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Objective: To report about the diagnosis, surgical treatment, and postoperative management of pharyngo-esophageal perforations (PEPs) after anterior cervical spine (ACS) surgery in 17 patients., Methods: A retrospective multicenter case series of patients surgically treated for PEP after ACS surgery was performed. Data regarding cervical spine pathology and surgery, comorbidities, diagnosis and surgical management of PEP, airway management, antibiotic therapy, postoperative course, and feeding route after repair surgery at discharge and last follow-up were collected., Results: Seventeen patients were included in the study, for a total of 22 surgical procedures for PEP repair. Seven PEPs (41%) had early onset, whereas 10 (59%) were delayed. All patients underwent PEP surgical repair through an anterior prevascular retrovisceral cervicotomic approach, consisting of multiple layer sutures of the perforation, with flap interposition. Despite the challenging management of these patients, 16 of 17 patients from our series restored oral feeding., Conclusions: PEPs are among the most appalling complications of cervical spine surgery. Because of their rarity and heterogeneous presentation, a standardized management is difficult to define. From our experience with the largest case series in the literature, a multidisciplinary approach is advisable to deal with these patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Population aging is an irreversible global trend with economic and socio-political consequences. One of the most invalidating outcomes of aging in the elderly is cognitive decline, leading to dementia and often related to neurodegenerative disorders. Among these latter, Alzheimer's disease (AD) is the major cause of dementia, affecting more than 30 million of individuals worldwide. To date, the treatment of AD remains a challenge because of an incomplete understanding of the events that lead to the selective neurodegeneration typical of Alzheimer's brains. There is an enormous global demand for new effective therapies and researchers are investigating new fields. One promising strategy is the use of nutraceuticals as integrative, complementary and preventive therapy. Curcumin is one example of natural product with anti-AD properties, with promising potential for prevention, treatment and diagnostic. The limitations in the use of curcumin as therapeutic are represented by its pharmacokinetics profile and the low bioavailability after oral administration. However, curcumin has been the focus of intense research for new drug development. Here we analyzed some new approaches that have been applied in the attempt to improve its use, particularly new formulations, changes in the way of administration, nanotechnology-based delivery systems and the hybridization strategy., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

In this work, we review and comment upon the challenges and the 'quo vadis' in Alzheimer's disease drug discovery at the beginning of the new millennium. We emphasize recent approaches that, moving on from a target-centric approach, have produced innovative molecular probes or drug candidates. In particular, the discovery of endosome-targeted BACE1 inhibitors and mitochondria-targeted antioxidants represents a significant advance in Alzheimer's research and therapy. The case study of the development of rasagiline provides an excellent example to support the validity of the multitarget-designed ligand approach to the search for effective medicines for combating Alzheimer's disease.

Notwithstanding the criticism to the so called " cholinergic hypothesis", the therapeutic strategies for the treatment of Alzheimer's disease (AD) have been mainly centered on the restoration of cholinergic functionality and, until the last year, the only drugs licensed for the management of AD were the acetycholinesterase (AChE) inhibitors. Target enzyme AChE consists of a narrow gorge with two separate ligand binding sites: an acylation site at the bottom of the gorge containing the catalytic triad and a peripheral site located at the gorge rim, which encompasses binding sites for allosteric ligands. The aim of this short review is to update the knowledge on heterocyclic AChE inhibitors able to interact with the two sites of enzymes, structurally related to the well known inhibitors physostigmine, rivastigmine and propidium. The therapeutic potential of the dual site inhibithors in inhibiting amyloid-beta aggregatrion and deposition is also briefly summarised.

Ambenonium (1), an old AChE inhibitor, is endowed with an outstanding affinity and a peculiar mechanism of action that, taken together, make it a very promising pharmacological tool for the treatment of Alzheimer's disease (AD). Unfortunately, the bisquaternary structure of 1 prevents its passage through the blood brain barrier. In a search of centrally active ambenonium derivatives, we planned to synthesize tertiary amines of 1, such as 2 and 3. In addition, to add new insights into the binding mechanism of the inhibitor, we designed constrained analogues of ambenonium by incorporating the diamine functions into cyclic moieties (4-12). The biological evaluation of the new compounds has been assessed in vitro against human AChE and BChE. All tertiary amine derivatives resulted more than 1000-fold less potent than 1 and, unlike prototype, did not show any selectivity between the two enzymes. This result, because of recent findings concerning the role of BChE in AD, makes our compounds, endowed with a well-balanced profile of AChE/BChE inhibition, valuable candidates for further development. To better clarify the interactions that account for the high affinity of 1, docking simulations and molecular dynamics studies on the AChE-1 complex were also carried out.

Several wasp venoms contain philanthotoxins (PhTXs) that act as noncompetitive inhibitors (NCIs) on cation-selective ion channels including the nicotinic acetylcholine receptor (nAChR). In the search for a ligand with high affinity and specificity for the nAChR we tested a series of newly developed PhTX analogues. Modulation of the structural elements of PhTXs can significantly influence their binding affinities. This approach resulted in the development of the photolabile compound MR44. In photoaffinity labelling studies 125I-MR44 was used to map the ligand-binding site at the Torpedo californica nAChR. Upon UV irradiation of the receptor-ligand complex, 125I-MR44 was mainly incorporated into the receptor alpha-subunit. Proteolytic mapping and microsequencing identified the site of 125I-MR44 cross-linking within the sequence alphaHis-186 to alphaLeu-199 that in its C-terminal region partially overlaps with the agonist-binding site. Since bound agonists had only minor influence on 125I-MR44 photocrosslinking, the site where the hydrophobic head group of 125I-MR44 binds must be located outside the zone that is sterically influenced by agonists bound at the nAChR. A possible site of interaction of 125I-MR44 would be the N-terminal region of the labelled sequence, in which aromatic amino-acid residues are accumulated. We suggest that the polyamine moiety of 125I-MR44 interacts with the high affinity non-competitive inhibitor site deep in the ion channel, while the aromatic ring of this compound binds in the vestibule of the nAChR to a hydrophobic region on the alpha-subunit that is located close to the agonist binding site.

The maturational patterns of 'tracé alternant' (TA) and sleep spindles obtained from 16 early detected phenylketonuric (PKU) children during their first months of life were compared with others that were evaluated in recordings taken from 42 controls of the same age group. The TA maturation evolved significantly later in the PKU group than in the control group during the 5th-8th week (the TA score for the PKU group was 64% vs. 10% in the control group, P < 0.001). Afterwards, during the 9th-12th week the score for the PKU group was 27% vs. 0% in the controls (P < 0.002). The sleep spindle evolution score also matured significantly later in the PKU than the control group: the score was 31% in PKU children vs. 85% in controls for the 5th-8th week of age (P < 0.01), and it was 66% vs. 96% for the 9th-12th week (P < 0.02). After the 12th week, TA pattern could not be detected, and spindles reached complete maturation in the PKU children as well. Our results show a consistent delay in the maturation of TA and spindle scores in PKU children. This trend of delay is parallel to the plasma phenylalanine normalization, but not necessarily dependent only on it. In conclusion, we suggest that studies on the critical maturational periods of different sleep components (TA and sleep spindles) might provide a sensitive tool for early diagnosis of neurophysiological brain alterations during the first trimester of life in a population of children "at risk'.