RUNX3 Regulates Intercellular Adhesion Molecule 3 (ICAM-3) Expression during Macrophage Differentiation and Monocyte Extravasation

The adhesion molecule ICAM-3 belongs to the immunoglobulin gene superfamily and functions as a ligand for the β2 integrins LFA-1, Mac-1 and αdβ2. The expression of ICAM-3 is restricted to cells of the hematopoietic lineage. We present evidences that the ICAM-3 gene promoter exhibits a leukocyte-specific activity, as its activity is significantly higher in ICAM-3+ hematopoietic cell lines. The activity of the ICAM-3 gene promoter is dependent on the occupancy of RUNX cognate sequences both in vitro and in vivo, and whose integrity is required for RUNX responsiveness and for the cooperative actions of RUNX with transcription factors of the Ets and C/EBP families. Protein analysis revealed that ICAM-3 levels diminish upon monocyte-derived macrophage differentiation, monocyte transendothelial migration and dendritic cell maturation, changes that correlate with an increase in RUNX3. Importantly, disruption of RUNX-binding sites led to enhanced promoter activity, and small interfering RNA-mediated reduction of RUNX3 expression resulted in increased ICAM-3 mRNA levels. Altogether these results indicate that the ICAM-3 gene promoter is negatively regulated by RUNX transcription factors, which contribute to the leukocyte-restricted and the regulated expression of ICAM-3 during monocyte-to-macrophage differentiation and monocyte extravasation

A glimpse of the ERM proteins

In all eukaryotes, the plasma membrane is critically important as it maintains the architectural integrity of the cell. Proper anchorage and interaction between the plasma membrane and the cytoskeleton is critical for normal cellular processes. The ERM (ezrin-radixin-moesin) proteins are a class of highly homologous proteins involved in linking the plasma membrane to the cortical actin cytoskeleton. This review takes a succinct look at the biology of the ERM proteins including their structure and function. Current reports on their regulation that leads to activation and deactivation was examined before taking a look at the different interacting partners. Finally, emerging roles of each of the ERM family members in cancer was highlighted

Viral RNA load in plasma is associated with critical illness and a dysregulated host response in COVID‑19

Background. COVID-19 can course with respiratory and extrapulmonary disease. SARS-CoV-2 RNA is detected in respiratory samples but also in blood, stool and urine. Severe COVID-19 is characterized by a dysregulated host response to this virus. We studied whether viral RNAemia or viral RNA load in plasma is associated with severe COVID-19 and also to this dysregulated response. Methods. A total of 250 patients with COVID-19 were recruited (50 outpatients, 100 hospitalized ward patients and 100 critically ill). Viral RNA detection and quantification in plasma was performed using droplet digital PCR, targeting the N1 and N2 regions of the SARS-CoV-2 nucleoprotein gene. The association between SARS-CoV-2 RNAemia and viral RNA load in plasma with severity was evaluated by multivariate logistic regression. Correlations between viral RNA load and biomarkers evidencing dysregulation of host response were evaluated by calculating the Spearman correlation coefficients. Results. The frequency of viral RNAemia was higher in the critically ill patients (78%) compared to ward patients (27%) and outpatients (2%) (p < 0.001). Critical patients had higher viral RNA loads in plasma than non-critically ill patients, with non-survivors showing the highest values. When outpatients and ward patients were compared, viral RNAemia did not show significant associations in the multivariate analysis. In contrast, when ward patients were compared with ICU patients, both viral RNAemia and viral RNA load in plasma were associated with critical illness (OR [CI 95%], p): RNAemia (3.92 [1.183–12.968], 0.025), viral RNA load (N1) (1.962 [1.244–3.096], 0.004); viral RNA load (N2) (2.229 [1.382–3.595], 0.001). Viral RNA load in plasma correlated with higher levels of chemokines (CXCL10, CCL2), biomarkers indicative of a systemic inflammatory response (IL-6, CRP, ferritin), activation of NK cells (IL-15), endothelial dysfunction (VCAM-1, angiopoietin-2, ICAM-1), coagulation activation (D-Dimer and INR), tissue damage (LDH, GPT), neutrophil response (neutrophils counts, myeloperoxidase, GM-CSF) and immunodepression (PD-L1, IL-10, lymphopenia and monocytopenia). Conclusions. SARS-CoV-2 RNAemia and viral RNA load in plasma are associated with critical illness in COVID-19. Viral RNA load in plasma correlates with key signatures of dysregulated host responses, suggesting a major role of uncontrolled viral replication in the pathogenesis of this disease.This work was supported by awards from the Canadian Institutes of Health Research, the Canadian 2019 Novel Coronavirus (COVID-19) Rapid Research Funding initiative (CIHR OV2 – 170357), Research Nova Scotia (DJK), Atlantic Genome/Genome Canada (DJK), Li-Ka Shing Foundation (DJK), Dalhousie Medical Research Foundation (DJK), the “Subvenciones de concesión directa para proyectos y programas de investigación del virus SARS‐CoV2, causante del COVID‐19”, FONDO–COVID19, Instituto de Salud Carlos III (COV20/00110, CIBERES, 06/06/0028), (AT) and fnally by the “Convocatoria extraordinaria y urgente de la Gerencia Regional de Salud de Castilla y León, para la fnanciación de proyectos de investigación en enfermedad COVID-19” (GRS COVID 53/A/20) (CA). DJK is a recipient of the Canada Research Chair in Translational Vaccinology and Infammation. APT was funded by the Sara Borrell Research Grant CD018/0123 funded by Instituto de Salud Carlos III and co-fnanced by the European Development Regional Fund (A Way to Achieve Europe programme). The funding sources did not play any role neither in the design of the study and collection, not in the analysis, in the interpretation of data or in writing the manuscript

The cardiomyopathy of cystic fibrosis: a modern form of Keshan disease

IntroductionWe conducted a study to determine the prevalence of structural heart disease in patients with CF, the characteristics of a cardiomyopathy not previously described in this population, and its possible relationship with nutritional deficiencies in CF.MethodsWe studied 3 CMP CF patients referred for heart-lung transplantation and a prospective series of 120 adult CF patients. All patients underwent a clinical examination, blood tests including levels of vitamins and trace elements, and echocardiography with evaluation of myocardial strain. Cardiac magnetic resonance imaging (CMR) was performed in patients with CMP and in a control group. Histopathological study was performed on hearts obtained in transplant or necropsy.ResultsWe found a prevalence of 10% (CI 4.6%–15.4%) of left ventricular (LV) dysfunction in the prospective cohort. Myocardial strain parameters were already altered in CF patients with otherwise normal hearts. Histopathological examination of 4 hearts from CF CMP patients showed a unique histological pattern of multifocal myocardial fibrosis similar to Keshan disease. Four of the five CF CMP patients undergoing CMR showed late gadolinium uptake, with a characteristic patchy pattern in 3 cases (p &lt; 0.001 vs. CF controls). Selenium deficiency (Se &lt; 60 µg/L) was associated with more severe LV dysfunction, higher prevalence of CF CMP, higher NTproBNP levels, and more severe pulmonary and digestive involvement.Conclusion10% of adults with CF showed significant cardiac involvement, with histological and imaging features resembling Keshan disease. Selenium deficiency was associated with the presence and severity of LV dysfunction in these patients

Cerium in human milk samples and its transfer from blood to milk: Is there an elevated nutritional risk for breast-fed babies?

The general population is increasingly exposed to cerium (Ce), which is contained in industrial products or is present as nuclear Ce fission products. Some studies suggested a link between elevated Ce levels and endomyocardial fibrosis. Since breast milk is the optimal, and directly after birth, usually the sole nutrition for newborns, exposure of females to Ce and its transfer to infants by breast-feeding is of concern in neonate protection. Consequently, the transfer rate of Ce from blood to breast milk is of interest for elucidating the Ce exposure of infants. Biomonitoring of paired serum and breast milk samples provides such information about Ce transfer to human milk. Therefore, this study is aimed at clarification of the relationship between Ce in human milk and serum from respective mothers for elucidating Ce enrichment in human milk with possible nutritional risk for newborns. As a prerequisite a strictly quality-controlled Ce determination method applicable to very low Ce concentration was developed, and its figures of merit were determined and found to be sufficient for our purpose. It turned out that Ce concentration in milk from Munich (Germany) and Madrid (Spain) showed a median of 13 ng/L. Ce concentrations in serum were at limit of quantification (LOQ) 10 ng/L (Munich) or 21.6&ndash;70.3 ng/L (Madrid), suggesting a higher Ce intake in Madrid. No enrichment from blood to milk was seen, and no elevated nutritional risk for breast-fed babies from Ce was found. Ce in serum, but not in milk, could indicate environmental Ce

Measurement of cerium in human breast milk and blood samples.

The aim of this study was to evaluate the relationship between cerium content in human breast milk and blood plasma or serum. Blood samples and breast milk at various stages of lactation, from 5 days to 51 weeks post partum, were donated by 42 healthy breast-feeding mothers from Munich, Germany and by 26 lactating Spanish mothers from Madrid at 4 weeks post partum. Inductively coupled plasma mass spectrometry was applied for the determination of cerium in the biological samples. Cerium concentration in the digested milk samples from Munich showed low values and the arithmetic mean values ranged between the quantification limit of 5 ng/L up to 65 ng/L. The median value amounted to 13 ng/L. The cerium concentrations in the Spanish breast milk samples amounted to similar low values. The data were about a factor of eight lower than values found in a former study of samples from an eastern German province. All cerium concentrations in the German plasma samples, except for two, were at the quantification limit of 10 ng/L. Interestingly, the serum samples of the Spanish mothers showed cerium values ranging between 21.6 and 70.3 ng/L; these higher data could be explained by an enhanced intake of cerium by humans in Madrid. This could be caused by increased cerium concentrations in particulate matter due to a higher traffic volume in Madrid compared to Munich. The results obtained in this study contribute to setting reference baseline values of cerium in human breast milk and blood plasma/serum and indicate a varying cerium amount depending on the cerium environmental pollution. Possibly, the cerium content in plasma/serum could be an indicator for environmental cerium, which is not valid for breast milk

Nutrient intake in Spanish adolescents SCOFF high-scorers: the AVENA study

[Purpose]: To evaluate whether adolescents with a positive score in a screening tool for possible eating disorders (ED) have a different diet intake in comparison with those with a negative score. [Methods]: Cross-sectional study performed in 235 adolescents (37.9 % boys) from Zaragoza (Spain). Age, gender, BMI, maternal education, nutrient intake (7-day record) and screening tool for detecting ED [sick control on fat food test (SCOFF)] were assessed. ANCOVA test was used to determine nutrient intake differences (namely energy, macronutrients and micronutrients) according to the SCOFF total score (SCOFF ≥2 indicates a possible case of ED). ANCOVA test was adjusted by age, maternal education and BMI. This research was based on data from the cross-sectional multicenter Alimentación y Valoración del Estado Nutricional en Adolescentes españoles (Feeding and Assessment of Nutritional status of Spanish Adolescents) study. [Results]: The proportion of adolescents with possible symptoms of ED was 21.7 %. Girls SCOFF high-scorers (SCOFF+) mean daily energy intake was significantly lower than in those SCOFF low-scorers (SCOFF−) (P < 0.001); however, in boys there was no difference. Both in girls and boys, there were no statistically significant differences according to SCOFF questionnaire for macronutrient intake, adjusted by daily energy intake. Concerning micronutrients, in girls with SCOFF+ sodium, potassium, phosphorus, iron, zinc, vitamin B and niacin intakes were significantly lower than in those with SCOFF−; however, in boys, there were no differences. [Conclusions]: Adolescent girls with current possible symptoms of ED presented lower total energy intake and several micronutrients intake compared with their peers without ED.The AVENA study was supported by the Spanish Ministry of Health (FIS 00/0015).Peer Reviewe