). Despite these limitations, ASD animal models (under standardized conditions) remain a useful tool to evaluate (i) the beneficial effects of manipulations of gut microbiota on behavioral abnormalities; (ii) underlying neurobiological mechanisms related to gut-brain axis; and (iii) to identify optimal time windows for therapeutic interventions.

A new cynodont from the Upper Triassic Los Colorados Formation (Argentina, South America) reveals a novel paleobiogeographic context for mammalian ancestors.

Probainognathia is a derived lineage of cynodonts which encompass Mammalia as their crown-group. The rich record of probainognathians from the Carnian of Argentina contrasts with their Norian representation, with only one named species. Here we describe a new probainognathian, Tessellatia bonapartei gen. et sp. nov., from the Norian Los Colorados Formation of the Ischigualasto-Villa Unión Basin of Argentina. The new taxon, represented by a partial cranium with associated lower jaws, was analyzed through neutron and X-rays micro-tomography (µCT). The high-resolution neutron µCT data allowed the identification of a unique character combination, including features inaccessible through traditional techniques. We constructed the largest phylogenetic data matrix of non-mammalian cynodonts. The new species and its sister taxon, the Brazilian Therioherpeton cargnini, are recovered as probainognathians, closely related to Mammaliamorpha. We conducted the first quantitative paleobiogeographic analysis of non-mammalian cynodonts, focusing in probainognathians. The results indicate that Probainognathia and Mammaliamorpha originated in southwestern Gondwana (in the Brazilian Paraná Basin), which was an important center of diversification during the Triassic. Finally, the Chinese Lufeng Basin is identified as the ancestral area of Mammaliaformes. These new findings, besides adding to the knowledge of the poorly represented Norian cynodonts from the Los Colorados Formation, are significant to improve our understanding of probainognathian diversity, evolution, and paleobiogeographic history.

New perspectives for neutron imaging through advanced event-mode data acquisition.

Imaging using scintillators is a widespread and cost-effective approach in radiography. While different types of scintillator and sensor configurations exist, it can be stated that the detection efficiency and resolution of a scintillator-based system strongly depend on the scintillator material and its thickness. Recently developed event-driven detectors are capable of registering spots of light emitted by the scintillator after a particle interaction, allowing to reconstruct the Center-of-Mass of the interaction within the scintillator. This results in a more precise location of the event and therefore provides a pathway to overcome the scintillator thickness limitation and increase the effective spatial resolution of the system. Utilizing this principle, we present a detector capable of Time-of-Flight imaging with an adjustable field-of-view, ad-hoc binning and re-binning of data based on the requirements of the experiment including the possibility of particle discrimination via the analysis of the event shape in space and time. It is considered that this novel concept might replace regular cameras in neutron imaging detectors as it provides superior detection capabilities with the most recent results providing an increase by a factor 3 in image resolution and an increase by up to a factor of 7.5 in signal-to-noise for thermal neutron imaging.

Altered responsiveness to pups in virgin female mice of the BTBR strain: Insights from pattern of c-Fos expression in brain regions involved in maternal behavior.

BTBR is an inbred mouse strain that displays several behavioral alterations resembling the core symptoms of Autism Spectrum Disorder, including deficit in sociability. In the present study, we investigated whether the pup-induced maternal behavior in virgin female mice, a naturally rewarding behavior, is impaired in this strain similarly to social interaction with adult conspecifics. We firstly assessed the maternal responsiveness towards newly born pups expressed by either virgin female mice of the BTBR strain or of the normo-social B6 strain. Next, we examined in both strains the expression of c-Fos as a marker of neuronal activity in selected brain areas involved in the regulation of maternal behavior in rodents including the olfactory bulb, the medial preoptic area and the paraventricular nucleus (PVN). We also examined the effects of pup presentation on oxytocinergic neurons of the PVN, the major brain site of synthesis of oxytocin, which has a pivotal role in facilitation of maternal response and social responsiveness in general. As a final step, we assessed the c-Fos expression pattern comparing the effect of exposure to pups with that induced by exposure to another social stimulus, focusing on other areas implicated in maternal responsiveness as well as in the affective component of social behavior such as pyriform cortex and central and basolateral amygdala. Our data showed that BTBR virgin females are less responsive to presentation of pups in comparison to B6, in parallel with lower activation of brain areas implicated in the maternal and social responsiveness.

Longitudinal cognitive decline in mild cognitive impairment subjects with early amyloid-ß neocortical deposition.

PURPOSE: The rate of clinical progression of cognitive impairment in subjects with early amyloid deposition is unknown. The primary aim of the study was to follow the rate of cognitive decline over 1 year in patients with amnestic mild cognitive impairment (aMCI) by determining amyloid retention levels in terms of standardized uptake value ratios (SUVr) that ranged from 0.85 to 1.57. The secondary objective was to compare the rate of cognitive decline between subjects with and without early amyloid positivity. METHODS: Of 66 aMCI subjects evaluated with [18F]florbetaben PET imaging and neuropsychological tests at baseline, 41 completed the 1-year follow-up. Amyloid status was determined with SUVr cut-off values generated from baseline images by visual assessment by three independent certified readers. Repeated-measures ANOVA with amyloid load and neuropsychological scores as the main effects was use to test group, time and group-by-time interactions. The Tukey post-hoc test was used to analyse all significant interactions. RESULTS: Of the 41 aMCI subjects, 38 completed the assessment according to the study protocol. Amyloid-positive (Aß+ ) subjects (N = 18, age 75.6 ± 5.8 years, six men, 12 women) showed greater clinical deterioration according to the Mattis Dementia Rating Scale (MDRS) score (p = 0.006). Amyloid-negative (Aß-) subjects (N = 20, age 72.4 ± 5.8 years, 11 men, 6 women) showed no significant changes in MDRS score over 1 year. MDRS score significantly decreased (MDRS+) in 37% of the aMCI subjects, and remained stable (MDRS-) in the remaining 63%. Among subjects with cognitive deterioration, 86% were Aß+ and 14% were Aß-, while 25% of the MDRS- subjects were Aß+ and 75% were Aß- (χ2 = 13, P = 0.0003). SUVr above 1.21 identified individuals who would show significant progression over 1 year, with a sensitivity of 67% and a specificity of 90%, as compared to Aß- subjects. The positive predictive value, negative predictive value, and likelihood ratio were 86% (95% CI 70-94%), 75% (95% CI 58-87%), 7 (95% CI 5-10). CONCLUSION: This study demonstrated that early amyloid deposition predicts cognitive decline in subjects with aMCI, with a higher rate of decline in those with SUVr above a threshold of 1.21. Detection of early amyloid positivity may help in selecting the target population for preventive therapeutic interventions and in designing treatment trials (Trial number, EudraCT 2015-001184-39).

Regenerative medicine in Huntington's disease: Strengths and weaknesses of preclinical studies.

Huntington's disease (HD) is an inherited neurodegenerative disorder, characterized by impairment in motor, cognitive and psychiatric domains. Currently, there is no specific therapy to act on the onset or progression of HD. The marked neuronal death observed in HD is a main argument in favour of stem cells (SCs) transplantation as a promising therapeutic perspective to replace the population of lost neurons and restore the functionality of the damaged circuitry. The availability of rodent models of HD encourages the investigation of the restorative potential of SCs transplantation longitudinally. However, the results of preclinical studies on SCs therapy in HD are so far largely inconsistent; this hampers the individuation of the more appropriate model and precludes the comparative analysis of transplant efficacy on behavioural end points. Thus, this review will describe the state of the art of in vivo research on SCs therapy in HD, analysing in a translational perspective the strengths and weaknesses of animal studies investigating the therapeutic potential of cell transplantation on HD progression.

Performance of the new SLICC classification criteria in childhood systemic lupus erythematosus: a multicentre study.

OBJECTIVES: The Systemic Lupus International Collaborating Clinics (SLICC) group has recently proposed a new set of criteria for the classification of systemic lupus erythematosus (SLE). We aimed to compare the sensitivity and specificity of the new SLICC criteria with those of the American College of Rheumatology (ACR) criteria in our childhood-onset SLE patients. METHODS: Three main paediatric lupus centres from Europe participated in this study. Of these centres, one was predominantly a paediatric nephrology centre (Great Ormond Street Hospital, London, UK), one was predominantly a paediatric rheumatology centre (Istituto Giannina Gaslini, Genoa, Italy), and one was a combined centre taking care of both group of patients (Hacettepe University, Ankara, Turkey). The features present at disease onset in patients with childhood-onset SLE, younger than 18 years of age, seen between January 2000 and December 2012 were retrospectively reviewed. For the evaluation of specificity, patients admitted to each centre between May and December 2012 for conditions other than SLE, in whom ANA was deemed necessary within the diagnostic work-up were included as controls. PASW 18.0 for Windows was used for statistical analyses. RESULTS: Both sets of classification criteria were analysed in 154 childhood SLE patients with a mean age at disease onset of 12.7 years and in 123 controls with a mean age of 8.9 years. The sensitivity and specificity of the ACR criteria were 76.6% and 93.4%, respectively, whereas those of the SLICC criteria were 98.7% and 85.3%, respectively. Four patients out of 5 with haemolytic uraemic syndrome (HUS) and 4 patients out of 8 with juvenile dermatomyositis (JDM) met four of the SLICC criteria, whereas 22 lupus nephritis patients failed to meet four of the ACR criteria. CONCLUSIONS: In our paediatric series, the SLICC criteria showed better sensitivity (p<0.001) and led to fewer misclassifications, but were less specific (p<0.001) than the ACR criteria.

Prompt gamma emissions in the reaction 115In(n,gamma)116In for neutrons around the 1.45 eV absorption resonance.

The relative intensities of different gamma emissions produced after the reaction (115)In(n,gamma)(116)In were analyzed for the particular case of incident neutron energies around the 1.45 eV indium absorption resonance. For this purpose, a pulsed neutron source in combination with the time-of-flight method for selecting the incident neutron energy range was employed. For neutrons around the mentioned absorption resonance the prompt gamma spectrum was extended to energies below 273 keV, and the intensities of gamma emissions not reported in the literature for epithermal neutrons were determined.

La magnitud del shunt derecha-izquierda no afecta al cuadro clínico de la migraña con aura: ¿qué significa / The magnitude of a right-to-left shunt does not affect the clinical features of migraine with aura: what does this mean?

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Impact of prebiotics on human health.

It is becoming clear that intestinal microflora plays an important role in the development of local and systemic immune response. Nutritional ingredients have been added to infant formula in an attempt to make its composition similar to that of human milk. The effects of these modifications have been observed in the composition of intestinal microflora. Prebiotics are non-digestible foods able to selectively stimulate the growth/activity of a limited number of colonic bacteria. A mixture of galacto-oligosaccharides and fructo-oligosaccharides (GOS/FOS) induces an increase in Bifidobacteria, similar to that of breast-fed infants. What is less clear is whether the modifications of intestinal microflora obtained by functional foods are associated with clinically measurable effects. Preliminary indirect data suggest that increasing the load of Bifidobacteria and Lactobacilli may protect from infections and allergies and this effect may persists beyond infancy. The emerging concept is that early nutritional intervention may be effective in modifying the intestinal microflora composition in a phase in which microbiological imprinting may drive immunological imprinting thereby producing clinical effects. Further investigations and well designed randomised clinical trials are needed to demonstrate the potential beneficial effects and to exclude the potential side effects.

The role of tissue harmonic imaging in fetal echocardiography.

OBJECTIVE: To define the role of tissue harmonic imaging (THI) in fetal echocardiography. METHOD: Three trials were conducted in a tertiary referral center: Study A was a prospective randomized trial including 50 women referred for fetal echocardiography. Those allocated to Arm 1 underwent conventional fundamental frequency ultrasound (FFU) and those allocated to Arm 2 underwent THI. Study B was conducted in 21 patients who were obese or overweight with significant weight gain in pregnancy. In these patients, both THI and FFU echocardiography were performed and compared. In Study C, THI was employed as a second-line rescue technique in cases of inadequate or incomplete examination by FFU. A subjective scoring system was used by a reviewer who had not performed the examinations to assess the comprehensiveness of the examination and the image resolution. The reviewer was blinded to the image modality. RESULTS: In Study A, no difference was found in the diagnostic accuracy between THI and FFU echocardiography but the resolution was significantly poorer in the THI arm. In studies B and C, THI performed significantly better than FFU (P < 0.001). CONCLUSIONS: THI echocardiography seems to be the best technique to employ in obese women and in those in whom FFU fails to provide diagnostic information. However, due its poorer resolution in women of average weight, FFU echocardiography should remain the technique of choice.

Prenatal ultrasound diagnosis of Nager syndrome.

Nager syndrome, or acrofacial dysostosis, is a rare malformation complex characterized by facial anomalies (external ear abnormalities and micrognathia) and limb defects (radial hypoplasia and absence of the thumb and/or other digits). Since its first description in 1948, more than 80 cases have been reported in the pediatric literature. However, there is only one previous report on the prenatal recognition of the syndrome, which was at 30 weeks of gestation. We report here a further case of Nager syndrome, prospectively diagnosed at 23 weeks of gestation.

Ultrasound evaluation of aortic valve anatomy in the fetus.

OBJECTIVE: To assess the feasibility of ultrasound identification of aortic valve anatomy in the fetus, with particular emphasis on the detection of bicuspid aortic valve. METHODS: This study was a prospective analysis of 21 fetuses with prenatally diagnosed congenital left heart obstructive lesions and 45 normal fetuses undergoing routine ultrasound evaluated at a tertiary referral center. These fetuses underwent detailed echocardiography, including the study of the aortic valve on a targeted short-axis view of the right ventricle. Necropsies or postnatal echocardiograms were available for confirmation of the diagnosis in all cases. RESULTS: Aortic cusps and commissures were satisfactorily visualized in 38/45 (84%) normal fetuses and in 18/21 (86%) fetuses with congenital heart disease. The aortic valve was correctly defined as bicuspid in one normal fetus and in six fetuses with congenital heart disease. In two fetuses with a positive family history, the bicuspid aortic valve was isolated. There was one incorrect diagnosis (a unicuspid unicommissural valve diagnosed prenatally as a bicuspid aortic valve in a fetus with severe aortic stenosis) and one false-positive diagnosis in a fetus diagnosed with a coarctation and a bicuspid aortic valve late in the third trimester of pregnancy and in which both anomalies were not confirmed at neonatal echocardiography. CONCLUSIONS: This study demonstrated that aortic valve anatomy can be satisfactorily assessed in fetuses with and without left heart obstructive lesions. We believe that a detailed search for a bicuspid aortic valve should be attempted in all patients referred for a positive family history of congenital heart disease, in general, and of left ventricle outflow tract obstruction or bicuspid aortic valve, in particular. In fact, the presence of an asymptomatic bicuspid aortic valve has been demonstrated to represent an important factor predisposing to the development of bacterial endocarditis and dissecting aortic aneurysm late in adult life. Therefore, an early detection of such an anomaly may contribute to ensure a longer symptom-free lifespan of individuals with the most common cardiac anomaly at birth.

Pena-Shokeir phenotype with variable onset in three consecutive pregnancies.

The Pena-Shokeir phenotype represents an autosomal recessive syndrome characterized by neurogenic arthrogryposis, facial anomalies and pulmonary hypoplasia. Prenatal diagnosis of this disease has been reported prospectively and in cases with positive family history. We describe here a patient who has had three consecutive pregnancies affected by the Pena-Shokeir syndrome. In these pregnancies, the onset of the arthrogryposis varied between the 12th and the 18th week of gestation. Therefore, the possibility of a variable chronological development of the main diagnostic feature of the syndrome, arthrogryposis, has to be taken into proper consideration while counseling families with a positive history for the Pena-Shokeir phenotype.

The association between congenital heart disease and Down syndrome in prenatal life.

OBJECTIVE: To assess the relationship between congenital heart disease (CHD) and Down syndrome (DS) in utero. DESIGN: Retrospective case series. SUBJECTS: Fifty-two fetuses with a cytogenetic diagnosis of DS managed at our Fetal Cardiology Unit in the study period. In particular, two populations of fetuses with DS were studied: a group of 41 DS fetuses referred to our unit for fetal echocardiography due to the chromosomal anomaly and a second group of 274 fetuses referred because of suspected CHD, 11 of which were found to have DS. METHODS: All fetuses were submitted to detailed ultrasound evaluation of fetal anatomy. Associated extracardiac anomalies, and presence and type of CHD, were recorded for all fetuses. Karyotyping was obtained by means of cordocentesis or amniocentesis. Necropsy or neonatal echocardiograms were sought for confirmation of the prenatal diagnosis. RESULTS: In the group of 41 fetuses with known DS, the incidence of CHD was 56% ([atrioventricular septal defect (AVSD) 44%, ventricular septal defect (VSD) 48%], the remainder having other heart defects). Conversely, considering the incidence of DS in fetuses with CHD, 43% of all AVSDs (53% of AVSD with normal visceral situs) were associated with DS, whereas none of the 39 cases of VSD was associated with trisomy 21. Ventricular septal defects were diagnosed only in fetuses referred to our center with a known diagnosis of aneuploidy. CONCLUSIONS: We have confined that more than half of the fetuses with DS bear a CHD, which is an AVSD in 44% of cases. Conversely, 43% of fetuses with an AVSD have trisomy 21. For VSDS, the situation is controversial, due to the relatively low detection level of this heart defect at the routine mid-trimester obstetric scan.

Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia.

Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a group of genetically heterogeneous neurodegenerative disorders characterized by pro- gressive spasticity of the lower limbs. Five AD-HSP loci have been mapped to chromosomes 14q, 2p, 15q, 8q and 12q. The SPG4 locus at 2p21-p22 has been shown to account for approximately 40% of all AD-HSP families. SPG4 encoding spastin, a putative nuclear AAA protein, has recently been identified. Here, sequence analysis of the 17 exons of SPG4 in 87 unrelated AD-HSP patients has resulted in the detection of 34 novel mutations. These SPG4 mutations are scattered along the coding region of the gene and include all types of DNA modification including missense (28%), nonsense (15%) and splice site point (26.5%) mutations as well as deletions (23%) and insertions (7.5%). The clinical analysis of the 238 mutation carriers revealed a high proportion of both asymptomatic carriers (14/238) and patients unaware of symptoms (45/238), and permitted the redefinition of this frequent form of AD-HSP.