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.
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.
•There is not a clear microbiota profile shared by different ASD murine models.•Preclinical studies are relevant to test microbiota-based therapies for treatment of ASD.•Efforts are required to reduce the inter-laboratory variability.
•Rodent models are crucial to assess the therapeutic efficacy of stem cell transplantation in HD.•Behavioural, morphological and molecular effects of cell therapy should be assessed ...longitudinally.•Experimental studies support moderate functional efficacy of SCs therapy in HD rodent models.•Training and environment can influence graft-derived functional recovery in HD rodent models.•Screening of different HD models would speed translation of cell therapy from bench to clinic.
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.
•BTBR virgin female mice are less responsive to presentation of pups in comparison of B6.•c-Fos expression in brain areas activated by pup-related cues is lower in BTBR mice.•Social impairment of ...BTBR mice extends to responsiveness to pups by virgin females.
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.
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.
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.
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.
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.
The effect of gamma-aminobutyric acid (GABA) on the bull sperm acrosome reaction was evaluated, and the interaction of progesterone, a physiologic inducer of the acrosome reaction, with the GABA ...receptor was explored. The acrosome reaction was stimulated by GABA in a dose-dependent manner. This effect was inhibited completely by bicuculline, a GABA A receptor antagonist, but GABA B and C receptor antagonists had no effect. Accordingly, muscimol, a GABA A receptor agonist, stimulated the acrosome reaction to the same extent as GABA, whereas baclofen (GABA B receptor agonist) and CACA (GABA C receptor agonist), had no effect. Preincubation with progesterone followed by the addition of GABA resulted in a significant increase in the percentage of acrosome reacted spermatozoa compared with progesterone or GABA alone. Taking into account that this increase was less than a simple addition of effects, it might be suggested that GABA and progesterone act through the same receptor and/or use the same mechanism of action. To test this hypothesis, the abilities of GABA and progesterone to induce acrosome reaction were tested in the presence of bicuculline, which suppressed both stimulatory effects. Given that the GABA A receptor is linked to the Cl− channel, we tested whether picrotoxin, a blocker of this channel, could modulate the effects of progesterone or GABA. Cl− channel blocker picrotoxin dramatically reduced the GABA and progesterone-initiated AR. In conclusion: GABA and progesterone stimulate the acrosome reaction in bull spermatozoa acting through a classical GABA A receptor. The mechanism of action requires the functional integrity of the Ca2+ Cl− channel.
Summary
Introduction
Growth hormone deficiency is considered the most important factor determining skeletal fragility in hypopituitary patients. Osteoblasts and chondrocytes express growth hormone ...(GH) receptor. Two GH receptor isoforms (GHRi) have been identified: they differ for the presence/absence of a protein fragment encoded by exon 3 of GHR gene. Consequently, three genotypes were identified: carriers of both the full‐length proteins (flfl‐GHR), carriers of one full‐length protein and one deleted protein (fld3‐GHR) and carriers of both deleted proteins (d3d3‐GHR). This polymorphism confers a higher sensitivity to endogenous GH and to recombinant human GH (rhGH); its effect on bone metabolism and skeletal fragility is unknown. The aim of this article was to investigate the role of GHRi in predicting skeletal fragility in adult‐onset GHD (AO‐GHD) patients.
Subjects and methods
A cross‐sectional study was conducted to investigate the association between the d3‐GHR isoform and the prevalence of morphometric vertebral fractures (VFs) in AO‐GHD. Ninety‐three AO‐GHD were enrolled. Forty‐nine patients carried flfl‐GHRi (52·7%), and 44 patients (47·3%) carried at least one allele of the d3‐GHR isoform. Thirty‐two VFs were documented. Fifty‐seven patients underwent rhGH replacement therapy.
Results
Median age was significantly higher in fractured patients as compared to nonfractured ones; d3‐carrier patients showed a lower VF risk as compared to flfl‐GHRi (OR: 0·37, 95% IC: 0·24–0·55, P < 0·0001). This finding was also confirmed in AO‐GHD undergoing rhGH replacement therapy.
Conclusion
This study suggests that d3‐GHR may protect AO‐GHD particularly when treated with rhGH from the risk of VFs.
The instrument suite of the European Spallation Source Jackson, A.J.; Toft-Petersen, R.; Beran, P. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
03/2020, Letnik:
957, Številka:
-
Journal Article
Recenzirano
Odprti dostop
An overview is provided of the 15 neutron beam instruments making up the initial instrument suite of the European Spallation Source (ESS), and being made available to the neutron user community. The ...ESS neutron source consists of a high-power accelerator and target station, providing a unique long-pulse time structure of slow neutrons. The design considerations behind the time structure, moderator geometry and instrument layout are presented.
The 15-instrument suite consists of two small-angle instruments, two reflectometers, an imaging beamline, two single-crystal diffractometers; one for macromolecular crystallography and one for magnetism, two powder diffractometers, and an engineering diffractometer, as well as an array of five inelastic instruments comprising two chopper spectrometers, an inverse-geometry single-crystal excitations spectrometer, an instrument for vibrational spectroscopy and a high-resolution backscattering spectrometer. The conceptual design, performance and scientific drivers of each of these instruments are described.
All of the instruments are designed to provide breakthrough new scientific capability, not currently available at existing facilities, building on the inherent strengths of the ESS long-pulse neutron source of high flux, flexible resolution and large bandwidth. Each of them is predicted to provide world-leading performance at an accelerator power of 2 MW. This technical capability translates into a very broad range of scientific capabilities. The composition of the instrument suite has been chosen to maximise the breadth and depth of the scientific impact of the early years of the ESS, and provide a solid base for completion and further expansion of the facility.
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.
The majority of patients with nonalcoholic fatty liver disease (NAFLD) have “simple steatosis,” which is defined by hepatic steatosis in the absence of substantial inflammation or fibrosis and is ...considered to be benign. However, 10%‐30% of patients with NAFLD progress to fibrosing nonalcoholic steatohepatitis (NASH), which is characterized by varying degrees of hepatic inflammation and fibrosis, in addition to hepatic steatosis, and can lead to cirrhosis. The cause(s) of progression to fibrosing steatohepatitis are unclear. We aimed to test the relative contributions of dietary fat and dietary cholesterol and their interaction on the development of NASH. We assigned C57BL/6J mice to four diets for 30 weeks: control (4% fat and 0% cholesterol); high cholesterol (HC; 4% fat and 1% cholesterol); high fat (HF; 15% fat and 0% cholesterol); and high fat, high cholesterol (HFHC; 15% fat and 1% cholesterol). The HF and HC diets led to increased hepatic fat deposition with little inflammation and no fibrosis (i.e., simple hepatic steatosis). However, the HFHC diet led to significantly more profound hepatic steatosis, substantial inflammation, and perisinusoidal fibrosis (i.e., steatohepatitis), associated with adipose tissue inflammation and a reduction in plasma adiponectin levels. In addition, the HFHC diet led to other features of human NASH, including hypercholesterolemia and obesity. Hepatic and metabolic effects induced by dietary fat and cholesterol together were more than twice as great as the sum of the separate effects of each dietary component alone, demonstrating significant positive interaction. Conclusion: Dietary fat and dietary cholesterol interact synergistically to induce the metabolic and hepatic features of NASH, whereas neither factor alone is sufficient to cause NASH in mice. (HEPATOLOGY 2013)
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