Browsing by Subject "STIMULATION"

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  • Kallio, Eeva-Liisa; Öhman, Hanna; Kautiainen, Hannu; Hietanen, Marja; Pitkala, Kaisu (2017)
    Background: Cognitive training (CT) refers to guided cognitive exercises designed to improve specific cognitive functions, as well as enhance performance in untrained cognitive tasks. Positive effects of CT on cognitive functions in healthy elderly people and persons with mild cognitive impairment have been reported, but data regarding the effects of CT in patients with dementia is unclear. Objective: We systematically reviewed the current evidence from randomized controlled trials (RCTs) to find out if CT improves or stabilizes cognition and/or everyday functioning in patients with mild and moderate Alzheimer's disease. Results: Altogether, 31 RCTs with CT as either the primary intervention or part of a broader cognitive or multi-component intervention were found. A positive effect was reported in 24 trials, mainly on global cognition and training-specific tasks, particularly when more intensive or more specific CT programs were used. Little evidence of improved everyday functioning was found. Conclusions: Despite some positive findings, the inaccurate definitions of CT, inadequate sample sizes, unclear randomization methods, incomplete datasets at follow-up and multiple testing may have inflated the results in many trials. Future high quality RCTs with appropriate classification and specification of cognitive interventions are necessary to confirm CT as an effective treatment option in Alzheimer's disease.
  • Kovacs, Zsuzsanna Z. A.; Szucs, Gergo; Freiwan, Marah; Kovacs, Monika G.; Marvanykovi, Fanni M.; Hoa Dinh; Siska, Andrea; Farkas, Katalin; Kovacs, Ferenc; Kriston, Andras; Horvath, Peter; Kovari, Bence; Cserni, Balint Gabor; Cserni, Gabor; Foldesi, Imre; Csont, Tamas; Sarkozy, Marta (2021)
    Uremic cardiomyopathy is characterized by diastolic dysfunction (DD), left ventricular hypertrophy (LVH), and fibrosis. Angiotensin-II plays a major role in the development of uremic cardiomyopathy via nitro-oxidative and inflammatory mechanisms. In heart failure, the beta-3 adrenergic receptor (beta 3-AR) is up-regulated and coupled to endothelial nitric oxide synthase (eNOS)-mediated pathways, exerting antiremodeling effects. We aimed to compare the antiremodeling effects of the angiotensin-II receptor blocker losartan and the beta 3-AR agonist mirabegron in uremic cardiomyopathy. Chronic kidney disease (CKD) was induced by 5/6th nephrectomy in male Wistar rats. Five weeks later, rats were randomized into four groups: (1) sham-operated, (2) CKD, (3) losartan-treated (10 mg/kg/day) CKD, and (4) mirabegron-treated (10 mg/kg/day) CKD groups. At week 13, echocardiographic, histologic, laboratory, qRT-PCR, and Western blot measurements proved the development of uremic cardiomyopathy with DD, LVH, fibrosis, inflammation, and reduced eNOS levels, which were significantly ameliorated by losartan. However, mirabegron showed a tendency to decrease DD and fibrosis; but eNOS expression remained reduced. In uremic cardiomyopathy, beta 3-AR, sarcoplasmic reticulum ATPase (SERCA), and phospholamban levels did not change irrespective of treatments. Mirabegron reduced the angiotensin-II receptor 1 expression in uremic cardiomyopathy that might explain its mild antiremodeling effects despite the unchanged expression of the beta 3-AR.
  • Kohtala, Henrik Samuel; Theilmann, Wiebke; Rosenholm, Marko; Penna, Leena; Karabulut, Gulsum; Uusitalo, Salla; Järventausta, Kaija; Yli-Hankala, Arvi; Yalcin, Ipek; Matsui, Nobuaki; Wigren, Henna-Kaisa; Rantamäki, Tomi (2019)
    Rapid antidepressant effects of ketamine become most evident when its psychotomimetic effects subside, but the neurobiological basis of this lag remains unclear. Laughing gas (N2O), another NMDA-R (N-methyl-d-aspartate receptor) blocker, has been reported to bring antidepressant effects rapidly upon drug discontinuation. We took advantage of the exceptional pharmacokinetic properties of N2O to investigate EEG (electroencephalogram) alterations and molecular determinants of antidepressant actions during and immediately after NMDA-R blockade. Effects of the drugs on brain activity were investigated in C57BL/6 mice using quantitative EEG recordings. Western blot and qPCR were used for molecular analyses. Learned helplessness (LH) was used to assess antidepressant-like behavior. Immediate-early genes (e.g., bdnf) and phosphorylation of mitogen-activated protein kinasemarkers of neuronal excitabilitywere upregulated during N2O exposure. Notably, phosphorylation of BDNF receptor TrkB and GSK3 (glycogen synthase kinase 3) became regulated only gradually upon N2O discontinuation, during a brain state dominated by slow EEG activity. Subanesthetic ketamine and flurothyl-induced convulsions (reminiscent of electroconvulsive therapy) also evoked slow oscillations when their acute pharmacological effects subsided. The correlation between ongoing slow EEG oscillations and TrkB-GSK3 signaling was further strengthened utilizing medetomidine, a hypnotic-sedative agent that facilitates slow oscillations directly through the activation of (2)-adrenergic autoreceptors. Medetomidine did not, however, facilitate markers of neuronal excitability or produce antidepressant-like behavioral changes in LH. Our results support a hypothesis that transient cortical excitability and the subsequent regulation of TrkB and GSK3 signaling during homeostatic emergence of slow oscillations are critical components for rapid antidepressant responses.
  • Egashira, Yuka; Kaga, Yoshimi; Gunji, Atsuko; Kita, Yosuke; Kimura, Motohiro; Hironaga, Naruhito; Takeichi, Hiroshige; Hayashi, Sayuri; Kaneko, Yuu; Takahashi, Hidetoshi; Hanakawa, Takashi; Okada, Takashi; Inagaki, Masumi (2022)
    Reading fluency is based on the automatic visual recognition of words. As a manifestation of the automatic processing of words, an automatic deviance detection of visual word stimuli can be observed in the early stages of visual recognition. To clarify whether this phenomenon occurs with Japanese kanji compounds-since their lexicality is related to semantic association-we investigated the brain response by utilizing three types of deviants: differences in font type, lexically correct or incorrect Japanese kanji compound words and pseudo-kanji characters modified from correct and incorrect compounds. We employed magnetoencephalography (MEG) to evaluate the spatiotemporal profiles of the related brain regions. The study included 22 adult native Japanese speakers (16 females). The abovementioned three kinds of stimuli containing 20% deviants were presented during the MEG measurement. Activity in the occipital pole region of the brain was observed upon the detection of font-type deviance within 250 ms of stimulus onset. Although no significant activity upon detecting lexically correct/incorrect kanji compounds or pseudo-kanji character deviations was observed, the activity in the posterior transverse region of the collateral sulcus (pCoS)-which is a fusiform neighboring area-was larger when detecting lexically correct kanji compounds than when detecting pseudo-kanji characters. Taken together, these results support the notion that the automatic detection of deviance in kanji compounds may be limited to a low-level feature, such as the stimulus stroke thickness.
  • Pyykko, Ilmari; Manchaiah, Vinaya; Zou, Jing; Levo, Hilla; Kentala, Erna (2017)
    The aim of the present study was to evaluate the prevalence and associated factors for syncope among patients with Meniere's disease (MD). An attack of syncope was defined as a sudden and transient loss of consciousness, which subsides spontaneously and without a localizing neurological deficit. The study used an across-sectional survey design. Information from a database consisting of 961 individuals was collected from the Finnish Meniere Association. The data contained case histories, general health-related quality of life (HRQoL), and impact measurements of the complaints. In the current study sample, syncope occurred in 12.3% of the patients with MD. It was more prevalent among elderly persons and among those with a longer duration of MD. Syncope was significantly associated with disturbances of otolith function reflected as Tumarkin attacks, gait and balance problems, environmental change of pressure, and physical strain. It was also associated with visual blurring; in fact, patients with otolith dysfunction in MD often experience visual field changes. It was also associated with headache, but not with migraine. Syncope was experienced as frightening and HRQoL was significantly worsened. The patient had higher anxiety scores, and suffered more from fatigue. The results demonstrate that neurally mediated syncope occurs in patients with an advanced form of MD who suffer from Tumarkin attacks due to failure in otolith function. The mechanism seems to be triggered through the vestibular sympathetic reflex when the otolith system fails due to disrupted utricular otolithic membrane mediate erroneous positional information from the otolith organ to the vasomotor centres in the brain stem and medulla.
  • Markkanen, Helene M.; Pekkarinen, Tuula; Hamalainen, Esa; Valimaki, Matti J.; Alfthan, Henrik V.; Stenman, Ulf-Hakan (2017)
    Objective: Data on the effect of gender on the interpretation of the GHRH plus arginine stimulation test (GHRH + ARG test) is controversial. We validated the GHRH + ARG stimulation test in control subjects and patients with organic or idiopathic pituitary disease and a suspicion of adult growth hormone deficiency (AGHD) using the Immulite 2000 XPi GH assay. Design: We studied 126 apparently healthy adults (median age 38.8 years) and 34 patients with a suspicion of AGHD (median age 42.2 years). Identification of AGHD with the GHRH + ARG test was investigated with commonly accepted BMI-related consensus cut-off limits for peak GH concentrations. Serum samples collected during the GHRH + ARG test were analysed for GH in 2014-2015. Serum IGF-1 concentrations were studied as a reference. Results: In 14 of 65 (22%) control males the GH peak value was below the BMI-related cut-off limits for GH sufficiency indicating a false diagnosis of AGHD. All control females had a normal GHRH + ARG response. Median peak GH response was significantly (p <0.001) higher in female (39.3 mu g/L) than in male controls (21 mu g/L). According to consensus cut-offs all but one young female patient had a deficient response compatible with a diagnosis of AGHD. Conclusions: The GH response to stimulation by GHRH + ARG is gender-dependent, being lower in healthy males than in females. Gender should be considered when defining cut-off limits for peak GH concentrations in the GHRH + ARG test. The presently used BMI-related cut-off levels will lead to a significant misclassification of males as GH deficient.
  • 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.
  • Harjunen, Ville Johannes; Sjö, Petja; Ahmed, Imtiaj; Saarinen, Aino; Farmer, Harry; Salminen, Mikko; Järvelä, Simo; Ruonala, Antti; Jacucci, Giulio; Ravaja, Niklas (2022)
    The tendency to simulate the pain of others within our own sensorimotor systems is a vital component of empathy. However, this sensorimotor resonance is modulated by a multitude of social factors including similarity in bodily appearance, e.g. skin colour. The current study investigated whether increasing self–other similarity via virtual transfer to another colour body reduced ingroup bias in sensorimotor resonance. A sample of 58 white participants was momentarily transferred to either a black or a white body using virtual reality technology. We then employed electroencephalography to examine event-related desynchronization (ERD) in the sensorimotor beta (13–23 Hz) oscillations while they viewed black, white and violet photorealistic virtual agents being touched with a noxious or soft object. While the noxious treatment of a violet agent did not increase beta ERD, amplified beta ERD in response to black agent’s noxious vs soft treatment was found in perceivers transferred to a black body. Transfer to the white body dismissed the effect. Further exploratory analysis implied that the pain-related beta ERD occurred only when the agent and the participant were of the same colour. The results suggest that even short-lasting changes in bodily resemblance can modulate sensorimotor resonance to others’ perceived pain.
  • Freiwan, Marah; Kovacs, Monika G.; Kovacs, Zsuzsanna Z. A.; Szucs, Gergo; Hoa Dinh; Losonczi, Reka; Siska, Andrea; Kriston, Andras; Kovacs, Ferenc; Horvath, Peter; Foldesi, Imre; Cserni, Gabor; Dux, Laszlo; Csont, Tamas; Sarkozy, Marta (2022)
    Despite the effectiveness of doxorubicin (DOXO) as a chemotherapeutic agent, dose-dependent development of chronic cardiotoxicity limits its application. The angiotensin-II receptor blocker losartan is commonly used to treat cardiac remodeling of various etiologies. The beta-3 adrenergic receptor agonist mirabegron was reported to improve chronic heart failure. Here we investigated the effects of losartan, mirabegron and their combination on the development of DOXO-induced chronic cardiotoxicity. Male Wistar rats were divided into five groups: (i) control; (ii) DOXO-only; (iii) losartan-treated DOXO; (iv) mirabegron-treated DOXO; (v) losartan plus mirabegron-treated DOXO groups. The treatments started 5 weeks after DOXO administration. At week 8, echocardiography was performed. At week 9, left ventricles were prepared for histology, qRT-PCR, and Western blot measurements. Losartan improved diastolic but not systolic dysfunction and ameliorated SERCA2a repression in our DOXO-induced cardiotoxicity model. The DOXO-induced overexpression of Il1 and Il6 was markedly decreased by losartan and mirabegron. Mirabegron and the combination treatment improved systolic and diastolic dysfunction and significantly decreased overexpression of Smad2 and Smad3 in our DOXO-induced cardiotoxicity model. Only mirabegron reduced DOXO-induced cardiac fibrosis significantly. Mirabegron and its combination with losartan seem to be promising therapeutic tools against DOXO-induced chronic cardiotoxicity.
  • Bourbia, N.; Pertovaara, A. (2018)
    Here we studied whether descending control of mechanical nociception by glutamate in the central nucleus of the amygdala (CeA) of healthy control animals is induced by amygdaloid NMDA receptors and relayed through the midbrain periaqueductal gray (PAG). Mechanical nociception in the hind paws was assessed in rats with chronic guide cannulae for glutamate administration in the right CeA and for inducing local anesthesia in the PAG. In a separate electrophysiological study, ON-like PAG neurons giving an excitatory response to noxious pinch of the tail were recorded in anesthetized rats following glutamate administration into the CeA. A high dose of glutamate (100 mu g) in the CeA induced mechanical antinociception in the contra- but not ipsilateral hind limb. Antinociception was prevented by an NMDA receptor antagonist in the CeA or local anesthesia of the PAG. Discharge rate of ON-like PAG neurons was increased by a high dose of glutamate (100 mu g) in the CeA and this increase was prevented by an NMDA receptor antagonist in the CeA. The results indicate that amygdaloid NMDA receptors in the CeA may induce contralaterally mechanical antinociception through a circuitry relaying in the PAG. Activation of ON-like PAG neurons is associated with the descending antinociceptive effect. Mechanisms and causality of this association still remain to be studied.
  • Boldt, Robert; Malinen, Sanna; Seppa, Mika; Tikka, Pia; Savolainen, Petri Ilmari; Hari, Riitta; Carlson, Synnöve (2013)
  • Satomaa, Anna-Liisa; Saarenpaa-Heikkila, Outi; Huupponen, Eero; Kirjavainen, Turkka; Heinonen, Juhani; Himanen, Sari-Leena (2018)
    Objective: Deep NREM sleep and its hallmark EEG phenomenon slow wave activity (SWA) are under homeostatic control in adults. SWA is also locally regulated as it increases in the brain areas that have been used intensively. Moreover, in children, SWA is a marker of cortical maturation. In the present study the local properties of NREM sleep depth were evaluated using the quantitative mean frequency method. We aimed to study if age is related to NREM sleep depth in young infants. In addition, we studied if young infants have local differences in their NREM sleep. Methods: Ambulatory over-night polysomnographies were recorded in 59 healthy and full-term infants at the age of one month. The infants were divided into two age groups (= 44 weeks) to allow maturational evaluations. Results: The quantitative sleep depth analysis showed differences between the age groups. In addition, there were local sleep depth differences within the age groups. Conclusions: The sleep depth change with age is most likely related to cortical maturation, whereas the local sleep depth gradients might also reflect the use-dependent properties of SWA. (C) 2017 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
  • Belz, Regina G.; Sinkkonen, Aki (2021)
    BACKGROUND Low toxin doses that do not affect mean responses in plant populations can still change the growth of subpopulations. Studies covering vegetative stages ascribed fast-growing plants higher thresholds for growth stimulation and inhibition, compared with the rest of the population. We hypothesized that such selective effects also play a role after reproduction; that is, the offspring of glyphosate-treated tolerant, fast-growing phenotypes is more tolerant than the offspring of untreated plants. An experimental, high-density barley population was exposed to a range of glyphosate concentrations in the greenhouse, and reproduction and final growth were analyzed for selective effects. Therefore, F0, F1 treated and F1 non-treated offspring were re-exposed to glyphosate. RESULTS Low doses of glyphosate inhibited the growth and reproduction of slow-growing plants at concentrations that did not change the population mean. Concentrations that inhibited average-sized plants hormetically increased the biomass and seed yield of fast-growing plants. Compared with F0 and F1 non-treated offspring, F1-treated offspring from hormetically stimulated fast-growing plants were more glyphosate tolerant. Hence, a pesticide can shape the reproductive pattern of a plant population and alter offspring tolerance at concentrations that have no effect on average yield. CONCLUSIONS Toxin levels that do not change the population mean still alter the reproductive output of individuals. Sensitive phenotypes suffer, whereas the reproduction of tolerant phenotypes is boosted compared with toxin-free conditions. Because glyphosate is one of the leading herbicides in the world, tolerant phenotypes may benefit from current agricultural practices. If these results apply to other toxicants, low toxin doses may increase the fitness of tolerant phenotypes in a way not previously anticipated.
  • Houssari, Mahmoud; Dumesnil, Anais; Tardif, Virginie; Kivela, Riikka; Pizzinat, Nathalie; Boukhalfa, Ines; Godefroy, David; Schapman, Damien; Hemanthakumar, Karthik A.; Bizou, Mathilde; Henry, Jean-Paul; Renet, Sylvanie; Riou, Gaetan; Rondeaux, Julie; Anouar, Youssef; Adriouch, Sahil; Fraineau, Sylvain; Alitalo, Kari; Richard, Vincent; Mulder, Paul; Brakenhielm, Ebba (2020)
    Objective: Lymphatics play an essential pathophysiological role in promoting fluid and immune cell tissue clearance. Conversely, immune cells may influence lymphatic function and remodeling. Recently, cardiac lymphangiogenesis has been proposed as a therapeutic target to prevent heart failure after myocardial infarction (MI). We investigated the effects of gene therapy to modulate cardiac lymphangiogenesis post-MI in rodents. Second, we determined the impact of cardiac-infiltrating T cells on lymphatic remodeling in the heart. Approach and Results: Comparing adenoviral versus adeno-associated viral gene delivery in mice, we found that only sustained VEGF (vascular endothelial growth factor)-C(C156S)therapy, achieved by adeno-associated viral vectors, increased cardiac lymphangiogenesis, and led to reduced cardiac inflammation and dysfunction by 3 weeks post-MI. Conversely, inhibition of VEGF-C/-D signaling, through adeno-associated viral delivery of soluble VEGFR3 (vascular endothelial growth factor receptor 3), limited infarct lymphangiogenesis. Unexpectedly, this treatment improved cardiac function post-MI in both mice and rats, linked to reduced infarct thinning due to acute suppression of T-cell infiltration. Finally, using pharmacological, genetic, and antibody-mediated prevention of cardiac T-cell recruitment in mice, we discovered that both CD4(+)and CD8(+)T cells potently suppress, in part through interferon-gamma, cardiac lymphangiogenesis post-MI. Conclusions: We show that resolution of cardiac inflammation after MI may be accelerated by therapeutic lymphangiogenesis based on adeno-associated viral gene delivery of VEGF-C-C156S. Conversely, our work uncovers a major negative role of cardiac-recruited T cells on lymphatic remodeling. Our results give new insight into the interconnection between immune cells and lymphatics in orchestration of cardiac repair after injury.
  • Muhammad, Sajjad; Lehecka, Martin; Huhtakangas, Justiina; Jahromi, Behnam Rezai; Niemelä, Mika; Hafez, Ahmad (2019)
    BackgroundNeurosurgeons are vulnerable to additional noise in their natural operating environment. Noise exposure is associated with reduced cognitive function, inability to concentrate, and nervousness. Mediation music provides an opportunity to create a calmer environment which may reduce stress during surgery.MethodsA pilot study was performed to find a suitable task, meditation music of surgeon's choice, and operation noise and to reach a certain level of training. For the main experiment, two neurosurgeons with different microsurgical experience used real operation noise and meditation music with delta waves as mediating music. Each surgeon performed 10 training bypasses (five with noise and five with music) with 16 stitches in each bypass. The total time to complete 16 stitches, a number of unachieved movements (N.U.Ms), length of thread consumed, and distribution of the stitches were quantified from the recorded videos and compared in both groups.ResultsA N.U.Ms were significantly reduced from 10938 with operation room (OR) noise to 38 +/- 13 (p
  • Imbery, Carolin Anna; Dieterle, Frank; Ottka, Claudia; Weber, Corinna; Schlotterbeck, Götz; Müller, Elisabeth; Lohi, Hannes; Giger, Urs (2022)
    The adrenal glands play a major role in metabolic processes, and both excess and insufficient serum cortisol concentrations can lead to serious metabolic consequences. Hyper- and hypoadrenocorticism represent a diagnostic and therapeutic challenge. Serum samples from dogs with untreated hyperadrenocorticism (n = 27), hyperadrenocorticism undergoing treatment (n = 28), as well as with untreated (n = 35) and treated hypoadrenocorticism (n = 23) were analyzed and compared to apparently healthy dogs (n = 40). A validated targeted proton nuclear magnetic resonance (H-1 NMR) platform was used to quantify 123 parameters. Principal component analysis separated the untreated endocrinopathies. The serum samples of dogs with untreated endocrinopathies showed various metabolic abnormalities with often contrasting results particularly in serum concentrations of fatty acids, and high- and low-density lipoproteins and their constituents, which were predominantly increased in hyperadrenocorticism and decreased in hypoadrenocorticism, while amino acid concentrations changed in various directions. Many observed serum metabolic abnormalities tended to normalize with medical treatment, but normalization was incomplete when compared to levels in apparently healthy dogs. Application of machine learning models based on the metabolomics data showed good classification, with misclassifications primarily observed in treated groups. Characterization of metabolic changes enhances our understanding of these endocrinopathies. Further assessment of the recognized incomplete reversal of metabolic alterations during medical treatment may improve disease management.
  • Shah, Disheet; Virtanen, Laura; Prajapati, Chandra; Kiamehr, Mostafa; Gullmets, Josef; West, Gun; Kreutzer, Joose; Pekkanen-Mattila, Mari; Heliö, Tiina; Kallio, Pasi; Taimen, Pekka; Aalto-Setälä, Katriina (2019)
    Dilated cardiomyopathy (DCM) is one of the leading causes of heart failure and heart transplantation. A portion of familial DCM is due to mutations in the LMNA gene encoding the nuclear lamina proteins lamin A and C and without adequate treatment these patients have a poor prognosis. To get better insights into pathobiology behind this disease, we focused on modeling LMNA-related DCM using human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM). Primary skin fibroblasts from DCM patients carrying the most prevalent Finnish founder mutation (p.S143P) in LMNA were reprogrammed into hiPSCs and further differentiated into cardiomyocytes (CMs). The cellular structure, functionality as well as gene and protein expression were assessed in detail. While mutant hiPSC-CMs presented virtually normal sarcomere structure under normoxia, dramatic sarcomere damage and an increased sensitivity to cellular stress was observed after hypoxia. A detailed electrophysiological evaluation revealed bradyarrhythmia and increased occurrence of arrhythmias in mutant hiPSC-CMs on beta -adrenergic stimulation. Mutant hiPSC-CMs also showed increased sensitivity to hypoxia on microelectrode array and altered Ca2+ dynamics. Taken together, p.S143P hiPSC-CM model mimics hallmarks of LMNA-related DCM and provides a useful tool to study the underlying cellular mechanisms of accelerated cardiac degeneration in this disease.
  • Ludwig, Anastasia; Kesaf, Sebnem; Heikkinen, Joonas; Sukhanova, Tatiana; Khakipoor, Shokoufeh; Molinari, Florence; Pellegrino, Christophe; Kim, Sung I.; Han, Jeon G.; Huttunen, Henri J.; Lauri, Sari E.; Franssila, Sami; Jokinen, Ville; Rivera, Claudio (2020)
    Different types of carbon materials are biocompatible with neural cells and can promote maturation. The mechanism of this effect is not clear. Here we have tested the capacity of a carbon material composed of amorphous sp3 carbon backbone, embedded with a percolating network of sp2 carbon domains to sustain neuronal cultures. We found that cortical neurons survive and develop faster on this novel carbon material. After 3 days in culture, there is a precocious increase in the frequency of neuronal activity and in the expression of maturation marker KCC2 on carbon films as compared to a commonly used glass surface. Accelerated development is accompanied by a dramatic increase in neuronal dendrite arborization. The mechanism for the precocious maturation involves the activation of intracellular calcium oscillations by the carbon material already after 1 day in culture. Carbon-induced oscillations are independent of network activity and reflect intrinsic spontaneous activation of developing neurons. Thus, these results reveal a novel mechanism for carbon material-induced neuronal survival and maturation.
  • Berg, Mika Erik Anthon; Naams, Jette-Britt; Hautala, Laura; Tolvanen, Tuomas; Ahonen, Jari; Lehtonen, Sanna; Wähälä, Kristiina (2020)
    A series of substituted sulfonanilide analogs were prepared and evaluated as novel potent inhibitors of SH2 domaincontaining inositol polyphosphate 5′-phosphatase 2 (SHIP2). SHIP2 has been shown to be a new attractive target for the treatment of insulin resistance in type 2 diabetes mellitus (T2D), which can lead to life-threatening diabetic kidney disease (DKD). Amongst the synthesized compounds, the two most promising candidates, 10 and 11, inhibited SHIP2 significantly. Additionally, these compounds induced Akt activation in a dose-dependent manner, increased the presence of glucose transporter 4 at the plasma membrane, and enhanced glucose uptake in cultured myotubes in vitro at lower concentrations than metformin, the most widely used antidiabetic drug. These results show that the novel SHIP2 inhibitors have insulin sensitizing capacity and provide prototypes for further drug development for T2D and DKD.
  • Bernardi, Luciano; Gordin, Daniel; Bordino, Marco; Rosengard-Barlund, Milla; Sandelin, Anna; Forsblom, Carol; Groop, Per-Henrik (2017)
    Hyperoxia and slow breathing acutely improve autonomic function in type-1 diabetes. However, their effects on arterial function may reveal different mechanisms, perhaps potentially useful. To test the effects of oxygen and slow breathing we measured arterial function (augmentation index, pulse wave velocity), baroreflex sensitivity (BRS) and oxygen saturation (SAT), during spontaneous and slow breathing (6 breaths/min), in normoxia and hyperoxia (5 L/min oxygen) in 91 type-1 diabetic and 40 age-matched control participants. During normoxic spontaneous breathing diabetic subjects had lower BRS and SAT, and worse arterial function. Hyperoxia and slow breathing increased BRS and SAT. Hyperoxia increased blood pressure and worsened arterial function. Slow breathing improved arterial function and diastolic blood pressure. Combined administration prevented the hyperoxia-induced arterial pressure and function worsening. Control subjects showed a similar pattern, but with lesser or no statistical significance. Oxygen-driven autonomic improvement could depend on transient arterial stiffening and hypertension (well-known irritative effect of free-radicals on endothelium), inducing reflex increase in BRS. Slow breathing-induced improvement in BRS may result from improved SAT, reduced sympathetic activity and improved vascular function, and/or parasympathetic-driven antioxidant effect. Lower oxidative stress could explain blunted effects in controls. Slow breathing could be a simple beneficial intervention in diabetes.