A szkizofrén betegek kognitív deficitjének jelentősége a klinikumban = The clinical importance of the cognitive deficits in schizophrenic patients.

A kutatási programunk célkitűzése a szkizofrén betegek első, illetve újabb akut epizódjaiban történő komplex pszichofiziológiai, neurokognitív és klinikai vizsgálata a kognitív deficitek pontos meghatározására. A kutatási programunk során a célkitűzésnek megfelelően vizsgáltuk a kognitív deficiteket negatív tünetes szkizofrén, továbbá prepszichotikus betegekben. A negatív tünetes betegek egy csoportjában a kognitív deficitet elektrofiziológiai módszerrel (auditoros kiváltott válasz) és pozitron emissziós tomográfia (PET) párhuzamos alkalmazásával is vizsgáltuk a funkcionális eltérések vizsgálatára. A klinikai alkalmazás és differenciál diagnózis számára fontos, hogy a kognitív deficitek eltéréseit különböző egyéb betegcsoportokban: alkohol-dependens, depressziós és Alzheimer demenciában szenvedő betegekben is megvizsgáltuk és jellemző kognitív mintázatokat találtunk. A kutatási program végrehajtása egy évet csúszott, ennek oka volt, hogy csak 2004-ben sikerült a CANTAB vizsgálati módszer legújabb verziójának adaptálása és a gyártó céggel folytatott egyeztetetett installálási folyamat, mely után a kognitív számítógépes battéria folyamatosan rendelkezésünkre áll. A meghosszabbított periódusnak megfelelően a feladattervek is módosultak és a 2004. év során a módosított terveknek megfelelően haladt a kutatási program megvalósítása. Az eredményeikről nemzetközi és hazai konferenciákon, illetve nemzetközi és magyar (peer-reviewed) publikáció formájában számoltunk be. | The research project was aimed to determine the cognitive deficits in the first and consecutive acute episodes of schizophrenic patients with the help of a complex psychophysiological, neurocognitive and clinical research battery. According to the project aims the cognitive deficits were studied in schizophrenic patients with predominant negative symptoms and also in prepsychotic patients. A subgroup of schizophrenic patients with negative symptoms the cognitive deficits were also studied by eletrophysiological method (auditory evoked potential) with the parallel use of positron emitting tomography (PET). Specific cognitive deficit patterns were also described in a group of patients suffering from depression, Alzheimer dementia and substance abuse. These specific cognitive patterns are important for the clinical use and differential diagnosis. The realization of the research project was delayed by one year due to the later-than-expected adaptation and installation of the new version of CANTAB system by the system provider, nevertheless from 2004 the new version of the computerized cognitive battery has been available at our Department. Accordingly, the initial term of contract was been extended by one year in 2004 and the tasks were rescheduled and carried out according to the new research plan. Our results were presented at international and national congresses and also reported in peer-reviewed national and international scientific journals

PARP Inhibition Attenuates Acute Kidney Allograft Rejection by Suppressing Cell Death Pathways and Activating PI-3K-Akt Cascade.

BACKGROUND Novel immunosuppressive therapy facilitates long term allograft survival, but acute tubular necrosis and ischemia-reperfusion during transplantation can compromise allograft function. These processes are related to oxidative stress which activates poly- (ADP-ribose) polymerase (PARP) contributing to the activation of cell death pathways. Here we raised the possibility that PARP inhibition curbs cell death pathways and shifts kinase signaling to improved graft survival. METHODS FINDINGS In an acute rat kidney rejection model, we provided evidence that the PARP inhibitor 4-hydroxy-quinazoline (4OHQ) attenuates rejection processes initiated oxidative/nitrosative stress, nuclear poly-ADP-ribosylation and the disintegration of the tubulo-interstitial structures. The PARP inhibitor attenuated rejection processes induced pro-apoptotic pathways by increasing Bcl-2/Bax ratio and suppressing pro-apoptotic t-Bid levels. In transplanted kidneys, the cell death inducing JNK1/2 is normally activated, but PARP inhibition suppressed this activation with having only modest effects on ERK1/2 and p38 MAP kinases. In untreated transplanted kidneys, no significant alterations were detected in the cytoprotective PI-3K-Akt pathway, but the PARP inhibitor significantly activated Akt (by S473 phosphorylation) and suppressed GSK-3β, as well as activated acute NF-kappaB activation contributing to graft protection. CONCLUSION These data show the protective role of PARP inhibition on graft survival by attenuating poly-ADP-ribosylation, oxidative stress, suppressing pro-apoptotic and increasing anti-apoptotic protein level, and by shifting MAP kinases and PI-3-K-Akt pathways to cytoprotective direction. Thus, addition of PARP inhibitors to standard immunosuppressive therapies during kidney transplantation may provide increased protection to prolong graft survival

A renin-angiotenzin-aldoszteron rendszer és a karbonil stressz szerepe a metabolikus syndroma és az általa okozott vesebetegség kialakulásában = Role of renin-angiotensin-aldosterone axis and carbonyl stress in the development of the metabolic syndrome and in its nephropathy

Az ACE és a glutation peroxidáz gén polimorfizmusa összefüggést mutat a metabolikus szindróma súlyosságával, és az oxidatív stressz mértékével. A karbonil stressz egyik forrásaként ismert dohányfüst a metabolikus szindróma pathogenezisében fontos szerepet játszó endothel funkciót károsítja. Az agyat ért karbonil stressz metabolikus szindrómára jellegzetes klinikai kép kialakulásához vezet. A metabolikus szindrómás állatok veséjében a karbonil stressz végtermékei és a renin kolokalizációt mutat. Izolált vörösvértestekben a karbonil stressz fokozott oxidatív stresszt okoz. A karbonil-stresszel járó diabeteszes glükózuria a vese tubuláris sejtjeiben hidroxil szabadgyök- termeléshez vezet. Az oxidatív stressz fontos szerepet játszik a diabeteszes cataracta, a diabeteszes mikroalbuminuria kialakulásában és mértéke összefügg a diabeteszes érkárosodás mértékével. A karbonil és oxidatív stressz hatására képződő glikációs végtermékek szintje a halálozás független prediktora. Diabeteszes betegekben az inzulinkezelés megkezdése csökkentette az oxidatív stresszt, és javította az endothelfunkciót. Kidolgoztuk az ACE-inhibítorok és az angiotenzin receptor blokkolók kombinálásának ajánlását a diabeteszes nephropathia kezelésében. Diabeteszes betegekben az antioxidáns rezveratrol javította a szénhidrátháztartást. A diabeteszes nephropathiában korán jelentkező anaemia hátterében álló erythropoetin-rezisztenciát az antioxidáns dózisban adott acetilszalicilsavval sikerült áttörnünk. | We have shown, that ACE and glutathion peroxidase gene polymorphisms have an effect on the severity of the metabolic syndrome and on the level of oxidative stress. Smoking, a known source of carbonyl stress causes endothelial dysfunction, which plays a crucial role in the pathogenesis of metabolic syndrome. Carbonyl stress in the brain leads to the development of a clinical picture characteristic for metabolic syndrome. In the kidneys of the animals with metabolic syndrome the end-products of carbonyl stress show co-localisation with renin. Carbonyl stress causes increased oxidative stress in isolated red blood cells. Diabetic glucoseuria accompanied with carbonyl stress induces hydroxyl radical production in renal tubular cells. Oxidative stress plays an important role in the development of diabetic cataract and diabetic microalbuminuria, and is related to the extent of diabetic vascular damage. Level of glycation end-products generated by carbonyl and oxidative stress is an independent predictor of mortality. Initiation of insulin treatment in diabetic patients decreased the oxidative stress and improved the endothelial function. We have formulated guidelines for the treatment of diabetic nephropathy with ACE inhibitors and angiotensin receptor blockers. The antioxidant resveratrol improves carbohydrate metabolism in diabetic patients. Erythropoetin resistance causing early anaemia in diabetic nephropathy was overrided by an antioxidant dose of acetylsalicylic acid

Molecular mechanisms underlying the nephroprotective effects of PACAP in diabetes

Diabetic nephropathy is the leading cause of end-stage renal failure and accounts for 30-40% of patients entering renal transplant programmes. Nephroprotective effects of the neuropeptide PACAP38 against diabetes has been shown previously, but the molecular mechanisms responsible for this effect remain unknown. In the present study, we showed that PACAP treatment counteracted the diabetes-induced increase in the level of the proapoptotic pp38MAPK and cleaved caspase-3 and also decreased the p60 subunit of NFκB. The examined antiapoptotic factors, including pAkt and pERK1/2 showed a slight increase in the diabetic kidneys, while PACAP treatment resulted in a notable elevation of these proteins. PCR and Western blot revealed the downregulation of fibrotic markers, like collagen IV and TGF-β1 in the kidney. PACAP treatment resulted in increased expression of the antioxidant glutathione. We conclude, that the nephroprotective effect of PACAP in diabetes is, at least partly, due to its antiapoptotic, antifibrotic and antioxidative effect in addition to the previously described antiinflammatory effect

Aldosterone Antagonists in Monotherapy Are Protective against Streptozotocin-Induced Diabetic Nephropathy in Rats

Angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) are the standard clinical therapy of diabetic nephropathy (DN), while aldosterone antagonists are only used as adjuncts. Previously in experimental DN we showed that Na/K ATPase (NKA) is mislocated and angiotensin II leads to superimposed renal progression. Here we investigated the monotherapeutic effect of aldosterone blockers on the progression of DN and renal NKA alteration in comparison to ACEi and ARBs. Streptozotocin-diabetic rats developing DN were treated with aldosterone antagonists; ACEi and ARB. Renal function, morphology, protein level and tubular localization of NKA were analyzed. To evaluate the effect of high glucose per se; HK-2 proximal tubular cells were cultured in normal or high concentration of glucose and treated with the same agents. Aldosterone antagonists were the most effective in ameliorating functional and structural kidney damage and they normalized diabetes induced bradycardia and weight loss. Aldosterone blockers also prevented hyperglycemia and diabetes induced increase in NKA protein level and enzyme mislocation. A monotherapy with aldosterone antagonists might be as, or more effective than ACEi or ARBs in the prevention of STZ-induced DN. Furthermore the alteration of the NKA could represent a novel pathophysiological feature of DN and might serve as an additional target of aldosterone blockers

Morphological changes in diabetic kidney are associated with increased O-GlcNAcylation of cytoskeletal proteins including α-actinin 4

Abstract Purpose The objective of the present study is to identify proteins that change in the extent of the modification with O-linked N-acetylglucosamine (O-GlcNAcylation) in the kidney from diabetic model Goto-Kakizaki (GK) rats, and to discuss the relation between O-GlcNAcylation and the pathological condition in diabetes. Methods O-GlcNAcylated proteins were identified by two-dimensional gel electrophoresis, immunoblotting and peptide mass fingerprinting. The level of O-GlcNAcylation of these proteins was examined by immunoprecipitation, immunoblotting and in situ Proximity Ligation Assay (PLA). Results O-GlcNAcylated proteins that changed significantly in the degree of O-GlcNAcylation were identified as cytoskeletal proteins (α-actin, α-tubulin, α-actinin 4, myosin) and mitochondrial proteins (ATP synthase β, pyruvate carboxylase). The extent of O-GlcNAcylation of the above proteins increased in the diabetic kidney. Immunofluorescence and in situ PLA studies revealed that the levels of O-GlcNAcylation of actin, α-actinin 4 and myosin were significantly increased in the glomerulus and the proximal tubule of the diabetic kidney. Immunoelectron microscopy revealed that immunolabeling of α-actinin 4 is disturbed and increased in the foot process of podocytes of glomerulus and in the microvilli of proximal tubules. Conclusion These results suggest that changes in the O-GlcNAcylation of cytoskeletal proteins are closely associated with the morphological changes in the podocyte foot processes in the glomerulus and in microvilli of proximal tubules in the diabetic kidney. This is the first report to show that α-actinin 4 is O-GlcNAcylated. α-Actinin 4 will be a good marker protein to examine the relation between O-GlcNAcylation and diabetic nephropathy.</p

Preference for novel faces in male infant monkeys predicts cerebrospinal fluid oxytocin concentrations later in life

The ability to recognize individuals is a critical skill acquired early in life for group living species. In primates, individual recognition occurs predominantly through face discrimination. Despite the essential adaptive value of this ability, robust individual differences in conspecific face recognition exist, yet its associated biology remains unknown. Although pharmacological administration of oxytocin has implicated this neuropeptide in face perception and social memory, no prior research has tested the relationship between individual differences in face recognition and endogenous oxytocin concentrations. Here we show in a male rhesus monkey cohort (N = 60) that infant performance in a task used to determine face recognition ability (specifically, the ability of animals to show a preference for a novel face) robustly predicts cerebrospinal fluid, but not blood, oxytocin concentrations up to five years after behavioural assessment. These results argue that central oxytocin biology may be related to individual face perceptual abilities necessary for group living, and that these differences are stable traits

Applying Customer Involvement in B2B Sales : case study on a medical device company

Thesis Title: Applying customer involvement in B2B Sales – Case study on a medical device company Date: 10th of June, 2012 Subject, Course: Business Administration, 15 hec. Enterprising and Business Development, 2EB00E. Author: Anna Degrell, 25-01-1989 6647 Advisor: Magnus Forslund Examiner: Richard Nakamura Keywords: Customer Involvement, B2B, Sales, Organize, Apply, Value, Case Study, Medical Device Company Purpose: The purpose of this thesis is to increase the understanding of how customer involvement can be applied in business to business (B2B) sales. Method: the method of choice for this thesis will be within a qualitative approach and contains a case study, with semi structured interviews based on Operationalization of theoretical concepts, and analyzed by grounded theory. Result: Customer Involvement can be presented in several ways within B2B sales; the case study on the medical device company in this thesis has applied the involvement in so-called Sight-visits and as a concept called doctor-to-doctor