Serum clusterin as a marker for diagnosing hepatocellular carcinoma

Background: Approximately 80% of patients with hepatocellular carcinoma (HCC) areuntreatable because of advanced tumor stages at presentation. Therefore, finding newer markers for screening and diagnosing HCC is of utmost importance. Clusterin (CLU) is a 449 amino acid, heterodimeric glycoprotein with a plausible role in the regeneration, migration, and anti-apoptosis of tumor cells. It has been implicated in many malignancies such as prostate and pancreatic adenocarcinomas, but its role in HCC is not well defined.Objective: We aimed to evaluate the diagnostic performance of serum CLU level in diagnosing HCC on top of hepatitis C virus-related liver cirrhosis, and comparing it to that of alpha fetoprotein (AFP).Methods: Twenty cases of apparently healthy subjects, 27 cases of hepatitis C virus-related liver cirrhosis (CHC cases), and 44 HCC cases on top of hepatitis C virus-related liver cirrhosis were included in this study. Serum CLU concentration was determined using a quantitative sandwich enzyme immunoassay technique.Results: Serum clusterin level showed a significant increase in the HCC group compared to the control group (151.96 ± 32.74 vs. 111.40 ±27.46) and to the CHC group (151.96 ± 32.74 vs. 89.12 ±31.62), while a significant decrease in serum clusterin level was found in the CHC group compared to the control group (89.12± 31.62 vs. 111.40± 27.46). Based on receiver operator characteristic curve analysis, serum AFP still surpassed serum CLU in diagnostic sensitivity (77.3% vs. 70.5%), specificity (100% vs. 90%), and positive and negative predictive values (100% vs. 86.1% and 83.3% vs. 77.6% respectively). The use of a combined parallel approach improved the diagnostic sensitivity (95.5%) and negative predictive value (95.7%) over the single use of AFP.Conclusions: Although the diagnostic performance of serum AFP outperformed that of serum CLU, their combined parallel approach improved the sensitivity which is required in screening high risk populations such as CHC patients. KEYWORDS Clusterin; Alpha fetoprotein; Tumor marker; Hepatitis C virus related liver cirrhosis; Hepatocellular carcinom

Current and prospective pharmacological targets in relation to antimigraine action

Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT2 receptor antagonists, Ca2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT1-7), adrenergic (α1, α2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP2), adenosine (A1, A2, and A3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Pilot assessment of the sensitivity of the malaria thin film

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Perspectives of the Apiaceae Hepatoprotective Effects - A Review

The liver has the crucial role in the regulation of various physiological processes and in the excretion of endogenous waste metabolites and xenobiotics. Liver structure impairment can be caused by various factors including microorganisms, autoimmune diseases, chemicals, alcohol and drugs. The plant kingdom is full of liver protective chemicals such as phenols, coumarins, lignans, essential oils, monoterpenes, carotenoids, glycosides, flavonoids, organic acids, lipids, alkaloids and xanthenes. Apiaceae plants are usually used as a vegetable or as a spice, but their other functional properties are also very important. This review highlights the significance of caraway, dill, cumin, aniseed, fennel, coriander, celery, lovage, angelica, parsley and carrot, which are popular vegetables and spices, but possess hepatoprotective potential. These plants can be used for medicinal applications to patients who suffer from liver damage

RNAi Screening in Drosophila Cells Identifies New Modifiers of Mutant Huntingtin Aggregation

The fruitfly Drosophila melanogaster is well established as a model system in the study of human neurodegenerative diseases. Utilizing RNAi, we have carried out a high-throughput screen for modifiers of aggregate formation in Drosophila larval CNS-derived cells expressing mutant human Huntingtin exon 1 fused to EGFP with an expanded polyglutamine repeat (62Q). 7200 genes, encompassing around 50% of the Drosophila genome, were screened, resulting in the identification of 404 candidates that either suppress or enhance aggregation. These candidates were subjected to secondary screening in normal length (18Q)-expressing cells and pruned to remove dsRNAs with greater than 10 off-target effects (OTEs). De novo RNAi probes were designed and synthesized for the remaining 68 candidates. Following a tertiary round of screening, 21 high confidence candidates were analyzed in vivo for their ability to modify mutant Huntingtin-induced eye degeneration and brain aggregation. We have established useful models for the study of human HD using the fly, and through our RNAi screen, we have identified new modifiers of mutant human Huntingtin aggregation and aggregate formation in the brain. Newly identified modifiers including genes related to nuclear transport, nucleotide processes, and signaling, may be involved in polyglutamine aggregate formation and Huntington disease cascades

Diabetes Is an Independent Risk Factor for Severe Nocturnal Hypoxemia in Obese Patients. A Case-Control Study

Type 2 diabetes mellitus (T2DM) and obesity have become two of the main threats to public health in the Western world. In addition, obesity is the most important determinant of the sleep apnea-hypopnea syndrome (SAHS), a condition that adversely affects glucose metabolism. However, it is unknown whether patients with diabetes have more severe SAHS than non-diabetic subjects. The aim of this cross-sectional case-control study was to evaluate whether obese patients with T2DM are more prone to severe SAHS than obese non-diabetic subjects.Thirty obese T2DM and 60 non-diabetic women closely matched by age, body mass index, waist circumference, and smoking status were recruited from the outpatient Obesity Unit of a university hospital. The exclusion criteria included chronic respiratory disease, smoking habit, neuromuscular and cerebrovascular disease, alcohol abuse, use of sedatives, and pregnancy. Examinations included a non-attended respiratory polygraphy, pulmonary function testing, and an awake arterial gasometry. Oxygen saturation measures included the percentage of time spent at saturations below 90% (CT90). A high prevalence of SAHS was found in both groups (T2DM:80%, nondiabetic:78.3%). No differences in the number of sleep apnea-hypopnea events between diabetic and non-diabetic patients were observed. However, in diabetic patients, a significantly increase in the CT90 was detected (20.2+/-30.2% vs. 6.8+/-13,5%; p = 0.027). In addition, residual volume (RV) was significantly higher in T2DM (percentage of predicted: 79.7+/-18.1 vs. 100.1+/-22.8; p<0.001). Multiple linear regression analyses showed that T2DM but not RV was independently associated with CT90.T2DM adversely affects breathing during sleep, becoming an independent risk factor for severe nocturnal hypoxemia in obese patients. Given that SAHS is a risk factor of cardiovascular disease, the screening for SAHS in T2DM patients seems mandatory

Global, regional, and national prevalence of adult overweight and obesity, 1990–2021, with forecasts to 2050: a forecasting study for the Global Burden of Disease Study 2021

Background: Overweight and obesity is a global epidemic. Forecasting future trajectories of the epidemic is crucial for providing an evidence base for policy change. In this study, we examine the historical trends of the global, regional, and national prevalence of adult overweight and obesity from 1990 to 2021 and forecast the future trajectories to 2050. Methods: Leveraging established methodology from the Global Burden of Diseases, Injuries, and Risk Factors Study, we estimated the prevalence of overweight and obesity among individuals aged 25 years and older by age and sex for 204 countries and territories from 1990 to 2050. Retrospective and current prevalence trends were derived based on both self-reported and measured anthropometric data extracted from 1350 unique sources, which include survey microdata and reports, as well as published literature. Specific adjustment was applied to correct for self-report bias. Spatiotemporal Gaussian process regression models were used to synthesise data, leveraging both spatial and temporal correlation in epidemiological trends, to optimise the comparability of results across time and geographies. To generate forecast estimates, we used forecasts of the Socio-demographic Index and temporal correlation patterns presented as annualised rate of change to inform future trajectories. We considered a reference scenario assuming the continuation of historical trends. Findings: Rates of overweight and obesity increased at the global and regional levels, and in all nations, between 1990 and 2021. In 2021, an estimated 1·00 billion (95% uncertainty interval [UI] 0·989–1·01) adult males and 1·11 billion (1·10–1·12) adult females had overweight and obesity. China had the largest population of adults with overweight and obesity (402 million [397–407] individuals), followed by India (180 million [167–194]) and the USA (172 million [169–174]). The highest age-standardised prevalence of overweight and obesity was observed in countries in Oceania and north Africa and the Middle East, with many of these countries reporting prevalence of more than 80% in adults. Compared with 1990, the global prevalence of obesity had increased by 155·1% (149·8–160·3) in males and 104·9% (95% UI 100·9–108·8) in females. The most rapid rise in obesity prevalence was observed in the north Africa and the Middle East super-region, where age-standardised prevalence rates in males more than tripled and in females more than doubled. Assuming the continuation of historical trends, by 2050, we forecast that the total number of adults living with overweight and obesity will reach 3·80 billion (95% UI 3·39–4·04), over half of the likely global adult population at that time. While China, India, and the USA will continue to constitute a large proportion of the global population with overweight and obesity, the number in the sub-Saharan Africa super-region is forecasted to increase by 254·8% (234·4–269·5). In Nigeria specifically, the number of adults with overweight and obesity is forecasted to rise to 141 million (121–162) by 2050, making it the country with the fourth-largest population with overweight and obesity. Interpretation: No country to date has successfully curbed the rising rates of adult overweight and obesity. Without immediate and effective intervention, overweight and obesity will continue to increase globally. Particularly in Asia and Africa, driven by growing populations, the number of individuals with overweight and obesity is forecast to rise substantially. These regions will face a considerable increase in obesity-related disease burden. Merely acknowledging obesity as a global health issue would be negligent on the part of global health and public health practitioners; more aggressive and targeted measures are required to address this crisis, as obesity is one of the foremost avertible risks to health now and in the future and poses an unparalleled threat of premature disease and death at local, national, and global levels. Funding: Bill & Melinda Gates Foundation

False negative rates in Drosophila cell-based RNAi screens: a case study

<p>Abstract</p> <p>Background</p> <p>High-throughput screening using RNAi is a powerful gene discovery method but is often complicated by false positive and false negative results. Whereas false positive results associated with RNAi reagents has been a matter of extensive study, the issue of false negatives has received less attention.</p> <p>Results</p> <p>We performed a meta-analysis of several genome-wide, cell-based <it>Drosophila </it>RNAi screens, together with a more focused RNAi screen, and conclude that the rate of false negative results is at least 8%. Further, we demonstrate how knowledge of the cell transcriptome can be used to resolve ambiguous results and how the number of false negative results can be reduced by using multiple, independently-tested RNAi reagents per gene.</p> <p>Conclusions</p> <p>RNAi reagents that target the same gene do not always yield consistent results due to false positives and weak or ineffective reagents. False positive results can be partially minimized by filtering with transcriptome data. RNAi libraries with multiple reagents per gene also reduce false positive and false negative outcomes when inconsistent results are disambiguated carefully.</p

Role of Germination in Murine Airway CD8+ T-Cell Responses to Aspergillus Conidia

Pulmonary exposure to Aspergillus fumigatus has been associated with morbidity and mortality, particularly in immunocompromised individuals. A. fumigatus conidia produce β-glucan, proteases, and other immunostimulatory factors upon germination. Murine models have shown that the ability of A. fumigatus to germinate at physiological temperature may be an important factor that facilitates invasive disease. We observed a significant increase in IFN-γ-producing CD8+ T cells in bronchoalveolar lavage fluid (BALF) of immunocompetent mice that repeatedly aspirated A. fumigatus conidia in contrast to mice challenged with A. versicolor, a species that is not typically associated with invasive, disseminated disease. Analysis of tissue sections indicated the presence of germinating spores in the lungs of mice challenged with A. fumigatus, but not A. versicolor. Airway IFN-γ+CD8+ T-cells were decreased and lung germination was eliminated in mice that aspirated A. fumigatus conidia that were formaldehyde-fixed or heat-inactivated. Furthermore, A. fumigatus particles exhibited greater persistence in the lungs of recipient mice when compared to non-viable A. fumigatus or A. versicolor, and this correlated with increased maintenance of airway memory-phenotype CD8+ T cells. Therefore, murine airway CD8+ T cell-responses to aspiration of Aspergillus conidia may be mediated in part by the ability of conidia to germinate in the host lung tissue. These results provide further evidence of induction of immune responses to fungi based on their ability to invade host tissue