Accurate and rapid prediction of pKa of transition metal complexes: semiempirical quantum chemistry with a data-augmented approach.

Rapid and accurate prediction of reactivity descriptors of transition metal (TM) complexes is a major challenge for contemporary quantum chemistry. The recently-developed GFN2-xTB method based on the density functional tight-binding theory (DFT-B) is suitable for high-throughput calculation of geometries and thermochemistry for TM complexes albeit with moderate accuracy. Herein we present a data-augmented approach to improve substantially the accuracy of the GFN2-xTB method for the prediction of thermochemical properties using pKa values of TM hydrides as a representative model example. We constructed a comprehensive database for ca. 200 TM hydride complexes featuring the experimentally measured pKa values as well as the GFN2-xTB-optimized geometries and various computed electronic and energetic descriptors. The GFN2-xTB results were further refined and validated by DFT calculations with the hybrid PBE0 functional. Our results show that although the GFN2-xTB performs well in most cases, it fails to adequately describe TM complexes featuring multicarbonyl and multihydride ligand environments. The dataset was analyzed with the ordinary least squares (OLS) fitting and was used to construct an automated machine learning (AutoML) approach for the rapid estimation of pKa of TM hydride complexes. The results obtained show a high predictive power of the very fast AutoML model (RMSE ∼ 2.7) comparable to that of the much slower DFT calculations (RMSE ∼ 3). The presented data-augmented quantum chemistry-based approach is promising for high-throughput computational screening workflows of homogeneous TM-based catalysts.

Directional Filter Design and Simulation for Superconducting On-Chip Filter-Banks.

Many superconducting on-chip filter-banks suffer from poor coupling to the detectors behind each filter. This is a problem intrinsic to the commonly used half-wavelength filter, which has a maximum theoretical coupling of 50 %. In this paper, we introduce a phase-coherent filter, called a directional filter, which has a theoretical coupling of 100 %. In order to study and compare different types of filter-banks, we first analyze the measured filter frequency scatter, losses, and spectral resolution of a DESHIMA 2.0 filter-bank chip. Based on measured fabrication tolerances and losses, we adapt the input parameters for our circuit simulations, quantitatively reproducing the measurements. We find that the frequency scatter is caused by nanometer-scale line width variations and that variances in the spectral resolution is caused by losses in the dielectric only. Finally, we include these realistic parameters in a full filter-bank model and simulate a wide range of spectral resolutions and oversampling values. For all cases, the directional filter-bank has significantly higher coupling to the detectors than the half-wave resonator filter-bank. The directional filter eliminates the need to use oversampling as a method to improve the total efficiency, instead capturing nearly all the power remaining after dielectric losses.

Analysis of procalcitonin and CRP concentrations in serum of patients with chronic spontaneous urticaria.

BACKGROUND: Our previous findings showed the importance of analysing the peripheral markers of acute phase response (APR) activation, C-reactive protein (CRP) and IL-6 in the context of urticaria activity and severity. However, these biomarkers do not reliably differentiate between APR to infectious and the disease severity. AIM: In order to investigate a possible association between the immune-inflammatory activation markers CRP and procalcitonin (PCT). METHODS: Serum PCT and CRP concentrations were measured in patients with CU of varying severity as well as in healthy subjects. RESULTS: Serum PCT and CRP concentrations were significantly increased in more severe CU patients when compared to healthy controls and mild CU, and within the CU population there was a significant correlation between concentrations of PCT and CRP. Serum PCT concentrations remained within normal ranges in most CU patients and were only slightly elevated in some severe CU cases. CONCLUSIONS: PCT serum concentration may be only slightly elevated in some cases of severe CU. Upregulation of PCT synthesis accompanied by parallel changes in CRP concentration reflects a low-grade systemic inflammatory response in CU. PCT should be considered as a better marker than CRP to distinguish between APR to infection and an active non-specific urticarial inflammation.

Increased plasma concentration of vascular endothelial growth factor in patients with atopic dermatitis and its relation to disease severity and platelet activation.

BACKGROUND: Overproduction of vascular endothelial growth factor (VEGF) in atopic dermatitis (AD) lesions has previously been observed. It is also known that platelet is an important source of VEGF and platelet factor 4 (PF-4), a potential marker of AD severity. AIM: To evaluate concentrations of VEGF and its soluble receptors (sVEGF-R1 and sVEGF-R2) in the plasma of AD patients and to examine its possible correlation with disease severity and plasma concentrations of PF-4, a platelet activation marker. METHODS: Plasma concentrations of VEGF and its receptors and levels of PF-4 were measured by an immunoenzymatic assay in 51 AD patients and in 35 healthy non-atopic controls. The severity of the disease was evaluated using the eczema area and severity index. RESULTS: AD patients showed significantly increased VEGF and PF-4 plasma concentrations as compared with the controls. Plasma concentrations of sVEGF-R1 and sVEGF-R2 did not differ between the groups. There were no remarkable correlations between plasma VEGF concentration and disease severity or between VEGF and PF-4 concentration. CONCLUSIONS: This study shows that plasma concentration of VEGF may be increased in patients suffering from AD. It seems that plasma VEGF concentration is not a useful marker of disease severity and, apart from platelets, other cells might also release the cytokine.

Congenital lung abnormality quantification by computed tomography: The CLAQ method.

INTRODUCTION: To date, no consensus has been reached on the optimal management of congenital lung abnormalities, and factors predicting postnatal outcome have not been identified. We developed an objective quantitative computed tomography (CT) scoring method, and assessed its value for clinical decision-making. METHODS: Volumetric CT-scans of all patients born with a congenital lung abnormality between January 1999 and 2018 were assessed. Lung disease was quantified using the newly-developed congenital lung abnormality quantification (CLAQ) scoring method. In 20 equidistant axial slices, cells of a square grid were scored according to the abnormality within. The scored CT parameters were used to predict development of symptoms, and SD scores for spirometry and exercise tolerance (Bruce treadmill test) at 8 years of age. RESULTS: CT-scans of 124 patients with a median age of 5 months were scored. Clinical diagnoses included congenital pulmonary airway malformation (49%), bronchopulmonary sequestration (27%), congenital lobar overinflation (22%), and bronchogenic cyst (1%). Forty-four patients (35%) developed symptoms requiring surgery of whom 28 (22%) patients became symptomatic before a CT-scan was scheduled. Lesional hyperdensity was found as an important predictor of symptom development and decreased exercise tolerance. Using receiver operating characteristic analysis, an optimal cut-off value for developing symptoms was found at 18% total disease. CONCLUSION: CT-quantification of congenital lung abnormalities using the CLAQ method is an objective and reproducible system to describe congenital lung abnormalities on chest CT. The risk for developing symptoms may increase when more than a single lung lobe is affected.

Evaluation of circulating vascular endothelial growth factor and its soluble receptors in patients suffering from persistent allergic rhinitis.

BACKGROUND: Overexpression and enhanced release of vascular endothelial growth factor (VEGF) have been detected in various types of allergic inflammation, including asthma. AIM: To further evaluate the pattern of systemic release of VEGF in atopic allergy, free circulating VEGF was measured in patients with persistent allergic rhinitis (PAR). METHODS: The concentrations of VEGF and its soluble receptors (sVEGF-R1 and VEGF-R2) in plasma were measured in patients with PAR sensitized to house dust mites and the healthy subjects. RESULTS: No significant differences were found between PAR patients and healthy subjects with respect to plasma levels of VEGF and its receptors. CONCLUSIONS: It seems that free circulating VEGF may not be elevated in PAR patients. Moreover, on the basis of the present study as well as the earlier ones, it appears likely that systemic release of VEGF varies among patients with distinct clinical manifestation of atopy; may depend on severity/activity and the extent of inflammatory response.

Involvement of the histaminergic system in the resuscitating effect of centrally acting leptin in haemorrhagic shock in rats.

Leptin, acting centrally as a neuromodulator, induces the activation of the sympathetic nervous system, which may lead to a pressor action in normotensive animals. In haemorrhagic shock, leptin administered intracerebroventricularly (icv.) evokes the resuscitating effect, with long-lasting rises in mean arterial pressure (MAP) and heart rate (HR), subsequent increase in peripheral blood flows, and a 100% survival at 2 h. Since leptin is able to activate histaminergic neurons, and centrally acting histamine also induces the resuscitating effect with the activation of the sympathetic nervous system, in the present study, we investigated an involvement of the histaminergic system in leptin-evoked cardiovascular effects in haemorrhagic shock. The model of irreversible haemorrhagic shock, with MAP decreased to and stabilised at 20 - 25 mmHg, has been used. Leptin (20 µg) given icv. at 5 min of critical hypotension evoked 181.5% increase in extracellular hypothalamic histamine concentration during the first 10 min after injection. Rises in MAP, HR and renal, mesenteric and hindquarters blood flows induced by leptin were inhibited by icv. pre-treatment with histamine H1 receptor antagonist chlorpheniramine (50 nmol). In contrast, there was no effect of H2, H3 and H4 receptor antagonists ranitidine (25 nmol), VUF 5681 (25 nmol) and JNJ 10191584 (25 nmol), respectively. In conclusion, the histaminergic system is involved in centrally-acting leptin-induced resuscitating effect in haemorrhagic shock in rats.

Central histamine-induced reversal of critical haemorrhagic hypotension in rats--haemodynamic studies.

Volume-controlled irreversible haemorrhagic shock in rats produced by blood withdrawal until stabilisation of critical mean arterial pressure (MAP) 20-25 mmHg is associated with an extreme decrease in cardiac index (CI) and an increase in total peripheral resistance index (TPRI), with reductions in renal (RBF), hindquarters (HBF) and mesenteric blood flow (MBF), and leads to the death of all control animals within 30 min. Histamine (100 nmol) injected intracerebroventricularly (i.c.v.) in the early phase of critical hypotension produces a prompt and long-lasting increase in MAP and heart rate, with a 100% survival for 2 h after treatment. The effects are associated with the rise in the circulating blood volume and CI, and the decrease in TPRI, with the increase in RBF and HBF, and persistently lowered MBF. Both splenectomy and ligation of the suprahepatic veins inhibit histamine-induced increase in circulating blood volume as well as cardiac and regional haemodynamic effects. It can be concluded that histamine administered icv activates central endogenous compensatory mechanisms, which leads to the reversal of haemorrhagic shock conditions due to the mobilisation of blood from venous reservoirs, the increase in circulating blood volume and its redistribution. Moreover, histamine evokes the rises in Cl and perfusion of the renal and skeletal muscle vascular regions.

Cardiovascular effects of histamine administered intracerebroventricularly in critical haemorrhagic hypotension in rats.

The study was designed to determine the cardiovascular effects of histamine administered intracerebroventricularly (icv) in a rat model of volume-controlled haemorrhagic shock. The withdrawal of approximately 50% of total blood volume resulted in the death of all control saline icv treated animals within 30 min. Icv injection of histamine produced a prompt dose-dependent (0.1-100 nmol) and long-lasting (10-100 nmol) increase in mean arterial pressure (MAP), pulse pressure (PP) and heart rate (HR), with a 100% survival of 2h after treatment (100 nmol). The increase in MAP and HR after histamine administration in bled rats in comparison to the normovolaemic animals was 2.7-3.3- and 1.3-3.6-fold higher, respectively. Pretreatment with chlorpheniramine (50 nmol icv), H1 receptor antagonist, inhibited the increase in MAP, PP, HR and survival rate produced by histamine, while chlorpheniramine given alone had no effect. Neither ranitidine (50 nmol icv), H2 histamine receptor antagonist, nor thioperamide (50 nmol icv), H3 receptor blocker, influenced the histamine action, however, when given alone, both evoked the pressor effect with elongation of survival time. It can be concluded that histamine administered icv reverses the haemorrhagic shock conditions, and histamine H1 receptors are involved.

Involvement of the renin-angiotensin system in endogenous central histamine-induced reversal of critical haemorrhagic hypotension in rats.

The study was undertaken to examine the involvement of the renin-angiotensin system in the reversal by endogenous central histamine of critical haemorrhagic hypotension in anaesthetised Wistar rats. Histamine N-methyltransferase inhibitor metoprine (20 microg) administered intracerebroventricularly at 5 min of critical hypotension 20-25 mmHg produced increases in histamine concentrations as measured 20 min after treatment in the hypothalamus (581.33 +/- 63.23 vs. 488.26 +/- 56.34 ng/g of wet tissue; P < 0.01) and medulla oblongata (53.42 +/- 14.65 vs. 34.68 +/- 13.52 ng/g of wet tissue; P < 0.05). That was accompanied by 34.7% higher plasma angiotensin II concentration in comparison to the control group. Metoprine produced dose-dependent (5-20 microg) rises in mean arterial pressure (MAP) and heart rate, which were significantly higher than those in normotensive animals. The resuscitating action of metoprine (20 microg) was associated with rises in renal, mesenteric and hindquarters blood flows, and a 100% survival at 2 h after treatment, while in the saline-treated group, all the animals died within 30 min. Angiotensin type 1 (AT(1)) receptor antagonist ZD 7155 (0.5 mg/kg; iv) decreased regional vascular resistance and inhibited metoprine-induced increase in MAP, whereas AT(2) receptor blocker PD 123319 (10 mg/kg; i.v.) had no effect. Angiotensin-converting enzyme inhibitor captopril (30 mg/kg; i.v.) reduced the increase in plasma angiotensin II level and the haemodynamic effects of metoprine. Neither capropril, nor angiotensin receptor antagonists influence the survival at 2 h after treatment. In conclusion, the renin-angiotensin system is involved in central histamine-induced resuscitating action in rats.

Involvement of proopiomenalocortin-derived peptides in endogenous central histamine-induced reversal of critical haemorrhagic hypotension in rats.

An increase in endogenous central histamine concentrations, after loading with histamine precursor L-histidine or inhibition of histamine N-methyltransferase (HNMT) activity, produces the reversal of critical hypotension with improvement in survival of haemorrhage-shocked rats. In the present study, the involvement of proopiomelanocortin (POMC)-derived peptides in central histamine-induced resuscitating action was examined in male anaesthetised Wistar rats subjected to a haemorrhagic hypotension of 20-25 mmHg resulting in the death of all control animals within 30 min. HNMT inhibitor metoprine (20 microg) administered intracerebroventricularly (i.c.v.) at 5 min of critical hypotension produced a long-lasting pressor effect with a 100% survival rate at 2 h. The action was accompanied by 34.5% and 28.9% higher plasma concentrations of ACTH and alpha-MSH, respectively, in comparison to concentrations in the saline-injected group as measured 20 min after treatment. Melanocortin type 4 (MC(4)) receptor antagonist HS014 (5 microg; i.c.v.) inhibited metoprine-induced increase in mean arterial pressure, which resulted from decreased regional vascular resistance, however, it did not affect the heart rate and the survival at 2 h. On the other hand, glucocorticoid type II receptor blocker mifepristone (30 mg/kg; sc) had no effect. In conclusion, POMC-derived peptides, acting centrally via MC(4) receptors, participate in endogenous central histamine-induced resuscitating effect in rats.

Haematological, blood gas and acid-base effects of central histamine-induced reversal of critical haemorrhagic hypotension in rats.

In a rat model of volume-controlled irreversible haemorrhagic shock, which results in a severe metabolic acidosis and the death of all control animals within 30 min., intracerebroventricular injection of histamine (100 nmol) produces a prompt and long-lasting increase in mean arterial pressure and heart rate, with a 100% survival of 2 h after treatment. Histamine action is accompanied by a decrease in haematocrit value, haemoglobin concentration, erythrocyte and platelet count, and an increase in residual blood volume at the end of the experiment (2 h). Cardiovascular effects are also associated with a long-lasting rise in respiratory rate and biphasic blood acid-base changes - initial increase of metabolic acidosis with the decrease in arterial and venous pH, bicarbonate concentration and base excess, followed by almost a complete recovery of blood gas and acid-base parameters to the pre-bleeding values, with normalisation of arterial and venous pH, Pco2 bicarbonate concentration and base excess at the end of experiment. It can be concluded that in the late phase of central histamine-induced reversal of haemorrhagic hypotension there is almost a complete restoration of blood gas and acid-base status due to circulatory and respiratory compensations, while accompanying haematological changes are the result of the haemodilution and the increase in residual blood volume.

Cardiac and regional haemodynamic effects of endothelin-1 in rats subjected to critical haemorrhagic hypotension.

In the present study, we examined cardiac and regional haemodynamic effects of endothelin-1 (ET-1), a potent vasoconstrictive factor, in a rat model of pressure-controlled irreversible haemorrhagic shock resulting in the death of all control animals within 30 min. Experiments were carried out in male ethylurethane-anaesthetised Wistar rats subjected to hypotension of 20-25 mmHg, which resulted in bradycardia, an extreme decrease in cardiac index (CI) and an increase in total peripheral resistance index (TPRI), with reductions in renal (RBF), hindquarters (HBF) and mesenteric blood flow (MBF). ET-1 (50, 200 pmol/kg) administered intravenously at 5 min of critical hypotension produced increases in mean arterial pressure (MAP) and heart rate (HR), which were significantly higher than those in normotensive animals, and a 100% survival at 2 h after treatment. The effects were accompanied by a rise in CI, a decrease in TPRI, with increases in RBF and HBF and persistently lowered MBF, and an increase in circulating blood volume 20 min after treatment. The cardiovascular effects of ET-1 were inhibited by the ETA receptor antagonist BQ-123 (1 mg/kg), while the ETB receptor antagonist BQ-788 (3 mg/kg) had no effect. In conclusion, ET-1 acting via ETA receptors produces reversal of haemorrhagic hypotension in rats due to the mobilisation of blood from venous reservoirs, with the improvements in cardiac function and the perfusion of peripheral tissues.

Cerebral angiogenesis after subarachnoid hemorrhage (SAH) and endothelin receptor blockage with BQ-123 antagonist in rats.

The aim of the study was to determine the effect of chronic vasospasm after SAH on angiogenesis and the effect of endothelin-1, the main causative factor in vasospasm, on this process. Male Wistar rats, 220-250 g, were examined. Seven days after cannulation of the cisterna magna (CM), a 100 microl dose of non-heparinized blood was administered to induce SAH. Sham SAH (aSAH) was induced by intracisternal injection of 100 microl of artificial cerebrospinal fluid. Endothelin receptor antagonist BQ-123 in a dose of 40 nmol in 50 microl of cerebrospinal fluid was given three times: 20 min. before SAH and aSAH, 60 min and 24 hours after SAH and aSAH. The same pattern of BQ-123 administration was used in the nonSAH group. The brains were removed 48 hours later for histological evaluation. Vascular surface density was measured in cerebral hemisphere sections (at the level of the dorsal part of the hippocampus) and brain stem sections (1/2 of the pons). An increase in angiogenesis was observed after SAH, compared to control values. The administration of BQ-123, a specific endothelin receptor blocker inhibits angiogenesis in cerebral hemispheres after SAH.

Expression of vascular endothelial growth factor (VEGF) in rat brain after subarachnoid haemorrhage and endothelin receptor blockage with BQ-123.

Cerebral vasospasm is one of the most severe complications of subarachnoid haemorrhage (SAH), leading to pathological changes in the vessel wall itself and in the nervous tissue, due to ischaemia of endothelial cells and neurones. Amongst the known substances inducing vasospasm, the most potent spasmogenic effect is exerted by endothelin-1 (ET1). The constriction of cerebral arteries and obliteration of capillaries highly stimulates the secretion of growth factors by endothelial cells and induces compensatory formation of collateral circulation in response to brain ischaemia. Expression of vascular endothelial growth factor (VEGF), the main factor responsible for angiogenesis and vascular permeability, was found to be increased in hypoxic cells (irrespective of the cause of hypoxia) as well as in neoplastic cells in the brain. The aim of the study was to determine whether chronic vasospasm and hypoxia of endothelial cells stimulate expression of VEGF, and whether blockage of the endothelin receptor ET(A) reduces this expression. The SAH was induced experimentally in male Wistar rats and the ET(A) receptor antagonist--BQ-123 was administered into the cisterna magna. After 48 hours the brain was removed and expression of VEGF studied immunohistochemically on paraffin sections. We found that hypoxia of endothelial cells, induced by chronic vasospasm after SAH, caused increased expression of VEGF in brain vessels and neurones of the cerebral hemispheres, brain stem and cerebellum. After administration of the endothelin receptor antagonist BQ-123, no changes in VEGF expression in the brain were found.

Inhibitory effect of local ischemic preconditioning on gamma ray-induced lipid peroxidation in rats: a preliminary study.

We examined the effect of local ischemic preconditioning on postradiation lipid peroxidation in the serum of total body irradiated rats. Markers of peroxidative damage provoked by radiation alone or radiation preceeded by ischemic preconditioning were thiobarbituric acid reactive substances, triglycerides and uric acid concentrations in serum. These data indicated that local ischemic preconditioning modifies the peroxidizing effects of radiation through inhibition of free radical-dependent lipid peroxidation. Other unrecognized mechanisms are probably also involved. Uric acid could act as an antioxidant against radiation alone and local preconditioned ischemia together with radiation.

Automated cerebral infarct volume measurement in follow-up noncontrast CT scans of patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: Cerebral infarct volume as observed in follow-up CT is an important radiologic outcome measure of the effectiveness of treatment of patients with acute ischemic stroke. However, manual measurement of CIV is time-consuming and operator-dependent. The purpose of this study was to develop and evaluate a robust automated measurement of the CIV. MATERIALS AND METHODS: The CIV in early follow-up CT images of 34 consecutive patients with acute ischemic stroke was segmented with an automated intensity-based region-growing algorithm, which includes partial volume effect correction near the skull, midline determination, and ventricle and hemorrhage exclusion. Two observers manually delineated the CIV. Interobserver variability of the manual assessments and the accuracy of the automated method were evaluated by using the Pearson correlation, Bland-Altman analysis, and Dice coefficients. The accuracy was defined as the correlation with the manual assessment as a reference standard. RESULTS: The Pearson correlation for the automated method compared with the reference standard was similar to the manual correlation (R = 0.98). The accuracy of the automated method was excellent with a mean difference of 0.5 mL with limits of agreement of -38.0-39.1 mL, which were more consistent than the interobserver variability of the 2 observers (-40.9-44.1 mL). However, the Dice coefficients were higher for the manual delineation. CONCLUSIONS: The automated method showed a strong correlation and accuracy with the manual reference measurement. This approach has the potential to become the standard in assessing the infarct volume as a secondary outcome measure for evaluating the effectiveness of treatment.

Involvement of the histaminergic system in cytidine 5'-diphosphocholine-induced reversal of critical haemorrhagic hypotension in rats.

Cytidine 5'-diphosphocholine (CDP-choline) is an endogenously synthesized mononucleotide which exerts a variety of physiological effects by altering central cholinergic transmission. Administered intracerebroventricularly (i.c.v.) or intravenously, it reverses haemorrhagic hypotension in rats, apparently by the activation of central cholinergic receptors. The study was undertaken to investigate the involvement of the central histaminergic system in CDP-choline-mediated reversal of haemorrhagic hypotension. Experiments were carried out in male ketamine/xylazine-anaesthetised Wistar rats subjected to haemorrhagic hypotension of 20-26 mmHg. CDP-choline (2 micromol; i.c.v.) administered at 5 min of critical hypotension produced a long-lasting pressor effect with increases in mean arterial pressure (MAP), heart rate (HR), and renal, hindquarters and mesenteric blood flows, resulting in a 100% survival at 2 h. The action was accompanied by approximately a 26% increase in extracellular histamine concentration at the posterior hypothalamus, as measured by microdialysis. Cardiovascular effects mediated by CDP-choline were almost completely blocked by pretreatment with H(1) receptor antagonist chlorpheniramine (50 nmol; i.c.v.), but not with H(2) receptor blocker ranitidine (25 nmol; icv) or H(3)/H(4) receptor antagonist thioperamide (50 nmol; i.c.v.). In conclusion, the present results show that he central histaminergic system, through the activation of H(1) histaminergic receptors, is involved in CDP-choline-induced resuscitating effect in haemorrhage-shocked rats.