In this review we will explore recent advances in the design and application of excited-state intramolecular proton-transfer (ESIPT) based fluorescent probes. Fluorescence based sensors and imaging agents (probes) are important in biology, physiology, pharmacology, and environmental science for the selective detection of biologically and/or environmentally important species. The development of ESIPT-based fluorescence probes is particularly attractive due to their unique properties, which include a large Stokes shift, environmental sensitivity and potential for ratiometric sensing.

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Excited-state intramolecular proton-transfer (ESIPT) based fluorescence sensors and imaging agents

The coronavirus disease 2019 (COVID-19) pandemic is a scientific, medical, and social challenge. The complexity of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is centered on the unpredictable clinical course of the disease that can rapidly develop, causing severe and deadly complications. The identification of effective laboratory biomarkers able to classify patients based on their risk is imperative in being able to guarantee prompt treatment. The analysis of recently published studies highlights the role of systemic vasculitis and cytokine mediated coagulation disorders as the principal actors of multi organ failure in patients with severe COVID-19 complications. The following biomarkers have been identified: hematological (lymphocyte count, neutrophil count, neutrophil-lymphocyte ratio (NLR)), inflammatory (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin (PCT)), immunological (interleukin (IL)-6 and biochemical (D-dimer, troponin, creatine kinase (CK), aspartate aminotransferase (AST)), especially those related to coagulation cascades in disseminated intravascular coagulation (DIC) and acute respiratory distress syndrome (ARDS). New laboratory biomarkers could be identified through the accurate analysis of multicentric case series; in particular, homocysteine and angiotensin II could play a significant role.

Biomarkers associated with COVID-19 disease progression.

Background
Cardiovascular disease, which includes coronary artery disease, stroke and peripheral vascular disease, is a leading cause of death worldwide. Homocysteine is an amino acid with biological functions in methionine metabolism. A postulated risk factor for cardiovascular disease is an elevated circulating total homocysteine level. The impact of homocysteine-lowering interventions, given to patients in the form of vitamins B6, B9 or B12 supplements, on cardiovascular events has been investigated. This is an update of a review previously published in 2009, 2013, and 2015.

Objectives
To determine whether homocysteine-lowering interventions, provided to patients with and without pre-existing cardiovascular disease are effective in preventing cardiovascular events, as well as reducing all-cause mortality, and to evaluate their safety.

Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 5), MEDLINE (1946 to 1 June 2017), Embase (1980 to 2017 week 22) and LILACS (1986 to 1 June 2017). We also searched Web of Science (1970 to 1 June 2017). We handsearched the reference lists of included papers. We also contacted researchers in the field. There was no language restriction in the search.

Selection criteria
We included randomised controlled trials assessing the effects of homocysteine-lowering interventions for preventing cardiovascular events with a follow-up period of one year or longer. We considered myocardial infarction and stroke as the primary outcomes. We excluded studies in patients with end-stage renal disease.

Data collection and analysis
We performed study selection, 'Risk of bias' assessment and data extraction in duplicate. We estimated risk ratios (RR) for dichotomous outcomes. We calculated the number needed to treat for an additional beneficial outcome (NNTB). We measured statistical heterogeneity using the I2 statistic. We used a random-effects model. We conducted trial sequential analyses, Bayes factor, and fragility indices where appropriate.

Main results
In this third update, we identified three new randomised controlled trials, for a total of 15 randomised controlled trials involving 71,422 participants. Nine trials (60%) had low risk of bias, length of follow-up ranged from one to 7.3 years. Compared with placebo, there were no differences in effects of homocysteine-lowering interventions on myocardial infarction (homocysteine-lowering = 7.1% versus placebo = 6.0%; RR 1.02, 95% confidence interval (CI) 0.95 to 1.10, I2 = 0%, 12 trials; N = 46,699; Bayes factor 1.04, high-quality evidence), death from any cause (homocysteine-lowering = 11.7% versus placebo = 12.3%, RR 1.01, 95% CI 0.96 to 1.06, I2 = 0%, 11 trials, N = 44,817; Bayes factor = 1.05, high-quality evidence), or serious adverse events (homocysteine-lowering = 8.3% versus comparator = 8.5%, RR 1.07, 95% CI 1.00 to 1.14, I2 = 0%, eight trials, N = 35,788; high-quality evidence). Compared with placebo, homocysteine-lowering interventions were associated with reduced stroke outcome (homocysteine-lowering = 4.3% versus comparator = 5.1%, RR 0.90, 95% CI 0.82 to 0.99, I2 = 8%, 10 trials, N = 44,224; high-quality evidence). Compared with low doses, there were uncertain effects of high doses of homocysteine-lowering interventions on stroke (high = 10.8% versus low = 11.2%, RR 0.90, 95% CI 0.66 to 1.22, I2 = 72%, two trials, N = 3929; very low-quality evidence).

We found no evidence of publication bias.

Authors' conclusions
In this third update of the Cochrane review, there were no differences in effects of homocysteine-lowering interventions in the form of supplements of vitamins B6, B9 or B12 given alone or in combination comparing with placebo on myocardial infarction, death from any cause or adverse events. In terms of stroke, this review found a small difference in effect favouring to homocysteine-lowering interventions in the form of supplements of vitamins B6, B9 or B12 given alone or in combination comparing with placebo.

There were uncertain effects of enalapril plus folic acid compared with enalapril on stroke; approximately 143 (95% CI 85 to 428) people would need to be treated for 5.4 years to prevent 1 stroke, this evidence emerged from one mega-trial.

Trial sequential analyses showed that additional trials are unlikely to increase the certainty about the findings of this issue regarding homocysteine-lowering interventions versus placebo. There is a need for additional trials comparing homocysteine-lowering interventions combined with antihypertensive medication versus antihypertensive medication, and homocysteine-lowering interventions at high doses versus homocysteine-lowering interventions at low doses. Potential trials should be large and co-operative.

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Homocysteine‐lowering interventions for preventing cardiovascular events

https://www.journal-of-hepatology.eu/article/S0168-8278(16)30107-6/pdf

Non-alcoholic fatty liver disease and cardiovascular risk: Pathophysiological mechanisms and implications.

Cardiovascular disease is a significant and ever-growing problem in the United Kingdom, accounting for nearly one-third of all deaths and leading to significant morbidity. It is also of particular and pressing interest as developing countries experience a change in lifestyle which introduces novel risk factors for cardiovascular disease, leading to a boom in cardiovascular disease risk throughout the developing world. The burden of cardiovascular disease can be ameliorated by careful risk reduction and, as such, primary prevention is an important priority for all developers of health policy. Strong consensus exists between international guidelines regarding the necessity of smoking cessation, weight optimisation and the importance of exercise, whilst guidelines vary slightly in their approach to hypertension and considerably regarding their approach to optimal lipid profile which remains a contentious issue. Previously fashionable ideas such as the polypill appear devoid of in-vivo efficacy, but there remain areas of future interest such as the benefit of serum urate reduction and utility of reduction of homocysteine levels.

https://journals.sagepub.com/doi/pdf/10.1177/2048004020949326

Primary prevention of cardiovascular disease: A review of contemporary guidance and literature:

It is well known that neuronal damage following a stroke has been attributed to the over stimulation of excitatory amino acids such as glutamate and aspartate through activation of NMDA receptors. The brain is exposed to most of the constituents of plasma including homocysteine as a result of the disruption of the blood–brain barrier after stroke, head trauma and stress. The question, therefore, arises as to whether or not homocysteine is able to selectively stimulate the release of excitatory amino acids in stroke. This review article will address the importance of homocysteine in nervous system specifically how these amino acids may trigger the release of catecholamines. Our data will thus strengthen the view that a mechanism for the association of hyperhomocysteinemia with increased brain lesion in stroke. As hypothalamus also controls the cardiac function via sympathetic system, the contractility of heart will be compromised. Homocysteine is also known to mediate cardiovascular problems by its adverse effects on cardiovascular endothelium and smooth muscle cells with resultant alterations in subclinical arterial structure and function. The present review will thus summarize both central and peripheral effects of homocysteine and will highlight some of the controversies associated with hyperhomocysteinemia-induced cardiovascular problems.

/pdf/role-of-homocysteine-in-the-development-of-cardiovascular-4b6vh5ao2p.pdf

Role of homocysteine in the development of cardiovascular disease

Today we are beginning to understand how phytochemicals can influence metabolism, cellular signaling and gene expression The hydroxybenzoic acids are related to salicylic acid and salicin, the first compounds isolated that have a pharmacological activity In this review we examine how a number of hydroxyphenolics have the potential to ameliorate cardiovascular problems related to aging such as hypertension, atherosclerosis and dyslipidemia The compounds focused upon include 2,3-dihydroxybenzoic acid (Pyrocatechuic acid), 2,5-dihydroxybenzoic acid (Gentisic acid), 3,4-dihydroxybenzoic acid (Protocatechuic acid), 3,5-dihydroxybenzoic acid (α-Resorcylic acid) and 3-monohydroxybenzoic acid The latter two compounds activate the hydroxycarboxylic acid receptors with a consequence there is a reduction in adipocyte lipolysis with potential improvements of blood lipid profiles Several of the other compounds can activate the Nrf2 signaling pathway that increases the expression of antioxidant enzymes, thereby decreasing oxidative stress and associated problems such as endothelial dysfunction that leads to hypertension as well as decreasing generalized inflammation that can lead to problems such as atherosclerosis It has been known for many years that increased consumption of fruits and vegetables promotes health We are beginning to understand how specific phytochemicals are responsible for such therapeutic effects Hippocrates’ dictum of ‘Let food be your medicine and medicine your food’ can now be experimentally tested and the results of such experiments will enhance the ability of nutritionists to devise specific health-promoting diets

/pdf/hydroxybenzoic-acid-isomers-and-the-cardiovascular-system-4vu6wulxqn.pdf

Hydroxybenzoic acid isomers and the cardiovascular system

Assessing teaching-learning outcomes in anatomical knowledge is a complex task that requires the evaluation of multiple domains: theoretical, practical, and clinical knowledge. In general, theoretical knowledge is tested by a written examination system constituted by multiple choice questions (MCQs) and/or short answer questions (SAQ). The assessment of practical knowledge (three-dimensional anatomical concepts) involves oral, spot, or objective structured practical examinations (OSPE). Finally, the application of anatomical knowledge to patients is tested mainly through objective structured clinical examinations (OSCE). The major focus of this study is the OSPE. Although many schools challenge students using this tool in practical examinations in the early phase of the curriculum, the true meaning of OSPE is frequently forgotten and it becomes, in reality, a spot examination. This article, for the first time, describes how the concept of the OSPE has evolved and is currently being used to assess the practical domain of anatomical knowledge in a problem-based curriculum at Alfaisal University College of Medicine. In addition, it describes the main differences from the spot examination, which is normally used in traditional medical curricula. The authors believe that the OSPE remains the most efficient tool to assess the practical aspects of anatomical knowledge in a system where basic knowledge is integrated with the clinical or functional part of anatomy. However, this contention only holds true if the OSPE process revolves around structured objectives.

What is an objective structured practical examination in anatomy

Alfaisal University is a new medical school in Riyadh, Kingdom of Saudi Arabia that matriculates eligible students directly from high school and requires them to participate in a hybrid problem-based learning (PBL) curriculum. PBL is a well-established student-centered approach, and the authors have sought to examine if a student-centered, integrated approach to learn human structures leads to positive perceptions of learning outcomes. Ten students were divided into four groups to rotate through wet and dry laboratory stations (integrated resource sessions, IRSs) that engaged them in imaging techniques, embryology, histology, gross anatomy (dissections and prosections), surface anatomy, and self-directed learning questions. All IRSs were primarily directed by students. During two second-semester organ system blocks, forty students responded to a structured questionnaire designed to poll students' perceptions of changes in their knowledge, skills, and attitudes as a result of IRS. The majority (60%) of students felt that the student-centered approach to learning enhanced their medical knowledge. Most students also felt that the IRS approach was advantageous for formulating clear learning objectives (55%) and in preparing for examinations (65%). Despite their positive feelings toward IRS, students did not view this learning approach as an adequate replacement for the knowledge gained from lectures and textbooks. Students' performance on objective structured practical examinations improved significantly for the two curricular blocks that included IRS compared with earlier non-IRS blocks. A student-centered approach to teach human structure in a hybrid PBL curriculum may enhance understanding of the basic sciences in first-year medical students.

Student-centered integrated anatomy resource sessions at Alfaisal University

Elevated plasma level of homocysteine is being increasingly associated with many diseases. There is a significant interest in the development of methods to determine the total homocysteine in biologically relevant tissues. Over the years, researchers use various methods to determine the exact concentrations of homocysteine in these tissues. However, the precise method used in many studies earlier was questionable. We have reviewed various methodologies for the measurement of homocysteine. We list the commonly used methodologies currently in use to determine homocysteine levels. Through extensive literature search, we have come up with the most popular as well as the newest measurement modalities and listed them with a brief discussion of each of the methodology. In conclusion, we have presented the historical perspective of homocysteine measurement in biological fluids in this manuscript. Thus, the precise understanding of its concentration in biological fluids coupled with its importance in health and disease should justify a newer but reliable technique in the area of ongoing research in homocysteine.

Paul Ganguly

Papers

Role of homocysteine in the development of cardiovascular disease

Hydroxybenzoic acid isomers and the cardiovascular system

What is an objective structured practical examination in anatomy

Student-centered integrated anatomy resource sessions at Alfaisal University

Measurement of homocysteine: a historical perspective