Browsing by Subject "ANIMAL-MODEL"

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  • Cooper, Ann E.; Ahonen, Saija; Rowlan, Jessica S.; Duncan, Alison; Seppala, Eija H.; Vanhapelto, Paivi; Lohi, Hannes; Komaromy, Andras M. (2014)
  • Di Saverio, Salomone; Coccolini, Federico; Galati, Marica; Smerieri, Nazareno; Biffl, Walter L.; Ansaloni, Luca; Tugnoli, Gregorio; Velmahos, George C.; Sartelli, Massimo; Bendinelli, Cino; Fraga, Gustavo Pereira; Kelly, Michael D.; Moore, Frederick A.; Mandala, Vincenzo; Mandala, Stefano; Masetti, Michele; Jovine, Elio; Pinna, Antonio D.; Peitzman, Andrew B.; Leppäniemi, Ari; Sugarbaker, Paul H.; Van Goor, Harry; Moore, Ernest E.; Jeekel, Johannes; Catena, Fausto (2013)
  • Pospelov, Alexey S.; Puskarjov, Martin; Kaila, Kai; Voipio, Juha (2020)
    Abstract Aim To study brain-sparing physiological responses in a rodent model of birth asphyxia which reproduces the asphyxia-defining systemic hypoxia and hypercapnia. Methods Steady or intermittent asphyxia was induced for 15-45 min in anesthetized 6- and 11-days old rats and neonatal guinea pigs using gases containing 5% or 9% O2 plus 20% CO2 (in N2). Hypoxia and hypercapnia were induced with low O2 and high CO2, respectively. Oxygen partial pressure (PO2) and pH were measured with microsensors within the brain and subcutaneous (?body?) tissue. Blood lactate was measured after asphyxia. Results Brain and body PO2 fell to apparent zero with little recovery during 5% O2 asphyxia and 5% or 9% O2 hypoxia, and increased more than twofold during 20% CO2 hypercapnia. Unlike body PO2, brain PO2 recovered rapidly to control after a transient fall (rat), or was slightly higher than control (guinea pig) during 9% O2 asphyxia. Asphyxia (5% O2) induced a respiratory acidosis paralleled by a progressive metabolic (lact)acidosis that was much smaller within than outside the brain. Hypoxia (5% O2) produced a brain-confined alkalosis. Hypercapnia outlasting asphyxia suppressed pH recovery and prolonged the post-asphyxia PO2 overshoot. All pH changes were accompanied by consistent shifts in the blood-brain barrier potential. Conclusion Regardless of brain maturation stage, hypercapnia can restore brain PO2 and protect the brain against metabolic acidosis despite compromised oxygen availability during asphyxia. This effect extends to the recovery phase if normocapnia is restored slowly, and it is absent during hypoxia, demonstrating that exposure to hypoxia does not mimic asphyxia.
  • Niskanen, Julia; Dillard, Kati; Arumilli, Meharji; Salmela, Elina; Anttila, Marjukka; Lohi, Hannes; Hytonen, Marjo K. (2017)
    A rare hereditary mechanobullous disorder called epidermolysis bullosa (EB) causes blistering in the skin and the mucosal membranes. To date, nineteen EB-related genes have been discovered in human and other species. We describe here a novel EB variant in dogs. Two newborn littermates of Central Asian Shepherd dogs with severe signs of skin blistering were brought to a veterinary clinic and euthanized due to poor prognosis. In post-mortem examination, the puppies were shown to have findings in the skin and the mucosal membranes characteristic of EB. A whole-genome sequencing of one of the affected puppies was performed to identify the genetic cause. The resequencing data were filtered under a recessive model against variants from 31 other dog genomes, revealing a homozygous case-specific nonsense variant in one of the known EB-causing genes, COL7A1 (c.4579C> T, p.R1527*). The variant results in a premature stop codon and likely absence of the functional protein in the basement membrane of the skin in the affected dogs. This was confirmed by immunohistochemistry using a COL7A1 antibody. Additional screening of the variant indicated full penetrance and breed specificity at similar to 28% carrier frequency. In summary, this study reveals a novel COL7A1 variant causing recessive dystrophic EB and provides a genetic test for the eradication of the disease from the breed.
  • Schwan, Stefan; Ludtka, Christopher; Wiesner, Ingo; Baerthel, Andre; Friedmann, Andrea; Göhre, Felix (2018)
    This work describes a minimally invasive damage model for ovine lumbar discs via partial nucleotomy using a posterolateral approach. Two cadavers were dissected to analyze the percutaneous corridor. Subsequently, 28 ovine had their annulus fibrosus punctured via awl penetration under fluoroscopic control and nucleus pulposus tissue removed via rongeur. Efficacy was assessed by animal morbidity, ease of access to T12-S1 disc spaces, and production of a mechanical injury as verified by discography, radiography, and histology. T12-S1 were accessible with minimal nerve damage morbidity. Scar tissue sealed the disc puncture site in all animals within 6 weeks, withstanding 1 MP of intradiscal pressure. Partial nucleotomy led to a significant reduction in intervertebral disk height and an increased histological degeneration score. Inducing a reproducible injury pattern of disc degeneration required minimal time, effort, and equipment. The posterolateral approach allows operation on several discs within a single surgery and multiple animal surgeries within a single day.
  • Kinfe, Thomas M.; Asif, Maria; Chakravarthy, Krishnan V.; Deer, Timothy R.; Kramer, Jeffery M.; Yearwood, Thomas L.; Hurlemann, Rene; Hussain, Muhammad Sajid; Motameny, Susanne; Wagle, Prerana; Nürnberg, Peter; Gravius, Sascha; Randau, Thomas; Gravius, Nadine; Chaudhry, Shafqat R.; Muhammad, Sajjad (2019)
    BackgroundIn our recent clinical trial, increased peripheral concentrations of pro-inflammatory molecular mediators were determined in complex regional pain syndrome (CRPS) patients. After 3months adjunctive unilateral, selective L4 dorsal root ganglion stimulation (L4-DRG(STIM)), significantly decreased serum IL-10 and increased saliva oxytocin levels were assessed along with an improved pain and functional state. The current study extended molecular profiling towards gene expression analysis of genes known to be involved in the gonadotropin releasing hormone receptor and neuroinflammatory (cytokines/chemokines) signaling pathways.MethodsBlood samples were collected from 12 CRPS patients for whole-transcriptome profiling in order to assay 18,845 inflammation-associated genes from frozen blood at baseline and after 3months L4-DRG(STIM) using PANTHER pathway enrichment analysis tool.ResultsPathway enrichment analyses tools (GOrilla and PANTHER) showed predominant involvement of inflammation mediated by chemokines/cytokines and gonadotropin releasing hormone receptor pathways. Further, screening of differentially regulated genes showed changes in innate immune response related genes. Transcriptomic analysis showed that 21 genes (predominantly immunoinflammatory) were significantly changed after L4-DRG(STIM). Seven genes including TLR1, FFAR2, IL1RAP, ILRN, C5, PKB and IL18 were down regulated and fourteen genes including CXCL2, CCL11, IL36G, CRP, SCGB1A1, IL-17F, TNFRSF4, PLA2G2A, CREB3L3, ADAMTS12, IL1F10, NOX1, CHIA and BDKRB1 were upregulated.ConclusionsIn our sub-group analysis of L4-DRG(STIM) treated CRPS patients, we found either upregulated or downregulated genes involved in immunoinflammatory circuits relevant for the pathophysiology of CRPS indicating a possible relation. However, large biobank-based approaches are recommended to establish genetic phenotyping as a quantitative outcome measure in CRPS patients.Trial registration The study protocol was registered at the 15.11.2016 on German Register for Clinical Trials (DRKS ID 00011267). https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011267
  • Wiberg, M.; Niskanen, J.E.; Hytönen, M.; Dillard, K.; Hagner, K.; Anttila, M.; Lohi, H. (2020)
    Introduction: To describe unexpected sudden cardiac death (SCD) in young Leonbergers ( Animals: Postmortem evaluations included 21 Leonbergers. Clinical evaluation consisted of 46 apparently healthy Leonbergers with and without a close family history of SCD. Materials and methods: Necropsy reports were reviewed retrospectively. Prospective clinical evaluation included physical examination, 5-min electrocardiogram, 24-h Hotter, echocardiography, and laboratory tests. Pedigree data were examined for mode of inheritance. Results: Based on necropsy reports, SCD occurred at a median age of 12 months (range, 2.0-32.0 months) without any previous clinical signs and usually in rest. No evidence of structural cardiac disease was found; arrhythmia-related death was suspected. Clinical evaluation and 24-h Hotter showed ventricular arrhythmia (VA) in 14 apparently healthy Leonbergers (median age, 18 months; range, 12-42 months). Severity of VA varied from infrequent couplets/triplets to frequent complexity (couplets, triplets, nonsustained ventricular tachycardias,VTs) characterized by polymorphology. During follow-up, two dogs with polymorphic VT died. Although breed specificity and high prevalence indicate a heritable disease, based on available pedigree data, the mode of inheritance could not be determined. Conclusions: Sudden cardiac death in young Leonbergers is associated with malignant VA characterized by complexity and polymorphic nature. Diagnosis is based on 24-h Hotter monitoring. Pedigree analysis suggests that the arrhythmia is familial. (C) 2019 Elsevier B.V. All rights reserved.
  • Letko, Anna; Leuthard, Fabienne; Jagannathan, Vidhya; Corlazzoli, Daniele; Matiasek, Kaspar; Schweizer, Daniela; Hytönen, Marjo K.; Lohi, Hannes; Leeb, Tosso; Droegemueller, Cord (2020)
    Craniomandibular osteopathy (CMO) and calvarial hyperostotic syndrome (CHS) are proliferative, non-neoplastic disorders affecting the skull bones in young dogs. Different forms of these hyperostotic disorders have been described in many dog breeds. However, an incompletely dominant causative variant for CMO affecting splicing of SLC37A2 has been reported so far only in three Terrier breeds. The purpose of this study was to identify further possible causative genetic variants associated with CHS in an American Staffordshire Terrier, as well as CMO in seven affected dogs of different breeds. We investigated their whole-genome sequences (WGS) and filtered variants using 584 unrelated genomes, which revealed no variants shared across all affected dogs. However, filtering for private variants of each case separately yielded plausible dominantly inherited candidate variants in three of the eight cases. In an Australian Terrier, a heterozygous missense variant in the COL1A1 gene (c.1786G>A; p.(Val596Ile)) was discovered. A pathogenic missense variant in COL1A1 was previously reported in humans with infantile cortical hyperostosis, or Caffey disease, resembling canine CMO. Furthermore, in a Basset Hound, a heterozygous most likely pathogenic splice site variant was found in SLC37A2 (c.1446+1G>A), predicted to lead to exon skipping as shown before in SLC37A2-associated canine CMO of Terriers. Lastly, in a Weimaraner, a heterozygous frameshift variant in SLC35D1 (c.1021_1024delTCAG; p.(Ser341ArgfsTer22)) might cause CMO due to the critical role of SLC35D1 in chondrogenesis and skeletal development. Our study indicates allelic and locus heterogeneity for canine CMO and illustrates the current possibilities and limitations of WGS-based precision medicine in dogs.