Role of pituitary adenylate cyclase-activating polypeptide in nociception and migraine

Energy-efficient buildings can make a major contribution to tackle the world’s climate change and energy use. A number of different environmental certification systems have been created to support energy-efficient and environmentally friendly buildings. In this project simulations are made on a building named Hjältarnas Hus. The building will be used as a support center for those affected by cancer or another critical illness and their families. Hjältarnas Hus will be built in the area next to the University Hospital of Umeå and is planned to be ready for use by the winter 2016/2017. The building project Hjältarnas Hus focuses on sustainability with recyclable materials and aims to achieve the Swedish Environmental Building Certification (Miljöbyggnad) grade GOLD. The main purpose of this project is to study heat transfer through windows. Due to the fact that the facade of Hjältarnas Hus contains large exterior windows, high indoor temperatures are expected during the summer if no solar shading system is installed. The simulations were made in IDA ICE and COMSOL Multiphysics. The focus of this study is to analyze the part of the building that will be used as a library because that part has 90 % windows in the façade. This part is thereby the thermally weakest part of the building envelope since windows are a critical component. The simulations have been based on three milestones. One of the targets was to investigate the temperature gradient that occurs in Hjältarnas Hus library for different ventilation flows, provided that the building achieves the Swedish Environmental Building Certification grade SILVER or GOLD. The second target was to investigate whether the projected solar shading system provides sufficient shading with respect to the certification requirements for Solar heat gain. The third target was to investigate the risk for appearance of external condensation on glass. An investigation of the profitability of an investment in a solar energy generating facility has also been conducted. The result from the simulations showed that the library will never be able to avoid overheating in the summer without any shading system. Even if the ventilation flow is at maximum speed, high temperatures will occur if no shading is installed. The simulations shows that the Swedish Environmental Building Certification grade SILVER can be achieved while the shading system is installed. Risk of external condensation on the window surfaces was greatest during the months of August, September and October. According to the simulations, condensations will appear during 7 % of these months. A calculation from the supplier shows that solar cells are a profitable investment for Hjältarnas Hus. The best option gave a payback period of 9.29 years without any contribution by the State where the investment cost was 950 000 (excl. VAT). För att komma tillrätta med de miljöproblem vi har i världen idag är ett klimatsmart byggande en viktig förutsättning. Som en del i utvecklingen för att minska energi- och resursanvändningen i byggnader har olika certifieringssystem vuxit fram. I detta arbete har simuleringar utförts på en byggnad med namnet Hjältarnas Hus. Byggnaden kommer att fungera som ett anhörighus för familjer där någon familjemedlem drabbats av en svår sjukdom. Hjältarnas Hus kommer att uppföras på området intill Umeå universitetssjukhus i Umeå och planeras att stå klart under vintern 2016/2017. Byggnationen har ett stort fokus på ett hållbart byggande med återvinningsbara material och har ett uppsatt mål om att kunna nå certifieringen av Miljöbyggnad nivå GULD. Detta arbete fokuserar i huvudsak på att undersöka energitransporten genom byggnadens fönsterytor. På grund av att byggnaden kommer att ha stora glaspartier i fasaden förväntas problem med övertemperaturer att uppstå under sommarhalvåret om ingen åtgärd för solavskärmning vidtas. Simuleringarna har utförts i simuleringsprogrammen IDA ICE och COMSOL Multiphysics och har begränsats till ett rum som kommer att brukas som ett allrum/bibliotek då detta rum anses vara byggnadens svagaste länk för att klara det termiska klimatet sommartid. Orsaken till detta är att 90 % av fasaden består av glaspartier. De simuleringar som utförts i detta arbete har baserats på tre delmål. Ett av delmålen var att undersöka mönstret för de temperaturskiktningar som uppstår i Hjältarnas Hus allrum/bibliotek för olika ventilationsflöden med hjälp av simuleringsprogrammet COMSOL Multiphysics. Detta förutsatt att byggnaden klarar certifieringen av Miljöbyggnad nivå GULD eller SILVER med avseende på indikatorn Solvärmelast. Det andra delmålet var att undersöka med hjälp av IDA ICE om den projekterade solavskärmningen ger en tillräcklig avskärmning i rummet för att certifieringen skall kunna uppnås. Det tredje delmålet var att simulera risken för bildning av utvändig kondens på fönsterytorna som uppstår till följd av fönstrens låga U-värden i IDA ICE. Förutom detta har även en utredning kring lönsamheten i en investering i en solcellsanläggning på Hjältarnas Hus takyta genomförts. Resultaten från simuleringarna av temperaturskiktningarna i rummet visade att allrummet/biblioteket aldrig kommer att kunna undvika övertemperaturer under sommarmånaderna om ingen solavskärmning vidtas. Även om ventilationsflödet går på maximal hastighet kommer övertemperaturer att uppnås om ingen solavskärmning är installerad. De alternativ av solavskärmning som studerades för byggnaden visade sig uppfylla kraven som ställs på SILVER-nivån i klassificeringen av Miljöbyggnad med avseende på indikatorn Solvärmelast. Resultaten från studien av bildning av utvändig kondens på årsbasis visade att risken för utvändig kondens på fönsterytorna var störst under månaderna augusti, september och oktober. Under dessa månader bildades det utvändig kondens på fönsterytorna under 7 % av tiden enligt gjorda simuleringar. En investering av solceller för placering på Hjältarnas Hus takyta är lönsamt enligt de beräkningar som erhållits från leverantör. Det bästa alternativet gav en återbetalningsperiod på 9,29 år utan stadsbidrag till en investeringskostnad på ca 950 000 kr (exklusive moms).

Gyógyszerfejlesztési perspektívák

Az érzőideg-végződésekből aktiváció hatására jelátviteli anyagok, köztük számos fehérje természetű, peptid szerkezetű anyag felszabadul, amelyek az erekre és az immunsejtekre hatnak.Ennek eredményeképpen az aktivált immunsejtekből felszabaduló anyagok visszahatnak az érzőideg-végződésekre, azok érzékenységét fokozhatják, vagy éppen gátol az érzőideg-végződésekre, azok érzékenységét fokozhatják, vagy éppen gátolhatják. E területek az utóbbi időben a nemzetközi kutatási irányok fókuszába kerültek a hosszan tartó, elsősorban idegi eredetű, neuropátiás fájdalom kezelési nehézségei és új hatásmechanizmusú fájdalomcsillapító gyógyszerek fejlesztési igényei miatt

Colour evolution of conventionally and organically cultivated Hungarian red spice paprika varieties

Colour evolution of conventionally and organically cultivated Szegedi-20, Meteorit, Mihálytelki and Kármin spice paprika varieties was studied in green, break, pale red, deep red and over-ripened maturity stages. As the ripening stages forwarded the organic samples gradually lost their initial extractable colour (ASTA value) gain toward their conventional counterparts. The over-ripened colour levels were satisfactorily high in the conventional (169.9-264.8 ASTA) and in the organic (160.8-210.5 ASTA) paprika varieties as well, although the colour accumulation was 9.0-62.8 ASTA lower in the organic samples. Significant and perceptible visual colour differences (ΔE*ab) were found between the organic and conventional crops. The lightness difference (ΔL*) indicated that the organic paprika generally were lighter than the conventional ones. The positive hue difference (ΔH*ab) showed that the colour of deep red and over-ripened organic Szegedi-20, Mihálytelki and Kármin paprika crops were more yellow compared with the conventional group. The lightness (L*) and hue angle (h°ab) were found the most suitable instrumental colour parameters to distinguish the ripening stages and the colour characteristics of the samples. The better colour evolution of conventional crops was attributed to the soil characteristics, nutrient supply and chemical plant protection that were specifically designed for the needs of paprika in the conventional farming

Gyulladásos és neuropátiás fájdalom farmakológiai befolyásolása primér szenzoros neuronokon ható szerekkel = Pharmacological modulation of inflammatory and neuropathic pain by agents acting on primary sensory neurones

A kapszaicin-érzékeny, VR1/TRPV1 receptort expresszáló primér szenzoros neuronok afferens működésükön kívül lokális és szisztémás efferens funkciókkal is rendelkeznek. A belőlük felszabaduló calcitonin gén-rokon peptid (CGRP) és tachykininek (pl. P-anyag) neurogén gyulladást váltanak ki az innervációs területen, míg a szomatosztatin gyulladásgátló és antinociceptív hatásokkal rendelkezik az sst4 receptorokon keresztül. Ezen neuronok jelentős szerepet játszanak gyulladásos (ízületi, légúti) és neuropátiás állapotok patomechanizmusában. A neurogén gyulladás és a neuropátiás fájdalom kezelésére jelenleg nincs megfelelő terápiás lehetőség. Kísérleteinkben a TRPV1 kapszaicin receptor, az sst4 szomatosztatin receptor, a hipofízis adenilát cikláz aktiváló polipeptid (PACAP-38), valamint az endomorphin-1 szerepét és ezeken ható vegyületek hatásait vizsgáltuk különféle akut és krónikus gyulladás, valamint neuropátia modellekben. Bár bizonyos gyulladásos folyamatokban a TRPV1, a neurokinin és CGRP receptorok blokkolása, valamint a PACAP és az endomorphin-1 anti-inflammációs és anti-nociceptív hatásokat fejtett ki, az sst4 receptor bizonyult minden modellünkben a legígéretesebb célpontnak. Eredményeink alapján ezen az érzőideg végződéseken és gyulladásos sejteken egyaránt expresszálódó receptoron ható stabil, per os is hatékony szelektív agonisták egy teljesen új hatásmechanizmusú gyulladáscsökkentő és fájdalomcsillapító gyógyszercsoport kifejlesztésére adhatnak lehetőséget. | Capsaicin-sensitive, VR1/TRPV1 receptor-expressing primary sensory neurons have local and systemic efferent functions besides their afferent role. Calcitonin gene-related peptide and tachykinins (e.g. substance P) induce neurogenic inflammation in the innervated area, somatostatin exerts anti-inflammatory and anti-nociceptive actions via sst4 receptor activation. Therefore, these neurons play an important role in the pathological mechanisms of several inflammatory (arthritis, asthma) and neuropathic conditions. At present there is no appropriate pharmacological treatment for the neurogenic component of inflammatory reactions and neuropathic pain. In the present series of experiments the roles of TRPV1 capsaicin receptors, sst4 somatostatin receptors, the effects of pituitary adenylate-cyclase activating polypeptide (PACAP-38) and endomorphin-1 as well as agents acting at these targets were investigated in different acute and chronic inflammation and neuropathy models. Although in certain inflammatory processes the blockade of TRPV1, neurokinin and CGRP receptors, and also PACAP and endomorphin-1 exerted anti-inflammatory and anti-nociceptive actions, the sst4 receptor proved to be the most promising target. On the basis of our results stable, orally active, selective sst4 agonist acting on both sensory nerve terminals and several inflammatory and immune cells could provide perspectives for the development of a completely novel type of anti-inflammatory and analgesic drugs

Pituitary adenylate cyclase activating polypeptide concentrations in the sheep mammary gland, milk, and in the lamb blood plasma after suckling

Pituitary adenylate cyclase activating polypeptide (PACAP) is involved in development and reproduction. We previously described elevated PACAP levels in the milk compared to the plasma, and the presence of its specific PAC1 receptor in the mammary gland. This study aimed to determine PACAP and vasoactive intestinal peptide (VIP) levels in female suckling lambs compared to ewe plasma and mammary gland, as well as their age-dependent alterations. mRNA expressions of PACAP, VIP, PAC1 receptor and brain-derived neurotrophic factor (BDNF) were quantified in the milk whey and mammary gland. PACAP38-like immunoreactivity (PACAP38-LI) was measured in plasma, milk whey and mammary gland by radioimmunoassay, VIP-LI by enzyme-linked immunoassay. PACAP38-LI was 5, 6 times higher in the milk compared to the plasma of lactating sheep. It significantly increased in the lamb plasma 1 h, but returned to basal level 2 h after suckling. However, VIP mRNA was not present in the mammary gland, we detected the VIP protein in the milk whey. BDNF mRNA significantly decreased with age to approximately 60% and 25% in the 3- and 10-year-old sheep respectively, compared to the 3-month-old lambs. No differences were found between mammary and jugular vein plasma PACAP and VIP concentrations, or during the daily cycle. We propose a rapid absorption of PACAP38 from the milk and/or its release in suckling lambs. PACAP accumulated in the milk might be synthesized in the mammary gland or secreted from the plasma of the mothers. PACAP is suggested to have differentiation/proliferation promoting and immunomodulatory effects in the newborns and/or a local function in the mammary gland

The fluorescent dye 3,3′-diethylthiatricarbocyanine iodide is unsuitable for in vivo imaging of myelination in the mouse

There is a growing interest to use non-invasive optical imaging methods to study central nervous system diseases. The application of a myelin-binding fluorescent dye, 3,3-diethylthiatricarbocyanine iodide (DBT) was recently described for in vivo optical imaging of demyelination in the mouse. In the present study we aimed at adapting the method to our optical imaging systems, the IVIS Lumina II to measure epifluorescence and the fluorescent molecular tomograph (FMT) for 3-dimensional quantification of the fluorophore. Epifluorescent imaging was performed 5−30 min after DBT injection which was followed by FMT imaging at 40 min. Two mice also underwent micro-CT imaging in the FMT cassette for the purpose of FMT-CT co-registration. Ex vivo imaging of the brain and other tissues of the head and neck was carried out 1 h after injection. Both the FMT-CT co-registration and the ex vivo imaging of organs proved that DBT poorly crossed the blood-brain barrier. The dye did not accumulate in the myelin sheath of the sciatic nerve. In contrast, there was an intense accumulation in the pituitary and salivary glands. The FMT-CT co-registration unequivocally demonstrated that the signal localized to the head did not originate from beyond the blood-brain barrier. No myelin binding was demonstrated by the ex vivo imaging either. In conclusion, DBT is unsuitable for in vivo imaging of myelination due to its poor BBB penetration, accumulation in other structures of the head and neck region and lack of selective binding towards myelin in vivo

Transcriptional Alterations in the Trigeminal Ganglia, Nucleus and Peripheral Blood Mononuclear Cells in a Rat Orofacial Pain Model

Orofacial pain and headache disorders are among the most debilitating pain conditions. While the pathophysiological basis of these disorders may be diverse, it is generally accepted that a common mechanism behind the arising pain is the sensitization of extra- and intracranial trigeminal primary afferents. In the present study we investigated gene expression changes in the trigeminal ganglia (TRG), trigeminal nucleus caudalis (TNC) and peripheral blood mononuclear cells (PBMC) evoked by Complete Freund's Adjuvant (CFA)-induced orofacial inflammation in rats, as a model of trigeminal sensitization. Microarray analysis revealed 512 differentially expressed genes between the ipsi- and contralateral TRG samples 7 days after CFA injection. Time-dependent expression changes of G-protein coupled receptor 39 (Gpr39), kisspeptin-1 receptor (Kiss1r), kisspeptin (Kiss1), as well as synaptic plasticity-associated Lkaaear1 (Lkr) and Neurod2 mRNA were described on the basis of qPCR results. The greatest alterations were observed on day 3 ipsilaterally, when orofacial mechanical allodynia reached its maximum. This corresponded well with patterns of neuronal (Fosb), microglia (Iba1), and astrocyte (Gfap) activation markers in both TRG and TNC, and interestingly also in PBMCs. This is the first description of up- and downregulated genes both in primary and secondary sensory neurones of the trigeminovascular system that might play important roles in neuroinflammatory activation mechanisms. We are the first to show transcriptomic alterations in the PBMCs that are similar to the neuronal changes. These results open new perspectives and initiate further investigations in the research of trigeminal pain disorders

A hipofízis adenilát cikláz aktiváló polipeptid (PACAP) neuroprotektív hatásmechanizmusa in vitro és in vivo rendszerekben valamint az endogén PACAP vizsgálata = The mechanism of neuroprotection of pituitary adenylate cyclase activating polypeptide (PACAP) in in vivo and in vitro systems and the examination of endogenous PACAP

A kutatás legfőbb eredményei az alábbiak: 1. Igazoltuk, hogy a PACAP neuroprotektív és általános citoprotektív hatásainak hátterében az apoptosis, gyulladás és oxidatív stressz okozta károsodás elleni hatások állnak. Számos ebben résztvevő jelátviteli útvonalat, gyulladásos és oxidatív stressz markert írtunk le. 2. Igazoltuk a PACAP sejtvédő hatását különböző károsodás modellekben retinában, belső fülben, koponyatraumában, ischemiás szervi károsodásokban, különböző perifériás szervekben. 3. Az endogén PACAP jelenlétét kimutattuk emberi mintákból biológiai folyadékokban, mint vérplazma, anyatej, likvor és könny. A biológiai mintákban előforduló PACAP mérést standardizáltuk, és klinikai állapotok súlyosságával mértük össze számos pathológiás folyamatokban. 4. Leírtuk PACAP génhiányos egerek idegrendszeri fejlődését. Igazoltuk, hogy PACAP hiányában az idegrendszer és a perifériás szervek is káros behatásokra érzékenyebben reagálnak. A támogatás segítségével született közlemények összesített impakt faktora 197,3 (absztraktok nélkül). | Major findings of the present project are: 1. We have shown the involvement of antiapoptotic, antiinflammatory and antioxidant effects in the PACAP-induced neuroprotective and general cytoprotective actions. We have described several signal transduction pathways in the apoptotic process, inflammatory markers and oxidative stress markers upon PACAP treatment. 2. We have described the cytoprotective effects of PACAP in different lesion models in the retina, inner ear, traumatic brain injury, ischemic organ lesions, and in several peripheral organs. 3. We have shown the presence of endogenous PACAP in human biological samples, like blood plasma, breast milk, cerebrospinal fluid and tear fluid. We have standardized the PACAP measurements in biological fluids and we have drawn correlations between PACAP levels and clinical status in several pathological conditions. 4. We have described the nervous development of PACAP knockout mice. We have shown that the lack of PACAP leads to increased vulnerability to different stressors both in the nervous system and in the periphery. The impact factor of peer reviewed papers published with the support of the present grant is 197,3

Myocardial ischemia reperfusion injury and cardioprotection in the presence of sensory neuropathy: therapeutic options

During the last decades, mortality of acute myocardial infarction has been dramatically improved, however, the incidence of post-infarction heart failure is still increasing. Cardioprotection by ischemic conditioning have been discovered more than 3 decades ago, however, its clinical translation is still an unmet need, mainly due to the disrupted cardioprotective signalling pathways in the presence of different cardiovascular risk factors and comorbidities and their medications. Sensory neuropathy is one of the comorbidities that has been shown to interfere with cardioprotection. In the present review we summarize the diverse aetiology of sensory neuropathies and the mechanisms by which neuropathies may interfere with ischemic heart disease and cardioprotective signalling. Moreover, we suggest future therapeutic options targeting ischemic heart and sensory neuropathy simultaneously

Long-Term Stress and Concomitant Marijuana Smoke Exposure Affect Physiology, Behavior and Adult Hippocampal Neurogenesis

Marijuana is a widely used recreational drug with increasing legalization worldwide for medical purposes. Most experimental studies use either synthetic or plant-derived cannabinoids to investigate the effect of cannabinoids on anxiety and cognitive functions. The aim of this study was to mimic real life situations where young people smoke cannabis regularly to relax from everyday stress. Therefore, we exposed young adult male NMRI mice to daily stress and concomitant marijuana smoke for 2 months and investigated the consequences on physiology, behavior and adult hippocampal neurogenesis. Animals were restrained for 6-h/day for 5-days a week. During the stress, mice were exposed to cannabis smoke for 2 × 30 min/day. We burned 2 “joints” (2 × 0.8 g marijuana) per occasion in a whole body smoking chamber. Cannabinoid content of the smoke and urine samples was measured by HPLC and SFC-MS/MS. Body weight gain was recorded daily and we did unrestrained, whole body plethysmography to investigate pulmonary functions. The cognitive performance of the animals was evaluated by the novel object recognition and Y maze tests. Anxietyrelated spontaneous locomotor activity and self-grooming were assessed in the open field test (OFT). Adult neurogenesis was quantified post mortem in the hippocampal dentate gyrus. The proliferative activity of the precursor cells was detected by the use of the exogenous marker 5-bromo-20-deoxyuridine. Treatment effects on maturing neurons were studied by the examination of doublecortin-positive neurons. Both stress and cannabis exposure significantly reduced body weight gain. Cannabis smoke had no effect on pulmonary functions, but stress delayed the maturation of several lung functions. Neither stress, nor cannabis smoke affected the cognitive functioning of the animals. Results of the OFT revealed that cannabis had a mild anxiolytic effect and markedly increased self-grooming behavior. Stress blocked cell proliferation in the dentate gyrus, but cannabis had no effect on this parameter. Marijuana smoke however had a pronounced impact on doublecortin-positive neurons influencing their number, morphology and migration. In summary, we report here that long-term stress in combination with cannabis smoke exposure can alter several health-related measures, but the present experimental design could not reveal any interaction between these two treatment factors except for body weight gain