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A new nanodevice based on gold nanoparticles (AuNPs) capped with poly(diethylvinylphosphonate) (PDEVP) has been synthesized, showing interesting photophysical and thermoresponsive properties. The synthesis involves a properly designed Yttriocene catalyst coordinating the vinyl-lutidine (VL) initiator active in diethyl vinyl phosphonate polymerization. The unsaturated PDEVP chain ending was thioacetylated, deacetylated, and reacted with tetrachloroauric acid and sodium borohydride to form PDEVP-VL-capped AuNPs. The NMR, UV-Vis, and ESI-MS characterization of the metal nanoparticles confirmed the formation of the synthetic intermediates and the expected colloidal systems. AuNPs of subnanometric size were determined by WAXD and UV-Vis analysis. UV-Vis and fluorescence analysis confirmed the effective anchoring of the thiolated PDEVP to AuNPs. The formation of 50-200 nm globular structures was assessed by SEM and AFM microscopy in solid state and confirmed by DLS in aqueous dispersion. Hydrodynamic radius studies showed colloidal contraction with temperature, demonstrating thermoresponsive behavior. These properties suggest potential biomedical applications for the photoablation of malignant cells or controlled drug delivery induced by light or heat for the novel PDEVP-capped AuNP systems.

The increase of knowledge on the composition of donkey milk has revealed marked similarities to human milk, which led to a growing number of investigations focused on testing the potential effects of donkey milk in vitro and in vivo. This paper examines the scientific evidence regarding the beneficial effects of donkey milk on human health. Most clinical studies report a tolerability of donkey milk in 82.6-98.5% of infants with cow milk protein allergies. The average protein content of donkey milk is about 18 g/L. Caseins, which are main allergenic components of milk, are less represented compared to cow milk (56% of the total protein in donkey vs. 80% in cow milk). Donkey milk is well accepted by children due to its high concentration of lactose (about 60 g/L). Immunomodulatory properties have been reported in one study in humans and in several animal models. Donkey milk also seems to modulate the intestinal microbiota, enhance antioxidant defense mechanisms and detoxifying enzymes activities, reduce hyperglycemia and normalize dyslipidemia. Donkey milk has lower calorie and fat content compared with other milks used in human nutrition (fat ranges from 0.20% to 1.7%) and a more favourable fatty acid profile, being low in saturated fatty acids (3.02 g/L) and high in alpha-linolenic acid (about 7.25 g/100 g of fat). Until now, the beneficial properties of donkey milk have been mostly related to whey proteins, among which β-lactoglobulin is the most represented (6.06 g/L), followed by α-lactalbumin (about 2 g/L) and lysozyme (1.07 g/L). So far, the health functionality of donkey milk has been tested almost exclusively on animal models. Furthermore, in vitro studies have described inhibitory action against bacteria, viruses, and fungi. From the literature review emerges the need for new randomized clinical trials on humans to provide stronger evidence of the potential beneficial health effects of donkey milk, which could lead to new applications as an adjuvant in the treatment of cardiometabolic diseases, malnutrition, and aging.

Theranostics based on two-photon excitation of therapeutics in the NIR region is an emerging and powerful tool in cancer therapy since this radiation deeply penetrates healthy biological tissues and produces selective cell death. Aggregates of gold nanoparticles coated with glutathione corona functionalized with the dansyl chromophore (a-DG-AuNPs) were synthesized and found efficient nanodevice for applications in photothermal therapy (PTT). Actually the nanoparticle aggregation enhances the quenching of radiative excitation and the consequent conversion into heat. The a-DG-AuNPs are readily internalized in Hep G2 where the chromophore acts as both antenna and transducer of the NIR radiation under two-photons excitation, determining efficient cell ablation via photothermal effect.

We report the synthesis of a series of Zr and Ti complexes bearing phosphasalen which differs from salen by the incorporation of two P atoms in the ligand backbone. The reaction of phosphasalen proligands (1a-1c)H 2 with Zr(CH 2 Ph) 4 led to different products depending on the nature of the N,N-linker in the ligand. In the case of ethylene-linked phosphasalen, octahedral Zr complex 2a formed as a single stereoisomer in trans geometry. With the phenylene linker, it was shown by dynamic NMR spectroscopy that complex 2b exists as a mixture of trans and cis-β isomers in solution, both enantiomers (Δ and Λ) of the cis-β isomer being in fast equilibrium with respect to the NMR time-scale. The use of a propylene-linked phosphasalen proligand 1cH 2 led to a mixture of complexes among which a binuclear Zr complex 2c bridged only by one phosphasalen ligand could be isolated and characterized. Addition of 2 equiv. of i PrOH to 2a and 2b afforded diisoproxy Zr complexes 3a and 3b as a mixture of trans and cis-β isomers, the latter undergoing fast Δ/Λ isomerization in solution. Addition of B(C 6 F 5 ) 3 to 2a and 2b gave cationic monobenzyl Zr complexes 4a and 4b which have been further converted into cationic alkoxy Zr complexes 5a-b and 6a-b by alcoholysis with i PrOH and (S)-methyl-lactate, respectively. The reaction of the phosphasalen proligands with Ti(NMe 2 ) 4 proceeded diastereoselectively giving rise to Ti complexes 7a-c in octahedral geometry with cis-β wrapping of the ligand. The complexes have been tested for the ROP of rac-lactide. The neutral phosphasalen Ti and Zr complexes showed only poor activity probably due to the encumbered and electron donating nature of the phosphasalen ligand. In contrast, the cationic Zr alkoxides 5a, 6a and 6b are effective initiators for the controlled and hetero-selective ROP of rac-lactide.

The reactivity of Zn II dialkyl species ZnMe 2 with a cyclic(alkyl)(amino)carbene, 1-[2,6-bis(1-methylethyl)phenyl]-3,3,5,5-tetramethyl-2-pyrrolidinylidene (CAAC, 1), was studied and extended to the preparation of robust CAAC-supported Zn II Lewis acidic organocations. CAAC adduct of ZnMe 2 (2), formed from a 1:1 mixture of 1 and ZnMe 2 , is unstable at room temperature and readily undergoes a CAAC carbene insertion into the Zn-Me bond to produce the ZnX 2 -type species (CAAC-Me)ZnMe (3), a reactivity further supported by DFT calculations. Despite its limited stability, adduct 2 was cleanly ionized to robust two-coordinate (CAAC)ZnMe + cation (5 + ) and derived into (CAAC)ZnC 6 F 5 + (7 + ), both isolated as B(C 6 F 5 ) 4 - salts, showing the ability of CAAC for the stabilization of reactive [ZnMe] + and [ZnC 6 F 5 ] + moieties. Due to the lability of the CAAC-ZnMe 2 bond, the formation of bis(CAAC) adduct (CAAC) 2 ZnMe + cation (6 + ) was also observed and the corresponding salt [6][B(C 6 F 5 ) 4 ] was structurally characterized. As estimated from experimental and calculations data, cations 5 + and 7 + are highly Lewis acidic species and the stronger Lewis acid 7 + effectively mediates alkene, alkyne and CO 2 hydrosilylation catalysis. All supporting data hints at Lewis acid type activation-functionalization processes. Despite a lower energy LUMO in 5 + and 7 + , their observed reactivity is comparable to those of N-heterocyclic carbene (NHC) analogues, in line with charge-controlled reactions for carbene-stabilized Zn II organocations., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Self-expandable metal stents (SEMSs) are frequently used in the setting of palliation for occluding, inoperable colorectal cancer (CRC). Among possible complications of SEMS positioning, re-obstruction is the most frequent. Its management is controversial, potentially involving secondary stent-in-stent placement, which has been poorly investigated. Moreover, the issue of secondary stent-in-stent re-obstruction and of more-than-two colonic stenting has never been assessed. We describe a case of tertiary SEMS-in-SEMS placement, and also discuss our practice based on available literature., Case Summary: A 66-year-old male with occluding and metastatic CRC was initially treated by positioning of a SEMS, which had to be revised 6 mo later when a symptomatic intra-stent tumor ingrowth was treated by a SEMS-in-SEMS. We hereby describe an additional episode of intestinal occlusion due to recurrence of intra-stent tumor ingrowth. This patient, despite several negative prognostic factors (splenic flexure location of the tumor, carcinomatosis with ascites, subsequent chemotherapy that included bevacizumab and two previously positioned stents (1 SEMS and 1 SEMS-in-SEMS)) underwent successful management through the placement of a tertiary SEMS-in-SEMS, with immediate clinical benefit and no procedure-related adverse events after 150 d of post-procedural follow-up. This endoscopic management has permitted 27 mo of partial control of a metastatic disease without the need for chemotherapy discontinuation and, ultimately, a good quality of life until death., Conclusion: Tertiary SEMS-in-SEMS is technically feasible, and appears to be a safe and effective option in the case of recurrent SEMS obstruction., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflicts of interest.

The dichloro titanium complexes (OSSO t Bu )TiCl 2 ( 1 ) and (OSSO Cum )TiCl 2 ( 2 ) bearing o -phenylene-bridged OSSO-type ligands [OSSO t Bu -H = 6,6'-((1,2-phenylenebis(sulfanediyl))bis(methylene))bis(2,4-di- tert -butyphenol) and OSSO Cum -H = 6,6'-((1,2-phenylenebis(sulfanediyl))bis(methylene))bis(2,4-bis(2-phenylpropan-2-yl)phenol)] were prepared and characterized. The X-ray structure of 1 revealed that Ti atom has an octahedral coordination geometry with an fac - fac wrapping of the [OSSO] ligand. In solution at 25 °C, 1 mainly retains the C 2 symmetric structure, whereas 2 shows an equilibrium between C 2 - and C 1 -symmetric stereoisomers. Activation of 2 with (Ph 3 C)[B(C 6 F 5 ) 4 ] led to a highly active catalytic system with an activity of 238 kg PE ·mol cat -1 ·bar -1 ·h -1 ; linear polyethylene with a T m of 122 °C and M w of 107 kDa were obtained under these conditions. Catalyst 1 displayed the moderate activity of 59 kg PE ·mol cat -1 ·bar -1 ·h -1 . Gel permeation chromatography analysis revealed the formation of high-molecular-weight polyethylenes with very large distributions of the molecular weights, indicating a low control of the polymerization process, probably becaue of the presence of different active species in solution. Density functional theory investigation provides a rational for the relative high-molecular-weight polymers obtained with these complexes. The precatalyst 2 was also active in propylene polymerization producing atactic oligomers terminated with unsaturated end groups., Competing Interests: The authors declare no competing financial interest.

High-fat diet (HFD) and metabolic diseases cause detrimental effects on hippocampal synaptic plasticity, learning, and memory through molecular mechanisms still poorly understood. Here, we demonstrate that HFD increases palmitic acid deposition in the hippocampus and induces hippocampal insulin resistance leading to FoxO3a-mediated overexpression of the palmitoyltransferase zDHHC3. The excess of palmitic acid along with higher zDHHC3 levels causes hyper-palmitoylation of AMPA glutamate receptor subunit GluA1, hindering its activity-dependent trafficking to the plasma membrane. Accordingly, AMPAR current amplitudes and, more importantly, their potentiation underlying synaptic plasticity were inhibited, as well as hippocampal-dependent memory. Hippocampus-specific silencing of Zdhhc3 and, interestingly enough, intranasal injection of the palmitoyltransferase inhibitor, 2-bromopalmitate, counteract GluA1 hyper-palmitoylation and restore synaptic plasticity and memory in HFD mice. Our data reveal a key role of FoxO3a/Zdhhc3/GluA1 axis in the HFD-dependent impairment of cognitive function and identify a novel mechanism underlying the cross talk between metabolic and cognitive disorders.

The synthesis and characterization of a series of group 4 metal complexes of general formula {OSSO X }M(OR) 2 (X = R = t Bu, M = Zr (1); X = cumyl, M = Zr, R = t Bu (2); X = cumyl, M = Ti, R = i Pr (4); X = cumyl, M = Hf, R = t Bu (5)) and {OSSO X } 2 Zr (X = Cl (3)) supported by o-phenylene-bridged bis(phenolato) ligands (OSSO tBu -H = 6,6'-((1,2-phenylenebis(sulfanediyl))bis(methylene))bis(2,4-di-tert-butyphenol); OSSO Cum -H = 6,6'-((1,2-phenylenebis(sulfanediyl))bis(methylene))bis(2,4-bis(2-phenylpropan-2-yl)phenol); OSSO Cl -H = 6,6'-((1,2-phenylenebis(sulfanediyl))bis(methylene))bis(2,4-dichlorophenol)) are described herein. Complexes 1-5 were readily obtained by σ-bond metathesis reactions between the proligand and the appropriate homoleptic metal precursor. The reaction with OSSO Cl yielded the bis-ligand complex{OSSO Cl } 2 Zr (3) regardless of the OSSO Cl -H/Zr(O t Bu) 4 molar ratio or experimental conditions. All complexes were characterized in solution using NMR spectroscopy and, in the case of 2, by single-crystal X-ray diffraction experiments. These complexes show a fac-fac ligand wrapping and a cis relationship between the other two monodentate ligands; zirconium and hafnium complexes 1-3 and 5 are configurationally stable, whereas titanium complex 4 is fluxional in solution at room temperature. The complexes tested in the ring-opening polymerization (ROP) of racemic-lactide showed, except in the case of 3, moderate rates and good levels of polymerization control. Upon addition of an exogenous alcohol (isopropyl alcohol or tert-butyl alcohol) efficient binary catalytic systems were achieved. Polymerizations were well-controlled, as testified by the linear growth of the molecular weight as polymerization proceeded, narrow polydispersity indices, and molecular weights close to those expected on the basis of added alcohol amounts. Experimental and theoretical evidence is provided that ROP reactions operate according to an activated monomer mechanism.

Background: Esophagojejunal anastomosis leakage after total gastrectomy (TG) for esophagogastric junction (EGJ) adenocarcinoma (ADC) constitutes one of the most serious and sometimes life-threatening complications. Management remains controversial and still challenging., Methods: A total of 198 patients operated for type I and II EGJ ADC were reviewed. Diagnosis of leakage was based on a combination of clinical and radiological findings. It was classified including objective endoscopic and clinical parameters requiring different type of treatment., Results: Anastomotic leakage was diagnosed in 14 patients (7%). Two cases recovered with conservative therapy. Six cases underwent endoscopy with clips placement in 2 and partially covered self-expandable metal stent placement in 4. Other two cases underwent reoperation with reconstruction of anastomosis and primary repair respectively. In the last four cases emergency surgery with total esophagectomy and diversion was required. Mortality occurred only in 3 of these patients and overall treatment was successful in 11 patients (78.5%)., Conclusions: No consensus has been reached on the best method of esophagojejunal anastomosis leakage management and the rate of failure remains significant. Different options of treatment are available but early detection and multidisciplinary approaches are the keys to obtain successful results irrespective of the employed strategy.

Background: Although much has been written on the implications of friction generated between orthodontic archwires and labial brackets, information on lingual brackets is still limited. Hence, we set out to investigate the frictional resistance exerted by different lingual and labial brackets, including both conventional and self-ligating designs. The effect of various factors, namely bracket/base width, slot size, inter-bracket distance, and first- (ΘcI) and second-order (ΘcII) critical contact angles were evaluated and compared., Methods: A plaster model of a pretreatment oral cavity was replicated to provide 18 (9 upper and 9 lower) identical versions. The anterior segments of each were taken, and the canine and lateral and central incisors were mounted with either lingual (7th Generation, STb, New STb, In-Ovation L, ORJ) or labial (Mini-Mono, Mini Diamond, G&H Ceramic) brackets. Mechanical friction tests were performed on each type of bracket using a universal testing machine. The maximum force necessary to displace NiTi wires of two different diameters (0.012, 0.014) was measured, using both elastic and metal ligatures with conventional brackets., Results: The frictional force necessary to displace the wires increased as the diameter of the wire increased in all tested brackets (p<0.01). Friction was significantly higher (p<0.001) with elastic ligatures, as compared with metal ones, in all conventional brackets. In the lower lingual group, significantly lower friction was generated at conventional lingual New STb brackets (p<0.01) and ORJ lingual brackets (p<0.05) than at self-ligating In-Ovation L lingual brackets. A significant statistical correlation between (ΘcI) and friction was detected in the lower labial bracket group., Conclusions: Friction resistance is influenced not only by the bracket type, type of ligation, and wire diameter but also by geometric differences in the brackets themselves.

Background: Neoplastic gastroduodenal inoperable stenosis require a palliative treatment to restore alimentary transit., Objective: Our purpose was to treat neoplastic gastroduodenal stenosis with self-expanding enteral stents., Material of Study: An endoscopic treatment with uncovered self-expanding metal stents has been performed in 45 patients: 37 duodenal stenosis (34 pancreatic neoplasia, 1 gallbladder neoplasia, 2 peritoneal carcinosis), 5 anthropyloric neoplastic stenosis and 3 gastro-jejunal anastomosis stenosis were treated. A total of 47 metal stent were positioned: in 43 patient 1 stent; in 2 patient, with a long stenosis, 2 stents., Main Outcome Measurement: Efficacy of endoscopic treatment to restore alimentary transit., Results: The positioning was successfull in all cases without any complication. All patients had a rapid and satisfying recovery from symptoms connected to the obstruction. The hospitalization period was averagely 3 days (range 1-7). In one patient another stent was inserted 2 months later because of tunoral ingrowth. The median survival period was 4 months (range 1-5). In one patient with duodenal stenosis due to pancreatic neoplasia,in which were inserted 2 stents, distal one dislocated in the jejunum 3 months later. It was removed by surgery., Conclusions: The endoscopic stenting is a valid treatment of inoperable gastric duodenal stenosis and may become the preferable option for the palliative treatment of this pathology., Key Words: Endoscopy, Gastroduodenal, Neoplasia, Obstruction, Stent.

Aim: To compare the adhesive potential, the mechanics implicated in adhesive failure, and the effect on the enamel of four brands of lingual brackets., Methods: One hundred sixty premolars and four types of commercially available lingual brackets (STB, ORG, Magic, and Stealth) were selected. Forty brackets per manufacturer were used, half bonded directly and half indirectly. Each of these bonding groups was further subdivided: 10 brackets were bonded without treatment, while the other 10 were sandblasted. Thus, a total of four groups were created for each type of bracket: (a) sandblasted and directly bonded, (b) sandblasted and indirectly bonded, (c) not sandblasted and directly bonded, and (d) not sandblasted and indirectly bonded. Immediately after bonding, each bracket was tested for adhesion strength, and each appliance was then examined via electron microscopy to calculate the ARI., Results: Statistical analysis showed a significant difference among the four bracket types; a general improvement in lingual appliance mechanical features provoked by sandblasting, albeit with some exceptions; and no significant effect of bonding method on the degree of bond strength. The ARI revealed that the most common area of adhesion crisis was at the adhesive-bracket interface., Conclusion: Overall, STB brackets performed better, and sandblasting proved to be an efficient way of improving the mechanical features of lingual brackets. Bonding technique, on the other hand, did not seem to exert a great influence on bonding success, and the bracket-adhesive interface was identified as the area most prone to failure.

In malignant dysphagia expandable metal stents are commonly used as palliative treatment, but early and late complications and the improvement of dysphagia have not been well described. This report summarizes our experience with expandable metal stents for malignant dysphagia. From 1995 to 2000, we placed 38 metal stents in 36 patients with malignant dysphagia from unresectable esophageal cancer (94.4%). Dysphagia scores, complications and modality of reintervention were evaluated. Dysphagia scores decreased from 3.2 before the stent placement to 2. Immediate complications occured in one patient because of severe pain, it was not possible to perform endoscopic treatments. Other complications included tracheoesophageal fistula (2 patients), tumor overgrowth (5 patients), new stent placements (2 patients), dislocation (2 patients). In conclusions expandable metal stents are safe and effective in the treatment of malignant dysphagia.

Purpose: Patients resected for colorectal cancer are at increased risk for an anastomotic recurrence, for adenomatous polyps and for a metachronous cancer. A regular colonoscopic surveillance in these patients is justified for early detection and potential resection of anastomotic recurrences, new primary cancer and adenomatous polyps., Patients and Methods: 322 patients were observed and resected for colorectal cancer between 1970 and 1988, with complete staging agreed to be included in a follow-up program (median follow-up: 105 months). To December 1993 all the patients were submitted to colonoscopy once yearly for the first 5 years and then every 2 years., Results: Anastomotic recurrence was observed in 22 of the 253 patients who underwent resection for rectal or sigmoid adenocarcinoma (8.7%). Sixteen of these patients were submitted to a second curative resection with a median survival of 35 months; the median survival was 6 months in the 6 patients who could not undergo this operation (p = 0.0018). Metachronous adenomas of the residual colon were found in 24 patients (7.4%) and metachronous cancers in 5 (1.5%) at Stage A, according to Dukes' classification., Conclusions: In patients resected for rectal or sigmoid carcinoma, a sigmoidoscopy should be performed every 6 months for the first 2 years for the early detection of anastomotic recurrences. In all cases, a colonoscopy should be performed every 5 years after surgery to detect metachronous lesions at early stage. Before surgery, a "clean colon" should always be established to detect possible synchronous lesions.

Background: An increasing amount of evidence suggests that progression from normal mucosa to colorectal cancer is accompanied by morphological and genetic alterations. Genetic abnormalities affect malignant transformation via a gradual imbalance of normal tissue homeostasis involving programmed cell death (PCD) or apoptosis. Therefore, it has been hypothesized that alterations in apoptosis may contribute to carcinogenesis. The aim of the present work was to investigate the relationship between frequency of spontaneous apoptosis during transition adenoma-to-carcinoma of the colorectal tract and the incidence of activation of c-myc and c-myb proto-oncogenes, involved both in colon tumorigenesis and apoptosis., Materials and Methods: Ninety-five tissue specimens (60 polyps and 35 adenocarcinomas) were removed with autologous normal adjacent mucosa from colon cancer patients. Genomic DNA was extracted and analyzed for both apoptosis frequency (DNA fragmentation assay) and proto-oncogene activation (Southern blot analysis). On the same samples, Bcl-2 protein expression was evaluated by immunohistochemistry., Results: Our results showed that: i) a significant relationship exists between apoptosis and genesis of colorectal cancer since, compared to adenomatous polyps and adjacent normal mucosa, cell death is markedly inhibited in tumors (p = 0.01); ii) during colon tumor progression, apoptosis and amplifications of c-myc/c-myb genes are inversely related; iii) Bcl-2 expression is retained in colon tumors even though at a significantly lower level with respect to adenomatous polyps., Conclusion: These results indicate that failure of the normal apoptotic process together with de-regulation of c-myc and c-myb proto-oncogenes might promote the development of colorectal tumors.

Patients resected for colorectal cancer are at risk for anastomotic recurrence, for adenomatous polyps and for metachronous cancer. The present retrospective study was conducted to evaluate the incidence of neoplasms of the colon, both metachronous or recurrent, in 322 patients. They were observed and resected for colorectal cancer between 1970 and 1988, with complete staging, and all agreed to be included in a follow-up program (median followup: 105 months). All the patients were submitted to colonoscopy once yearly for the first 5 years and then every 2 years. Anastomotic recurrence was observed in 22 of the 253 patients who underwent resection for rectal or sigmoid adenocarcinoma (8.7%). Sixteen of these patients were submitted to a second curative resection with a median survival of 35 months; the median survival was 6 months in the 6 patients who could not undergo this operation (p=0.0018). Metachronous adenomas of the residual colon were found in 24 patients and metachronous cancers in 5 at Stage A, according to Dukes' classification. In conclusion, a regular colonoscopic surveillance in patients resected for colorectal cancer is justified for early detection and potential resection of anastomotic recurrences, new primary cancer and adenomatous polyps. In patients resected for rectal or sigmoid carcinoma, a sigmoidoscopy should be performed every 6 months for the first 2 years for the early detection of anastomotic recurrences. In all cases, a colonoscopy should be performed every 5 years after surgery to detect metachronous lesions. Before surgery, a "clean colon" should always be established to detect possible synchronous lesions.