Browsing by Subject "Bradycardia"

Now showing 1 - 4 of 4
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    A 2-year-old boy with hemolytic uremic syndrome and pneumocephalus
    (Wiley, 2012-01) Martin, Sarah E.; Allen, Steven D.; Faught, Phillip; Hawley, Dean A.; Bonnin, Jose M.; Hattab, Eyas M.; Pathology and Laboratory Medicine, School of Medicine
    Clostridium septicum infection following hemolytic uremic syndrome is rare and carries a poor prognosis, especially when the brain is involved. We report a case of a previously healthy 2-year-old boy who presented with two days of anuria and bloody diarrhea. He was admitted to the local children's hospital with a diagnosis of hemolytic uremic syndrome, presumably secondary to E. coli O157. He soon required intubation and was noted to have fixed and dilated pupils. Head CT revealed left frontal subcortical white matter vasogenic edema and scattered pockets of pneumocephalus. The patient expired 14 hours after admission. Antemortem blood cultures grew C. septicum. Gross pathologic examination of the brain revealed a large intraparenchymal cerebral hemorrhage in the left frontal and parietal lobes. There was extensive cystic changes as well. Microscopic examination revealed vacuolization and diffuse colonization with rod-shaped bacteria, but without the expected tissue response. There have been only six previously reported cases of C. septicum infection following hemolytic uremic syndrome, four of which had brain involvement. Mortality rate is high, with the only known survivor among those with brain involvement having a brain abscess rather than diffuse pneumocephalus.
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    Loss of Hand2 in a population of Periostin lineage cells results in pronounced bradycardia and neonatal death
    (Elsevier, 2014-04-15) VanDusen, Nathan J.; Vincentz, Joshua W.; Firulli, Beth A.; Howard, Marthe J.; Rubart, Michael; Firulli, Anthony B.; Department of Pediatrics, IU School of Medicine
    The Periostin Cre (Postn-Cre) lineage includes endocardial and neural crest derived mesenchymal cells of the cardiac cushions, neural crest-derived components of the sympathetic and enteric nervous systems, and cardiac fibroblasts. In this study, we use the Postn-Cre transgenic allele to conditionally ablate Hand2 (H2CKO). We find that Postn-Cre H2CKOs die shortly after birth despite a lack of obvious cardiac structural defects. To ascertain the cause of death, we performed a detailed comparison of the Postn-Cre lineage and Hand2 expression at mid and late stages of embryonic development. Gene expression analyses demonstrate that Postn-Cre ablates Hand2 from the adrenal medulla as well as the sphenopalatine ganglia of the head. In both cases, Hand2 loss-of-function dramatically reduces expression of Dopamine Beta Hydroxylase (Dbh), a gene encoding a crucial catecholaminergic biosynthetic enzyme. Expression of the genes Tyrosine Hydroxylase (Th) and Phenylethanolamine N-methyltransferase (Pnmt), which also encode essential catecholaminergic enzymes, were severely reduced in postnatal adrenal glands. Electrocardiograms demonstrate that 3-day postnatal Postn-Cre H2CKO pups exhibit sinus bradycardia. In conjunction with the aforementioned gene expression analyses, these results strongly suggest that the observed postnatal lethality occurs due to a catecholamine deficiency and subsequent heart failure.
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    Shp2 deletion in post-migratory neural crest cells results in impaired cardiac sympathetic innervation
    (2014-05) Lajiness, Jacquelyn D.; Ingram, David A., Jr.; Harrington, Maureen A.; Mirmira, Raghavendra G.; Payne, Mark; Rubart, Michael
    Autonomic innervation of the heart begins in utero and continues during the neonatal phase of life. A balance between the sympathetic and parasympathetic arms of the autonomic nervous system is required to regulate heart rate as well as the force of each contraction. Our lab studies the development of sympathetic innervation of the early postnatal heart in a conditional knockout (cKO) of Src homology protein tyrosine phosphatase 2 (Shp2). Shp2 is a ubiquitously expressed non-receptor phosphatase involved in a variety of cellular functions including survival, proliferation, and differentiation. We targeted Shp2 in post-migratory neural crest (NC) lineages using our novel Periostin-Cre. This resulted in a fully penetrant mouse model of diminished cardiac sympathetic innervation and concomitant bradycardia that progressively worsen. Shp2 is thought to mediate its basic cellular functions through a plethora of signaling cascades including extracellular signal-regulated kinases (ERK) 1 and 2. We hypothesize that abrogation of downstream ERK1/2 signaling in NC lineages is primarily responsible for the failed sympathetic innervation phenotype observed in our mouse model. Shp2 cKOs are indistinguishable from control littermates at birth and exhibit no gross structural cardiac anomalies; however, in vivo electrocardiogram (ECG) characterization revealed sinus bradycardia that develops as the Shp2 cKO ages. Significantly, 100% of Shp2 cKOs die within 3 weeks after birth. Characterization of the expression pattern of the sympathetic nerve marker tyrosine hydroxylase (TH) revealed a loss of functional sympathetic ganglionic neurons and reduction of cardiac sympathetic axon density in Shp2 cKOs. Shp2 cKOs exhibit lineage-specific suppression of activated pERK1/2 signaling, but not of other downstream targets of Shp2 such as pAKT (phosphorylated-Protein kinase B). Interestingly, restoration of pERK signaling via lineage-specific expression of constitutively active MEK1 (Mitogen-activated protein kinase kinase1) rescued TH-positive cardiac innervation as well as heart rate. These data suggest that the diminished sympathetic cardiac innervation and the resulting ECG abnormalities are a result of decreased pERK signaling in post-migratory NC lineages.