Efficacy of polyunsaturated fatty acids (PUFAs) on impulsive behaviours and aggressiveness in psychiatric disorders

It is the focus of increasing interest to investigate the effects of long-chain n-3 and long-chain n-6 polyunsaturated fatty acids (LC n-3 PUFAs; LC n-6 PUFAs) on psychiatric symptoms in a transdiagnostic perspective. There is some evidence that low levels of LC n-3 PUFAs and a higher ratio of LC n-6 to LC n-3 PUFAs in plasma and blood cells are associated with aggressive and impulsive behaviours. Therefore, implementation of LC n-3 PUFAs may produce positive effects on hostility, aggression, and impulsivity in both psychiatric and non-psychiatric samples across different stages of life. A possible mechanism of action of LC n-3 PUFAs in conditions characterized by a high level of impulsivity and aggression is due to the effect of these compounds on the serotonin system and membrane stability. Studies that evaluated the effects of LC n-3 PUFAs on impulsivity and aggressiveness indicated that addition of rather low doses of these agents to antipsychotic treatment might reduce agitation and violent behaviours in psychosis, attention deficit hyperactivity disorder, personality disorders, and impulsive control and conduct disorders. The present review is aimed at examining and discussing available data from recent trials on this topic

Interplay among unstable modes in films over permeable walls

The stability of open-channel flows (or film flows) has been extensively investigated for the case of impermeable smooth walls. In contrast, despite its relevance in many geophysical and industrial flows, the case that considers a permeable rather than an impermeable wall is almost unexplored. In the present work, a linear stability analysis of a film falling over a permeable and inclined wall is developed and discussed. The focus is on the mutual interaction between three modes of instability, namely, the well-known free-surface and hydrodynamic (i.e. shear) modes, which are commonly observed in open-channel flows over impermeable walls, plus a new one associated with the flow within the permeable wall (i.e. the porous mode). The flow in this porous region is modelled by the volume-averaged Navier-Stokes equations and, at the wall interface, the surface and subsurface flow are coupled through a stress-jump condition, which allows one to obtain a continuous velocity profile throughout the whole flow domain. The generalized eigenvalue problem is then solved via a novel spectral Galerkin method, and the whole spectrum of eigenvalues is presented and physically interpreted. The results show that, in order to perform an analysis with a full coupling between surface and subsurface flow, the convective terms in the volume-averaged equations have to be retained. In previous studies, this aspect has never been considered. For each kind of instability, the critical Reynolds number (${\mathit{Re}}_{c}$) is reported for a wide range of bed slopes ($\theta$) and permeabilities ($\sigma$). The results show that the free-surface mode follows the behaviour that was theoretically predicted by Benjamin and Yih for impermeable walls and is independent of wall permeability. In contrast, the shear mode shows a high dependence on $\sigma$: at $\sigma = 0$ the behaviour of ${\mathit{Re}}_{c} (\theta )$ recovers the well-known non-monotonic behaviour of the impermeable-wall case, with a minimum at \theta \sim 0. 05\textdegree . However, with an increase in wall permeability, ${\mathit{Re}}_{c}$ gradually decreases and eventually recovers a monotonic decreasing behaviour. At high values of $\sigma$, the porous mode of instability also occurs. A physical interpretation of the results is presented on the basis of the interplay between the free-surface-induced perturbation of pressure, the increment of straining due to shear with the increase in slope, and the shear stress condition at the free surface. Finally, the paper investigates the extent to which Squire's theorem is applicable to the problem presented herei

Automated detection and characterization of Antarctic basal units using radar sounding data: demonstration in Institute Ice Stream, West Antarctica

Basal units – visibly distinct englacial structures near the ice-bed interface – warrant investigation for a number of reasons. Many are of unknown composition and origin, characteristics that could provide substantial insight into subglacial processes and ice-sheet history. Their significance, moreover, is not limited to near-bed depths; these units appear to dramatically influence the flow of surrounding ice. In order to enable improved characterization of these features, we develop and apply an algorithm that allows for the automatic detection of basal units. We use a tunable layer-optimized SAR processor to distinguish these structures from the bed, isochronous englacial layers and the ice-sheet surface, presenting a conceptual framework for the use of radio-echo character in the identification of ice-sheet features. We also outline a method by which our processor could be used to place observational constraints on basal units’ configuration, composition and provenance

Microenvironment in neuroblastoma: Isolation and characterization of tumor-derived mesenchymal stromal cells

Background: It has been proposed that mesenchymal stromal cells (MSCs) promote tumor progression by interacting with tumor cells and other stroma cells in the complex network of the tumor microenvironment. We characterized MSCs isolated and expanded from tumor tissues of pediatric patients diagnosed with neuroblastomas (NB-MSCs) to define interactions with the tumor microenvironment. Methods: Specimens were obtained from 7 pediatric patients diagnosed with neuroblastoma (NB). Morphology, immunophenotype, differentiation capacity, proliferative growth, expression of stemness and neural differentiation markers were evaluated. Moreover, the ability of cells to modulate the immune response, i.e. inhibition of phytohemagglutinin (PHA) activated peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cytotoxic function, was examined. Gene expression profiles, known to be related to tumor cell stemness, Wnt pathway activation, epithelial-mesenchymal transition (EMT) and tumor metastasis were also evaluated. Healthy donor bone marrow-derived MSCs (BM-MSC) were employed as controls. Results: NB-MSCs presented the typical MSC morphology and phenotype. They showed a proliferative capacity superimposable to BM-MSCs. Stemness marker expression (Sox2, Nanog, Oct3/4) was comparable to BM-MSCs. NB-MSC in vitro osteogenic and chondrogenic differentiation was similar to BM-MSCs, but NB-MSCs lacked adipogenic differentiation capacity. NB-MSCs reached senescence phases at a median passage of P7 (range, P5-P13). NB-MSCs exhibited greater immunosuppressive capacity on activated T lymphocytes at a 1:2 (MSC: PBMC) ratio compared with BM-MSCs (p = 0.018). NK cytotoxic activity was not influenced by co-culture, either with BM-MSCs or NB-MSCs. Flow-cytometry cell cycle analysis showed that NB-MSCs had an increased number of cells in the G0-G1 phase compared to BM-MSCs. Transcriptomic profiling results indicated that NB-MSCs were enriched with EMT genes compared to BM-MSCs. Conclusions: We characterized the biological features, the immunomodulatory capacity and the gene expression profile of NB-MSCs. The NB-MSC gene expression profile and their functional properties suggest a potential role in promoting tumor escape, invasiveness and metastatic traits of NB cancer cells. A better understanding of the complex mechanisms underlying the interactions between NB cells and NB-derived MSCs should shed new light on potential novel therapeutic approaches

Nature of the global fluctuations in the spherical model at criticality

We study the universal nature of global fluctuations in the critical regime of the spherical model by evaluating the exact distribution of the magnetization and its absolute value in the thermodynamical limit, in the presence of a conjugate field. We show that the probability distribution function for this model is described by non-Gaussian asymptotics and non-symmetric characteristics which depend on the dimension of the system 2<d<4. Relation with extreme statistics of independent wavelength modes is discussed.Comment: 22 pages, 8 figures; 05.70.Jk, 05.40.-a, 05.50.+q, 68.35.R

Hpv-specific systemic antibody responses and memory b cells are independently maintained up to 6 years and in a vaccine-specific manner following immunization with cervarix and gardasil in adolescent and young adult women in vaccination programs in Italy

Human papillomavirus (HPV) persistent infections are associated with cervical cancer and other HPV-related diseases and tumors. Thus, the characterization of long lasting immunity to currently available HPV vaccines is important. A total of 149 female subjects vaccinated with Cervarix or Gardasil participated to the study and they were stratified according to age (10–12-year-old and 16–20-year-old). Humoral immune responses (IgG and neutralizing antibody titers, antibody avidity) and circulating memory B cells were analyzed after an average of 4–6 years from the third immunization. The humoral responses against HPV-16 and HPV-18 (and HPV-6 and HPV- 11 for Gardasil) were high in both age groups and vaccines up to six years from the third dose. However, Cervarix induced significantly higher and more persistent antibody responses, while the two vaccines were rather equivalent in inducing memory B cells against HPV-16 and HPV-18. Moreover, the percentage of subjects with vaccine-specific memory B cells was even superior among Gardasil vaccinees and, conversely, Cervarix vaccinated individuals with circulating antibodies, but undetectable memory B cells were found. Finally, a higher proportion of Cervarix-vaccinated subjects displayed cross-neutralizing responses against non-vaccine types HPV-31 and HPV-45. Gardasil and Cervarix may, thus, differently affect long-lasting humoral immunity from both the quantitative and qualitative point of view

In vitro biosafety profile evaluation of multipotent mesenchymal stem cells derived from the bone marrow of sarcoma patients.

BACKGROUND: In osteosarcoma (OS) and most Ewing sarcoma (EWS) patients, the primary tumor originates in the bone. Although tumor resection surgery is commonly used to treat these diseases, it frequently leaves massive bone defects that are particularly difficult to be treated. Due to the therapeutic potential of mesenchymal stem cells (MSCs), OS and EWS patients could benefit from an autologous MSCs-based bone reconstruction. However, safety concerns regarding the in vitro expansion of bone marrow-derived MSCs have been raised. To investigate the possible oncogenic potential of MSCs from OS or EWS patients (MSC-SAR) after expansion, this study focused on a biosafety assessment of MSC-SAR obtained after short- and long-term cultivation compared with MSCs from healthy donors (MSC-CTRL). METHODS: We initially characterized the morphology, immunophenotype, and differentiation multipotency of isolated MSC-SAR. MSC-SAR and MSC-CTRL were subsequently expanded under identical culture conditions. Cells at the early (P3/P4) and late (P10) passages were collected for the in vitro analyses including: the sequencing of genes frequently mutated in OS and EWS, evaluation of telomerase activity, assessment of the gene expression profile and activity of major cancer pathways, cytogenetic analysis on synchronous MSC, and molecular karyotyping using a comparative genomic hybridization (CGH) array. RESULTS: MSC-SAR displayed comparable morphology, immunophenotype, proliferation rate, differentiation potential, and telomerase activity to MSC-CTRL. Both cell types displayed signs of senescence in the late stages of culture with no relevant changes in cancer gene expression. However, cytogenetic analysis detected chromosomal anomalies in the early and late stages of MSC-SAR and MSC-CTRL after culture. CONCLUSIONS: Our results demonstrated that the in vitro expansion of MSC does not influence or favor malignant transformation since MSC-SAR were not more prone than MSC-CTRL to deleterious changes during culture. However, the presence of chromosomal aberrations supports rigorous phenotypic, functional and genetic evaluation of the biosafety of MSCs, which is important for clinical applications

Bilateral diffuse choroidal hemangioma in Sturge Weber syndrome: a case report highlighting the role of multimodal imaging and a brief review of the literature

Purpose: The purpose of this paper is to present a patient with bilateral choroidal hemangioma in Sturge-Weber syndrome (SWS) and highlight multimodal imaging techniques for early detection and management of ocular alterations. Methods: A 37-year-old woman with diagnosis of SWS presented to our unit. The patient had been treated with pulsed dye laser for bilateral nevus flammeus and had right leptomeningeal angiomatosis. She had glaucoma, but ultrasound biomicroscopy did not show anterior chamber or ciliary body alterations. Results: Enhanced depth imaging (EDI) spectral domain optical coherence tomography (SD-OCT) showed bilateral diffuse choroidal hemangiomas in both eyes with choroidal thickness above 1000 μm. B-scan ultrasound examination showed diffuse choroidal hemangioma in both eyes, with a choroidal thickness of 1.53 mm and 1.94 mm in the right and left eye (RE, LE), respectively. Peripapillary retinal nerve fiber evaluation showed thinning of the retinal nerve fiber layer in both eyes. Conclusions: This report highlights multimodal imaging techniques for the critical assessment of patients with SWS, especially in rare cases with bilateral choroidal hemangioma of the choroid. Novel imaging modalities enable optimal management and follow-up of rare conditions, and our case adds further evidence to the existing literature

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

Phase II Randomized, Double-Masked, Vehicle-Controlled Trial of Recombinant Human Nerve Growth Factor for Neurotrophic Keratitis

Purpose: To evaluate the safety and efficacy of topical recombinant human nerve growth factor (rhNGF) for treating moderate-to-severe neurotrophic keratitis (NK), a rare degenerative corneal disease resulting from impaired corneal innervation. Design: Phase II multicenter, randomized, double-masked, vehicle-controlled trial. Participants: Patients with stage 2 (moderate) or stage 3 (severe) NK in 1 eye. Methods: The REPARO phase II study assessed safety and efficacy in 156 patients randomized 1:1:1 to rhNGF 10 \u3bcg/ml, 20 \u3bcg/ml, or vehicle. Treatment was administered 6 drops per day for 8 weeks. Patients then entered a 48- or 56-week follow-up period. Safety was assessed in all patients who received study treatment, whereas efficacy was by intention to treat. Main Outcome Measures: Corneal healing (defined as &lt;0.5-mm maximum diameter of fluorescein staining in the lesion area) was assessed by masked central readers at week 4 (primary efficacy end point) and week 8 (key secondary end point) of controlled treatment. Corneal healing was reassessed post hoc by masked central readers using a more conservative measure (0-mm staining in the lesion area and no other persistent staining). Results: At week 4 (primary end point), 19.6% of vehicle-treated patients achieved corneal healing (&lt;0.5-mm lesion staining) versus 54.9% receiving rhNGF 10 \u3bcg/ml (+35.3%; 97.06% confidence interval [CI], 15.88\u201354.71; P &lt; 0.001) and 58.0% receiving rhNGF 20 \u3bcg/ml (+38.4%; 97.06% CI, 18.96\u201357.83; P &lt; 0.001). At week 8 (key secondary end point), 43.1% of vehicle-treated patients achieved less than 0.5-mm lesion staining versus 74.5% receiving rhNGF 10 \u3bcg/ml (+31.4%; 97.06% CI, 11.25\u201351.49; P = 0.001) and 74.0% receiving rhNGF 20 \u3bcg/ml (+30.9%; 97.06% CI, 10.60\u201351.13; P = 0.002). Post hoc analysis of corneal healing by the more conservative measure (0-mm lesion staining and no other persistent staining) maintained statistically significant differences between rhNGF and vehicle at weeks 4 and 8. More than 96% of patients who healed after controlled rhNGF treatment remained recurrence free during follow-up. Treatment with rhNGF was well tolerated; adverse effects were mostly local, mild, and transient. Conclusions: Topical rhNGF is safe and more effective than vehicle in promoting healing of moderate-to-severe NK