Plasma microglial-derived extracellular vesicles are increased in frail patients with Mild Cognitive Impairment and exert a neurotoxic effect.

Extracellular vesicles (EVs) are mediators of cellular communication that can be released by almost all cell types in both physiological and pathological conditions and are present in most biological fluids. Such characteristics make them attractive in the research of biomarkers for age-related pathological conditions. Based on this, the aim of the present study was to examine the changes in EV concentration and size in the context of frailty, a geriatric syndrome associated with a progressive physical and cognitive decline. Specifically, total EVs and neural and microglial-derived EVs (NDVs and MDVs respectively) were investigated in plasma of frail and non-frail controls (CTRL), mild cognitive impairment (MCI) subjects, and in Alzheimer's disease (AD) patients. Results provided evidence that AD patients displayed diminished NDV concentration (3.61 × 109 ± 1.92 × 109 vs 7.16 × 109 ± 4.3 × 109 particles/ml) and showed high diagnostic performance. They are able to discriminate between AD and CTRL with an area under the curve of 0.80, a sensitivity of 78.95% and a specificity of 85.7%, considering the cut-off of 5.27 × 109 particles/ml. Importantly, we also found that MDV concentration was increased in frail MCI patients compared to CTRL (5.89 × 109 ± 3.98 × 109 vs 3.16 × 109 ± 3.04 × 109 particles/ml, P < 0.05) and showed high neurotoxic effect on neurons. MDV concentration discriminate frail MCI vs non-frail CTRL (AUC = 0.76) with a sensitivity of 80% and a specificity of 70%, considering the cut-off of 2.69 × 109 particles/ml. Altogether, these results demonstrated an alteration in NDV and MDV release during cognitive decline, providing important insight into the role of EVs in frailty status.

Thermally controlled optical resonator for vacuum squeezed states separation.

Future gravitational-wave detectors will use frequency-dependent squeezed vacuum states to obtain broadband reduction of quantum noise. Quantum noise is one of the major limitations to the sensitivity of these detectors. Advanced LIGO+, Advanced Virgo+, and KAGRA plan to generate frequency-dependent squeezed states by coupling a frequency-independent squeezed light state with a filter cavity. An alternative technique is under consideration, based on conditional squeezing with quantum entanglement: Einstein-Podolsky-Rosen (EPR) squeezing. In the EPR scheme, two vacuum entangled states, the signal field at ω0 and the idler field at ω0+Δ, must be spatially separated with an optical resonator and sent to two separate homodyne detectors. In this framework, we have designed and tested a solid Fabry-Perot etalon, to be used in an EPR table-top experiment prototype, thermally controlled without the use of a control probe optical beam. This device can also be used in optical experiments where the use of a bright beam to control an optical resonator is not possible, or where a simpler optical device is preferred.

Automated source of squeezed vacuum states driven by finite state machine based software.

In the last few decades, much effort has been made for the production of squeezed vacuum states in order to reduce quantum noise in the audio-frequency band. This technique has been implemented in all running gravitational-wave interferometric detectors and helped to improve their sensitivity. While the detectors are acquiring data for astrophysical observations, they must be kept in the operating condition, also called "science mode," that is, a state that requires the highest possible duty-cycle for all the instrumental parts and controls. We report the development of a highly automated setup for the generation of optical squeezed states, where all the required control loops are supervised by a software based on finite state machines; we took special care to grant ease of use, stability of operation, and possibility of auto-recovery. Moreover, the setup has been designed to be compatible with the existing software and hardware infrastructure of the Virgo detector. In this paper, we discuss the optical properties of this squeezing setup, the locking techniques, and the automation algorithms.

Prenatal visualisation of the torcular herophili by means of a Doppler technology highly sensitive for low-velocity flow in the expert assessment of the posterior fossa: a prospective study.

OBJECTIVE: To evaluate the usefulness of a Doppler technology highly sensitive for low-velocity flow in the antenatal imaging of the torcular herophili (TH) in the second trimester of pregnancy. DESIGN: Prospective study. SETTING: Referral Fetal Medicine Unit. POPULATION: Non-consecutive series of singleton pregnancies submitted to antenatal neurosonogram between 20 and 28 weeks of gestation. METHODS: A midsagittal section of the fetal brain was obtained by insonating through the anterior fontanelle, then the MV-Flow™ and LumiFlow™ presets were selected to visualise the TH as the posterior confluence of the superior sagittal sinus and the straight sinus. MAIN OUTCOME MEASURES: Evaluation of the anatomic relationship of the TH with the 'transpalatal line' joining the upper bony palate to the fetal skull. RESULTS: A total of 99 pregnant women were recruited, including one fetus with open spina bifida, one with Dandy-Walker malformation (DWM) and two with Blake's pouch cysts. In normal fetuses, the TH appeared to lie on or just below the 'transpalatal line'. In the cases of Blake's pouch cyst, the position of the TH appeared normal if compared with controls, whereas in DWM a supra-elevated position of the TH in respect of the transpalatal line was demonstrated. Finally, in the fetus with Chiari II malformation the TH was identified below the 'transpalatal plane'. CONCLUSIONS: Prenatal ultrasound visualisation of the TH by means of newly developed Doppler technologies characterised by high sensitivity for low-velocity flow is feasible and allows the indirect evaluation of the insertion of cerebellar tentorium in the second trimester. TWEETABLE ABSTRACT: Prenatal imaging of the torcular herophili using a Doppler technology highly sensitive for low-velocity flow.

Late-onset presentation and phenotypic heterogeneity of the rare R377W PSEN1 mutation.

BACKGROUND AND PURPOSE: Mutations in the PSEN1 gene are the most common cause of autosomal-dominant Alzheimer's disease and have been associated with the earliest disease onset. We describe an unusual presentation of the rare R377W PSEN1 mutation with a late age of onset, and we provide for the first time in vivo pathological evidence for this mutation. METHODS: A 71-year-old female patient with progressive cognitive decline in the past 3 years and positive family history for dementia underwent neurological evaluation, neuropsychological testing, lumbar puncture, conventional brain imaging, amyloid-positron emission tomography (PET) and extensive genetic screening with a next-generation sequencing technique. RESULTS: The diagnostic workup revealed mixed behavioural and amnestic disease features on neuropsychological tests, magnetic resonance imaging, and 18-fluorodeoxyglucose (FDG)-PET. Amyloid-PET detected amyloid deposition in the frontal areas, in the parietal lobes and the precunei. The genetic screening revealed the presence of the rare R377W mutation in the PSEN1 gene. CONCLUSIONS: Extensive genetic screening is also advisable for late-onset presentations of Alzheimer's disease, especially in the presence of a positive family history or atypical clinical features.

Pathophysiology of hypoxic-ischemic encephalopathy: a review of the past and a view on the future.

Hypoxic-ischemic encephalopathy, also referred as HIE, is a type of brain injury or damage that is caused by a lack of oxygen to the brain during neonatal period. The incidence is approximately 1.5 cases per 1000 live births in developed countries. In low and middle-income countries, the incidence is much higher (10‒20 per 1000 live births). The treatment for neonatal HIE is hypothermia that is only partially effective (not more than 50% of the neonates treated achieve an improved outcome). HIE pathophysiology involves oxidative stress, mitochondrial energy production failure, glutaminergic excitotoxicity, and apoptosis. So, in the last years, many studies have focused on peptides that act somewhere in the pathway activated by severe anoxic injury leading to HIE. This review describes the pathophysiology of perinatal HIE and the mechanisms that could be the target of innovative HIE treatments.

Shallow bore-hole three-axial fiber Bragg grating strain sensor for Etna volcano monitoring.

We present the realization, installation, and first results of a three-axial Fiber Bragg Grating (FBG) strain sensor prototype. This sensor has been developed in the framework of the Mediterranean supersite volcanoes (http://www.med-suv.eu, 2013) project and, in particular, with the aim at contributing to the study and monitoring of Etna volcano. The FBG sensor was installed in the facilities of the Serra La Nave Astrophysical Observatory (Catania, Italy) about 7 km south-west from the summit craters, at an elevation of about 1740 m. The three-axial device showed a dynamic range of some hundreds of microstrains with microstrain resolution (submicrostrain concerning the vertical component). That is a good trade-off among performances, cost, and power consumption. The sensor structure and its read-out system are innovative in their assembly and offers practical advantages in comparison with traditional strain meters. As a demonstration of the performances of our device, the data of about 28 months of operation are presented together with the records of some local, regional, and teleseismic events. The sensor along the vertical axis showed to be the best performing one, having a power spectral density of about -90 dB re. 1ε2/Hz around one day period.

The experience of virtual reality: are individual differences in mental imagery associated with sense of presence?

The concept of "presence" describes the quality of subjective experience in immersive virtual reality (IVR). Presence refers to a specific state of consciousness: we behave and feel as if we actually were in the virtual world even though we know there is nothing there. In their handbook of Virtual Reality, Burdea and Coiffet (Virtual reality technology, Wiley, New York, 2003) suggested that the experience of presence in IVR would emerge from the combination of three Is: Immersion or capacity to isolate from the external world, Interaction or capacity to naturally exploring the virtual environment, and Imagination or individual aptitudes with mental imagery. So far, several studies have investigated the technological and psychological factors affecting the degree of immersion and interaction. However, no study has explored the relationship between perceived presence and mental imagery. Here we aim at filling this gap through a correlational study comparing self-reports about sense of presence and mental imagery abilities. After experiencing two IVR scenarios (an art gallery and a living room), 142 male and female users were administered with questionnaires assessing the degree of presence (Igroup Presence Questionnaire), the degree of vividness (Vividness of Visual Imagery Questionnaire) and control (Test of Visual Imagery Control) of subjective mental images. Results showed a clear positive correlation between presence and vividness: the higher the vividness of mental images the stronger the reported sense of presence felt in IVR scenarios. Instead, the capacity to control mental imagery showed a weaker association with presence. We may conclude that individual differences in the degree of perceived presence and mental imagery ability are associated.

Quantum test of the equivalence principle for atoms in coherent superposition of internal energy states.

The Einstein equivalence principle (EEP) has a central role in the understanding of gravity and space-time. In its weak form, or weak equivalence principle (WEP), it directly implies equivalence between inertial and gravitational mass. Verifying this principle in a regime where the relevant properties of the test body must be described by quantum theory has profound implications. Here we report on a novel WEP test for atoms: a Bragg atom interferometer in a gravity gradiometer configuration compares the free fall of rubidium atoms prepared in two hyperfine states and in their coherent superposition. The use of the superposition state allows testing genuine quantum aspects of EEP with no classical analogue, which have remained completely unexplored so far. In addition, we measure the Eötvös ratio of atoms in two hyperfine levels with relative uncertainty in the low 10-9, improving previous results by almost two orders of magnitude.

A novel mutation in NDUFB11 unveils a new clinical phenotype associated with lactic acidosis and sideroblastic anemia.

NDUFB11, a component of mitochondrial complex I, is a relatively small integral membrane protein, belonging to the "supernumerary" group of subunits, but proved to be absolutely essential for the assembly of an active complex I. Mutations in the X-linked nuclear-encoded NDUFB11 gene have recently been discovered in association with two distinct phenotypes, i.e. microphthalmia with linear skin defects and histiocytoid cardiomyopathy. We report on a male with complex I deficiency, caused by a de novo mutation in NDUFB11 and displaying early-onset sideroblastic anemia as the unique feature. This is the third report that describes a mutation in NDUFB11, but all are associated with a different phenotype. Our results further expand the molecular spectrum and associated clinical phenotype of NDUFB11 defects.

A challenge to the striking genotypic heterogeneity of retinitis pigmentosa: a better understanding of the pathophysiology using the newest genetic strategies.

Retinitis pigmentosa (RP) is a group of inherited retinal disorders characterized by a complex association between tremendous genotypic multiplicity and great phenotypic heterogeneity. The severity of the clinical manifestation depends on penetrance and expressivity of the disease-gene. Also, various interactions between gene expression and environmental factors have been hypothesized. More than 250 genes with ~4500 causative mutations have been reported to be involved in different RP-related mechanisms. Nowadays, not more than the 50% of RPs are attributable to identified genes, whereas the rest of molecular defects are still undetectable, especially in populations where few genetic screenings have been performed. Therefore, new genetic strategies can be a remarkably useful tool to aid clinical diagnosis, potentially modifying treatment options, and family counseling. Genome-wide analytical techniques (array comparative genomic hybridization and single-nucleotide polymorphism genotyping) and DNA sequencing strategies (arrayed primer extension, Sanger sequencing, and ultra high-throughput sequencing) are successfully used to early make molecular diagnosis detecting single or multiple mutations in the huge heterogeneity of RPs. To date, further research needs to be carried out to better investigate the genotype/phenotype correlation, putting together genetic and clinical findings to provide detailed information concerning the risk of RP development and novel effective treatments.

Development of novel tricalcium silicate-based endodontic cements with sintered radiopacifier phase.

OBJECTIVES: All implants, bone and endodontic cements need to be sufficiently radiopaque to be able to be distinguished from neighbouring anatomical structures post-operatively. For this purpose, radiopacifying materials are added to the cements to render them sufficiently radiopaque. Bismuth oxide has been quite a popular choice of radiopacifier in endodontic materials. It has been shown to cause dental discoloration. The aim of this study was to develop, characterize and assess the properties of tricalcium silicate cement with alternative radiopacifiers, which are either inter-ground or sintered to the tricalcium silicate cement. METHODS: Custom-made endodontic cements based on tricalcium silicate and 20 % barium, calcium or strontium zirconate, which were either inter-ground or sintered at high temperatures, were produced. The set materials stored for 28 days in Hank's balanced salt solution were characterized by scanning electron microscopy and X-ray diffraction analysis. Assessment of pH, leaching, interaction with physiological solution, radiopacity, setting time, compressive strength and material porosity were investigated. Mineral trioxide aggregate (MTA) Angelus was used as control. RESULTS: Addition of radiopacifying materials improved the radiopacity of the material. The sintered cements exhibited the formation of calcium zirconate together with the respective radiopacifier phase. All materials produced calcium hydroxide on hydration, which interacted with tissue fluids forming hydroxyapatite on the material surface. The physical properties of the tricalcium silicate-based cements were comparable to MTA Angelus. CONCLUSIONS: A novel method of producing radiopaque tricalcium silicate-based cements was demonstrated. The novel materials exhibited properties, which were either comparable or else improved over the control. CLINICAL RELEVANCE: The novel materials can be used to replace MTA for root-end filling, perforation repair and other clinical applications where MTA is indicated.

Bilateral salpingo-oophorectomy and adhesiolysis with single port access laparoscopy and use of diode laser in a BRCA carrier.

Herein the authors report the first case of prophylactic bilateral salpingo-ovariectomy (BSO) in single port access laparoscopy (SPAL) with use of diode laser in a patient with BRCA1 mutation. As fimbria could be considered the site of origin for many serous carcinomas in BRCA mutation carriers, many studies are carried out to evaluate the possibility of preventing ovarian carcinoma with BSO. SPAL is a development of endoscopic surgery which further reduces invasiveness of surgical procedures. Diode laser presents a recognized precision for tissue cutting and coagulation and its use could be highly advantageous in SPAL surgery and in particular in such situations avoiding fallopian tube histology distortion and consequently improve the prognosis of BRCA carriers.

Measurement of the gravity-field curvature by atom interferometry.

We present the first direct measurement of the gravity-field curvature based on three conjugated atom interferometers. Three atomic clouds launched in the vertical direction are simultaneously interrogated by the same atom interferometry sequence and used to probe the gravity field at three equally spaced positions. The vertical component of the gravity-field curvature generated by nearby source masses is measured from the difference between adjacent gravity gradient values. Curvature measurements are of interest in geodesy studies and for the validation of gravitational models of the surrounding environment. The possibility of using such a scheme for a new determination of the Newtonian constant of gravity is also discussed.

Transcriptomic resources for environmental risk assessment: a case study in the Venice lagoon.

The development of new resources to evaluate the environmental status is becoming increasingly important representing a key challenge for ocean and coastal management. Recently, the employment of transcriptomics in aquatic toxicology has led to increasing initiatives proposing to integrate eco-toxicogenomics in the evaluation of marine ecosystem health. However, several technical issues need to be addressed before introducing genomics as a reliable tool in regulatory ecotoxicology. The Venice lagoon constitutes an excellent case, in which the assessment of environmental risks derived from the nearby industrial activities represents a crucial task. In this context, the potential role of genomics to assist environmental monitoring was investigated through the definition of reliable gene expression markers associated to chemical contamination in Manila clams, and their subsequent employment for the classification of Venice lagoon areas. Overall, the present study addresses key issues to evaluate the future outlooks of genomics in the environmental monitoring and risk assessment.

Characterization of un-hydrated and hydrated BioAggregate™ and MTA Angelus™.

OBJECTIVES: BioAggregate™ is a novel material introduced for use as a root-end filling material. It is tricalcium silicate-based, free of aluminium and uses tantalum oxide as radiopacifier. BioAggregate contains additives to enhance the material performance. The purpose of this research was to characterize the un-hydrated and hydrated forms of BioAggregate using a combination of techniques, verify whether the additives if present affect the properties of the set material and compare these properties to those of MTA Angelus™. METHODS: Un-hydrated and hydrated BioAggregate and MTA Angelus were assessed. Un-hydrated cement was tested for chemical composition, specific surface area, mineralogy and kinetics of hydration. The set material was investigated for mineralogy, microstructure and bioactivity. Scanning electron microscopy, X-ray energy dispersive spectroscopic analysis, X-ray fluorescence spectroscopy, X-ray diffraction and isothermal calorimetry were employed. The specific surface area was investigated using a gas adsorption method with nitrogen as the probe. RESULTS: BioAggregate was composed of tricalcium silicate, tantalum oxide, calcium phosphate and silicon dioxide and was free of aluminium. On hydration, the tricalcium silicate produced calcium silicate hydrate and calcium hydroxide. The former was deposited around the cement grains, while the latter reacted with the silicon dioxide to form additional calcium silicate hydrate. This resulted in reduction of calcium hydroxide in the aged cement. MTA Angelus reacted in a similar fashion; however, since it contained no additives, the calcium hydroxide was still present in the aged cement. Bioactivity was demonstrated by deposition of hydroxyapatite. BioAggregate exhibited a high specific surface area. Nevertheless, the reactivity determined by isothermal calorimetry appeared to be slow compared to MTA Angelus. The tantalum oxide as opposed to bismuth oxide was inert, and tantalum was not leached in solution. BioAggregate exhibited high calcium ion release early, which was maintained over the 28-day period as opposed to MTA Angelus, which demonstrated low early calcium ion release which increased as the material aged. CONCLUSIONS: The mineralogical composition of BioAggregate was different to MTA Angelus. As opposed to MTA Angelus, BioAggregate did not contain aluminium and contained additives such as calcium phosphate and silicon dioxide. As a consequence, BioAggregate reacted more slowly and formation of calcium hydroxide and leaching of calcium ions in solution were not evident as the material aged. The additives in BioAggregate modify the kinetics and the end products of hydration. CLINICAL SIGNIFICANCE: Although newer generation tricalcium silicate-based materials contain similar constituents to MTA, they do not undergo the same setting reactions, and thus, their clinical performance will not be comparable to that of MTA.

Measuring the Newtonian constant of gravitation G with an atomic interferometer.

We have recently completed a measurement of the Newtonian constant of gravitation G using atomic interferometry. Our result is G=6.67191(77)(62)×10(-11) m(3) kg(-1) s(-2) where the numbers in parenthesis are the type A and type B standard uncertainties, respectively. An evaluation of the measurement uncertainty is presented and the perspectives for improvement are discussed. Our result is approaching the precision of experiments based on macroscopic sensing masses showing that the next generation of atomic gradiometers could reach a total relative uncertainty in the 10 parts per million range.

Precision measurement of the Newtonian gravitational constant using cold atoms.

About 300 experiments have tried to determine the value of the Newtonian gravitational constant, G, so far, but large discrepancies in the results have made it impossible to know its value precisely. The weakness of the gravitational interaction and the impossibility of shielding the effects of gravity make it very difficult to measure G while keeping systematic effects under control. Most previous experiments performed were based on the torsion pendulum or torsion balance scheme as in the experiment by Cavendish in 1798, and in all cases macroscopic masses were used. Here we report the precise determination of G using laser-cooled atoms and quantum interferometry. We obtain the value G = 6.67191(99) × 10(-11) m(3) kg(-1) s(-2) with a relative uncertainty of 150 parts per million (the combined standard uncertainty is given in parentheses). Our value differs by 1.5 combined standard deviations from the current recommended value of the Committee on Data for Science and Technology. A conceptually different experiment such as ours helps to identify the systematic errors that have proved elusive in previous experiments, thus improving the confidence in the value of G. There is no definitive relationship between G and the other fundamental constants, and there is no theoretical prediction for its value, against which to test experimental results. Improving the precision with which we know G has not only a pure metrological interest, but is also important because of the key role that G has in theories of gravitation, cosmology, particle physics and astrophysics and in geophysical models.

The role of hysteroscopy in the diagnostic work-up of infertile asymptomatic patients.

PURPOSE OF INVESTIGATION: To demonstrate that office hysteroscopy has a key-role in the diagnostic work-up of infertile couples. MATERIALS AND METHODS: The entire database of hysteroscopies performed in 572 menstruated women from 2008 to 2011, was retrospectively analyzed. A two-dimensional correspondence analysis among endometrial patterns, age ranges, and indication for hysteroscopies was made. A main-effect hierarchical log-linear model was built to assess the goodness of the correspondences found. RESULTS: A clear cluster of aggregation appears in case of both primary and secondary infertility, with and without other indications for hysteroscopy, as well as in case of primary infertility with irregular menstrual bleeding. In such patients, chronic endometritis, normal pattern, and uterine malformations were frequently found. The most significant correspondence was found for normal pattern and chronic endometritis in case of secondary infertility and primary infertility, respectively. CONCLUSIONS: Office hysteroscopy should be reconsidered in the diagnostic work-up of infertile couples. It is able to assess or rule out endometrial factor for female infertility.

[Differentiated microcarcinoma of the thyroid gland]. / Il microcarcinoma differenziato della tiroide.

BACKGROUND: The thyroid microcarcinoma is a tumor with maximum diameter of 10 mm (WHO). For the most part is not clinically palpable and not evident by imaging investigations. The papillary microcarcinoma is the most common form of thyroid cancer, followed by follicular microcarcinoma. The aim of our study is to assess the frequency of microcarcinoma, the association of benign thyroid disease himself and the controversial surgery. PATIENTS AND METHODS: We analyzed 391 patients (321 F and 70 M) who underwent total thyroidectomy from 2004 to 2009 at a Unit of General Surgery, Uremic and Organ Transplant, Hospital of Palermo. RESULTS: 42 carcinomas were detected, of which 24 PTMC and 1 follicular microcarcinoma. The PTMC was associated with cancer in only 2 cases (papillary carcinoma and parathyroid carcinoma) in the remaining thyroid tissue was suffering from benign disease (20 goiters, 3 Hashimoto thyroiditis, a trabecular adenoma). TALK: Controversial is still the type of surgery to be performed in case of differentiated thyroid microcarcinomas, as well as the indication is still debated to lymphadenectomy. CONCLUSIONS: Papillary microcarcinoma of the thyroid in our series, represents 57% of all thyroid cancers. Microcarcinoma and benign thyroid disease association (76.92% of cases) was high. The therapeutic attitude adopted by us was total thyroidectomy associated with conservative lymphadenectomy in the presence of palpable lymph nodes, instead to abstaining in the absence of clinical evidence of nodal metastases.