Miracle-dz/UniFAR-FTUs huggingface dataset:
The Contribution of Homocysteine Metabolism Disruption to Endothelial Dysfunction: State-of-the-Art

Homocysteine (Hcy) is a sulfur-containing non-proteinogenic amino acid formed during the metabolism of the essential amino acid methionine. Hcy is considered a risk factor for atherosclerosis and cardiovascular disease (CVD), but the molecular basis of these associations remains elusive. The impairment of endothelial function, a key initial event in the setting of atherosclerosis and CVD, is recurrently observed in hyperhomocysteinemia (HHcy). Various observations may explain the vascular toxicity associated with HHcy. For instance, Hcy interferes with the production of nitric oxide (NO), a gaseous master regulator of endothelial homeostasis. Moreover, Hcy deregulates the signaling pathways associated with another essential endothelial gasotransmitter: hydrogen sulfide. Hcy also mediates the loss of critical endothelial antioxidant systems and increases the intracellular concentration of reactive oxygen species (ROS) yielding oxidative stress. ROS disturb lipoprotein metabolism, contributing to the growth of atherosclerotic vascular lesions. Moreover, excess Hcy maybe be indirectly incorporated into proteins, a process referred to as protein N-homocysteinylation, inducing vascular damage. Lastly, cellular hypomethylation caused by build-up of S-adenosylhomocysteine (AdoHcy) also contributes to the molecular basis of Hcy-induced vascular toxicity, a mechanism that has merited our attention in particular. AdoHcy is the metabolic precursor of Hcy, which accumulates in the setting of HHcy and is a negative regulator of most cell methyltransferases. In this review, we examine the biosynthesis and catabolism of Hcy and critically revise recent findings linking disruption of this metabolism and endothelial dysfunction, emphasizing the impact of HHcy on endothelial cell methylation status.
Could angiotensin-modulating drugs be relevant for the treatment of Trypanosoma cruzi infection? A systematic review of preclinical and clinical evidence

Abstract Although leucocytes are targets of renin-angiotensin system (RAS) effector molecules and RAS-modulating drugs exert immunomodulatory effects, their impact on Trypanosoma cruzi infection remains poorly understood. By using the framework of a systematic review, we integrated the preclinical and clinical evidence to investigate the relevance of angiotensin-inhibiting drugs on T. cruzi infections. From a comprehensive and structured search in biomedical databases, only original studies were analysed. In preclinical and clinical studies, captopril, enalapril and losartan were RAS-modulating drugs used. The main in vitro findings indicated that these drugs increased parasite uptake per host cells, IL-12 expression by infected dendritic cells and IFN-γ by T lymphocytes, in addition to attenuating IL-10 and IL-17 production by CD8 + T cells. In animal models, reduced parasitaemia, tissue parasitism, leucocytes infiltration and mortality were often observed in T. cruzi-infected animals receiving RAS-modulating drugs. In patients with Chagas’ disease, these drugs exerted a controversial impact on cytokine and hormone levels, and a limited effect on cardiovascular function. Considering a detailed evaluation of reporting and methodological quality, the current preclinical and clinical evidence is at high risk of bias, and we hope that our critical analysis will be useful in mitigating the risk of bias in further studies.
Pain Intensity and Fear Avoidance Explain Disability Related to Chronic Low Back Pain in a Saudi Arabian Population.

MINI: This study examined individual, psychosocial and physical factors in a Saudi population with CLBP and their association with CLBP-related disability. Participants demonstrated moderate disability, high BMI and low physical activity. Moderate-severe distress was evident in 26-39%. Pain intensity, fear avoidance beliefs, psychological distress and age emerged as important factors associated with disability. STUDY DESIGN A cross sectional study. OBJECTIVE The aim of this study was to describe multi-dimensional profiles for people with chronic low back pain (CLBP) and to examine the associations between CLBP-related disability and individual, psychosocial and physical factors in a Saudi population. SUMMARY OF BACKGROUND DATA CLBP-related disability is a multidimensional phenomenon. There is growing interest in exploring factors associated with CLBP-related disability in Saudi Arabia but research is limited in comparison to other countries. METHODS Participants completed questionnaires covering demographics, pain intensity, back beliefs, fear avoidance, psychological distress and physical activity. Oswestry Disability Index (ODI) was used to measure disability. Participants also performed a standardized sequence of physical performance tests and a Pain Behaviour Scale was used to evaluate pain behaviours during performance of these tests. The relationships between disability and all variables were explored using univariate and multivariate regression analyses. RESULTS One hundred and fifteen participants were included, 63% of whom were female. Participants demonstrated moderate disability (mean (SD): 26.6 (13.5)). The mean (SD) back beliefs score was 28.6 (7.3). Mean depression, anxiety and stress (DASS 21) scores indicated mild distress; however, 26-39% scored in the moderate-severe range for at least one subscale. In univariate analyses, pain intensity and fear avoidance beliefs (physical activity and work) were moderately associated with disability (r = 0.56, 0.49, 0.52, respectively, p < 0.001), with all other factors demonstrating weak association. Multivariate regression revealed that pain intensity, fear avoidance beliefs, psychological distress and participants' age were all found to be associated with disability, accounting for 52.9% (adjusted R = 0.529) of variability. CONCLUSION This study provides a unique insight into the clinical profile of people with CLBP in a Saudi Arabian population. Pain and psychosocial factors were significantly associated with disability. This study supports the contention that CLBP-related disability is a multifactorial biopsychosocial condition across different cultures. LEVEL OF EVIDENCE 3.
Low Expression of IL-10 in Circulating Bregs and Inverted IL-10/TNF-α Ratio in Tears of Patients with Perennial Allergic Conjunctivitis: A Preliminary Study

Allergic conjunctivitis (AC) is one of the most common ophthalmological disorders seen in clinical practice. Growing evidence from recent years suggests that a subset of IL-10-expressing B cells is involved in inflammatory allergic diseases. In this study, we aimed to evaluate the potential involvement of blood Bregs cells in perennial allergic conjunctivitis (PAC), and interleukins (IL)-1β, IL-6, IL-8, IL-10, and IL-12, and tumor necrosis factor (TNF)-α, were measured in tear samples and compared with healthy controls (HC) using flow cytometry. Non-significant differences in CD19+IL-10+ cell frequency between PAC patients and healthy controls (HC) were observed. Nevertheless, when we analyzed the mean fluorescence intensity (MFI) of IL-10 on CD19+CD38Lo/Med/Hi-gated cells, we observed a significant decrease in MFI in all Bregs subsets in PAC patients. Additionally, tear cytokines showed 2.8 times lower levels of IL-10 than TNF-α in PAC patients when compared to HC. Our findings demonstrate an immunological dysregulation in patients with allergic conjunctivitis, characterized by the low expression of IL-10 in circulating CD19+CD38+ Bregs subsets and an inverted tear IL-10/TNF-α ratio, promoting a local pro-inflammatory microenvironment. These findings highlight the novel pathologic changes involved in ocular allergic diseases. Understanding systemic and local mechanisms will aid the design of immunomodulating therapeutics at different levels.
Time-domain near-infrared spectroscopy in acute ischemic stroke patients

Abstract. Large vessel occlusion (LVO) stroke might cause different degrees of hemodynamic impairment that affects microcirculation and contributes to metabolic derangement. Time-domain near-infrared spectroscopy (TD-NIRS) estimates the oxygenation of microcirculation of cerebral outer layers. We measure hemoglobin species and tissue oxygen saturation (StO2) of anterior circulation stroke patients, classified as LVO or lacunar, and assess the differences compared with controls and according to LVO recanalization status. Fiducial markers categorize the brain region below each TD-NIRS probe as ischemic or nonstroke areas. The study includes 47 consecutive acute ischemic stroke patients and 35 controls. The ischemic area has significantly higher deoxy-hemoglobin (HbR) and total hemoglobin (HbT) compared with controls in both recanalized and nonrecanalized patients but lower StO2 only in recanalized patients. Recanalized patients have significantly lower mean StO2 in the ipsilateral hemisphere compared with nonrecanalized patients. This is the first study to report TD-NIRS measurements in acute ischemic stroke patients. TD-NIRS is able to detect significant differences in hemoglobin species in LVO stroke compared with controls and according to recanalization status. This preliminary data might suggest that StO2 can serve as a surrogate functional marker of the metabolic activity of rescued brain tissue.
Sirolimus‐eluting BiOSS LIM dedicated bifurcation stent in the treatment of unprotected distal left main stenosis

Proximal optimization technique (POT) has been proposed to adapt the conventional drug‐eluting stent (DES) with the fractal anatomy of the bifurcation. However, only few DES are labeled for post‐expansion beyond 5.0 mm. Furthermore, recrossing in the side branch (SB) through the main vessel (MV) stent cells may be challenging.
Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension.

RATIONALE Patients with idiopathic pulmonary arterial hypertension (IPAH) present circulating autoantibodies against vascular wall components. Pathogenic antibodies may be generated in tertiary (ectopic) lymphoid tissues (tLTs). OBJECTIVES To assess the frequency of tLTs in IPAH lungs, as compared with control subjects and flow-induced PAH in patients with Eisenmenger syndrome, and to identify local mechanisms responsible for their formation, perpetuation, and function. METHODS tLT composition and structure were studied by multiple immunostainings. Cytokine/chemokine and growth factor expression was quantified by real-time polymerase chain reaction and localized by immunofluorescence. The systemic mark of pulmonary lymphoid neogenesis was investigated by flow cytometry analyses of circulating lymphocytes. MEASUREMENTS AND MAIN RESULTS As opposed to lungs from control subjects and patients with Eisenmenger syndrome, IPAH lungs contained perivascular tLTs, comprising B- and T-cell areas with high endothelial venules and dendritic cells. Lymphocyte survival factors, such as IL-7 and platelet-derived growth factor-A, were expressed in tLTs as well as the lymphorganogenic cytokines/chemokines, lymphotoxin-α/-β, CCL19, CCL20, CCL21, and CXCL13, which might explain the depletion of circulating CCR6(+) and CXCR5(+) lymphocytes. tLTs were connected with remodeled vessels via an ER-TR7(+) stromal network and supplied by lymphatic channels. The presence of germinal center centroblasts, follicular dendritic cells, activation-induced cytidine deaminase, and IL-21(+)PD1(+) follicular helper T cells in tLTs together with CD138(+) plasma cell accumulation around remodeled vessels in areas of immunoglobulin deposition argued for local immunoglobulin class switching and ongoing production. CONCLUSIONS We highlight the main features of lymphoid neogenesis specifically in the lungs of patients with IPAH, providing new evidence of immunological mechanisms in this severe condition.
Does the left aorta provide proton-rich blood to the gut when crocodilians digest a meal?

ABSTRACT Reptiles have the capacity to differentially perfuse the systemic and pulmonary vascular circuits via autonomic regulation of the heart and the vascular trees. While this aptitude is widely recognized, the role of ‘shunting’ as a homeostatic mechanism to match convective transport with tissue demand remains unknown. In crocodilians, it has been hypothesized that a pulmonary vascular bypass of systemic venous blood – a right-to-left (R–L) shunt – serves to deliver CO2-rich blood with protons needed for gastric acid secretion during digestion. This hypothesis is partially based on the unique crocodilian vascular anatomy where a left aorta (LAo) arises from the right ventricle, and appears to preferentially supply the gastrointestinal system, whereas the right aorta emerges from the left ventricle. Recent theoretical considerations imply that a R–L shunt would have minuscule effects on PCO2, but direct measurements of blood gases in both the right and left aortae or both the right and left atria in fed animals have not been conducted. For this reason, we measured blood parameters including PO2, PCO2, pHe and [HCO3−] in the right and left aortae and atria following ingestion of a gavage-fed standardized meal (5% body mass). Blood samples were taken at 3, 6, 12, 24, 36 and 48 h into the digestive period to encompass the period of maximal gastric acid secretion. At no point did PCO2 or pH differ between the left and right aortae, whereas PO2 was significantly lower in the left aorta at several time points during digestion. Our findings do not support the hypothesis that a R–L shunt serves to deliver CO2 for the gastrointestinal system after feeding in crocodilians. Summary: Blood in the left aorta of American alligators does not contain elevated PCO2 levels during digestion.
Immune Modulation of Head and Neck Squamous Cell Carcinoma and the Tumor Microenvironment by Conventional Therapeutics

Head and neck squamous cell carcinoma (HNSCC) accounts for more than 600,000 cases and 380,000 deaths annually worldwide. Although human papillomavirus (HPV)–associated HNSCCs have better overall survival compared with HPV-negative HNSCC, loco-regional recurrence remains a significant cause of mortality and additional combinatorial strategies are needed to improve outcomes. The primary conventional therapies to treat HNSCC are surgery, radiation, and chemotherapies; however, multiple other targeted systemic options are used and being tested including cetuximab, bevacizumab, mTOR inhibitors, and metformin. In 2016, the first checkpoint blockade immunotherapy was approved for recurrent or metastatic HNSCC refractory to platinum-based chemotherapy. This immunotherapy approval confirmed the critical importance of the immune system and immunomodulation in HNSCC pathogenesis, response to treatment, and disease control. However, although immuno-oncology agents are rapidly expanding, the role that the immune system plays in the mechanism of action and clinical efficacy of standard conventional therapies is likely underappreciated. In this article, we focus on how conventional and targeted therapies may directly modulate the immune system and the tumor microenvironment to better understand the effects and combinatorial potential of these therapies in the context and era of immunotherapy.
Pump down the prep to pump up the uptake: dream or nightmare?

represents one of the most universal and strongest recommendations adopted in any national or international guideline [1]. Unexpectedly, a substantial proportion of the target population does not participate in screening programs [2]. It could be argued that this is not specific for CRC screening and that it is related to personal disbelief in the risk of developing cancer and the efficacy of the recommended interventions, or to attitudes such as fatalism, denial of CRC risk, and a low socio-economic status. Several interventions aimed at removing these barriers by engaging and motivating nonadherent individuals have been recommended, with variable and generally disappointing results [3].
Saliva, a Magic Biofluid Available for Multilevel Assessment and a Mirror of General Health—A Systematic Review †

Background: Saliva has been recently proposed as an alternative to classic biofluid analyses due to both availability and reliability regarding the evaluation of various biomarkers. Biosensors have been designed for the assessment of a wide spectrum of compounds, aiding in the screening, diagnosis, and monitoring of pathologies and treatment efficiency. This literature review aims to present the development in the biosensors research and their utility using salivary assessment. Methods: a comprehensive literature search has been conducted in the PubMed database, using the keywords “saliva” and “sensor”. A two-step paper selection algorithm was devised and applied. Results: The 49 papers selected for the present review focused on assessing the salivary biomarkers used in general diseases, oral pathologies, and pharmacology. The biosensors proved to be reliable tools for measuring the salivary levels of biochemical metabolic compounds such as glucose, proteinases and proteins, heavy metals and various chemical compounds, microorganisms, oncology markers, drugs, and neurotransmitters. Conclusions: Saliva is a biofluid with a significant clinical applicability for the evaluation and monitoring of a patient’s general health. Biosensors designed for assessing a wide range of salivary biomarkers are emerging as promising diagnostic or screening tools for improving the patients’ quality of life.
Self-harm in older adults: systematic review.

BACKGROUND Self-harm is a major public health concern. Increasing ageing populations and high risk of suicide in later life highlight the importance of identification of the particular characteristics of self-harm in older adults.AimTo systematically review characteristics of self-harm in older adults. METHODS A comprehensive search for primary studies on self-harm in older adults was conducted in e-databases (AgeLine, CINAHL, PsycINFO, MEDLINE, Web of Science) from their inception to February 2018. Using predefined criteria, articles were independently screened and assessed for methodological quality. Data were synthesised following a narrative approach. A patient advisory group advised on the design, conduct and interpretation of findings. RESULTS A total of 40 articles (n = 62 755 older adults) were included. Yearly self-harm rates were 19 to 65 per 100 000 people. Self-poisoning was the most commonly reported method. Comorbid physical problems were common. Increased risk repetition was reported among older adults with self-harm history and previous and current psychiatric treatment. Loss of control, increased loneliness and perceived burdensome ageing were reported self-harm motivations. CONCLUSIONS Self-harm in older adults has distinct characteristics that should be explored to improve management and care. Although risk of further self-harm and suicide is high in all age cohorts, risk of suicide is higher in older adults. Given the frequent contact with health services, an opportunity exists for detection and prevention of self-harm and suicide in this population. These results are limited to research in hospital-based settings and community-based studies are needed to fully understand self-harm among older adults.Declaration of interestNone.
Cannabis and Its Secondary Metabolites: Their Use as Therapeutic Drugs, Toxicological Aspects, and Analytical Determination

Although the medicinal properties of Cannabis species have been known for centuries, the interest on its main active secondary metabolites as therapeutic alternatives for several pathologies has grown in recent years. This potential use has been a revolution worldwide concerning public health, production, use and sale of cannabis, and has led inclusively to legislation changes in some countries. The scientific advances and concerns of the scientific community have allowed a better understanding of cannabis derivatives as pharmacological options in several conditions, such as appetite stimulation, pain treatment, skin pathologies, anticonvulsant therapy, neurodegenerative diseases, and infectious diseases. However, there is some controversy regarding the legal and ethical implications of their use and routes of administration, also concerning the adverse health consequences and deaths attributed to marijuana consumption, and these represent some of the complexities associated with the use of these compounds as therapeutic drugs. This review comprehends the main secondary metabolites of Cannabis, approaching their therapeutic potential and applications, as well as their potential risks, in order to differentiate the consumption as recreational drugs. There will be also a focus on the analytical methodologies for their analysis, in order to aid health professionals and toxicologists in cases where these compounds are present.
Gene–environment interactions related to blood pressure traits in two community‐based Korean cohorts

Hypertension is a complex disorder caused by genetic and environmental risk factors. Recently, genome‐wide association studies (GWASs) identified more than 100 genetic variants for blood pressure traits and hypertension. However, the interactions between these genetic variants and environmental factors have not been systematically investigated. Therefore, we examined the interaction between genetic and environmental risk factors in blood pressure traits using the genetic risk score (GRS). Two Korean community‐based cohorts, Cohort I (KARE; N = 8,840) and Cohort II (CAVAS; N = 9,599), were used for this study, and GRSs were calculated from 42 GWAS single‐nucleotide polymorphisms (SNPs) that were validated for their association in these cohorts. We calculated GRSs in both ways by considering the effect sizes of each SNP (weighted GRS) and not considering the effect sizes (unweighted GRS). The unweighted GRS was strongly associated with systolic blood pressure, diastolic blood pressure, and hypertension (p = 9.03 × 10 –47, p = 9.41 × 10 –48, and p = 3.22 × 10 –55 by meta‐analysis, respectively) and the weighted GRS showed the similar results. The environmental factors of body mass index, waist circumference, and drinking status were significantly associated with blood pressure traits, and the interaction between these factors and GRSs were examined. However, no interactions were found with either the GRS or the individual SNPs considered for the GRS. Our findings show that it is challenging to find GRS–environment interactions regarding blood pressure traits.
Association between alcohol use and periodontal pockets in Finnish adult population

Abstract Objective: To investigate whether alcohol use is associated with deepened periodontal pockets and whether this association is dependent on age, gender or socioeconomic position (SEP). Material and methods: This cross-sectional study, based on the Health 2000 Survey, consisted of dentate, non-smoking Finnish adults aged 30−65 years (n = 3059). The outcome was the number of teeth with deepened (≥4 mm) periodontal pockets. The exposure was self-reported alcohol use assessed as amount, frequency, and use over the risk limit. Zero-inflated negative binomial regression models were used to estimate relative risks (RRs) and 95% confidence intervals (95% CI). Results: In this study, alcohol use did not consistently associate with the number of teeth with deepened periodontal pockets. An association with the number of teeth with deepened periodontal pockets was found among men, older participants, and those participants belonging to basic or intermediate educational groups. An association with poor periodontal health was observed among men or older participants who belonged to the basic or intermediate educational group, whereas such associations were not observed among those participants belonging to the higher educational group. Conclusions: The association between alcohol use and periodontal health appears to be confounded by individual characteristics such as age, gender, and especially one’s SEP.