Browsing by Subject "MODULATION"

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  • Beauchamp, Philippe; Jackson, Christopher B.; Ozhathil, Lijo Cherian; Agarkova, Irina; Galindo, Cristi L.; Sawyer, Douglas B.; Suter, Thomas M.; Zuppinger, Christian (2020)
    Purpose: Both cardiomyocytes and cardiac fibroblasts (CF) play essential roles in cardiac development, function, and remodeling. Properties of 3D co-cultures are incompletely understood. Hence, 3D co-culture of cardiomyocytes and CF was characterized, and selected features compared with single-type and 2D culture conditions.Methods: Human cardiomyocytes derived from induced-pluripotent stem cells (hiPSC-CMs) were obtained from Cellular Dynamics or Ncardia, and primary human cardiac fibroblasts from ScienCell. Cardiac spheroids were investigated using cryosections and whole-mount confocal microscopy, video motion analysis, scanning-, and transmission-electron microscopy (SEM, TEM), action potential recording, and quantitative PCR (qPCR).Results: Spheroids formed in hanging drops or in non-adhesive wells showed spontaneous contractions for at least 1 month with frequent media changes. SEM of mechanically opened spheroids revealed a dense inner structure and no signs of blebbing. TEM of co-culture spheroids at 1 month showed myofibrils, intercalated disc-like structures and mitochondria. Ultrastructural features were comparable to fetal human myocardium. We then assessed immunostained 2D cultures, cryosections of spheroids, and whole-mount preparations by confocal microscopy. CF in co-culture spheroids assumed a small size and shape similar to the situation in ventricular tissue. Spheroids made only of CF and cultured for 3 weeks showed no stress fibers and strongly reduced amounts of alpha smooth muscle actin compared to early spheroids and 2D cultures as shown by confocal microscopy, western blotting, and qPCR. The addition of CF to cardiac spheroids did not lead to arrhythmogenic effects as measured by sharp-electrode electrophysiology. Video motion analysis showed a faster spontaneous contraction rate in co-culture spheroids compared to pure hiPSC-CMs, but similar contraction amplitudes and kinetics. Spontaneous contraction rates were not dependent on spheroid size. Applying increasing pacing frequencies resulted in decreasing contraction amplitudes without positive staircase effect. Gene expression analysis of selected cytoskeleton and myofibrillar proteins showed more tissue-like expression patterns in co-culture spheroids than with cardiomyocytes alone or in 2D culture.Conclusion: We demonstrate that the use of 3D co-culture of hiPSC-CMs and CF is superior over 2D culture conditions for co-culture models and more closely mimicking the native state of the myocardium with relevance to drug development as well as for personalized medicine.
  • Abdurakhmanova, Shamsiiat; Semenova, Svetlana; Piepponen, T. Petteri; Panula, Pertti (2019)
    Hypothalamic histaminergic neurons regulate a variety of homeostatic, metabolic and cognitive functions. Recent data have suggested a modulatory role of histamine and histamine receptors in shaping striatal activity and connected the histaminergic system to neuropsychiatric disorders. We characterized exploratory behavior and striatal neurotransmission in mice lacking the histamine producing enzyme histidine decarboxylase (Hdc). The mutant mice showed a distinct behavioral pattern during exploration of novel environment, specifically, increased frequency of rearing seated against the wall, jumping and head/body shakes. This behavioral phenotype was associated with decreased levels of striatal dopamine and serotonin and increased level of dopamine metabolite DOPAC. Gene expression levels of dynorphin and enkephalin, opioids released by medium spiny neurons of striatal direct and indirect pathways respectively, were lower in Hdc mutant mice than in control animals. A low dose of amphetamine led to similar behavioral and biochemical outcomes in both genotypes. Increased striatal dopamine turnover was observed in Hdc KO mice after treatment with dopamine precursor l-Dopa. Overall, our study suggests a role for striatal dopamine and opioid peptides in formation of distinct behavioral phenotype of Hdc KO mice.
  • Mahalka, Ajay K.; Code, Christian; Jahromi, Behnam Rezai; Kirkegaard, Thomas; Jaattela, Marja; Kinnunen, Paavo K. J. (2011)
  • Harjumaki, Riina; Zhang, Xue; Nugroho, Robertus Wahyu N.; Farooq, Muhammad; Lou, Yan-Ru; Yliperttula, Marjo; Valle-Delgado, Juan Jose; Osterberg, Monika (2020)
    Transmembrane protein integrins play a key role in cell adhesion. Cell-biomaterial interactions are affected by integrin expression and conformation, which are actively controlled by cells. Although integrin structure and function have been studied in detail, quantitative analyses of integrin-mediated cell-biomaterial interactions are still scarce. Here, we have used atomic force spectroscopy to study how integrin distribution and activation (via intracellular mechanisms in living cells or by divalent cations) affect the interaction of human pluripotent stem cells (WA07) and human hepatocarcinoma cells (HepG2) with promising biomaterials.human recombinant laminin-521 (LN-521) and cellulose nanofibrils (CNF). Cell adhesion to LN-521-coated probes was remarkably influenced by cell viability, divalent cations, and integrin density in WA07 colonies, indicating that specific bonds between LN-521 and activated integrins play a significant role in the interactions between LN-521 and HepG2 and WA07 cells. In contrast, the interactions between CNF and cells were nonspecific and not influenced by cell viability or the presence of divalent cations. These results shed light on the underlying mechanisms of cell adhesion, with direct impact on cell culture and tissue engineering applications.
  • Leino, Sakari; Koski, Sini K.; Hänninen, Raisa; Tapanainen, Tuukka; Rannanpää, Saara; Salminen, Outi (2018)
    Preclinical studies suggest the involvement of various subtypes of nicotinic acetylcholine receptors in the pathophysiology of Parkinson's disease, a neurodegenerative disorder characterized by the death of dopaminergic neurons in the substantia nigra pars compacta (SNC). We studied for the first time the effects of alpha 5 nicotinic receptor subunit gene deletion on motor behavior and neurodegeneration in mouse models of Parkinson's disease and levodopa-induced dyskinesia. Unilateral dopaminergic lesions were induced in wild-type and alpha 5-KO mice by 6-hydroxydopamine injections into the striatum or the medial forebrain bundle. Subsequently, rotational behavior induced by dopaminergic drugs was measured. A subset of animals received chronic treatments with levodopa and nicotine to assess levodopa-induced dyskinesia and antidyskinetic effects by nicotine. SNC lesion extent was assessed with tyrosine hydroxylase immunohistochemistry and stereological cell counting. Effects of alpha 5 gene deletion on the dopaminergic system were investigated by measuring ex vivo striatal dopamine transporter function and protein expression, dopamine and metabolite tissue concentrations and dopamine receptor mRNA expression. Hemiparkinsonian alpha 5-KO mice exhibited attenuated rotational behavior after amphetamine injection and attenuated levodopa-induced dyskinesia. In the intrastriatal lesion model, dopaminergic cell loss in the medial cluster of the SNC was less severe in alpha 5-KO mice. Decreased striatal dopamine uptake in alpha 5-KO animals suggested reduced dopamine transporter function as a mechanism of attenuated neurotoxicity. Nicotine reduced dyskinesia severity in wild-type but not alpha 5-KO mice. The attenuated dopaminergic neurodegeneration and motor dysfunction observed in hemiparkinsonian alpha 5KO mice suggests potential for alpha 5 subunit-containing nicotinic receptors as a novel target in the treatment of Parkinson's disease. (C) 2018 The Authors. Published by Elsevier Ltd.
  • COSINE-100 Collaboration; Sogang Phenomenology Grp; Adhikari, G.; Yoon, Jong-Hyun (2019)
    Assuming a standard Maxwellian for the WIMP velocity distribution, we obtain the bounds from null WIMP search results of 59.5 days of COSINE-100 data on the DAMA/LIBRA-phase2 modulation effect within the context of the non-relativistic effective theory of WIMP-nucleus scattering. Here, we systematically assume that one of the effective operators allowed by Galilean invariance dominates in the effective Hamiltonian of a spin-1/2 dark matter (DM) particle. We find that, although DAMA/LIBRA and COSINE-100 use the same sodium-iodide target, the comparison of the two results still depends on the particle-physics model. This is mainly due to two reasons: i) the WIMP signal spectral shape; ii) the expected modulation fractions, when the upper bound on the time-averaged rate in COSINE-100 is converted into a constraint on the annual modulation component in DAMA/LIBRA. We find that the latter effect is the dominant one. For several effective operators the expected modulation fractions are larger than in the standard spin-independent or spin-dependent interaction cases. As a consequence, compatibility between the modulation effect observed in DAMA/LIBRA and the null result from COSINE-100 is still possible for several non-relativistic operators. At low WIMP masses such relatively high values of the modulation fractions arise because COSINE-100 is mainly sensitive to WIMP-sodium scattering events, due to the higher threshold compared to DAMA/LIBRA. A next COSINE analysis is expected to have a full sensitivity for the 5 a region of DAMA/LIBRA.
  • Wiencke, Kathleen; Horstmann, Annette; Mathar, David; Villringer, Arno; Neumann, Jane (2020)
    Computational modeling of dopamine transmission is challenged by complex underlying mechanisms. Here we present a new computational model that (I) simultaneously regards release, diffusion and uptake of dopamine, (II) considers multiple terminal release events and (III) comprises both synaptic and volume transmission by incorporating the geometry of the synaptic cleft. We were able to validate our model in that it simulates concentration values comparable to physiological values observed in empirical studies. Further, although synaptic dopamine diffuses into extra-synaptic space, our model reflects a very localized signal occurring on the synaptic level, i.e. synaptic dopamine release is negligibly recognized by neighboring synapses. Moreover, increasing evidence suggests that cognitive performance can be predicted by signal variability of neuroimaging data (e.g. BOLD). Signal variability in target areas of dopaminergic neurons (striatum, cortex) may arise from dopamine concentration variability. On that account we compared spatio-temporal variability in a simulation mimicking normal dopamine transmission in striatum to scenarios of enhanced dopamine release and dopamine uptake inhibition. We found different variability characteristics between the three settings, which may in part account for differences in empirical observations. From a clinical perspective, differences in striatal dopaminergic signaling contribute to differential learning and reward processing, with relevant implications for addictive- and compulsive-like behavior. Specifically, dopaminergic tone is assumed to impact on phasic dopamine and hence on the integration of reward-related signals. However, in humans DA tone is classically assessed using PET, which is an indirect measure of endogenous DA availability and suffers from temporal and spatial resolution issues. We discuss how this can lead to discrepancies with observations from other methods such as microdialysis and show how computational modeling can help to refine our understanding of DA transmission. Author summary The dopaminergic system of the brain is very complex and affects various cognitive domains like memory, learning and motor control. Alterations have been observed e.g. in Parkinson's or Huntington's Disease, ADHD, addiction and compulsive disorders, such as pathological gambling and also in obesity. We present a new computational model that allows to simulate the process of dopamine transmission from dopaminergic neurons originated in source brain regions like the VTA to target areas such as the striatum on a synaptic and on a larger, volume-spanning level. The model can further be used for simulations of dopamine related diseases or pharmacological interventions. In general, computational modeling helps to extend our understanding, gained from empirical research, to situations were in vivo measurements are not feasible.
  • Breneman, A. W.; Halford, A. J.; Millan, R. M.; Woodger, L. A.; Zhang, X. -J.; Sandhu, J. K.; Capannolo, L.; Li, W.; Ma, Q.; Cully, C. M.; Murphy, K. R.; Brito, T.; Elliott, S. S. (2020)
    We present observations of similar to 10-60 min solar wind dynamic pressure structures that drive large-scale coherent similar to 20-100 keV electron loss from the outer radiation belt. A combination of simultaneous satellite and Balloon Array for Radiation-belt Relativistic Electron Losses (BARREL) observations on 11-12 January 2014 shows a close association between the pressure structures and precipitation as inferred from BARREL X-rays. Specifically, the structures drive radial ExB transport of electrons up to 1 Earth radii, modulating the free electron energy available for low-frequency plasmaspheric hiss growth, and subsequent hiss-induced loss cone scattering. The dynamic pressure structures, originating near the Sun and commonly observed advecting with the solar wind, are thus able to switch on scattering loss of electrons by hiss over a large spatial scale. Our results provide a direct link between solar wind pressure fluctuations and modulation of electron loss from the outer radiation belt and may explain long-period modulations and large-scale coherence of X-rays commonly observed in the BARREL data set. Plain Language Summary The Earth's low-density magnetosphere is a region of enclosed magnetic field lines that contains energetic electrons ranging from eV to MeV energies. These populations can be greatly enhanced in response to solar driving. Following enhancements, energetic electron populations are depleted on timescales of hours to days by various processes. One important depletion process occurs when an electromagnetic plasma wave called plasmaspheric hiss, which exists within a high plasma density region called the plasmasphere and its (occasional) radial extension called the plume, scatters energetic electrons into the atmosphere. In this paper, we show that these hiss waves can be switched on by compressions of the magnetosphere which occur in response to similar to 1 hr long pressure structures in the solar wind. These structures originate at or near the Sun and are very common in the solar wind at 1 AU. The newly excited hiss waves scatter electrons into the atmosphere where they are observed on balloon-borne X-ray detectors. Our results suggest that magnetospheric models that predict the loss of electrons from hiss waves may be improved by consideration of solar wind pressure-driven dynamics.
  • Lei, Jing; Ye, Gang; Pertovaara, Antti; You, Hao-Jun (2020)
    Here we investigated effects of intramuscular (i.m.) heating-needle stimulation on persistent muscle nociception evoked by i.m. injection of different doses (50-200 mu l) of complete Freund's adjuvant (CFA) in rats. Paw withdrawal reflexes evoked by noxious mechanical and heat stimulation as well as hind limb swelling were determined prior to and two weeks after the CFA injection. The unilateral injection of CFA induced a dose-related and long-lasting (5-14 d), bilateral secondary mechanical hyperalgesia and heat hypoalgesia associated with long-term limb swelling. A period of 30-45 min 43 degrees C heating-needle stimulation significantly enhanced the i.m. CFA-induced bilateral heat hypoalgesia and alleviated hind limb swelling. In contrast, 30-45 min 46 degrees C heatingneedle stimulation markedly enhanced both mechanical hyperalgesia and heat hypoalgesia, but failed to influence the CFA-induced hind limb swelling. Microinjection of P2X3 receptor antagonist A-317491 (0.5-4.5 nmol/0.5 mu l) into the thalamic ventromedial (VM) nucleus dose-dependently inhibited the 43 degrees C and 46 degrees C heating-needle stimulation-induced heat hypoalgesia, whereas the 46 degrees C heating-needle stimulation-induced mechanical hyperalgesia was significantly prevented by microinjection of A-317491 into the thalamic mediodorsal (MD) nucleus. In contrast, the hind limb swelling was not affected by the microinjection of A-317491 into the thalamic VM or MD nucleus. The present study indicates that in the CFA-induced persistent muscle nociception condition, 43 degrees C heating-needle stimulation selectively increases descending inhibition, which effect is modulated by the thalamic VM nucleus. In addition to the antinociceptive role of P2X3 receptors in the thalamic VM nucleus, P2X3 receptors within the thalamic MD nucleus participate in the descending facilitation evoked by i.m. 46 degrees C heating-needle stimulation. (C) 2020 IBRO. Published by Elsevier Ltd. All rights reserved.
  • Leopold, Anna V.; Shcherbakova, Daria; Verkhusha, Vladislav V. (2019)
    Understanding how neuronal activity patterns in the brain correlate with complex behavior is one of the primary goals of modern neuroscience. Chemical transmission is the major way of communication between neurons, however, traditional methods of detection of neurotransmitter and neuromodulator transients in mammalian brain lack spatiotemporal precision. Modern fluorescent biosensors for neurotransmitters and neuromodulators allow monitoring chemical transmission in vivo with millisecond precision and single cell resolution. Changes in the fluorescent biosensor brightness occur upon neurotransmitter binding and can be detected using fiber photometry, stationary microscopy and miniaturized head-mounted microscopes. Biosensors can be expressed in the animal brain using adeno-associated viral vectors, and their cell-specific expression can be achieved with Cre-recombinase expressing animals. Although initially fluorescent biosensors for chemical transmission were represented by glutamate biosensors, nowadays biosensors for GABA, acetylcholine, glycine, norepinephrine, and dopamine are available as well. In this review, we overview functioning principles of existing intensiometric and ratiometric biosensors and provide brief insight into the variety of neurotransmitter-binding proteins from bacteria, plants, and eukaryotes including G-protein coupled receptors, which may serve as neurotransmitter-binding scaffolds. We next describe a workflow for development of neurotransmitter and neuromodulator biosensors. We then discuss advanced setups for functional imaging of neurotransmitter transients in the brain of awake freely moving animals. We conclude by providing application examples of biosensors for the studies of complex behavior with the single-neuron precision.
  • Rinne, Teemu; Muers, Ross S.; Salo, Emma; Slater, Heather; Petkov, Christopher I. (2017)
    The cross-species correspondences and differences in how attention modulates brain responses in humans and animal models are poorly understood. We trained 2 monkeys to perform an audio-visual selective attention task during functional magnetic resonance imaging (fMRI), rewarding them to attend to stimuli in one modality while ignoring those in the other. Monkey fMRI identified regions strongly modulated by auditory or visual attention. Surprisingly, auditory attention-related modulations were much more restricted in monkeys than humans performing the same tasks during fMRI. Further analyses ruled out trivial explanations, suggesting that labile selective-attention performance was associated with inhomogeneous modulations in wide cortical regions in the monkeys. The findings provide initial insights into how audio-visual selective attention modulates the primate brain, identify sources for "lost" attention effects in monkeys, and carry implications for modeling the neurobiology of human cognition with nonhuman animals.
  • Koski, Sini K.; Leino, Sakari; Panula, Pertti; Rannanpää, Saara; Salminen, Outi (2020)
    The brain histaminergic and dopaminergic systems closely interact, and some evidence also suggests significant involvement of histamine in Parkinson’s disease (PD), where dopaminergic neurons degenerate. To further investigate histamine-dopamine interactions, particularly in the context of PD, a genetic lack of histamine and a mouse model of PD and levodopa-induced dyskinesia were here combined. Dopaminergic lesions were induced in histidine decarboxylase knockout and wildtype mice by 6-hydroxydopamine injections into the medial forebrain bundle. Post-lesion motor dysfunction was studied by measuring drug-induced rotational behavior and dyskinesia. Striatal tissue from both lesioned and naïve animals was used to investigate dopaminergic, serotonergic and histaminergic biomarkers. Histamine deficiency increased amphetamine-induced rotation but did not affect levodopa-induced dyskinesia. qPCR measurements revealed increased striatal expression of D1 and D2 receptor, DARPP-32, and H3 receptor mRNA, and synaptosomal release experiments in naïve mice indicated increased dopamine release. A lack of histamine thus causes pre- and postsynaptic upregulation of striatal dopaminergic neurotransmission which may be reflected in post-lesion motor behavior. Disturbances or manipulations of the histaminergic system may thus have significant consequences for dopaminergic neurotransmission and motor behavior in both healthy and disease conditions. The findings also represent new evidence for the complex interplay between dopamine and histamine within the nigrostriatal pathway.
  • Montonen, Risto; Kassamakov, Ivan; Lehmann, Peter; Österberg, Kenneth; Haeggström, Edward (2018)
    The group refractive index is important in length calibration of Fourier domain interferometers by transparent transfer standards. We demonstrate accurate group refractive index quantification using a Fourier domain short coherence Sagnac interferometer. Because of a justified linear length calibration function, the calibration constants cancel out in the evaluation of the group refractive index, which is then obtained accurately from two uncalibrated lengths. Measurements of two standard thickness coverslips revealed group indices of 1.5426 +/- 0.0042 and 1.5434 +/- 0.0046, with accuracies quoted at the 95% confidence level. This agreed with the dispersion data of the coverslip manufacturer and therefore validates our method. Our method provides a sample specific and accurate group refractive index quantification using the same Fourier domain interferometer that is to be calibrated for the length. This reduces significantly the requirements of the calibration transfer standard. (C) 2018 Optical Society of America
  • Nagaeva, Elina; Zubarev, Ivan; Gonzales, Carolina Bengtsson; Forss, Mikko; Nikouei, Kasra; de Miguel, Elena; Elsilä, Lauri; Linden, Anni-Maija; Hjerling-Leffler, Jens; Augustine, George J.; Korpi, Esa R. (2020)
    The cellular architecture of the ventral tegmental area (VTA), the main hub of the brain reward system, remains only partially characterized. To extend the characterization to inhibitory neurons, we have identified three distinct subtypes of somatostatin (Sst)-expressing neurons in the mouse VTA. These neurons differ in their electrophysiological and morphological properties, anatomical localization, as well as mRNA expression profiles. Importantly, similar to cortical Sst-containing interneurons, most VTA Sst neurons express GABAergic inhibitory markers, but some of them also express glutamatergic excitatory markers and a subpopulation even express dopaminergic markers. Furthermore, only some of the proposed marker genes for cortical Sst neurons were expressed in the VTA Sst neurons. Physiologically, one of the VTA Sst neuron subtypes locally inhibited neighboring dopamine neurons. Overall, our results demonstrate the remarkable complexity and heterogeneity of VTA Sst neurons and suggest that these cells are multifunctional players in the midbrain reward circuitry.
  • Lobier, Muriel; Palva, J. Matias; Palva, Satu (2018)
    Visuospatial attention prioritizes processing of attended visual stimuli. It is characterized by lateralized alpha-band (8-14 Hz) amplitude suppression in visual cortex and increased neuronal activity in a network of frontal and parietal areas. It has remained unknown what mechanisms coordinate neuronal processing among frontoparietal network and visual cortices and implement the attention-related modulations of alpha-band amplitudes and behavior. We investigated whether large-scale network synchronization could be such a mechanism. We recorded human cortical activity with magnetoencephalography (MEG) during a visuospatial attention task. We then identified the frequencies and anatomical networks of inter-areal phase synchronization from source localized MEG data. We found that visuospatial attention is associated with robust and sustained long-range synchronization of cortical oscillations exclusively in the high-alpha (10-14 Hz) frequency band. This synchronization connected frontal, parietal and visual regions and was observed concurrently with amplitude suppression of low-alpha (6-9 Hz) band oscillations in visual cortex. Furthermore, stronger high-alpha phase synchronization was associated with decreased reaction times to attended stimuli and larger suppression of alpha-band amplitudes. These results thus show that high-alpha band phase synchronization is functionally significant and could coordinate the neuronal communication underlying the implementation of visuospatial attention.
  • Jian, Ching; Luukkonen, Panu; Sädevirta, Sanja; Yki-Järvinen, Hannele; Salonen, Anne (2021)
    Backgrounds & aims: Intestinal microbiota may be causally involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). We aimed to study the effect of short-term overfeeding on human gut microbiota in relation to baseline and overfeeding-induced liver steatosis. We also asked whether the baseline microbiota composition is associated to the overfeeding-induced increase in liver fat. Methods: In a randomized trial, 38 overweight and obese subjects were assigned to consume an excess of 1000 kcal/day of diets rich in either saturated fat, unsaturated fat, or simple sugars for 3 weeks. Fasting blood samples and H-1-MR spectroscopy were used for extensive clinical phenotyping as previously reported (PMID: 29844096). Fecal samples were collected for the analysis of the gut microbiota using 16S rRNA amplicon sequencing, imputed metagenomics and qPCR. Microbiota results were correlated with dietary intakes and clinical measurements before and during overfeeding. Results: The overall community structure of the microbiota remained highly stable and personalized during overfeeding based on between-sample Bray-Curtis dissimilarity, but the relative abundances of individual taxa were altered in a diet-specific manner: overfeeding saturated fat increased Proteobacteria, while unsaturated fat increased butyrate producers. Sugar overfeeding increased Lactococcus and Escherichia coli. Imputed functions of the gut microbiota were not affected by overfeeding. Several taxa affected by overfeeding significantly correlated with the changes in host metabolic markers. The baseline levels of proteobacterial family Desulfovibrionaceae, and especially genus Bilophila, were significantly associated to overfeeding-induced liver fat increase independently of the diet arm. In general, limited overlap was observed between the overfeeding-induced microbiota changes and the liver fat-associated microbiota features at baseline. Conclusions: Our work indicates that the human gut microbiota is resilient to short-term overfeeding on community level, but specific taxa are altered on diet composition-dependent manner. Generalizable microbiota signatures directly associated with liver steatosis could not be identified. Instead, the carriage of Bilophila was identified as a potential novel risk factor for diet-induced liver steatosis in humans. (C) 2020 Published by Elsevier Ltd.
  • Kirss, Jaan; Pinta, Tarja; Rautio, Tero; Varpe, Pirita; Kairaluoma, Matti; Hyöty, Marja; Hurme, Saija; Böckelman, Camilla; Kairaluoma, Valtteri; Salmenkylä, Sinikka; Victorzon, Mikael (2018)
    PurposeThe aim of this multicentre study was to analyse the effects of patent sphincter lesions and previous sphincter repair on the results of sacral neuromodulation (SNM) treatment on patients with faecal incontinence (FI).MethodsPatients examined by endoanal ultrasound (EAUS) with FI as the indication for SNM treatment were included in the study. Data was collected from all the centres providing SNM treatment in Finland and analysed for differences in treatment outcomes.ResultsA total of 237 patients treated for incontinence with SNM had been examined by EAUS. Of these patients, 33 had a history of previous delayed sphincter repair. A patent sphincter lesion was detected by EAUS in 128 patients. The EAUS finding did not influence the SNM test phase outcome (p=0.129) or the final treatment outcome (p=0.233). Patient's history of prior sphincter repair did not have a significant effect on the SNM test (p=0.425) or final treatment outcome (p=0.442).ConclusionsResults of our study indicate that a sphincter lesion or previous sphincter repair has no significant effect on the outcome of SNM treatment. Our data suggests that delayed sphincter repair prior to SNM treatment initiation for FI is not necessary.
  • Wikman, Patrik; Rinne, Teemu (2019)
    A number of previous studies have implicated regions in posterior auditory cortex (AC) in auditory-motor integration during speech production. Other studies, in turn, have shown that activation in AC and adjacent regions in the inferior parietal lobule (IPL) is strongly modulated during active listening and depends on task requirements. The present fMRI study investigated whether auditory-motor effects interact with those related to active listening tasks in AC and IPL. In separate task blocks, our subjects performed either auditory discrimination or 2-back memory tasks on phonemic or nonphonemic vowels. They responded to targets by either overtly repeating the last vowel of a target pair, overtly producing a given response vowel, or by pressing a response button. We hypothesized that the requirements for auditory-motor integration, and the associated activation, would be stronger during repetition than production responses and during repetition of nonphonemic than phonemic vowels. We also hypothesized that if auditory-motor effects are independent of task-dependent modulations, then the auditory-motor effects should not differ during discrimination and 2-back tasks. We found that activation in AC and IPL was significantly modulated by task (discrimination vs. 2-back), vocal-response type (repetition vs. production), and motor-response type (vocal vs. button). Motor-response and task effects interacted in IPL but not in AC. Overall, the results support the view that regions in posterior AC are important in auditory-motor integration. However, the present study shows that activation in wide AC and IPL regions is modulated by the motor requirements of active listening tasks in a more general manner. Further, the results suggest that activation modulations in AC associated with attention-engaging listening tasks and those associated with auditory-motor performance are mediated by independent mechanisms.
  • Kringel, Dario; Kaunisto, Mari A.; Kalso, Eija; Lötsch, Jörn (2019)
    Cancer and its surgical treatment are among the most important triggering events for persistent pain, but additional factors need to be present for the clinical manifestation, such as variants in pain-relevant genes. In a cohort of 140 women undergoing breast cancer surgery, assigned based on a 3-year follow-up to either a persistent or nonpersistent pain phenotype, next-generation sequencing was performed for 77 genes selected for known functional involvement in persistent pain. Applying machine-learning and item categorization techniques, 21 variants in 13 different genes were found to be relevant to the assignment of a patient to either the persistent pain or the nonpersistent pain phenotype group. In descending order of importance for correct group assignment, the relevant genes comprised DRD1, FAAH, GCH1, GPR132, OPRM1, DRD3, RELN, GABRA5, NF1, COMT, TRPA1, ABHD6, and DRD4, of which one in the DRD4 gene was a novel discovery. Particularly relevant variants were found in the DRD1 and GPR132 genes, or in a cis-eCTL position of the OPRM1 gene. Supervised machine-learning-based classifiers, trained with 2/3 of the data, identified the correct pain phenotype group in the remaining 1/3 of the patients at accuracies and areas under the receiver operator characteristic curves of 65% to 72%. When using conservative classical statistical approaches, none of the variants passed α-corrected testing. The present data analysis approach, using machine learning and training artificial intelligences, provided biologically plausible results and outperformed classical approaches to genotype-phenotype association.
  • Koroleva, Ksenia; Gafurov, Oleg; Guselnikova, Valeriia; Nurkhametovez, Dilyara; Giniatullina, Raisa; Sitdikova, Guzel; Mattila, Olli S.; Lindsberg, Perttu J.; Malm, Tarja Maarit; Giniatullin, Rashid (2019)
    Peripheral mechanisms of primary headaches such as a migraine remain unclear. Meningeal afferents surrounded by multiple mast cells have been suggested as a major source of migraine pain. Extracellular ATP released during migraine attacks is a likely candidate for activating meningeal afferents via neuronal P2X receptors. Recently, we showed that ATP also increased degranulation of resident meningeal mast cells (Nurkhametova et al., 2019). However, the contribution of ATP-induced mast cell degranulation in aggravating the migraine pain remains unknown. Here we explored the role of meningeal mast cells in the pro-nociceptive effects of extracellular ATP. The impact of mast cells on ATP mediated activation of peripheral branches of trigeminal nerves was measured electrophysiologically in the dura mater of adult wild type (WT) or mast cell deficient mice. We found that a spontaneous spiking activity in the meningeal afferents, at baseline level, did not differ in two groups. However, in WT mice, meningeal application of ATP dramatically (24.6-fold) increased nociceptive firing, peaking at frequencies around 10 Hz. In contrast, in mast cell deficient animals, ATP-induced excitation was significantly weaker (3.5-fold). Application of serotonin to meninges in WT induced strong spiking. Moreover, in WT mice, the 5-HT3 antagonist MDL-7222 inhibited not only serotonin but also the ATP induced nociceptive firing. Our data suggest that extracellular ATP activates nociceptive firing in meningeal trigeminal afferents via amplified degranulation of resident mast cells in addition to direct excitatory action on the nerve terminals. This highlights the importance of mast cell degranulation via extracellular ATP, in aggravating the migraine pain.