We present a combined report on the results of three editions of the Cell Tracking Challenge, an ongoing initiative aimed at promoting the development and objective evaluation of cell segmentation ...and tracking algorithms. With 21 participating algorithms and a data repository consisting of 13 data sets from various microscopy modalities, the challenge displays today's state-of-the-art methodology in the field. We analyzed the challenge results using performance measures for segmentation and tracking that rank all participating methods. We also analyzed the performance of all of the algorithms in terms of biological measures and practical usability. Although some methods scored high in all technical aspects, none obtained fully correct solutions. We found that methods that either take prior information into account using learning strategies or analyze cells in a global spatiotemporal video context performed better than other methods under the segmentation and tracking scenarios included in the challenge.
To investigate the relationships between history of falls and cholinergic vs dopaminergic denervation in patients with Parkinson disease (PD).
There is a need to explore nondopaminergic mechanisms of ...gait control as the majority of motor impairments associated with falls in PD are resistant to dopaminergic treatment. Alterations in cholinergic neurotransmission in PD may be implicated because of evidence that gait control depends on cholinergic system-mediated higher-level cortical and subcortical processing, including pedunculopontine nucleus (PPN) function.
In this cross-sectional study, 44 patients with PD (Hoehn & Yahr stages I-III) without dementia and 15 control subjects underwent a clinical assessment and (11)Cmethyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) and (11)Cdihydrotetrabenazine (DTBZ) vesicular monoamine transporter type 2 (VMAT2) brain PET imaging.
Seventeen patients (38.6%) reported a history of falls and 27 patients had no falls. Analysis of covariance of the cortical AChE hydrolysis rates demonstrated reduced cortical AChE in the PD fallers group (-12.3%) followed by the PD nonfallers (-6.6%) compared to control subjects (F = 7.22, p = 0.0004). Thalamic AChE activity was lower only in the PD fallers group (-11.8%; F = 4.36, p = 0.008). There was no significant difference in nigrostriatal dopaminergic activity between PD fallers and nonfallers.
Unlike nigrostriatal dopaminergic denervation, cholinergic hypofunction is associated with fall status in Parkinson disease (PD). Thalamic AChE activity in part represents cholinergic output of the pedunculopontine nucleus (PPN), a key node for gait control. Our results are consistent with other data indicating that PPN degeneration is a major factor leading to impaired postural control and gait dysfunction in PD.
Summary
Background
Plaque psoriasis is a chronic and often debilitating skin disorder and proinflammatory cytokines are known to play a key role in the disease process.
Objectives
To evaluate the ...safety and efficacy of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor, in patients with moderate‐to‐severe psoriasis in a randomized, double‐blind, placebo‐controlled, dose‐ranging phase 2b study.
Methods
Patients were randomized (n = 271) to receive placebo or oral baricitinib at 2, 4, 8 or 10 mg once daily for 12 weeks (Part A). Dose adjustment for 12 additional weeks was based on percentage improvement in the Psoriasis Area and Severity Index (PASI) score. The primary end point was Psoriasis Area and Severity Index (PASI) 75% (PASI‐75) at 12 weeks for North American patients (n = 238); secondary end points were safety and efficacy measures in the entire population.
Results
At week 12, more North American patients in the 8‐mg (43%) and 10‐mg (54%) baricitinib groups than in placebo group (17%; P < 0·05) achieved PASI‐75. All baricitinib‐treated groups had greater mean changes from baseline in their PASI scores (P < 0·05) at 12 weeks and (except 2 mg) had higher rates of PASI‐50 than the placebo group; statistically significant PASI‐90 responses were achieved in the 8‐mg and 10‐mg groups at 8 and 12 weeks. More than 81% of PASI‐75 responders maintained their scores through 24 weeks. During Part A, study discontinuations due to adverse events (AEs) were 0%, 0%, 2·8%, 6·3% and 5·8% and treatment‐emergent AE rates were 44%, 50%, 47%, 58% and 64% for placebo and 2‐, 4‐, 8‐ and 10‐mg baricitinib groups, respectively. No opportunistic infections were observed in any treatment group. Dose‐dependent changes in laboratory values were observed.
Conclusions
Patients with moderate‐to‐severe psoriasis treated with baricitinib for 12 weeks achieved significant improvements in PASI‐75.
What's already known about this topic?
Psoriasis is a common, chronic, immune‐mediated inflammatory skin disease.
Key cytokines involved in the pathogenesis of psoriasis use the Janus kinase–signal transducer and activator of transcription (JAK‐STAT) pathway.
New safe and effective therapies are needed for patients.
What does this study add?
Baricitinib, a selective JAK1/JAK2 inhibitor, demonstrates clinical efficacy in the treatment of psoriasis.
Baricitinib was well tolerated over the 24‐week trial period.
Linked Comment: Albrecht and Gerdes. Br J Dermatol 2016; 174: 1183–1184.
Cancer patients may experience a decrease in cognitive functioning before, during and after cancer treatment. So far, the Quality of Life Group of the European Organisation for Research and Treatment ...of Cancer (EORTC QLG) developed an item bank to assess self-reported memory and attention within a single, cognitive functioning scale (CF) using computerized adaptive testing (EORTC CAT Core CF item bank). However, the distinction between different cognitive functions might be important to assess the patients' functional status appropriately and to determine treatment impact. To allow for such assessment, the aim of this study was to develop and psychometrically evaluate separate item banks for memory and attention based on the EORTC CAT Core CF item bank. In a multistep process including an expert-based content analysis, we assigned 44 items from the EORTC CAT Core CF item bank to the memory or attention domain. Then, we conducted psychometric analyses based on a sample used within the development of the EORTC CAT Core CF item bank. The sample consisted of 1030 cancer patients from Denmark, France, Poland, and the United Kingdom. We evaluated measurement properties of the newly developed item banks using confirmatory factor analysis (CFA) and item response theory model calibration. Item assignment resulted in 31 memory and 13 attention items. Conducted CFAs suggested good fit to a 1-factor model for each domain and no violations of monotonicity or indications of differential item functioning. Evaluation of CATs for both memory and attention confirmed well-functioning item banks with increased power/reduced sample size requirements (for CATs greater than or equal to 4 items and up to 40% reduction in sample size requirements in comparison to non-CAT format). Two well-functioning and psychometrically robust item banks for memory and attention were formed from the existing EORTC CAT Core CF item bank. These findings could support further research on self-reported cognitive functioning in cancer patients in clinical trials as well as for real-word-evidence. A more precise assessment of attention and memory deficits in cancer patients will strengthen the evidence on the effects of cancer treatment for different cancer entities, and therefore contribute to shared and informed clinical decision-making.
A novel theory in the field of tumor biology postulates that cancer growth is driven by a population of stem‐like cells, called tumor‐initiating cells (TICs). We previously identified a TIC ...population derived from hepatocellular carcinoma (HCC) that is characterized by membrane expression of CD133. Here, we describe a novel mechanism by which these cells mediate tumor growth and angiogenesis by systematic comparison of the gene expression profiles between sorted CD133 liver subpopulations through genome‐wide microarray analysis. A significantly dysregulated interleukin‐8 (IL‐8) signaling network was identified in CD133+ liver TICs obtained from HCC clinical samples and cell lines. IL‐8 was found to be overexpressed at both the genomic and proteomic levels in CD133+ cells isolated from HCC cell lines or clinical samples. Functional studies found enhanced IL‐8 secretion in CD133+ liver TICs to exhibit a greater ability to self‐renew, induce tumor angiogenesis, and initiate tumors. In further support of these observations, IL‐8 repression in CD133+ liver TICs by knockdown or neutralizing antibody abolished these effects. Subsequent studies of the IL‐8 functional network identified neurotensin (NTS) and CXCL1 to be preferentially expressed in CD133+ liver TICs. Addition of exogenous NTS resulted in concomitant up‐regulation of IL‐8 and CXCL1 with simultaneous activation of p‐ERK1/2 and RAF‐1, both key components of the mitogen‐activated protein kinase (MAPK) pathway. Enhanced IL‐8 secretion by CD133+ liver TICs can in turn activate an IL‐8‐dependent feedback loop that signals through the MAPK pathway. Further, in its role as a liver TIC marker CD133 also plays a functional part in regulating tumorigenesis of liver TICs by way of regulating NTS, IL‐8, CXCL1, and MAPK signaling. Conclusion: CD133+ liver TICs promote angiogenesis, tumorigenesis, and self‐renewal through NTS‐induced activation of the IL‐8 signaling cascade. (Hepatology 2012)
The antibody response magnitude and kinetics may impact clinical severity, serological diagnosis and long-term protection of COVID-19, which may play a role in why children experience lower ...morbidity. We therefore tested samples from 122 children in Hong Kong with symptomatic (n = 78) and asymptomatic (n = 44) SARS-CoV-2 infections up to 200 days post infection, relative to 71 infected adults (symptomatic n = 61, and asymptomatic n = 10), and negative controls (n = 48). We assessed serum IgG antibodies to a 14-wide antigen panel of structural and accessory proteins by Luciferase Immuno-Precipitation System (LIPS) assay and circulating cytokines. Infected children have lower levels of Spike, Membrane, ORF3a, ORF7a, ORF7b antibodies, comparable ORF8 and elevated E-specific antibodies than adults. Combination of two unique antibody targets, ORF3d and ORF8, can accurately discriminate SARS-CoV-2 infection in children. Principal component analysis reveals distinct pediatric serological signatures, and the highest contribution to variance from adults are antibody responses to non-structural proteins ORF3d, NSP1, ORF3a and ORF8. From a diverse panel of cytokines that can modulate immune priming and relative inflammation, IL-8, MCP-1 and IL-6 correlate with the magnitude of pediatric antibody specificity and severity. Antibodies to SARS-CoV-2 internal proteins may become an important sero surveillance tool of infection with the roll-out of vaccines in the pediatric population.
The burden of inflammatory bowel disease (IBD) is rising globally, with substantial variation in levels and trends of disease in different countries and regions. Understanding these geographical ...differences is crucial for formulating effective strategies for preventing and treating IBD. We report the prevalence, mortality, and overall burden of IBD in 195 countries and territories between 1990 and 2017, based on data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017.
We modelled mortality due to IBD using a standard Cause of Death Ensemble model including data mainly from vital registrations. To estimate the non-fatal burden, we used data presented in primary studies, hospital discharges, and claims data, and used DisMod-MR 2.1, a Bayesian meta-regression tool, to ensure consistency between measures. Mortality, prevalence, years of life lost (YLLs) due to premature death, years lived with disability (YLDs), and disability-adjusted life-years (DALYs) were estimated. All of the estimates were reported as numbers and rates per 100 000 population, with 95% uncertainty intervals (UI).
In 2017, there were 6·8 million (95% UI 6·4–7·3) cases of IBD globally. The age-standardised prevalence rate increased from 79·5 (75·9–83·5) per 100 000 population in 1990 to 84·3 (79·2–89·9) per 100 000 population in 2017. The age-standardised death rate decreased from 0·61 (0·55–0·69) per 100 000 population in 1990 to 0·51 (0·42–0·54) per 100 000 population in 2017. At the GBD regional level, the highest age-standardised prevalence rate in 2017 occurred in high-income North America (422·0 398·7–446·1 per 100 000) and the lowest age-standardised prevalence rates were observed in the Caribbean (6·7 6·3–7·2 per 100 000 population). High Socio-demographic Index (SDI) locations had the highest age-standardised prevalence rate, while low SDI regions had the lowest age-standardised prevalence rate. At the national level, the USA had the highest age-standardised prevalence rate (464·5 438·6–490·9 per 100 000 population), followed by the UK (449·6 420·6–481·6 per 100 000). Vanuatu had the highest age-standardised death rate in 2017 (1·8 0·8–3·2 per 100 000 population) and Singapore had the lowest (0·08 0·06–0·14 per 100 000 population). The total YLDs attributed to IBD almost doubled over the study period, from 0·56 million (0·39–0·77) in 1990 to 1·02 million (0·71–1·38) in 2017. The age-standardised rate of DALYs decreased from 26·5 (21·0–33·0) per 100 000 population in 1990 to 23·2 (19·1–27·8) per 100 000 population in 2017.
The prevalence of IBD increased substantially in many regions from 1990 to 2017, which might pose a substantial social and economic burden on governments and health systems in the coming years. Our findings can be useful for policy makers developing strategies to tackle IBD, including the education of specialised personnel to address the burden of this complex disease.
Bill & Melinda Gates Foundation.
Epidemiological studies have demonstrated that elevated levels of plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) are the major risk factors for coronary heart disease ...(CHD), whereas high concentrations of plasma high-density lipoprotein cholesterol (HDL-C) and a low ratio of TC to HDL-C are protective against CHD. A relationship between plasma TC and the risk of CHD is well established at concentrations above 240 mg/dL. In addition to the use of three main classes of cholesterol-lowering medications, including HMG-CoA reductase inhibitors, anion-exchange resins, and fibrates, a nutritionally balanced diet that reduces saturated fat and cholesterol intake has traditionally been the first goal of dietary therapy in lowering plasma TC. In recent years, nutraceuticals and functional foods have attracted much interest as possible alternative therapies for lowering plasma TC, especially for hypercholesterolemia patients, whose blood cholesterol level is marginally high (200−240 mg/dL) but not high enough to warrant the prescription of cholesterol-lowering medications. This review summarizes the findings of recent studies on the production, application, efficacy, and mechanisms of popular cholesterol-lowering nutraceuticals and functional foods.
...consideration of the value-laden nature of policy interventions and the creation of forums to debate the moral and ethical dimensions of different approaches to urban health and city environments ...are essential. ...attention to health inequalities within urban areas should be a key focus of planning the urban environment.
Viral and microbial infections constitute one of the most important life-threatening problems. The emergence of new viral and bacterial infectious diseases increases the demand for new therapeutic ...drugs.
The objective of this study was to use the aqueous and hexane extracts of
and
F. Aizoaceae for the synthesis of silver nanoparticles, and to investigate its possible antiviral activity. In addition to the investigation of the phytochemical composition of the crude methanolic extracts of the two plants through UPLC-MS metabolomic profiling, and it was followed by molecular docking in order to explore the chemical compounds that might contribute to the antiviral potential.
The formation of SNPs was further confirmed using a transmission electron microscope (TEM), UV-Visible spectroscopy and Fourier transform infrared spectroscopy. The antiviral activity of the synthesized nanoparticles was evaluated using MTT assay against HSV-1, HAV-10 virus and Coxsackie B4 virus. Metabolomics profiling was performed using UPLC-MS and molecular docking was performed via Autodock4 and visualization was done using the Discovery studio.
The early signs of SNPs synthesis were detected by a color change from yellow to reddish brown color. The TEM analysis of SNPs showed spherical nanoparticles with mean size ranges between 10.12 nm to 27.89 nm, and 8.91 nm 14.48 nm for
and
aqueous and hexane extracts respectively. The UV-Visible spectrophotometric analysis showed an absorption peak at λmax of 417 nm.The green synthesized SNPs of
and
showed remarkable antiviral activity against HSV-1, HAV-10, and CoxB4 virus. Metabolomics profiling of the methanolic extract of
and
resulted in identifying 12 compounds. The docking study predicted the patterns of interactions between the compounds of
and
with herpes simplex thymidine kinase, hepatitis A 3c proteinase, and Coxsackievirus B4 3c protease, which was similar to those of the co-crystal inhibitors and this can provide a supposed explanation for the antiviral activity of the aqueous and nano extracts of
and
.
These results highlight that SNPs of
and
could have antiviral activity against HSV-1, HAV-10, and CoxB4 virus.
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