COVID-19 infections in infants.

The study aimed to analyse the clinical course of COVID-19 in 300 infants, selected from 1283 children diagnosed with COVID-19 between March and December 2020, registered in the SARSTerPED multicenter database. Most of the infants were registered in October and November 2020. 44% of the group were girls, and 56% were boys. At diagnosis, the most common symptoms were fever in 77% of the children, cough in 40%, catarrh in 37%. Pneumonia associated with COVID-19 was diagnosed in 23% of the children, and gastrointestinal symptoms in 31.3%. In 52% of the infants, elevated levels of D-dimers were observed, and in 40%, elevated levels of IL-6 serum concentration were observed. During the second wave of the pandemic, 6 times more infants were hospitalized, and the children were statistically significantly younger compared to the patients during the first wave (3 months vs 8 months, p < 0.0001 respectively). During the second wave, the infants were hospitalized for longer. COVID-19 in infants usually manifests as a mild gastrointestinal or respiratory infection, but pneumonia is also observed with falls in oxygen saturation, requiring oxygen therapy. Gastrointestinal symptoms are common in infants infected with SARS-CoV-2, and infant appetite disorders may lead to hospitalization. The clinical course of the disease differed significantly between the first and second wave of the pandemic. It seems that infants may play a role in the transmission of SARS-COV-2 infections in households, despite mild or asymptomatic courses; eating disorders in infants should be an indication for COVID-19 testing.

Effectiveness of the Influence of Selected Essential Oils on the Growth of Parasitic Fusarium Isolated from Wheat Kernels from Central Europe.

The aim of the study was to determine the effectiveness of selected seven commercial essential oils (EsO) (grapefruit, lemongrass, tea tree (TTO), thyme, verbena, cajeput, and Litsea cubeba) on isolates of common Central European parasitic fungal species of Fusarium obtained from infected wheat kernels, and to evaluate the oils as potential natural fungicides. The study was conducted in 2 stages. At each stage, the fungicidal activity of EsO (with concentrations of 0.025; 0.05; 0.125; 0.25; 0.50; 1.0, and 2.0%) against Fusarium spp. was evaluated using the disc plate method and zones of growth inhibition were measured. At the first stage, the fungistatic activity of EsO was evaluated against four species of Fusarium from the Polish population (F. avenaceum FAPL, F. culmorum FCPL, F. graminearum FGPL and F. oxysporum FOPL). The correlation coefficient between the mycelial growth rate index (T) and the fungistatic activity (FA) was calculated. At the second stage, on the basis of the mycelium growth rate index, the effectiveness of the EsO in limiting the development of Fusarium isolates from the German population (F. culmorum FC1D, F. culmorum FC2D, F. graminearum FG1D, F. graminearum FG2D and F. poae FP0D) was assessed. The first and second stage results presented as a growth rate index were then used to indicate essential oils (as potential natural fungicides) effectively limiting the development of various common Central European parasitic species Fusarium spp. Finally, the sensitivity of four Fusarium isolates from the Polish population and five Fusarium isolates from the German population was compared. The data were compiled in STATISTICA 13.0 (StatSoft, Inc, CA, USA) at the significance level of 0.05. Fusarium isolates from the German population were generally more sensitive than those from the Polish population. The sensitivity of individual Fusarium species varied. Their vulnerability, regardless of the isolate origin, in order from the most to the least sensitive, is as follows: F. culmorum, F. graminearum, F. poae, F. avenaceum and F. oxysporum. The strongest fungicidal activity, similar to Funaben T, showed thyme oil (regardless of the concentration). Performance of citral oils (lemongrass and Litsea cubeba) was similar but at a concentration above 0.025%.

The Influence of Paracetamol on the Penetration of Sorafenib and Sorafenib N-Oxide Through the Blood-Brain Barrier in Rats.

BACKGROUND AND OBJECTIVE: Sorafenib is an oral, multikinase inhibitor with established single-agent activity in several tumor types. Sorafenib was moderately transported by P-glycoprotein (P-gp) and more efficiently by breast cancer resistance protein. The constitutive androstane receptor (CAR) is a ligand-activated transcription factor involved in P-gp regulation in the brain microvasculature. Paracetamol is a CAR activator. The purpose of this study was to investigate the effect of paracetamol on the brain uptake of sorafenib and sorafenib N-oxide. METHODS: The rats were assigned to two groups-rats receiving oral paracetamol 100 mg/kg and sorafenib 100 mg/kg (n = 42, ISR+PA) and rats receiving oral vehicle and sorafenib 100 mg/kg (n = 42, IISR). The sorafenib and sorafenib N-oxide concentrations in blood plasma and brain tissue were determined by a high-performance liquid chromatography method with ultraviolet detection. Brain-to-plasma partition coefficient (Kp) was calculated as a ratio of the area under the curve from zero to 24 h (AUC) in the brain and plasma. A drug targeting index (DTI) was estimated as the group ISR+PA Kp to group IISR Kp ratio. RESULTS: Pharmacokinetic analysis revealed increased brain exposure to sorafenib and sorafenib N-oxide after co-administration of paracetamol. The brain maximum concentration (Cmax) and the AUC of the parent drug in the ISR+PA group compared with the IISR group were greater by 49.5 and 77.8%, respectively, and the same parameters for the metabolite were higher by 51.4 and 50.9%. However, the Kp values of sorafenib and sorafenib N-oxide did not differ significantly between the two animal groups and the DTI values were close to 1. CONCLUSION: Paracetamol increases exposure to sorafenib and sorafenib N-oxide in the brain, likely due to increased exposure in plasma.

The oxidation and hypoglycaemic effect of sorafenib in streptozotocin-induced diabetic rats.

BACKGROUND: Diabetes reduces the activity of CYP3A4 and may increase the exposure for the drugs metabolized by the isoenzyme. Sorafenib is a multi-targeted tyrosine kinase inhibitor (TKI), used for the treatment of advanced renal cell carcinoma, hepatocellular carcinoma and radioactive iodine resistant thyroid carcinoma. The TKI undergoes CYP3A4-dependent oxidative transformation, which may be influenced by hyperglycaemia. The aim of the study was to compare the oxidation for sorafenib between healthy and streptozotocin-induced diabetic rats. Additionally, the effect of sorafenib on glucose levels was investigated. METHODS: The rats were assigned to the groups: streptozotocin-induced diabetic (DG, n = 8) or healthy (HG, n = 8). The rats received sorafenib orally as a single dose of 100 mg/kg. The plasma concentrations of sorafenib and its metabolite N-oxide were measured with the validated high-performance liquid chromatography with ultraviolet detection. RESULTS: The difference between groups in Cmax and AUC0-t values for sorafenib were significant (p = 0.0004, p = 0.0104), and similarly for the metabolite (p = 0.0008, p = 0.0011). Greater exposure for the parent drug and analysed metabolite was achieved in diabetic group. However, the Cmax, AUC0-t, and AUC0-∞ ratios between the metabolite and sorafenib were similar in both groups. The significant reduction of glycaemia was observed only in the diabetic animals. CONCLUSION: The findings of the study provide evidence that diabetes significantly influence on the exposition for sorafenib and its metabolite, but similar ratios N-oxide/sorafenib for AUC and Cmax in healthy and diabetic animals suggest that oxidation of the TKI is rather unchanged. Additionally, sorafenib-associated hypoglycaemia was confirmed in diabetic animals.

Topological traits of a cellular pattern versus growth rate anisotropy in radish roots.

The topology of a cellular pattern, which means the spatial arrangement of cells, directly corresponds with cell packing, which is crucial for tissue and organ functioning. The topological features of cells that are typically analyzed are the number of their neighbors and the cell area. To date, the objects of most topological studies have been the growing cells of the surface tissues of plant and animal organs. Some of these researches also provide verification of Lewis's Law concerning the linear correlation between the number of neighboring cells and the cell area. Our aim was to analyze the cellular topology and applicability of Lewis's Law to an anisotropically growing plant organ. The object of our study was the root apex of radish. Based on the tensor description of plant organ growth, we specified the level of anisotropy in specific zones (the root proper, the columella of the cap and the lateral parts of the cap) and in specific types of both external (epidermis) and internal tissues (stele and ground tissue) of the apex. The strongest anisotropy occurred in the root proper, while both zones of the cap showed an intermediate level of anisotropy of growth. Some differences in the topology of the cellular pattern in the zones were also detected; in the root proper, six-sided cells predominated, while in the root cap columella and in the lateral parts of the cap, most cells had five neighbors. The correlation coefficient rL between the number of neighboring cells and the cell area was high in the apex as a whole as well as in all of the zones except the root proper and in all of the tissue types except the ground tissue. In general, Lewis's Law was fulfilled in the anisotropically growing radish root apex. However, the level of the applicability (rL value) of Lewis's Law was negatively correlated with the level of the anisotropy of growth, which may suggest that in plant organs in the regions of anisotropic growth, the number of neighboring cells is less dependent on the cell size.

The Influence of Diabetes Mellitus on Glucuronidation and Sulphation of Paracetamol in Patients with Febrile Neutropenia.

BACKGROUND AND OBJECTIVES: Numerous studies have confirmed the influence of diabetes mellitus on the pharmacokinetics of drugs. Paracetamol (APAP) is an antipyretic that is commonly used in febrile neutropenia (FN) therapy. APAP is chiefly metabolised by glucuronidation and sulphation. This study assessed the influence of diabetes on the pharmacokinetics of paracetamol and its metabolites: glucuronide (APAP-glu) and sulfate (APAP-sulfate) in FN patients. METHODS: Patients with FN received single intravenous dose 1000 mg of APAP. The FN patients were allocated to one of two groups: diabetics (DG, n = 7) or non-diabetics (NDG, n = 11). The plasma concentrations of paracetamol and its metabolites were measured with the validated high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. RESULTS: Pharmacokinetic parameters (mean [SD]) of APAP in the DG and NDG groups were as follows: Cmax (maximum comcentration) = 21.50 [11.23] vs. 23.42 [9.79] mg/L, AUC0-t (area under the concentration-time curve) = 44.23 [17.93] vs. 41.43 [14.57] mg·h/L, t1/2kel (elimination half-life) = 2.28 [0.80] vs. 2.11 [0.80] h. In both groups the exposure to APAP was comparable. The study did not reveal differences between the two groups in the pharmacokinetics of APAP-glu and APAP-sulfate. The Cmax and AUC0-t ratio between the metabolites and APAP were similar. CONCLUSIONS: No differences in the pharmacokinetics of APAP, APAP-glu and APAP-sulfate in patients with FN indicates that diabetes does not influence glucuronidation and sulfatation of paracetamol.

Autophagy and Alzheimer's Disease: From Molecular Mechanisms to Therapeutic Implications.

Alzheimer's disease (AD) is the most common cause of progressive dementia in the elderly. It is characterized by a progressive and irreversible loss of cognitive abilities and formation of senile plaques, composed mainly of amyloid ß (Aß), and neurofibrillary tangles (NFTs), composed of tau protein, in the hippocampus and cortex of afflicted humans. In brains of AD patients the metabolism of Aß is dysregulated, which leads to the accumulation and aggregation of Aß. Metabolism of Aß and tau proteins is crucially influenced by autophagy. Autophagy is a lysosome-dependent, homeostatic process, in which organelles and proteins are degraded and recycled into energy. Thus, dysfunction of autophagy is suggested to lead to the accretion of noxious proteins in the AD brain. In the present review, we describe the process of autophagy and its importance in AD. Additionally, we discuss mechanisms and genes linking autophagy and AD, i.e., the mTOR pathway, neuroinflammation, endocannabinoid system, ATG7, BCL2, BECN1, CDK5, CLU, CTSD, FOXO1, GFAP, ITPR1, MAPT, PSEN1, SNCA, UBQLN1, and UCHL1. We also present pharmacological agents acting via modulation of autophagy that may show promise in AD therapy. This review updates our knowledge on autophagy mechanisms proposing novel therapeutic targets for the treatment of AD.

A method to generate the surface cell layer of the 3D virtual shoot apex from apical initials.

BACKGROUND: The development of cell pattern in the surface cell layer of the shoot apex can be investigated in vivo by use of a time-lapse confocal images, showing naked meristem in 3D in successive times. However, how this layer is originated from apical initials and develops as a result of growth and divisions of their descendants, remains unknown. This is an open area for computer modelling. A method to generate the surface cell layer is presented on the example of the 3D paraboloidal shoot apical dome. In the used model the layer originates from three apical initials that meet at the dome summit and develops through growth and cell divisions under the isotropic surface growth, defined by the growth tensor. The cells, which are described by polyhedrons, divide anticlinally with the smallest division plane that passes depending on the used mode through the cell center, or the point found randomly near this center. The formation of the surface cell pattern is described with the attention being paid to activity of the apical initials and fates of their descendants. RESULTS: The computer generated surface layer that included about 350 cells required about 1200 divisions of the apical initials and their derivatives. The derivatives were arranged into three more or less equal clonal sectors composed of cellular clones at different age. Each apical initial renewed itself 7-8 times to produce the sector. In the shape and location and the cellular clones the following divisions of the initial were manifested. The application of the random factor resulted in more realistic cell pattern in comparison to the pure mode. The cell divisions were analyzed statistically on the top view. When all of the division walls were considered, their angular distribution was uniform, whereas in the distribution that was limited to apical initials only, some preferences related to their arrangement at the dome summit were observed. CONCLUSIONS: The realistic surface cell pattern was obtained. The present method is a useful tool to generate surface cell layer, study activity of initial cells and their derivatives, and how cell expansion and division are coordinated during growth. We expect its further application to clarify the question of a number and permanence or impermanence of initial cells, and possible relationship between their shape and oriented divisions, both on the ground of the growth tensor approach.

External validation of the IOTA ADNEX model performed by two independent gynecologic centers.

OBJECTIVES: The external, two-center validation of the IOTA ADNEX model for differential diagnosis of adnexal tumors. METHODS: A total of 204 patients with adnexal masses (134 benign and 70 malignant) treated at the Division of Gynecologic Surgery, Poznan University of Medical Sciences, Poland (Center I), and 123 patients (89 benign and 34 malignant) from the Department of Obstetrics and Gynecology, Clinica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain (Center II), were enrolled into the study. RESULTS: ADNEX achieved high accuracy in discriminating between malignant and benign ovarian tumors in both centers (79.9% and 81.3% in Centers I and II, respectively). Multiclass accuracy was substantially lower than in binary classification (malignant vs. benign): 64.2% and 74.0% in Centers I and II, respectively. Sensitivity and specificity for the diagnosis of specific tumor types in Center I were as follows: benign tumors - 72.4% and 94.3%; borderline tumors - 33.3% and 87.0%, stage I ovarian cancers - 00.0% and 91.8%; stage II-IV ovarian cancers - 68.2% and 83.1%; and metastatic tumors - 00.0% and 99.5%. Sensitivity and specificity in Center II were as follows: benign tumors - 75.3% and 97.1%; borderline tumors - 50.0% and 88.2%, stage I ovarian cancers - 40.0% and 97.5%; stage II-IV ovarian cancers - 95.0% and 88.3%; and metastatic tumors - 20.0% and 98.3%. CONCLUSIONS: ADNEX is characterized by very high accuracy in differentiating between malignant and benign adnexal tumors. However, prediction of ovarian tumor types could be more accurate.

Characterization of equine CSN1S2 variants considering genetics, transcriptomics, and proteomics.

Currently, research interest is increasing in horse milk composition and its effect on human health. Despite previously published studies describing the presence of intra- and interbreed variability of equine milk components, no investigations have focused on the genetic background of this variation. Among horse caseins and the genes encoding them, least is known about the structure and expression of the α-S2 casein gene, CSN1S2. Herein, based on direct sequencing of the equine CSN1S2 coding sequence, we describe the presence of 51-bp insertion-deletion (in/del) polymorphism, which significantly changes the protein sequence (lack or presence of 17-amino acid serine-rich peptide). Bioinformatic analysis revealed that the observed in/del polymorphism spanned exactly 2 exons; therefore, we hypothesized that we were observing different CSN1S2 splicing isoforms. However, further investigation indicated that the detected sequence variation was caused by a large (1.3-kb) deletion in the genomic DNA. We found that the polymorphic forms (A, longer; B, shorter; KP658381 and KP658382 GenBank records, respectively) were unevenly distributed among different horse breeds (the highest frequency of variant B was observed in coldblood horses and Haflingers). We propose that the analyzed polymorphism is associated with CSN1S2 expression level (the highest expression was recorded for individuals carrying the BB genotype), which was much more pronounced for milk CSN1S2 protein content than for relative transcript abundance (measured in milk somatic cells). Our results provide insight into the equine CSN1S2 structure and lay a foundation for further functional analyses regarding, for example, allergenicity or physiochemical properties of the observed CSN1S2 variants.

Menopausal status strongly influences the utility of predictive models in differential diagnosis of ovarian tumors: an external validation of selected diagnostic tools.

OBJECTIVES: The aim of this study was to externally validate the diagnostic performance of the International Ovarian Tumor Analysis logistic regression models (LR1 and LR2, 2005) and other popular prognostic models including the Timmerman logistic regression model (1999), the Alcazar model (2003), the risk of malignancy index (RMI, 1990), and the risk of malignancy algorithm (ROMA, 2009). We compared these models to subjective ultrasonographic assessment performed by an experienced ultrasonography specialist, and with our previously developed scales: the sonomorphologic index and the vascularization index. Furthermore, we evaluated diagnostic tests with regard to the menopausal status of patients. MATERIALS AND METHODS: This study included 268 patients with adnexal masses; 167 patients with benign ovarian tumors and 101 patients with malignant ovarian tumors were enrolled. All tumors were evaluated by using trans- vaginal ultrasonography according to the diagnostic criteria of the analyzed models. MATERIALS AND METHODS: This study included 268 patients with adnexal masses; 167 patients with benign ovarian tumors and 101 patients with malignant ovarian tumors were enrolled. All tumors were evaluated by using trans- vaginal ultrasonography according to the diagnostic criteria of the analyzed models. RESULTS: The subjective ultrasonographic assessment and all of the studied predictive models achieved similar diagnostic performance in the whole study population. However significant differences were observed when pre- and postmenopausal patients were analyzed separately In the subgroup of premenopausal patients, the highest area under the curve (AUC) was achieved by subjective ultrasonographic assessment (0.931), the Alcazar model (0.912), and LR1 (0.909). Alternatively in the group of postmenopausal patients, the highest AUC was noted for the Timmerman model (0.973), ROMA (0.951), and RMI (0.938). CONCLUSIONS: Menopausal status is a key factor that affects the utility of prognostic models for differential diagno sis of ovarian tumors. Diagnostic models of ovarian tumors are reasonable tools for predicting tumor malignancy

The tensor-based model of plant growth applied to leaves of Arabidopsis thaliana: a two-dimensional computer model.

Plant organs grow in coordinated and continuous way. Such growth is of a tensor nature, hence there is an infinite number of different directions of growth rate in each point of the growing organ. Three mutually orthogonal directions of growth can be recognized in which growth achieves extreme values (principal directions of growth [PDGs]). Models based on the growth tensor have already been successfully applied to the root and shoot apex. This paper presents the 2D model of growth applied to the arabidopsis leaf. The model employs the growth tensor method with a non-stationary velocity field. The postulated velocity functions are confirmed by growth measurements with the aid of the replica method.

The simulation model of growth and cell divisions for the root apex with an apical cell in application to Azolla pinnata.

In contrast to seed plants, the roots of most ferns have a single apical cell which is the ultimate source of all cells in the root. The apical cell has a tetrahedral shape and divides asymmetrically. The root cap derives from the distal division face, while merophytes derived from three proximal division faces contribute to the root proper. The merophytes are produced sequentially forming three sectors along a helix around the root axis. During development, they divide and differentiate in a predictable pattern. Such growth causes cell pattern of the root apex to be remarkably regular and self-perpetuating. The nature of this regularity remains unknown. This paper shows the 2D simulation model for growth of the root apex with the apical cell in application to Azolla pinnata. The field of growth rates of the organ, prescribed by the model, is of a tensor type (symplastic growth) and cells divide taking principal growth directions into account. The simulations show how the cell pattern in a longitudinal section of the apex develops in time. The virtual root apex grows realistically and its cell pattern is similar to that observed in anatomical sections. The simulations indicate that the cell pattern regularity results from cell divisions which are oriented with respect to principal growth directions. Such divisions are essential for maintenance of peri-anticlinal arrangement of cell walls and coordinated growth of merophytes during the development. The highly specific division program that takes place in merophytes prior to differentiation seems to be regulated at the cellular level.

Absence of isolation by distance patterns at the regional scale in the fungal plant pathogen Leptosphaeria maculans.

Outcomes of host-pathogen coevolution are influenced by migration rates of the interacting species. Reduced gene flow with increasing spatial distance between populations leads to spatial genetic structure, as predicted by the isolation by distance (IBD) model. In wind-dispersed plant-pathogenic fungi, a significant spatial genetic structure is theoretically expected if local spore dispersal is more frequent than long-distance dispersal, but this remains to be documented by empirical data. For 29 populations of the oilseed rape fungus Leptosphaeria maculans sampled from two French regions, genetic structure was determined using eight minisatellite markers. Gene diversity (H = 0.62-0.70) and haplotypic richness (R = 0.96-1) were high in all populations. No linkage disequilibrium was detected between loci, suggesting the prevalence of panmictic sexual reproduction. Analysis of molecular variance showed that > 97% of genetic diversity was observed within populations. Genetic differentiation was low among populations (F(st) < 0.05). Although direct methods previously revealed short-distance dispersal for L. maculans, our findings of no correlation between genetic and geographic distances among populations illustrate that the IBD model does not account for dispersal of the fungus at the spatial scale we examined. These results indicate high gene flow among French populations of L. maculans, suggesting high dispersal rates and/or large effective population sizes, two characteristics giving the pathogen high evolutionary potential against the deployment of resistant oilseed rape cultivars.

Effector diversification within compartments of the Leptosphaeria maculans genome affected by Repeat-Induced Point mutations.

Fungi are of primary ecological, biotechnological and economic importance. Many fundamental biological processes that are shared by animals and fungi are studied in fungi due to their experimental tractability. Many fungi are pathogens or mutualists and are model systems to analyse effector genes and their mechanisms of diversification. In this study, we report the genome sequence of the phytopathogenic ascomycete Leptosphaeria maculans and characterize its repertoire of protein effectors. The L. maculans genome has an unusual bipartite structure with alternating distinct guanine and cytosine-equilibrated and adenine and thymine (AT)-rich blocks of homogenous nucleotide composition. The AT-rich blocks comprise one-third of the genome and contain effector genes and families of transposable elements, both of which are affected by repeat-induced point mutation, a fungal-specific genome defence mechanism. This genomic environment for effectors promotes rapid sequence diversification and underpins the evolutionary potential of the fungus to adapt rapidly to novel host-derived constraints.