Dual inhibitory action of trazodone on dorsal raphe serotonergic neurons through 5-HT1A receptor partial agonism and α1-adrenoceptor antagonism

Trazodone is an antidepressant drug with considerable affinity for 5-HT1A receptors and α1-adrenoceptors for which the drug is competitive agonist and antagonist, respectively. In this study, we used cell-attached or whole-cell patch-clamp recordings to characterize the effects of trazodone at somatodendritic 5-HT1A receptors (5-HT1AARs) and α1-adrenoceptors of serotonergic neurons in rodent dorsal raphe slices. To reveal the effects of trazodone at α1-adrenoceptors, the baseline firing of 5-HT neurons was facilitated by applying the selective α1-adrenoceptor agonist phenylephrine at various concentrations. In the absence of phenylephrine, trazodone (1-10 μM) concentration-dependently silenced neurons through activation of 5-HT1AARs. The effect was fully antagonized by the selective 5-HT1A receptor antagonist Way-100635. With 5-HT1A receptors blocked by Way-100635, trazodone (1-10 μM) concentration-dependently inhibited neuron firing facilitated by 1 μM phenylephrine. Parallel rightward shift of dose-response curves for trazodone recorded in higher phenylephrine concentrations (10-100 μM) indicated competitive antagonism at α1-adrenoceptors. Both effects of trazodone were also observed in slices from Tph2-/- mice that lack synthesis of brain serotonin, showing that the activation of 5-HT1AARs was not mediated by endogenous serotonin. In whole-cell recordings, trazodone activated 5-HT1AAR-coupled G protein-activated inwardly-rectifying (GIRK) channel conductance with weak partial agonist efficacy (~35%) compared to that of the full agonist 5-CT. Collectively our data show that trazodone, at concentrations relevant to its clinical effects, exerts weak partial agonism at 5-HT1AARs and disfacilitation of firing through α1-adrenoceptor antagonism. These two actions converge in inhibiting dorsal raphe serotonergic neuron activity, albeit with varying contribution depending on the intensity of α1-adrenoceptor stimulation

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Contains reports on seven research projects.Lincoln Laboratory (Purchase Order DDL-B222

Forebulge migration in the foreland basin system of the central-southern Apennine fold-thrust belt (Italy): New high-resolution Sr-isotope dating constraints

The Apennines are a retreating collisional belt where the foreland basin system, across large domains, is floored by a subaerial forebulge unconformity developed due to forebulge uplift and erosion. This unconformity is overlain by a diachronous sequence of three lithostratigraphic units made of (a) shallow-water carbonates, (b) hemipelagic marls and shales and (c) siliciclastic turbidites. Typically, the latter two have been interpreted regionally as the onset of syn-orogenic deposition in the foredeep depozone, whereas little attention has been given to the underlying unit. Accordingly, the rate of migration of the central-southern Apennine fold-thrust belt-foreland basin system has been constrained, so far, exclusively considering the age of the hemipelagites and turbidites, which largely post-date the onset of foredeep depozone. In this work, we provide new high-resolution ages obtained by strontium isotope stratigraphy applied to calcitic bivalve shells sampled at the base of the first syn-orogenic deposits overlying the Eocene-Cretaceous pre-orogenic substratum. Integration of our results with published data indicates progressive rejuvenation of the strata sealing the forebulge unconformity towards the outer portions of the fold-thrust belt. In particular, the age of the forebulge unconformity linearly scales with the pre-orogenic position of the analysed sites, pointing to an overall constant migration velocity of the forebulge wave in the last 25 Myr

the isolpharm project a new isol production method of high specific activity beta emitting radionuclides as radiopharmaceutical precursors

The ISOLPHARM project explores the feasibility of exploiting an innovative technology to produce extremely high specific activity beta-emitting radionuclides as radiopharmaceutical precursors. This technique is expected to produce radiopharmaceuticals that are virtually mainly impossible to obtain in standard production facilities, at lower cost and with less environmental impact than traditional techniques. The groundbreaking ISOLPHARM method investigated in this project has been granted an international patent (INFN). As a component of the SPES (Selective Production of Exotic Species) project at the Istituto Nazionale di Fisica Nucleare–Laboratori Nazionali di Legnaro (INFN–LNL), a new facility will produce radioactive ion beams of neutron-rich nuclei with high purity and a mass range of 80–160 amu. The radioactive isotopes will result from nuclear reactions induced by accelerating 40 MeV protons in a cyclotron to collide on a target of UC[Formula: see text]. The uranium in the target material will be [Formula: see text]U, yielding radioactive isotopes that belong to elements with an atomic number between 28 and 57. Isotope separation on line (ISOL) is adopted in the ISOLPHARM project to obtain pure isobaric beams for radiopharmaceutical applications, with no isotopic contaminations in the beam or subsequent trapping substrate. Isobaric contaminations may potentially affect radiochemical and radionuclide purity, but proper methods to separate chemically different elements can be developed

Geoelectrical Subsurface Characterization for Foundation Purposes in the College of Agricultural Sciences (CAS) Campus, Ebonyi State University, Abakaliki, Southeastern Nigeria

The study area is underlain by shales and volcanoclastics with subordinate lenses of sandstones and sandy limestone (Abakaliki Formation) of the Albian Asu River Group, southeastern Nigeria. Geophysical investigation was carried out at the College of Agricultural Sciences (CAS) Campus, Ebonyi State University (EBSU) to determine the structural competence of the subsurface geological strata for building construction and other foundation purposes, using vertical electrical sounding (VES) survey technique of the electrical resistivity method. From the result of the survey, two major zones have been established within the study area for building construction purposes. Zone A comprises of areas around the catholic church building, EBSU primary school up to the school of post graduate studies, while zone B  is made up of areas around the EBSU secondary school, proposed student centre up to the main entrance gate which led to the Ogoja road. Zone A has been recommended for bungalows and other forms of low rising buildings, while zone B has been recommended for storey buildings and other heavy engineering structures. Overburden thickness for the two zones ranges from 1.3 m to 2.7 m, and 0.6 m to 2.7 m for zones A and B respectively. The cracks on walls of the buildings within the campus have been attributed to either the inability of the engineers to dig the foundation to the required depth or the construction of heavier structures on very weak subsurface layers which triggered off movement. Keywords: Geoelectrical, Characterization, Foundation, Ebonyi State University, Nigeria

Iloprost in Acute Post-kidney Transplant Atheroembolism: A Case Report of Two Successful Treatments

Cholesterol embolization (CE) is a rare and alarming post-transplant complication, responsible for primary non-function (PNF) or delayed graft function (DGF). Its incidence is expected to rise due to increasingly old donors and recipients and the extended criteria for donation. Therapy with statins and steroids has not been shown to be effective, while agonism of prostaglandin I2 has been reported to be useful in systemic CE. We report two cases of acute post-transplant CE in which intravenous iloprost (0.05 mg/kg/day) was added to standard statin and steroid therapy. In the first instance, CE was due to embolization from the kidney artery resulting in embolization of the small vessels; after a long DGF and 15 days of iloprost therapy, renal function recovered. The second instance is a case of embolization from the iliac artery of the recipient, where CE manifested as a partial renal infarction. After 5 days of iloprost administration, creatinine levels improved. Iloprost acts on vasodilation and on different inflammatory pathways, improving the anti-inflammatory profile. Post-transplant CE is difficult to diagnose and, if not treated, can lead to loss of function. Iloprost added to standard therapy could be beneficial in accelerating renal function recovery immediately after transplant

Late-stage tectonic evolution of the Al-Hajar Mountains, Oman: New constraints from Palaeogene sedimentary units and low-temperature thermochronometry

Mountain building in the Al-Hajar Mountains (NE Oman) occurred during two major shortening stages, related to the convergence between Africa-Arabia and Eurasia, separated by nearly 30 Ma of tectonic quiescence. Most of the shortening was accommodated during the Late Cretaceous, when northward subduction of the Neo-Tethys Ocean was followed by the ophiolites obduction on top of the former Mesozoic margin. This shortening event lasted until the latest Santonian - early Campanian. Maastrichtian to Eocene carbonates unconformably overlie the eroded nappes and seal the Cretaceous foredeep. These neo-autochthonous post-nappe sedimentary rocks were deformed, along with the underlying Cretaceous tectonic pile, during the second shortening event, itself including two main exhumation stages. In this study we combine remotely sensed structural data, seismic interpretation, field-based structural investigations and apatite (U-Th)/He (AHe) cooling ages to obtain new insights into the Cenozoic deformation stage. Seismic interpretation indicates the occurrence of a late Eocene flexural basin, later deformed by an Oligocene thrusting event, during which the post-nappe succession and the underlying Cretaceous nappes of the internal foredeep were uplifted. This stage was followed by folding of the post-nappe succession during the Miocene. AHe data from detrital siliciclastic deposits in the frontal area of the mountain chain provide cooling ages spanning from 17.3 to 42 Ma, consistent with available data for the structural culminations of Oman. Our work points out how renewal of flexural subsidence in the foredeep and uplift of the mountain belt were coeval processes, followed by layer-parallel shortening preceding final fold amplification

Normothermic and hypothermic oxygenated perfusion for donation after circulatory death in kidney transplantation: Do we pay higher risk of severe infection after transplantation?: A case report

Background: Normothermic and hypothermic oxygenated perfusion for donation after circulatory death in kidney transplantation are becoming popular in Italy, with the purpose of reducing the risk of primary non function and delayed graft function due to the prolonged warm ischemia time. Potential complications related to these procedures are currently under investigation and are continuously emerging with the increasing experience. Post-operative infections - in particular graft arteritis - are a rare complication but determine high risk of mortality and of graft loss. The acute onset of the arterial complications makes it very difficult to find an effective treatment, and early diagnosis is crucial for saving both patient and graft. Prevention of such infections in this particular setting are advisable. Case presentation: We present a patient with an acute arterial rupture after transplantation of a DCD graft treated in-vivo hypothermic oxygenated perfusion. The cause was a severe arteritis of the renal artery caused by Candida krusei and Pseudomonas aeruginosa. We discussed our treatment and we compared it to the other reported series. Conclusion: Fungal infections in DCD transplant may be treacherous and strategies to prevent them should be advocated

Perfusion of isolated rat kidney with Mesenchymal Stromal Cells/Extracellular Vesicles prevents ischaemic injury

Kidney donation after circulatory death (DCD) is a less than ideal option to meet organ shortages. Hypothermic machine perfusion (HMP) with Belzer solution (BS) improves the viability of DCD kidneys, although the graft clinical course remains critical. Mesenchymal stromal cells (MSC) promote tissue repair by releasing extracellular vesicles (EV). We evaluated whether delivering MSC-/MSC-derived EV during HMP protects rat DCD kidneys from ischaemic injury and investigated the underlying pathogenic mechanisms. Warm ischaemic isolated kidneys were cold-perfused (4 hrs) with BS, BS supplemented with MSC or EV. Renal damage was evaluated by histology and renal gene expression by microarray analysis, RT-PCR. Malondialdehyde, lactate, LDH, glucose and pyruvate were measured in the effluent fluid. MSC-/EV-treated kidneys showed significantly less global ischaemic damage. In the MSC/EV groups, there was up-regulation of three genes encoding enzymes known to improve cell energy metabolism and three genes encoding proteins involved in ion membrane transport. In the effluent fluid, lactate, LDH, MDA and glucose were significantly lower and pyruvate higher in MSC/EV kidneys as compared with BS, suggesting the larger use of energy substrates by MSC/EV kidneys. The addition of MSC/EV to BS during HMP protects the kidney from ischaemic injury by preserving the enzymatic machinery essential for cell viability and protects the kidney from reperfusion damage