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This work describes the coupling methodology between a modified version of RELAP5/Mod3.3 and ANSYS Fluent CFD code developed at the University of Pisa. The described coupling procedure can be classified as “two-way,” nonoverlapping, “online” coupling. In this work, a semi-implicit numerical scheme has been implemented, giving greater stability to the simulations. A MATLAB script manages both the codes, oversees the reading and writing of the boundary conditions at the interfaces, and handles the exchange of data. A new tool was used to control the Fluent session, allowing a reduction of the time required for the exchange of data. The coupling tool was used to simulate a loop system (NACIE facility) and a pool system (CIRCE facility), both working with Lead Bismuth Eutectic and located at ENEA Brasimone Research Centre. Some modifications in the coupling procedure turned out to be necessary to apply the methodology in the pool system. In this paper, the comparison between the obtained coupled numerical results and the experimental data is presented. The good agreement between experiments and calculations evinces the capability of the coupled calculation to model correctly the involved phenomena.

The paper summarizes the lesson learned from theoretical and experimental activities performed at the University of Pisa, Pisa, Italy, in past decades in order to develop a general methodology of analysis of heat and mass transfer phenomena of interest for nuclear reactor applications. An overview of previously published results is proposed, highlighting the rationale at the basis of the performed work and its relevant conclusions. Experimental data from different sources provided information for model development and assessment. They include condensation experiments performed at SIET (Piacenza, Italy) on the PANTHERS prototypical PCCS module, falling film evaporation tests for simulating AP600-like outer shell spraying conditions, performed at the University of Pisa, experimental data concerning condensation on finned tubes, collected by CISE (Piacenza, Italy) in the frame of the INCON EU Project, and experimental tests performed in the CONAN experimental facility installed at the University of Pisa. The experience gained in these activities is critically reviewed and discussed to highlight the relevant obtained conclusions and the perspectives for future work.

Spinal cord injury (SCI) results in the development of detrimental autoantibodies against the lesioned spinal cord. IgM immunoglobulin maintains homeostasis against IgG-autoantibody responses, but its effect on SCI recovery remains unknown. In the present study we investigated the role of IgM immunoglobulin in influencing recovery after SCI. To this end, we induced cervical SCI at the C6/C7 level in mice that lacked secreted IgM immunoglobulin [IgM-knock-out (KO)] and their wild-type (WT) littermate controls. Overall, the absence of secretory IgM resulted in worse outcomes as compared with WT mice with SCI. At two weeks after injury, IgM-KO mice had significantly more IgG antibodies, which fixed the complement system, in the injured spinal cord parenchyma. In addition to these findings, IgM-KO mice had more parenchymal T-lymphocytes as well as CD11b+ microglia/macrophages, which co-localized with myelin. At 10 weeks after injury, IgM-KO mice showed significant impairment in neurobehavioral recovery, such as deteriorated coordination, reduced hindlimb swing speed and print area. These neurobehavioral detriments were coupled with increased lesional tissue and myelin loss. Taken together, this study provides the first evidence for the importance of IgM immunoglobulin in modulating recovery after SCI and suggests that modulating IgM could be a novel therapeutic approach to enhance recovery after SCI., (Copyright © 2021 Ulndreaj et al.)

Type 2 diabetes management can be improved by the use of second-generation basal insulin analogues as the first choice on commencement of insulin, in this instance focussing on insulin glargine 300 U/mL (Gla-300). The clinical application of the use of Gla-300 include advantages such as less intra- and interpatient variability in glucose control resulting in rather less hypoglycaemia, longer duration of action and greater flexibility in the timing of administration thus suiting a wide range of patient presentations.Funding: Sanofi Australia.

Several Australian obesity management guidelines have been developed for general practice but, to date, implementation of these guidelines has been shown to be inadequate. In this review, we explore the barriers to obesity treatment and propose a four-stage plan to manage individuals with obesity in general practice using a framework of a multidisciplinary team., Funding: Novo Nordisk.

Cervical spinal cord injury (cSCI) occurs in over half of all cases of traumatic spinal cord injury (SCI), yet we lack therapies that can generate significant functional recovery in these patients. The development of animal models of cSCI will aid in the pre-clinical assessment of therapies and in understanding basic pathophysiological mechanisms. Here, we describe a clinically relevant model of cervical contusion-compression injury in the mouse. Using a modified aneurysm clip, we generated a bilateral, incomplete injury that mimics contusion-compression injuries most commonly observed in humans. We followed the recovery of injured and sham-operated (laminectomy-only) animals for 8 weeks post-surgery. Behavioral tests, including the Basso Mouse Scale (BMS), wire hanging, grip strength, and CatWalk automated gait analysis, showed that while natural recovery is limited, it occurs in a clinically relevant window during the subacute phase of injury (7-14 days post-SCI). BMS scoring demonstrated that, while injured animals are ambulatory, they do not recover normal locomotor ability. CatWalk analysis quantitatively showed a loss of coordination and motor ability, with minimal recovery. The wire hanging and grip strength tests confirmed a significant decrease in forelimb motor strength in injured animals. Histological analysis carried out during the subacute phase (7-day time point) and chronic phase (8-week time point) demonstrated that the lesion epicenter is formed by 7 days post-SCI. Volumetric analysis of protein kinase C gamma (PKCgamma)-stained axons revealed that this injury results in significant damage to the corticospinal tract caudal to the injury site. Finally, we used quantitative real-time polymerase chain reaction to show that genes associated with inflammation and glial scarring are upregulated as a result of injury. This study confirms that we can effectively model bilateral cervical injury in the mouse and provides a framework for future studies using this model to assess therapies.

Spinal cord injuries (SCI) cause serious neurological impairment and psychological, economic, and social consequences for patients and their families. Clinically, more than 50% of SCI affect the cervical spine. As a consequence of the primary injury, a cascade of secondary mechanisms including inflammation, apoptosis, and demyelination occur finally leading to tissue scarring and development of intramedullary cavities. Both represent physical and chemical barriers to cell transplantation, integration, and regeneration. Therefore, shaping the inhibitory environment and bridging cavities to create a supportive milieu for cell transplantation and regeneration is a promising therapeutic target. Here, a contusion/compression model of cervical SCI using an aneurysm clip is described. This model is more clinically relevant than other experimental models, since complete transection or ruptures of the cord are rare. Also in comparison to the weight drop model, which in particular damage the dorsum columns, circumferential compression of the spinal cord appears advantageous. Clip closing force and duration can be adjusted to achieve different injury severity. A ring spring facilitates precise calibration and constancy of clip force. Under physiological conditions, synthetic self-assembling peptides (SAP) self-assemble into nanofibers and thus, are appealing for application in SCI. They can be injected directly into the lesion minimizing damage to the cord. SAPs are biocompatible structures erecting scaffolds to bridge intramedullary cavities and thus, equip the damaged cord for regenerative treatments. K2(QL)6K2 (QL6) is a novel SAP introduced by Dong et al. In comparison to other peptides, QL6 self-assembles into β-sheets at neutral pH. 14 days after SCI, after the acute stage, SAPs are injected into the center of the lesion and neural precursor cells (NPC) are injected into adjacent dorsal columns. In order to support cell survival, transplantation is combined with continuous subdural administration of growth factors by osmotic micro pumps for 7 days.

Despite the increasing incidence and prevalence of cervical spinal cord injury (cSCI), we lack clinically relevant animal models that can be used to study the pathomechanisms of this injury and test new therapies. Here, we characterize a moderate cervical contusion-compression model in rats that is similar to incomplete traumatic cSCI in humans. We characterized the effects of 18-g clip-compression injury at cervical level C6 over an 8-week recovery period. Using Luxol fast blue/hematoxylin-eosin staining in combination with quantitative stereology, we determined that 18-g injury results in loss of gray matter (GM), white matter (WM), as well as in cavity formation. Magnetization transfer and T2-weighted magnetic resonance imaging were used to analyze lesion dynamics in vivo. This analysis demonstrated that both techniques are able to differentiate between the injury epicenter, subpial rim, and WM distal to the injury. Neurobehavioral assessment of locomotor function using Basso, Beattie, and Bresnahan (BBB) scoring and CatWalk revealed limited recovery from clip-compression injury at C6. Testing of forelimb function using grip strength demonstrated significant forelimb dysfunction, similar to the loss of upper-limb motor function observed in human cSCI. Sensory-evoked potentials recorded from the forelimb and Hoffman reflex recorded from the hindlimb confirmed the fore- and hindlimb deficits observed in our neurobehavioral analysis. Here, we have characterized a clip-compression model of incomplete cSCI that closely models this condition in humans. This work directly addresses the current lack of clinically relevant models of cSCI and will thus contribute to improved success in the translation of putative therapies into the clinic.

Background: The Rho pathway has been shown to have a role in the pathophysiology of spinal cord injury (SCI). Upregulation of the Rho signaling pathway occurs as a result of SCI. Activation of Rho and its downstream effector kinases triggers growth cone collapse and represents a significant barrier to axon regeneration. Furthermore, there is evidence that Rho-ROCK signaling mediates the inhibitory effects of chondroitin sulfate proteoglycans on neurons, and that inhibition of Rho and ROCK can reverse chondroitin sulfate proteoglycan-mediated inhibition of neurite outgrowth. Work building on these findings suggests that inhibition of this pathway may boost neuroprotection and axonal regeneration after SCI., Methods: A narrative review., Results: Investigators have identified a C3 transferase, which selectively inhibits Rho without affecting other guanine triphosphatases. This has been shown to promote axonal sprouting and recovery of locomotor function after hemisection of the thoracic spinal cord in a mouse model of SCI. The neuroprotective properties of Rho inhibitors in animal models of SCI have been reinforced by studies carried out in vitro using retinal ganglion cells. In light of this, a Rho inhibitor known as Cethrin has been evaluated as a therapeutic intervention for SCI in a phase I/IIa clinical trial with promising results., Conclusions: The Rho pathway has been shown to have a role in the pathophysiology of SCI and preclinical and clinical work and is currently a promising target for the treatment of patients with SCI., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The mechanisms by which neural precursor cells (NPCs) enhance functional recovery from spinal cord injury (SCI) remain unclear. Spinal cord injured rats were transplanted with wild-type mouse NPCs, shiverer NPCs unable to produce myelin, dead NPCs, or media. Most animals also received minocycline, cyclosporine, and perilesional infusion of trophins. Motor function was graded according to the BBB scale. H&E/LFB staining was used to assess gray and white matter, cyst, and lesional tissue. Mature oligodendrocytes and ED1(+) inflammatory cells were quantitated. Confocal and electron microscopy were used to assess the relationship between the transplanted cells and axons. Pharmacotherapy and trophin infusion preserved gray matter, white matter, and oligodendrocytes. Trophin infusion also significantly increased cyst and lesional tissue volume as well as inflammatory infiltrate, and functional recovery was reduced. Animals transplanted with wild-type NPCs showed greatest functional recovery; animals transplanted with shiverer NPCs performed the worst. Wild-type NPCs remyelinated host axons. Shiverer NPCs ensheathed axons but did not produce MBP. These results suggest that remyelination by NPCs is an important contribution to functional recovery following SCI. Shiverer NPCs may prevent remyelination by endogenous cells capable of myelin formation. These findings suggest that remyelination is an important therapeutic target following SCI.

Objectives: Potential health hazards for the environment and people living nearby landfills and incinerators are claimed to be related to several methods of waste management. Independent systematic review of the scientific literature is a key procedure to support the lay public and policy makers to achieve informed decisions., Methods: The study design and potential biases of papers retrieved in this comprehensive literature search were analyzed., Results: The most consistent result is that the risks of congenital anomalies and hospitalization due to respiratory disease are likely to be real nearby special waste landfills. From the very little information on exclusively urban waste depots it is reasonable to say that correct management of landfill does not increase the risk of these health effects. It is confirmed that historically incinerators are an important source of pollution and harm for the health of populations living nearby; however, changes in technology are producing more reassuring results., Conclusions: A moderate level of confidence is possible in limited areas of knowledge, implying the need to overcome the limitations of current studies about exposure assessment and to control confounders at the individual level.

Histone deacetylase (HDAC) proteins have a role in promoting neuronal survival in vitro, but the mechanism underlying this function has not been identified. Here we provide evidence that components of the neuronal microenvironment, including non-neuronal cells and defined culture media, can mitigate midbrain neuronal cell death induced by HDAC inhibitor treatment. Using microarrays we further identified gene expression changes taking place in non-neuronal cells as a result of HDAC inhibition. This analysis demonstrated that HDAC inhibitor treatment results in the down-regulation of immunity related signaling factors, in particular the Toll-like receptors (TLR). TLR signaling is active in cultured midbrain cells, yet blocking TLR receptors is not sufficient to cause neuronal cell death. In contrast, selective activation of this pathway using TLR ligands can modestly block the effects of HDAC inhibition. Furthermore, we observed that the negative effects of HDAC inhibitor treatment on neuronal survival could be more substantially blocked by the cytokine Interleukin-6 (IL-6), which is a major downstream target of TLR signaling. These data suggest that HDACs function to promote neuronal survival by activating a TLR and IL-6 dependent pathway.

Inhibition of histone deacetylase (HDAC) activity results in dedifferentiation of various neural precursor cell populations, but is also known to promote neuronal differentiation. We sought to determine the effects of HDAC inhibition on differentiated and non-differentiated midbrain cells in order to examine more closely the consequences of HDAC inhibition on cell fate in a heterogeneous population. We demonstrate that HDAC inhibitor (HDACi) treatment causes a significant attenuation in the numbers of neurons, but not astrocytes, within 48h, with no evidence of neuronal dedifferentiation. The loss of neurons is due to an initial morphological destabilization, which is not recoverable upon inhibitor removal, and ultimately leads to cell death. HDACi treatment results in progenitor cell cycle arrest and Caspase-dependent apoptosis. In contrast, the loss of midbrain neurons does not correlate with activated Caspase-3 expression. Treating cultures transiently with Caspase inhibitors blocks overall HDACi-induced cell death in the cultures, but does not prevent the loss of neurons. These data suggest that HDACi treated midbrain neurons undergo Caspase-independent cell death. Finally, we demonstrate that cortical neurons do not undergo cell death in response to HDACi treatment, suggesting that there may be tissue-specific or microenvironmental factors that promote the susceptibility of midbrain neurons to the neurotoxic effects of HDAC inhibition., (Copyright © 2011 Elsevier Inc. All rights reserved.)

To develop in vitro models of cells, tissues and organs we have designed and realized a series of cell culture chambers. Each chamber is purpose designed to simulate a particular feature of the in vivo environment. The bioreactor system is user friendly, and the chambers are easy to produce, sterilize and assemble. In addition they can be connected together to simulate inter-organ or tissue cross-talk. Here we discuss the design philosophy of the bioreactor system and then describe its construction. Preliminary results of validation tests obtained with hepatocytes and endothelial cells are also reported. The results show that endothelial cells are extremely sensitive to small levels of shear stress and that the presence of heterotypic signals from endothelial cells enhances the endogenous metabolic function of hepatocytes., (Copyright © 2011 Wiley Periodicals, Inc.)

Human male infertility affects approximately 5% of men, with one-third suffering from testicular failure, likely the result of an underlying genetic abnormality that disrupts spermatogenesis during development. Mouse models of male infertility such as the Ppp1cc knockout mouse display very similar phenotypes to humans with testicular failure. Male Ppp1cc mutant mice are sterile due to disruptions in spermatogenesis that begin during prepubertal testicular development, and continue into adulthood, often resulting in loss of germ cells to the point of Sertoli cell-only syndrome. The current study employs light and electron microscopy to identify new morphological abnormalities in Ppp1cc mutant seminiferous epithelium. This study reveals that germ cells become delayed in their development around stages VII and VIII of spermatogenesis. Loss of these cells likely results in the reduced numbers of elongating spermatids and spermatozoa previously observed in mutant animals. Interestingly, Ppp1cc mutants also display reduced numbers of spermatogonia compared with their wild-type counterparts. Using electron microscopy, we have shown that junction complexes in Ppp1cc mutants are ultrastructurally normal, and therefore do not contribute to the breakdown in tissue architecture seen in mutants. Electron microscopy revealed major acrosomal and chromatin condensation defects in Ppp1cc mutants. Our observations are discussed in the context of known molecular changes in Ppp1cc mutant testes.

We describe a case of fatal myocardial rupture and tamponade following a successful transcoronary chemical ablation of incessant ventricular tachycardia. Pathological examination showed a subepicardial dissection of the heart at the ablation site with fibrous and fatty degeneration of the myocardium. The present report calls for caution, underlying a possible lethal complication of ethanol ablation which has not been described before.

A wealth of data about the clinical use and the therapeutic efficacy of chronic treatment with amiodarone has been reported, while the acute effects of this agent are less known. In one case of acute oral intoxication with 8 g of amiodarone for suicidal purposes, we have investigated the pharmacokinetics of amiodarone, the thyroid function and the variations of some clinical parameters, such as heart rate and QT interval. Other possible side-effects have been looked for. We have not observed substantial pharmacokinetic differences between our case and studies carried out after chronic oral or intravenous administration. Unlike chronic administration, the acute oral load was not followed by the appearance of toxic effects. The absence of toxic phenomena can be explained by the poor bioavailability of amiodarone, which is known to require long periods for a complete distribution to the tissues and target organs.