Case Report: Post-gastrectomy reactive hyperinsulinemic hypoglicaemia: glucose trends before and after canagliflozin treatment.

The pathogenesis of post-gastrectomy reactive hyperinsulinaemic hypoglycaemia is not yet fully clarified. Recent studies suggest an up-regulation of the intestinal glucose transporter SGLT-1 aimed to prevent carbohydrate malabsorption. The overexpression of SGLT-1 could therefore represents one of the mechanisms underlying the wide glycemic excursions found in patients after gastrectomy, but studies investigating the use of SGLT-1/SGLT-2 inhibitors in patients with post-gastrectomy reactive hyperinsulinemic hypoglycaemia are very scant in the literature. We report the case of a 37-year-old non diabetic man who frequently presented symptoms of hypoglycaemia in the postprandial period. In 2012, he underwent Roux en-Y gastric bypass (RYGB) and after two years, he started to experience typical symptoms of reactive hyperinsulinaemic hypoglycaemia. We suggested healthy modifications of dietary habits and periodic follow-up visits with a dietitian. After three months, the patient still presented symptoms of reactive hypoglycaemia; we provided him with Flash Glucose Monitoring (FGM) to assess trend of glucose levels in interstitial fluid during the day and we decided to introduce canagliflozin 300 mg/day before the main meal. Hypoglycaemic events previously referred by the patient and clearly recorded by FGM completely disappeared taking canagliflozin. We found a reduction of time spent in hypoglycaemia, an improvement of glycemic variability and an increase of time in target range. It was also noted a reduction of time spent in hyperglicemia with consequent improvement of average glucose values and of glucose main indicator. This is the first report with FGM supporting a role of canagliflozin in the management of post-gastrectomy reactive hyperinsulinaemic hypoglycaemia. Our preliminary results are very limited but in line with those of the literature and showed for the first time a reduction of hypoglycaemic events and an improvement of glycemic variability through a flash glucose monitoring system. Further studies are mandatory to confirm this therapeutic opportunity.

How long does it take to diagnose young-onset dementia? A comparison with late-onset dementia.

INTRODUCTION: Dementia occurring in young people may be difficult to recognize. We compared the time to diagnosis between young- (YOD, age < 65) and late-onset dementia (LOD). METHODS: Time between the onset of symptoms and the diagnosis was measured in YOD and LOD patients consecutively seen in a cognitive neurology clinic. Multivariable regression analyses were performed to identify determinants of time to diagnosis. RESULTS: Mean time to diagnosis in 95 YOD patients was 11.2 months longer than in 73 LOD patients (p = 0.022). The delay was driven by a longer time taken by YOD patients to be seen in the specialist centre, which in turn was related to the presence of language disturbances and coexisting depression. DISCUSSION: Young people take longer than elderly people to receive a dementia diagnosis because they take longer to be referred to dementia specialist centres. More awareness on YOD is needed in primary care and the public.

Transition from unclassified Ktedonobacterales to Actinobacteria during amorphous silica precipitation in a quartzite cave environment.

The orthoquartzite Imawarì Yeuta cave hosts exceptional silica speleothems and represents a unique model system to study the geomicrobiology associated to silica amorphization processes under aphotic and stable physical-chemical conditions. In this study, three consecutive evolution steps in the formation of a peculiar blackish coralloid silica speleothem were studied using a combination of morphological, mineralogical/elemental and microbiological analyses. Microbial communities were characterized using Illumina sequencing of 16S rRNA gene and clone library analysis of carbon monoxide dehydrogenase (coxL) and hydrogenase (hypD) genes involved in atmospheric trace gases utilization. The first stage of the silica amorphization process was dominated by members of a still undescribed microbial lineage belonging to the Ktedonobacterales order, probably involved in the pioneering colonization of quartzitic environments. Actinobacteria of the Pseudonocardiaceae and Acidothermaceae families dominated the intermediate amorphous silica speleothem and the final coralloid silica speleothem, respectively. The atmospheric trace gases oxidizers mostly corresponded to the main bacterial taxa present in each speleothem stage. These results provide novel understanding of the microbial community structure accompanying amorphization processes and of coxL and hypD gene expression possibly driving atmospheric trace gases metabolism in dark oligotrophic caves.

New insights into vitamin D regulation: is there a role for alkaline phosphatase?

PURPOSE: The diagnosis of vitamin D deficiency is based on the determination of total plasma 25-hydroxyvitamin D (25-OHD) concentrations, but the regulation of vitamin D 25-hydroxylation is not a major consideration and very little information is available on this activity. To check what factors could interfere with the activity of vitamin D-25-hydroxylase and thus alter the 25-OHD concentrations, we looked for potential correlations between 25-OHD and results of liver function tests in healthy adults. METHODS: This single-centre study was retrospective and consisted of evaluating the correlations between 25-OHD and the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), and bone alkaline phosphatase (BALP) in 349 healthy subjects aged from 18 to 65 years. In particular, in Group 1 (n = 119), we looked for correlations between 25OHD and all liver function tests and in Group 2 (n = 230) the correlation between 25OHD and BALP. RESULTS: In Group 1, we found no correlation between 25OHD and AST (r = - 0.03; p = 0.8), ALT (r = - 0.02; p = 0.91), GGT (r = - 0.08; p = 0.68), direct bilirubin (r = - 0.02; p = 0.89), indirect bilirubin (r = - 0.24; p = 0.21), and total bilirubin (r = - 0.24; p = 0.21) but one between 25OHD and ALP (r = - 0.2; p = 0.007); in Group 2, we found a significant negative correlation between 25-OHD and BALP (r = - 0.2; p = 0.0008). CONCLUSIONS: The correlations that we found suggest that ALP and BALP might be involved in the regulation of vitamin D-25-hydroxylase activity, but further studies are mandatory to confirm our assumptions.

Topologization of ß-antimonene on Bi2Se3 via proximity effects.

Topological surface states usually emerge at the boundary between a topological and a conventional insulator. Their precise physical character and spatial localization depend on the complex interplay between the chemical, structural and electronic properties of the two insulators in contact. Using a lattice-matched heterointerface of single and double bilayers of ß-antimonene and bismuth selenide, we perform a comprehensive experimental and theoretical study of the chiral surface states by means of microscopy and spectroscopic measurements complemented by first-principles calculations. We demonstrate that, although ß-antimonene is a trivial insulator in its free-standing form, it inherits the unique symmetry-protected spin texture from the substrate via a proximity effect that induces outward migration of the topological state. This "topologization" of ß-antimonene is found to be driven by the hybridization of the bands from either side of the interface.

Dual-drugs delivery in solid lipid nanoparticles for the treatment of Candida albicans mycosis.

Nowadays, a combinatorial drug delivery system that simultaneously transports two or more drugs to the targeted site in a human body, also recognized as a dual-drugs delivery system, represents a promising strategy to overcome drug resistance. Solid lipid nanoparticles loaded with clotrimazole (CLZ) and alphalipolic acid (ALA), considered as an effective agent in the reduction of reactive oxygen species, can enhance anti-infective immunity being proposed as a non-toxic and mainly non-allergic dual-drugs delivery system. In this study, uncoated and cationic CLZ-ALA-loaded SLN were prepared and compared. Suspensions with a narrow size distribution of particles of mean size below 150 nm were obtained, having slight negative or highly positive zeta potential values, due to the presence of the cationic lipid, which also increased nanoparticles stability, as confirmed by Turbiscan® results. Calorimetric studies confirmed the rationale of separately delivering the two drugs in a dual-delivery system. Furthermore, they confirmed the formation of SLN, without significant variation in presence of the cationic lipid. In vitro release studies showed a prolonged drug release without the occurrence of any burst effect. In vitro studies performed on 25 strains of Candida albicans showed the antimicrobial drug activity was not altered when it was loaded into lipid nanoparticles. The study has proved the successfully encapsulation of CLZ and ALA in solid lipid nanoparticles that may represent a promising strategy to combine ALA protective effect in the treatment with CLZ.

3D printing in the design of pharmaceutical dosage forms.

Three-dimensional (3D) printing technologies are manufacturing approaches with widespread use in industry (e.g. automotive, automobile, pharmaceutical industries). With regard to its use in pharmaceutical industry, 3D printing is demonstrating to be of added value attributed to the possibility of printing tailored pharmaceutical products, namely personalized medical devices, such as implants and other dosage forms. However, with the approval of the first 3D-printed drug-product in 2015, a new perspective has arisen, i.e. the use of this technology to produce solid oral dosage forms exhibiting complex drug release profiles and allowing for individual dosing. Technological hurdles and regulatory issues still have to be overcome before this technology can truly find its place in the healthcare sector, where it can certainly contribute to a personalized and patient-centered healthcare. This manuscript offers a comprehensive analysis of the most extensively used methods of 3D printing in the pharmaceutical field, with examples of solid oral dosage forms and other medical devices currently under development or already marketed.

Uveal melanoma: physiopathology and new in situ-specific therapies.

Uveal melanoma is the most common primary intraocular tumor in adults. It can arise from melanocytes in the anterior (iris) or posterior uveal tract (choroid and ciliary body). Uveal melanoma has a particular molecular pathogenesis, being characterized by specific chromosome alterations and gene mutations (e.g., GNAQ/GNA11; BAP1), which are considered promising targets for molecular therapy. Primary treatment of uveal melanoma includes radiotherapy (brachytherapy and charged-particle therapy), phototherapy (photocoagulation, transpupillary thermal therapy, and photodynamic therapy) and surgery (local resection, enucleation and exenteration). Approximately half of patients with uveal melanoma will, however, develop metastasis, especially in the liver. The treatment of metastatic uveal melanoma includes systemic chemotherapy, immunotherapy and molecular targeted therapy. Liver-directed therapies, such as resection, chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion and percutaneous hepatic perfusion, are also available to treat metastatic uveal melanoma. Several clinical trials are being developed to study new therapeutic options to treat uveal melanoma, mainly for those with identified liver metastases. The present work discusses the physiopathology and new in situ-specific therapies for the treatment of uveal melanoma.

Mediterranean essential oils as precious matrix components and active ingredients of lipid nanoparticles.

Essential oils are recognized as valuable active pharmaceutical ingredients attributed to a set of biological properties, which include antibacterial, antifungal, antiviral, antioxidant, anticancer, immune-modulatory, analgesic and anti-inflammatory activities. Their use in pharmaceutics is however compromised by their limited water solubility and low physicochemical stability (i.e. volatility, oxidation). In order to overcome these limitations, we aimed to develop nanostructured lipid carriers (NLC) as delivery systems for Mediterranean essential oils, in particular Rosmarinus officinalis L., Lavandula x intermedia "Sumian", Origanum vulgare subsp. hirtum and Thymus capitatus essential oils, selected on the basis of their antioxidant and anti-inflammatory activities. NLC composed of Softisan (as solid lipid) have been produced by phase inversion temperature (PIT) and high-pressure homogenization (HPH), using two different emulsifiers systems. Particles have been further characterized for their mean particle size, polydispersity, zeta potential, morphology and chemical interactions. Best NLC formulations were obtained with Kolliphor/Labrafil as surfactants, and using Rosmarinus, Lavandula and Origanum as essential oils (PDI between 0.126 and 0.141, Zave < 200 nm). Accelerated stability studies have also been carried out to estimate the effect of the production method and surfactant composition on the long-term stability of EOs-loaded NLC. In vitro biological cell viability and anti-inflammatory activities were evaluated in Raw 264.7 cells (macrophage cell line), while in vitro antioxidant activity was checked by DPPH assay. Lavandula and Rosmarinus NLC were shown to be the most biocompatible formulations up to a concentration of 0.1% (v/v), whereas they were able to induce a dose-dependent anti-inflammatory activity in the order Lavandula > Rosmarinus ≥ Origanum.

Repurposing itraconazole to the benefit of skin cancer treatment: A combined azole-DDAB nanoencapsulation strategy.

In this work, we aimed at developing an improved topical SLN formulation combining itraconazole delivery with a coating layer of didodecyldimethylammonium bromide, thus repurposing the drug effectiveness by synergistic skin anticancer effectiveness. In order to obtain a stable SLN formulation with small homogeneously dispersed particles, a deep formulative study was developed screening three different solid lipids (Suppocire NB, Cetyl Palmitate and Dynasan 114) for the SLN preparation by the phase inversion temperature. A bluishcolored shade formulation, with homogeneous small particles size (<50 nm) was obtained only using Suppocire NB. The cytotoxicity of all SLN was tested after 24 h exposure against three adherent skin cell lines (A431, HaCaT and SK-MEL-5). Results demonstrate that both unloaded and drugloaded SLN did not significantly affect the cell viability of the non-tumoral HaCaT cell line, thus confirming the safe potential topical application of these formulations. A dose-dependent decrease in cell viability was observed for the tumoral cell lines, A431 and SK-MEL-5, with a significant reduction of the A431 cancer cell line viability. The drug molecule addition to the uncoated nanoparticles was able to increase of almost 20% the reduction of the viability of the cancer cells treated. Ours results demonstrate the potentiality of repurposing itraconazole activity by using the combined nanoencapsulation strategy with the positively charged coating layer on SLN, which can be further investigated as a promising stable and safe approach to significantly reduce the viability of skin cancer cells.

Novelty-related behavior of young and adult dopamine transporter knockout rats: Implication for cognitive and emotional phenotypic patterns.

Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric disorder characterized by a developmentally inappropriate, pervasive and persistent pattern of severe inattention, hyperactivity and impulsivity. Despite onset in early childhood, ADHD may continue into adulthood with substantial impairment in social, academic and occupational functioning. A new animal model of this disorder was developed in rats with genetic deletion of the dopamine transporter (DAT) gene (dopamine transporter knockout rats; DAT-KO rats). We analyzed the behavior of DAT-KO rats for a deeper phenotypical characterization of this model. We first tested rats of the 3 genotypes at different ages (preadolescent, adolescent and adult), in a novelty-seeking test using a black/white box (Experiment 1). After that, we tested adult rats in a novelty-preference test using a 3-chamber apparatus with different shapes (Experiment 2). Experiment 1: as evidenced by analysis of time spent in the novel environment, adult DAT heterozygous (DAT-HET) rats show an increased curiosity-driven exploration compared with wild-type (WT) controls while DAT-KO rats did not recognize novelty. The locomotor activity data show a minimal difference between genotypes at adolescent age while the preadolescent and adult DAT-KO rats have significantly increased activity rate compared with WT and DAT-HET subjects. Experiment 2: in this case, due to more clearly evident spatial differences, time spent in novel environment was not significantly different among genotypes. During first 10 minutes, DAT-KO rats showed a decreased hyperactivity, apparently related to curiosity and attention to the new environments. In conclusion, DAT-KO rats may show some inattention while more novelty-seeking traits appear in DAT-HET rats.

Evidence of ß-antimonene at the Sb/Bi2Se3 interface.

We report a study of the interface between antimony and the prototypical topological insulator Bi2Se3. Scanning tunnelling microscopy measurements show the presence of ordered domains displaying a perfect lattice match with bismuth selenide. Density functional theory calculations of the most stable atomic configurations demonstrate that the ordered domains can be attributed to stacks of ß-antimonene.

Revisiting the role of sucrose in PLGA-PEG nanocarrier for potential intranasal delivery.

The efficient design of nanocarriers is a major challenge and must be correlated with the route of administration. Intranasal route is studied for local, systemic or cerebral treatments. In order to develop nanocarriers with suitable properties for intranasal delivery, to achieve brain and to market the product, it is extremely important the simplification of the formulation in terms of raw materials. Surfactants and cryoprotectants are often added to improve structuration and/or storage of polymeric nanoparticles. PLGA-PEG nanocarriers were prepared by nanoprecipitation method evaluating the critical role of sucrose as surfactant-like and cryoprotectant, with the aim to obtain a simpler formulation compared to those proposed in other papers. Photon correlation spectroscopy and Turbiscan analysis show that sucrose is a useful excipient during the preparation process and it effectively cryoprotects nanoparticles. Among the investigated nanocarriers with different degree of PEG, PEGylated PLGA (5%) confers weak interaction between nanoparticles and mucin as demonstrated by thermal analysis and mucin particle method. Furthermore, in vitro biological studies on HT29, as epithelium cell line, does not show cytotoxicity effect for this nanocarrier at all texted concentrations. The selected nanosystem was also studied to load docetaxel, as model drug, and characterized by a technological point of view.

Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling.

BACKGROUND: Solid epidemiological evidences connect obesity with incidence, stage and survival in pancreatic cancer. However, the underlying mechanistic basis linking adipocytes to pancreatic cancer progression remain largely elusive. We hypothesized that factors secreted by adipocytes could be responsible for epithelial-to-mesenchymal transition (EMT) induction and, in turn, a more aggressive phenotype in models of pancreatic preneoplastic lesions. METHODS: We studied the role of factors secreted by two adipogenic model systems from primary human bone marrow stromal cells (hBMSCs) in an in vitro experimental cell transformation model system of human pancreatic ductal epithelial (HPDE) cell stably expressing activated KRAS (HPDE/KRAS),Results:We measured a significant induction of EMT and aggressiveness in HPDE and HPDE/KRAS cell lines when cultured with medium conditioned by fully differentiated adipocytes (ADIPOCM) if compared with the same cells cultured with medium conditioned by hBMSC (hBMSCCM) from two different healthy donors. Several genes coding for soluble modulators of the non-canonical WNT signaling pathway, including FRZB, SFRP2, RSPO1, WNT5A and 5B were significantly overexpressed in fully differentiated adipocytes than in their respective in hBMSC. ADIPOCM induced the overexpression and the nuclear translocation of the Frizzled family member receptor tyrosine kinase-like orphan receptor (Ror) 2 in HPDE and HPDE/KRAS cells. Vantictumab, an anti-Frizzled monoclonal antibody, reduced ROR2 nuclear translocation and in turn the EMT and aggressiveness in HPDE and HPDE/KRAS cells. CONCLUSIONS: We demonstrated that adipocytes could induce EMT and aggressiveness in models of pancreatic preneoplastic lesions by orchestrating a complex paracrine signaling of soluble modulators of the non-canonical WNT signaling pathway that determine, in turn, the activation and nuclear translocation of ROR2. This signaling pathway could represent a novel target for pancreatic cancer chemoprevention. Most importantly, these factors could serve as novel biomarkers to select a risk population among obese subjects for screening and, thus, early diagnosis of pancreatic cancer.

Spin-polarized confined states in Ag films on Fe(1 1 0).

Spin- and angle-resolved photoemission spectroscopy of thin Ag(1 1 1) films on ferromagnetic Fe(1 1 0) shows a series of spin-polarized peaks. These features derive from Ag sp-bands, which form quantum well states and resonances due to confinement by a spin-dependent interface potential barrier. The spin-up states are broader and located at higher binding energy than the corresponding spin-down states at [Formula: see text], although the differences attenuate near the Fermi level. The spin-down states display multiple gap openings, which interrupt their parabolic-like dispersion. First-principles calculations attribute these findings to the symmetry- and spin-selective hybridization of the Ag states with the exchange-split bands of the substrate.

Beyond liposomes: Recent advances on lipid based nanostructures for poorly soluble/poorly permeable drug delivery.

Solid lipid nanoparticle (SLN), nanostructured lipid carriers (NLC) and hybrid nanoparticles, have gained increasing interest as drug delivery systems because of their potential to load and release drugs from the Biopharmaceutical classification system (BCS) of class II (low solubility and high permeability) and of class IV (low solubility and low permeability). Lipid properties (e.g. high solubilizing potential, biocompatibility, biotolerability, biodegradability and distinct route of absorption) contribute for the improvement of the bioavailability of these drugs for a set of administration routes. Their interest continues to grow, as translated by the number of patents being field worldwide. This paper discusses the recent advances on the use of SLN, NLC and lipid-polymer hybrid nanoparticles for the loading of lipophilic, poorly water-soluble and poorly permeable drugs, being developed for oral, topical, parenteral and ocular administration, also discussing the industrial applications of these systems. A review of the patents filled between 2014 and 2017, concerning the original inventions of lipid nanocarriers, is also provided.

Targeting dendritic cells for the treatment of autoimmune disorders.

In the last decades, it has been recognized that extracellular vesicles (EVs) are not only cell debris with no biological role, but instead they play a key role in information exchange between cells either in health and disease conditions. EVs exhibit indeed their biological role in a pleiotropic manner. They can modulate immune responses through the activation, transfer or removal of surface receptors on target cells, the removal of cytolytic components such as membrane attack complexes, and the transfer of signaling molecules/effectors, such as nucleic acid species, infectious particles, and oncogenes. Among the naturally-derived nanoparticles that have been developed in the last years, stimuli responsive exosomes drew special attention since they intrinsically possess many attributes of a desirable drug delivery system. Their small size allows them to bypass the mononuclear phagocytic system (MPS) clearance, thereby prolonging their circulation time for passive targeting to inflammatory tissues. Moreover, they can deliver their cargo directly into the cytosol, avoiding the lysosomal/endosomal pathway and thus, increasing the transfection efficiency when they are used as gene delivery systems. of This review offers the state of the art knowledge on the physiology and properties of EVs, namely, apoptotic vesicles, microvesicles and exosomes as innovative drug delivery systems for gene therapy, with a special focus on targeting dendritic cells for the treatment of autoimmune disorders.

The role of new zinc incorporated monetite cements on osteogenic differentiation of human mesenchymal stem cells.

ß-Tricalcium phosphate particles were sintered in the presence of different amounts (0-0.72mol) of zinc oxide (ZnO) to prepare zinc doped ß-TCP (Znß-TCP) particles for further use in novel monetite (DCPA: CaHPO4) zinc incorporated bone cements with osteogenic differentiation potential towards human mesenchymal stem cells (hMSCs). XRD analysis of zinc incorporated cements prepared with ß-TCP reagent particles doped with different amount of ZnO (i.e. 0.03, 0.09 and 0.18mol ZnO) revealed the presence of unreacted Znß-TCP and monetite. Furthermore, it was shown that zinc ions preferentially occupied the ß-TCP crystal lattice rather than the monetite one. Release experiments indicated a burst release of ions from the different fabricated cements during the first 24h of immersion with zinc concentrations ranging between 85 and 100% of the total concentration released over a period of 21days. Cell proliferation significantly increased (P<0.05) on zinc incorporated monetite respect to control samples (Zinc-free cement) at 7 and 14days post seeding. The expression of Runx-2 was significantly up regulated (P<0.05) in the case of cells seeded on monetite prepared with ß-TCP doped with 0.03 moles of ZnO. On the other hand, the cell mineralization as well as the expression of osteogenic marker genes ALP and OSC decreased significantly (P<0.05) at 14days post cell seeding. In conclusion, these results suggest that the zinc ions released from the cements during the first 24h of culture played a critical role in regulating the osteogenic differentiation of hMSCs.

Environmental complexity of a port: Evidence from circulation of the water masses, and composition and contamination of bottom sediments.

Ports are complex environments due to their complicated geometry (quays, channels, and piers), the presence of human activities (vessel traffic, shipyards, industries, and discharges), and natural factors (stream and torrent inputs, sea action, and currents). Taking these factors into consideration, we have examined the marine environment of a port from the point of view of the circulation of the water masses, hydrological characteristics, distribution of the sediment grain-size, mineralogical characteristics, and metal concentrations of the bottom sediments. Our results show that, in the case of the Port of Genoa (north-western Italy), the impact of human activities (such as a coal power-plant, oil depots, shipyards, dredging of the bottom sediments, etc.), natural processes (such as currents, fresh water and sediment inputs from the torrents), and the morphology of the basin, are important factors in the sediment, water, and metal distributions that have given rise to a complex environment.