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  1. Article ; Online: Diabetic ketoacidosis in juvenile rats is associated with reactive gliosis and activation of microglia in the hippocampus.

    Lo, Weei / O'Donnell, Martha / Tancredi, Daniel / Orgain, Myra / Glaser, Nicole

    Pediatric diabetes

    2015  Volume 17, Issue 2, Page(s) 127–139

    Abstract: Background: Type 1 diabetes may be associated with structural and functional alterations in the brain. The role of diabetic ketoacidosis (DKA) in causing these alterations has not been well explored.: Methods: We used immunohistochemical staining to ... ...

    Abstract Background: Type 1 diabetes may be associated with structural and functional alterations in the brain. The role of diabetic ketoacidosis (DKA) in causing these alterations has not been well explored.
    Methods: We used immunohistochemical staining to investigate cellular alterations in brain specimens from juvenile rats with DKA before, during, and after treatment with insulin and saline, and compared these to samples from diabetic rats and normal controls.
    Results: Glial fibrillary acidic protein (GFAP) staining intensity was increased in the hippocampus during DKA and increased further during insulin/saline treatment. Twenty-four and 72 h after treatment, hippocampal GFAP intensity declined but remained above control levels. There were no significant changes in GFAP intensity in the cortex or striatum. OX42 staining intensity was increased during untreated DKA and increased further during insulin/saline treatment in the hippocampus and cortex. NeuN staining intensity was decreased after DKA treatment in the striatum but not in other regions.
    Conclusions: DKA causes inflammatory changes in the brain including reactive gliosis and activation of microglia. These findings are present during untreated DKA, but intensify during insulin/saline treatment. The hippocampus was disproportionately affected, consistent with previous studies showing deficits in hippocampal functions in rats after DKA recovery and decreased memory capacity in children with a history of DKA.
    MeSH term(s) Animals ; Antigens, CD/metabolism ; Antigens, Differentiation, Myelomonocytic/metabolism ; Antigens, Nuclear/metabolism ; CD11b Antigen/metabolism ; Diabetes Mellitus, Experimental/complications ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/pathology ; Diabetic Ketoacidosis/complications ; Diabetic Ketoacidosis/metabolism ; Diabetic Ketoacidosis/pathology ; Glial Fibrillary Acidic Protein/metabolism ; Gliosis/etiology ; Gliosis/metabolism ; Gliosis/pathology ; Hippocampus/metabolism ; Hippocampus/pathology ; Microglia/metabolism ; Microglia/pathology ; Nerve Tissue Proteins/metabolism ; Rats ; Rats, Sprague-Dawley
    Chemical Substances Antigens, CD ; Antigens, Differentiation, Myelomonocytic ; Antigens, Nuclear ; CD11b Antigen ; CD68 antigen, human ; Glial Fibrillary Acidic Protein ; Nerve Tissue Proteins ; Rbfox3 protein, rat
    Language English
    Publishing date 2015-01-16
    Publishing country Denmark
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1502504-4
    ISSN 1399-5448 ; 1745-1426 ; 1399-543X
    ISSN (online) 1399-5448
    ISSN 1745-1426 ; 1399-543X
    DOI 10.1111/pedi.12251
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Treatment with the KCa3.1 inhibitor TRAM-34 during diabetic ketoacidosis reduces inflammatory changes in the brain.

    Glaser, Nicole / Little, Christopher / Lo, Weei / Cohen, Michael / Tancredi, Daniel / Wulff, Heike / O'Donnell, Martha

    Pediatric diabetes

    2016  Volume 18, Issue 5, Page(s) 356–366

    Abstract: Background: Diabetic ketoacidosis (DKA) causes brain injuries in children ranging from subtle to life-threatening. Previous studies suggest that DKA-related brain injury may involve both stimulation of Na-K-Cl cotransport and microglial activation. ... ...

    Abstract Background: Diabetic ketoacidosis (DKA) causes brain injuries in children ranging from subtle to life-threatening. Previous studies suggest that DKA-related brain injury may involve both stimulation of Na-K-Cl cotransport and microglial activation. Other studies implicate the Na-K-Cl cotransporter and the Ca-activated K channel KCa3.1 in activation of microglia and ischemia-induced brain edema. In this study, we determined whether inhibiting cerebral Na-K-Cl cotransport or KCa3.1 could reduce microglial activation and decrease DKA-related inflammatory changes in the brain.
    Methods: Using immunohistochemistry, we investigated cellular alterations in brain specimens from juvenile rats with DKA before, during and after insulin and saline treatment. We compared findings in rats treated with and without bumetanide (an inhibitor of Na-K-Cl cotransport) or the KCa3.1 inhibitor TRAM-34.
    Results: Glial fibrillary acidic protein (GFAP) staining intensity was increased in the hippocampus during DKA, suggesting reactive astrogliosis. OX42 staining intensity was increased during DKA in the hippocampus, cortex and striatum, indicating microglial activation. Treatment with TRAM-34 decreased both OX42 and GFAP intensity suggesting a decreased inflammatory response to DKA. Treatment with bumetanide did not significantly alter OX42 or GFAP intensity.
    Conclusions: Inhibiting KCa3.1 activity with TRAM-34 during DKA treatment decreases microglial activation and reduces reactive astrogliosis, suggesting a decreased inflammatory response.
    MeSH term(s) Animals ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Biomarkers/metabolism ; Brain/drug effects ; Brain/immunology ; Brain/metabolism ; Brain/pathology ; Bumetanide/therapeutic use ; CD11b Antigen/antagonists & inhibitors ; CD11b Antigen/metabolism ; Cerebral Cortex/drug effects ; Cerebral Cortex/immunology ; Cerebral Cortex/metabolism ; Cerebral Cortex/pathology ; Corpus Striatum/drug effects ; Corpus Striatum/immunology ; Corpus Striatum/metabolism ; Corpus Striatum/pathology ; Diabetic Ketoacidosis/drug therapy ; Diabetic Ketoacidosis/immunology ; Diabetic Ketoacidosis/metabolism ; Diabetic Ketoacidosis/pathology ; Encephalitis/etiology ; Encephalitis/prevention & control ; Female ; Glial Fibrillary Acidic Protein/antagonists & inhibitors ; Glial Fibrillary Acidic Protein/metabolism ; Gliosis/etiology ; Gliosis/prevention & control ; Hippocampus/drug effects ; Hippocampus/immunology ; Hippocampus/metabolism ; Hippocampus/pathology ; Male ; Microglia/drug effects ; Microglia/immunology ; Microglia/metabolism ; Microglia/pathology ; Nerve Tissue Proteins/antagonists & inhibitors ; Nerve Tissue Proteins/metabolism ; Potassium Channel Blockers/therapeutic use ; Pyrazoles/therapeutic use ; Random Allocation ; Small-Conductance Calcium-Activated Potassium Channels/antagonists & inhibitors ; Small-Conductance Calcium-Activated Potassium Channels/metabolism ; Sodium Potassium Chloride Symporter Inhibitors/therapeutic use
    Chemical Substances Anti-Inflammatory Agents, Non-Steroidal ; Biomarkers ; CD11b Antigen ; GFAP protein, rat ; Glial Fibrillary Acidic Protein ; Kcnn3 protein, rat ; Nerve Tissue Proteins ; Potassium Channel Blockers ; Pyrazoles ; Small-Conductance Calcium-Activated Potassium Channels ; Sodium Potassium Chloride Symporter Inhibitors ; TRAM 34 ; Bumetanide (0Y2S3XUQ5H)
    Language English
    Publishing date 2016-05-13
    Publishing country Denmark
    Document type Comparative Study ; Journal Article
    ZDB-ID 1502504-4
    ISSN 1399-5448 ; 1745-1426 ; 1399-543X
    ISSN (online) 1399-5448
    ISSN 1745-1426 ; 1399-543X
    DOI 10.1111/pedi.12396
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Levels of S100B in brain and blood of rats with diabetic ketoacidosis.

    Glaser, Nicole / Lo, Weei / Tancredi, Daniel / Orgain, Myra / Puvenna, Vikram / Janigro, Damir / O'Donnell, Martha

    Brain research

    2015  Volume 1624, Page(s) 536–544

    Abstract: Diabetic ketoacidosis (DKA) frequently causes subtle brain injuries in children. Rarely, these injuries can be severe and life threatening. The physiological processes leading to brain injury during DKA are poorly understood. S100B is a calcium-binding ... ...

    Abstract Diabetic ketoacidosis (DKA) frequently causes subtle brain injuries in children. Rarely, these injuries can be severe and life threatening. The physiological processes leading to brain injury during DKA are poorly understood. S100B is a calcium-binding protein secreted by astrocytes. Elevated serum S100B levels are documented in several types of brain injuries. S100B may have either neuroprotective or neurotoxic effects, depending upon the concentration. We undertook the current studies to measure alterations in S100B production and secretion during DKA. We measured serum S100B concentrations in juvenile rats during and after DKA, and used immunohistochemistry to measure S100B expression in the hippocampus, cortex and striatum. Compared to levels in both normal and hyperglycemic control rats, serum S100B levels during DKA were significantly reduced. Serum S100B gradually rose after DKA, returning to levels of hyperglycemic controls by 72 h. S100B expression in the hippocampus was also significantly reduced 24h after DKA. There were no significant changes in S100B expression in other brain regions. Our findings contrast with those for other types of brain injuries in which both serum S100B levels and astrocyte S100B expression are typically elevated. These data suggest that serum S100B measurement cannot be used as an indicator of brain injury during DKA. Whether reduced S100B production or secretion is involved in the pathogenesis of DKA-related brain injury should be investigated.
    MeSH term(s) Animals ; Antibiotics, Antineoplastic/toxicity ; Brain/metabolism ; Brain/pathology ; Diabetic Ketoacidosis/blood ; Diabetic Ketoacidosis/chemically induced ; Diabetic Ketoacidosis/pathology ; Disease Models, Animal ; Glial Fibrillary Acidic Protein/metabolism ; Hyperglycemia/blood ; Hyperglycemia/etiology ; Hyperglycemia/pathology ; Rats ; Rats, Sprague-Dawley ; S100 Calcium Binding Protein beta Subunit/metabolism ; Streptozocin/toxicity ; Time Factors
    Chemical Substances Antibiotics, Antineoplastic ; Glial Fibrillary Acidic Protein ; S100 Calcium Binding Protein beta Subunit ; Streptozocin (5W494URQ81)
    Language English
    Publishing date 2015-10-22
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1200-2
    ISSN 1872-6240 ; 0006-8993
    ISSN (online) 1872-6240
    ISSN 0006-8993
    DOI 10.1016/j.brainres.2015.07.044
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Brain cell swelling during hypocapnia increases with hyperglycemia or ketosis.

    Glaser, Nicole / Bundros, Angeliki / Anderson, Steve / Tancredi, Daniel / Lo, Weei / Orgain, Myra / O'Donnell, Martha

    Pediatric diabetes

    2014  Volume 15, Issue 7, Page(s) 484–493

    Abstract: Background: Severe hypocapnia reduces cerebral blood flow (CBF) and is known to be a risk factor for diabetic ketoacidosis (DKA)-related cerebral edema and cerebral injury in children. Reductions in CBF resulting from hypocapnia alone, however, would ... ...

    Abstract Background: Severe hypocapnia reduces cerebral blood flow (CBF) and is known to be a risk factor for diabetic ketoacidosis (DKA)-related cerebral edema and cerebral injury in children. Reductions in CBF resulting from hypocapnia alone, however, would not be expected to cause substantial cerebral injury. We hypothesized that either hyperglycemia or ketosis might alter the effects of hypocapnia on CBF and/or cerebral edema associated with CBF reduction.
    Methods: We induced hypocapnia (pCO₂ 20 ± 3 mmHg) via mechanical ventilation in three groups of juvenile rats: 25 controls, 22 hyperglycemic rats (serum glucose 451 ± 78 mg/dL), and 15 ketotic rats (β-hydroxy butyrate 3.0 ± 1.0 mmol/L). We used magnetic resonance imaging to measure CBF and apparent diffusion coefficient (ADC) values in these groups and in 17 ventilated rats with normal pCO₂ (40 ± 3 mmHg). In a subset (n = 35), after 2 h of hypocapnia, pCO₂ levels were normalized (40 ± 3 mmHg) and ADC and CBF measurements were repeated.
    Results: Declines in CBF with hypocapnia occurred in all groups. Normalization of pCO₂ after hypocapnia resulted in hyperemia in the striatum. These effects were not substantially altered by hyperglycemia or ketosis. Declines in ADC (suggesting brain cell swelling) during hypocapnia, however, were greater during both hyperglycemia and ketosis.
    Conclusions: We conclude that brain cell swelling associated with hypocapnia is increased by both hyperglycemia and ketosis, suggesting that these metabolic conditions may make the brain more vulnerable to injury during hypocapnia.
    MeSH term(s) 3-Hydroxybutyric Acid/blood ; Animals ; Blood Glucose/analysis ; Brain Edema/etiology ; Carbon Dioxide/blood ; Cell Size ; Cerebral Cortex/blood supply ; Cerebral Cortex/pathology ; Cerebrovascular Circulation ; Corpus Striatum/blood supply ; Corpus Striatum/pathology ; Diabetes Mellitus, Experimental/complications ; Diabetic Ketoacidosis/physiopathology ; Disease Susceptibility ; Hydrogen-Ion Concentration ; Hyperglycemia/physiopathology ; Hypocapnia/etiology ; Magnetic Resonance Imaging ; Neurons/pathology ; Rats, Sprague-Dawley ; Water-Electrolyte Imbalance/complications ; Water-Electrolyte Imbalance/etiology ; Water-Electrolyte Imbalance/pathology ; Water-Electrolyte Imbalance/physiopathology
    Chemical Substances Blood Glucose ; Carbon Dioxide (142M471B3J) ; 3-Hydroxybutyric Acid (TZP1275679)
    Language English
    Publishing date 2014-01-20
    Publishing country Denmark
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1502504-4
    ISSN 1399-5448 ; 1745-1426 ; 1399-543X
    ISSN (online) 1399-5448
    ISSN 1745-1426 ; 1399-543X
    DOI 10.1111/pedi.12114
    Database MEDical Literature Analysis and Retrieval System OnLINE

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