Investigating the pharmacological potential of phytol on experimental models of gastric ulcer in rats.

Phytol is a diterpene constituent of many essential oils, belonging to the group of unsaturated acyclic alcohols. Although phytol possesses antimycobacterial and anti-inflammatory effects, no reports of a gastrointestinal action are available from the literature. Due to the well-known shortcomings of classical anti-ulcer drugs (e.g. side effects or relapses), natural products may offer an attractive alternative. In this study, a potential gastroprotective activity of phytol was evaluated using acute and chronic ulcer models in rats. Phytol 12.5, 25 and 50 mg/kg, administered orally 1 h prior to induction of gastric lesions by absolute ethanol, inhibited the lesion area by 96, 90 and 95%, respectively. When lesions were induced by ischemia and reperfusion, phytol 12.5 and 25 mg/kg per os decreased the lesion areas by 89 and 46%, respectively. In the third acute ulcer model (lesions induced by ibuprofen), phytol 12.5 mg/kg reduced the lesion area by 55%. Phytol restored the decreased level of reduced glutathione, the increased levels of myeloperoxidase and malondialdehyde and the decreased levels of catalase and superoxide dismutase in rats with gastric ulcer induced by ethanol to levels obtained in vehicle group. Finally, in a chronic model in which gastric ulcer was induced by acetic acid directly instilled into the stomach, phytol administered orally over a time period of 7 days at 12.5, 25, 50 and 100 mg/kg reduced lesion areas by 84, 81, 83 and 68%. Our data suggest a gastroprotective and cicatrizing effect of phytol, possibly associated with its antioxidant effect.

Anti-TIF1γ-Dermatomyositis and Sjögren's Syndrome As the Inaugural Presentation for Rectal Cancer.

Dermatomyositis (DM) is an inflammatory myopathy often paraneoplastic in nature. Patients have characteristic cutaneous findings and possible muscle involvement. In the latter, muscle enzymes are elevated, and the electromyogram shows varied changes. Muscle or skin biopsy and myositis-specific antibodies confirm the diagnosis. Here, we report the case of an 86-year-old woman with cutaneous lesions, proximal weakness, and sicca symptoms. Muscle enzymes and electromyogram were normal. Antinuclear antibodies were elevated, and anti-TIF1γ and anti-Ro52 antibodies were positive. Muscle biopsy was compatible with the diagnosis of DM, and salivary gland biopsy confirmed Sjögren's syndrome. Malignancy investigation identified a rectal cancer, which was resected. This case illustrates a rare form of cancer presentation - anti-TIF1γ DM with normal muscle enzymes and electromyogram and concomitant secondary Sjögren's syndrome. Malignancy screening and multidisciplinary management were crucial to a successful approach.

Coronary physiology instantaneous wave-free ratio (iFR) derived from x-ray angiography using artificial intelligence deep learning models: a pilot study.

OBJECTIVES: Coronary angiography (CAG)-derived physiology methods have been developed in an attempt to simplify and increase the usage of coronary physiology, based mostly on dynamic fluid computational algorithms. We aimed to develop a different approach based on artificial intelligence methods, which has seldom been explored. METHODS: Consecutive patients undergoing invasive instantaneous free-wave ratio (iFR) measurements were included. We developed artificial intelligence (AI) models capable of classifying target lesions as positive (iFR ≤ 0.89) or negative (iFR > 0.89). The predictions were then compared to the true measurements. RESULTS: Two hundred-fifty measurements were included, and 3 models were developed. Model 3 had the best overall performance: accuracy, negative predictive value (NPV), positive predictive value (PPV), sensitivity, and specificity were 69%, 88%, 44%, 74%, and 67%, respectively. Performance differed per target vessel. For the left anterior descending artery (LAD), model 3 had the highest accuracy (66%), while model 2 the highest NPV (86%) and sensitivity (91%). PPV was always low/modest. Model 1 had the highest specificity (68%). For the right coronary artery, model 1's accuracy was 86%, NPV was 97%, and specificity was 87%, but all models had low PPV (maximum 25%) and low/modest sensitivity (maximum 60%). For the circumflex, model 1 performed best: accuracy, NPV, PPV, sensitivity, and specificity were 69%, 96%, 24%, 80%, and 68%, respectively. CONCLUSIONS: We developed 3 AI models capable of binary iFR estimation from CAG images. Despite modest accuracy, the consistently high NPV is of potential clinical significance, as it would enable avoiding further invasive maneuvers after CAG. This pivotal study offers proof of concept for further development.

Forgotten Goiter Presenting As Acute Respiratory Distress Following a Thyroidectomy: A Case Report.

Airway complications account for a significant amount of post-thyroidectomy complications. Forgotten goiter is a residual thyroid mass left after total thyroidectomy, an event already depicted in the literature. Clinical presentation is diverse, ranging from asymptomatic tracheal deviation to symptoms caused by hormonally active thyroid tissue or airway obstruction due to mass effect. However, it has never been documented as the cause of acute respiratory distress following thyroid surgery. We report the case of a 65-year-old female undergoing left hemithyroidectomy due to long-standing substernal goiter. Anesthesia induction and surgery were uneventful. On extubation, the patient presented with acute respiratory distress requiring prompt airway management. A computed tomography scan revealed residual intrathoracic goiter resulting in significant airway compression. Therefore, although a rare event, a forgotten goiter should be considered by a multidisciplinary team when patients undergoing surgery for substernal goiter develop acute postoperative airway obstruction after common post-thyroidectomy complications have been excluded.

Proteomic Profiling of Plasma- and Gut-Derived Extracellular Vesicles in Obesity.

Obesity entails metabolic alterations across multiple organs, highlighting the role of inter-organ communication in its pathogenesis. Extracellular vesicles (EVs) are communication agents in physiological and pathological conditions, and although they have been associated with obesity comorbidities, their protein cargo in this context remains largely unknown. To decipher the messages encapsulated in EVs, we isolated plasma-derived EVs from a diet-induced obese murine model. Obese plasma EVs exhibited a decline in protein diversity while control EVs revealed significant enrichment in protein-folding functions, highlighting the importance of proper folding in maintaining metabolic homeostasis. Previously, we revealed that gut-derived EVs' proteome holds particular significance in obesity. Here, we compared plasma and gut EVs and identified four proteins exclusively present in the control state of both EVs, revealing the potential for a non-invasive assessment of gut health by analyzing blood-derived EVs. Given the relevance of post-translational modifications (PTMs), we observed a shift in chromatin-related proteins from glycation to acetylation in obese gut EVs, suggesting a regulatory mechanism targeting DNA transcription during obesity. This study provides valuable insights into novel roles of EVs and protein PTMs in the intricate mechanisms underlying obesity, shedding light on potential biomarkers and pathways for future research.

Estimating Type 2 Diabetes Prevalence: A Model of Drug Consumption Data.

Observational, cross-sectional prevalence studies are costly and time-consuming. The development of indirect methods estimating prevalence used to obtain faster, less-expensive, and more robust results would be an advantage for several healthcare applications. This study aimed to use the drug dispensing data from community pharmacies to estimate the prevalence of Type 2 Diabetes mellitus (T2DM) in the Portuguese population. A cross-sectional study was conducted using a database of dispensed medicines with an indication for Diabetes mellitus in 2018 and 2021, stratified by geographic region. The methodology was based on a sequential method of acquiring prevalence estimates obtained through exposure to medicines using the daily doses defined per thousand inhabitants per day and adjusted to the rate of adherence to therapy, prescription patterns, and concomitance of antidiabetic drugs. The estimated overall T2DM prevalence in 2018 was 13.9%, and it was 14.2% for 2021. The results show the increased consumption of antidiabetic drugs, with fixed-dose combination antidiabetics and new antidiabetics being particularly important in 2021. This work allowed for the development of a model to obtain the estimated prevalence of T2DM based on drug consumption, using a simple, fast, and robust method that is in line with the available evidence. However, with the recent expanding indications for new antidiabetics, the inclusion of further data in the model needs to be studied.

Humulus lupulus aqueous extract and hydrolate as a potential ingredient for cosmetics: chemical characterization and in vitro antimicrobial, cytotoxicity, antioxidant and anti-inflammatory assessment.

Humulus lupulus extracts have in their composition different molecules, such as polyphenols, α-acids, ß-acids, and hydrocarbons, which contribute to the plant's medicinal properties. These molecules are associated with antimicrobial, antioxidant and anti-inflammatory activities. OBJECTIVE: This work focuses on the evaluation of H. lupulus biological activities, with the aim of evaluating its potential for inclusion in cosmetic formulations. METHODS: Two distinct aqueous extracts and two hydrolates obtained via hydrodistillation were evaluated. These include the flower parts (FE, FH) and the mix of aboveground parts (ME, MH). The chemical profiles for both aqueous extracts and hydrolates were identified by high performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS). Antimicrobial, antioxidant, cytotoxicity, and anti-inflammatory activity were tested in vitro using standard methods. RESULTS: Rutin was the major compound found in FE (40.041 µg mg-1 of extract) and ME (2.909 µg mg-1 of extract), while humulenol II was the most abundant compound in hydrolates (FH: 20.83%; MH: 46.80%). Furthermore, FE was able to inhibit the growth of Staphylococcus aureus and Staphylococcus epidermis with MIC values of 50% and 25% (v/v), respectively. FH showed the same effect in Staphylococcus aureus (50% v/v). FH evidenced poor antioxidant potential in DPPH scavenging test and demonstrated significant antioxidant and anti-inflammatory effects by reducing (***p < 0.001) intracellular reactive oxygen species (ROS), NO (nitric oxide) levels (***p < 0.001) and cyclooxygenase-2 (COX-2) protein expression (***p < 0.001) in lipopolysaccharide (LPS)-stimulated macrophages. Nevertheless, it is important to note that FH exhibited cytotoxicity at high concentrations in 3T3 fibroblasts and RAW 264.7 macrophages. CONCLUSION: The studied H. lupulus aqueous extracts and hydrolates revealed that FH stands out as the most promising bioactive source for cosmetic formulations. However, future research addressing antimicrobial activity is necessary to confirm its potential incorporation into dermatological and cosmetic formulations.

Chromatographic Methods Developed for the Quantification of Quercetin Extracted from Natural Sources: Systematic Review of Published Studies from 2018 to 2022.

Quercetin (QUE) is the most widely used flavonoid for therapeutic purposes. To improve the available knowledge about the properties of some natural products, determining the amount of QUE is crucial. The main objective of this systematic review is to identify the analytical methods validated for detecting and quantifying QUE in different matrices and characterize their sensitivity. A search was conducted until 30 June 2023 in the PubMed database for experimental studies that addressed the validation of chromatographic analytical methods to detect and quantify QUE from consumable natural products. Only studies published between 2018 and 2022, written in English, were included. The risk of bias was assessed by emphasizing methods of comparison according to previously published studies. Descriptive statistics were used to depict the obtained results. The studies were analyzed based on the type of QUE source, chromatographic method, and validation parameters. A total of 17 studies were included in this review. Plants were the most commonly analyzed source of QUE. Among the detection methods, spectrophotometry proved to be the most widely used, surpassing mass spectrometry (MS). After analyzing the bias, all the included studies mentioned/presented, totally or partially, at least four of the eight parameters.

Validation of an HPLC-DAD Method for Quercetin Quantification in Nanoparticles.

The evaluation of the efficacy of incorporation of quercetin in nanoparticles is crucial, both for the development and quality control of pharmaceutical formulations. The validation of analytical methods for the precise quantification of quercetin is useful for the evaluation of various potential quercetin delivery systems and quercetin pharmacokinetics. This work aimed to validate a high-performance liquid chromatography with diode array detection (HPLC-DAD) method for quercetin detection and quantification in nanoparticles. Different mobile phase conditions and detection wavelengths (254 and 368 nm) were tested, and the major validation parameters were assessed (precision, accuracy, linearity, sensitivity, stability, and selectivity). The best peak resolution was obtained when quercetin was analyzed at 368 nm with a mobile phase of 1.5% acetic acid and a water/acetonitrile/methanol ratio of 55:40:5. Under these conditions, quercetin also eluted rapidly (retention time of 3.6 min). The method proved to be linear (R2 > 0.995), specific, and repeatable (variation coefficient between 2.4% and 6.7%) and presented intermediate precision (variation coefficient between 7.2% and 9.4%). The accuracy of the analysis ranged between 88.6% and 110.7%, and detection and quantification limits were 0.046 and 0.14 µg/mL, respectively. Quercetin solutions were more stable when stored at 4 °C than at room temperature or -20 °C. This validated method satisfied more parameters of bias assessment than most recent methods for quercetin determination and presented itself as more sensitive and efficient than general spectrophotometric methods. The method was successfully used for the analysis of quercetin incorporation in nanoparticles and will be evaluated in the future for its adequacy for the determination of quercetin in more complex matrices.

Bifidobacteria metabolize lactulose to optimize gut metabolites and prevent systemic infection in patients with liver disease.

Progression of chronic liver disease is precipitated by hepatocyte loss, inflammation and fibrosis. This process results in the loss of critical hepatic functions, increasing morbidity and the risk of infection. Medical interventions that treat complications of hepatic failure, including antibiotic administration for systemic infections and lactulose treatment for hepatic encephalopathy, can impact gut microbiome composition and metabolite production. Here, using shotgun metagenomic sequencing and targeted metabolomic analyses on 847 faecal samples from 262 patients with acute or chronic liver disease, we demonstrate that patients hospitalized for liver disease have reduced microbiome diversity and a paucity of bioactive metabolites, including short-chain fatty acids and bile acid derivatives, that impact immune defences and epithelial barrier integrity. We find that patients treated with the orally administered but non-absorbable disaccharide lactulose have increased densities of intestinal bifidobacteria and reduced incidence of systemic infections and mortality. Bifidobacteria metabolize lactulose, produce high concentrations of acetate and acidify the gut lumen in humans and mice, which, in combination, can reduce the growth of antibiotic-resistant bacteria such as vancomycin-resistant Enterococcus faecium in vitro. Our studies suggest that lactulose and bifidobacteria serve as a synbiotic to reduce rates of infection in patients with severe liver disease.

Ubiquitin-specific protease 7 (USP7): an emerging drug target for cancer treatment.

INTRODUCTION: Ubiquitin-specific protease 7 (USP7) also known as herpesvirus-associated ubiquitin-specific protease (HAUSP) is a well-characterized cysteine protease that belongs to the largest subfamily of deubiquitinating enzymes (DUBs). It is involved in multiple signaling pathways, some of them dysregulated in malignant tumors. USP7 inhibition can lead to cell growth arrest and apoptosis through inhibition of tumor promoters and stabilization of tumor suppressors, making it a promising druggable target for cancer therapy. AREAS COVERED: This review covers the structure of USP7, its function in multiple signaling pathways and relevance in cancer, as well as recent advances and future perspectives in the development of USP7 inhibitors for cancer therapy. EXPERT OPINION: Literature reports display the multiple antitumor activities of USP7 inhibitors, both in vitro and in vivo. Nonetheless, none have entered clinical trials so far, highlighting the need to delve into a deeper understanding of USP7 binding sites and the development of more accurate compound screening methods. Despite these challenges, further development of USP7 inhibitors is promising as a valuable new approach for cancer treatment, including the ability to address chemoresistance.

Study of Ecological Relationship of Yeast Species with Candida albicans in the Context of Vulvovaginal Infections.

The role of the fungal community, the mycobiota, in the health of the vagina is currently an important area of research. The emergence of new sequencing technologies and advances in bioinformatics made possible the discovery of novel fungi inhabiting this niche. Candida spp. constitutes the most important group of opportunistic pathogenic fungi, being the most prevalent fungal species in vulvovaginal infections. However, fungi such as Rhodotorula spp., Naganishia spp. and Malassezia spp. have emerged as potential pathogens in this niche, and therefore it is clinically relevant to understand their ecological interaction with Candida spp. The main aim of this study was to evaluate the impact of yeasts on Candida albicans' pathogenicity, focusing on in-vitro growth, and biofilm formation at different times of co-culture and germ tube formation. The assays were performed with isolated species or with co-cultures of C. albicans (ATCC10231) with one other yeast species: Rhodotorula mucilaginosa (DSM13621), Malassezia furfur (DSM6170) or Naganishia albida (DSM70215). The results showed that M. furfur creates a symbiotic relationship with C. albicans, enhancing the growth rate of the co-culture (149.69%), and of germ tube formation of C. albicans (119.8%) and inducing a higher amount of biofilm biomass of the co-culture, both when mixed (154.1%) and preformed (166.8%). As for the yeasts R. mucilaginosa and N. albida, the relationship is antagonistic (with a significant decrease in all assays), thus possibly repressing the mixture's pathogenicity. These results shed light on the complex interactions between yeasts in the vaginal mycobiome.

Artificial intelligence for prediction of biological activities and generation of molecular hits using stereochemical information.

In this work, we develop a method for generating targeted hit compounds by applying deep reinforcement learning and attention mechanisms to predict binding affinity against a biological target while considering stereochemical information. The novelty of this work is a deep model Predictor that can establish the relationship between chemical structures and their corresponding [Formula: see text] values. We thoroughly study the effect of different molecular descriptors such as ECFP4, ECFP6, SMILES and RDKFingerprint. Also, we demonstrated the importance of attention mechanisms to capture long-range dependencies in molecular sequences. Due to the importance of stereochemical information for the binding mechanism, this information was employed both in the prediction and generation processes. To identify the most promising hits, we apply the self-adaptive multi-objective optimization strategy. Moreover, to ensure the existence of stereochemical information, we consider all the possible enumerated stereoisomers to provide the most appropriate 3D structures. We evaluated this approach against the Ubiquitin-Specific Protease 7 (USP7) by generating putative inhibitors for this target. The predictor with SMILES notations as descriptor plus bidirectional recurrent neural network using attention mechanism has the best performance. Additionally, our methodology identify the regions of the generated molecules that are important for the interaction with the receptor's active site. Also, the obtained results demonstrate that it is possible to discover synthesizable molecules with high biological affinity for the target, containing the indication of their optimal stereochemical conformation.

Opioid-Free Anaesthesia Reduces Complications in Head and Neck Microvascular Free-Flap Reconstruction.

Head and neck free-flap microvascular surgeries are complex and resource-intensive procedures where proper conduct of anaesthesia plays a crucial role in the outcome. Flap failure and postoperative complications can be attributed to multiple factors, whether surgical- or anaesthesia-related. The anesthesiologist should ensure optimised physiological conditions to guarantee the survival of the flap and simultaneously decrease perioperative morbidity. Institutions employ different anaesthetic techniques and results vary across centres. In our institution, two different total intravenous approaches have been in use: a remifentanil-based approach and a multimodal opioid-sparing approach, which is further divided into an opioid-free anaesthesia (OFA) subgroup. We studied every consecutive case performed between 2015 and 2022, including 107 patients. Our results show a significant reduction in overall complications (53.3 vs. 78.9%, p = 0.012), length of stay in the intensive care unit (3.43 ± 5.51 vs. 5.16 ± 4.23 days, p = 0.046), duration of postoperative mechanical ventilation (67 ± 107 vs. 9 ± 38 h, p = 0.029), and the need for postoperative vasopressors (10% vs. 46.6%, p = 0.001) in the OFA group (vs. all other patients). The multimodal and OFA strategies have multiple differences regarding the fluid therapy, intraoperative type of vasopressor used, perioperative pathways, and various drug choices compared to the opioid-based technique. Due to the small number of cases in our study, we could not isolate any attitude, as an independent factor, from the success of the OFA strategy as a whole. Large randomised controlled trials are needed to improve knowledge and help define the ideal anaesthetic management of these patients.

Statistical analyses of motion-corrupted MRI relaxometry data computed from multiple scans.

BACKGROUND: Consistent noise variance across data points (i.e. homoscedasticity) is required to ensure the validity of statistical analyses of MRI data conducted using linear regression methods. However, head motion leads to degradation of image quality, introducing noise heteroscedasticity into ordinary-least square analyses. NEW METHOD: The recently introduced QUIQI method restores noise homoscedasticity by means of weighted least square analyses in which the weights, specific for each dataset of an analysis, are computed from an index of motion-induced image quality degradation. QUIQI was first demonstrated in the context of brain maps of the MRI parameter R2 * , which were computed from a single set of images with variable echo time. Here, we extend this framework to quantitative maps of the MRI parameters R1, R2 * , and MTsat, computed from multiple sets of images. RESULTS: QUIQI restores homoscedasticity in analyses of quantitative MRI data computed from multiple scans. QUIQI allows for optimization of the noise model by using metrics quantifying heteroscedasticity and free energy. COMPARISON WITH EXISTING METHODS: QUIQI restores homoscedasticity more effectively than insertion of an image quality index in the analysis design and yields higher sensitivity than simply removing the datasets most corrupted by head motion from the analysis. CONCLUSION: QUIQI provides an optimal approach to group-wise analyses of a range of quantitative MRI parameter maps that is robust to inherent homoscedasticity.

Perioperative Challenges of Heroin Addiction: A Case Report of Opioid-Free Anesthesia in Tongue Carcinoma Excision With Free-Flap Reconstruction.

Anesthesia for major head and neck surgery is historically heavily reliant on opioids with deleterious consequences. We reported a case of a patient with a history of heroin abuse submitted to a tongue carcinoma excision, followed by free-flap reconstruction under opioid-free anesthesia. We used a propofol total intravenous anesthesia and perfusions of ketamine, dexmedetomidine, lidocaine, and magnesium sulfate for analgesia, complemented by boluses of dexamethasone, acetaminophen, parecoxib, and metamizole. Hemodynamic needs of the procedure were addressed by titrating perfusions of sodium nitroprusside or dobutamine. The patient was weaned from the ventilator at the end of the surgery. Surgical outcomes were achieved and opioid-free analgesia allowed early reestablishment of bodily functions without compromise of adequate pain control. Anesthesia protocols for free-flap surgery still lack scientific evidence, especially in the context of substance abuse: opioid-sparing approaches seem a viable option, which requires further studies and familiarity by health care professionals.

Single-subject electroencephalography measurement of interhemispheric transfer time for the in-vivo estimation of axonal morphology.

Assessing axonal morphology in vivo opens new avenues for the combined study of brain structure and function. A novel approach has recently been introduced to estimate the morphology of axonal fibers from the combination of magnetic resonance imaging (MRI) data and electroencephalography (EEG) measures of the interhemispheric transfer time (IHTT). In the original study, the IHTT measures were computed from EEG data averaged across a group, leading to bias of the axonal morphology estimates. Here, we seek to estimate axonal morphology from individual measures of IHTT, obtained from EEG data acquired in a visual evoked potential experiment. Subject-specific IHTTs are computed in a data-driven framework with minimal a priori constraints, based on the maximal peak of neural responses to visual stimuli within periods of statistically significant evoked activity in the inverse solution space. The subject-specific IHTT estimates ranged from 8 to 29 ms except for one participant and the between-session variability was comparable to between-subject variability. The mean radius of the axonal radius distribution, computed from the IHTT estimates and the MRI data, ranged from 0 to 1.09 µm across subjects. The change in axonal g-ratio with axonal radius ranged from 0.62 to 0.81 µm-α . The single-subject measurement of the IHTT yields estimates of axonal morphology that are consistent with histological values. However, improvement of the repeatability of the IHTT estimates is required to improve the specificity of the single-subject axonal morphology estimates.

Hypokinetic Activity of Menthofuran on the Gastrointestinal Tract in Rodents.

The acute toxicity and hypokinetic activity induced by menthofuran on the gastrointestinal tract of rodents were investigated in the present study. An absence of acute toxicity was observed. Menthofuran delayed gastric emptying at oral doses of 25, 50, and 100 mg/kg in the experimental model of phenol red, as well as it reduced the intestinal transit at oral doses of 50 and 100 mg/kg. Interestingly, a scopolamine-similar hypokinetic effect was observed for menthofuran. In the experimental model of castor oil-induced intestinal hypermotility, menthofuran (50 and 100 mg/kg) reduced the number of loose stools as observed for the normal group. Additionally, menthofuran induced a marked concentration-dependent relaxation in rat ileum segments precontracted with KCl (EC50 = 0.059 ± 0.008 µg/mL) or carbachol (EC50 = 0.068 ± 0.007 µg/mL). These results suggest the possible decrease of calcium influx underlying the effects of menthofuran on the gastrointestinal tract, which opens the door for further study regarding this potential application for the treatment of gastrointestinal disorders, noting possible limitations of its use due to adverse effects in children.