Enteric dysfunctions in experimental Parkinson's disease: alterations of excitatory cholinergic neurotransmission regulating colonic motility in rats

Parkinson's disease (PD) is frequently associated with gastrointestinal symptoms, mostly represented by constipation and defecatory dysfunctions. This study examined the impact of central dopaminergic denervation, induced by injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, on distal colonic excitatory cholinergic neuromotor activity in rats. Animals were euthanized 4 and 8 weeks after 6-OHDA injection. In vivo colonic transit was evaluated by radiological assay. Electrically and carbachol-induced cholinergic contractions were recorded in vitro from longitudinal and circular muscle colonic preparations, while acetylcholine levels were assayed in their incubation media. Choline acetyltransferase (ChAT), HuC/D (pan-neuronal marker), muscarinic M2 and M3 receptors. As compared with control rats, at week 4 6-OHDA-treated animals displayed the following changes: decreased in vivo colonic transit rate; impaired electrically evoked neurogenic cholinergic contractions; enhanced carbachol-induced contractions; decreased basal and electrically stimulated acetylcholine release from colonic tissues; decreased ChAT immunopositivity in the neuromuscular layer; unchanged density of HuC/D immunoreactive myenteric neurons; increased expression of colonic muscarinic M2 and M3 receptors. The majority of such alterations were detected also at week 8 post-6-OHDA injection. These findings indicate that central nigrostriatal dopaminergic denervation is associated with an impaired excitatory neurotransmission characterized by a loss of myenteric neuronal ChAT positivity and decrease in acetylcholine release, resulting in a dysregulated smooth muscle motor activity, which likely contributes to the concomitant decrease in colonic transit rate

Hydroxyurea in essential thrombocythemia: rate and clinical relevance of responses by European LeukemiaNet criteria

Abstract A definition of response by cytoreductive therapy in essential thrombocythemia was recently provided by the European LeukemiaNet (ELN). Complete, partial, or no clinicohematologic responses were defined on the bases of platelet count, disease-related symptoms, spleen size, and white blood cell count. To provide estimates and clinical correlation of responses according to these criteria, we retrospectively examined 416 essential thrombocythemia patients treated with hydroxyurea for at least 12 months. Complete response, partial response, and no response were 25%, 58%, and 17%, respectively. Age more than 60 years and JAK2V617F mutation were significant predictors of response. After a median follow-up of 3.9 years, we registered 23 deaths, 16 hematologic transformations, and 27 thrombotic events (rate, 1.66% patients/year). Age, previous thrombosis, leukocytosis (white blood cell count > 10 × 109/L), but not ELN responses, were independently associated with higher risk of thrombosis. The actuarial probability of thrombosis was significantly influenced by leukocytosis (P = .017) and not by platelet count, indicating that platelet number does not seem of prime relevance in the definition of ELN response

A Comparative Study on the Efficacy of NLRP3 Inflammasome Signaling Inhibitors in a Pre-clinical Model of Bowel Inflammation

Nucleotide-binding oligomerization domain leucine rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome is pivotal in maintaining intestinal homeostasis and sustaining enteric immune responses in the setting of inflammatory bowel diseases. Drugs acting as NLRP3 blockers could represent innovative strategies for treatment of bowel inflammation. This study was performed in rats with dinitrobenzenesulfonic acid (DNBS)-induced colitis, to investigate how the direct blockade of NLRP3 inflammasome with an irreversible inhibitor (INF39) compares with Ac-YVAD-cmk (YVAD, caspase-1 inhibitor) and anakinra (IL-1β receptor antagonist), acting downstream on NLRP3 signaling. Animals with DNBS-colitis received YVAD (3 mg/kg) or anakinra (100 mg/Kg) intraperitoneally, and INF39 (25 mg/kg) or dexamethasone (DEX, 1 mg/kg) orally for 6 days, starting on the same day of colitis induction. Under colitis, there was a body weight decrease, which was attenuated by YVAD, anakinra or INF39, but not DEX. All test drugs counteracted the increase in spleen weight. The colonic shortening and morphological colonic alterations associated with colitis were counteracted by INF39, anakinra and DEX, while YVAD was without effects. Tissue increments of myeloperoxidase, tumor necrosis factor and interleukin-1β were more effectively counteracted by INF39 and DEX, than YVAD and anakinra. These findings indicate that: (1) direct inhibition of NLRP3 inflammasome with INF39 is more effective than caspase-1 inhibition or IL-1β receptor blockade in reducing systemic and bowel inflammatory alterations; (2) direct NLRP3 inhibition can be a suitable strategy for treatment of bowel inflammation

Investigating the diet of Mesolithic groups in the Southern Alps: An attempt using stable carbon and nitrogen isotope analyses

Stable isotopic data (δ13C; δ15N) were obtained from Mesolithic human and faunal remains from north- eastern Italy in order to document the human diet and provide information on the relationship between landscape use and subsistence strategies. The bone samples were from an adult female individual (Early Mesolithic, Late Sauveterrian) buried at Vatte di Zambana (Trento), an adult male (Late Mesolithic, Castelnovian) buried at Mondeval de Sora (Belluno), and an adult female from Mezzocorona Borgonuovo (Trento). For the latter, the stratigraphic position of the burial pit and evidence of the associated ritual suggest a Mesolithic attribution. Carbon (13C/12C) and nitrogen (15N/14N) stable isotope compositions of human bone collagen were compared with those of animal remains from different taxa found in stratigraphic association with the burial. The isotopic data and the Bayesian model developed from the latter and from data in the literature indicate a very significant proportion of terrestrial resources in the protein fraction of the human diet, particularly from red deer compared to other ungulates and potentially from freshwater fish and small mammals. These results add to the information provided by zooarchaeological studies and reopen the debate on the role of secondary resources such as chamois, ibex, small mammals and fish, such as pike, in the diet of these mobile human societies. However, as this is a preliminary study based on a very small sample size, interpretations should be considered with caution.Les compositions isotopiques en carbone et en azote (δ13C ; δ15N) ont été mesurées sur des restes osseux humains et animaux du Mésolithique dans le nord-est de l’Italie afin de documenter l’alimentation de ces dernières communautés de chasseurs-cueilleurs et les liens entre l’environnement et les stratégies de subsistance. Les restes osseux analysés proviennent d’une femme adulte (Mésolithique ancien, Sauveterrien récent) inhumée à Vatte di Zambana (Trento), d’un homme adulte (Mésolithique récent, Castelnovien) inhumé à Mondeval de Sora (Belluno) et d’une femme adulte du site de Mezzocorona-Borgonuovo (Trento). La position stratigraphique de la sépulture à Mezzocorona-Borgonuovo ainsi que les pratiques funéraires suggèrent une attribution au Mésolithique. Les ratios isotopiques du carbone et de l’azote du collagène osseux des sujets humains ont été comparés avec ceux d’animaux de différentes espèces associés stratigraphiquement aux sépultures. Les résultats isotopiques ainsi qu’un modèle bayésien, réalisé à partir de ces données et celles de la littérature, indiquent une contribution très significative des protéines animales du milieu terrestre, et surtout la consommation importante de cerfs par rapport aux autres ongulés, ainsi qu’un rôle potentiel des poissons d’eau douce et de petits mammifères. Ces données complètent les informations apportées par les études archéozoologiques et relancent la discussion sur le rôle secondaire que peuvent avoir le chamois, l’ibex, les petits mammifères et les ressources aquatiques, comme le brochet, dans la subsistance de ces nomades. Cette étude reste toutefois préliminaire et le faible corpus d’échantillons analysés nous amène à considérer ces interprétations avec prudence