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Hormonal peptides like ghrelin, orexin A (OXA) or nesfatin-1 not only regulate appetite, which is their basic biological function, but also contribute to mechanisms responsible for maintaining integrity of the gastric mucosa. Previous studies including those from our laboratory have revealed that their gastroprotective effect results from cooperation with other factors responsible for protection of the gastric mucosa, including prostaglandin (PG) synthesis pathway, nitric oxide (NO) and the sensory afferent fibres releasing the vasoactive neurotransmitters. The aim of the present study was to determine whether ghrelin, orexin-A (OX-A) or nesfatin-1 with their protective effect on the gastric mucosa, also can modify the healing of chronic gastric ulcers. Furthermore, an attempt was made to explain participation of these peptides in healing processes of chronic gastric ulcers with comorbid conditions for the human beings resulted from diabetes mellitus. In our study, a model of gastric ulcers caused by concentrated acetic acid to induce the chronic gastric ulcers was used, while the clinical condition corresponding to diabetes was induced by single injection of streptozotocin (STZ). We found that ghrelin, OX-A and nesfatin-1 accelerate dynamics of the acetic acid ulcers healing, confirmed by a reduction in the ulcer area and this effect was accompanied by an increase in gastric blood flow at the ulcer margin. Destruction of sensory afferent fibres with capsaicin or blocking of vanilloid receptors with capsazepine resulted in a significant reduction of ghrelin, OX-A and nesfatin-1-induced acceleration of ulcer healing. Similar results were obtained when an NO-synthase blocker, L-NNA was used in a combination with these peptides. Moreover, it was found that OX-A and nesfatin-1 failed to accelerate the healing process under diabetic condition because both these hormones induced reduction in the ulcer area and the increase in blood flow in normal, non-diabetic rats were completely lost in the group of animals with diabetes. Treatment with OX-A and nesfatin-1 increased superoxide dismutase (SOD) mRNA expression even in acetic acid ulcers concurrent with diabetes. However, the treatment with OX-A and nesfatin-1 failed to alter the increase in gastric mucosal mRNA expression for ghrelin and hypoxia-inducible factor 1-alpha (HIF-1α), this latter effect that had been strongly pronounced in diabetic animals. We conclude that the hormonal peptides involved in the regulation of satiety and hunger such as ghrelin, OX-A and nesfatin-1 contribute to the process of chronic gastric ulcers healing cooperating with NO and sensory afferent nerve endings releasing vasoactive neuropeptide CGRP. Furthermore, OX-A and nesfatin-1, the two relatively unrecognized peptides, play an essential role in healing process of chronic gastric ulcers activating the gastric blood flow at ulcer margin and the mucosal regeneration and both ulcer healing and accompanying hyperemia at ulcer margin are greatly impaired during diabetes. Possibly, loss of the healing effect of these peptides during diabetes results from an interaction with radical generation processes as reflected by an increase of mRNA expression for SOD as well as the failure of their attenuating activity on proinflammatory factors such as HIF-1α.

Treatment with small doses of topical capsaicin protects the gastric mucosa from the damage by strong irritants but functional ablation of sensory nerves by pretreatment with larger dose of parenteral capsaicin augments the formation of gastric lesions via unknown mechanism. This study was designed to determine the role of gastric acid secretion, mucosal blood flow (GBF) and prostaglandins (PG) generation in the gastroprotection induced by small doses of topical or parenteral capsaicin in rats with intact or capsaicin-deactivated sensory nerves. Gastric lesions were produced in rats with intact sensory nerves (series A) or capsaicin-deactivated nerves (series B) using intragastric (i.g.) application of 100% ethanol, acidified aspirin (ASA) or water immersion and restraint stress (WRS). Pretreatment with i.g. capsaicin (0.12-1.0 mg/kg) in rats with intact sensory nerves (series A) reduced dose-dependently the mucosal damage caused by ethanol, ASA or WRS, the dose inhibiting the lesion area by 50% (ID5o) being 0.3, 0.5 and 0.7 mg/kg, respectively. This protection was accompanied by a significant rise in gastric mucosal blood flow (GBF). Parenteral application of capsaicin (1.2-10 mg/kg s.c.) that in intact rats dose-dependently increased GBF, also dose-dependently reduced gastric damage induced by ASA or WRS (but not by ethanol), the ID50 being 5 and 3 mg/kg, respectively. The reduction by i.g. capsaicin of ethanol- or WRS-induced mucosal lesions was accompanied by a rise in GBF and this effect was reversed by indomethacin at a dose that suppressed endogenous PG biosynthesis by about 90%, indicating that PG are involved in the protective activities of topical capsaicin. Furthermore, topical and to a lesser extent parenteral capsaicin given to rats with intact or deactivated sensory nerves inhibited gastric acid and pepsin outputs, suggesting that this inhibition could contribute to the capsaicin-induced gastroprotection against acid-dependent mucosal lesions (ASA or WRS). Capsaicin deactiva-tion of sensory nerves aggravated mucosal lesions induced by all three ulcerogens and this effect was accompanied by a marked decrease in GBF. In such capsaicin-deactivated rats, topical capsaicin also reduced ethanol-, ASA- or WRS-induced lesions, while parenteral capsaicin was effective only in the protection against the damage induced by acidified ASA and WRS but not by ethanol. The protection against WRS lesions and accompanying rise in GBF by parenteral capsaicin were also reversed by the pretreatment with indomethacin applied in a dose suppressing the generation of PG. We conclude that capsaicin is capable of protecting gastric mucosa in rats with both intact and capsaicin-deactivated rats and that this protective activity depends, at least in part, upon its hyperemic and antisecretory effects that may be mediated, at least in part, by endogenous release of PG.

This paper discusses basic problem formulation, and solution procedures for solving a particular large-scale two-dimensional cutting stock problem at a furniture factory. In recent years there has been an explosion of interests in this application area. The cutting stock problems are met in many branches of industry. There is a large economical incentive to find more effective solution procedures, and it is easy to compare alternative solution procedures and to identify potential benefits of using a proposed procedure. The paper concentrates on the case in which both stock and ordered sizes are rectangular. We present a mathematical model of the problem, propose an optimization algorithm and describe its basic properties. The mathematical model of the optimization problem relies on the Gilmore and Gomory approach. To decrease the total computing time we propose an interactive procedure based on the forecasting of the criterion functions values.

Nesfatin-1 belongs to a family of anorexigenic peptides, which are responsible for satiety and are identified in the neurons and endocrine cells within the gut. These peptides have been implicated in the control of food intake; however, very little is known concerning its contribution to gastric secretion and gastric mucosal integrity. In this study the effects of nesfatin-1 on gastric secretion and gastric lesions induced in rats by 3.5h of water immersion and restraint stress (WRS) were determined. Exogenous nesfatin-1 (5-40μg/kg i.p.) significantly decreased gastric acid secretion and attenuated gastric lesions induced by WRS, and this was accompanied by a significant rise in plasma NUCB2/nefatin-1 levels, the gastric mucosal blood flow (GBF), luminal NO concentration, generation of PGE2 in the gastric mucosa, an overexpression of mRNA for NUBC2 and cNOS, as well as a suppression of iNOS and proinflammatory cytokine IL-1β and TNF-α mRNAs. Nesfatin-1-induced protection was attenuated by suppression of COX-1 and COX-2 activity, the inhibition of NOS with L-NNA, the deactivation of afferent nerves with neurotoxic doses of capsaicin, and the pretreatment with capsazepine to inhibit vanilloid VR1 receptors. This study shows for the first time that nesfatin-1 exerts a potent protective action in the stomach of rats exposed to WRS and these effects depend upon decrease in gastric secretion, hyperemia mediated by COX-PG and NOS-NO systems, the activation of vagal and sensory nerves and vanilloid receptors.

This review was designed to provide an update on the role of asymmetric arginine (ADMA), the endogenous inhibitor of nitric oxide (NO) synthase in the pathophysiology of the upper gastrointestinal (GI) tract. Numerous studies in the past confirmed that NO is a multifunctional endogenous gas molecule involved in most of the body organs' functional and metabolic processes including the regulation of gastrointestinal (GI) secretory functions, motility, maintenance of GI integrity, gastroprotection and ulcer healing. NO is metabolized from L-arginine by enzymatic reaction in the presence of constitutive NO synthase. In upper GI tract, NO acts as a potent vasodilator known to increase gastric mucosa blood flow, regulates the secretion of mucus and bicarbonate, inhibits the gastric secretion and protects the gastric mucosa against the damage induced by a variety of damaging agents and corrosive substances. In contrast, ADMA first time described by Vallance and coworkers in 1992, is synthesized by the hydrolysis of proteins containing methylated arginine amino acids located predominantly within the nucleus of cells. This molecule has been shown to competitively inhibit NO synthase suggesting its regulatory role in the functions of vascular endothelial cells and systemic circulation in humans and experimental animals. Nowadays, ADMA is a potentially important risk factor for coronary artery diseases and a marker of cardiovascular risk. Increased plasma levels of ADMA have been documented in several conditions that are characterized by endothelial dysfunction, including hypertension, hypercholesterolemia, hyperglycemia, renal failure and tobacco exposure. The role of ADMA in other systems including GI-tract has been so far less documented. Nevertheless, ADMA was shown to directly induce oxidative stress and cell apoptosis in gastric mucosal cells in vitro and to contribute to the inflammatory reaction associated with major human pathogen to gastric mucosa, Helicobacter pylori (H.pylori). Infection of gastric mucosa with this germ or H. pylori water extract led to marked increase in the plasma concentration of ADMA and significantly inhibited bicarbonate secretion, considered as one of the important components of upper GI-tract defense system. When administered to rodents, ADMA aggravated gastric mucosal lesions injury induced by cold stress, ethanol and indomethacin and this worsening effect on gastric lesions was accompanied by the significant increase in the plasma level of ADMA. This exaggeration of gastric lesions by ADMA was coincided with the inhibition of NO, the suppression of gastric blood flow and excessive release of proinflammatory cytokine TNF-α. This metabolic analog of L-arginine applied to rats was exposed to water immersion and restraint stress and ischemia-reperfusion, causing an elevation of plasma levels of ADMA and gastric MDA content, which is the marker of lipid peroxidation. These effects, including the rise in the plasma levels of ADMA in rats with stress and ischemia-reperfusion-induced gastric lesions, were attenuated by concomitant treatment with L-arginine, the substrate for NO-synthase, and superoxide dismutase (SOD), a reactive oxygen metabolite scavenger added to ADMA. We conclude that ADMA could be considered as an important factor contributing to the pathogenesis of gastric mucosal damage and inflammatory reaction in H. pylori-infected stomach due to inhibition of NO, suppression of GI microcirculation, and the proinflammatory and proapoptotic actions of this arginine analog.

The crystal structure of the title compound, C 22 H 26 S 4 2I 2 , contains two centrosymmetric molecules of 1,2,4,5-bis{8 0 ,11 0 -dithia[4.3.3]propella(3 0 ,4 0 )}benzene, and four I 2 molecules in the unit cell of space group P 2 1 / c . The cyclohexene rings adopt boat conformation, whereas tetrahydrothiophene rings have envelope conformation. The iodine molecules are linked to one type of the sulphur atoms of the propellane mol- ecule by a charge-transfer bond, with S I distance of 2.7844(12) and I–I = 2.8153(5) Å. The second type of symmetrically independent sulphur atoms are engaged in a weak interaction of C–H S type with the H S distance of 3.09(1) Å. The geometry optimisation of the crystal structure at the B3LYP level with MIDI! basis set gave good agreement with the experimental data (S I distance of 2.754 and I– I = 2.923 Å). NBO analysis for the complex showed that the S I interaction is due to charge transfer from the lone pair on the sulphur to the vacant r orbital of the I 2 accepto.

Muscleblind-like (MBNL) proteins are critical RNA processing factors in development. MBNL activity is disrupted in the neuromuscular disease myotonic dystrophy type 1 (DM1), due to the instability of a non-coding microsatellite in the DMPK gene and the expression of CUG expansion (CUGexp) RNAs. Pathogenic interactions between MBNL and CUGexp RNA lead to the formation of nuclear complexes termed foci and prevent MBNL function in pre-mRNA processing. The existence of multiple MBNL genes, as well as multiple protein isoforms, raises the question of whether different MBNL proteins possess unique or redundant functions. To address this question, we coexpressed three MBNL paralogs in cells at equivalent levels and characterized both specific and redundant roles of these proteins in alternative splicing and RNA foci dynamics. When coexpressed in the same cells, MBNL1, MBNL2 and MBNL3 bind the same RNA motifs with different affinities. While MBNL1 demonstrated the highest splicing activity, MBNL3 showed the lowest. When forming RNA foci, MBNL1 is the most mobile paralog, while MBNL3 is rather static and the most densely packed on CUGexp RNA. Therefore, our results demonstrate that MBNL paralogs and gene-specific isoforms possess inherent functional differences, an outcome that could be enlisted to improve therapeutic strategies for DM1.

The 1H-pyrazolo[3,4-b]quinoline (PQ) core of the title molecule, C23H14F3N3, is aromatic and essentially planar (r.m.s. deviation = 0.015 Å) and the two phenyl substituents at positions 1 and 3 are twisted relative to this fragment by 29.74 (7) and 25.63 (7)°, respectively. In the crystal, molecules are arranged along the b axis into stacks via π–π interactions, with an interplanar distance of the PQ core of 3.489 (4) Å.

Introduction: Physical activity is presumed to improve cardiovascular disease (CVD), of which carotid artery intima-media thickness (CIMT) is a common indicator. Individuals with spinal cord injury (SCI) have limited mobility and therefore an expected increased risk for CVD. The purpose of this study was to determine which CVD risk factors predict CIMT among women with SCI, with the ultimate goal of targeting therapy to improve CVD in this population. Methods: One hundred twenty-two women with SCI who attended an outpatient SCI clinic and met inclusion and exclusion criteria participated in this study. SCI was categorized into 1 of 4 categories: complete tetraplegia, incomplete tetraplegia, complete paraplegia, and incomplete paraplegia. Maximum heart rate and VO2 max were obtained using bicycle ergometry with ventilatory gas exchange and continuous electrocardiogram. Hierarchical regression was used to predict CIMT, with the first block including demographic variables (age, race, smoking status) and the second block including physiologic variables (total cholesterol, heart rate, VO2 max, BMI, fasting serum glucose, hemoglobin A1c, and blood pressure). Results: Similar findings were observed for left and right CIMT, therefore only results from right CIMT are reported. The overall model was significant, F(16,46)=8.53, p=.000. Adjusted R square was .54 for the first block of variables and increased significantly (p=.006) to .66 when the second block of variables was added. Significant predictors at alpha=.05 included age (beta=.51, t=4.79, p=.000) and max/peak heart rate (beta=−.336, t=−2.39, p=.02). At alpha=.10, A1c was significant (beta=.187, t=1.99, p=.053). Conclusions: Although low aerobic conditioning is a purported CVD risk factor, quantitative measurements of such lack a demonstrable relationship with subclinical atherosclerosis (CIMT), perhaps because of its reduced importance relative to other CVD risk factors in a mobile population. We found expected relationships with CIMT in our SCI population (i.e., age), however we also found a quantitative measure of aerobic conditioning (max/peak heart rate) to be associated with CIMT. Our data indicate that SCI individuals may bear a greater CVD burden from cardiac de-conditioning than the general population and that investigation of a cohort with mobility limitation may provide a unique opportunity to study the impact of physical conditioning on CVD risk.

The renin-angiotensin system (RAS) plays an important role in the maintenance of blood pressure, cardiovascular functions, body fluids homeostasis and kidney reabsorption process but little is known w

Nesfatyna 1 jest 82-aminokwasowym peptydem powstałym w wyniku potranslacyjnej hydrolizy N-końcowego fragmentu innego białka nucleobindin2 (NUCB2), będącego prekursorem dla nesfatyny 1 o rozpoznanej i ustalonej sekwencji aminokwasów, występującej powszechnie wśród ssaków. Interesujący jest fakt, że genową ekspresję peptydowego układu NUCB2/nesfatyna 1 zaobserwowano w przewodzie pokarmowym gryzoni, zwłaszcza w błonie śluzowej szczurzego żołądka, szczególnie w bliskiej lokalizacji komórek neuroendokrynnych części trzonowej odpowiedzialnych m.in. za uwalnianie greliny. Pierwotnie wykryto, że NUCB2 i nesfatyna 1 podawane do komór bocznych mózgu hamują przyjmowanie pokarmu w fazie nocnej u szczurów i że efekt ten jest połączony ze zmniejszeniem masy ciała tych zwierząt, co sugeruje, że nesfatyna 1 jest peptydem anoreksygenicznym, hamującym apetyt. Dalsze badania nad fizjologicznym znaczeniem nesfatyny 1 dowodzą, że podobnie jak w przypadku innych hormonów pobudzających apetyt (np. grelina) czy hamujących apetyt (np. leptyna), peptyd ten odznacza się właściwościami gastroprotekcyjnymi i chroni błonę śluzową żołądka przed uszkodzeniami indukowanymi przez czynniki korozyjne oraz mikrokrwawienia wywoływane przez stres. W ten gastroprotekcyjny mechanizm działania nesfatyny 1 zaangażowane są układy endogennych prostaglandyn (PG) uwalnianych na drodze aktywacji cyklooksygenaz (COX) - COX-1 i COX-2 - oraz tlenku azotu (NO) produkowanego przez enzymy syntaz NO, odpowiedzialne za wzrost żołądkowego przepływu krwi, któremu towarzyszy wzrost stężenia nesfatyny 1 w osoczu. Podsumowując - endogenne PG i NO są mediatorami gastroprotekcji i przekrwienia obserwowanego w błonie śluzowej żołądka szczurów pod wpływem nesfatyny 1. Dlatego autorzy sądzą, że dalsze badania, zwłaszcza kliniczne, mające na celu poznanie mechanizmu działania i wyjaśnienie roli nesfatyny 1 w przewodzie pokarmowym powinny rzucić nieco więcej światła na problem potencjalnego terapeutycznego wykorzystania tego peptydu w zapobieganiu uszkodzeniom żołądka, w tym mikrokrwawieniom żołądkowym u ludzi. Nesfatin-1 is an 82-amino-acid peptide derived from posttranslational processing of the N-terminal fragment of nucleobindin 2 (NUCB2), a protein precursor for nesfatin-1, which is highly conserved across mammalian species. The expression of NUCB2/nesfatin-1 has been detected in the stomach, most prominently within ghrelin cells of the rat gastric oxyntic mucosa. The first biological action ascribed to NUCB2 and nesfatin-1 was the reduction of dark-phase food intake with a concomitant reduction in body weight gain when these peptides were injected intracerebroventricularly, suggesting their anorexigenic action in rodents. Studies on the potential physiological importance of nesfatin-1 have shown that nesfatin1, similarly as for other appetite peptides such as ghrelin and leptin studied before, exerts protective activity against gastric mucosal lesions induced by topical damaging agents and seems to be also effective against those caused by stress. This gastroprotective action of exogenous nesfatin-1 may involve the activation of PG/COX and NO/NOS systems, resulting in an increase in gastric blood flow accompanied by a rise in plasma nesfatin-1 levels. Thus, it is concluded that 1) endogenous PG and NO may mediate the nesfatin-1- induced gastroprotection in the rat stomach, and 2) clinical studies regarding the potential benefit of nesfatin-1 observed in animals should shed more light on the efficacy of this peptide to prevent gastric disorders including the formation of gastric microbleeding in humans.

In the paper a few algorithms for determination the parameters of nonlinear transportation networks with heuristic starting points procedures are analyzed. The suitable illustrations of the proposed algorithms are based on the water distribution networks and computer networks.

The regulation of appetite is regulated by complex mechanism involving brain-gut axis and hormonal and non-hormonal factors acting through the activity of satiety and hunger centers located in the hypothalamus [Wren & Bloom, 2007]. Among hormones controlling appetite are gastrointestinal hormones such as cholecystokinin, PYY, pancreatic polypeptide, glucagon-like peptide 1, oxyntomedulin, the endocrine pancreatic hormones including insulin and glucagon and endocannabinoids [Wren B Tomasetto et al., 2000]. This peptide was also shown to enhance the gastric motility and gastric secretion [Tschop et al., 2000; Date et al., 2001]. Ghrelin is considered as an orexigenic peptide produced by the stomach, acting as a meal initiator [Masuda et al., 2000; Ariyasu et al., 2001]. Little is known about other factors that might affect ghrelin secretion in the stomach and its influence on gastrointestinal integrity has not been fully elucidated. A recent study in humans revealed that stomach is a major source of circulating ghrelin and that gastrectomy produced dramatic fall in the plasma ghrelin levels, whereas fasting and anorexia nervosa was accompanied by elevated plasma ghrelin levels [Ariyasu et al., 2001]. The orexins also called hypocretins, are neuropeptides novel originally discovered in a small group of neurons in the hypothalamic area (LHA) [Sakurai et al., 1998; de Lecea et al., 1998]. identified two peptides that were endogenous ligands to orphan receptor HFGAN72 [Sakurai et al., 1998]. They found that these peptides after i.c.v. injection stimulated food

Previous studies revealed that prostaglandins contribute to the mechanism of maintenance of gastrointestinal integrity and mediate various physiological aspects of mucosal defense. The suppression of prostaglandin synthesis in the stomach is a critical event in terms of the development of mucosal injury after administration of various NSAID including aspirin (ASA). A worldwide use of ASA is now accepted due to its remarkable analgesic, antipyretic and anti-thrombotic prophylactics against myocardial infarct and coronary disorders despite the fact that the use of NSAIDs is associated with the risk of gastrointestinal bleedings, haemorrhagic lesions and ulcerations. It has become clear that other mediators besides prostaglandins can similarly act to protect the gastrointestinal mucosa of experimental animals and humans from injury induced by ASA. For instance, nitric oxide (NO) released from vascular epithelium, epithelial cells of gastrointestinal tract and sensory nerves can influence many of the same components of mucosal defense as do prostaglandins. This review was designed to provide an updated overview based on the experimental and clinical evidence on the involvement COX-2 derived products, lipoxins in the mechanism of gastric defense, gastroprotection and gastric adaptation to ASA. Lipoxins were recently considered as another group of lipid mediators that can protect the stomach similarly as NO-donors known to exert protective influence on the stomach from the injury under condition where the mucosal prostaglandin levels are suppressed. The new class of NO-releasing NSAIDs, including NO-aspirin or NO-naproxen, represent a very promising approach to reducing the toxicity of their parent NSAIDs. Aspirin-triggered lipoxin (ATL) synthesis, via COX-2, acts to reduce the severity of damage induced by this NSAID. Lipoxin analogues may prove to be useful for preventing mucosal injury and for modulating mucosal inflammation. Evidence presented in this review documents that ATL also play in important role in gastric adaptation during chronic ASA administration. Suppression of COX-2 activity by selective COX-2 inhibitors such as rofecoxib or celecoxib was shown to abolish the production of ATL and to diminish the gastric tolerability of ASA and gastric adaptation developed in response to repetitive administration of this NSAID. Synthetic analogues of lipoxins as well as newer class of NSAIDs releasing NO may be used in the future as the therapeutic approach to counteract adverse effects in the stomach associated with NSAIDs ingestion.

The study was designed to determine the gastroprotective and ulcer healing efficacy of basic transforming growth factor (bFGF) and to assess whether this peptide contributes to the action of sucralfate on the rat stomach. Application of human recombinant bFGF (1-100 micrograms/kg/hour subcutaneously) failed to affect the formation of acute gastric lesions induced by 100% ethanol and acidified aspirin but reduced the stress induced by gastric lesions. Sucralfate (100-200 mg/kg given orally) protected gastric mucosa against the ethanol, aspirin, and stress induced acute gastric lesions but the addition of bFGF (100 micrograms/kg subcutaneously or intragastrically) failed to affect sucralfate induced protection against ethanol or aspirin but increased that against stress. Administration of bFGF (3-300 micrograms/kg/day) by an intragastric or an intraperitoneal route or sucralfate (400 mg/kg/day) orally to rats with acetic acid induced gastric ulcers, enhanced the healing rate of these ulcers during seven day treatment in a dose dependent manner. This was accompanied by a pronounced increase in the number of capillaries and myofibroblasts and in DNA synthesis and DNA and RNA concentrations in the granulation tissue in the ulcer area. [125I]bFGF (1 microCi) applied subcutaneously or intragastrically accumulated in two to threefold higher amounts in the ulcer area than in the intact mucosa, particularly in rats treated with sucralfate. Concurrent treatment with indomethacin (2 mg/kg intraperitoneally) delayed ulcer healing and reduced the binding of labelled bFGF to the ulcer area, angiogenesis, and DNA synthesis by sucralfate. Addition of [125I]bFGF to sucralfate at various pHs resulted in the coprecipitation of bFGF by sucralfate in a pH dependent manner from about 10% at pH 7.0 to 90% at pH 1.5. Thus bFGF shows little protective activity and is not essential for gastroprotection afforded by sucralfate but plays an important part in healing of gastric ulcers possibly due to its growth promoting and angiogenic actions.

Capsaicin and papaverine are potent vasorelaxants with strong gastroprotective activity against damage induced by absolute ethanol. This protection was originally attributed to the increase in gastric mucosal blood flow (GBF) and the present study was designed to determine the possible role of nitric oxide (NO) and prostaglandins (PG) in the protective and hyperemic effects of capsaicin and papaverine on rat gastric mucosa. We found that the pretreatment with capsaicin (0.1-0.5 mg/kg i.g.) or papaverine (0.1-2 mg/kg i.g.) reduced dose dependently the area of ethanol-induced lesions, the ED50 being 0.3 and 1 mg/kg, respectively. This protection was accompanied by a gradual increase in the GBF. Intravenous injection of N omega-nitro-L-arginine (L-NNA; 1.2-5 mg/kg), a selective blocker of NO synthase, which by itself caused only a small increase in ethanol lesions, reversed dose dependently the protective and hyperemic effects of capsaicin and papaverine against ethanol-induced damage and attenuated the increase in GBF induced by each of these agents alone. This deleterious effect of L-NNA on the gastric mucosa and the GBF was fully antagonized by L-arginine (200 mg/kg i.v.) but not by D-arginine. L-arginine partly restored the decrease in GBF induced by L-NNA. Pretreatment with indomethacin (5 mg/kg i.p.), which suppressed the generation of PG by 85%, slightly enhanced the mucosal lesions induced by ethanol but failed to affect the fall in GBF induced by this irritant. Gastroprotective and hyperemic effects of capsaicin and papaverine were partly reversed by indomethacin suggesting that endogenous PG are also implicated in these effects.(ABSTRACT TRUNCATED AT 250 WORDS)

An increasing number of proteins are currently available on the market as therapeutics and this branch of the pharmaceutical industry will expand substantially during the coming years. As many diseases result from dysfunction of proteins forming multicomponent complexes, protein drugs with their inherent high specificity and affinity seem to be optimal medical agents. On the other hand, proteins are often highly instable and sensitive to degradation, which questions their applicability as effective therapeutics. Therefore, redesign and engineering of proteins is usually a required step in the present day drug development. Several approaches have been applied to optimize the protein properties central to their pharmaceutical use. This review focuses on different strategies that improve two crucial factors influencing protein drug efficiency: protein stability and its in vivo half-life. We provide examples of successful genetic and chemical modifications applied in the design of effective protein therapeutics.

The synthesis of three new mono-substituted 8,11-dioxa(3,4-benzo)-[4.3.3]propellanes is described. The method of synthesis of propellanes depends on the substituent, which we want to introduce. The structure of the compounds was determined by chemical and spectral evidences. Some aspects of the conformation of the compounds were studied.

In the paper an adapted version of the differential evolution algorithm has been created to solve a multi-objective optimization problem. Multi-objective Differential Evolution Algorithm using vector differences for perturbing the vector population with self adaptation is introduced. Through the combination of mutation strategies and self adaptation of crossover and differentiation constants the proposed MO algorithm performs better than the one with the simple DE scheme in terms of computation speed and quality of the generated multi-objective non-dominated solutions.

In this paper, we propose a portfolio selection method based on a set of technical trading rules, which are optimized by a genetic algorithm. The aim of the research was to check if it is possible to obtain a set of trading rules deriving from technical indicators, which could be used to create a portfolio able to outperform standard portfolio models based upon Modern Portfolio Theory. On the contrary to the typical portfolio approach incorporating expected return and variance, presented method relies on market momentum analysis and stock timing using selected technical indicators.

Theoretical simulations of UV–vis spectra for organic chromophores: 3-(4-fluorophenyl)-1,4-diphenyl-, 1-(4-fluorophenyl)-3,4-diphenyl- and 4-(4-fluorophenyl)-1,3-diphenyl-1H-pyrazolo[3,4-b]quinoline. Density Functional Theory 6-31G calculations were performed. The molecular geometry and UV–vis spectra were simulated with the time-dependent DFT calculations. Influence of number of occupied and excited states on the behavior of the spectra is explored. To further improve the calculations a Polarizable Continuum Model (PCM) [1] , [2] was employed to simulate the influence of solvent polarity. It was used in both geometry optimization and spectra simulation. An attempt to find a correlation between the values of dipole moments and the spectral shifts was performed. The results were compared with experiment.

Nash MS, Lewis JE, Dyson-Hudson TA, Szlachcic Y, Yee F, Mendez AJ, Spungen AM, Bauman WA. Safety, tolerance, and efficacy of extended-release niacin monotherapy for treating dyslipidemia risks in persons with chronic tetraplegia: a randomized multicenter controlled trial. Objective To test the safety, tolerance, and efficacy of extended-release niacin monotherapy on dyslipidemia in persons with chronic tetraplegia. Design Placebo-controlled, blinded, multicenter, randomized controlled trial. Setting Three spinal cord injury research/rehabilitation centers. Participants Persons with chronic tetraplegia (N=54) and low plasma high-density lipoprotein cholesterol (HDL-C) levels. Intervention Extended-release niacin monotherapy (48 weeks; n=31) on a dose-titration schedule versus matched placebo (n=23). Main Outcome Measures Safety was assessed by using percentages of treatment-emergent adverse events and increased levels of hepatic transaminases, uric acid, glycosylated hemoglobin, and fasting glucose. Tolerance was assessed by using participant reports for frequency and intensity of adverse effects of extended-release niacin. Primary effectiveness outcomes were fasting HDL-C level and plasma total cholesterol (TC)/HDL-C ratio. Secondary outcomes included plasma low-density lipoprotein cholesterol (LDL-C) and TC levels and LDL-C/HDL-C ratio. Results Significant increases in fasting HDL-C levels (24.5%) were accompanied by decreases in TC/HDL-C and LDL-C/HDL-C ratios, LDL-C levels, and TC levels (all P Conclusions Extended-release niacin monotherapy is safe, tolerated, and effective for most persons with chronic tetraplegia. Special precautions for changes in bowel habits and postadministration hypotension should be observed.

Targeting of newly synthesized membrane proteins to the endoplasmic reticulum is an essential cellular process. Most membrane proteins are recognized and targeted co-translationally by the signal recognition particle. However, nearly 5% of membrane proteins are ‘tail-anchored’ (TA) by a single C-terminal transmembrane domain that cannot access the co-translational pathway. Instead, TA proteins are targeted post-translationally by a conserved ATPase termed Get3. The mechanistic basis for TA protein recognition or targeting by Get3 is not known. Here we present crystal structures of Get3 in ‘open’ (nucleotide-free) and ‘closed’ (ADP•AlF4--bound) dimer states. In the closed state, the dimer interface of Get3 contains an enormous hydrophobic groove implicated by mutational analyses in TA protein binding. In the open state, Get3 undergoes a dramatic rearrangement that disrupts the groove and shields its hydrophobic surfaces. These data provide a molecular mechanism for nucleotide-regulated binding and release of TA proteins during their membrane targeting by Get3.

An influence of phenoxy groups for the luminescent and electroluminescent properties of spiro-compounds with pyrazolo [3,4-b] quinoline structure (fluorophore) chromophore has been studied. All the compounds exhibit strong fluorescence in solution and in solid state as well. The prepared compounds were used as dopant chromophore in PVK polymer matrices for electroluminescent (EL) and light-emitting diode (LED) devices with configuration ITO/PEDOT-PSS/PVK/PQ/Ca/Al. Role of the bathochromic shifts and solvent polarity in absorption and photoluminescent maxima is considered. Relation between the number of pyrazoloquinoline chromophore and presence of phenyl group on the fluorescence spectra is explored. Polarizability of the particular pyrazoloquinoline compounds on the solvatochromic effects is investigated. Possible ways of enhancement of the brightness in the light-emitting properties of the mentioned chromophore are discussed.

The results of experimental research and quantum-chemical simulations of the absorption spectra of 1-(4-fluorophenyl)-3,4-diphenyl, 3-(4-fluorophenyl)-1,4-diphenyl, and 4-(4-fluorophenyl)-1,3-diphenyl-pyrazolo[3,4- b ] quinoline are presented. Although the fluorine atom is located on different phenyl rings in these molecules, the absorption spectra do not differ significantly. Semi-empirical AM1, PM3 and RM1 methods, as well as ab initio ADF code-based calculations were used to optimize geometry, calculate the infrared and visible spectra of the afore mentioned compounds and analyze the molecular orbitals schemes. The results of calculations are in good agreement with the experimental data. It was also demonstrated that the positions of the fluorescence maxima depend significantly on the solvent (contrary to the absorption spectra), in which the molecules are embedded, which allows for manipulating with fluorescence properties of the synthesized molecules by changing the solvent.

Ventricular arrhythmias are not uncommon in patients with hypertension, are often attributed to left ventricular hypertrophy and are thought to be associated with an increased risk of sudden death. However, underlying silent coronary artery disease, another potential cause of ventricular arrhythmias, is often present in the same patient group. Therefore, the prevalence of ventricular arrhythmias was prospectively examined in 183 consecutive asymptomatic men with hypertension with neither clinical nor electrocardiographic (ECG) evidence of coronary artery disease in whom technically adequate echocardiograms could be obtained. After previous therapy had been withdrawn for ≥4 days, each patient underwent exercise or dipyridamole thallium-201 scintigraphy, 48-h Holter ambulatory ECG monitoring and echocardiography for measurement of the left ventricular mass index. Forty patients (22%) had frequent ventricular ectopic activity, defined on the basis of >10 premature ventricular complexes/h (38 patients) or ventricular tachycardia (11 patients), or both.A higher proportion of patients with than without a reversible thallium-201 defect had frequent premature ventricular complexes (33% vs. 18%, p < 0.02) or ventricular tachycardia (14% vs. 4%, p < 0.02). Similarly, more patients with than without left ventricular hypertrophy (defined as left ventricular mass index ≥134 g/m2) had frequent premature ventricular complexes (29% vs. 15%. p < 0.05) and ventricular tachycardia (12% vs. 2%, p < 0.01). By stepwise logistic regression analysis, both findings were independent predictors of ventricular arrhythmia, which was present in 53% of patients with both abnormalities, but in only 12% of those with neither abnormality. In addition, ventricular arrhythmias were more common in patients who had than in those who had not previously been treated with a diuretic drug, even though there were no differences between patients in serum electrolytes at the time of study.These results indicate that silent myocardial ischemia and left ventricular hypertrophy are independently associated with ventricular arrhythmias in patients who are asymptomatic and have mild to moderate hypertension.

Diabetes mellitus increases susceptibility to acute gastric injury and impairs ulcer healing. Pioglitazone as an agonist of peroxisome proliferator-activated receptor gamma (PPARgamma) is used as anti-diabetic drug and has additionally gastroprotective activities. However, the effect of pioglitazone on the protection and healing of gastric mucosa under diabetic conditions is poorly understood. The aim of the present study was: 1) to compare the effects of treatment with PPARg ligand (pioglitazone) on healing of acetic acid-induced gastric ulcers and prevention of acute water immersion and restraint stress (WRS)-induced gastric lesions in normal rats and those with streptozotocin (STZ)-induced diabetes mellitus; 2) to assess the effects of pioglitazone on the mRNA expression of cyclooxygenase-2 (COX-2), c-NOS, interleukin-1beta and hypoxia inducible factor-1 alpha (HIF-1alpha) in the gastric mucosa of rats with or without STZ-induced diabetes mellitus; 3) to investigate the involvement of endogenous NO and proinflammatory cytokines (IL-1beta, TNF-alpha) in healing of chronic gastric ulcers and in prevention of acute stress lesions by pioglitazone in rats with or without STZ-induced diabetes mellitus. Diabetes was induced in rats by single injection of STZ (70 mg/kg i.p.) four weeks prior to production of gastric ulcers by acetic acid method or induction of stress lesions by 3.5 hours of WRS. Non-diabetic rats were used as controls. Two major animal groups (A and B) were tested; A) diabetic and non-diabetic rats with chronic gastric ulcers treated with 1) pioglitazone (40 mg/kg-d i.g.), 2) pioglitazone in combination of blocker of NO synthase (L-NNA 20 mg/kg-d i.p.), and 3) saline (vehicle-control); and B) diabetic and non-diabetic rats exposed to 3.5 hours of WRS and pretreated with 1) pioglitazone (40 mg/kg i.g.), 2) pioglitazone in combination of blocker of NO synthase (L-NNA 20 mg/kg i.p.), and 3) saline (vehicle-control). The gastric mucosal blood flow was assessed by H(2)-gas clearance method. The area of chronic acetic acid ulcers and number of acute WRS-induced gastric lesions were assessed by planimetry or by counting of number of lesions, respectively. In rats with chronic ulcers, the mRNA expression of HIF-1alpha, IL-1beta and COX-2 was assessed by RT-PCR and protein expression of platelet endothelial cell adhesion molecule-1 (PECAM-1), COX-2 and cNOS was examined by Western blot. In rats with stress lesions, the protein expression of COX-2, cNOS, catalase, PPAR and heat shock protein 70 (HSP70) was examined by Western blot. In diabetic rats, a marked delay in ulcer healing and increased susceptibility to WRS lesions were observed and these effects were accompanied by a significant decrease in GBF. Pioglitazone significantly increased healing of chronic gastric ulcers and exerted a strong protective effect against WRS-induced lesions, but these effects were attenuated by NO-inhibition with L-NNA. Interestingly, the ulcer healing and gastroprotective effects of pioglitazone were weak under diabetic conditions, and this effect on ulcer healing was accompanied by impaired angiogenesis due to decreased PECAM-1 expression, attenuated expression of COX-2 and the increased expression of proinflammatory cytokines compared to those in diabetic rats treated with vehicle. We conclude that: 1) experimental diabetes in rats impairs healing of chronic ulcers and enhances acute stress lesions due to an increase in the expression and release of proinflammatory cytokines such as TNF-alpha and IL-1beta; 2) the ulcer healing effect of pioglitazone, which is, at least in part, mediated by endogenous NO, is significantly attenuated by L-NNA in diabetic rats despite increased COX-2 expression at the ulcer edge; 3) the formation of acute gastric lesions induced by WRS is also attenuated by pretreatment with pioglitazone due to increased GBF probably mediated by NO, as the administration of L-NNA reversed, in part, the preventive action induced by this PPARgamma ligand, and 4) pioglitazone is effective both in healing of chronic ulcers and protection against WRS lesions though its action under diabetic conditions seems to be attenuated, possibly due to reduction in NOS-NO system, angiogenesis and increased expression and release of proinflammatory cytokines.

Orexigenic peptides are group of endocrine hormones exerting a pleiotropic influence on many physiological functions including regulation of the feeding behaviour and energy expenditure, release of growth hormone (GH) and inotropic effects on the heart. Some of these peptides such as ghrelin, originally identified in the gastric mucosa, has been involved not only in control of food intake and growth hormone release but also exerts the immunomodulatory and anti-inflammatory properties. This review summarizes the recent attempts to prove the concept that orexigenic peptides such as ghrelin, orexin-A and obestatin besides playing an important role in the mechanism of food intake, exhibit a potent gastroprotective action against the formation of acute gastric mucosal injury induced by various ulcerogens. This protective effect depends upon vagal activity and hyperemia mediated by NOS/NO and COX/PG systems and CGRP released from sensory afferent nerves. In addition, the appetite peptides such as ghrelin and orexin-A are implicated in the mechanism of the healing of preexisting gastric ulcers due to an activation of specific GHS-R1a and OX-R1 receptors and PG/COX system.

The purpose of this work was synthesis of a new copolymer consisting of poly(N-vinylcarbazole) and pyrazoloquinoline based dye, suitable to provide electroluminescence in the wavelength range corresponding to the blue. The obtained material was tested in a simple, single layer electroluminescent device. It were studied both its electronic and optical performances. It was found that the maximum of electroluminescence spectrum can be tuned within the wavelength of 450 nm and 490 nm (what reads in terms of colours as the blue and the cyan) by simple variation of the dye content.

Targeting of newly synthesized membrane proteins to the endoplasmic reticulum is an essential cellular process. Most membrane proteins are recognized and targeted co-translationally by the signal recognition particle. However, nearly 5% of membrane proteins are ‘tail-anchored’ by a single carboxy-terminal transmembrane domain that cannot access the co-translational pathway. Instead, tail-anchored proteins are targeted post-translationally by a conserved ATPase termed Get3. The mechanistic basis for tail-anchored protein recognition or targeting by Get3 is not known. Here we present crystal structures of yeast Get3 in ‘open’ (nucleotide-free) and ‘closed’ (ADP·AlF (4)(−)-bound) dimer states. In the closed state, the dimer interface of Get3 contains an enormous hydrophobic groove implicated by mutational analyses in tail-anchored protein binding. In the open state, Get3 undergoes a striking rearrangement that disrupts the groove and shields its hydrophobic surfaces. These data provide a molecular mechanism for nucleotide-regulated binding and release of tail-anchored proteins during their membrane targeting by Get3.

In many Multi-Objective Optimization Problems it is required to evaluate a great number of objective functions and constraints and the calculation effort is very high. The use of parallelism in Multi-Objective Genetic Algorithms is one of the solutions of this problem. In this work we propose an algorithm, based on parallelization scheme using island model with spatially isolated populations. The intent of the proposed paper is to illustrate that modifications made to a selection and resolution processes and to a migration scheme have further improved the efficiency of the algorithm and good distribution of Pareto front.

Increasing attention is being recently devoted to various problems in the topological design of communication networks. In the paper we propose to solve a bi-criteria network topology design problem for considering a message delay and global cost as an objective functions vector under the connectivity constraint. An approach based on the bi-criteria genetic algorithm VEGA is developed for the network topology design problem. We present some experiments in order to certify the influence of genetic algorithm parameters for the quality of optimal design variable space and of an objective functions space. Finally a global network efficiency measure is proposed as an indicator for the designer to determine an efficient network communication topology from the Pareto-optimal set of solutions. Numerical results provide to illustrate that the proposed methodology can search effectively one communication network topology

Electrocardiographic abnormalities develop in patients with chronic aortic regurgitation (AR). Although vasodilator drugs may reduce left ventricular (LV) volume overload, the effects of such therapy on electrocardiographic abnormalities have not been previously evaluated. Accordingly, electrocardiograms were analyzed before and after double-blind, randomized administration of either hydralazine or placebo in 54 patients with chronic AR. These patients were without limiting symptoms and had preserved ejection fraction on entry in the study. The magnitude of ST-segment depression and Romhilt-Estes point score for LV hypertrophy were assessed. Baseline ST depression and LV hypertrophy scores in the placebo and hydralazine groups were not significantly different. At follow-up, after a mean of 19 ± 6 months, there was a significant reduction in ST depression in patients taking hydralazine (n = 28) compared with patients given placebo (n = 26): −0.023 ± 0.044 vs 0.029 ± 0.055 mV, respectively (p = 0.0001); and in the LV hypertrophy score (−1.1 ± 2.2 vs 0.9 ± 2.3 points, respectively; p = 0.002). Hydralazine-treated patients also had significant decreases in LV end-diastolic and end-systolic volume indexes, and a significant increase in ejection fraction. These results suggest that such vasodilator therapy may be beneficial in patients with chronic AR.

Fibroblast growth factors (FGFs) are involved in diverse cellular processes such as cell migration, angiogenesis, osteogenesis, wound healing and embryonic and foetal development. Human acidic fibroblast growth factor (FGF-1) is the only member of the FGF family that binds with high affinity to all four FGF receptors and thus is considered to be the human mitogen with the broadest specificity. However, pharmacological applications of FGF-1 are limited owing to its low stability. It has previously been reported that the introduction of single mutations can significantly improve the stability of FGF-1 and its resistance to proteolytic degradation. Here, the structure of the Q40P/S47I/H93G triple mutant of FGF-1, which exhibits much higher stability, a prolonged half-life and enhanced mitogenic activity, is presented. Compared with the wild-type structure, three localized conformational changes in the stable triple mutant were observed, which is in agreement with the perfect energetic additivity of the single mutations described in a previous study. The huge change in FGF-1 stability (the denaturation temperature increased by 21.5 K, equivalent to DeltaDeltaG(den) = 24.3 kJ mol(-1)) seems to result from the formation of a short 3(10)-helix (position 40), an improvement in the propensity of amino acids to form beta-sheets (position 47) and the rearrangement of a local hydrogen-bond network (positions 47 and 93).

Hypertensive patients with left ventricular hypertrophy (LVH) have increased cardiovascular morbidity and mortality. Experimental studies indicate the importance of both the alpha and beta components of the adrenergic nervous system in the development and reversal of LVH. Therefore labetalol (L), a combined alpha and beta blocker, and propranolol (P), a nonselective beta blocker, were evaluated in a randomized, double-blind study of 35 hypertensive patients with echocardiographic evidence of LVH. Following 2 weeks of placebo, L or P was titrated as needed and tolerated to maximum total daily doses of 1600 mg and 640 mg, respectively. A thiazide diuretic was added if necessary for blood pressure control. M-mode echocardiograms were performed at baseline and after 1, 3, 6 and 12 months of blood pressure control. The echocardiograms were read independently by two blinded observers for end-diastolic dimension and wall thicknesses, and left ventricular mass. Fractional shortening, cardiac output, and peripheral vascular resistance were derived using standard formulas. Both drugs reduced blood pressure significantly and comparably. Significant changes in the echocardiographic measurements were observed as early as 1 month and usually persisted throughout the study. Both drugs decreased posterior wall thickness; however, only the decrease in propranolol group achieved statistical significance. Septal wall thickness was reduced by L at 3 and 12 months. End-diastolic dimension increased significantly in the L-treated group at 3, 6, and 12 months of therapy, whereas P had no effect on this measurement. As a consequence, the calculated left ventricular mass index was reduced by P throughout the study, but remained essentially unchanged by L until the twelfth month. Neither drug adversely affected fractional shortening. Cardiac output was significantly reduced by P, but unchanged by L, despite similar effects on heart rate by both drugs. Thus, despite their similar effects on blood pressure, L and P had different effects on cardiac morphology, which may reflect varying responses to alpha-and beta-adrenergic blockade.

The coadsorption of chloral hydrate and ethyl alcohol at free surface of water was investigated. The additive effect of the electric surface potentials and surface tensions of mixed adsorbed films was observed. Using the parameter β related to molecular interaction in the mixture and calculated values of ΔV (changes in surface potential), the lack of interactions between adsorbed molecules was found.

Background Barrett's Esophagus (BE) is the precancerous lesion for esophageal adenocarcinoma (EAC). Several studies have indicated that obesity, especially abdominal, is a risk factor for BE. In addition, recent studies have shed light on the role of adipokines (leptin, adiponectin) and inflammatory biomarkers in the development of BE. However, the role of obesity and its biomarkers in the neoplastic progression of BE is unclear. The goal of our cohort study was to evaluate the association between baseline obesity (measured by WHR and BMI) and proand anti-inflammatory biomarkers (circulating adiponectin, leptin, IL1b, IL-6, IL-8, IL-10, and IL-12) and risk of progression to dysplasia or EAC. Methods We evaluated prospectively recruited BE cases during 2008-2013. All patients completed a questionnaire on GERD symptoms and medication use, and had anthropometric measurements (height, weight, waist and hip circumference) and a research blood sample was collected at baseline. BE was defined by endoscopic appearance combined with pathologic findings of intestinal metaplasia. We included patients who had at least one follow up endoscopy through November 19th 2014. BE neoplastic progression was defined as change from non-dysplastic BE to low grade dysplasia (LGD), high grade dysplasia (HGD), or EAC; or change from LGD to HGD or EAC; or change of HGD to EAC. The main exposures were baseline BMI, WHR and circulating levels of biomarkers. Major confounding factors were medications (PPI, statin, H2RA, aspirin, NSAID), GERD (symptoms, severity, frequency) and demographics (race, age, sex). The risk of neoplastic progression was examined in multivariate Cox proportional hazards analysis. Results A total of 178 patients with BE met the inclusion and exclusion criteria; 98% men, 92% white and average age 61.8 years. At baseline, 94% of patients had non-dysplastic BE. In a follow up of 804 patient years, 34 patients (19.10%) progressed to dysplastic BE, and the other 144 patients (80.9%) remained nondysplastic. The likelihood of BE neoplastic progression showed a non-significant increase with obesity (BMI>30) (adjusted HR=3.07, 95%CI 0.74-12.7) and high WHR (adjusted HR: 1.66, 0.22-12.7), and a significant decrease with elevated log IL-1 β I (HR=0.33, 95%C0.120.88) adjusted for age, race, sex, NSAID and statin. There were no associations with circulating serum levels of adiponectin, leptin, IL-6, IL-8, IL-10 or IL-12 levels. Conclusions The data are suggestive of a role for obesity and low levels of anti-inflammatory cytokine (IL-1 β) in the neoplastic progression of BE. These preliminary findings need to be confirmed in a larger dataset and longer follow up. Associations between baseline obesity and inflammation and risk of progression

Substantial anisotropy of photoinduced change of third harmonic generation (THG) was observed during investigation of the 3-(4-nitrophenyl)-6- N , N -diphenylamin-1-phenyl-1 H -pyrazolo [3,4- b ]quinoline chromophores embedded into polymethylmethacrylate polymer matrix. Large THG decay was observed for the co-polarized pump–probe configuration, and small increase (weak pump intensity) or decrease (strong pump intensity) of THG signal for the cross-polarized pump–probe configuration. The performed molecular geometry optimization and quantum chemical evaluations have shown that the observed effect is originated from photoinduced anisotropy of electronic charge density distribution within the separate molecule contrary to the generally adopted model of the hole burning typical for the cis – trans isomerization.