Neurotensin as Modulator of Glutamatergic Signalling: Relevance in Neurodegenerative Diseases

Rationale: Neurotensin (NT) is a tridecapeptide widely distributed in mammalian brain, where acts as a neurotransmitter or neuromodulator of classical neurotransmitters, mainly through the activation of its receptor NTS1. Several in vitro and in vivo studies have demonstrated the existence of close interactions between NT and dopamine (DA) systems both in limbic and striatal brain regions (Nemeroff CB., 1985; Binder EB., 2001; Caceda R., 2006). Because of the involvement of an over-activation of DA system in the development of neurological disorders such as schizophrenia, psychosis and dyskinesia, a strong attention was given to the study of complex interactions between NTS1 and D2 dopamine receptor, highlighting the existence of receptor-receptor interaction, potential target for developing new anti-schizophrenic drugs (Ferraro L., 2007). In addition, neurochemical and biochemical data indicate that NT plays a crucial role in regulating glutamatergic transmission, probably inducing an amplification of NMDA receptor signalling, even at threshold concentrations (lOnM) (Antonelli T., 2004). Results I: The neuromodulatory function of NT on glutamatergic signalling was studied in an in vitro model of primary cortical cultures, highlighting a dose-dependent effect (NT 0.1-300 nM) on glutamate release. In addition, NT show the ability to amplify the NMDA-induced (lOOnM) increase of glutamate release. The use of the NTS1 receptor antagonists, SR48692 (lOOnM) and the NMDA receptor antagonist MK-801 (l[iM), in combination with an effective concentration of NT, made possible to hypothesize that the mechanism involved could be an NTSl/NMDA receptor-receptor interaction (Antonelli T., 2004; Ferraro L., 2008) both at striatal and cortical level. It has been postulated that the accumulation of extracellular glutamate level and the consequent excessive activation of NMDA receptors (excitotoxic mechanism) contributes to neuronal death associated with chronic and acute neurodegenerative diseases (Olney JW., 1978). Since the data obtained to date suggest a NT-mediated strengthening on several glutamatergic functions in the central nervous system, our work was intended to deepen its possible involvement in glutamate-induced neurodegenerative mechanisms. The in vitro model of cerebral ischemia obtained by oxygen and glucose deprivation (OGD) showed a significant increase in extracellular levels of glutamate. In addition, significant alterations of biochemical and morphological parameters measured were observed. Increase the release of LDH, reduction of mitochondrial oxidative capacity (MTT levels), increased activity of caspase-3, increased number of apoptotic (fragmented) nuclei, increasead level of AN(+)/PI(-) immunoreactive cells and MAP-2 dendritic aggregations was measured 24 hours after the ischemic insult. The addition of NT (lOOnM) to the culture medium showed a significant increase in the OGD-induced changes, while cells pre-exposure to the NTS1 antagonist SR48692 (lOOnM) blocked the effect of both the neuropeptide and OGD exposure, alone or in combination. The results obtained with this in vitro model of cerebral ischemia, stress the involvement of NT activity in the eziopathogenesis of an acute neurodegenerative disease (Antonelli T., 2008). Results II: At basal ganglia level, NT induces an amplification of glutamate release, probably through a NTS1/D2 antagonistic interaction. This phenomenon could contribute to the degeneration of dopaminergic nigro-striatal neurons by the means of an excitotoxic mechanism, pathogenetic feature of Parkinson's disease (PD). In this contex, experiments were conducted with the in vivo microdialysis technique at striatal and cortical level, anatomical areas notoriously involved in PD. The results obtained again showed that a, potential, NTS1/NMDA receptor-receptor interaction induces a glutamatergic signalling amplification. The observed increase in glutamate extracellular levels induced by treatment with NMDA (100 and 500 uM) and NT (lO nM), showed once again to be partially blocked by treatment with NT antagonist SR48692 (Ferraro L., 2008). Given the potential neuroprotective role played SR48692, successive studies in an vivo model of PD achieved through unilateral lesion of the nigro-striatalpathway with the neurotoxin 6-idroxydopamine (6-OHDA) were done. Three experimental groups were tested for the turning rotation behaviour and by a challenge with NMDA lOOuM: lesioned rats, rats exposed only to vehicle and lesioned rats treated with the neurotensinergic antagonist. The animals exposed to SR48692 have shown a significant recovery for both the parameter of turning behaviour and responsiveness to pharmacological challenge with NMDA (Ferraro L., 2008). The results obtained can lead to the hypothesis that the use of selective NTS1 receptor antagonists, in combination with conventional drug treatments, could provide a new terapeutic approach for chronic and acute neurodegenerative diseases treatment, such as cerebral ischemia and Parkinson's disease

Descriptions and the materiality of texts

From SAGE Publishing via Jisc Publications RouterHistory: epub 2021-03-02Publication status: PublishedThis article builds on the notions of thick and thin description elaborated by Geertz and looks at what descriptive methods have been used in the field of papyrology, a sub-discipline of classics that studies ancient manuscripts on papyrus fragments recovered through legal and illegal excavations in Egypt from the 19th century. Past generations of papyrologists have described papyri merely as resources to retrieve ancient ‘texts’. In the article I argue these descriptions have had negative effects in the way this ancient material has been studied, preserved, and also exchanged through the antiquities market. Through a series of case studies, I offer an alternative description of papyrus fragments as things, which have a power that can be activated under specific circumstances or entanglements. In demonstrating papyrus manuscripts’ unstable nature and shifting meanings, which are contingent on such entanglements, the article calls for a new politics and ethics concerning their preservation and exchange

Longitudinal study on <i>Listeria monocytogenes</i> in Sardinian fermented meat products processing plants: contamination routes, pathogenic profile and evaluation of gene expression in persistent and non-persistent isolates

Detection and enumeration of L. monocytogenes have been carried out in 385 samples of raw materials, fermented sausages and environments of different processing plants located in Sardinia (Italy). A subset of ninety - seven strains isolated during a period from 2004 to 2011 were characterized by multiplex PCR-based serogrouping, multiplex PCRs for the presence of virulence genes, PFGE, and quantitative assessment of the in vitro biofilm formation. In addition, Relative and Absolute Quantification of genes expression of pocR, mdr, eutG and cbiD, probably involved in the persistence of the pathogen in the environment have been evaluated, in persistent and non-persistent isolates by Real-Time PCR. The 22% of the samples were positive for the presence of L. monocytogenes. The 31.51% and 15% of the samples tested, food and environment, respectively, were positive for Listeria monocytogenes. Isolates were serotyped as 1/2a, 1/2c, 1/2c and 4b, and presented all the considered virulence genes. PFGE revealed a high heterogeneity of pulsotypes within the plants. PFGE results did not showed the presence of persistent strains among the selection included in this study. The 44% of the tested strains were able to attach to abiotic surfaces forming biofilm. Relative and Absolute qRTi-PCR showed that the genes selected were not involved in persistence

Primary stroke prevention and hypertension treatment: which is the first-line strategy?

Hypertension (HT) is considered the main classic vascular risk factor for stroke and the importance of lowering blood pressure (BP) is well established. However, not all the benefit of antihypertensive treatment is due to BP reduction per se, as the effect of reducing the risk of stroke differs among classes of antihypertensive agents. Extensive evidences support that angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), dihydropyridine calcium channel blockers (CCB) and thiazide diuretics each reduced risk of stroke compared with placebo or no treatment. Therefore, when combination therapy is required, a combination of these antihypertensive classes represents a logical approach. Despite the efficacy of antihypertensive therapy a large proportion of the population, still has undiagnosed or inadequately treated HT, and remain at high risk of stroke. In primary stroke prevention current guidelines recommend a systolic/diastolic BP goal of <140/<90 mmHg in the general population and <130/80 mmHg in diabetics and in subjects with high cardiovascular risk and renal disease. The recent release in the market of the fixed-dose combination (FDC) of ACEI or ARB and CCB should provide a better control of BP. However to confirm the efficacy of the FDC in primary stroke prevention, clinical intervention trials are needed

The Role of Metformin in the Management of NAFLD

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder worldwide. Its prevalence ranges 10–24% in the general population, reaching 60–95% and 28–55% in obese and diabetic patients, respectively. Although the etiology of NAFLD is still unclear, several lines of evidences have indicated a pathogenetic role of insulin resistance in this disorder. This concept has stimulated several clinical studies where antidiabetic drugs, such as insulin sensitizers including metformin, have been evaluated in insulin-resistant, NAFLD patients. These studies indicate that metformin might be of benefit in the treatment of NAFLD, also in nondiabetic patients, when associated to hypocaloric diet and weight control. However, the heterogeneity of these studies still prevents us from reaching firm conclusions about treatment guidelines. Moreover, metformin could have beneficial tissue-specific effects in NAFLD patients irrespective of its effects as insulin sensitizer

Effects of enramycin and sodium monensin on nutrients digestibility in bovine fed with high-concentrate diets

Estudaram-se os efeitos da administração de enramicina e monensina sódica sobre a digestão total dos nutrientes da dieta e o consumo de matéria seca digestível em bovinos. Doze fêmeas bovinas não-gestantes e não-lactantes (675 &plusmn; 63 kg PV) foram distribuídas inteiramente ao acaso em três tratamentos (controle, enramicina e monensina) e alimentados com dieta contendo 60% de concentrados (milho, farelo de soja e minerais) e 40% de volumoso (cana-de-açúcar). A enramicina foi administrada na dose de 20 mg/animal/dia e a monensina na dose de 300 mg/animal/dia. O experimento teve duração total de 21 dias, de modo que os últimos dez dias foram utilizados para administração do marcador externo (15 g de óxido crômico/animal/dia) e os últimos cinco dias para a coleta de fezes e amostragem dos alimentos. Nenhum dos antibióticos alterou os consumos de matéria seca digestível e NDT e a digestibilidade de matéria seca, proteína bruta, extrato etéreo, fibra em detergente ácido, fibra em detergente neutro, amido, energia bruta e nutrientes digestíveis totais.The objective of this trial was to study the effects of enramycin and sodium monensin administration on total digestibility of diet nutrients and digestible dry matter intake in bovine. Twelve non-pregnant and non-lactating cows (675 kg &plusmn; 63 BW) were randomly assigned to three treatments: control group, enramycin-treated group or monensin-treated group. Animals received a diet containing 60% of concentrates (corn, soy bean meal and minerals) and 40% of forage (sugarcane). Treatments were 20 mg/animal/day of enramycin or 300 mg/animal/day of monensin. Trial lasted 21 days, the last 10 used for external marker administration (15 g of chromic oxide/animal/day) and the last 5 for feces collection and feed sampling. None of the antibiotics affected digestible dry matter and TDN intake and the digestibilities of dry matter, crude protein, ether extract, acid detergent fiber, neutral detergent fiber, starch, gross energy or total digestible nutrients

Internal carotid artery fibromuscular dysplasia in arterial hypertension: Management in clinical practice

Fibromuscular dysplasia (FMD) reminds of a rare form of secondary arterial hypertension occurring in young people and involving the renal arteries. FMD may also involve vertebral, subclavian, mesenteric, iliac arteries and carotid arteries. FMD of internal carotid arteries is a rare finding that is frequently incidental and asymptomatic. It usually occurs in middle-aged women and is secondary to media-intima fibrodysplasia. The carotid artery may be elongated or kinked and associated cerebral aneurysms have been reported. Symptoms including transient ischaemic attack or stroke are uncommon and are related to decrease of blood flow or embolization by platelet aggregates. At the onset, differential diagnosis with vasculitis must be placed. Computed tomography or magnetic resonance imaging (MRI) angiography demonstrates bilateral high-grade stenosis with the characteristic "string of beads" pattern. Antiplatelet medication is the accepted therapy for asymptomatic lesions. Graduated endoluminal surgical dilation is an outmoded therapy, no longer used in most medical centres. Current percutaneous angioplasty is the preferred treatment for symptomatic carotid FMD, but no randomized controlled trials comparing this methodology with surgery is available. The management of a case of arterial systemic FMD in a 52-year-old women, diagnosed after a hypertensive crysis, is discussed. Imaging methods disclosed stenoses of carotid arteries, of celiac tripod and of superior mesenteric artery. Because of high risk associated to endovascular surgery, medical therapy was started. In the first year of follow-up, no events have been reported

Shelf life of fresh air packaged and precooked vacuum packaged quails

The shelf-life of 3 batches (Q1, Q2, Q3) of quail meat, were examined. Q1 were cut and seasoned with commercial olive oil, stoned green olive and sliced bacon. Q2 were divided into two subgroups: Q2.1 produced in the previously described conditions; Q2.2 seasoned also with rosemary. Quails were placed in lowdensity polystirene barrier trays and aerobically packaged. Q3 quails were boiled in salted hot water for 40 min, seasoned with myrtle leafs, placed in low density polyethylene bags and vacuum packaged. All samples were stored at +2 and +7°C. Analysis were conducted at 0, 3, 7, 9 and 14 days (T0, T3, T7, T9, and T14, respectively). For all the samples, pH measurement and microbial analysis [total viable count (TVC), Enterobacteriaceae, E. coli, Lactobacillus spp. (LAB), Pseudomonas spp., Brochothrix thermosphacta, coagulase-negative Staphylococci (CNS), Enterococcus spp., yeasts and moulds, Salmonella spp., Listeria monocytogenes] were performed. Initial TVC levels of fresh quails (ca. 4 log CFU/g) were rather high and this may be due to the microbial population of the raw material. In Q1 and Q2.1 samples, TVC reached the value of 7 log, which is considered as the upper acceptability limit for fresh poultry meat (after T9 under storage at +2°C and after T7 at +7°C). In Q2.2 samples such limit was reached earlier, after T3. In Q3 samples, lower TVC levels were recorded and did not reach the above mentioned limit, not even at the end of storage. However, mean counts >5 log were reached, maybe because of a post-cooking cross-contamination. Salmonella spp. prevalence was 33% in Q1, Q2.1 and Q2.2 samples