Dietary nitrate supplementation and cognitive health: the nitric oxide-dependent neurovascular coupling hypothesis.

Diet is currently recognized as a major modifiable agent of human health. In particular, dietary nitrate has been increasingly explored as a strategy to modulate different physiological mechanisms with demonstrated benefits in multiple organs, including gastrointestinal, cardiovascular, metabolic, and endocrine systems. An intriguing exception in this scenario has been the brain, for which the evidence of the nitrate benefits remains controversial. Upon consumption, nitrate can undergo sequential reduction reactions in vivo to produce nitric oxide (•NO), a ubiquitous paracrine messenger that supports multiple physiological events such as vasodilation and neuromodulation. In the brain, •NO plays a key role in neurovascular coupling, a fine process associated with the dynamic regulation of cerebral blood flow matching the metabolic needs of neurons and crucial for sustaining brain function. Neurovascular coupling dysregulation has been associated with neurodegeneration and cognitive dysfunction during different pathological conditions and aging. We discuss the potential biological action of nitrate on brain health, concerning the molecular mechanisms underpinning this association, particularly via modulation of •NO-dependent neurovascular coupling. The impact of nitrate supplementation on cognitive performance was scrutinized through preclinical and clinical data, suggesting that intervention length and the health condition of the participants are determinants of the outcome. Also, it stresses the need for multimodal quantitative studies relating cellular and mechanistic approaches to function coupled with behavior clinical outputs to understand whether a mechanistic relationship between dietary nitrate and cognitive health is operative in the brain. If proven, it supports the exciting hypothesis of cognitive enhancement via diet.

Polyphenol Composition by HPLC-DAD-(ESI-)MS/MS and Bioactivities of Extracts from Grape Agri-Food Wastes.

BACKGROUND: Grape agri-food wastes, such as skin, seeds, and other discarded by-products, contain phytochemical compounds that offer potential health benefits. METHODS: This study aimed to investigate the polyphenol composition and bioactivities of different extracts obtained from grape marc and seeds, with the goal of exploring their potential for application as natural food additives. RESULTS: Regardless of the extraction method used (dynamic maceration, ultrasound-assisted extraction (UAE), and microwave-assisted extraction (MAE)), all extracts exhibited relatively high concentrations of phenolic compounds. The chemical characterization of the extracts revealed the presence of specific compounds and chemical groups associated with each extraction methodology. Moreover, the extracts displayed satisfactory antioxidant activities, especially in inhibiting lipoperoxidation as assessed by the TBARS assay. Additionally, the extracts demonstrated effective inhibition against different strains of bacteria and fungi known as food contaminants. Taken together, these findings indicate that those extracts have the potential to be tested as natural antioxidants and preservatives with sustainable origins in food and beverage systems. Among the extraction methods evaluated, traditional maceration and UAE provided extracts with the highest antioxidant and antimicrobial activities. CONCLUSIONS: Our results suggest the opportunity to explore grape marc and seeds discarded by the winery industry in Portugal as natural sources of bioactive compounds, which could be employed as functional food ingredients or technological additives. The valorization of grape biowastes offers a promising strategy to reduce waste and harness their potential health benefits.

Insight into the cryptic diversity and phylogeography of the peculiar fried egg jellyfish Phacellophora (Cnidaria, Scyphozoa, Ulmaridae).

The fried egg jellyfish Phacellophora camtschatica (senso lato) is a morphologically peculiar and conspicuous species occurring mostly in the cold waters of the North Pacific. It is less common in the cold waters of the NW Atlantic, and occasionally has been reported in the Mediterranean, Arctic, East and South Pacific, and E, SW and NE Atlantic. However, sightings of this scyphozoan jellyfish have intensified during the past two to three decades in Macaronesia, the Iberian Peninsula and the Mediterranean. These jellyfish are known to be voracious predators of other jellies, but also of other taxa, including fish of commercial interest. Therefore, Phacellophora aggregations may threaten local fisheries, aquaculture, and local biodiversity structuring. We report the first known occurrences of Phacellophora in the Azores Islands, which apparently become more frequent in recent years of the past decade. We confirm, through DNA barcoding of COI and 16S mitochondrial markers, the genetic identity of Phacellophora occurring in the Azores (NE Atlantic). We reveal, with COI sequence data, three (potentially four) cryptic species within the Phacellophora camtschatica complex. Two Phacellophora species co-occur in the North Pacific. In the North Atlantic (and possibly in the Mediterranean) one or two distinct species exist. Three nominal species of the genus that are currently synonymized, with type localities in the N Pacific, NW Atlantic, and the Mediterranean, need reassessment. The morphotypes previously defined for the four putative species names given for Phacellophora might be eventually differentiated by the number and disposition of the marginal lappets of umbrellae. This morphologic character has to be further inspected in vouchers of the four genetic lineages of Phacellophora, to decide between the description of new species, and the resurrection of junior synonyms through the designation of neotypes with DNA Barcodes, to validate the identity of the cryptic taxa detected. More haplotype sampling is necessary across the distribution of the genus to further investigate the genetic diversity and phylogeographic history of Phacellophora. The high genetic relatedness of Phacellophora from the cold NW Atlantic and the sub-tropical shores of the Azores, revealed by 16S and COI sequence data, suggests a recent invasion, in terms of geologic time, of the temperate waters of the NE Atlantic (and possibly of the Mediterranean). The medusivorous habits of Phacellophora, and especially its predation on the mauve stinger (Pelagia spp.) which frequently blooms in Macaronesia and Mediterranean waters, could relate to the recent reports of Phacellophora in the Azores, Madeira, Canary Islands, and the Mediterranean. More investment, including on scientific staff, is necessary to catalog, DNA barcode and monitor jellyfish dynamics more accurately worldwide.

Highly sensitive screening and analytical characterization of synthetic cannabinoids in nine different herbal mixtures.

The popularity of new psychoactive substances among drug users has become a public health concern worldwide. Among them, synthetic cannabinoids (SCs) represent the largest, most diversified and fastest growing group. Commonly known as 'synthetic marijuana' as an alternative to cannabis, these synthetic compounds are easily accessible via the internet and are sold as 'herbal incenses' under different brand names with no information about the chemical composition. In the present work, we aim to integrate gas chromatography-tandem mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) data as useful strategy for the identification and confirmation of synthetic cannabinoids present in nine seized herbal incenses. The analysis of all samples allowed the initial identification of 9 SCs, namely 5 napthoylindoles (JWH-018, JWH-073, JWH-122, JWH-210, MAM-2201), APINACA, XLR-11 and CP47,497-C8 and its enantiomer. JWH-018 was the most frequently detected synthetic compound (8 of 9 samples), while APINACA and XLR-11 were only identified in one herbal product. Other non-cannabinoid drugs, including oleamide, vitamin E and vitamin E acetate, have also been detected. Oleamide and vitamin E are two adulterants, frequently added to herbal products to mask the active ingredients or added as preservatives. However, to our knowledge, no analytical data about vitamin E acetate was reported in herbal products, being the first time that this compound is identified on this type of samples. The integration data obtained from the used analytical technologies proved to be useful, allowing the preliminary identification of the different SCs in the mixture. Furthermore, the examination of mass spectral fragment ions, as well as the results of both 1D and 2D NMR experiments, enabled the identification and confirmation of the molecular structure of SCs.

3D Slicer Craniomaxillofacial Modules Support Patient-Specific Decision-Making for Personalized Healthcare in Dental Research.

The biggest challenge to improve the diagnosis and therapies of Craniomaxillofacial conditions is to translate algorithms and software developments towards the creation of holistic patient models. A complete picture of the individual patient for treatment planning and personalized healthcare requires a compilation of clinician-friendly algorithms to provide minimally invasive diagnostic techniques with multimodal image integration and analysis. We describe here the implementation of the open-source Craniomaxillofacial module of the 3D Slicer software, as well as its clinical applications. This paper proposes data management approaches for multisource data extraction, registration, visualization, and quantification. These applications integrate medical images with clinical and biological data analytics, user studies, and other heterogeneous data.

Effectiveness and Safety of Rivaroxaban Compared to Acenocumarol after Infrainguinal Surgical Revascularization.

BACKGROUND: Optimal antithrombotic therapy after lower limb infrainguinal revascularization remains a controversial topic. The use of anticoagulants, alone or in combination with antiplatelet drugs, can potentially improve patency rate and limb salvage, particularly in patients with risk factors for early thrombosis. Bleeding is the main complication of long-term anticoagulant use. New oral anticoagulants can represent an attractive alternative to the standard vitamin K antagonists. The objective of the study is to evaluate the effectiveness (bypass occlusion and major amputation) and safety (major bleeding and all-cause mortality) of rivaroxaban compared to acenocumarol after infrainguinal lower limb surgical revascularization. MATERIAL AND METHODS: Retrospective cohort study of patients with peripheral arterial disease submitted to lower limb infrainguinal bypass revascularization with vein or expanded polytetrafluoroethylene conduit, who were anticoagulated with acenocumarol or rivaroxaban after hospital discharge. Patients with proximal revascularization, revascularization due to any pathology other than peripheral arterial disease, coagulation disorder, stroke or acute myocardial infarction in less than 30 days, glomerular filtration rate <15 mL/min, or on hemodialysis were excluded. RESULTS: One hundred nine patients were included (78.9% male), with a mean age of 64.8 years. After hospital discharge, 40 patients (36.7%) were medicated with rivaroxaban and 69 patients (63.3%) with acenocumarol. At 1 year of follow-up, patients under rivaroxaban and acenocumarol presented comparable major amputation rates (12.5 % vs. 10.1%, P = 0.756), bypass occlusion (22.5% vs. 24.6 %, P = 0.769), and mortality rate (10% vs. 8.7%, P = 0.756). Major bleeding occurred in 13.8% of patients. Patients with renal dysfunction had significantly higher bleeding risk with acenocumarol (45.5% vs. 0%, P = 0.028) compared to rivaroxaban, while patients with normal renal function presented similar bleeding rates with both anticoagulants (6.1% vs. 6.4%, P = 0.953). CONCLUSIONS: Rivaroxaban has equivalent effectiveness to acenocumarol after infrainguinal bypass revascularization, with similar occlusion, major amputation, and mortality rates. Rivaroxaban has an improved safety profile in patients with moderate renal dysfunction due to a significantly lower incidence of major bleeding. In patients with normal renal function, rivaroxaban and acenocumarol present equivalent major bleeding rates.

On the dual nature of lichen-induced rock surface weathering in contrasting micro-environments.

Contradictory evidence from biogeomorphological studies has increased the debate on the extent of lichen contribution to differential rock surface weathering in both natural and cultural settings. This study, undertaken in Côa Valley Archaeological Park, aimed at evaluating the effect of rock surface orientation on the weathering ability of dominant lichens. Hyphal penetration and oxalate formation at the lichen-rock interface were evaluated as proxies of physical and chemical weathering, respectively. A new protocol of pixel-based supervised image classification for the analysis of periodic acid-Schiff stained cross-sections of colonized schist revealed that hyphal spread of individual species was not influenced by surface orientation. However, hyphal spread was significantly higher in species dominant on northwest facing surfaces. An apparently opposite effect was noticed in terms of calcium oxalate accumulation at the lichen-rock interface; it was detected by Raman spectroscopy and complementary X-ray microdiffraction on southeast facing surfaces only. These results suggest that lichen-induced physical weathering may be most severe on northwest facing surfaces by means of an indirect effect of surface orientation on species abundance, and thus dependent on the species, whereas lichen-induced chemical weathering is apparently higher on southeast facing surfaces and dependent on micro-environmental conditions, giving only weak support to the hypothesis that lichens are responsible for the currently observed pattern of rock-art distribution in Côa Valley. Assumptions about the drivers of open-air rock-art distribution patterns elsewhere should also consider the micro-environmental controls of lichen-induced weathering, to avoid biased measures of lichen contribution to rock-art deterioration.

Biosimilar monoclonal antibodies: preclinical and clinical development aspects.

Biological drugs and their originated biosimilars are large, highly complex molecules derived from living cells or organisms. Traditional medicines, by contrast, are usually simple molecules of low molecular weight, synthesised by chemical means. The distinct complexities and methods of manufacture create an important difference between biosimilars and conventional generic drugs: while chemical generics can be fully characterised as identical to the originator product, biosimilars cannot. In addition, biological therapies are inherently variable, creating unavoidable differences between even subsequent batches of the same product. An expiring patent does not necessarily mean that the manufacturing process of the originator product becomes available to the biosimilar developers (for instance, the relevant cell line clone and growth medium). Therefore, it cannot be guaranteed that biosimilar products are identical to their reference product on a molecular level. This difference has important implications for the regulation and licensing of biosimilars. While conventional generic drugs require only a limited comparison and demonstration of identical chemical structure to the reference product, biosimilars require far more rigorous testing. In general, there must be a thorough comparison of structural and functional characteristics between biosimilar and originator drug. Stepwise nonclinical in vitro and in vivo approaches are recommended to evaluate the similarity of both drugs and any identified micro-heterogeneities must then be assessed for their impact on safety and clinical performance. Subsequently, clinical pharmacokinetic (PK) studies need to be performed in order to demonstrate a similar PK profile, prior to conducting clinical efficacy trials.

Mitochondrial thioredoxin reductase inhibition, selenium status, and Nrf-2 activation are determinant factors modulating the toxicity of mercury compounds.

The thioredoxin system has essential functions in the maintenance of cellular redox homeostasis in the cytosol, nucleus, and mitochondria. Thioredoxin (Trx) and thioredoxin reductase (TrxR) are targets for mercury compounds in vitro and in vivo. This study aimed at understanding mechanistically how the mitochondrial and cytosolic thioredoxin systems were affected by mercurials, including the regulation of TrxR transcription. The effects of coexposure to selenite and mercurials on the thioredoxin system were also addressed. Results in HepG2 cells showed that TrxR1 expression was enhanced by Hg(2+), whereas exposure to MeHg decreased expression. Selenite exposure also increased the expression of TrxR1 and resulted in higher specific activity. Coexposure to 2 µM selenite and up to 5 µM Hg(2+) increased even further TrxR1 expression. This synergistic effect was not verified for MeHg, because TrxR1 expression and activity were reduced. Analysis of Nrf-2 translocation to the nucleus and TrxR mRNA suggests that induction of TrxR1 transcription was slower upon exposure to MeHg in comparison to Hg(2+). Subcellular fractions showed that MeHg affected the activity of the thioredoxin system equally in the mitochondria and cytosol, whereas Hg(2+) inhibited primarily the activity of TrxR2. The expression of TrxR2 was not upregulated by any treatment. These results show important differences between the mechanisms of toxicity of Hg(2+) and MeHg and stress the narrow range of selenite concentrations capable of antagonizing mercury toxicity. The results also highlight the relevance of the mitochondrial thioredoxin system (TrxR2 and Trx2) in the development of mercury toxicity.

Headspace solid-phase microextraction combined with mass spectrometry as a powerful analytical tool for profiling the terpenoid metabolomic pattern of hop-essential oil derived from Saaz variety.

Hop (Humulus lupulus L., Cannabaceae family) is prized for its essential oil contents, used in beer production and, more recently, in biological and pharmacological applications. In this work, a method involving headspace solid-phase microextraction and gas chromatography-mass spectrometry was developed and optimized to establish the terpenoid (monoterpenes and sesquiterpenes) metabolomic pattern of hop-essential oil derived from Saaz variety as a mean to explore this matrix as a powerful biological source for newer, more selective, biodegradable and naturally produced antimicrobial and antioxidant compounds. Different parameters affecting terpenoid metabolites extraction by headspace solid-phase microextraction were considered and optimized: type of fiber coatings, extraction temperature, extraction time, ionic strength, and sample agitation. In the optimized method, analytes were extracted for 30 min at 40°C in the sample headspace with a 50/30 µm divinylbenzene/carboxen/polydimethylsiloxane coating fiber. The methodology allowed the identification of a total of 27 terpenoid metabolites, representing 92.5% of the total Saaz hop-essential oil volatile terpenoid composition. The headspace composition was dominated by monoterpenes (56.1%, 13 compounds), sesquiterpenes (34.9%, 10), oxygenated monoterpenes (1.41%, 3), and hemiterpenes (0.04%, 1) some of which can probably contribute to the hop of Saaz variety aroma. Mass spectrometry analysis revealed that the main metabolites are the monoterpene ß-myrcene (53.0 ± 1.1% of the total volatile fraction), and the cyclic sesquiterpenes, α-humulene (16.6 ± 0.8%), and ß-caryophyllene (14.7 ± 0.4%), which together represent about 80% of the total volatile fraction from the hop-essential oil. These findings suggest that this matrix can be explored as a powerful biosource of terpenoid metabolites.

Anestesia local (com sedaçäo) em vitrectomias via "pars plana" / Local anesthesia for pars plana vitrectomy

Anestesia local com sedaçäo foi realizada com sucesso em 268 pacientes submetidos à vitrectomia via pars plana. Em 109 pacientes a duraçäo dos procedimentos cirúrgicos estendeu-se por tempo superior a 2 horas e, mesmo nesses casos, näo houve intercorrências que impossibilitassem a continuaçäo. O emprego de soluçäo de Bupivacaína 0,75 por cento associado a lidocaína 2 por cento com epinefrina e hialuronidase administrada via retrobulbar e peribulbar possibilitou anestesia e imobilidade ocular satisfatórias. A sedaçäo intra-operatória realizada por anestesiologista competente foi considerada fundamental para o sucesso do procedimento