SAS CARE 1: Sleep architecture changes in a cohort of patients with Ischemic Stroke/TIA.

OBJECTIVE: Changes in sleep architecture following ischemic stroke have been poorly investigated. Our objective was to explore changes of sleep structure in patients with ischemic stroke or transient ischemic attack in order to verify a possible predictive value of sleep with respect to clinical outcome. METHODS: Patients recruited in the prospective SAS-CARE study received two polysomnographies (PSG) in the acute and chronic phases after stroke/TIA. Sleep parameters were compared between the two time-points and matched with a non-stroke population randomly selected from the HypnoLaus cohort. RESULTS: Of the 169 patients investigated with PSG in the acute phase, 104 were again studied 3 months after stroke symptom onset and compared with 162 controls. The acute phase of stroke/TIA was associated with sleep disruption, which significantly improved in the chronic phase, but remained worse than controls (total sleep time improve from 318.8 ± 90.8 to 348.4 ± 81.5 min, compared to 388.2 ± 71.3 in controls, sleep latency from 49.9 ± 58.4 to 27.9 min, compared to 20.2 ± 22 in controls, sleep efficiency from 58.2 ± 18.1% to 27.9 ± 36.4 min, compared to 83.4 ± 10.3% in controls, wakefulness after sleep onset percentage from 36.5 ± 17.3 to 29.3 ± 15.6, compared to 13.2 ± 9.2 in controls). The percentage of REM sleep was negatively associated with stroke severity, whereas stroke topography did not correlate with sleep parameters. CONCLUSIONS: This study confirmed a severe sleep disruption in the acute phase of stroke. Although a significant improvement of sleep quality was observed during the three months after stroke, sleep architecture did not normalize. In particular, sleep efficiency and REM sleep seem to be particularly affected by stroke in the acute phase, with a relative preservation of NREM sleep. We suggest that these sleep architecture changes represent a persistent marker of brain damage due to stroke. Further studies are needed to assess the relationship with stroke topographic and outcome.

Sleep/wake rhythm modifications in the Italian population during SARS-CoV2 pandemic: a web-based cross-sectional survey.

OBJECTIVE: The study aims to investigate in a representative sample of the Italian population whether the SARS-CoV2 pandemic and the subsequent home isolation had repercussion on the daily sleep/wake cycling and habits. MATERIALS AND METHODS: A web-based cross-sectional survey consisted of various multiple-choice questions concerning demographic characteristics, sleep habits, and sleep-related problems was broadcast through mainstream social-media. Individuals were randomly allowed to participate from April 29th to May 17th, namely 50 days after the lockdown imposition and the day before its abrogation. RESULTS: 58.84% of respondents experienced a change in their sleep habits. 71% of those whose sleep changed showed a delayed sleep pattern. Overall, a two-fold risk of delayed sleep pattern without any change in total sleep time emerged during the investigation period. Females emerged almost 2 times more likely to modify their sleep habits than males. Youths were also more likely to experience modifications than old people, who conversely appeared protected. A significant improvement in daytime sleepiness occurred during the home isolation which additionally correlated with delayed bedtime and less sleep time. CONCLUSIONS: A high rate of change in sleep habits, especially among youths and females, occurred in Italian population during the home isolation to limit the SARS-CoV2 pandemic. Moreover, self-reported daytime sleepiness decreased in severity.

SAS CARE 2 - a randomized study of CPAP in patients with obstructive sleep disordered breathing following ischemic stroke or transient ischemic attack.

OBJECTIVE/BACKGROUND: The benefit of Continuous Positive Airway Pressure (CPAP) treatment following ischemic stroke in patients with obstructive sleep-disordered breathing (SDB) is unclear. We set out to investigate this open question in a randomized controlled trial as part of the SAS-CARE study. PATIENTS/METHODS: Non-sleepy patients (ESS < 10) with ischemic stroke or transient ischemic attack (TIA) and obstructive SDB (AHI ≥ 20) 3 months post-stroke were randomized 1:1 to CPAP treatment (CPAP+) or standard care. Primary outcome was the occurrence of vascular events (TIA/stroke, myocardial infarction/revascularization, hospitalization for heart failure or unstable angina) or death within 24 months post-stroke. Secondary outcomes included Modified Rankin Scale (mRS) and Barthel Index. RESULTS: Among 238 SAS-CARE patients 41 (17%) non-sleepy obstructive SDB patients were randomized to CPAP (n = 19) or standard care (n = 22). Most patients (80%) had stroke and were males (78%), mean age was 64 ± 7 years and mean NIHSS score 0.6 ± 1.0 (range: 0-5). The primary endpoint was met by one patient in the standard care arm (a new stroke). In an intent-to treat analysis disregarding adherence, this corresponds to an absolute risk difference of 4.5% or an NNT = 22. mRS and Barthel Index were stable and similar between arms. CPAP adherence was sufficient in 60% of evaluable patients at month 24. CONCLUSION: No benefit of CPAP started three months post-stroke was found in terms of new cardio- and cerebrovascular events over 2 years. This may be related to the small size of this study, the mild stoke severity, the exclusion of sleepy patients, the delayed start of treatment, and the overall low event rate.

Novel drug delivery systems for natural extracts: The case study of Vitis Vinifera extract-SiO2 nanocomposites.

Ball Milling technique has been used to prepare for the first time Vitis Vinifera extract-silica nanocomposites (VV-SiO2 NCs), which combine the pharmacological effects of the extract with the effectiveness of silica as drug delivery system and active component in the treatment of wound healing. Different contents (1.0, 9.0 and 33.0 wt%) of Vitis Vinifera ethanolic extract were loaded into the silica matrix by grinding the extract with fumed silica using a planetary mill apparatus. The effect of the starting mixture composition and milling time on the final products was examined. The efficiency of the milling process was studied by X-ray Powder Diffraction, Nuclear Magnetic Resonance, and Infrared Spectroscopy, indicating that the natural extract was not affected by the increasing of the milling time. The successful loading of the extract was demonstrated by Nitrogen adsorption/desorption measurements, which showed a decrease in the SSA and pore volume of the silica with the increasing of the extract amount. Morphology of the nanocomposites, investigated by Scanning Electron Microscopy, showed an increased agglomeration in the nanocomposites with the increment of the VV extract amount. Studies on the total phenol quantification and antioxidant activity of the natural extract before and after incorporation in the silica matrix were also carried out. The obtained results indicate that the milling process does not alter the VV extract components, which result to be embedded in the silica matrix. An increase of the antioxidant activity with the increment of the extract amount in the nanocomposites, up to values comparable to the pure VV extract, was also observed.

Morphometric traits of gizzard in relation to feeding habits of wild Sardinian partridges (Alectoris barbara barbara, Bonnaterre, 1790) with particular regard to clast selection.

Housing and feeding practices of wild birds for conservation management of biodiversity or restocking play a crucial role in determining the survival rates of animals when released into nature. Failure in coping with the environment might be one of the main flaws captive animals can experience when put into natural habitat. The present investigation aimed at exploring feeding habits and related morphometric traits of gizzard with respective content from wild partridges in comparison with captive ones. A total of 52 hunted wild Sardinian adult partridges (Alectoris barbara barbara Bonnaterre, 1790) were used. By comparison, 42 captive adult partridges reared in cages were enrolled. From each animal, the morphology of gizzard was investigated and respective content analysed for gross composition and taxonomical determination of fractions. Wet sieving analysis of each gizzard content was carried out (four-sieve towers with different mesh sizes: 1 mm, 500 µm, 250 µm and 125 µm), and relative and absolute weight of fresh filled and empty gizzards were recorded. Thickness of muscular layer of gizzard wall was measured by stereomicroscope. Carcass weight significantly (p < 0.05) differed between captive vs. wild partridges (478 ± 21 and 305 ± 35 g respectively). Post-mortem inspection highlighted gross morphological differences of gizzards between the two groups. Fresh weight of empty gizzards was 6.37 ± 0.80 vs. 11.25 ± 1.82 g, with average pH values of digesta 4.97 ± 0.11 vs. 4.38 ± 0.28 in captive vs. wild partridges respectively. Gizzard content from wild partridges accounted a 61.7% vs. 38.3% of biological vs. non-biological material proportions (DM basis). The non-biological material was mostly represented by lithic fragments and minerals (quartz, feldspar, calcite and mica) with specific peculiarities in terms of granulometry and morphometry. Feeding the captive partridges should point to support morphological and functional adaptation of gizzards to the feeding stuffs naturally available in the environment.

World Association of Sleep Medicine (WASM) 2016 standards for recording and scoring leg movements in polysomnograms developed by a joint task force from the International and the European Restless Legs Syndrome Study Groups (IRLSSG and EURLSSG).

This report presents the results of the work by a joint task force of the International and European Restless Legs Syndrome Study Groups and World Association of Sleep Medicine that revised and updated the current standards for recording and scoring leg movements (LM) in polysomnographic recordings (PSG). First, the background of the decisions made and the explanations of the new rules are reported and then specific standard rules are presented for recording, detecting, scoring and reporting LM activity in PSG. Each standard rule has been classified with a level of evidence. At the end of the paper, Appendix 1 provides algorithms to aid implementation of these new standards in software tools. There are two main changes introduced by these new rules: 1) Candidate LM (CLM), are any monolateral LM 0.5-10 s long or bilateral LM 0.5-15 s long; 2) periodic LM (PLM) are now defined by runs of at least four consecutive CLM with an intermovement interval ≥10 and ≤ 90 s without any CLM preceded by an interval <10 s interrupting the PLM series. There are also new options defining CLM associated with respiratory events. The PLM rate may now first be determined for all CLM not excluding any related to respiration (providing a consistent number across studies regardless of the rules used to define association with respiration) and, subsequently, the PLM rate should also be calculated without considering the respiratory related events. Finally, special considerations for pediatric studies are provided. The expert visual scoringof LM has only been altered by the new standards to require accepting all LM > 0.5 s regardless of duration, otherwise the technician scores the LM as for the old standards. There is a new criterion for the morphology of LM that applies only to computerized LM detection to better match expert visual detection. Available automatic scoring programs will incorporate all the new rules so that the new standards should reduce technician burden for scoring PLMS.

Development of curcumin loaded sodium hyaluronate immobilized vesicles (hyalurosomes) and their potential on skin inflammation and wound restoring.

In the present work new highly biocompatible nanovesicles were developed using polyanion sodium hyaluronate to form polymer immobilized vesicles, so called hyalurosomes. Curcumin, at high concentration was loaded into hyalurosomes and physico-chemical properties and in vitro/in vivo performances of the formulations were compared to those of liposomes having the same lipid and drug content. Vesicles were prepared by direct addition of dispersion containing the polysaccharide sodium hyaluronate and the polyphenol curcumin to a commercial mixture of soy phospholipids, thus avoiding the use of organic solvents. An extensive study was carried out on the physico-chemical features and properties of curcumin-loaded hyalurosomes and liposomes. Cryogenic transmission electron microscopy and small-angle X-ray scattering showed that vesicles were spherical, uni- or oligolamellar and small in size (112-220 nm). The in vitro percutaneous curcumin delivery studies on intact skin showed an improved ability of hyalurosomes to favour a fast drug deposition in the whole skin. Hyalurosomes as well as liposomes were biocompatible, protected in vitro human keratinocytes from oxidative stress damages and promoted tissue remodelling through cellular proliferation and migration. Moreover, in vivo tests underlined a good effectiveness of curcumin-loaded hyalurosomes to counteract 12-O-tetradecanoilphorbol (TPA)-produced inflammation and injuries, diminishing oedema formation, myeloperoxydase activity and providing an extensive skin reepithelization. Thanks to the one-step and environmentally-friendly preparation method, component biocompatibility and safety, good in vitro and in vivo performances, the hyalurosomes appear as promising nanocarriers for cosmetic and pharmaceutical applications.

Neurology and psychiatry: waking up to opportunities of sleep. : State of the art and clinical/research priorities for the next decade.

In recent years, evidence has emerged for a bidirectional relationship between sleep and neurological and psychiatric disorders. First, sleep-wake disorders (SWDs) are very common and may be the first/main manifestation of underlying neurological and psychiatric disorders. Secondly, SWDs may represent an independent risk factor for neuropsychiatric morbidities. Thirdly, sleep-wake function (SWF) may influence the course and outcome of neurological and psychiatric disorders. This review summarizes the most important research and clinical findings in the fields of neuropsychiatric sleep and circadian research and medicine, and discusses the promise they bear for the next decade. The findings herein summarize discussions conducted in a workshop with 26 European experts in these fields, and formulate specific future priorities for clinical practice and translational research. More generally, the conclusion emerging from this workshop is the recognition of a tremendous opportunity offered by our knowledge of SWF and SWDs that has unfortunately not yet entered as an important key factor in clinical practice, particularly in Europe. Strengthening pre-graduate and postgraduate teaching, creating academic multidisciplinary sleep-wake centres and simplifying diagnostic approaches of SWDs coupled with targeted treatment strategies yield enormous clinical benefits for these diseases.

High-density electroencephalography as an innovative tool to explore sleep physiology and sleep related disorders.

High density EEG represents a promising tool to achieve new insights regarding sleep physiology and pathology. It combines the advantages of an EEG technique as an optimal temporal resolution with the spatial resolution of the neuroimaging. So far its application in sleep research contributed to better characterize some of the peculiar microstructural figures of sleep such as spindles and K-complexes, and to understand the fundamental relationships between sleep and synaptic plasticity, learning and consciousness. Its application is not limited to neurophysiology, being recently also applied to study some sleep related psychiatric and neurological disorders such as depression, schizophrenia, attention-deficit hyperactivity disorder, and stroke. adding some interesting new pieces in the pathophysiological puzzle of these diseases. Due to its non-invasive, repetitive and reliable tempo-spatial resolution it is reasonable that the field of application of this tool will be soon enlarged to other areas of neuroscience. The present review aims to offer a complete overview regarding the use of high density EEG over the last decade in sleep research and sleep medicine, including its possible future perspective.

Penetration enhancer-containing vesicles: composition dependence of structural features and skin penetration ability.

In this work, we focused on how composition and preparation method of vesicles might affect their morphological features and delivery performances. Penetration Enhancer-containing Vesicles, PEVs, vesicles containing a water miscible penetration enhancer (Transcutol® P; 10%, 20%, 30% v/v) and encapsulating diclofenac sodium, were formulated and compared with conventional liposomes. A cheap and unpurified commercial mixture of phospholipids, fatty acids, and triglycerides (Phospholipon® 50) was used, and the effects of this heterogeneous composition (along with the presence or absence of transcutol and the production method) on vesicle morphology, size, surface charge, drug loading, and stability were investigated. The variations in vesicle structure, bilayer thickness, and number of lamellae were assessed by TEM and Small and Wide Angle X-ray Scattering, which also proved the liquid state of the vesicular bilayer. Further, vesicles were evaluated for ex vivo (trans)dermal delivery, and their mode of action was studied performing a pre-treatment test and confocal laser scanning microscopy analyses. Results showed the formation of multi- and unilamellar vesicles that provided improved diclofenac delivery to pig skin, influenced by vesicle lipid composition and structure. Images of the qualitative CLSM analyses support the conclusion that PEVs enhance drug transport by penetrating intact the stratum corneum, thanks to a synergic effect of vesicles and penetration enhancer.

Design, characterization and in vitro evaluation of 5-aminosalicylic acid loaded N-succinyl-chitosan microparticles for colon specific delivery.

The objective of this study was to prepare NS-chitosan microparticles for the delivery of 5-aminosalicylic acid (5-ASA) to the colon. Microparticles can spread out over a large area of colon allowing a more effective local efficacy of 5-ASA. N-Succinyl-chitosan was chosen as carrier system because of its excellent pharmaceutical properties in colon drug targeting such as poor solubility in acid environment, biocompatibility, mucoadhesive properties, and low toxicity. It was prepared by introducing succinic group into chitosan N-terminals of the glucosamine units. 5-ASA loaded NS-chitosan microparticles were prepared using spray-drying. As a control, a matrix obtained by freeze-drying technique was also prepared and tested. Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC) and X-ray diffraction studies show the 5-ASA/NS-chitosan electrostatic interactions in both the systems. Mean size of the microparticles was around 5 µm, zeta potential value of both systems was always negative. Scanning electron microscopy (SEM) images show an acceptable spherical non porous structure of microparticles. In vitro swelling and drug release studies were in accordance with the polymer properties, showing the highest swelling ratio and drug release at pH=7.4 (colonic pH) where microparticles were able to deliver more than 90% of 5-ASA during 24h experiments. Rheological studies are in accordance with the swelling and release studies.

Bruxism and nocturnal groaning.

Sleep bruxism (SB) is a sleep-related movement disorder, characterized by tooth grinding and/or clenching. The causes of SB range from psychosocial factors to an excessive sleep arousal response. Some studies showed that SB episodes during sleep are under the influences of transient activity of the brainstem arousal. Nocturnal groaning (NG) is a parasomnia characterized by an expiratory monotonous vocalization occurring during sleep, especially in REM sleep and during the second half of the night. The pathogenesis of NG remains still unclear and many hypotheses arose, ranging from the persistence of a vestigial ventilatory pattern rather than an expiratory upper airways' obstruction. Sleep microstructure fluctuation might modulate the NG, since the end of the NG episode usually is synchronized with a cortical arousal and an autonomic activation. Further studies should clarify the pathophysiology of SB and NG, especially when the two phenomena are associated.

N-Succinyl-chitosan systems for 5-aminosalicylic acid colon delivery: in vivo study with TNBS-induced colitis model in rats.

5-Aminosalicylic acid (5-ASA) loaded N-Succinyl-chitosan (SucCH) microparticle and freeze-dried system were prepared as potential delivery systems to the colon. Physicochemical characterization and in vitro release and swelling studies were previously assessed and showed that the two formulations appeared to be good candidates to deliver the drug to the colon. In this work the effectiveness of these two systems in the treatment of inflammatory bowel disease was evaluated. In vitro mucoadhesive studies showed excellent mucoadhesive properties of both the systems to the inflamed colonic mucosa. Experimental colitis was induced by rectal instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS) into male Wistar rats. Colon/body weight ratio, clinical activity score system, myeloperoxidase activity and histological evaluation were determined as inflammatory indices. The two formulations were compared with drug suspension and SucCH suspension. The results showed that the loading of 5-ASA into SucCH polymer markedly improved efficacy in the healing of induced colitis in rats.

Preferential D2 or preferential D3 dopamine agonists in restless legs syndrome.

OBJECTIVE: A comparison between equivalent low doses of the D2 preferential agonist bromocriptine and the D3 preferential agonist pramipexole was performed in order to understand which dopamine agonist receptor subtype plays the main role in the treatment of restless legs syndrome (RLS) with periodic leg movements during sleep (PLMS). METHODS: A placebo-controlled, prospective, single-blind investigation was carried out on 45 drug-naive patients with idiopathic RLS. Each patient underwent 2 consecutive full night polysomnographic studies. The first night was performed without medication. Prior to the second night, one group received a single oral dose of 0.25 mg pramipexole while a second group received a single oral dose of 2.5 mg bromocriptine, and the remaining patients received placebo. Additionally, symptoms of restlessness were assessed. RESULTS: Subjective symptoms improved with both pramipexole and bromocriptine; however, the amelioration after pramipexole was scored higher. Only pramipexole induced an improvement in sleep efficiency and a reduction in wakefulness after sleep onset. Pramipexole was more effective than bromocriptine in reducing periodic leg movements, in particular in patients with a high baseline periodic leg movements index. Typical periodic leg movements, with an interval ranging between 10 and 40 seconds, disappeared completely after pramipexole treatment but persisted, even if reduced, after bromocriptine. CONCLUSIONS: Dopamine agonists targeting the dopamine D3 receptor subtype have a higher efficacy on periodic leg movements and RLS than a drug that preferentially targets the D2 receptor subtype. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with RLS pramipexole as compared to an estimated equivalent dose of bromocriptine results in greater improvement in some measures of RLS and PLMS severity after one night of treatment.

Transient RLS during pregnancy is a risk factor for the chronic idiopathic form.

OBJECTIVE: Pregnancy is a risk factor for transient restless legs syndrome, which usually recovers during the postdelivery period. The goal of the present survey is to investigate whether restless legs syndrome during pregnancy represents a risk factor for later development of restless legs syndrome. METHODS: A long-term follow-up study, planned as an extension of a previous survey on restless legs syndrome during pregnancy, was carried out. After a mean interval of 6.5 years, 207 parous women were contacted again to compare the incidence of restless legs syndrome among subjects who never experienced the symptoms with those who reported restless legs syndrome during the previously investigated pregnancy. RESULTS: Seventy-four women who experienced restless legs syndrome during previous pregnancy, and 133 who did not, were included in the study. The incidence of restless legs syndrome was 56% person/year in women who experienced the transient pregnancy restless legs syndrome form, and 12.6% person/year in subjects who did not, with a significant 4-fold increased risk of developing chronic restless legs syndrome in women who presented restless legs in the previous pregnancy. Considering further new pregnancies during the follow-up period, the restless legs symptoms reappeared in 58% of the cases, while they emerged for the first time in only 3% of women who had never experienced restless legs syndrome. CONCLUSIONS: The transient pregnancy restless legs syndrome form is a significant risk factor for the development of a future chronic idiopathic restless legs syndrome form, and for a new transient symptomatology in a future pregnancy.

Chitosomes as drug delivery systems for C-phycocyanin: preparation and characterization.

The aim of this work was to investigate chitosomes, i.e. liposomes coated by a polyelectrolyte complex between chitosan (CH) and xantan gum (XG), as potential delivery system for oral administration of the protein C-phycocyanin. To this purpose several CH-XG-microcomplexes were prepared in aqueous lactic acid at different chitosan-xanthan gum percent ratios and rheological properties of the microcomplexes were studied to analyse the contribution of chitosan and xanthan gum in the reaction of microcomplexation. After establishing the best microcomplexes, chitosomes were prepared by coating C-phycocyanin loaded liposomes with the CH-XG hydrogels using spray-drying or freeze-drying. The chitosomes were characterized in terms of morphology, size distribution, zeta potential, swelling properties, drug release, and mucoadhesive properties. Rheological studies showed the influence of xanthan gum in the microcomplex properties. Moreover, obtained results demonstrated the effects of formulation and process variables on particle size, drug content, swelling, drug release, and especially on the mucoadhesiveness of C-PC chitosomes of CH-XG. In particular, chitosomes prepared by spray-drying technique using CH-XG in 0.5/8.0 (w/w) ratio showed a regular surface and a drug release characteristic for a Fickian diffusion of the active ingredient. The in vitro mucoadhesive study revealed that the spray-drying method is advantageous to prepare C-phycocyanin loaded chitosomes with excellent mucoadhesive properties for colonic drug delivery.