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The dorsal capsule of the wrist and the DCSS may play a significant role in the conduction of nerve signals transmitted from proprioceptors present in SL to PIN, which is located above the dorsal capsule. Hence, this study aimed to determine if nerve fibers of PIN penetrate inside the dorsal capsule. The dorsal capsules of the wrist were dissected from both sides from 15 cadavers. Eventually, 30 dorsal capsules were dissected. It can be concluded that the PIN nerve fibers penetrate the dorsal capsule of the wrist, as the penetration was noticeable in every part evaluated. The present study proves that afferent fibers from the mechanoreceptors of the SLIL potentially pass through the DCSS and subsequently through the dorsal capsule of the wrist to the PIN. This knowledge can surely be of great use for hand surgeons that perform procedures on the dorsal wrist.

Background/Aim: Deregulated activation of signaling through the RAS/RAF/mitogen-activated protein kinase/extracellular signal-regulated kinase (RAS/RAF/MEK/ ERK) and signal transducer and activator of transcription (STAT) pathways is involved in numerous hematological malignancies, making it an attractive therapeutic target. This study aimed to assess the effect of the combination of ERK2 inhibitor VX-11e and STAT3 inhibitor STA-21 on acute lymphoblastic leukemia cell lines REH and MOLT-4. Materials and Methods: REH and MOLT-4 cell lines were cultured with each drug alone and in combination. Cell viability, ERK activity, cell cycle distribution, apoptosis and oxidative stress induction were assessed by flow cytometry. Protein levels of STAT3, phospho-STAT3, protein tyrosine phosphatase 4A3 (PTP4A3), survivin, p53 and p21 were determined by western blotting. Results: VX-11e in combination with STA-21 significantly inhibited cell viability, induced G(0)/G(1) cell-cycle arrest, enhanced production of reactive oxygen species, and induced apoptosis. These effects were associated with an increased level of p21 protein in REH cells and with reduced levels of phopho-STAT3, survivin and PTP4A3 proteins in MOLT-4 cells. Conclusion: Our findings provide a rationale for combined inhibition of RAS/RAF/MEK/ERK and STAT3 pathways in order to enhance anticancer effects against acute lymphoblastic leukemia cells.

A 137-m continuous core from the Jurassic-Early Cretaceous marine derived oil shale with the maturity Ro about 0.7 %, representing the oil window in the Vaca Muerta Formation, Neuquen Basin, Argentina, was examined using geological, mineralogical, petrographic, and geochemistry techniques. Three distinct intervals were identified within the core: the upper carbonate-rich section with intense bioturbation, indicating dysoxic to oxic conditions that resulted in poor organic matter preservation; a middle section with decreasing carbonate content, suboxic bottom conditions, and higher organic matter content; and a lower section with higher detrital input and low carbonate content, suboxic to anoxic water conditions, and enhanced preservation of organic matter. Based on the presence of indicator fossils and geochemical parameters, a general trend of increasing organic matter content with lower paleo-oxygen levels was observed. The proportion of solid bitumen within organic matter increases with decreasing oxygen content, suggesting that organic matter deposited in anoxic conditions is more prone to transformation and hydrocarbon generation. There is a negative impact of increasing paleo-oxygen levels on the quantity and quality of organic matter, represented by its potential to generate hydrocarbons.

Intervertebral disc (IVD) degeneration is a multifaceted pathology that is the main morphological cause of lower back pain. This study aimed to determine the link between the vitamin D receptor gene single nucleotide polymorphisms (SNPs) and degenerative processes of the lumbar spine. The complete lumbar spinal columns were collected from 100 Caucasian cadavers via ventral dissection. The specimens for the histological analysis were harvested from the L5/S1 IVDs and endplates. Then, the tissues were cut into slices, inserted into paraffin blocks, and stained. The histology was evaluated according to the Boos' protocol. Moreover, TaqI(rs731236), FokI(rs2228570), and ApaI(rs7975232) genotyping were performed. Lastly, the histological scores for different genotypes were analyzed. The overall Boos' score in the study group was 12.49. It consisted of a mean IVD score of 7.46 and endplate score of 5.39. The determination of the SNPs was successful in 99 specimens and had a distribution of all alleles in accordance with the Hardy-Weinberg equilibrium. No significant differences in overall histological degeneration scores were found between samples from donors with different genotypes. However, in subgroup analysis of specific regions on the IVD, the significant difference was found in posterior inner anulus fibrosus for ApaI. The results of this study suggest that one must be careful when interpreting the results of the clinical and/or radiological studies on vitamin D receptor gene polymorphisms and lumbar spine degeneration risk, because such a relationship, if present, is likely to be very subtle.

Introduction The muscular sleeves (or myocardial extensions) derived from the right ventricle infundibulum myocardium are considered the true anatomic substrate for right ventricular outflow tract arrhythmias. Methods Pulmonary valve specimens obtained from 65 donors (24.6% females, mean age 45.9 ± 15.8 years) were investigated micro-anatomically. Specimens were histologically processed, stained with Masson's Trichrome, and examined under a light microscope. Results The myocardial extensions were present in the left anterior pulmonary valve sinus in 86.2% of cases, in the right anterior sinus in 89.2% of cases and in 90.7% of cases in the posterior sinus (p = .699). In 69.2% of examined hearts, the myocardial extensions were present in all sinuses. The mean height of the extensions was 4.12 ± 1.76 (left anterior) versus 3.69 ± 1.47 (right anterior) versus 4.28 ± 1.73 mm (posterior) (p = .137). The myocardial extensions occupied an average of 28.9 ± 10.4% of the left anterior sinus, 26.7 ± 11.2% of the right anterior sinus, and 31.9 ± 11.3% of the posterior sinus (p = .044). Sleeves extending beyond the fibro-arterial transition zone were present in at least one sinus in 33.8% of hearts (in 7.7% (5/65) of the left and right anterior sinuses and 21.5% (14/65) of posterior sinus, p = .021). Conclusions The myocardial extensions of the pulmonary valve are common anatomical entities. Although the length of the myocardial sleeves is similar in all pulmonary valve sinuses, their relative extent is greatest in the posterior sinus. Long sleeves that spread beyond the fibro-arterial transition zone were observed in one-third of hearts, predominantly in the posterior sinus. Myocardial and fibrous tissue layer thicknesses varied considerably.

Introduction The number of anaphylaxis diagnoses in children is rising, being still based on the clinical picture. Aim To determine whether triggers of anaphylaxis influence its clinical characteristics in children and adolescents. Material and methods The study group included 114 children (5 months-17 years, mean age: 8.0 ±4.8 years), (66%: boys) with the episode of anaphylaxis up to 1 year back. Medical data were entered to the NORA Registry by means of a validated structured on-line questionnaire. Results Three most frequent triggers of anaphylaxis were: insect venom (47.4%), food (35.1%), drugs (5.3%), with a predominance of food (egg white, cow's milk, nuts and peanuts) in the 0-6 years age group, while insect venom (bee predominance) in the 7-17 years age group (p = 0.016). Clinical manifestations differed between food vs. venom allergic reactions and presented as gastro-intestinal (GI) (61.4%) (p = 0.004), respiratory (RS) (93.9%) (p = 0.036), and cardiovascular (CVS) (74.6%) (p = 0.022) symptoms. Among objective symptoms, vomiting was the most common symptom in the 0-2 years age group (47.1%) (p = 0.006), while hypotension in those aged 7-12 years (40%) (p = 0.010). Severity of symptoms evaluated as Mueller's grade (IV - 74.5%) and as Ring and Messmer's grade (III - 65.8%), depended on the trigger (p = 0.028, p = 0.029, respectively). Life-threatening symptoms occurred in 26 children (fall of the blood pressure - 22%, loss of consciousness - 4.4%). Conclusions The clinical manifestation of anaphylaxis in children is both trigger and age dependent, irrespective of the gender. A typical patient with food anaphylaxis was younger, presenting predominantly GI symptoms, while a typical patient with venom anaphylaxis was older, with mostly cardiovascular symptoms.

The circadian rhythmicity changes the density and shape of dendritic spines in mouse somatosensory barrel cortex, influencing their stability and maturation. In this study, we analyzed the main geometric parameters of dendritic spines reflecting the strength of synapses located on these spines under light/dark (12:12) and constant darkness conditions, in order to distinguish between endogenously regulated and light-driven parameters. Using morphological analysis of serial electron micrographs, as well as three-dimensional reconstructions, we found that the light induces elongation of single-synapse spine necks and increases in the diameter of double-synapse spine necks, increasing and decreasing the isolation of synapses from the parent dendrite, respectively. During the subjective night of constant darkness, we observed an enlargement of postsynaptic density area in inhibitory synapses and an increase in the number of polyribosomes inside double-synapse spines. The results show that both endogenous effect (circadian clock/locomotor activity) and light affect the morphological parameters of single- and double-synapse spines in the somatosensory cortex: light reduces the efficiency of excitatory synapses on single-synapse spines, increases the effect of synaptic transmission in double-synapse spines, and additionally masks the endogenous clock-driven enlargement of inhibitory synapses located on double-synapse spines. This indicates a special role of double-synapse spines and their inhibitory synapses in the regulation of synaptic transmission during both circadian and diurnal cycles in the mouse somatosensory cortex.

Purpose The aim of the work was to create an appropriate substrate for organ transplantation using bioactive tissue-based scaffold populated by cells of the graft recipient. The purpose of the modeling was to investigate the mechanical effects of wave loading of aortic and pulmonary tissue material. Methods The biological properties of tissues of aortic and pulmonary valves were modified by the process of decellularization. The host cells were removed by various physical methods with focus on minimal degradation of the extracellular matrix. Thus, the decellularization process was controlled by histological methods. The tissue decellularization process was simulated by finite element modelling. Results The mechanical results represented by a displacement at the center of the sample were coherent and the heterogeneity of the distribution of the caves on the surface of the samples was confirmed, both by experiment and in the simulation by the alternate occurrence of local minima and maxima. The latter results from the uneven removal of cells from the effect of the wave causing decellularization were also predicted by the numerical model. Laser radiation had a destructive effect on the components of the extracellular matrix (e.g., collagen and elastic fibers), mainly depending on the fluence and number of pulses in a single exposure. Conclusions The differences between the valve tissue materials were shown, and the impact of the process of decellularization on the properties of the tissues was analyzed. It should be emphasized that due to low absorption and high scattering, laser radiation can deeply penetrate the tissue, which allows for effective decellularization process in the entire volume of irradiated tissue.

The mitogen-activated protein kinase (MAPK)/extracellular signal kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signal transduction pathways have been implicated in the pathogenesis of leukemia. The aim of this study was to investigate the effect of the combination of ERK1/2 inhibitor AZD0364 and PI3K inhibitor ZSTK474 on acute lymphoblastic leukemia (ALL) REH, MOLT-4, acute myeloid leukemia (AML) MOLM-14, and chronic myeloid leukemia (CML) K562 cell lines. To evaluate the interactions of the drugs, cells were treated for 48 h with AZD0364 or ZSTK474 alone and in combination at fixed ratios. The combinatorial effects of both inhibitors were synergistic over a wide range of concentrations in REH, MOLT-4, and MOLM-14 cell lines. However, in K562 cells, the effects were found to be antagonistic. Furthermore, AZD0364 and ZSTK474 significantly decreased both ERK1/2 and AKT activation in REH, MOLT-4, and MOLM-14 cells. The results showed that incubation with both AZD0364 and ZSTK474 inhibited cell viability, increased reactive oxygen species (ROS) production, and induced apoptosis in leukemia cells. We observed that combined treatment with AZD0364 and ZSTK474 affected nuclear factor-&kappa, B (NF-&kappa, B) and antioxidant protein levels: NF-E2-related factor 2 (NRF2), heme oxygenase-1 (HO-1), thioredoxin (Trx), thioredoxin reductase (TrxR), and the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio. These effects were accompanied with decreased antiapoptotic survivin protein level. However, distinct cell line dependent effects were observed. In conclusion, the combination of AZD0364 and ZSTK474 can exert a synergistic anticancer effect in ALL and AML cells, which is associated with the induction of oxidative stress and the involvement of cellular antioxidant defense mechanisms.

Experimental autoimmune encephalomyelitis (EAE) is a commonly used mouse model of multiple sclerosis, a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination leading to brain and spinal cord malfunctions. We postulate that not only biological but also biomechanical properties play an important role in impairements of CNS function. Atomic force microscopy (AFM) was applied to investigate mechanical properties of spinal cords collected from EAE mice in preonset, onset, peak, and chronic disease phases. Biomechanical changes were compared with histopathological alterations observed in the successive phases. The deformability of gray matter did not change, while rigidity of white matter increased during the onset phase, remained at the same level in the peak phase and decreased in the chronic phase. Inflammatory infiltration and laminin content accompanied the tissue rigidity increase, whereas demyelination and axonal damage showed an opposite effect. The increase in white matter rigidity can be regarded as an early signature of EAE.

A quadricuspid pulmonary valve obtained upon autopsy of a 26-year-old male was examined. The macroscopic evaluation revealed three normal (posterior, right anterior and left anterior) leaflets and one additional leaflet of the pulmonary valve. Except that, the heart showed neither other anatomical variabilities nor any signs of heart disease. The additional leaflet was located between the left anterior and right anterior leaflets and was significantly smaller in size. Under the microscope, all leaflets showed preservation of the typical, layered structure. The thickness and extracellular matrix composition of the particular layers differed between the leaflets. Right ventricular myocardium (myocardial sleeves) exceeded the level of the hinge line in all three normal leaflets, which was not observed in the additional leaflet. Autonomic nerves and ganglia were not seen in the perivalvular epicardial adipose tissue surrounding the additional leaflet. The sinus wall of all the leaflets revealed typical organization of collagen bundles as well as elastic fibers and showed no signs of disruption. The abnormality seen in the structure of the pulmonary valve is likely to be a result of disturbed embryonic development and may affect the clinical management of patients with such variation.

INTRODUCTION Hymenoptera insect stings (ISs) in the head and neck (HN) region are commonly considered to be a risk factor for grade IV systemic reactions (SRs) in patients with Hymenoptera venom allergy (HVA). However, clinical data addressing this issue are scarce. OBJECTIVES The aim of our study was to verify whether ISs in the HN region were related to a higher risk of grade IV SRs in patients with HVA. PATIENTS AND METHODS This retrospective cross‑sectional study included 195 patients aged 2 to 74 years and treated with venom immunotherapy due to at least a grade II SR to ISs. The study sample comprised 109 adults (56%; mean [SD] age, 41.08 [14.62] years; male, 50.5%) and 86 children (mean [SD] age, 9.53 [4.37] years; male, 72.1%; P0.001 for age and P = 0.002 for sex). The IS site was divided into 7 categories. RESULTS The HN region was the most common site for the IS (one‑third of the study group). In the entire study population, the risk of grade IV SRs was numerically, though insignificantly higher for ISs in the trunk (odds ratio [OR], 1.58; 95% CI, 0.42-5.92; P = 0.50) and legs (OR, 1.56; 95% CI, 0.49-5.10; P = 0.45), as compared with the HN region. The HN region showed a similar risk of grade IV SRs when compared with all the other IS sites combined into a single category (OR, 0.87; 95% CI, 0.43-1.75, P = 0.7). CONCLUSIONS ISs in the HN region were not confirmed to be a risk factor for grade IV SRs in patients with HVA, regardless of age and sex.

INTRODUCTION Hymenoptera insect stings (ISs) in the head and neck (HN mean [SD] age, 41.08 [14.62] years; male, 50.5%) and 86 children (mean [SD] age, 9.53 [4.37] years; male, 72.1%; P

Circadian rhythmicity affects neuronal activity induced changes in the density of synaptic contacts and dendritic spines, the most common location of synapses, in mouse somatosensory cortex. In the present study we analyzed morphology of single- and double-synapse spines under light/dark (12:12) and constant darkness conditions. Using serial electron micrographs we examined the shape of spines (stubby, thin, mushroom) and their content (smooth endoplasmic reticulum, spine apparatus), because these features are related to the maturation and stabilization of spines. We observed significant diurnal and circadian changes in the shape of spines that are differentially regulated: single-synapse spines remain under circadian clock regulation, while changes of double-synapse spines are driven by light. The thin and mushroom single-synapse spines, regardless of their content, are more stable comparing with the stubby single-synapse spines that show the greatest diversity. All types of double-synapse spines demonstrate a similar level of stability. In light/dark regime, formation of new mushroom single-synapse spines occurs, while under constant darkness new stubby single-synapse spines are formed. There are no shape preferences for new double-synapse spines. Diurnal and circadian alterations also concern spine content: both light exposure and the clock influence translocation of smooth endoplasmic reticulum from dendritic shaft to the spine. The increasing number of mushroom single-synapse spines and the presence of only those mushroom double-synapse spines that contain spine apparatus in the light phase indicates that the exposure to light, a stress factor for nocturnal animals, promotes enlargement and maturation of spines to increase synaptic strength and to enhance the effectiveness of neurotransmission.

Introduction and objectives The study aimed at evaluating the impact of Hymenoptera venom allergy (HVA) in children and adolescents, on their parents' QoL, taking into account their socio-demographic characteristics. Material and methods The study sample consisted of 101 parents of children and adolescents aged 9-17 years, with a history of systemic reaction after insect sting who were referred for consultations in the tertiary level allergology department. The mean age of the parents was 39 years (SD=8.1; range 25-65 years); the majority were mothers (68%) and rural inhabitants (62%). QoL in parents of HVA children and adolescents was measured with the Parents of Children with Hymenoptera Venom Allergy Quality of Life Scale, a questionnaire covering 5 dimensions: anxiety, caution, limitations and discomfort, support provided to the child and feeling of safety, each measured on the scale ranging from 1 to 5. Independent predictors of QoL were estimated using the Generalized Linear Model. Results Parents of urban children and adolescents treated with venom immunotherapy (VIT) up to 3 years (B=-1.37, 95CI= (-2.22;-0.53); p=0.001) and of rural children treated for more than 3 years (B=-0.94, 95CI=(-1.55;-0.33); p=0.003) reported lower anxiety than parents studied at diagnosis. In urban parents, individuals studied at VIT beginning reported a lower feeling of safety (B=-0.63, 95CI=(-1.11;-0.15); p=0.010); those studied up to 3 years of treatment reported a higher feeling of safety (B=0.64, 95CI=(0.11;1.16); p=0.018) than those studied at diagnosis. Contrariwise, in rural parents, those studied at the beginning of immunotherapy reported a higher feeling of safety than those studied at diagnosis (B=0.51, 95CI=(0.13;0.88); p=0.008). Conclusions The longest VIT duration in children and adolescents with HVA is related to the decreased anxiety of their parents. Parent's feeling of safety depends on the stage of treatment and place of residence.

ERK1/2 inhibitors are new promising anticancer drugs. The aim of this study was to investigate the effect of the combination of ERK2 inhibitor VX-11e and voreloxin on MOLM-14, K562, REH and MOLT-4 leukemia cell lines. We found that VX-11e alone and in combination with voreloxin significantly decreased ERK activation in all cell lines tested. To evaluate the interactions of the drugs, cells were treated for 24 h with VX-11e or voreloxin alone and in combination at fixed ratios based on IC50 values. The combinatorial effects of both drugs were synergistic over a wide range of concentrations in MOLM-14, REH and MOLT-4 cell lines. In K562 cells, three effects were found to be additive, one antagonistic and only one synergistic. The results showed that incubation with both VX-11e and voreloxin inhibited the growth of leukemia cells, affected cell cycle and induced apoptosis. Furthermore, the molecular mechanism of these effects might be attributed to an increased expression of p21 and a decreased expression of survivin and NF-κB in all cell lines tested except from K562 cells. In conclusion, combination of VX-11e and voreloxin can exert a synergistic anticancer effect in leukemia cells.

Asthma is a chronic, inflammatory, heterogenic disease of the bronchi. It is characterised by bronchial obstruction in the form of wheezing, coughing, shortness of breath and breathing difficulty, showing variable intensity and resolving after medication, or sometimes spontaneously. Making the diagnosis of asthma in children under 5 years of age is based on clinical criteria – the presence of symptoms of bronchial constriction, confirmation of its reversibility and lack of symptoms suggestive of other clinical diagnosis. The criterion for diagnosis are usually three episodes of bronchial obstruction, or a single episode of severe intensity. A detailed history and physical examination allows in most cases to rule out other diseases with similar clinical course. Frequent recurrence of symptoms is an indication for the initial differential diagnosis in primary health care, including a chest X-ray, blood count, often an ENT and/or allergological consultation. However severe, frequent and not responding to treatment episodes of bronchoconstriction indicate the need for diagnostics in specialist hospital wards. Chronic treatment of asthma is based on the administration of anti-inflammatory drugs, inhaled therapy is the treatment of choice in most patients. The assessment of the severity of asthma exacerbation determines the range of treatment, on an outpatient basis consisting of bronchodilators, corticosteroids and oxygen therapy. An important element of treatment is appropriate patient education, with particular attention to the exacerbation risk factors and correct inhalation technique. Children suffering from asthma should be vaccinated against pneumococcal disease and against influenza annually.

Introduction Calcific aortic valve disease is associated with inflammation and calcification, thus the osteoprotegerin (OPG), receptor activator of nuclear factor κB (RANK) and its ligand (RANKL) system involved in osteoclastogenesis and inflammation may play a significant role in valve degeneration. Objectives The aim of this study was to assess whether circulating OPG, sRANKL, and other bone metabolism markers can predict the presence of osteoclasts in stenotic valves and to evaluate their impact on the mode of degeneration. Patients and methods The study involved 60 patients with aortic stenosis who underwent valve replacement surgery and subsequently were divided into 2 groups: osteoclastic (n = 12) and nonosteoclastic (n = 48), according to the presence or absence of intravalvular osteoclasts. Before the surgery, we measured serum levels of OPG, sRANKL, osteocalcin, osteopontin, tumor necrosis factor α (TNF-α), interleukin (IL) 1β, and IL-6. Immunohistochemistry and morphometry were used to determine the extent of valve calcification, lipid accumulation, neovascularization, and the number and phenotype of macrophages. Results Compared with the nonosteoclastic group, patients with intravalvular osteoclasts had lower levels of OPG (P = 0.0006) and TNF-α (P = 0.02) and less frequently had diabetes (P = 0.04). Their valves showed higher incidence of ossification (P = 0.002), higher total (P = 0.008) and M2 macrophage counts (P = 0.0002), increased neovascularization (P = 0.003), and lower accumulation of lipids (P = 0.04). They also showed a negative correlation between valve calcification and age (r = -0.79, P = 0.002), which was not observed in patients without osteoclasts. In a multivariate analysis, low circulating OPG levels and the absence of diabetes were predictors of intravalvular osteoclastic differentiation. Conclusions The presence of osteoclasts in stenotic valves associated with low circulating OPG levels and an enhanced proportion of M2 macrophages can represent a variant of calcific aortic valve disease with a specifically regulated calcification process.

In order to investigate changes in chemical state of iron in normal and pathologically altered human aortic valves X-ray absorption spectroscopy was applied. Since Fe is suspected to play detrimental role in aortic valve stenosis pathogenesis the oxidation state of this element has been determined. The experimental material consisted of 10 μm sections of valves excised during routine surgery and from autopsies. The experiment was performed at the MicroXAS beamline of the SLS synchrotron facility in Villigen (Switzerland). The Fe K-edge XANES spectra obtained from tissue samples were carefully analyzed and compared with the spectra of reference compounds containing iron in various chemical structures. The analysis of absorption edge position and shape of the spectra revealed that both chemical forms of iron are presented in valve tissue but Fe 3+ is the predominant form. Small shift of the absorption edge toward higher energy in the spectra from stenotic valve samples indicates higher content of the Fe 3+ form in pathological tissue. Such a phenomenon suggests the role of Fenton reaction and reactive oxygen species in the etiology of aortic valve stenosis. The comparison of pre-edge regions of XANES spectra for control and stenotic valve tissue confirmed no differences in local symmetry or spin state of iron in analyzed samples.

Aortic valve interstitial cells (VICs) constitute a heterogeneous population involved in the maintenance of unique valvular architecture, ensuring proper hemodynamic function but also engaged in valve degeneration. Recently, cells similar to telocytes/interstitial Cajal-like cells described in various organs were found in heart valves. The aim of this study was to examine the density, distribution, and spatial organization of a VIC subset co-expressing CD34 and PDGFR&alpha, in normal aortic valves and to investigate if these cells are associated with the occurrence of early signs of valve calcific remodeling. We examined 28 human aortic valves obtained upon autopsy. General valve morphology and the early signs of degeneration were assessed histochemically. The studied VICs were identified by immunofluorescence (CD34, PDGFR&alpha, vimentin), and their number in standardized parts and layers of the valves was evaluated. In order to show the complex three-dimensional structure of CD34+/PDGFR&alpha, + VICs, whole-mount specimens were imaged by confocal microscopy, and subsequently rendered using the Imaris (Bitplane AG, Z&uuml, rich, Switzerland) software. CD34+/PDGFR&alpha, + VICs were found in all examined valves, showing significant differences in the number, distribution within valve tissue, spatial organization, and morphology (spherical/oval without projections, numerous short projections, long, branching, occasionally moniliform projections). Such a complex morphology was associated with the younger age of the subjects, and these VICs were more frequent in the spongiosa layer of the valve. Both the number and percentage of CD34+/PDGFR&alpha, + VICs were inversely correlated with the age of the subjects. Valves with histochemical signs of early calcification contained a lower number of CD34+/PDGFR&alpha, + cells. They were less numerous in proximal parts of the cusps, i.e., areas prone to calcification. The results suggest that normal aortic valves contain a subpopulation of CD34+/PDGFR&alpha, + VICs, which might be involved in the maintenance of local microenvironment resisting to pathologic remodeling. Their reduced number in older age could limit the self-regenerative properties of the valve stroma.

Background/aim MEK inhibitors are new promising anticancer drugs. The aim of this study was to investigate the effect of the combination treatment of voreloxin with the MEK inhibitor TAK-733 on HL60 myeloid leukemia cells. Materials and methods MAPK activity, cell viability, apoptosis, oxidative stress induction and AIF (apoptosis-inducing factor) distribution were assessed in HL60 cells cultured with each drug alone or with both drugs. Results TAK-733 alone at 5 μM significantly reduced MAPK activity and did not influence viability and apoptosis in HL60 cells. Voreloxin at concentration of 0.03-0.48 μM reduced cell viability and increased apoptosis rate. Incubation with both drugs caused further inhibition of cell viability and increased apoptosis associated with generation of reactive oxygen species (ROS) and nuclear translocation of AIF. Conclusion Combination of TAK-733 and voreloxin can exert a synergistic anticancer effect in myeloid leukemia cells.

Objective: The aim of this study was to compare the efficacy of two different papaverine concentrations (0.5 mg/ml and 2 mg/ml) for vasospasm prevention and their impact on endothelium integrity. Methods: We have studied distal segments of radial arteries obtained by no-touch technique from coronary artery bypass graft (CABG) patients (n=10). The vasodilatory effect of papaverine (concentrations of 0.5 mg/ml and 2 mg/ml) was assessed in vitro, in isometric tension studies using ex vivo myography (organ bath technique) and arterial rings precontracted with potassium chloride (KCl) and phenylephrine. The impact of papaverine on endothelial integrity was studied by measurement of the percentage of vessel's circumference revealing CD34 endothelial marker. Results: 2 mg/ml papaverine concentration showed stronger vasodilatatory effect than 0.5 mg/ml, but it caused significantly higher endothelial damage. Response to KCl was 7.35±3.33 mN for vessels protected with papaverine 0.5 mg/ml and 2.66±1.96 mN when papaverine in concentration of 2 mg/ml was used. The histological examination revealed a significant difference in the presence of undamaged endothelium between vessels incubated in papaverine 0.5 mg/ml (72.86±9.3%) and 2 mg/ml (50.23±13.42%), P=0.002. Conclusion: Papaverine 2 mg/ml caused the higher endothelial damage. Concentration of 0.5 mg/ml caused better preservation of the endothelial lining.

Mast cell (MC) mediators, among them prostaglandin D2 (PGD2) and 9α,11β-PGF2, PGD2’s metabolite, play a key role in allergic reactions, including bee venom anaphylaxis (BVA). Assessment of these mediators has never been performed in BVA. The aim of the study was to assess the activation of MC during in vivo provocation with bee venom (BV) and to measure PGD2 and 9α,11β-PGF2 in the course of an allergen challenge. The second aim was to determine if assessment of these mediators could be useful for predicting adverse events during venom immunotherapy (VIT). In 16 BV-VIT patients and 12 healthy subjects, levels of PGD2 and 9α,11β-PGF2 were assessed during BV provocation by means of the skin chamber method. Chamber fluids, collected at 5 and 15 min, were analyzed for both mediators by gas chromatography mass spectrometry negative ion chemical ionization. BVA in comparison to non-allergic patients had a significantly higher ratio of 9α,11β-PGF2 in allergen-challenged chambers to 9α,11β-PGF2 in allergen-free chambers after 15 min of provocation (p = 0.039). Allergen challenge resulted in a significant increase of 9α,11β-PGF2 levels between 5 and 15 min after provocation only in BVA patients (p

Vascular rings are congenital defects of great vessels. They cause compression of the trachea or/and the esophagus and therefore result in symptoms like inspiratory stridor, cough, wheezing, recurrent respiratory tract infections or dysphagia. In some cases, the correct diagnosis can be delayed for many years, especially when vascular rings produce less severe symptoms or symptoms mimicking other diseases (most of all asthma). In this article, we would like to emphasis the usefulness of pulmonary function test (spirometry) in the initial diagnosis of vascular rings in school-aged children, as well as the importance of spirometry in evaluating patients with asthma presumption.

Aortic valve is a part of the heart most frequently affected by pathological processes in humans what constitute a very serious health problem. Therefore, studies of morphology and molecular microstructure of the AV are needed. µSR- FTIR spectroscopy and microscopy represent unique tools to study chemical composition of the tissue and to identify spectroscopic markers characteristic for structural and functional features. Normal AV reveals a multi-layered structure and the compositional and structural changes within particular layers may trigger degenerative processes within the valve. Thus, deep insight into the structure of the valve to understand pathological processes occurring in AV is needed. In order to identify differences between three layers of human AV, tissue sections of macroscopically normal AV were studied using µSR- FTIR spectroscopy in combination with histological and histochemical stainings. Tissue sections deposited onto CaF2 substrates were mapped and representative set of IR spectra collected from fibrosa, spongiosa and ventricularis were analysed by Principal Component Analysis (PCA) in the spectral range between 1850–1000 cm−1 and 3050–2750 cm−1. PCA revealed a layered molecular structure of the valve and it was possible to identify IR bands associated to different tissue parts. Spongiosa layer was well differentiated from other two layers mainly based on IR bands characteristic for the distribution of glycosaminoglycans (GAGs) in the tissue – like 1170 cm−1 (υas(C-O-S)) and 1380 cm−1 (acetyl amino group). Additionally, it was distinguished from fibrosa and ventricularis based on 1085 cm−1 and 1240 cm−1 bands characteristic for GAGs and for carbohydrates- ν(C-O) and ν(C-O-C) respectively and nucleic acids -νsym(PO2−) and νasym(PO2−) respectively, which were less specific for this layer. The use of µSR- FTIR spectroscopy demonstrated co-localization of GAGs and lipids in spongiosa layer what may indicate their contribution in the very early phase of aortic valve calcific degeneration.

PurposeThe purpose of this paper is to present the application of low temperature cofired ceramics (LTCC) technology in the fabrication of a novel electronic device, which consists of an antenna amplifier integrated with temperature stabilizer. The temperature controller consists of a thick‐film thermistor and heater, which has been optimized using geometry to achieve uniform temperature distribution on the whole electronic substrate.Design/methodology/approachLTCC technology was applied in the fabrication process of the novel device. The temperature distribution on the ceramic substrate and temperature stabilization time were analyzed using an IR camera. The heating ability of the heater was tested in a climatic chamber. The heater and thermistors parameters variability were estimated using a basic mathematical statistic.FindingsThe integrated device ensures proper temperature conditions of electronic components if the ambient temperature is lower than −40°C.Research limitations/implicationsThe presented device is just a first prototype. Therefore, the fabrication of the next structures and further experiments will be needed to improve structural drawbacks and to analyze precisely the device reliability and parameters repeatability.Practical implicationsThe device presented in the paper can be applied in systems working at very low ambient temperatures (even at −5°C). Moreover, a temperature stabilizer can increase the temperature of the whole device above −40°C, therefore, standard electronic components (which can work down to −40°C) can be used instead of specialized ones (which can work below −40°C).Originality/valueThis paper presents a novel temperature stabilizer.

Background The direct comparison between children and adults with Hymenoptera venom anaphylaxis (HVA) has never been extensively reported. Severe HVA with IgE-documented mechanism is the recommendation for venom immunotherapy, regardless of age. Objective To determine the differences in the basic diagnostic profile between children and adults with severe HVA and its practical implications. Methods We reviewed the medical records of 91 children and 121 adults. Results Bee venom allergy was exposure dependent, regardless of age ( P P = .01), whereas cardiovascular comorbidities were present almost exclusively in adults ( P = .001). In the bee venom allergic group, specific IgE levels were significantly higher in children (29.5 kU A /L; interquartile range, 11.30-66.30 kU A /L) compared with adults (5.10 kU A /L; interquartile range, 2.03–8.30 kU A /L) ( P P P = .002), as well as in bee ( P = .002) and wasp venom allergic groups ( P = .049). Conclusion The basic diagnostic profile in severe HVA reactors is age dependent. Lower skin test reactivity to culprit venom in children may have practical application in starting the intradermal test procedure with higher venom concentrations.

BACKGROUND The ultrarush protocol is an attractive approach in the buildup phase of venom immunotherapy (VIT-UR). However, the degree of risk of VIT-UR in children remains unknown. The objective of this study was to compare the safety of VIT-UR in children and adults. METHODS We performed a study based on prospectively gathered medical records of children and adults with hymenoptera venom allergy treated with VIT-UR in 3 allergy centers in Poland. RESULTS The study population comprised 134 children (mean [SD] age, 12.6 [3.7] years; males, 70.1%) and 207 adults (mean age, 42.4 [14.0] years; males, 47.8%). The number of children in the subgroups of bee venom (BV) allergy and wasp venom (WV) allergy were comparable, although sensitization to WV was more predominant in the adult group (70.1%). Skin reactivity to both venoms was more common in children than in adults (P < .001); however, children had higher concentrations of total IgE and specific IgE to BV (both P < .001). Systemic allergic reactions (VIT-SARs) occurred in 6.2% of the patients (3.7% in children and 7.7% in adults; nonsignificant). In adults, SARs occurred more frequently in patients treated with BV than WV extracts (21.4% vs 2.6%; P < .001). The same pattern was observed in children (7.2% vs 0%; P = .058). However, VIT-SARs to BV were less frequent in children than in adults (P = .034). Similarly, no significant relationship was noted between children and adults receiving WV VIT (2.6% vs 0%; nonsignificant). The severity of VIT-SAR did not differ between children and adults. CONCLUSIONS VIT-UR is safer in children. Age below 18 is not a risk factor for VIT-SARs.

The effect of cultured autologous oral keratinocyte suspension in fibrin glue on the healing of surgically produced oral mucosal wounds was assessed in the rabbit model. Using the light microscope and a digital image analysis system, the epithelization parameters (marginal epithelization and percentage of wound re-epithelization) were measured in haematoxylin–eosin stained sections of the wound area and compared with those of wounds treated with fibrin glue alone and untreated ones. The epithelization was significantly higher in keratinocytes plus fibrin glue-treated wounds on postoperative days 3 and 7. No significant differences were observed on postoperative day 1, when the healing process had just begun, and on postoperative day 14, when re-epithelization was completed or nearly completed in all groups. The inflammatory infiltration of the wounded mucosa was weakest in keratinocyte-treated wounds and strongest in untreated wounds. In conclusion, suspension of cultured autologous oral keratinocytes in fibrin glue significantly accelerates oral wound healing in the rabbit model and could be beneficial in the treatment of oral wounds in patients.

Cyclins, cyclin-dependent kinases, as well as proteins cooperating with them are responsible for cell cycle regulation which is crucial for normal development, injury repair, and tumorigenesis. D-type cyclins regulate G1 cell cycle progression by enhancing the activities of cyclin-dependent kinases, and their expression is frequently altered in tumors. Disturbances in cyclin expression were also reported in melanocytic skin lesions. The objective of the study was to evaluate the expression of cyclins D1 and D3 in common, dysplastic, and malignant melanocytic skin lesions. Forty-eight melanocytic skin lesions including common nevi (10), dysplastic nevi (24), and melanomas (14) were diagnosed by dermoscopy and excised. Expression of cyclin D1 and D3 was detected by immunohistochemistry and quantified as percentage of immunostained cell nuclei in each sample. In normal skin, expression of cyclins D1 and D3 was not detected. The mean percentage of cyclin D1-positive nuclei was 7.75% for melanoma samples, 5% for dysplastic nevi samples, and 0.34% for common nevi samples. For cyclin D3, the respective values were 17.8, 6.4, and 1.8%. Statistically significant differences in cyclin D1 expression were observed between melanomas and common nevi as well as between dysplastic and common nevi (p = 0.0001), but not between melanomas and dysplastic nevi. Cyclin D3 expression revealed significant differences between all investigated lesion types (p = 0.0000). The mean cyclin D1 and D3 scores of melanomas with Breslow thickness 1 mm were not significantly different. G1/S abnormalities are crucial for the progression of malignant melanoma, and enhanced cyclin D1 and D3 expression leading to increased melanocyte proliferation is observed in both melanoma and dysplastic nevi. In histopathologically ambiguous cases, lower cyclin D3 expression in dysplastic nevi can be a diagnostic marker for that lesion type.

Poprawa opieki perinatalnej w ostatnich latach spowodowała wzrost przeżywalności dzieci przedwcześnie urodzonych. Przerwanie prawidłowego, wewnątrzmacicznego rozwoju płuc wraz z następowym urazem, związanym z koniecznością stosowania wentylacji mechanicznej i tlenoterapii, powoduje rozwój zaburzeń określanych dysplazją oskrzelowo-płucną (BPD). W pierwszym okresie życia zasadniczym problemem tych chorych jest zależność od tlenu. Zwiększona zapadalność na infekcje o ciężkim przebiegu (zwłaszcza o etiologii RSV) jest przyczyną rehospitalizacji w ciągu 1. roku życia u około 50% wcześniaków z rozpoznaniem BPD. U takich dzieci dużym problemem staje się zwalczanie objawów obturacji dróg oddechowych, które w wielu wypadkach słabo ustępują po podaniu bronchodylatatorów. Prawdopodobnie u podłoża tego zjawiska leżą zaburzenia prawidłowego rozwoju układu oddechowego i następujący remodeling w obrębie dróg oddechowych. Nieprawidłowości w wynikach badań czynnościowych (obniżenie FEV₁, PEF, FVC) utrzymują się do późnego okresu dojrzewania, a przyspieszenie tempa spadku wskaźnika FEV1/FVC z wiekiem może sugerować, że osoby te stanowią grupę ryzyka rozwoju “nowej POChP”. Ocena radiogramów płuc w 11. roku życia w grupie byłych wcześniaków z rozpoznaną BPD wykazuje obecność przetrwałych zmian rozedmowych z obecnością jednego lub więcej pęcherzy u 86% dzieci. Nieprawidłowości w obrazie tomografii komputerowej wysokiej rozdzielczości stwierdza się u większości tych pacjentów (u 81.3% w grupie badanych w 10. roku życia i u 92.5% w wieku 18 lat). Dalsze prospektywne badania obejmujące wieloletnią obserwacją dzieci przedwcześnie urodzone są niezbędne dla określenia odległego rokowania i wyznaczenia standardów ich leczenia.

Background: Current data suggest an influence of the hypothalamic-pituitary-adrenal axis on suicidal behavior. The frequency of pituitary adenomas in suicide victims has not yet been investigated. Objectives: The aim of this study was to assess whether the incidence of pituitary adenomas is correlated with suicide. Methods: Serial sections of 151 human pituitary glands obtained upon autopsy were examined microscopically. The glands were collected from 70 suicide victims and 81 subjects whose deaths were classified as unexpected or accidental (nonsuicidal group). The sections were stained with hematoxylin-eosin and the presence of adenoma was confirmed by immunostaining for collagen III. Results: In the suicidal group, pituitary microadenomas were found in 32 cases (47.7%), while in the nonsuicidal group microadenomas were detected in 15 cases (18.3%). The observed difference was statistically significant (p = 0.0003). The relative risk ratio of suicide in persons with pituitary adenomas was estimated at 1.9. Logistic regression analysis in a model controlled for age and sex showed that microadenomas constituted a unique risk factor in this model. The immunohistochemical phenotyping revealed a higher percentage of immunopositive (secreting) microadenomas in the nonsuicidal group as compared to the suicidal group (80.0 vs. 59.38%) and a predominance of growth hormone-secreting microadenomas in both groups. However, these differences as well as differences in the hormonal profiles of microadenomas between the groups were not significant. Conclusions: These results suggest that pituitary adenomas belong to suicide risk factors.

The purpose of this study was to describe clinical manifestations, laboratory findings and outcome of granulomatosis with polyangiitis (GPA) in pediatric patients living in two regions (Southern and Central) of Poland.Retrospective analysis of patient hospital records from four large hospitals during a period from 1995 to 2013. Patients with confirmed diagnosis of GPA according to American College of Rheumatology (ACR) and EULAR/PRINTO/PRES criteria for GPA were analyzed. All patients were subjected to clinical, laboratory, radiological and immunological assessment.During this 18-year period only 9 children with confirmed diagnosis of GPA (6 girls, 3 boys) were identified. The average age of the disease onset was 12 years (range: 8-16 years). Average delay between first symptoms and diagnosis was approx. 20 months (range: 0-84 months). Organ system involvement at presentation included: kidneys 88.8% (8/9), lungs 77.7% (7/9), ear/nose/ throat 55.5% (5/9), gastrointestinal tract 55.5% (5/9), skin 44.4% (4/9), joints 22.2% (2/9), eyes 11.1% (1/9) and nervous system 11.1% (1/9). In 5 children disease course was progressive (constant progression of sinusitis in one case, end-stage renal disease in two, chronic kidney disease stage IV in one and one child died due to alveolar hemorrhage).The majority of our patients were females. Clinical features of pediatric GPA were similar to those described in adults. None of our patients developed subglottic stenosis and in only 2 children saddle-nose deformity was observed. Although GPA was treated according to contemporary standards care, disease progression was observed in more than a half of children.