Pulmonary pattern in systemic vasculitis: granulomatosis,lung cancer or both?

As clinical manifestations of systemic vasculitides share many common features with other conditions, the rate of diagnostic errors and delayed diagnoses is high. Hence we performed an analysis of the available data regarding misdiagnosis of vasculitis as lung cancer and vice versa, as well as coexistence of vasculitis and lung cancer. The present case-based review highlights the diagnostic challenges encountered when granulomatosis with polyangiitis (GPA) mimics lung cancer. The importance of a multidisciplinary team approach to patients with pulmonary involvement and multisystem manifestations is essential for appropriate planning of further diagnostic steps and for minimizing the delay in correct diagnosis and treatment. In the present case, although computed tomography raised suspicion for lung cancer, further biopsies and laboratory screening for systemic vasculitides rejected malignancy and confirmed the diagnosis of GPA.     

Hybrid compound based on diethylenetriaminecopper(ii) cations and scarce V-monosubstituted β-octamolybdate as water oxidation catalyst

Herein, we report on a new hybrid compound (NH₄){[Cu(dien)(H₂O)₂]₂[β-VMo₇O₂₆]}·1.5H₂O (1), where dien = diethylenetriamine, containing an extremely rare mixed-metal pseudo-octamolybdate cluster. An ex situ EPR spectroscopy provided insights into the formation of paramagnetic species in reaction mixture and in solution of 1. The magneto-structural correlations revealed weak antiferromagnetic exchange interactions between the [Cu(dien)]²⁺ cations transmitted by intermolecular pathways. The cyclic voltammetry showed the one-electron process associated with the Cu³⁺/Cu²⁺ oxidation followed by the multi-electron catalytic wave due to water oxidation with a faradaic yield of 86%. The title compound was thus employed in homogeneous water oxidation catalysis using tris(bipyridine)ruthenium photosensitizer. At pH 8.0, efficiency of the catalytic system attained 0.19 turnovers per second supported by the relatively mild water oxidation overpotential of 0.54 V.

A new hybrid compound (NH₄){[Cu(dien)(H₂O)₂]₂[β-VMo₇O₂₆]}·1.5H₂O was employed in homogeneous water oxidation catalysis. At pH 8.0, its efficiency attains 0.19 turnovers per second, supported by the relatively mild water oxidation overpotential of 0.54 V.     

The Impact of Element–Element Interactions on Antioxidant Enzymatic Activity in the Blood of White Stork (Ciconia ciconia) Chicks

The aim of this work was to determine interrelationships among macroelements Na, K, Ca, Mg, and Fe, microelements Zn, Cu, Mn, and Co, and toxic heavy metals Pb and Cd in the blood of white stork Ciconia ciconia, during postnatal development, in different Polish environments, and their impact on the activity of antioxidant enzymes. We considered the content of thiobarbituric acid-reactive substances (TBARSs), i.e., malondialdehyde (MDA), and activity of superoxide dismutase (SOD), catalase (CAT), ceruloplasmine (CP), glutathione peroxidase (GPx), and glutathione reductase (GR). Blood samples were collected from storks developing at Odra meadows (Kłopot; southwestern Poland). They were compared with blood of chicks from several suburban sites located 20 km away from Zielona Góra (0.1 million inhabitants; southwestern Poland) and near Głogów, where a copper smelter is situated. We also conducted research in the Pomeranian region (Cecenowo; northern Poland). We collected blood samples via venipuncture of the brachial vein of chicks in 2005–2007. They were retrieved from the nest and placed in individual ventilated cotton sacks. The blood was collected using a 5-ml syringe washed with ethylenediaminetetraacetic acid (EDTA). We found significant interactions between macro- and microelements and enzymatic activity and TBARS products. We noticed the predominance of Cd and Pb participation in element–enzyme interactions. Simultaneously, we found interrelationships between cadmium and Na, K, Ca, Mg, and Fe and the activity of antioxidant enzymes SOD, CAT, CP, GR, and TBARS products in the blood of white stork chicks. In the case of lead these relationships were not numerous and they were significant for Ca, Mg, Cu, Mn, and Co. Correlations with enzymes were significant for Pb-CAT and Pb-TBARS. We noted that activities of most enzymes (SOD, CAT, CP, GR) and TBARS products are determined by their interactions with physiological elements Na, Ca, Mg, Fe, and Zn and toxic heavy metals. White stork chicks ranged in age from 17 to 59 days. Concentrations of elements in the blood were age related. Among enzymes, only SOD, CAT, and GPx were age related. Young storks differed in the case of element concentration (except for Ca, Zn, and Cd) and enzymatic activity. We found that significant element–element interaction/enzyme activity predominated in the case of physiological elements and toxic metals, which we explain by the intensive and prevailing access of toxic metals in redox reactions. This causes changes in the priority of these metals, reflected by their influence on the enzymatic activity of antioxidant enzymes. The content of Cd and Pb in blood of young storks from different regions tends to affect the lipid peroxidation process negatively. However, in many cases we observed an increase in enzymatic activity with an increase in heavy metals. This indicates the changes in oxidative stress intensity in chicks in response to environmental differentiation. The increase in lipoperoxidation modifies antioxidant enzyme activity and causes changes in SOD, CAT, CP, GPx, and GR activity in chicks from various regions, principally increases in enzyme activity in chicks from polluted environments and suburbs. We suggest that the source of heavy metals in chicks’ blood might be used as a biological test system of adaptation to oxidative stress. We also report that a high level of heavy metals is accompanied by increased lipid peroxidation. Thus young storks are probably significantly susceptible to environmental conditions. They demonstrated initiation of lipoperoxidation and oxidative modification of proteins that coincide with chemical elements, as a possible antioxidant defense system.     

Psychometric properties of the Ukrainian version of the Childhood Health Assessment Questionnaire (CHAQ)

Background: The objective of this study was to develop and validate the Ukrainian version of the Childhood Health Assessment Questionnaire (CHAQ) in sick by juvenile idiopathic arthritis (JIA) children. Methods: The Ukrainian version of the CHAQ was fully cross-culturally adapted from the original American-English version with 3 forward and 3 backward translations. The CHAQ has been validated in a cross-sectional study in 55 patients with and 30 healthy children. Results: The results were characterized by a high level of internal consistency and good reliability (the Cronbach alpha coefficient was 0.86 for 8/8 domains). The constructive validity was considered by the correlation of the CHAQ scales with each other. For the discriminant validity correlation of the domains and the disability index with the evaluation of pain was significant. The convergent validity was confirmed by correlation of the CHAQ and the Child Health Questionnaire (CHQ) physical summary score. The divergent validity was confirmed because there was no correlation between the CHAQ items and the CHQ psychosocial summary score. The discovered correlations between disability index and morning stiffness, number of active joints, number of joints with limited range of motion, number of joints with pain, number of swollen joints, Ritchie articular index, DAS, DAS28, SDAI, and CDAI have confirmed the external validity of the CHAQ. Sensitivity of the CHAQ to minimal changes of joints functions in patients with JIA also has been proven. Conclusions: The Ukrainian version of the CHAQ is a reliable, valid, and sensitive tool for the functional assessment of children with JIA.     

Cardiovascular lesions in giant cell arteritis

IntroductionGiant cell arteritis (GCA) is a systemic vasculitis that affects large vessels. Cardiovascular complications that develop with GCA have high morbidity and can be fatal. The aim of this work was to discuss epidemiology, clinical picture, etiopathology and risk of development of cardiovascular complications in GCA.Material and methodsA literature review was performed for 2002 to 2021 using PubMed and Medline scientific search databases. The following keywords were used to search academic journal databases: “giant cell arteritis”, “heart attack”, “cardiovascular system”, “aortic aneurysm”, “coronary heart disease”, “aortic dissection”, “myocardium” and “stroke”. Articles written in languages, other than English, were excluded.ResultsThe analysis of studies showed an increased risk of an aneurysm, aortic dissection, coronary heart disease, cerebrovascular events, and peripheral artery disease in patients with GCA. This was not surprising as it has been shown that, cardiovascular complications worsens the prognosis in GCA. According to the results of observations and cited studies the most significant risk of cardiovascular complications was observed in the first year following the diagnosis of GCA.ConclusionsPatients with GCA have an increased risk of cardiovascular disease, but research data/findings are somewhat conflicting, and there is limited information/knowledge on how to treat the patients. Awareness of the risk of cardiovascular disease in GCA is essential, and monitoring these potentially fatal consequences is mandatory in patients with GCA. It is critical to be aware of the danger of cardiovascular illness in GCA patients and to keep track of these potentially deadly outcomes.     

Ecophysiological determinations of antioxidant enzymes and lipoperoxidation in the blood of White Stork Ciconia ciconia from Poland

The aim of this study was to investigate the activity of antioxidant enzymes in the blood of White Stork Ciconia ciconia chicks (aged 19-54 days) in Poland in 2006. We took under consideration superoxide dismutase (SOD), catalase (CAT), ceruloplasmine (CP), glutathione peroxidase (GPx), glutathione reductase (GR) and the content of thiobarbituric acid-reactive substances (malondialdehyde) in polluted (copper manufacture), suburban areas, at the Odra meadows, and at swamps near Baltic Sea in the Pomeranian region. We examined the levels of Na, K, Ca, Mg, Fe, Zn, Cu, Mn, Co, Cd, and Pb and compared ecophysiological determinations for developing storks.Blood samples of wing venous were collected from 91 chicks from 33 nests. The degree of activity of antioxidant enzymes studied has been different in White Stork chicks’ blood from Poland regions, as a rule. We have stated a relatively high level of CAT, GPx, SOD, and GR activity and malondialdehyde (MDA) content in chicks from polluted areas. However, relative value for GR in storks from Odra meadows was considerably higher (about 112 nmol NADPH₂/min ml) than those in chicks from other environments (56-84 nmol on average). Relatively high levels of CAT, CP, and GPx (2.7 mkM/min l, 22.2 mg/l, and 3.8 nmol GSH/min ml, respectively) were also stated in chicks nested in swamps near Baltic Sea. Simultaneously, we have stated differences (p<0.02-p<0.001) in the level of elements (besides Ca) in blood of young storks from the studied areas. We found a high level of toxic metals, e.g. Cd, either from swamps near Baltic Sea (2.7 mg/kg) or from G?ogów smelter (2.2 mg/kg), whilst Pb concentration was high in chicks from G?ogów (7.2 mg/kg). Cd and Pb levels in blood of chicks were different in individuals from each region (p<0.001). Birds from a smelter have the highest level of these elements, whereas the lowest one was stated in chicks from Odra meadows (Cd: 1.45, Pb: 0.84 mg/kg). Thus, Cd could be a useful marker of response for polluted stress. We also observed a relatively high level of Mg in chicks from both Pomeranian (7000 mg/kg) and polluted (about 6000 mg/kg) areas. Potassium, zinc, and cobalt levels were highest in chicks from suburbs (4.65, 10.1, and 2.7 mg/kg, respectively) and polluted regions (3.8, 9.7, and 5.6 mg/kg, respectively), whilst Cu and Mn were highest in those from polluted (10.9 and 47.6 mg/kg, respectively) and Pomeranian regions (11 and 42.2 mg/kg, respectively).Concentrations of Na, K, and Ca in chicks from G?ogów smelter (143.2, 3.8, and 115.9 mg/kg, respectively) were often similar to those from Odra meadows (147.8, 3.6, and 112.5 mg/kg, respectively). This was probably due to a similar degree of homeostatic regulations of an organism. The levels of Mg, Fe, Zn, and Cu were often different (p<0.02-p<0.001) in the blood of White Stork chicks from the studied areas. Co, Pb, and Cd levels were higher (p<0.001) in chicks from G?ogów smelter than in those from Odra meadows. It is evidence for importance of anthropopression, which influenced the course of biogeochemical processes and the bioaccumulation of toxic metals locally. This takes place also in chicks from swamps near Baltic Sea, in which the level of Cd was high (2.7 mg/kg); so we can state the high intensity of intoxication in this region. We can conclude that the use of hematological research assesses the condition of birds and might give a positive association with miscellaneous environmental loads. The high concentration of toxic heavy metals involved greater intensity of antioxidant enzymes’ activity. Environmental intoxication causes an increase of lipoperoxidation intensity in growing chicks and changes the response of their immunological system.     

The human D2 dopamine receptor synergizes with the A2A adenosine receptor to stimulate adenylyl cyclase in PC12 cells.

The adenosine A(2A) receptor and the dopamine D(2) receptor are prototypically coupled to G(s) and G(i)/G(o), respectively. In striatal intermediate spiny neurons, these receptors are colocalized in dendritic spines and act as mutual antagonists. This antagonism has been proposed to occur at the level of the receptors or of receptor-G protein coupling. We tested this model in PC12 cells which endogenously express A(2A) receptors. The human D(2) receptor was introduced into PC12 cells by stable transfection. A(2A)-agonist-mediated inhibition of D(2) agonist binding was absent in PC12 cell membranes but present in HEK293 cells transfected as a control. However, in the resulting PC12 cell lines, the action of the D(2) agonist quinpirole depended on the expression level of the D(2) receptor: at low and high receptor levels, the A(2A)-agonist-induced elevation of cAMP was enhanced and inhibited, respectively. Forskolin-stimulated cAMP formation was invariably inhibited by quinpirole. The effects of quinpirole were abolished by pretreatment with pertussis toxin. A(2A)-receptor-mediated cAMP formation was inhibited by other G(i)/G(o)-coupled receptors that were either endogenously present (P(2y12)-like receptor for ADP) or stably expressed after transfection (A(1) adenosine, metabotropic glutamate receptor-7A). Similarly, voltage activated Ca(2+) channels were inhibited by the endogenous P(2Y) receptor and by the heterologously expressed A(1) receptor but not by the D(2) receptor. These data indicate functional segregation of signaling components. Our observations are thus compatible with the proposed model that D(2) and A(2A) receptors are closely associated, but they highlight the fact that this interaction can also support synergism.     

Hormetic Effect of H2O2 in Saccharomyces cerevisiae: Involvement of TOR and Glutathione Reductase

In this study, we investigated the relationship between target of rapamycin (TOR) and H₂O₂-induced hormetic response in the budding yeast Saccharomyces cerevisiae grown on glucose or fructose. In general, our data suggest that: (1) hydrogen peroxide (H₂O₂) induces hormesis in a TOR-dependent manner; (2) the H₂O₂-induced hormetic dose–response in yeast depends on the type of carbohydrate in growth medium; (3) the concentration-dependent effect of H₂O₂ on yeast colony growth positively correlates with the activity of glutathione reductase that suggests the enzyme involvement in the H₂O₂-induced hormetic response; and (4) both TOR1 and TOR2 are involved in the reciprocal regulation of the activity of glucose-6-phosphate dehydrogenase and glyoxalase 1.     

Predicting the spatiotemporal dynamics of hair follicle patterns in the developing mouse

Reaction–diffusion models have been used as a paradigm for describing the de novo emergence of biological patterns such as stripes and spots. In many organisms, these initial patterns are typically refined and elaborated over the subsequent course of development. Here we study the formation of secondary hair follicle patterns in the skin of developing mouse embryos. We used the expression of sex-determining region Y box 2 to identify and distinguish the primary and secondary hair follicles and to infer the spatiotemporal dynamics of the follicle formation process. Quantitative analysis of the specific follicle patterns observed reveals a simple geometrical rule governing the formation of secondary follicles, and motivates an expansion–induction (EI) model in which new follicle formation is driven by the physical growth of the embryo. The EI model requires only one diffusible morphogen and provides quantitative, accurate predictions on the relative positions and timing of secondary follicle formation, using only the observed configuration of primary follicles as input. The same model accurately describes the positions of additional follicles that emerge from skin explants treated with an activator. Thus, the EI model provides a simple and robust mechanism for predicting secondary space-filling patterns in growing embryos.In mouse skin development, well defined waves of induction during embryogenesis give rise to several major hair types. The first wave, starting around embryonic day 13 (E13), generates the future guard hair. This primary hair is the longest and is surrounded by Merkel cells (1, 2). The second wave (around E14.5–E16.5) generates two types of secondary hair: awls and auchenes. The third wave (around E17) generates the “Z” shape zigzag tertiary hair. During the formation of these hair types, smaller secondary follicles appear in the interstitial space of the larger primary follicles (1, 3). Unlike the feather buds in chick, which are organized in a highly ordered hexagonal array (4–6), mouse hair follicles are distributed in characteristic but less orderly space-filling patterns, the specifics of which have not been quantitatively characterized (Fig. 1A), and without which a quantitative assessment of pattern integrity in mutants cannot be made.Open in a separate windowFig. 1.Spatial regularity in hair follicle patterns as revealed by Voronoi analysis. (A) Whole-mount X-gal staining of an E15.5 Sox2^Ysb/+ mouse embryo. (B) Sox2 is coexpressed with Merkel cell marker Atoh1 in E17.5 skin. (C) Schematic diagram of LacZ expression in primary and secondary follicles during hair morphogenesis in Sox2^Ysb/+ embryos. At E14.5, the primary and secondary follicles, marked by LacZ (X-gal staining) expressed from the dermal papillae (DP), can be distinguished by their relative sizes because secondary follicles (fainter) are just beginning to emerge (blue arrowhead, D). (E) A Voronoi diagram is generated according to the positions of the primary hair follicles (red dots) in E14.5 skin. All secondary follicles (blue dots) are located near the vertices of the Voronoi cells (white polygons). (F) The average area of the Voronoi cells generated by the primary hair follicles. The E15.5 Voronoi cells are ∼2.8-fold larger than (*P < 0.05) the E14.5 Voronoi cells, indicating expansion of the epithelium during this time. At E15.5, primary follicles are distinguished by the characteristic associated presence of Merkel cells (MC), which also express LacZ (red arrowhead in G). (H) The same Voronoi diagram as (E) is generated for E15.5 skin. Two groups of secondary follicles are seen: IIA (blue dots) located close to the Voronoi boundaries, and IIB (orange dots) located in the interior of the Voronoi cells; see Supplemental Methods. (I) A Voronoi diagram generated according to the positions of the primary and IIA follicles. (J) In the Sox2^Ysb/Ysb E15.5 skin, the X-gal signal is stronger, hence more juvenile IIB hair follicles could be observed (M). (K and L) IIA (blue) and IIB (orange) follicles are distinguished by the Voronoi diagrams as shown in H. (L) Similar to the Sox2^Ysb/+ E15.5 skin, the IIB follicles fall on the vertices of the Voronoi diagrams generated by the primary and IIB follicles.Turing’s analysis of the reaction–diffusion (RD) model, involving the diffusion of two types of morphogens (“activator” and “inhibitor”) whose interaction regulates their own synthesis, has been regarded as a paradigm to explain the de novo emergence of approximately periodic patterns of epidermal appendages (reviewed in refs. 1, 3, and 7–11; SI Appendix, Note 1). The Turing class of RD models were postulated long ago to explain the initiation of skin appendage patterns (8, 12–15), the secondary follicle patterns (16), the coat pattern (17), and skin pigmentation (7, 18, 19). Sick et al. (3) provided molecular evidence for regulators necessary in the formation of hair follicles patterns. They further extended the Turing model developed by Nagorcka and Mooney (8) to describe the patterning of the wave of secondary follicles in between preexisting primary follicles. However, direct assessment of the applicability of Turing-class models to an observed pattern is difficult due to the lack of quantitative information including the biophysical properties and the initial distribution of the morphogens, all of which can significantly affect quantitative predictions by these models (20).Equally importantly, the physical growth of the embryo is often not taken into account in typical applications of Turing models. In a number of cases where physical growth was considered, the models were found to generate peak doubling via either tip-splitting bifurcations or tip insertion depending on model parameters and the specifics of the growth kinetics (17, 21–23). Because tip-splitting processes have never been observed in hair follicle development, even qualitative assessment of the applicability of Turing-type RD models to follicle development requires quantitative knowledge of the model parameters, which is difficult. Moreover, existing studies of Turing models with growth have been done in one spatial dimension (24, 25), or on the effective 1D problem of stripe formation in two dimensions (26, 27), but not on the geometrically more complex case of spot formation in 2D.Here we describe an alternative approach to characterize the formation of secondary hair follicle patterns in the developing mouse, after the establishment of the primary follicles (13). We show quantitative spatiotemporal data for the formation and placement of newly generated hair follicles. These data motivate a simple mathematical model that predicts the timing and location of newly formed follicles without knowledge of the morphogen profiles or the growth dynamics.