ORCID Profile
0000-0003-3159-6321
Current Organisations
University of Montreal
,
Friedreich's Ataxia Research Alliance
,
Universite de Montreal
,
University of Washington
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Publisher: Cold Spring Harbor Laboratory
Date: 02-01-2017
DOI: 10.1101/097295
Abstract: Neuroinflammation in utero may result in life-long neurological disabilities. Microglia play a pivotal role, but the mechanisms are poorly understood. No early postnatal treatment strategies exist to enhance neuroprotective potential of microglia. We hypothesized that agonism on α7 nicotinic acetylcholine receptor (α7nAChR) in fetal microglia will augment their neuroprotective transcriptome profile, while the antagonistic stimulation of α7nAChR will achieve the opposite. Using an in vivo - in vitro model of developmental programming of neuroinflammation induced by lipopolysaccharide (LPS), we validated this hypothesis in primary fetal sheep microglia cultures re-exposed to LPS in presence of a selective α7nAChR agonist or antagonist. Our RNAseq and protein level findings show that a pro-inflammatory microglial phenotype acquired in vitro by LPS stimulation is reversed with α7nAChR agonistic stimulation. Conversely, antagonistic α7nAChR stimulation potentiates the pro-inflammatory microglial phenotype. Surprisingly, under conditions of LPS double-hit an interference of a postulated α7nAChR - ferroportin signaling pathway may impede this mechanism. These results suggest a therapeutic potential of α7nAChR agonists in early re-programming of microglia in neonates exposed to in utero inflammation via an endogenous cerebral cholinergic anti-inflammatory pathway. Future studies will assess the role of interactions between inflammation-triggered microglial iron sequestering and α7nAChR signaling in neurodevelopment.
Publisher: IOP Publishing
Date: 19-08-2015
Publisher: Springer Science and Business Media LLC
Date: 06-09-2017
DOI: 10.1038/S41598-017-09439-Z
Abstract: Neuroinflammation in utero may result in life-long neurological disabilities. Microglia play a pivotal role, but the mechanisms are poorly understood. No early postnatal treatment strategies exist to enhance neuroprotective potential of microglia. We hypothesized that agonism on α7 nicotinic acetylcholine receptor (α7nAChR) in fetal microglia will augment their neuroprotective transcriptome profile, while the antagonistic stimulation of α7nAChR will achieve the opposite. Using an in vivo - in vitro model of developmental programming of neuroinflammation induced by lipopolysaccharide (LPS), we validated this hypothesis in primary fetal sheep microglia cultures re-exposed to LPS in presence of a selective α7nAChR agonist or antagonist. Our RNAseq and protein level findings show that a pro-inflammatory microglial phenotype acquired in vitro by LPS stimulation is reversed with α7nAChR agonistic stimulation. Conversely, antagonistic α7nAChR stimulation potentiates the pro-inflammatory microglial phenotype. Surprisingly, under conditions of LPS double-hit an interference of a postulated α7nAChR - ferroportin signaling pathway may impede this mechanism. These results suggest a therapeutic potential of α7nAChR agonists in early re-programming of microglia in neonates exposed to in utero inflammation via an endogenous cerebral cholinergic anti-inflammatory pathway. Future studies will assess the role of interactions between inflammation-triggered microglial iron sequestering and α7nAChR signaling in neurodevelopment.
Publisher: IOP Publishing
Date: 07-2019
Abstract: Fetal heart rate variability (fHRV) is an important indicator of health and disease, yet its physiological origins, neural contributions, in particular, are not well understood. We aimed to develop novel experimental and data analytical approaches to identify fHRV measures reflecting the vagus nerve contributions to fHRV. In near-term ovine fetuses, a comprehensive set of 46 fHRV measures was computed from fetal pre-cordial electrocardiogram recorded during surgery and 72 h later without (n = 24) and with intra-surgical bilateral cervical vagotomy (n = 15). The fetal heart rate did not change due to vagotomy. We identify fHRV measures specific to the vagal modulation of fHRV: multiscale time irreversibility asymmetry index (AsymI), detrended fluctuation analysis (DFA) α We provide a systematic delineation of vagal contributions to fHRV across signal-analytical domains which should be relevant for the emerging field of bioelectronic medicine and the deciphering of the 'vagus code'. Our findings also have clinical significance for in utero monitoring of fetal health during surgery. Key points •Fetal surgery causes a complex pattern of changes in heart rate variability measures with an overall reduction of complexity or variability. •At 72 h after surgery, many of the HRV measures recover and this recovery is delayed by an intrasurgical cervical bilateral vagotomy. •We identify HRV pattern representing complete vagal withdrawal that can be understood as part of 'HRV code', rather than any single HRV measure. •We identify HRV biomarkers of recovery from fetal surgery and discuss the effect of anticholinergic medication on this recovery.
Publisher: Elsevier BV
Date: 06-2011
Publisher: Public Library of Science (PLoS)
Date: 21-04-2016
Publisher: Springer New York
Date: 2018
DOI: 10.1007/978-1-4939-7828-1_18
Abstract: The non-neuronal, immunological effects of the cholinergic signaling are exerted on the system's scale of observation via the vagus nerve and on the cellular scale via α7 nicotinic acetylcholine receptor (nAChR) signaling in myeloid cells of the periphery or brain's microglia and astrocytes. The developmental effects of such multi-scale signaling can be conceived of as an ex le of psychoneuroimmunological (PNI) homeokinesis and, while reported in the literature, are not yet systematically well studied. To be better understood, the intricacy of the multi-scale interactions requires relevant preclinical animal models. Chronically instrumented non-anesthetized fetal sheep model comes with a strong track record of bench-to-bed translation and a large body of evidence for its strong resemblance to and relevance for human physiology on various scales of organization. Recently, there has been growing interest in pleiotropic effects of vagus nerve stimulation (VNS) on various organ systems such as innate immunity, metabolism, and emotion with implications for programming of PNI phenotype. Here we describe the procedures required to record and manipulate the vagus nerve activity in this large pregnant mammalian organism. Extending this in vivo model to in vitro, on the cellular scale, we present the method to manipulate the cholinergic signaling in ovine fetal microglia and astrocytes and analyze their responses on protein and RNA levels. Together these models can provide multi-scale-level mechanistic insights into the effects of cholinergic signaling on PNI phenotype.
Publisher: Frontiers Media SA
Date: 04-08-2015
Publisher: Frontiers Media SA
Date: 09-05-2019
Publisher: American Physiological Society
Date: 12-2018
DOI: 10.1152/AJPREGU.00391.2017
Abstract: Experimental studies that are relevant to human pregnancy rely on the selection of appropriate animal models as an important element in experimental design. Consideration of the strengths and weaknesses of any animal model of human disease is fundamental to effective and meaningful translation of preclinical research. Studies in sheep have made significant contributions to our understanding of the normal and abnormal development of the fetus. As a model of human pregnancy, studies in sheep have enabled scientists and clinicians to answer questions about the etiology and treatment of poor maternal, placental, and fetal health and to provide an evidence base for translation of interventions to the clinic. The aim of this review is to highlight the advances in perinatal human medicine that have been achieved following translation of research using the pregnant sheep and fetus.
Publisher: IOP Publishing
Date: 27-03-2018
Abstract: The utility of fetal heart rate (FHR) monitoring can only be achieved with an acquisition s ling rate that preserves the underlying physiological information on the millisecond time scale (1000 Hz rather than 4 Hz). For such acquisition, fetal ECG (fECG) is required, rather than the ultrasound to derive FHR. We tested one recently developed algorithm, SAVER, and two widely applied algorithms to extract fECG from a single-channel maternal ECG signal recorded over the xyphoid process rather than the routine abdominal signal. At 126dG, ECG was attached to near-term ewe and fetal shoulders, manubrium and xyphoid processes (n = 12). fECG served as the ground-truth to which the fetal ECG signal extracted from the simultaneously-acquired maternal ECG was compared. All fetuses were in good health during surgery (pH 7.29 ± 0.03, pO In all animals, single lead fECG extraction algorithm could not extract fECG from the maternal ECG signal over the xyphoid process with the F1 less than 50%. The applied fECG extraction algorithms might be unsuitable for the maternal ECG signal over the xyphoid process, or the latter does not contain strong enough fECG signal, although the lead is near the mother's abdomen. Fetal sheep model is widely used to mimic various fetal conditions, yet ECG recordings in a public data set form are not available to test the predictive ability of fECG and FHR. We are making this data set openly available to other researchers to foster non-invasive fECG acquisition in this animal model.
Publisher: Wiley
Date: 25-03-2016
DOI: 10.1111/VSU.12455
Abstract: To compare a knotless, barbed suture to standard suture using laparoscopic suturing methods in an ex vivo model of equine bladder repair. Cadaveric study. Equine cadaver bladders (n=42). A 5-cm incision was created and repaired in a laparoscopic training box with 4 different suture materials. Groups 1 and 2 used 2-0 poliglecaprone and 2-0 glycomer knotless, barbed suture, respectively, placed using laparoscopic instruments. Groups 3 and 4 used 0 and 2-0 polyglyconate knotless, barbed suture, respectively, placed using an automated laparoscopic suturing device. All groups used a double-layer inverting pattern. Time for suture placement was recorded. Bladders were inflated with water and bursting strength pressures recorded, including a control group of intact bladders. Statistical analysis using a linear model and taking into account the unequal variances was followed by a post-hoc Tukey's test. Significance was set at P<.05. Bursting strength did not vary significantly between treatment groups, but was significantly decreased compared to the control group (P<.001). Time to place the sutures with the 2 automated suture device groups (groups 3 and 4) was significantly faster than those in which the suture was placed using laparoscopic needle holders and forceps (groups 1 and 2 P=.001). Knotless, barbed suture may be a viable alternative to standard suture material for laparoscopic closure of the urinary bladder in horses. Further cyclic and in vivo testing should be performed before use in clinical cases.
Publisher: Elsevier BV
Date: 2017
Publisher: Elsevier BV
Date: 08-2021
Publisher: MyJove Corporation
Date: 25-10-2015
DOI: 10.3791/52581
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2016
Location: Ukraine
No related grants have been discovered for Martin Frasch.