Elevated Serum Levels of Osteopontin in HCV-Associated Lymphoproliferative Disorders.

Hepatitis C virus (HCV) infection is associated with chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Recent evidences have also suggested that HCV infection contributes to development of autoimmune disorders and B-cell nonHodgkin's lymphoma (NHL). Mechanisms by which HCV infection promotes B-cell NHL development remain unclear. Increased serum osteopontin (OPN) levels have been associated with several autoimmune diseases as well as a variety of cancers. However, the association between OPN and B-cell NHL or HCV-associated B-cell proliferation has not previously been reported. In the present study, we determined whether serum OPN differences were associated with HCV infection, type II mixed cryglobulinemia (MC) syndrome and B-cell NHL. Serum OPN levels were measured by capture enzyme-linked immunosorbent assay. Our results show that high serum OPN levels are associated with B-cell NHL and HCV infection. Interestingly, highest serum OPN concentrations were found among HCV-infected patients with concomitant type II MC syndrome with and without B-cell NHL. These data indicate that OPN is involved in the lymphomagenesis, especially, in the context of HCV infection and autoimmune diseases

On no man’s land: Subjective experiences during unresponsive and responsive sedative states induced by four different anesthetic agents

To understand how anesthetics with different molecular mechanisms affect consciousness, we explored subjective experiences recalled after responsive and unresponsive sedation induced with equisedative doses of dexmedetomidine, propofol, sevoflurane, and S-ketamine in healthy male participants (N = 140). The anesthetics were administered in experimental setting using target-controlled infusion or vapouriser for one hour. Interviews conducted after anesthetic administration revealed that 46.9% (n = 46) of arousable participants (n = 98) reported experiences, most frequently dreaming or memory incorporation of the setting. Participants receiving dexmedetomidine reported experiences most often while S-ketamine induced the most multimodal experiences. Responsiveness at the end of anesthetic administration did not affect the prevalence or content of reported experiences. These results demonstrate that subjective experiences during responsive and unresponsive sedation are common and anesthetic agents with different molecular mechanisms of action may have different effects on the prevalence and complexity of the experiences, albeit in the present sample the differences between drugs were minute.</p

Foundations of human consciousness: Imaging the twilight zone

What happens in the brain when conscious awareness of the surrounding world fades? We manipulated consciousness in two experiments in a group of healthy males and measured brain activity with positron emission tomography. Measurements were made during wakefulness, escalating and constant levels of two anesthetic agents (Experiment 1, n=39) and during sleep-deprived wakefulness and Non-Rapid Eye Movement sleep (Experiment 2, n=37). In Experiment 1, the subjects were randomized to receive either propofol or dexmedetomidine until unresponsiveness. In both experiments, forced awakenings were applied to achieve rapid recovery from an unresponsive to a responsive state, followed by immediate and detailed interviews of subjective experiences during the preceding unresponsive condition. Unresponsiveness rarely denoted unconsciousness, as the majority of the subjects had internally generated experiences. Unresponsive anesthetic states and verified sleep stages, where a subsequent report of mental content included no signs of awareness of the surrounding world, indicated a disconnected state. Functional brain imaging comparing responsive and connected vs. unresponsive and disconnected states of consciousness during constant anesthetic exposure revealed that activity of the thalamus, cingulate cortices and angular gyri are fundamental for human consciousness. These brain structures were affected independent from the pharmacologic agent, drug concentration and direction of change in the state of consciousness. Analogous findings were obtained when consciousness was regulated by physiological sleep. State-specific findings were distinct and separable from the overall effects of the interventions, which included widespread depression of brain activity across cortical areas. These findings identify a central core brain network critical for human consciousness.</p

Hypermethylation of the DLC1 CpG island does not alter gene expression in canine lymphoma

<p>Abstract</p> <p>Background</p> <p>This study is a comparative epigenetic evaluation of the methylation status of the <it>DLC1 </it>tumor suppressor gene in naturally-occurring canine lymphoma. Canine non-Hodgkin's lymphoma (NHL) has been proposed to be a relevant preclinical model that occurs spontaneously and may share causative factors with human NHL due to a shared home environment. The canine <it>DLC1 </it>mRNA sequence was derived from normal tissue. Using lymphoid samples from 21 dogs with NHL and 7 normal dogs, the methylation status of the promoter CpG island of the gene was defined for each sample using combined bisulfite restriction analysis (COBRA), methylation-specific PCR (MSP), and bisulfite sequencing methods. Relative gene expression was determined using real-time PCR.</p> <p>Results</p> <p>The mRNA sequence of canine <it>DLC1 </it>is highly similar to the human orthologue and contains all protein functional groups, with 97% or greater similarity in functional regions. Hypermethylation of the 5' and 3' flanking regions of the promoter was statistically significantly associated with the NHL phenotype, but was not associated with silencing of expression or differences in survival.</p> <p>Conclusion</p> <p>The canine <it>DLC1 </it>is constructed highly similarly to the human gene, which has been shown to be an important tumor suppressor in many forms of cancer. As in human NHL, the promoter CpG island of <it>DLC1 </it>in canine NHL samples is abnormally hypermethylated, relative to normal lymphoid tissue. This study confirms that hypermethylation occurs in canine cancers, further supporting the use of companion dogs as comparative models of disease for evaluation of carcinogenesis, biomarker diagnosis, and therapy.</p

“Gli aspetti innovativi dell’informativa finanziaria nelle “entità” del settore pubblico: gli IPSAS 5, 15, 18, 19 e 21”

Per il citato lavoro, che rappresenta un contributo alla ricerca della Scuola Superiore della Pubblica Amministrazione “Principi e metodi di contabilità economico-patrimoniale per lo Stato e le Pubbliche Amministrazioni nel quadro teorico ed operativo internazionale” (coordinatore Prof. L. Anselmi, anni 2007/2008), sono stati assolti gli obblighi di pubblicazione direttamente dall’autore, ai sensi della Legge 15.4.2006 n. 106 e del D.P.R. 03.05.2006, n. 252

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Health Professional Training and Capacity Strengthening Through International Academic Partnerships: The First Five Years of the Human Resources for Health Program in Rwanda

Abstract Background: The Rwanda Human Resources for Health Program (HRH Program) is a 7-year (2012-2019) health professional training initiative led by the Government of Rwanda with the goals of training a large, diverse, and competent health workforce and strengthening the capacity of academic institutions in Rwanda. Methods: The data for this organizational case study was collected through official reports from the Rwanda Ministry of Health (MoH) and 22 participating US academic institutions, databases from the MoH and the College of Medicine and Health Sciences (CMHS) in Rwanda, and surveys completed by the co-authors. Results: In the first 5 years of the HRH Program, a consortium of US academic institutions has deployed an average of 99 visiting faculty per year to support 22 training programs, which are on track to graduate almost 4600 students by 2019. The HRH Program has also built capacity within the CMHS by promoting the recruitment of Rwandan faculty and the establishment of additional partnerships and collaborations with the US academic institutions. Conclusion: The milestones achieved by the HRH Program have been substantial although some challenges persist. These challenges include adequately supporting the visiting faculty; pairing them with Rwandan faculty (twinning); ensuring strong communication and coordination among stakeholders; addressing mismatches in priorities between donors and implementers; the execution of a sustainability strategy; and the decision by one of the donors not to renew funding beyond March 2017. Over the next 2 academic years, it is critical for the sustainability of the 22 training programs supported by the HRH Program that the health-related Schools at the CMHS significantly scale up recruitment of new Rwandan faculty. The HRH Program can serve as a model for other training initiatives implemented in countries affected by a severe shortage of health professionals