Identification of distinct pathological signatures induced by patient-derived α-synuclein structures in nonhuman primates.

Dopaminergic neuronal cell death, associated with intracellular α-synuclein (α-syn)-rich protein aggregates [termed "Lewy bodies" (LBs)], is a well-established characteristic of Parkinson's disease (PD). Much evidence, accumulated from multiple experimental models, has suggested that α-syn plays a role in PD pathogenesis, not only as a trigger of pathology but also as a mediator of disease progression through pathological spreading. Here, we have used a machine learning-based approach to identify unique signatures of neurodegeneration in monkeys induced by distinct α-syn pathogenic structures derived from patients with PD. Unexpectedly, our results show that, in nonhuman primates, a small amount of singular α-syn aggregates is as toxic as larger amyloid fibrils present in the LBs, thus reinforcing the need for preclinical research in this species. Furthermore, our results provide evidence supporting the true multifactorial nature of PD, as multiple causes can induce a similar outcome regarding dopaminergic neurodegeneration.

Search for γ-Ray Line Signals from Dark Matter Annihilations in the Inner Galactic Halo from 10 Years of Observations with H.E.S.S.

Spectral lines are among the most powerful signatures for dark matter (DM) annihilation searches in very-high-energy γ rays. The central region of the Milky Way halo is one of the most promising targets given its large amount of DM and proximity to Earth. We report on a search for a monoenergetic spectral line from self-annihilations of DM particles in the energy range from 300 GeV to 70 TeV using a two-dimensional maximum likelihood method taking advantage of both the spectral and spatial features of the signal versus background. The analysis makes use of Galactic center observations accumulated over ten years (2004-2014) with the H.E.S.S. array of ground-based Cherenkov telescopes. No significant γ-ray excess above the background is found. We derive upper limits on the annihilation cross section ⟨σv⟩ for monoenergetic DM lines at the level of 4×10^{-28} cm^{3} s^{-1} at 1 TeV, assuming an Einasto DM profile for the Milky Way halo. For a DM mass of 1 TeV, they improve over the previous ones by a factor of 6. The present constraints are the strongest obtained so far for DM particles in the mass range 300 GeV-70 TeV. Ground-based γ-ray observations have reached sufficient sensitivity to explore relevant velocity-averaged cross sections for DM annihilation into two γ-ray photons at the level expected from the thermal relic density for TeV DM particles.

Glioplasticity in irritable bowel syndrome.

BACKGROUND: Growing evidence indicates a wide array of cellular remodeling in the mucosal microenvironment during irritable bowel syndrome (IBS), which possibly contributes to pathophysiology and symptom generation. Here, we investigated whether enteric glial cells (EGC) may be altered, and which factors/mechanisms lead to these changes. METHODS: Colonic mucosal biopsies of IBS patients (13 IBS-Constipation [IBS-C]; 10 IBS-Diarrhea [IBS-D]; 11 IBS-Mixed [IBS-M]) and 24 healthy controls (HC) were analyzed. Expression of S100ß and GFAP was measured. Cultured rat EGC were incubated with supernatants from mucosal biopsies, then proliferation and Ca2+ response to ATP were analyzed using flow cytometry and Ca2+ imaging. Histamine and histamine 1-receptor (H1R) involvement in the effects of supernatant upon EGC was analyzed. KEY RESULTS: Compared to HC, the mucosal area immunoreactive for S100ß was significantly reduced in biopsies of IBS patients, independently of the IBS subtype. IBS-C supernatants reduced EGC proliferation and IBS-D and IBS-M supernatants reduced Ca2+ response to ATP in EGC. EGC expressed H1R and the effects of supernatant upon Ca2+ response to ATP in EGC were blocked by pyrilamine and reproduced by histamine via H1R. IBS supernatants reduced mRNA expression of connexin-43. The S100ß-stained area was negatively correlated with the frequency and intensity of pain and bloating. CONCLUSION AND INFERENCES: Changes in EGC occur in IBS, involving mucosal soluble factors. Histamine, via activation of H1R-dependent pathways, partly mediates altered Ca2+ response to ATP in EGC. These changes may contribute to the pathophysiology and the perception of pain and bloating in patients with IBS.

L. fermentum CECT 5716 prevents stress-induced intestinal barrier dysfunction in newborn rats.

BACKGROUND: Intestinal epithelial barrier (IEB) dysfunction plays a critical role in various intestinal disorders affecting infants and children, including the development of food allergies and colitis. Recent studies highlighted the role of probiotics in regulating IEB functions and behavior in adults, but their effects in the newborn remain largely unknown. We therefore characterized in rat pups, the impact of Lactobacillus fermentum CECT 5716 (L. fermentum) on stress-induced IEB dysfunction, systemic immune response and exploratory behavior. METHODS: Newborn rats received daily by gavage either L. fermentum or water. Intestinal permeability to fluorescein sulfonic acid (FSA) and horseradish peroxidase (HRP) was measured following maternal separation (MS) and water avoidance stress (WAS). Immunohistochemical, transcriptomic, and Western blot analysis of zonula occludens-1 (ZO-1) distribution and expression were performed. Anxiety-like and exploratory behavior was assessed using the elevated plus maze test. Cytokine secretion of activated splenocytes was also evaluated. KEY RESULTS: L. fermentum prevented MS and WAS-induced IEB dysfunction in vivo. L. fermentum reduced permeability to both FSA and HRP in the small intestine but not in the colon. L. fermentum increased expression of ZO-1 and prevented WAS-induced ZO-1 disorganization in ileal epithelial cells. L. fermentum also significantly reduced stress-induced increase in plasma corticosteronemia. In activated splenocytes, L. fermentum enhanced IFNγ secretion while it prevented IL-4 secretion. Finally, L. fermentum increased exploratory behavior. CONCLUSIONS & INFERENCES: These results suggest that L. fermentum could provide a novel tool for the prevention and/or treatment of gastrointestinal disorders associated with altered IEB functions in the newborn.

H.E.S.S. Limits on Linelike Dark Matter Signatures in the 100 GeV to 2 TeV Energy Range Close to the Galactic Center.

A search for dark matter linelike signals iss performed in the vicinity of the Galactic Center by the H.E.S.S. experiment on observational data taken in 2014. An unbinned likelihood analysis iss developed to improve the sensitivity to linelike signals. The upgraded analysis along with newer data extend the energy coverage of the previous measurement down to 100 GeV. The 18 h of data collected with the H.E.S.S. array allow one to rule out at 95% C.L. the presence of a 130 GeV line (at l=-1.5°, b=0° and for a dark matter profile centered at this location) previously reported in Fermi-LAT data. This new analysis overlaps significantly in energy with previous Fermi-LAT and H.E.S.S. RESULTS: No significant excess associated with dark matter annihilations was found in the energy range of 100 GeV to 2 TeV and upper limits on the gamma-ray flux and the velocity weighted annihilation cross section are derived adopting an Einasto dark matter halo profile. Expected limits for present and future large statistics H.E.S.S. observations are also given.

Search for Dark Matter Annihilations towards the Inner Galactic Halo from 10 Years of Observations with H.E.S.S.

The inner region of the Milky Way halo harbors a large amount of dark matter (DM). Given its proximity, it is one of the most promising targets to look for DM. We report on a search for the annihilations of DM particles using γ-ray observations towards the inner 300 pc of the Milky Way, with the H.E.S.S. array of ground-based Cherenkov telescopes. The analysis is based on a 2D maximum likelihood method using Galactic Center (GC) data accumulated by H.E.S.S. over the last 10 years (2004-2014), and does not show any significant γ-ray signal above background. Assuming Einasto and Navarro-Frenk-White DM density profiles at the GC, we derive upper limits on the annihilation cross section ⟨σv⟩. These constraints are the strongest obtained so far in the TeV DM mass range and improve upon previous limits by a factor 5. For the Einasto profile, the constraints reach ⟨σv⟩ values of 6×10^{-26} cm^{3} s^{-1} in the W^{+}W^{-} channel for a DM particle mass of 1.5 TeV, and 2×10^{-26} cm^{3} s^{-1} in the τ^{+}τ^{-} channel for a 1 TeV mass. For the first time, ground-based γ-ray observations have reached sufficient sensitivity to probe ⟨σv⟩ values expected from the thermal relic density for TeV DM particles.

Maternal exposure to GOS/inulin mixture prevents food allergies and promotes tolerance in offspring in mice.

BACKGROUND: Food allergies affect 4-8% of children and are constantly on the rise, thus making allergies a timely issue. Most importantly, prevention strategies are nonexistent, and current therapeutic strategies have limited efficacy and need to be improved. One alternative to prevent or reduce allergies, particularly during infancy, could consist of modulating maternal immunity and microbiota using nondigestible food ingredients, such as prebiotics. For this purpose, we studied the preventive effects of prebiotics in Balb/c mothers during pregnancy and breastfeeding on food allergy development in offspring mice. METHODS: After weaning, the offspring from mothers that were exposed to GOS/inulin mixture or fed a control diet were intraperitoneally sensitized to wheat proteins to induce a systemic allergic response and orally exposed to the same allergen. Immunological, physiological, and microbial parameters were analyzed. RESULTS: GOS/inulin mixture diet modified the microbiota of mothers and their offspring. Offspring from mothers that received GOS/inulin prebiotics were protected against food allergies and displayed lower clinical scores, specifically of IgE and histamine levels, compared to offspring from mothers fed a control diet. Moreover, GOS/inulin supplementation for the mother resulted in stronger intestinal permeability in the offspring. Enhancement of the regulatory response to allergic inflammation and changes in the Th2/Th1 balance toward a dampened Th2 response were observed in mice from GOS/inulin mixture-exposed mothers. CONCLUSION: The treatment of pregnant and lactating mice with nondigestible GOS/inulin prebiotics promotes a long-term protective effect against food allergies in the offspring.

Memristive and neuromorphic behavior in a Li(x)CoO2 nanobattery.

The phenomenon of resistive switching (RS), which was initially linked to non-volatile resistive memory applications, has recently also been associated with the concept of memristors, whose adjustable multilevel resistance characteristics open up unforeseen perspectives in cognitive computing. Herein, we demonstrate that the resistance states of Li(x)CoO2 thin film-based metal-insulator-metal (MIM) solid-state cells can be tuned by sequential programming voltage pulses, and that these resistance states are dramatically dependent on the pulses input rate, hence emulating biological synapse plasticity. In addition, we identify the underlying electrochemical processes of RS in our MIM cells, which also reveal a nanobattery-like behavior, leading to the generation of electrical signals that bring an unprecedented new dimension to the connection between memristors and neuromorphic systems. Therefore, these LixCoO2-based MIM devices allow for a combination of possibilities, offering new perspectives of usage in nanoelectronics and bio-inspired neuromorphic circuits.

Signal enhancement of electrochemical biosensors via direct electrochemical oxidation of silver nanoparticle labels coated with zwitterionic polymers.

A new electrochemical label has been developed, which is made up of silver nanoparticles (AgNPs) coated with a mixture of zwitterionic and biotinylated zwitterionic polymers. These polymers improve colloidal stability in physiological medium and ensure biorecognition while direct electrochemical oxidation of silver nanoparticles strongly enhances the detection signal. The resulting hybrid nanomaterials are used as labels in the electrochemical sensing of avidin using sandwich assays elaborated using the biotin-avidin biorecognition system.

Effects of 1-week sacral nerve stimulation on the rectal intestinal epithelial barrier and neuromuscular transmission in a porcine model.

BACKGROUND: Sacral nerve stimulation (SNS) is a validated treatment for fecal incontinence, although the mechanism of action remains unknown. Short-term effects of SNS on the intestinal epithelial barrier (IEB) have been reported previously. The aim of our study was to assess the impact of a 1-week SNS on the IEB in a preclinical model. METHODS: Fourteen pigs were implanted for bilateral SNS. Seven pigs received 7-day stimulation, whereas the remaining animals received no stimulation. Rectal biopsies were performed before and after SNS. We assessed IEB permeability, mucosal tight junction and cytokine mRNA expression, IL-6 production in an organotypic culture model, and neuromuscular transmission in muscle strips. KEY RESULTS: IEB permeability was not modified after stimulation, as compared with baseline. The PAR-induced increase in IEB permeability and the mucosal ZO-1 mRNA decrease observed in the controls were not observed into the stimulated group. Cytokine overexpression was not observed in the mucosa in either group. SNS decreased IL-6 production in the organotypic culture model. In the stimulated group, the area-under-the-curve of the EFS-induced contractile response was significantly increased. CONCLUSIONS & INFERENCES: The main conclusions of our work are (i) the successful development of a preclinical model of bilateral SNS and (ii) in physiological conditions, 1-week SNS did not lead to functional changes in the mucosa. While under stress-induced conditions, SNS modified the properties of the IEB, leading to a decrease in its permeability. Neuromuscular transmission was modified by SNS, leading to neuronal hyperexcitability. These results add evidence to the reinforcement of the IEB by SNS.

Abdominal wall and intra-peritoneal abscess by Propionibacterium avidum as a complication of abdominal parietoplasty.

Propionibacteria are organisms of low pathogenicity and only a minority of clinical Propionibacterium isolates is clinically significant. Herein, we report a rare case of Propionibacterium avidum abdominal wall and intra-peritoneal abscess that developed in 46-year-old woman after abdominal parietoplasty.

Effects of oral administration of rotenone on gastrointestinal functions in mice.

BACKGROUND: The systemic rotenone model of Parkinson's disease (PD) accurately replicates many aspects of the pathology of human PD, especially neurodegeneration of the substantia nigra and lesions in the enteric nervous system (ENS). Nevertheless, the precise effects of oral rotenone on the ENS have not been addressed yet. This study was therefore designed to assess the effects of a chronic oral treatment by rotenone on enteric neurochemical phenotype, gastrointestinal (GI) motility, and intestinal epithelial barrier permeability. METHODS: Male C57BL6N mice received once daily oral rotenone administration for 28 days. GI functions were analyzed 4 weeks after rotenone treatment. Gastrointestinal motility was assessed by measuring gastric emptying, total transit time, fecal pellet output, and bead latency. Intestinal barrier permeability was evaluated both in vivo and ex vivo. The number of enteric neurons and the enteric neurochemical phenotype were analyzed by immunohistochemistry. Tyrosine hydroxylase (TH) immunostaining of dopaminergic neurons of the substantia nigra was performed in a subset of animals. KEY RESULTS: Mice treated orally with rotenone had a decrease in fecal pellet output and in jejunal alpha-synuclein expression as compared with control animals. This was associated with a significant decrease in TH-immunoreactive neurons in the substantia nigra. No change in gastric emptying, total transit time, intestinal epithelial barrier permeability, and enteric neurochemical phenotype was observed. CONCLUSIONS & INFERENCES: Chronic oral treatment with rotenone only induced minor changes in the ENS and did not recapitulate the GI abnormalities seen in PD, while it replicates neurodegeneration of the substantia nigra.

One or two types of death? Attitudes of health professionals towards brain death and donation after circulatory death in three countries.

This study examined health professionals' (HPs) experience, beliefs and attitudes towards brain death (BD) and two types of donation after circulatory death (DCD)--controlled and uncontrolled DCD. Five hundred and eighty-seven HPs likely to be involved in the process of organ procurement were interviewed in 14 hospitals with transplant programs in France, Spain and the US. Three potential donation scenarios--BD, uncontrolled DCD and controlled DCD--were presented to study subjects during individual face-to-face interviews. Our study has two main findings: (1) In the context of organ procurement, HPs believe that BD is a more reliable standard for determining death than circulatory death, and (2) While the vast majority of HPs consider it morally acceptable to retrieve organs from brain-dead donors, retrieving organs from DCD patients is much more controversial. We offer the following possible explanations. DCD introduces new conditions that deviate from standard medical practice, allow procurement of organs when donors' loss of circulatory function could be reversed, and raises questions about "death" as a unified concept. Our results suggest that, for many HPs, these concerns seem related in part to the fact that a rigorous brain examination is neither clinically performed nor legally required in DCD. Their discomfort could also come from a belief that irreversible loss of circulatory function has not been adequately demonstrated. If DCD protocols are to achieve their full potential for increasing organ supply, the sources of HPs' discomfort must be further identified and addressed.

Sacral nerve stimulation enhances epithelial barrier of the rectum: results from a porcine model.

BACKGROUND: The mechanism of action of sacral nerve stimulation (SNS) remains largely elusive. The aims of this study were to develop a clinically relevant animal model for percutaneous SNS and to describe its effect on the epithelial barrier of the rectum. METHODS: Under general anesthesia and after percutaneous electrode placement for S3 nerve root stimulation, six pigs underwent unilateral stimulation and six bilateral stimulation. Animals were stimulated for 3 h using an external pulse generator (1-2.5 V; 14 Hz; 210 µs). Six animals underwent electrode implantation without stimulation and served as controls. Full-thickness rectal biopsies were performed prior to and after stimulation. Paracellular permeability was evaluated by measuring sulfonic acid flux across the rectal mucosa in Ussing chambers. Histological assessment of mucosal thickness, epithelial desquamation, and mucus expression were performed. KEY RESULTS: Percutaneous stimulation resulted in successful anal contractions whose amplitude and uniformity was enhanced following bilateral compared with unilateral stimulation. In controls, paracellular permeability significantly increased during the stimulation period whereas it remained unchanged following unilateral stimulation. In contrast, permeability was significantly reduced by bilateral stimulation. This effect was associated with a concomitant reduction in mucosal thickness and a trend toward increased amount of mucus on surface epithelium compared with controls. CONCLUSIONS & INFERENCES: The development of a porcine model of percutaneous SNS revealed the ability of neuromodulation to reinforce rectal epithelial barrier. Furthermore, our results suggest that SNS could be used for treatment of gastrointestinal pathologies with reduced rectal mucosal barrier functions.

[Cavernous hemangioma: rare incidentaloma of the adrenal gland]. / L'hémangiome caverneux : un incidentalome rare de la surrénale.

The hemangioma of the adrenal gland is an adrenal gland lesion rare, benign and usually asymptomatic. Discovered incidentally during an abdominal imaging study, it is part of incidentalomas. Imagery is the best to characterise these silent adrenal masses (computed tomography [CT], Magnetic Resonance Imaging [MRI]± Positron Emission Tomography [PET scan] with 18F-FDG). The main risks of the hemangioma are ignorance of malignancy, bleeding and abdominal mass syndrome. The analysis of the literature shows the importance of laparoscopy. A multidisciplinary discussion on this type of lesion appears indispensable both diagnostic and therapeutic.

[Hyperparathyroidism during pregnancy: dangerous association for the mother and her infant]. / Hyperparathyroïdie et grossesse : association à risque pour la mère et l'enfant.

Hypercalcaemia during pregnancy is rare but requires a systematic approach for its diagnosis and its treatment. We report a 32-year-old pregnant female at 32 weeks of gestation who presented a severe hypercalcaemia, due to primary hyperparathyroidism. The delivery allowed the birth of a healthy child who had a serum calcium level in the normal range. Eight days later, the mother was operated from a parathyroid adenoma allowing normalisation of calcaemia. Hyperparathyroidism during pregnancy is rarely reported; it can lead to severe complications for both the mother and the infant. The newborn can present tetania due to hypocalcaemia and hypoparathyroidism can be definitive. Surgery should be discussed when serum calcium level of the mother is markedly elevated.

Malignant T cells in cutaneous T-cell lymphoma lesions contain decreased levels of the antiapoptotic protein Ku70.

BACKGROUND: Malignant T cells in primary cutaneous T-cell lymphoma (CTCL) are genetically unstable and exhibit prolonged lifespans potentially explained by dysregulation of apoptosis, yet are responsive to apoptosis-inducing therapies. The heterodimeric protein Ku70/80 is known to play a role in DNA repair (Ku70 and Ku80) and inhibition of apoptosis (Ku70 only). OBJECTIVES: To investigate the expression of Ku70/80 in CD3+ T cells derived from skin and blood in patients with CTCL and normal samples, as well as benign dermatoses. METHODS: Normal (n=10), CTCL (n=9) and benign dermatoses (n=13) skin samples were stained for confocal imaging of Ku70/80 and CD3 and analysed using imaging software. Circulating CD4+ T cells in normal and CTCL peripheral blood were analysed by flow cytometry and Western blot for Ku70/80 expression (n=6). RESULTS: Ku70 and Ku80 were significantly diminished in T cells of CTCL lesions relative to T cells of control skin. Decreased T-cell Ku70 expression was not a feature of the benign dermatoses psoriasis and contact dermatitis, suggesting that loss of Ku70/80 in CTCL is not simply the result of cutaneous inflammation. Reduced Ku70 was also noted in circulating CD4+ T cells in patients with CTCL with peripheral blood involvement. CONCLUSIONS: Deficient expression or lack of Ku70/80 may result in genomic instability and play a role in tumorigenesis, as well as account for the increased susceptibility of malignant T cells to apoptosis-inducing treatment modalities in the setting of intrinsic resistance to apoptosis.

Impaired intestinal barrier integrity in the colon of patients with irritable bowel syndrome: involvement of soluble mediators.

BACKGROUND: Growing evidence suggests that patients with irritable bowel syndrome (IBS) have increased intestinal permeability. In addition, mucosal soluble mediators are involved in the pathophysiology of pain in IBS. We aimed to investigate (1) paracellular permeability in colonic biopsies of patients with IBS; and (2) the ability of soluble factors from colonic biopsies to reproduce these alterations in vitro. METHODS: Paracellular permeability in colonic biopsies of healthy subjects and patients with IBS was measured by mounting the biopsies in Ussing chambers. Cleared supernatant (SUP) of the culture from colonic biopsies was collected and applied to Caco-2 cells for 48 h. Paracellular permeability and transepithelial resistance (TER) were evaluated. mRNA expression of the tight junction proteins, zonula occludens (ZO)-1 and occludin, was assessed in colonic biopsies. Abdominal pain was assessed using a validated questionnaire. RESULTS: Permeability of colonic biopsies was significantly higher in patients with IBS compared to healthy subjects. These changes were associated with significantly lower expression of ZO-1 mRNA in biopsies of IBS as compared to healthy subjects. Compared to healthy subjects, SUP of IBS markedly reduced TER and significantly increased permeability in Caco-2 cells. SUP of IBS patients induced a significant decrease of ZO-1 mRNA in Caco-2 as compared to healthy subjects. SUP-induced increased paracellular permeability correlated with the severity of abdominal pain. CONCLUSIONS: Our study shows that colonic soluble mediators are able to reproduce functional (permeability) and molecular (ZO-1 mRNA expression) alterations observed in IBS patients. These findings might pave the way both to identify novel biomarkers as well as new therapeutic targets in IBS.

Neurochemical plasticity in the enteric nervous system of a primate animal model of experimental Parkinsonism.

Emerging evidences suggest that the enteric nervous system (ENS) is affected by the degenerative process in Parkinson's disease (PD). In addition lesions in the ENS could be associated with gastrointestinal (GI) dysfunctions, in particular constipation, observed in PD. However, the precise alterations of the ENS and especially the changes in the neurochemical phenotype remain largely unknown both in PD and experimental Parkinsonism. The aim of our study was thus to characterize the neurochemical coding of the ENS in the colon of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, a well-characterized model of PD. In the myenteric plexus, there was a significant increase in the number of neurons per ganglia (identified with Hu), especially nitric oxide synthase immunoreactives (IR) neurons in MPTP-treated monkeys compared to controls. A concomitant 72% decrease in the number of tyrosine hydroxylase-IR neurons was observed in MPTP-treated monkeys compared to controls. In contrast no change in the cholinergic or vasoactive intestinal peptide-IR population was observed. In addition, the density of enteric glial cells was not modified in MPTP-treated monkeys. Our results demonstrate that MPTP induces major changes in the myenteric plexus and to a lesser extent in the submucosal plexus of monkeys. They further reinforce the observation that lesions of the ENS occur in the course of PD that might be related to the GI dysfunction observed in this pathology.