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).

Cluster headache and kynurenines

The glutamatergic neurotransmission has important role in the pathomechanism of primary headache disorders. The kynurenine metabolites derived from catabolism of tryptophan (Trp) have significant involvement not only in glutamatergic processes, but also in the neuroinflammation, the oxidative stress and the mitochondrial dysfunctions. Previously we identified a depressed peripheral Trp metabolism in interictal period of episodic migraineurs, which prompted us to examine this pathway in patients with episodic cluster headache (CH) as well. Our aims were to compare the concentrations of compounds both in headache-free and attack periods, and to find correlations between Trp metabolism and the clinical features of CH. Levels of 11 molecules were determined in peripheral blood plasma of healthy controls (n = 22) and interbout/ictal periods of CH patients (n = 24) by neurochemical measurements.Significantly decreased L-kynurenine (KYN, p < 0.01), while increased quinolinic acid (QUINA, p < 0.005) plasma concentrations were detected in the interbout period of CH patients compared to healthy subjects. The levels of KYN are further reduced during the ictal period compared to the controls (p < 0.006). There was a moderate, negative correlation between disease duration and interbout QUINA levels (p < 0.048, R = - 0.459); and between the total number of CH attacks experienced during the lifetime of patients and the interbout KYN concentrations (p < 0.024, R = - 0.516). Linear regression models revealed negative associations between age and levels of Trp, kynurenic acid, 3-hdyroxyanthranilic acid and QUINA in healthy control subjects, as well as between age and ictal level of anthranilic acid.Our results refer to a specifically altered Trp metabolism in CH patients. The onset of metabolic imbalance can be attributed to the interbout period, where the decreased KYN level is unable to perform its protective functions, while the concentration of QUINA, as a toxic compound, increases. These processes can trigger CH attacks, which may be associated with glutamate excess induced neurotoxicity, neuroinflammation and oxidative stress. Further studies are needed to elucidate the exact functions of these molecular alterations that can contribute to identify new, potential biomarkers in the therapy of CH

Temporal instability of salience network activity in migraine with aura.

This study aims to investigate whether intra-network dynamic functional connectivity and causal interactions of the salience network is altered in the interictal term of migraine. 32 healthy controls, 37 migraineurs without aura and 20 migraineurs with aura were recruited. Participants underwent a T1-weighted scan and resting-state fMRI protocol inside a 1.5T MR scanner. We obtained average spatial maps of resting-state networks using group independent component analysis, which yielded subject-specific time series via a dual regression approach. Salience network ROIs (bilateral insulae and prefrontal cortices, dorsal anterior cingulate cortex) were obtained from the group average map via cluster-based thresholding. To describe intra-network connectivity, average and dynamic conditional correlation was calculated. Causal interactions between the default-mode, dorsal attention and salience network were characterised by spectral Granger's causality. Time-averaged correlation was lower between the right insula and prefrontal cortex in migraine without aura vs. with aura and healthy controls (p<0.038, p<0.037). Variance of dynamic conditional correlation was higher in migraine with aura vs. healthy controls and migraine with aura vs. without aura between the right insula and dorsal anterior cingulate cortex (p<0.011, p<0.026), and in migraine with aura vs. healthy controls between the dorsal anterior cingulate and left prefrontal cortex (p<0.021). Causality was weaker in the <0.05 Hz frequency range between the salience and dorsal attention networks in migraine with aura (p<0.032). Overall, migraineurs with aura exhibit more fluctuating connections in the salience network, which also affect network interactions, and could be connected to altered cortical excitability and increased sensory gain

Identification of Disease- and Headache-Specific Mediators and Pathways in Migraine Using Blood Transcriptomic and Metabolomic Analysis

Recent data suggest that gene expression profiles of peripheral white blood cells can reflect changes in the brain. We aimed to analyze the transcriptome of peripheral blood mononuclear cells (PBMC) and changes of plasma metabolite levels of migraineurs in a self-controlled manner during and between attacks.Twenty-four patients with migraine were recruited and blood samples were collected in a headache-free (interictal) period and during headache (ictal) to investigate disease- and headache-specific alterations. Control samples were collected from 13 age- and sex-matched healthy volunteers. RNA was isolated from PBMCs and single-end 75 bp RNA sequencing was performed using Illumina NextSeq 550 instrument followed by gene-level differential expression analysis. Functional analysis was carried out on information related to the role of genes, such as signaling pathways and biological processes. Plasma metabolomic measurement was performed with the Biocrates MxP Quant 500 Kit.We identified 144 differentially-expressed genes in PBMCs between headache and headache-free samples and 163 between symptom-free patients and controls. Network analysis revealed that enriched pathways included inflammation, cytokine activity and mitochondrial dysfunction in both headache and headache-free samples compared to controls. Plasma lactate, succinate and methionine sulfoxide levels were higher in migraineurs while spermine, spermidine and aconitate were decreased during attacks.It is concluded that enhanced inflammatory and immune cell activity, and oxidative stress can play a role in migraine susceptibility and headache generation

Release of PACAP-38 in episodic cluster headache patients - an exploratory study

BACKGROUND: Activation of the trigeminal-autonomic reflex, involving the trigeminal ganglion, the superior salivatory nucleus and the sphenopalatine ganglion (SPG) is crucial in the pathophysiology of cluster headache (CH). Since pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) is present both in the SPG and the trigeminal ganglion (TG) and its role in migraine has been described, our aim was to determine the plasma PACAP-38 levels in different phases of episodic CH (ECH). Peripheral cubital fossa blood samples were taken during the ictal and inter-bout periods of male ECH patients and from age-matched healthy controls (n = 9). Plasma PACAP-38-like immunoreactivity (LI) was measured with specific and sensitive radioimmunoassay. FINDINGS: Significantly lower plasma PACAP-38-LI was detected in the inter-bout period of ECH patients than in healthy controls. However, PACAP-38 was significantly elevated in the plasma during CH attacks as compared to the inter-bout phase in the same subjects (n = 5). CONCLUSIONS: This exploratory study suggests that PACAP-38 may be released during the attacks of ECH. Further patients and long-term follow-up are necessary to reveal its function

Evidence for Plastic Processes in Migraine with Aura: A Diffusion Weighted MRI Study

Background: Formerly white matter abnormalities in a mixed group of migraine patients with and without aura were shown. Here, we aimed to explore white matter alterations in a homogeneous group of migraineurs with aura and to delineate possible relationships between white matter changes and clinical variables.Methods: Eighteen patients with aura, 25 migraine patients without aura and 28 controls were scanned on a 1.5T MRI scanner. Diffusivity parameters of the white matter were estimated and compared between patients’ groups and controls using whole-brain tract-based spatial statistics.Results: Decreased radial diffusivity (p &lt; 0.036) was found bilaterally in the parieto-occipital white matter, the corpus callosum, and the cingular white matter of migraine with aura (MwA) patients compared to controls. Migraine without aura (MwoA) patients showed no alteration compared to controls. MwA compared to MwoA showed increased fractional anisotropy (p &lt; 0.048) in the left parieto-occipital white matter. In MwA a negative correlation was found between axial diffusivity and disease duration in the left superior longitudinal fascicle (left parieto-occipital region) and in the left corticospinal tract (p &lt; 0.036) and with the number of the attacks in the right superior longitudinal fascicle (p &lt; 0.048).Conclusion: We showed for the first time that there are white matter microstructural differences between these two subgroups of migraine and hence it is important to handle the two groups separately in further researches. We propose that degenerative and maladaptive plastic changes coexist in the disease and the diffusion profile is a result of these processes