Björn gustafsson

Björn Gustafsson

Xenidis1, K. Amarantidis1, A. Karayiannakis4, G. Kolios2, E. Chatzaki2, and S. The serum of cancer patients often contains increased free DNA levels, which could potentially offer material for early cancer detection or even information for the development of new therapeutic interventions.

Genetic and epigenetic alterations of the adenomatous polyposis coli APC gene are common events in gastrointestinal tumor development.

Methylation was strongly correlated with metastasis. The secretion of inflammatory mediators was analysed in vivo immunohistochemistry and in vitro Luminex technology 48 h after induction of ischemia.

Preliminary results suggest a decrease in interleukinbeta ILbeta and monocyte chemoattractant protein-1 MCP-1 after treatment, respectively.

Lesion size at 48 h was significantly reduced in the treated group. We quantified microglial cells CD11b by measuring the average intensity of CD11b labelling infra-red emission within the ischemic tissue.

No significant difference was found between groups. In contrast, in vitro data show a modulation of microglial activation after treatment.

Further experiments will show whether D-JNKI1 reduces inflammatory mediators in the brain and in peripheral tissue or systemic circulation.

Borsello et al. Hirt et al. Wiegler et al. Bonovolias, Lefkothea C. Asterios S. Although IM is a designed molecular inhibitor of Bcr-Abl tyrosine kinase, additional mechanisms perhaps are involved leading to IM-induced drug resistance and cardiovascular toxicity.

Our most recent observations that hemin the oxidized form of heme can counteract the cytotoxic effect of IM, prompted us to investigate the question whether IM dismantles the mitochondrial cell respiration pathway by blocking the expression of several genes encoding vital hemoproteins and other related proteins involved in the biosynthesis of cytochrome c oxidase.

These results indicate that IM selectively represses the expression of key-genes and provide novel mechanism s of IM that may explain its cardiovascular toxicity.

Furthermore, it is also known that mutations in SCO2 gene, encoding a cytochrome c oxidase COX assembly protein, lead to fatal infantile cardioencephalomyopathy and COX deficiency 5.

In this study, we further explored the question whether IM represses the transcription of various genes involved in the biosynthesis of heme, hemoproteins and COX assembly genes.

IM at concentrations as low as 1 M inhibited cell growth and caused cell cycle arrest after 24 to 96h. Moreover, IM was found to repress the expression of Bcl-2a, Bcl-2b as well as Nrf2 genes, which are involved in cell survival However, despite these beneficial antineoplastic effects, a portion of patients undergoing IM treatment relapse by exhibiting acquired resistance to IM 2 , while some of them exhibit cardiovascular toxicity 3, 4.

This is an interesting, although unexplored, aspect of IM action. Capdeville R. Drug Discov. Melo J. Cancer Lett.

Kerkela R. Will Y. Bonovolias I. Blood 8. Mayerhofer M. Blood Bonovolias, I. Foltopoulou P. Acta: Lozzio B.

Leuk Res. Chomczynski P. The aim of the present study was to clarify the exact role of L-NAME on memory using different testing procedures.

In a last experiment aiming to evaluate the effects of the treatment conditions acute vs. For this pur- pose, the novel object recognition task was selected.

Kenchappa2,8, Anastasia Simi A. Bastiaens4, Peter J. Verveer4, Wilma J. Friedman5, Giampietro Schiavo6, Bruce D.

Carter2, Carlos F. Equal first authors Ligand-mediated receptor dimerization has emerged as a universal mechanism of growth factor receptor activation.

Neurotrophins interact with dimers of the p75 neurotrophin receptor NTR p75 , but the mechanism of receptor activation has remained elusive.

Here, we show that NTR p75 forms disulphide-linked dimers independently of neurotrophin binding through the highly conserved Cys in its transmembrane domain.

In addition, we also show that cross-linking of NTR p75 dimers by cysteine-scanning mutagenesis results in constitutive, ligand-independent activity in several pathways that are normally engaged upon neurotrophin stimulation of native receptors.

The activity profiles of different disulfideNTR crosslinked p75 mutants were similar but not identical, suggesting that different configurations NTR of p75 dimers might be endowed with different functions.

Together, these results indicate that dimeric NTR mutants of p75 functionally resemble neurotrophin bound, not neurotrophin-free, receptors, support formation or stabilization of receptor dimers and oligomers as the mechanism by NTR which neurotrophins activate p75 , and reveal a genetic approach to generate gain-of-function receptor variants with distinct functional profiles.

The use of dietary supplements, including herbals, vitamins and minerals, is extensive. The majority of patients have little or no information about the possible risks and adverse effects from interactions with prescribed medicines.

Concerns about herbal medications include their actual pharmacological properties. Among the more common herbs used for weight loss are Ephedra sinica ephedra , Hoodia gordonii hoodia , Citrus aurantium bitter orange and Larrea tridentate chaparral , and are mostly used in an effort to enhance metabolism.

Receiving ephedra with various medications may lead to interactions, i. Hoodia has been found to suppress appetite, however it has a potential hepatoxicity and therefore safety and efficacy have to be validated.

Bitter orange acts similarly to ephedra and when received together with MAOIs can lead to tachycardia and hypertension. Chaparral acts similarly to caffeine and also has a mild diuretic effect.

Patients should be extremely cautious when receiving herbal medicines especially when are on any prescribed medication. In general, herbals are less potent than drugs and thus pose a lesser threat to the person taking them.

Herbal-drug interactions depend on the active s ingredient s of the herb or herbs in case of a multi-herbal mixture. Both herbals and drugs are metabolized by the cytochrome P enzyme system of the liver, thus increasing the potential for interactions.

Different herbs are used for weight loss and these include ephedra, hoodia, bitter orange and chaparral, which are mostly used in an effort to enhance metabolism.

They are thought to act as thermogenics and mild diuretics. Most herbal products have not been scientifically evaluated, and therefore information regarding pharmacokinetics, pharmacodynamics, efficacy and safety is in most cases limited.

It can be found in traditional Chinese herbal medications, herbal teas and also other products available via the web Ephedra contains among others the alkaloids ephedrine, pseudoephedrine isoephedrine , and norpseudoephedrine cathine and other constituents, including quinoline.

The stem contains approximately 0. Ephedrine and pseudoephedrine are found in the leaves and stems of ephedra and are structurally related to amphetamines and therefore ephedra is considered a herbal amphetamine 1.

It has been shown to increase the availability and action of the endogenous neurotransmitters norepinephrine and epinephrine and stimulates catecholamine receptors in the brain, heart, and blood vessels both directly and indirectly 2.

There is strong evidence that ephedra is associated with an increased risk of side effects, possibly even fatal ones, and therefore it was banned by the US FDA in 3.

Ephedra or ephedrine alkaloids are considered toxic to the cardiovascular system, and potentially toxic to the neurological, gastrointestinal and endocrine systems.

Another possible effect worth mentioning is the reduced effect of certain drugs antihypertensives, antiseizures, benzodiazepines, antiglycemics when received together with ephedra 4.

Hoodia gordonii hoodia Also known as Kalahari cactus and xhoba. Hoodia gordonii is widely distributed through the arid areas of South Africa and Namibia.

The active appetite suppressant component of Hoodia gordonii was identified as a triglycoside of 12 tigloyloxy -hydroxypregnenone, a minor component in the plant extract 5.

This has been found to suppress appetite for several hours, by signaling satiety on hypothalamic cells far more intensely than glucose 6.

There are not any known herb-drug interactions of hoodia; however it has a potential hepatoxicity and therefore its safety and efficacy have to be validated 6.

Citrus aurantium bitter orange Other common names include Seville orange, zhi zhi or sour orange.

Bitter orange contains several compounds including synephrine alkaloids 7. It is commonly used as a substitute for ephedra in dietary supplements 8 and has a mechanism of action which is similar to ephedra and may therefore also lead to cardiovascular and neurologic toxicity when received together with other stimulants e.

When received together with MAOIs can lead to tachycardia and hypertension 9. Larger clinical trials are necessary to draw adequate conclusions regarding the safety and efficacy of Citrus aurantium and synephrine alkaloids for promoting weight loss 7.

Larrea divaricata chaparral It is synonymous with for Larrea tridentate and can also be found as creosote bush, hediondilla and greasewood.

Chaparral grows in deserts and is used as a herbal remedy among Native Americans in the Southwestern United States and Northern Mexico It is thought to act as an energy booster and a possible appetite suppressant, having a mechanism of action similar to caffeine and also a mild diuretic effect Chaparral use has been associated with severe hepatotoxicity 10 and is also considered to be a carcinogenic substance 9.

There are not any known herb-drug interactions of chaparral. Many patients think that receiving a dietary supplement herbals are thought to be dietary supplements and not medicines, and therefore their purity, efficacy and safety do not have to be tested or proven is not going to lead to any adverse effects or interfere with prescribed medication Physicians should always ask their patients about possible use of any dietary supplement or herbal product in order to counsel them in the most proper way.

Since there are numerous possible adverse effects and herbdrug interactions of herbs used for weight loss, patients should be able to receive all the needed information from their physician or pharmacist in order to avoid them.

Herbs at a Glance Kalix P. Consumer Advisory ! Tachjian A. Phytochemistry 6. Bent S. Haaz S. Kuhn M. Rodriguez-Fragoso L. Holcomb S.

Nurse Pract. Bishop F. Nitric oxide NO , produced by endothelial nitric oxide synthase eNOS , plays a key role in the regulation of vascular tone.

The study population consisted of patients with a history of MI and control subjects. All subjects were of Greek origin.

The risk for the T allele was estimated at 1. Moreover, strong evidence was found for an increased risk for MI among carriers of the TT genotype who were smokers, hypertensive and had a family history of CAD.

It is possible that TT genotype is closely linked to the etiology of MI even after adjusting for known MI risk factors. Nitric oxide, produced by eNOS, diffuses from the endothelium to vascular smooth muscle cells, where it increases the concentration of cyclic guanosine monophosphate cGMP by stimulating soluble guanylate cyclase, leading to vascular relaxation 1.

The gene encoding eNOS is located on chromosome 7q and contains 26 exons that span 21 kb 2. This is the only known polymorphism changing the eNOS protein sequence, leading to speculation that genetic variation at this site may alter e-NOS activity or regulation and possibly leads to endothelial dysfunction and to pathogenesis of several cardiovascular diseases 3.

The D variant has been associated with myocardial infarction MI in Japanese 4 , English 5 , German 6 and American 7 populations, whereas other studies do not support these findings in Koreans 8 and in Caucasians, i.

Austrian 9 , French-Nothern Irish 10 and Dutch 11 populations. In Greece studies of the ED polymorphism had controversial results Thus, it was the aim of the present study to investigate in a subgroup of the Greek population whether the ED gene variation was related to the risk of myocardial infarction in the total population and among subjects who were at lower or higher risk to this disease.

The control group consisted of volunteers who were selected from the general population of the greater Athens area.

Controls were not eligible to participate if they had a history of MI or angina, clinical evidence of coronary artery disease CAD , stroke, or any atherosclerotic disease in the past, based on a detailed medical history and a physical examination followed by a normal electrocardiogram.

From each participant genomic DNA was extracted from peripheral blood leukocytes. The prevalence of atherogenic risk factors such as smoking, family history of CAD, hypertension, diabetes mellitus and hypercholesterolemia was significantly higher in the patient group.

Concerning the allele frequencies of the E to D transition in the MI and control group were calculated at Similarly to recent studies [, ], we found a significant association between homozygous carriers of the T allele and the occurrence of MI in the Greek population.

This finding confirms previous presumptions of a recessive gene effect. MI is a multifactorial disease. Further genetic and environmental risk factors, such as age, gender, BMI, smoking habits and family history as well as accompanying disorders like high blood pressure and hyperholesterolemia contribute significantly to the susceptibility of MI.

The homozygous T allele carriers, as suggested by the univariate analysis of the present study, have an increased risk to develop MI.

These data, possibly suggest, that presence of established underlying endothelial dysfunction, as observed among cigarette smokers, may be necessary for this polymorphism to attenuate endothelial function and predispose patients to increased cardiovascular risk.

This study suggests that an alteration in the activity of the vascular NO system and the decreased amount of endothelial NO, due to the ED mutation, may promote atherosclerosis and thrombosis that lead to MI.

However, the relation of the ED mutation to the severity of coronary atherosclerosis has not been proven yet [4].

We found evidence that homozygous TT is positively related to the risk of MI and this association is independent of possible effects of other known MI risk factors.

Moncada S. Marsden P. Hingorani A. Hibi K. Hypertension 5. Circulation 6. Gardemann A. Atherosclerosis 7. Morray B. Acta : 9. Schmoelzer I.

Poirier O. Agema W. London Antoniades C. Andrikopoulos G. BMC Med. Alpert J. Dai1, A. Michalopoulos2, A. Papasavvas2, C. Stavropoulos-Gioka2 and S.

Topouzis1 1 Lab. The aim of this work was to characterize two in vitro models for the study of the molecular control of SMC phenotype.

In addition, minimal promoters of the above genes and of SM , another SMC marker, driving a luciferase reporter, also showed similar low activity in MSCs.

These results are compatible with a phenotypical change referred to as Epithelial-to-Mesenchymal Transition EMT , a process that plays a crucial role in organ growth, physiological and pathological tissue remodeling and cancer.

Both cell systems are therefore useful in understanding how Myocardin can induce undifferentiated cells MSCs or epithelial-type cells HUVECs to acquire a Smooth Muscle Cell-like phenotype, and ultimately how its expression may modulate the onset and course of human disease.

Delis, Efstathios Nikolaidis, Theophano A. Psarra, Georgios C. The present study investigates the effects of the fluoroquinolone norfloxacin, the methylxanthine theophylline, as well as of the combined norfloxacin-theophylline application on the responses of the guinea pig ileum to the inhibitory neurotransmitter aminobutyric acid GABA.

According to the results, GABA from 1. Norfloxacin, at concentrations equal or higher than M, and theophylline, at concentrations equal or higher than 3x M, inhibited the contractile responses of the ileum to GABA, without modifying its relaxing effect, whereas lower norfloxacin and theophylline levels were required to cause a similar degree of inhibition when the above drugs were combined.

In conclusion, the inhibitory effect of either norfloxacin or theophylline on the contractile response of the guinea pig ileum to GABA is enhanced when the two drugs are combined.

This amplification could be attributed to the pharmacodynamic interaction of norfloxacin and theophylline at the level of GABAA-receptors.

The presence of GABA in the mammalian gastrointestinal tract, where it behaves as a neurotransmitter in the myenteric plexus neurons, has been demonstrated 4.

It has been shown that GABA evokes transient contraction in the guinea pig ileum which are thought to be mediated through GABAA-receptors located on cholinergic post-ganglionic neurons 5,6.

On the other hand, the antagonistic effect of fluoroquinolones on the GABAA-elicited contraction in the guinea pig ileum has been shown 7,8 , and it has been suggested that these antimicrobial agents act as antagonists not only on central, but also on peripheral GABAA-receptors.

After euthanasia and laparotomy of the guinea pigs, according to the experimental principles of laboratory animals, the ileum was removed and placed in Krebs solution millimolar composition: NaCl The preparations were connected to isotonic myograph transducers Narco Co.

The preparations were allowed to equilibrate for 45 minutes with intervening washings before any compound addition.

The preparation of the strips, as well as the whole experimental procedure equilibration period, resting tensions, aeration of the tissues , were based on in vitro methods previously described.

GABA was dissolved in distilled water, while theophylline and norfloxacin were dissolved in distilled water and 0. Serial dilutions were made using the same vehicle.

When tested, these solvent vehicles did not alter the resting activity of the preparations and did not alter the drug responses.

All solutions were gently added directly into the organ bath fluid by use of a micropipette. Procedures: In order to obtain full concentrationresponse curves for GABA, after the 45 min equilibration period the ileal preparations were exposed to single concentrations of GABA from -6 -3 10 to 10 M.

The tissue was washed out after the contractile lasting approximately 5 seconds and the consecutive relaxing responses to GABA were obtained; the contact time of the tissue with every single GABA-concentration was about 30 seconds.

The occurrence of desensitization to GABA was prevented by allowing 30 minutes to elapse between adding single concentrations of the above compound 5.

In a second series of experiments the effect of norfloxacin on the GABA-induced responses of the ileum was studied. For this reason, the ileal preparations were exposed to various single con-7 -6 -5 centrations of norfloxacin 3x10 , 10 and 10 M 20 minutes prior to the addition of single con-6 -3 centrations of GABA from 10 to 10 M.

In a third series of experiments the effect of theophylline on the GABA-induced responses of the ileum was studied; thus, the ileal preparations were exposed to various single concentrations of -5 -4 -4 theophylline 3x10 , 10 and 3x10 M 10 min prior to the addition of single concentrations of -6 -3 GABA from 10 to 10 M.

In a fourth series of experiments the ileal preparations were exposed to single concentrations of GABA in the presence of theophylline at the -5 -4 concentrations of 3x10 and 10 M 10 minutes after pretreatment with norfloxacin at the con-7 -6 centrations of 3x10 and 10 M.

The contractile effect was concentration-dependent and the minimum effective concentration was -6 1. Responsiveness to GABA in the presence of various concentrations of norfloxacin -7 Norfloxacin, at the concentrations of 3x10 and -6 10 M did not modify, while, at the concentration -5 of 10 M, it significantly reduced the contractile response of the ileum to GABA Figure 1.

The relaxing response of the ileum to GABA was not modified at any of the norfloxacin concentrations tested data not shown.

The ordinate is expressed as a percentage of the mean maximum response induced by GABA alone control. As observed with norfloxacin, the relaxing response of the ileum to GABA was not modified at any of the above theophylline concentrations tested data not shown.

Both receptor types are located on cholinergic enteric neurons and mediate the release of endogenous acetylcholine 5,6. As far as the effect of norfloxacin on the GABA-induced effects is concerned, results of this study are in agreement with previous studies showing that several fluoroquinolones, norfloxacin included, antagonize the GABAA-elicited contraction in the guinea pig ileum, in a noncompetitive manner, but do not influence the GABA-induced relaxation 7,8.

Moreover, according to in vitro studies performed on Xenopus laevis oocytes, theophylline inhibits the GABAA-induced currents in a competitive manner 2 , while it does not modify the responses of the guinea pig isolated ileal preparations to GABAB-agonists Interestingly, the combination of ciprofloxacin a fluoroquinolone with theophylline is known to result to an additive reduction of muscimol binding to the GABA receptor 9 , giving evidence for the interaction of the above drugs with the GABAA-receptors.

Considering the here observed antagonistic effect on the contractile responses of the guinea pig ileum to GABA following the combined application of norfloxacin and theophylline at concentrations that fail to produce any effect when the drugs are applied independently, the present study supports the hypothesis for a pharmacodynamic interaction between fluoroquinolones and theophylline.

In conclusion, this study gives evidence for a pharmacodynamic interaction of theophylline and norfloxacin with peripheral GABAA-receptors.

Neurosci Lett. Amabeoku GJ: Gamma-aminobutyric acid and glutamic acid receptors may mediate theophylline-induced seizures in mice.

Gen Pharmacol. J Neurochem. Br J Pharmacol. Eur J Pharmacol. J Pharm Pharmacol. Segev S, Rehavi M, Rubinstein E: Quinolones, theophylline, and diclofenac interactions with the gammaaminobutyric acid receptor.

Antimicrob Agents Chemother. Obesity is associated with chronic systemic low grade inflammation as well as inflame-mation of adipose tissue with ad hoc accumulation of macrophages.

Like macrophages, the adipocytes have the ability to detect circulating lipopolysaccharides LPS via toll-like receptos-4 TLR4 and produce inflammatory cytokines.

Human adipocytes also ex-press the corticotrophin-releasing factor CRF family of neuropeptides and their receptors, a system affecting innate immunity at the level of macrophages.

Aim of the present study was to examine the effects of CRF on the immune phenotype of adipocytes and specifically on their expression of the TLR4 receptor.

Upon entering the adipose tissue, monocytes are activated to macrophages which further activate adipocytes to produce more chemotactic factors and pro-inflammatory cytokines.

Adipocytes and macrophages share several common characteristics including the TLR4- NFkB-pro-inflammatory cytokine cascade.

Furthermore, adipocytes and monocytes have a common precursor cells. CRF promotes TLR4 expression in undifferentiated adipocytes while it suppress its expression in differentiated adipocytes, suggesting that stress neuropeptides may have distinct effects on pre- and mature adipocytes.

Hotamisligil G. Seres J. Friedberg M. Gregoire F. Endocannabinoids modulate neurochemical processes in which a variety of neurotransmitters are involved.

The excitatory neurotransmitter system, including glutamate and aspartate, partakes in cognitive function and neuroplasticity but is also involved in neurotoxicity processes.

The aim of the present study was to in-vestigate the effects of cannabinoids on tissue levels of glutamate in two rat phenotypes previously differentiated as High Responders HR or Low Responders LR , according to their response to a novel environment.

Our results have shown that HR displayed increased motor activity as compared to LR rats. Cannabinoids modified motor activity in a dose-dependent manner, indicating a biphasic behavioral profile.

Concerning glutamate tissue content, cannabinoids induced notable differences in glutamate content in a region-, phenotype- and drug dose- dependent manner.

This study addresses the role of cannabinoids in modulating glutamate function and reveals a drug dose-, phenotype- and region- dependent effect on glutamate status.

These results contribute to the emergent evidence indicating that cannabinoids are implicated in a variety of physiological functions such as cognition and neuroplasticity as well as pathological states such as neurotoxicity.

The neurochemical effects of exogenously administered cannabinoids and endocannabinoids are mediated via stimulation of cannabinoid receptors.

Amongst the neurotransmitter systems with which the endocannabinoid system interacts and plays a modulatory role , is the excitatory.

The excitatory neurotransmitter system partakes in cognitive function and neuroplasticity but is also involved in neurotoxicity processes.

Two key players involved in this modulation are the excitatory amino acids EAAs , glutamate and aspartate. In the present 9 study, we investigated the effects of - tetrahydrocannabinol THC and WIN55, WIN , two CB1 receptor agonists with distinct pharmacological profiles, on tissue levels of glutamate in two rat phenotypes previously differentiated as High Responders HR or Low Responders LR , according to their response to a novel environment.

Ambulatory and vertical locomotor activities were automatically registered. Another subset of rats received THC, WIN or vehicle and glutamate tissue levels were measured in discrete rat brain regions using High Performance Liquid Chromatography with electrochemical detection.

Concerning glutamate tissue content, THC modified glutamatergic status in a region-, phenotype- and dose-dependent manner. This neurochemical profile was similar to some extent following WIN administration.

These results demonstrate the ability of cannabinoids to produce distinct neurochemical events in EAA status which is greatly implicated in a variety of physiological functions such as cognition and neuro- plasticitity as well as pathological states such as neurotoxicity.

Brown T. Ferraro L. Cortex 3. Navarrete M. Neuron 4. Tarantilis2, Moschos G. Saffron and its active constituents affect a number of neural processes anxiety, depression memory etc.

Crocins are among the active constituents of Crocus Sativus L. Ketamine is a non-competitive NMDA receptor antagonists with known psychotomimetic profile.

The first aim of the present study was to investigate in the rat the effects of crocins on recognition memory deficits produced by ketamine.

For this aim, the novel object recognition task was chosen. Subse- quently, we evaluated whether or not crocins were able to reduce mCPP-induced excessive grooming.

The present results a support and extend the enhancing effects of crocins on memory and b provide evidence that these active constituents of Crocus Sativus L.

Giannogonas, N. Mastrodimou, I. Charalampopoulos, A. Gravanis and K. Many strategies have been employed to develop therapeutic agents for the successful treatment of ischemia induced retinopathies and the prvention of visual loss.

The aim of the present study was to investigate the putative neuroprotective properties of DHEA, and the involvement of NGF receptor signaling, in a model of retinal chemical ischemia.

The eye cups were subsequently fixed and sectioned for PKC, ChAT, and bNOS immunoreactivity, retinal markers for rod bipolar, nitric oxide and cholinergic containing amacrine cells, respectively.

TUNEL staining was also employed to ex- amine apoptotic cell loss. DHEA 10 , 10 , 10 M protected the retina in a concentration-dependent manner.

In addition, the neuroprotective effects appear to be mediated via the NGF receptor and its signaling cascades. Further studies are essential in order to elucidate the therapeutic relevance of these results.

Charalambopoulos I. Mastrodimou N. Recently we have shown that, similar to family A, GPCRs, the TMs of CRF1 form a water-accessible crevice, the binding-site crevice, which extends from the extracellular surface of the receptor into the plane of the membrane.

The surface of this crevice must be formed by residues that contact ligands, as well as, by other residues that may play a structural role and affect binding indirectly.

We achieved this by applying the cysteine-substituted accessibility method SCAM and using as background the Cys mutant of CRF1, which has near normal functional properties and it is relatively insensitive to the methanethiosulfonate MTS reagents.

Four of these mutants reacted with the hydrophilic, positively charged sulfhydryl-specific reagent, methane-thiosulfonate ethylammonium MTSEA , added extracellularly.

We therefore suggest that the side chains of the residues at the reactive loci Thr, Ala, Tyr, and Asn are on the water-accessible surface of the binding-site crevice of CRF1.

The pattern of accessibility is consistent with an alpha-helical conformation for this portion of TM3.

The CRF1, like all GPCRs, is a protein that spans the plasma membrane seven times thus forming seven membrane-spanning segments TMs , which have been proposed to bind small non-peptide ligands, such as antalarmin.

This leads to the hypothesis that similar to family A, rhodopsin-like, GPCRs, the membrane-spanning segments of CRF1 as well as all family B GPCRs form a wateraccessible crevice, the binding-site crevice, which extends from the extracellular surface of the receptor into the plane of the membrane.

The surface of this crevice is formed not only by residues that can contact small ligands but also by residues that may play a structural role and affect binding indirectly.

However, the lack of considerable structural information for the family B GPCRs precludes the support of this hypothesis.

To test this hypothesis we started obtaining information about the structure of family B GPCRs, using as prototype the CRF1 and testing its reaction with the positively charged sulfhydryl-specific methanethiosulfonate ethylammonium MTSEA.

To identify the susceptible cysteine s , we mutated, one at a time, four endogenous cysteines to serine. Thus, Cys, Cys and Cys at the cytoplasmic ends of the third, fourth and seventh membranespanning segments are exposed in the bindingsite crevice of CRF1.

These studies will ultimately provide us with the required information for the structure of CRF1 and will be used to construct a CRF1 molecular model.

This model will be used as a prototype, for the understanding of the structure and function of all receptors belonging to the family B of GPCRs.

This molecular model will also help us to determine the residues in the membrane-spanning segments of CRF1 that interact with small non-peptide ligands, thus putting the basis for the rational design of new small CRF1-selective ligands.

We investigated whether inhibition of Il-1 activity reduces apoptosis and thus, improves myocardial deformation in rheumatoid arthritis patients RA.

No changes were observed after placebo. At baseline and 3-hours after the single injection, we assessed a LV longitudinal, circumferential and radial strain and strain rate, using speckle tracking echocardiography and c Fas and caspase-9 serum levels, as apoptotic markers.

Patients were reassessed after 30 days of anakinra treatment. Kremastinos4, Efstathios K. The pathogenesis of DXR-induced heart failure is complex and the role of iNOS, nitrosative and oxidative stress is not completely understood.

Oleuropein OLEU is a natural phenolic antioxidant, which is present in elevated concentration in olives, olive oil and olive tree leaves conferring protection to the heart.

The aim of the present study was to evaluate a possible protective role of OLEU in DXRinduced heart failure and to investigate a possible mechanism of action.

At the end of the injection protocols the rats were anesthetized and subjected transthoracic echocardiography examination Vivid-i, GE Healthcare with a 12MHz probe.

Then the rats were sacrificed and the hearts were rapidly excised for histological evaluation and for tissue assessment of malondialdehyde MDA and protein carbonyl concentration PCs as an index of oxidative stress, nitrotyrosine NT as indicator of nitrosative stress, for interleukin-6 IL-6 and Big endothelin-1 Big ET-1 which are important indicators of cardiac remodeling and apoptosis.

Finally, cardiac tissue sample was used for qualitative and quantitative evaluation of inducible synthesis of nitric oxide iNOS , as a marker of inflammation, both by immunohistochemistry method and Western-Blot.

The mortality in the DXR group was DXR induced a small decrease in wall thickness, a decrease in left ventricular LV mass, a decrease in fractional shortening an index of systolic function , an increase in endsystolic LV diameter, and a trend towards adverse cardiac remodeling.

DXR-induced heart failure produced a significant induction in iNOS and nitrotyrosine formation in the myocardium.

Kanelleas1, C. Liakou1, A. Katoulis1, P. Giannoukos, T. Economopoulos3 and N. Key words: Psoriasis, etanercept, inflammation, biological treatment Correspondence: A.

Psoriasis is a chronic, systemic, inflammatory disease affecting mainly the skin and the joints.

It is an immune cell-mediated disease in which T-lymphocyte activation and a subsequent inflammatory response are of great importance in its pathogenesis.

It will lead you to your favourite radioshows automagically. Ts first single, we created a small video sequence which works like a paintbrush, reacting to the changes in the music and the meaning of the lyrics.

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The rich are the big gainers in America's new prosperity. Add this article to your reading list by clicking this button. The gap between rich and poor is bigger than in any other advanced country, but most people are unconcerned.

Whereas Europeans fret about the way the economic pie is divided, Americans want to join the rich, not soak them. Eight out of ten, more than anywhere else, believe that though you may start poor, if you work hard, you can make pots of money.

It is a central part of the American Dream. Thanks to a jump in productivity growth after , America's economy has outpaced other rich countries' for a decade.

In the late s everybody shared in this boom. Though incomes were rising fastest at the top, all workers' wages far outpaced inflation.

But after something changed. The pace of productivity growth has been rising again, but now it seems to be lifting fewer boats.

If you take into account the value of employee benefits, such as health care, the contrast is a little less stark.

But, whatever the measure, it seems clear that only the most skilled workers have seen their pay packets swell much in the current economic expansion.

The fruits of productivity gains have been skewed towards the highest earners, and towards companies, whose profits have reached record levels as a share of GDP.

Even in a country that tolerates inequality, political consequences follow when the rising tide raises too few boats. The impact of stagnant wages has been dulled by rising house prices, but still most Americans are unhappy about the economy.

The White House professes to be untroubled. He is right, but his claim is misleading, since the median worker—the one in the middle of the income range—has done less well than the average, whose gains are pulled up by the big increases of those at the top.

Privately, some policymakers admit that the recent trends have them worried, and not just because of the congressional elections in November.

The statistics suggest that the economic boom may fade. Americans still head to the shops with gusto, but it is falling savings rates and rising debts made possible by high house prices , not real income growth, that keep their wallets open.

A bust of some kind could lead to widespread political disaffection. Eventually, the country's social fabric could stretch.

America is nowhere near Brazil yet see chart 1. Despite a quarter century during which incomes have drifted ever farther apart, the distribution of wealth has remained remarkably stable.

The richest Americans now earn as big a share of overall income as they did a century ago see chart 2 , but their share of overall wealth is much lower.

Indeed, it has barely budged in the few past decades. The elites in the early years of the 20th century were living off the income generated by their accumulated fortunes.

Today's rich, by and large, are earning their money. The rise of the working rich reinforces America's self-image as the land of opportunity.

But, by some measures, that image is an illusion. In America about half of the income disparities in one generation are reflected in the next.

In Canada and the Nordic countries that proportion is about a fifth. It is not clear whether this sclerosis is increasing: the evidence is mixed.

Many studies suggest that mobility between generations has stayed roughly the same in recent decades, and some suggest it is decreasing.

Even so, ordinary Americans seem to believe that theirs is still a land of opportunity. The proportion who think you can start poor and end up rich has risen 20 percentage points since That helps explain why voters who grumble about the economy have nonetheless failed to respond to class politics.

Americans tend to blame their woes not on rich compatriots but on poor foreigners. More than six out of ten are sceptical of free trade. A new poll in Foreign Affairs suggests that almost nine out of ten worry about their jobs going offshore.

Congressmen reflect their concerns. Though the economy grows, many have become vociferous protectionists. Other rich countries are watching America's experience closely.

For many Europeans, America's brand of capitalism is already far too unequal. Such sceptics will be sure to make much of any sign that the broad middle-class reaps scant benefit from the current productivity boom, setting back the course of European reform even further.

The conventional tale is that the changes of the past few years are simply more steps along paths that began to diverge for rich and poor in the Reagan era.

During the s and s, the halcyon days for America's middle class, productivity boomed and its benefits were broadly shared.

The gap between the lowest and highest earners narrowed. After the oil shocks, productivity growth suddenly slowed. A few years later, at the start of the s, the gap between rich and poor began to widen.

The exact size of that gap depends on how you measure it. Look at wages, the main source of income for most people, and you understate the importance of health care and other benefits.

Look at household income and you need to take into account that the typical household has fallen in size in recent decades, thanks to the growth in single-parent families.

Look at statistics on spending and you find that the gaps between top and bottom have widened less than for income. But every measure shows that, over the past quarter century, those at the top have done better than those in the middle, who in turn have outpaced those at the bottom.

The gains of productivity growth have become increasingly skewed. If all Americans were set on a ladder with ten rungs, the gap between the wages of those on the ninth rung and those on the first has risen by a third since Economists have long debated why America's income disparities suddenly widened after The consensus is that the main cause was technology, which increased the demand for skilled workers relative to their supply, with freer trade reinforcing the effect.

Some evidence suggests that institutional changes, particularly the weakening of unions, made the going harder for people at the bottom. Whether these shifts were good or bad depends on your political persuasion.

Those on the left lament the gaps, often forgetting that the greater income disparities have created bigger incentives to get an education, which has led to a better trained, more productive workforce.

In their haste to applaud or lament this tale, both sides of the debate tend to overlook some nuances. First, America's rising inequality has not, in fact, been continuous.

The gap between the bottom and the middle—whether in terms of skills, age, job experience or income—did widen sharply in the s.

But during the s, particularly towards the end of the decade, that gap stabilised and, by some measures, even narrowed.

Real wages rose faster for the bottom quarter of workers than for those in the middle. After most people lost ground, but, by many measures, those in the middle of the skills and education ladder have been hit relatively harder than those at the bottom.

People who had some college experience, but no degree, fared worse than high-school dropouts. Some statistics suggest that the annual income of Americans with a college degree has fallen relative to that of high-school graduates for the first time in decades.

So, whereas the s were hardest on the lowest skilled, the s and this decade have squeezed people in the middle.

The one truly continuous trend over the past 25 years has been towards greater concentration of income at the very top.

The scale of this shift is not visible from most popular measures of income or wages, as they do not break the distribution down finely enough.

But several recent studies have dissected tax records to investigate what goes on at the very top.

The figures are startling. Put these pieces together and you do not have a picture of ever-widening inequality but of what Lawrence Katz of Harvard University, David Autor of the Massachusetts Institute of Technology and Melissa Kearney of the Brookings Institution call a polarisation of the labour market.

The bottom is no longer falling behind, the top is soaring ahead and the middle is under pressure. Can changes in technology explain this revised picture?

Up to a point. Computers and the internet have reduced the demand for routine jobs that demand only moderate skills, such as the work of bank clerks, while increasing the productivity of the highest-skilled.

Studies in Britain and Germany as well as America show that the pace of job growth since the early s has been slower in occupations that are easy to computerise.

For the most talented and skilled, technology has increased the potential market and thus their productivity. Top entertainers or sportsmen, for instance, now perform for a global audience.

Some economists believe that technology also explains the soaring pay of chief executives. One argument is that information technology has made top managers more mobile, since it no longer takes years to master the intricacies of any one industry.

As a result, the market for chief executives is bigger and their pay is bid up. Global firms plainly do compete globally for talent: Alcoa's boss is a Brazilian, Sony's chief executive is American and Welsh.

But the scale of America's income concentration at the top, and the fact that no other country has seen such extreme shifts, has sent people searching for other causes.

The typical American chief executive now earns times the average wage, up tenfold from the s. Continental Europe's bosses have seen nothing similar.

Whichever explanation you choose for the signs of growing inequality, none of the changes seems transitory. The middle rungs of America's labour market are likely to become ever more squeezed.

And that squeeze feels worse thanks to another change that has hit the middle class most: greater fluctuations in people's incomes.

The overall economy has become more stable over the past quarter century. America has had only two recessions in the past 20 years, in and , both of which were mild by historical standards.

But life has become more turbulent for firms and people's income now fluctuates much more from one year to the next than it did a generation ago.

Some evidence suggests that the trends in short-term income volatility mirror the underlying wage shifts and may now be hitting the middle class most.

What of the future? It is possible that the benign pattern of the late s will return. The disappointing performance of the Bush era may simply reflect a job market that is weaker than it appears.

Although unemployment is low, at 4. More likely, the structural changes in America's job market that began in the s are now being reinforced by big changes in the global economy.

The integration of China's low-skilled millions and the increased offshoring of services to India and other countries has expanded the global supply of workers.

This has reduced the relative price of labour and raised the returns to capital. That reinforces the income concentration at the top, since most stocks and shares are held by richer people.

More important, globalisation may further fracture the traditional link between skills and wages. As Frank Levy of MIT points out, offshoring and technology work in tandem, since both dampen the demand for jobs that can be reduced to a set of rules or scripts, whether those jobs are for book-keepers or call-centre workers.

Alan Blinder of Princeton, by contrast, says that the demand for skills depends on whether they must be used in person: X -rays taken in Boston may be read by Indians in Bangalore, but offices cannot be cleaned at long distance.

So who will be squeezed and who will not is hard to predict. The number of American service jobs that have shifted offshore is small, some 1m at the most.

And most of those demand few skills, such as operating telephones. Mr Levy points out that only 15 radiologists in India are now reading American X -rays.

But nine out of ten Americans worry about offshoring. That fear may be enough to hold down the wages of college graduates in service industries.

All in all, America's income distribution is likely to continue the trends of the recent past.

While those at the top will go on drawing huge salaries, those in the broad middle of the middle class will see their incomes churned.

The political consequences will depend on the pace of change and the economy's general health. With luck, the offshoring of services will happen gradually, allowing time for workers to adapt their skills while strong growth will keep employment high.

But if the economy slows, Americans' scepticism of globalisation is sure to rise. And even their famous tolerance of inequality may reach a limit.

Inequality and the American Dream. The world's most impressive economic machine needs a little adjusting.

A hidden industry has changed all our lives; but some companies are operating rather close to the. The battle for Arcelor is about more than steel.

It is time to look rationally at the idea of resuming whaling. There is no easy path towards peace, but Hamas cannot yet be wished away.

America's war for hearts and minds. A little politeness goes a long way. Of meat, Mexicans and social mobility. Among the very poor, the American Dream is alive and well.

The public buys its own campaigns, thank you very much. A Democratic candidate in sand-coloured combat boots.

A sudden rush of better news, and not entirely fortuitous. Should the dwellings of the poorest be rebuilt at all?

A story especially for those not watching the football. Violent crime appears to have stopped falling. Democrats have growing worries about the front-runner for the presidential nomination.

But can they. The public sector in Latin America is not spending enough on transport, electricity and water, but. Fidel Castro declares war on corruption.

Roberto Lavagna edges towards a presidential candidacy. The rising sun leaves some Japanese in the shade. An emotional debate about those untouched by the economic recovery.

But the president should survive. Chinese propaganda just isn't what it used to be. The remarkable but little-discussed story of the world's most durable monarch.

A sad case of post-prime-ministerial syndrome. John Howard blocks Canberra's gay marriages. The Palestinians' Hamas government is increasingly besieged.

But it is clinging to power, and to its. The prime minister's good start. The message from Russia and China. An odd saga with Armenians has mocked the government.

Zambia has managed to avoid the crises plaguing its neighbours. Russian worries about Western encirclement are premature.

After the Catalans, Basques and Andalusians want autonomy too. Locals dream of reopening the frontier between Turkey and Armenia.

The ruins of a contested capital are still hostage to geopolitics. The annual report of the European Union as a club. Labour has focused too much on benefits and not enough on work.

The devil in the details. Not everyone who claims to. How to keep the Tube cool. The world's biggest civil IT project has not yet convinced Britain's doctors.

Company pension funds are being saved from destruction. How changes in the market have revived an ancient Egyptian art. The limits of compassionate conservatism.

Philosophical consistency is not David Cameron's priority. Companies are having to find new ways.

Like information on the internet, goods are moving around the world with ever greater efficiency. How three large and successful companies are using their supply chains to compete.

As distinctions between ownership and control become blurred, supply chains are getting more twisted. With more and more stuff being moved around the globe, efficiency is at a premium.

Winging it to the pot. Delivery companies are consolidating. A courier company goes online. Being too lean and mean is a dangerous thing.

Google dominates the lucrative market for web-search, but its rivals are setting out to change that. A pioneering blogger moves on to the next big thing.

Two historic German drugs firms scrap for control of a third. Airbus's jumbo-sized problem threatens the firm's future. Mittal Steel's chances of taking over Arcelor are improving.

A turning point in relations between company owners and bosses? Doing business in a lawless part of Italy. Wind power has propelled Tulsi Tanti into the ranks of India's corporate titans.

America's Treasury market is unsettled by inflation, in another jittery week for the world's. The future of the central bank's governor is in doubt.

Why it pays to become America's treasury secretary. A sign that times are good in the overlooked world of accountants. Securitising intellectual property.

Companies are borrowing against their copyrights, trademarks and patents. The World Bank reveals what it thinks of its clients.

Tackling unemployment requires a careful mixture of policies. America's most famous weapons laboratory is under new management.

The reason HIV is so virulent may have been found. Evidence that Prozac stops people committing suicide. Amid controversy over immigration and the proper role of ethnography, Jacques Chirac prepares to.

The challenges of starting a business in China can be clearly seen from the experiences of two. Next in Economic and financial indicators.

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Full Professor W3 and Chair for Biochemistry. Research topic: Molecular signaling mechanisms in aging and aging-related diseases.

Ruhr-University Bochum, Dept. Physiological Chemistry, Jun. Research topic: Structural and biochemical studies on the regulation of signaling enzymes in aging and disease.

Research Topic: Structural studies on intracellular signaling systems. Thesis Advisor: Professor Robert Huber.

Diploma M. Awards and other responsibilities. Molecular signalling mechanisms in aging and disease. Li, Jun; Bonkowski, Michael S.

In: Science Bd. In: Journal of Medicinal Chemistry Bd. In: PLoS biology Bd. In: Nature Chemical Biology Bd. Gertz, Melanie; Steegborn, Clemens.

Lawrence; Lo, Donald C. In: Cell Chemical Biology Bd. Fraser; Levin, Lonny R. In: Autophagy Bd. In: Scientific Reports Bd. Suenkel, Benjamin; Steegborn, Clemens.

In: Methods in Enzymology Bd. In: ChemBioChem Bd. Schweizer, Ulrich; Steegborn, Clemens. In: Journal of Molecular Endocrinology Bd.

In: ChemMedChem Bd. In: Proteomics Bd. In: Nature Communications Bd. Suhre, Michael H. In: Molecular Cell Bd. In: Journal of Structural Biology Bd.

In: Aging Bd. In: Bioscience Reports Bd. In: Journal of Molecular Biology Bd. In: Frontiers in Pharmacology Bd. In: Proteins Bd.

Lakshminarasimhan, Mahadevan; Steegborn, Clemens. In: Experimental Gerontology Bd. In: Cell Cycle Bd. Baur, Joseph A.

Hall, Rebecca A. Innocenti, Alessio; Hall, Rebecca A. Schlicker, Christine; Hall, Rebecca A. Supuran, Claudiu T.

Hoboken, NJ : Wiley, In: Biochemistry Bd. Garzia, Livia; D'Angelo, A. In: Oncogene Bd. In: Biochemical Journal Bd.

In: Eukaryotic Cell Bd. Steegborn, Clemens; Litvin, Tatiana N. Augustin, Martin A. In: Biological Chemistry Bd.

Xu, Guozhou; Rich, Rebecca L. Stabler, Sally P. In: Metabolism Bd. In: Human Molecular Genetics Bd. In: Structure Bd.

Clausen, Tim; Kaiser, Jens T. In: Molecular microbiology Bd. Clausen, Tim; Wahl, Markus C. In: Biosensors and Bioelectronics Bd.

Metzger, Armin U. In: Nucleic Acids Research Bd. This manuscript represents one of the earliest manuscripts of the Key of Solomon Clavicula Salomonis , dated Mathers places his earliest manuscript, the Latin MS Add.

The present manuscript is in English and occasionally Latin, with orations in Latin. Its most notable characteristics are the strong Christian elements not found in the Colorno class of manuscripts.

Although it has many parallels with two other English manuscripts, Additional Ms. Rather, it appears to be an independent translation, probably from the Latin.

By contrast, Add. MS , Sl. The drawing shows this with a curved blade, distinct from but similar to the black-handled and white-handled knives "cuttellus niger" and "cuttellus albus".

Other manuscripts show it drawn more like a sickle. Mathers' translation from Add. The term evidently derives from the Latin word artavus quill knife or penknife.

A book by this name is also mentioned in Weyer's Pseudomonarchia Daemonum cf, 36 Gaap. Lylet, per honorem patris tui Arieth. Catalogue entries as follows: For convenience, I have taken the liberty of copying the Table of Contents for Book 2 to the beginning of this transcript.

I have also amended it, since it does not actually agree with the layout of the text. The unamended version remains at the beginning of Book 2.

Salomon the Wise. Called his Clauicle Reuealed. The fumigation of is Saffron. Toward y e South.

Nastegon, Sexagip. Truly copyed verbum pro. Christo Roboam sayd what haue I deserued, why should I in any case be likned to my father.

I pray god that y t he desireth may neuer come to passe and effect; and as Ptolomeus the grecian coaduanced by the grace of god hath made cleare the profound and obscure secrets of this arte, as he was that y t foloweth, that were closed in the cheast of Iuory, and these be the words of y e said Clauicle that he declared marueilously in these two Bookes followinge.

Heare beginneth the rubrice of y e 2 d Book. Adiuva me exaudi in quacunque die invocauero ne derelinquas me domine Ihesu Christe et per tuam immensam miserecordiam ne dissesseris a me, intende in adiutorium meum domine deus salutis mee, iudues me domine Ihesu Christe viscem misericordie tue, et voluntatem, benignitatem, prudentiam, iusticiam, fortitudinem temperantiam, modestam patientiam, concordiam, pacem et in hijs omnibus perseuerantiam et castitatem tribuere digneris.

These prayers followinge ought to be sayed at your uprisinge. And incontinently by these wordes let him beginne to call them, as it is playne in that craft that ye goe about, and when this is said and donne he shall see them cominge, one euery side, and if they haue impediment one any part, and then cannot or will not come, ye shall begin with such a coniuration as followeth and note, they that be bound with chaynes of Iron if they cannot come to thee, they will send certaine messengers, and handle them as well as you can.

Amen, Amen, Amen. Adiuro vos per Dominum Nostrum natum ex maria virgine passum a Judeis suspensum in cruce motuum [sic] et sepultum inde venturum indicare vivos et mortuos et seculum per ignem.

Coniuro vos spiritus per dei tonitrua corustaciones et fulgura qui si mihi non obedieritis in vobis et in personis vestris ternent et per 7 ens candelabra ante altare dei lutentia, et per 7 em dona spiritui sancti, sancti paracleti, et per omnium sanctorum angelorum archangelorum et sanctorum miracula et per omnia documenta que fidei Christianae sunt instituta et per sanctorum aginna agni immaculati et per omnis sanctos quos deus elegit ante constitutionem mundi et per eorum merita deo benignissima placentia.

Coniuro vos demones spiritus per virtutes omnes herbarum lapidum Verborum et per omnia celestia terrestria et infernalia, et per omnem creaturam et per 2.

Coniuro vos demones per dominum totius creature artificem nostrum et admirabilem et per enoc et heliam morituros, a manibus Leviathan, et per angelum sanctum qui ante diem Iudicii spiritoris?

Adiuro vos demones spiritus per hec ineffabilia nomina dei, Radrnnnlas Asaac, Zephice, Phany, Harn, Chara, Adonay, Harneatha, Philac, avos hyra, bolera, volem, ladadoc, acazel, heloy, amagir, abraicio, archadul, Baratho, Jamull, Mel, Chadoc, Tracha, ely, aya Annstram, hungnna, mathea, dauid, dama?

Coniuro et contestor vos demones in quacunque parte mundi, sitis ut note habeatis licentiam morandi in aere, nec in terra, nec in aqua, nec in igne, nec in aliqua, parte mundi, nec in aliquo loco estimabitur infernus et penitus impleatus.

Coniuro vos per duas tabulas moysi et per quinque libris moysis et per 7 m Ierias que fuerunt in Chanaan galilee, et per 7 m candelabra aurea que ardent in celesti Iherusalem ante dominum, et per 7 m lampades ardentes que sunt 7 m spiritus dei, et per 7 m vasi aurea que sunt ante conspectum dei plena adoribus et orationibus sanctorum et per sanctas animas iustorum que salue facte sunt in archa Noe, et per nomen sanctum atque admirabile atque potentissime cuius nomen est Gabriel, qui omnes spiritus sustinet et detinet ab ipsa damnatione temperali usque in celestem consummationem et per ista ineffabilia atque inenarrabilia dei nomina que quotidie tremitis.

Et si tunc apparuerint ea hora ostende eis pentaculum et cum non apparuerint exaltet vocem suam sibilam magnum exeat cum magna impetu?

After you have donne in the East and South, then say to the West and North parts. Then if they be bound in Chaynes of Iron they will come excpt [sic] they be in some greevous place or [17v] holden or els they will send some certaine messengers wherby you shall know what they will doe, if they doe not appeare, then for these words, then let the coniurer rise up boldly, and strongly and comfort his fellowes, and let him beate the Ayre toward the 4 parts of y e world and standinge in the middes of y e circle upon his knees and his fellowes with him kneelinge and holdinge the booke, let him say with submissiue voice toward the east, Ubi est vos tales spiritus Angeli fuisti de g m ordinibus venite, venite per celestia signa et ineffabilia nomina nostri creatoris et per nomina Illorum angellorum qui vestri socii extiterunt, Iterum et iterum atque iterum vos exorsizamus, atque imperamus per potentissimum et corroboratum nomen dei Em?

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The following is why his transformation tends to make total sense Ladies and also gentlemen, I give people Kevin Durant 2.

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In so doing, he' s knowingly slipped into jeopardy his richly earned brand since the game' s kindest celeb, opening himself up to your barrage of criticism generally lobbed by alt-right trolls.

And why pretty much everything hatred for a guy who did things appropriate, carried a franchise in his back for nine years whilst it tried to win a championship within the cheap?

Because, for the first time in his life, Durant prioritized themself, chose to pursue his own joy, not his sense of obligation to an incredible number of strangers.

Then suddenly, two periods ago, the hamster wheel quit when he fractured a little bone in his foot. He was 25 along with had never gone anywhere or done something that wasn' t in this service of his sport.

He needed to make some changes, and not really the small-bore kind. No, what was called regarding was a top-down replace, a blank-slate reassessment involving his soul.

It could begin and end using one fundamental question: Consider some of the things in life that provide me pleasure? In Chicago, where I joined Durant' azines business tour all 5 towns and four declares in five days , we sat together at stephen curry shoes an outdoor bistro, chatting about the town he' d just still left.

Later inside day, Kevin Love pushes by, waving from this window of his Porsche. Since Durant quit Oklahoma from the outset of July, all anyone had needed to ask him was precisely why he' d ditched his boys there to the squad of supervillains with Golden State.

He' debbie been called everything nevertheless a radical Muslim simply by otherwise mannerly Oklahomans, their presumption being which Durant was basket-hanging in pursuit of a ring.

That appeared, to put it kindly, ungrateful. Six years before, he spurned free agency to re-sign on the very day LeBron James abandoned Cleveland.

And also he held his language when, summer after summer season, the Thunder declined to include a proven third choice think Ray Allen inside Boston, or Love inside Cleveland.

Apparently it' s exhausting, even in memory space, to carry a team on your own back. Until 2 yrs ago, Durant had in no way taken a week' azines vacation or been wherever exotic for pleasure.

His sport is plagued by Type-A legends Kobe Bryant, in reference to his manic year-round drills; James doing three-a-day exercises but Durant is right up there stephen curry shoes with him or her.

He' d go morning, noon and night for the Thunder' s facility, fixing his soft spots from the three-point stripe or mastering back-to-the-rim moves within the low blocks.

He' d already won this scoring title four years outside of five, been the league' utes MVP in , as well as been a five-time All-NBA first-teamer.

Therefore, two winters ago, he or she sat on his settee and began the psychological accounting of full adulthood. For two decades, his inner life had been in a cryonic freeze; almost every decision, big and small, was deferred for the health of his craft.

His house in Oklahoma had full of guys he' d acknowledged growing up in Seats Pleasant, Maryland, though to hear Durant tell it, he' d had few if any friends for the reason that hard-knock town.

His houseguests lived this up at his location and drove his cars towards the clubs, but did very little or nothing to improve their cause or, for instance, his.

Videos surfaced about TMZ: Durant shot using a toy dart by Justin Bieber; a vial of medicinal weed falling out of his truck.

He' d avoided the typical leg-traps of extended adolescence drunk busts, baby-mamas along with after-hours beefs. Subsequently, phosphorylated dimerizes and translocates to the nucleus where it binds to specific DNA target sequences, altering gene transcription.

The formation of dynamic complexes between -OR, G protein subunits and STAT5B uncovers a novel signaling pathway through which -opioid receptor might regulate gene transcription in the nervous system and alter synaptosomal plasticity.

Mazarakou G. Levy D. Stats: transcriptional control and biological impact. McWhinney, C. Angiotensin II activates Stat5 through Jak2 kinase in cardiac myocytes.

Wu, E. Georgoussi, Z. Effect of delta-opioid antagonists on the functional coupling between opioid receptors and G-proteins in rat brain membranes.

Biochem Pharmacol. Megaritis, G. Functional domains of delta- and mu-opioid receptors responsible for adenylyl cyclase inhibition.

Channels 7, Tso, P. Molecular basis of opioid dependence: role of signal regulation by G-proteins. Novel interacting partners regulating opioid receptor signaling.

In: Ciruela, F. Nova Science Publishers Inc, pp. Leontiadis, L. Regulator of G protein signaling 4 confers selectivity to specific G proteins to modulate - and -opioid receptor signaling.

The other side of opioid receptor signalling: Regulation by protein-protein interaction. Drug Targets. In press. Morou, E. Expression of the third intracellular loop of the -opioid receptor inhibits signaling by opioid receptors and other G protein coupled receptors.

Swevers, L. Functional expression of mammalian opioid receptors in insect cells and high-throughput screening platforms for receptor ligand mimetics.

Life Sci. Douris, V. Stably transformed insect cell lines: tools for expression of secreted and membrane-anchored proteins and high-throughput screening platforms for drug and insecticide discovery.

Virus Res. Selective interactions between G protein subunits and RGS4 with the Cterminal domains of the - and -opioid receptors regulate opioid receptor signalling.

Cao, X. Activation and association of Stat3 with Src in v-Src-transformed cell lines. IL-8, a pro-inflammatory cytokine, is produced from a variety of cancer cells and it was found to contribute to a more aggressive attitude of cancer cells.

In the present study, we have found that K cells produce some basal levels of IL-8 mRNA, which are increased by several folds by hemin.

The mechanism that contributes to this increase is found to be highly and rapidly-responsive.

The biological significance of IL-8 production for the progression of leukeamia is being proposed.

Moreover, IL8 was also found to be produced by nonimmune cells and especially by a large variety of cancer cells ovarian cancer, breast cancer, lung cancer, pancreatic adenocarcinoma and by leukemic cells 2.

Interleukin-8 is a secreted protein of 79 amino acids, which is processed extracellularly to yield the signaling protein of either 77 amino acids in nonimmune or 72 amino acids in immune cells.

IL-8 has been shown to contribute to human cancer progression through its potential functions as a mitogenic, motogenic and angiogenic factor 2,3.

IL-8 acts in an autocrine loop on cancer cells by increasing their proliferation and migration capacity and in a paracrine loop by influencing endothelial cells and promoting angiogenesis 4.

Finally, IL-8 derived from cancer cells can attract neutrophils in the site of tumor, which can either produce growth factors in a way to en- hance the growth of cancer cells or attack them and reducing their proliferative capacity.

Apart from the constitutive production of IL-8 protein from a variety of cancer cells, IL-8 gene expression is activated by environmental stimuli, such as acidosis 5 , hypoxia, NO and other interleukins like TNF and INF- 6.

Mechanistically, the increase in IL-8 mRNA levels by the above mentioned stimuli has been attributed either to an increase in the rate of transcription, or to stabilization at the mRNA level or both.

These elements were found in many labile mRNAs to act as destabilizing determinants by promoting the deadenylation of mRNA, which results in the subsequent mRNA decay 8.

In our study we have observed that K CML cells express some basal levels of mRNA of IL-8, which are increased proportionally with the density of the cells in the culture.

Furthermore, we have noticed that hemin, the oxidised form of heme and a key microenvironmental regulator of erythropoiesis[9], increases the levels of mRNA of IL-8 by several folds.

Hemin Fluka was prepared as stock solution at 4 mM concentration in slightly alkaline solution.

Cells were cultured with hemin at concentrations varying from or in absence of hemin for time periods between h.

Total cytoplasmic RNA was isolated from the cells with acid phenol-guanidium thiocyanate-chloroform extraction protocol as described The concentration of RNA in the aqueous solution was estimated by measuring the absorbance at nm.

In particular, we have found that the increase in mRNAs is dose-dependent to hemin in concentrations of 5 to 25 M.

The last concentration seems to be the optimum of inducing IL-8 by hemin in K cells Figure 1. Results are representative of two independent experiments.

Moreover, we have found that K cells were able to produce some basal levels of mRNA of IL8, which are increased proportionally with the density of the cells in the culture Figure 2A.

This observation may reflects that the constitutive production of mRNA of IL-8 from K cells depends on cell cycle phase, since the majority of cells at 96 h are in G1 phase.

In the immediate future, we are going to investigate the time that has to lapse in order the mechanism of increase of IL-8 mRNAs stimulated by hemin to begin, by analysing with RT-PCR RNAs isolated at time points varying from 2 to 10 h.

Our next goal is to investigate in which level transcriptional or post-transcriptional the mechanism of increase of mRNA of IL-8 induced by hemin functions.

Furthermore, it would be useful to see if the increase in mRNA levels is accompanied with an increase in the protein level by performing ELISA in the cell culture medium.

In conclusion, we tend to suggest that as leukeamia cells are exposed to hemin in the microenvironment of bone marrow, the specific mechanism of increase of IL-8 mRNA levels is activated in a way to influence the proliferation capacity of cancer cells and enhance the angiogenesis in the bone marrow.

So, understanding the mechanisms of both constitutive and inducible Il-8 expression will be helpful in designing potential therapeutic strategies of targeting Il-8 to control tumor growth and metastasis.

Baggiolini M. FEBS 97 2. Xie Keping: Interleukin-8 and human cancer biology. Cytokine and Growth Factors Review 3. Waugh D.

Cancer Res. Heidemann J. Domschke W. Yasumoto K. Mukaida N. Leukocyte Biol. Zublaga A. Tsiftsoglou A. Papadopoulou L.

Sambrook J. Russel DW, Laboratory. CSH: Molecular cloning: A laboratory manual. Cold Spring Harbor, NY, Hyman R. Shah2, Tsutomu Matsubara2 and Frank J.

It is worthy of note that PPAR agonists are effective in raising HDL-cholesterol and reducing triglycerides, properties that prevent atherosclerosis and reduce the risk for cardiovascular diseases.

The data of this study showed that adrenergic receptors ARs , major components of the stress system and targets of various drugs, used in the treatment of cardiovascular diseases hold key roles in PPAR regulation.

Overall, the data of this study set the basis of a better understanding the complex physiopathological states related to lipid disturbances and potentially introduce innovative therapeutic approaches.

Prion diseases are fatal neurodegenerative disorders characterized by the structural conversion of a normal, cellular protein, PrPC, into an aberrant isoform, termed PrPSc.

The physiological function of PrPC has remained enigmatic, although there is evidence that PrPC may play a role in protecting cells from oxidative stress, which, per se, has been implicated in prion pathogenesis.

Benzoxazines are bicyclic heterocyclic compounds with several pharma-ceutically important properties, including neuropro-tection and antioxidation.

In this study, a series of novel benzoxazine derivatives was evaluated in vitro regarding their effect on the levels of both the physiological PrPC and the abnormal PrPSc.

A possible involvement in the inhibition of neuronal cell death, would render these compounds valuable neuroprotective agents.

Moreover, our in vitro system could serve as a particularly useful model in further screening assays. Prion diseases are invariably fatal, involving the structural conversion of a normal, endogenous C protein, called PrP into its conformational, proteinase K PK - resistant, possibly pathogenic Sc isoform, termed PrP.

Although substantial research has been performed during the last 30 years, in order to better comprehend prion pathoC genesis, principal issues, including PrP physiological role, prion pathogenic mechanism and transmissibility, still remain elusive.

Several compounds have been considered to display anti-prion activity both in vitro and in vivo 1. The most effective ones include inhibitors of Sc PrP accumulation in infected cell lines, whereas strategies for both eliminating the physiological C PrP as the substrate for prion conversion and for Sc enhancing PrP degradation have also been employed 2.

On an attempt to identify novel neuroprotective compounds, a series of new 2,3-dihydro-2H-1,4benzoxazine derivatives modified at positions 2-, 3-, 4- and 6-, was examined regarding their putaC tive protective effect on the levels of both PrP Sc and PrP in vitro.

Here we report our findings on three out of seventeen compounds. Control cell cultures received only DMSO. For each treatment duplicate cultures were used.

The dosage scheme for each compound included administration of the compound on day 1 post subpassaging for TC; days 1, 2 and 3 for TC and TC medium was exchanged before the second administration.

Cells were lysed on the fourth day post subpassaging. Trypsinization, Lysis and Proteinase K treatment: Trypsin treatment and lysis were performed as described elsewhere 7.

Following lysis, the lysates were centrifuged for 1 min at rpm. Following centrifugation at rpm for 40 min, the protein pellets were solubilized in 2.

Western blot analysis: Western blotting was performed as previously described [8]. Monoclonal anti-actin antibody, Santa Cruz Biotechnology was used for estimation of endogenous actin levels.

Densitometry: Normalization of protein levels was performed based on actin and using Gel-Pro Analyzer Version 3. As indicated by the prion-characteristic three bandpattern following treatment with PK, the cells were able to accumulate adequate amounts of Sc PrP.

Figure 1. PK treatment of prion-infected cells and brain homogenates. ScN2a, 22LScN2a cells [ Western blotting using 6H4 monoclonal antibody The molecular weight protein markers are indicated in kDa.

Figure 3. Normalization was performed based on actin levels in treated and non treated cell lysates. Consequently, cells were either treated or not treated with PK and PrP-immunolabeling was compared to the one of control cells Figs 2 and 3.

Effect of benzoxazine derivatives on PrP levels. For PrP-immunostaining, 6H4 was used, whereas for protein content normalization, blots were probed with anti-actin monoclonal antibody Preliminary data indicate that certain benzoxazines may exert a diminishing effect on the levels Sc of PrP.

Further in vitro studies are required, in order to define the structureactivity relationships and also assess issues concerning dose dependence and cytotoxicity.

Ultimately, in vivo assays should be employed, in order to evaluate the therapeutic potential of these benzoxazine derivatives.

Trevitt C. Brain 2. Gilch S. Race R. Caughey B. Bosque P. Nishida N. Greenwood A. Salta E. Specifically, we have shown that siRNA against prosurvival TrkA receptors blocked the anti-apoptotic effect of DHEA and reversed its stimulatory action on anti-apoptotic Bcl-2 proteins.

DHEA-polyethylene-glycol beads effectively pulled down recombinant TrkA NTR and p75 proteins, and precipitated both pro- teins from extracts prepared from cells expressing both receptors.

Finally, DHEA rescued from apoptosis sensory neurons of dorsal root ganglia in NGF null embryos and compensated NGF in rescuing sympathetic neurons of embryonic superior cervical ganglia.

Phylogenetic findings on the evolution of neurotrophins, their receptors and CYP17, the enzyme responsible for DHEA biosynthesis, combined with our data support the hypothesis that DHEA served as a phylogenetically ancient neurotrophic factor.

Basal and nitric oxide-stimulated sGC activity was determined using purified rat recombinant sGC. Vasodilation was determined using pre-contracted rat aortic rings after incubation with a CORM, in the presence or absence of S-nitroso N-acetylpenicillamine.

Concentration-response curves were bell- shaped for most of the CORMs studied. We conclude that CORMs have variable, contextdependent effects on vessel tone as they can directly dilate blood vessels and also block NOinduced vasorelaxation.

Its use is not associated with a substantial survival improvement for most lung cancer patients, while it is associated with significant toxicity and it is clear that chemotherapy has reached a plateau of activity in the treatment of NSCLC 2.

Thus, there is a clear need for new more active and more tolerant agents. Advances in our understanding of molecular biology of cancer and mechanisms of tumorigenesis, have enabled the discovery of several potential molecular targets and development of novel targeted therapies.

These therapies inhibit signaling pathways involved in the development and progression of cancer. As these pathways are preferentially activated in cancer cells as contrasted to normal cells, targeted therapies are presumably better tolerated compared to classical cytotoxic agents.

The receptors exist as inactive monomers that homo- or heterodimerize between EGFR and another member of the Erb family after ligand binding.

Binding of these specific ligands to EGFR, results in activation of this receptor via autophosphorylation of the associated tyrosine kinase, which initiates an intracellular signal transduction cascade that affects DNA synthesis, cell growth, and survival 4.

Strategies to block EGFR include tyrosine kinase inhibitors, monoclonal antibodies, antisense approaches and ligand-linked toxins. Among these approaches only tyrosine kinase inhibitors and monoclonal antibodies have reached clinical development.

However, a similarly designed bigger phase III trial that randomly allocated NSCLC patients to gefitinib or placebo as second line treatment ISEL trial failed to demonstrate a benefit in terms of survival in favor of gefitinib.

It is not clear why these conflicting results were observed between these two trials. Three phase III trials compared TKIs with chemotherapy either in first-line setting 10,11 or in second-line setting This trial met its primary end-point of showing non-inferiority of gefitinib, but furthermore demonstrated its superiority compared to chemotherapy HR: 0.

This was also a positive trial and non-inferiority of gefitinib compared to docetaxel was confirmed for overall survival HR 1. Monoclonal antibodies Two prospective, randomized phase III trials of the combination of cetuximab with cytotoxic drugs are published.

Although, PFS was identical between the two arms 4. Furthermore, a new analysis demonstrated that OS for patients receiving cetuximab, who experienced any grade of rash acne-like rash within three weeks of treatment initiation was The magnitude of benefit while statistically significant was modest 1.

A possible explanation for the discrepancy between the FLEX and the BMS study might be related to the relatively low number of patients participating in the latter trial.

Published results are conflicting and both positive and negative correlations have been reported However, it should be underlined that these differences could be attributed to differences regarding the methodologies used in all these studies Most common of these are in-frame deletions in exon 19 codons and a missense mutation leading to a substitution of arginine for leucine at codon LR.

This study failed to show survival improvement, although time-to-progression was significantly longer for either dose of the drug Squamous histology, metastases to central nervous system, history of hemoptysis, and history of documented hemorrhagic diathesis were reported as exclusion criteria in both studies, limiting the potential use of bevacizumab to selected NSCLC patients.

The ECOG study reported significantly higher toxicity for patients receiving bevacizumab. Importantly, there were only two treatment related deaths in the chemotherapy arm and 15 in the bevacizumab arm Jemal A.

Cancer J. Carney D. To Move On From Chemotherapy. Franklin W. Sedlacek H. Drugs 5. Ciardiello F. Cappuzzo F. Takeda K. Thatcher N.

Lancet 9. Shepherd F. Mok T. Engl J. Mitsudomi T. Lancet Oncol. Kim E. Lancet : Pirker R. Gatzemeier U. Langer C. Lung Cancer 9: Lynch T.

Pallis A. Cancer Sandler A. Reck M. Pitychoutis, Christina Dalla and Zeta PapadopoulouDaifoti Department of Pharmacology, Medical School, University of Athens, Athens, Greece Key words: In situ hybridization; antidepressant, serotonin 5-HT , major depression, psychopharmacology S u m m a r y: Chronic mild stress CMS was developed in the late s and is one of the most extensively investigated animal models of depression to-date.

Research from our lab has underlined the importance of serotonin in the manifestation of sexually dimorphic neurochemical, behavioural and immune responses.

This sexdependent differentiation has been largely attributed to the pronounced sex differences that predominate in both the anatomy and function of the human brain, as well as to the sexually dimorphic hormonal milieu.

Chronic mild stress CMS was developed in the late s and is one of the most extensively investigated animal models of depression to-date.

In our initial studies in male rats exposed to a CMS regimen, we observed a decrease in the prefrontocortical serotonergic activity accompanied by an increase in hippocampal serotonergic activity; all alterations were reversed by chronic imipramine treatment [1].

In further comparative studies between male and female rats, we used a milder CMS protocol, which did not induce neurochemical alterations in male rats, but resulted in a significant decrease in hippocampal serotonergic activity in females [2].

Accordingly, exposure to CMS induces a wide spectrum of relevant neurobiological alterations in specific brain regions implicated in the pathophysiology of major depression.

Given the prominent role of the hippocampus in the sex-dependent processing of stressful stimuli, in the present study we investigated whether sex differences exist in the expression of hippocampal 5-HT1A receptor upon CMS application and chronic antidepressant treatment.

Bekris S. Brain Res. Dalla C. Neuroscience 3. Papp M. Psychopharmacology Berl 4. Pitychoutis P. The endocannabinoid system ECS modulates many neurotransmitter systems and is implicated in reward, addiction and the effects of psychostimulants.

The psychostimulant d-amphetamine damp is well known to modulate locomotor activity as well as dopamine and glutamate function; however, it is yet unclear how the ECS is able to intervene in these effects of d-amp.

Thus, the aim of the present study was to investigate the effects of CB1 antagonism on damp-induced behavioural and neurochemical effects.

Sprague- Dawley rats were either observed for locomotor activity after administration of vehicle, d-amp, SR or SR and d-amp or underwent surgery for probe implantation and administered the same treatments in microdialysis experiments measuring dopamine and glutamate in the nucleus accumbens.

Our results showed that d-amp on its own induced hyperlocomotion and increased dopamine and glutamate.

When coadministered with SR, these effects on locomotor activity and neurotransmitter levels were modulated. This study provides further evidence for the role of the ECS in damp- induced behavioural and neurochemical effects in vivo, and furthermore, emphasizes the importance of this modulatory neurotransmitter system in psychostimulant addiction.

The effects of drugs of abuse such as cannabinoids and the psychostimulant d-amp on the brain and on behaviour are not only mediated by the mesolimbic dopaminergic system but also by the excitatory glutamatergic neurotransmitter system.

Amphetamine, an indirect dopamine agonist, is universally known to modulate locomotor activity and extracellular dopamine and glutamate. Evidence demonstrates that cannabinoids also modify locomotor activity as well as the neurotransmitters dopamine and glutamate, mainly via their action on the CB1 receptor in the brain.

In the present study, we chose to investigate the effects of SR, a CB1 receptor antagonist, coadministered with the psychostimulant, d-amp on locomotor activity, in vivo extracellular dopamine levels and glutamate levels in the nucleus acccumbens, the epicentre of reward.

This interaction can also be extended to pathological states such as drug dependence and addiction. Interestingly, the ECS has been impli- Male Sprague-Dawley rats were divided into two groups; the first group was intraperitoneally i.

Sample collection began 24 h later. Once baseline samples were collected, the rats were injected i. All samples were then measured for dopamine and glutamate using High Performance Liquid Chromatography with electrochemical detection.

Likewise, increased extracellular dopamine and glutamate observed after d-amp administration in the nucleus accumbens, were also modified by SR.

Our results show that SR was indeed able to modulate both locomotor activity and neurotransmitter release induced by d-amp, thus providing us with further evidence for a role of the ECS in the effects of d-amp.

On a larger scale, these results contribute to the expansively growing literature on the significance of the ECS in reward and addiction.

Corbille A. J Neurosci 2. Gardner E. Parolaro D. Drug News Perspect. Polissidis A. Neuropsychopharmacol: 5. Wiskerke J.

Margioris2, Katia P. The latter is further supported by that, CRH and its receptors are expressed in human and murine skin. In the process of wounded skin repair, fibroblasts from the wound edges migrate into the wound and proliferate in order to fill the site of the wound.

IL-6 is a pro-inflammatory cytokine critically involved in cutaneous wound healing. We have previously shown that CRH regulates IL-6 expression during inflammation and that Crh deficient mice have accelerated wound healing in vivo and suppressed tissue IL-6 expression.

Based on the above, the aim of our study was to clarify the role of endogenous CRH on the function of primary dermal fibroblasts, in vitro.

Evaluation of the proliferation rate of all cells was performed using the MTT and the thymidine incorporation methods.

Apoptotic cell death was measured with FACS analysis. Evaluation of the migration rate was performed using the scratch assay. Treatment with CRH 10 nM had no effect on the proliferation rate of cells of either genotype.

No difference was observed in apoptosis between the two genotypes. These experiments revealed increased proliferation and migration rate and suppressed IL-6 secretion of CRF1 antagonisttreated fibroblasts.

Our findings support the direct effects of CRH in skin biology and provide interesting insights for the potential usefulness of the developing specific agonists and antagonists of the CRH family in dermal injury or other skin diseases.

Extracellular matrix molecules, like hyaluronan, are highly implicated in both processes 1. Proteoglycans are major components of the extracellular matrix of the skin.

However, they have been poorly studied in intrinsic and extrinsic skin ageing. In the present study we have tried to elucidate the involvement of certain important proteoglycans in intrinsic and extrinsic skin ageing in humans.

Gene expression of versican 1, versican 0, biglycan, decorin, perlecan and syndecan-3 was down regulated in intrinsic skin ageing, whereas the exception of aggrecan, was up regulated.

Extrinsic skin aging was associated with decreased expression of perlecan and decorin and increased expression of versican 0, versican 1 and aggrecan.

Biglycan and syndecan-3 remained practically unaltered. Photo-protected skin tissue specimens were also obtained from juvenile mean age 5 years patients.

Gene expression of versican 1, versican 0, biglycan, decorin, aggrecan, perlecan and syndecan-3 was analyzed using RT-PCR.

Tzellos T. One capsule of either formulation was administered with low-carbonate water after 10 h of overnight fasting.

After dosing, serial blood samples were collected during a period of 48 hours. Based on these statistical inferences it was concluded that the two brands exhibited comparable pharmacokinetics profiles.

Gabapentin has been shown to increase -aminobutyric acid concentrations in the brain of epilepsy patients 4. Gabapentin is well established in the treatment of seizures and also has a demonstrated analgesic effect in patients with chronic neuropathic pain 5.

The absorption of gabapentin is saturable in a dose dependent manner involving an active transport process mechanism by an Lamino acid transporter 6.

In humans, GBP is eliminated exclusively by renal excretion of unchanged drug, and plasma protein binding is negligible.

Renal clearance CL is similar to glomerular filtration rate indicating that no net renal secretion or reabsorption takes place 7.

The study was conducted in a randomized, single-dose, two-way, cross-over design with a 10 days washout period between two doses.

During each period, the volunteers were admitted to hospital and after an overnight fasting they received a single reference or tested mg Gabapentin capsule.

Low-carbonate water mL was given immediately after drug administration. All volunteers fasted 2 h after the drug administration.

No other food was permitted during the first 24 h after drug administration. The study was performed in accordance with the guidelines of the revised Declaration of Helsinki on biomedical research involving subjects and the requirements of Good Clinical Practice.

Blood samples were drawn at 0. The blood samples were centrifuged at rpm for 15 min and the separated plasma was collected and stored at o 20 C until drug analysis.

After a wash-out period of 10 days, the study was repeated in the same manner to complete the cross-over design.

The mixture was vortex-mixed on a vortex mixer Scientific Industries, Inc. The mixture was then centrifuged at 17, g for 5.

Two hundred fifty microliters of the supernatant was transferred into a 2. Chromatographic conditions Chromatographic analysis was carried out at 30 o C.

Detection was carried out at excitation and emission wavelengths of and nm, respectively. The mobile phase was filtered by passing through a 0.

The plasma standard curves were prepared over the range of 0. Standard curves were analyzed and for each standard curve; determined the variability of the slopes and intercepts.

Pharmacokinetic and statistical analysis For computation and analysis of the drugs plasma concentration versus time data and the graphics, the computer software Microsoft Excel 7.

The area under the plasma concentration-time curve AUC and the area to the infinity AUC0- were calculated by using the linear trapezoidal method.

RESULTS After a single oral administration of Gabapentin mg capsule of test and reference in 20 healthy male subjects, the pharmacokinetic parameters showed in Table 1.

And the mean plasma concentration-time curve of Gabapentin is shown in Figure 1. Table 1 Pharmacokinetic parameters of Gabapentin after a single oral administration of test or reference tablet containing mg Gabapentin in 20 healthy subjects!

Plasma GBP concentrations peaked at h after the dose of mg capsule mean, 3. And the peak plasma levels Cmax of gaba-1 pentin of 2.

The elimination half-life of gabapentin is between 4. The obtained values were in good agreement with reported studies.

The main objective of bioequivalence studies is to assure the safety and efficacy of generic formulations.

Two formulations of the same drug are considered to be bioequivalent and therapeutically equivalent if they exhibit a comparable extent and rate of absorption, when they are administered in the same molar dose and under similar experimental conditions 9.

Hengy H. Goa K. Drugs 3. Upton N. Patsalos P. Rowbotham M. JAMA 6. Stewart B. Vollmer K. Chow S.

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