Isolation and Characterization of Water-Soluble Fluorescent Species from Human Serum

Lipid peroxidation (LP) proceeds by a free radical chain reaction mechanism in which molecular oxygen is incorporated into polyunsaturated fatty acids (PUFA) to yield lipid hydroperoxides (LOOH). The ultimate end-products of LP are the production of alpha, beta unsaturated aldehydes, such as acrolein, 4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA). These aldehydes are very reactive and exhibit facile reactivity with various biomolecules, particularly proteins, resulting in the formation of fluorescent adducts that could be useful biological marker in diseases. These fluorescent adducts typically emit light between 400 and 600 nm when excited at wavelengths ranging from 300-400 nm. Lysine residues are the major amino-acids that are predicated to react with aldehydes to yield fluorescent adducts. LP has been implicated in several diseases such as atherosclerosis, Parkinson, Alzheimer, and diabetes. Water-soluble fluorescent species (WSF) are fluorescent species that exhibited similar fluorescence characteristics for excitation and emission to those from aldehyde-modified proteins and amino-acids analogues. WSF showed also direct correlation with age, so it suggested that its components could serve as a useful biomarker for in vivo LP. We determined that WSF was composed of two main components, a high molecular weight protein component and a low molecular weight non-protein component. The non-protein component was unreactive towards proteins. We were able to identify four major protein species in the protein component that contributed to the fluorescence. These protein species were HSA, HST, Ig-G and carbonic anhydrase, with HSA and HST being the major species contributing to the overall fluorescence in the protein component. The fluorophore was determined to be covalently bound to the protein component. Using CNBr digestion on isolated HSA and HST, we were able to determine multiple fluorophore binding sites within both proteins. We determined by MALDI TOF/MS that there were indeed MW increases in HSA and HST after aldehyde modification due to the fluorophores formation. In vitro studies on HSA determined a change in the pI due to aldehyde modifications. In vitro functional studies on HST suggested that there might be a loss of one the HST Fe binding sites due to aldehyde modification

LC-MS/MS Tandem Mass Spectrometry for Analysis of Phenolic Compounds and Pentacyclic Triterpenes in Antifungal Extracts of Terminalia brownii (Fresen)

Decoctions and macerations of the stem bark and wood of Terminalia brownii Fresen. are used in traditional medicine for fungal infections and as fungicides on field crops and in traditional granaries in Sudan. In addition, T. brownii water extracts are commonly used as sprays for protecting wooden houses and furniture. Therefore, using agar disc diffusion and macrodilution methods, eight extracts of various polarities from the stem wood and bark were screened for their growth-inhibitory effects against filamentous fungi commonly causing fruit, vegetable, grain and wood decay, as well as infections in the immunocompromised host. Ethyl acetate extracts of the stem wood and bark gave the best antifungal activities, with MIC values of 250 ug/mL against Nattrassia mangiferae and Fusarium verticillioides, and 500 ug/mL against Aspergillus niger and Aspergillus flavus. Aqueous extracts gave almost as potent effects as the ethyl acetate extracts against the Aspergillus and Fusarium strains, and were slightly more active than the ethyl acetate extracts against Nattrassia mangiferae. Thin layer chromatography, RP-HPLC-DAD and tandem mass spectrometry (LC-MS/MS), were employed to identify the chemical constituents in the ethyl acetate fractions of the stem bark and wood. The stem bark and wood were found to have a similar qualitative composition of polyphenols and triterpenoids, but differed quantitatively from each other. The stilbene derivatives, cis- (3) and trans- resveratrol-3-O-b-galloylglucoside (4), were identified for the first time in T. brownii. Moreover, methyl-(S)-flavogallonate (5), quercetin-7-b-O-di-glucoside (8), quercetin-7-O-galloyl-glucoside (10), naringenin-40-methoxy-7-pyranoside (7), 5,6-dihydroxy-30,40,7-tri-methoxy flavone (12), gallagic acid dilactone (terminalin) (6), a corilagin derivative (9) and two oleanane type triterpenoids (1) and (2) were characterized. The flavonoids, a corilagin derivative and terminalin, have not been identified before in T. brownii. We reported earlier on the occurrence of methyl-S-flavogallonate and its isomer in the roots of T. brownii, but this is the first report on their occurrence in the stem wood as well. Our results justify the traditional uses of macerations and decoctions of T. brownii stem wood and bark for crop and wood protection and demonstrate that standardized extracts could have uses for the eco-friendly control of plant pathogenic fungi in African agroforestry systems. Likewise, our results justify the traditional uses of these preparations for the treatment of skin infections caused by filamentous fungi.Peer reviewe

Sustained proliferation in cancer: mechanisms and novel therapeutic targets

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression

Burden of disease scenarios for 204 countries and territories, 2022–2050: a forecasting analysis for the Global Burden of Disease Study 2021

Background: Future trends in disease burden and drivers of health are of great interest to policy makers and the public at large. This information can be used for policy and long-term health investment, planning, and prioritisation. We have expanded and improved upon previous forecasts produced as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) and provide a reference forecast (the most likely future), and alternative scenarios assessing disease burden trajectories if selected sets of risk factors were eliminated from current levels by 2050. Methods: Using forecasts of major drivers of health such as the Socio-demographic Index (SDI; a composite measure of lag-distributed income per capita, mean years of education, and total fertility under 25 years of age) and the full set of risk factor exposures captured by GBD, we provide cause-specific forecasts of mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) by age and sex from 2022 to 2050 for 204 countries and territories, 21 GBD regions, seven super-regions, and the world. All analyses were done at the cause-specific level so that only risk factors deemed causal by the GBD comparative risk assessment influenced future trajectories of mortality for each disease. Cause-specific mortality was modelled using mixed-effects models with SDI and time as the main covariates, and the combined impact of causal risk factors as an offset in the model. At the all-cause mortality level, we captured unexplained variation by modelling residuals with an autoregressive integrated moving average model with drift attenuation. These all-cause forecasts constrained the cause-specific forecasts at successively deeper levels of the GBD cause hierarchy using cascading mortality models, thus ensuring a robust estimate of cause-specific mortality. For non-fatal measures (eg, low back pain), incidence and prevalence were forecasted from mixed-effects models with SDI as the main covariate, and YLDs were computed from the resulting prevalence forecasts and average disability weights from GBD. Alternative future scenarios were constructed by replacing appropriate reference trajectories for risk factors with hypothetical trajectories of gradual elimination of risk factor exposure from current levels to 2050. The scenarios were constructed from various sets of risk factors: environmental risks (Safer Environment scenario), risks associated with communicable, maternal, neonatal, and nutritional diseases (CMNNs; Improved Childhood Nutrition and Vaccination scenario), risks associated with major non-communicable diseases (NCDs; Improved Behavioural and Metabolic Risks scenario), and the combined effects of these three scenarios. Using the Shared Socioeconomic Pathways climate scenarios SSP2-4.5 as reference and SSP1-1.9 as an optimistic alternative in the Safer Environment scenario, we accounted for climate change impact on health by using the most recent Intergovernmental Panel on Climate Change temperature forecasts and published trajectories of ambient air pollution for the same two scenarios. Life expectancy and healthy life expectancy were computed using standard methods. The forecasting framework includes computing the age-sex-specific future population for each location and separately for each scenario. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. Findings: In the reference scenario forecast, global and super-regional life expectancy increased from 2022 to 2050, but improvement was at a slower pace than in the three decades preceding the COVID-19 pandemic (beginning in 2020). Gains in future life expectancy were forecasted to be greatest in super-regions with comparatively low life expectancies (such as sub-Saharan Africa) compared with super-regions with higher life expectancies (such as the high-income super-region), leading to a trend towards convergence in life expectancy across locations between now and 2050. At the super-region level, forecasted healthy life expectancy patterns were similar to those of life expectancies. Forecasts for the reference scenario found that health will improve in the coming decades, with all-cause age-standardised DALY rates decreasing in every GBD super-region. The total DALY burden measured in counts, however, will increase in every super-region, largely a function of population ageing and growth. We also forecasted that both DALY counts and age-standardised DALY rates will continue to shift from CMNNs to NCDs, with the most pronounced shifts occurring in sub-Saharan Africa (60·1% [95% UI 56·8–63·1] of DALYs were from CMNNs in 2022 compared with 35·8% [31·0–45·0] in 2050) and south Asia (31·7% [29·2–34·1] to 15·5% [13·7–17·5]). This shift is reflected in the leading global causes of DALYs, with the top four causes in 2050 being ischaemic heart disease, stroke, diabetes, and chronic obstructive pulmonary disease, compared with 2022, with ischaemic heart disease, neonatal disorders, stroke, and lower respiratory infections at the top. The global proportion of DALYs due to YLDs likewise increased from 33·8% (27·4–40·3) to 41·1% (33·9–48·1) from 2022 to 2050, demonstrating an important shift in overall disease burden towards morbidity and away from premature death. The largest shift of this kind was forecasted for sub-Saharan Africa, from 20·1% (15·6–25·3) of DALYs due to YLDs in 2022 to 35·6% (26·5–43·0) in 2050. In the assessment of alternative future scenarios, the combined effects of the scenarios (Safer Environment, Improved Childhood Nutrition and Vaccination, and Improved Behavioural and Metabolic Risks scenarios) demonstrated an important decrease in the global burden of DALYs in 2050 of 15·4% (13·5–17·5) compared with the reference scenario, with decreases across super-regions ranging from 10·4% (9·7–11·3) in the high-income super-region to 23·9% (20·7–27·3) in north Africa and the Middle East. The Safer Environment scenario had its largest decrease in sub-Saharan Africa (5·2% [3·5–6·8]), the Improved Behavioural and Metabolic Risks scenario in north Africa and the Middle East (23·2% [20·2–26·5]), and the Improved Nutrition and Vaccination scenario in sub-Saharan Africa (2·0% [–0·6 to 3·6]). Interpretation: Globally, life expectancy and age-standardised disease burden were forecasted to improve between 2022 and 2050, with the majority of the burden continuing to shift from CMNNs to NCDs. That said, continued progress on reducing the CMNN disease burden will be dependent on maintaining investment in and policy emphasis on CMNN disease prevention and treatment. Mostly due to growth and ageing of populations, the number of deaths and DALYs due to all causes combined will generally increase. By constructing alternative future scenarios wherein certain risk exposures are eliminated by 2050, we have shown that opportunities exist to substantially improve health outcomes in the future through concerted efforts to prevent exposure to well established risk factors and to expand access to key health interventions

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Controlling Surveillance Systems and PTZ Cameras from a Mobile Device

A data center is a physical facility that organizations use to house their critical applications and data. An application delivery controller, router, switch, firewall, storage system, and server make up the design for the data center. Data security in the data center is critical due to these components' role in storing and managing critical business data and applications. An Android application has therefore been developed that can be used on smart phones to monitor and follow the performance of the data center camera monitoring system. Surveillance cameras in the data center allows the data center manager to monitor employees, machines, and all data center facilities from his office via his mobile phone, or even when he is out of the office, and to view a report of faults and maintenance to ensure the efficiency of the system. Using the application, the engineer can also control the cameras by panning and zooming in on the camera images in the data center, playback previous recordings of cameras, and review fault reports to find out the malfunctions of the monitoring system from anywhere with an Internet connection

Acute abdomen -like-presentation associated with SARS-CoV-2 infection

As the cases of COVID-19 are flooding around the world, atypical presentations are being recognized, making the diagnosis challenging. Gastrointestinal symptoms and mild abdominal pain are common. However, severe abdominal pain associated with COVID-19 warranting surgical evaluation has been rarely described; recognizing such presentations and differentiating them from a surgical abdomen is critical to effectively and safely manage COVID-19 patients. Here we present a case of a middle-aged gentleman who developed features resembling secondary peritonitis. Eventually, he was found to have COVID-19 and was managed conservatively. In this report, we discuss his management course, and we explore pertinent relevant literature

An online module to evaluate the validity of an algorithm to assess the risk for drug-induced QTc prolongation in the psychiatric population

Introduction: QTc interval prolongation leads to serious complications making it a concern for all clinicians. Assessing the risk of QTc interval prolongation, especially in the psychiatric population, can be challenging for pharmacists due to the complexity of regimens in this population and the difficulty in retrieving the needed information for the risk assessment. Guidelines and protocols for QTc prolongation risk assessment may vary among clinicians and few algorithms exist that address the prevention, management or monitoring of drug-induced QTc prolongation in the psychiatric population. Hence, there is a need for a validated comprehensive algorithm that helps clinicians in with the assessment of the risk of QTc prolongation. The study aims to pilot an educational module that guides experts through an algorithm for the assessment, management and monitoring of drug-induced QTc prolongation in the psychiatric population. Methods: This study involved developing an online education module using Articulate Presenter' to introduce a comprehensive literature-based algorithm to subject-matter experts. The orientation was followed by an anonymous, self-administered survey with quantitative and qualitative components to assess the content validity of the QTc Prolongation Algorithm. Results: Feedback from the first pilot test with faculty members indicated that the module's interface was crowded. The module was updated accordingly. The results from the second pilot test with cardiologists were that the module provided a thorough explanation of the algorithm steps and rationale. Furthermore, some cardiologists commented that the algorithm was time consuming, however, most supported the implementation of the algorithm saying that it is easy to use, systematic, step-based and would be helpful if implemented. Conclusion/Future Directions: The results show that the module was helpful in introducing cardiologists to the algorithm and that the implementation of the algorithm after minor alterations can prove to be useful as a tool for risk assessment of QTc prolongatio

Proteomics and Lipidomics in Inflammatory Bowel Disease Research: From Mechanistic Insights to Biomarker Identification

Inflammatory bowel disease (IBD) represents a group of progressive disorders characterized by recurrent chronic inflammation of the gut. Ulcerative colitis and Crohn′s disease are the major manifestations of IBD. While our understanding of IBD has progressed in recent years, its etiology is far from being fully understood, resulting in suboptimal treatment options. Complementing other biological endpoints, bioanalytical “omics” methods that quantify many biomolecules simultaneously have great potential in the dissection of the complex pathogenesis of IBD. In this review, we focus on the rapidly evolving proteomics and lipidomics technologies and their broad applicability to IBD studies; these range from investigations of immune-regulatory mechanisms and biomarker discovery to studies dissecting host–microbiome interactions and the role of intestinal epithelial cells. Future studies can leverage recent advances, including improved analytical methodologies, additional relevant sample types, and integrative multi-omics analyses. Proteomics and lipidomics could effectively accelerate the development of novel targeted treatments and the discovery of complementary biomarkers, enabling continuous monitoring of the treatment response of individual patients; this may allow further refinement of treatment and, ultimately, facilitate a personalized medicine approach to IBD