Browsing by Subject "Hypoxia"
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Item Chronic cor pulmonale(1963-12-12) Pierce, Alan K.Item Determination of Respiratory Depression Measured by Capnography of Acutely Intoxicated Patients Presenting to an Urban Emergency Department(2015-01-26) Danko, Colin; Au, Vincent; Onisko, Nancy S.; Severson, Katie; Kleinschmidt, KurtINTRODUCTION: The standard of care for monitoring the respiratory status of patients with altered sensorium until recently has been pulse oximetry and observation. While pulse oximetry measures peripheral arterial oxygen saturation, it does not adequately detect hypoventilatory status. We hypothesized that intoxicated patients would demonstrate clinically significant signs of hypoventilation and that ETCO2 monitoring may detect these changes earlier than pulse oximetry. METHODS: This was a pilot observational data collection study of intoxicated patients presenting to a single urban emergency department between June 6, 2014 and August 1, 2014. Research assistants (RA's) monitored the ED tracking board for patients presenting with chief complaints suggesting possible intoxication with drugs or alcohol. Patients eligible for enrollment were between age 18-80 years, had a baseline Rikers Sedation Agitation Scale Score of < 3 and the treating ED physician believed that the patient's altered mental status was "possibly" or "probably" related to use of an intoxicant. Vital sign data and end-tidal CO2 readings were collected at Baseline, 30, 60, 90 and 120 minutes then hourly there after. End points for data collection were: 1) demonstration of alertness for at least 60 consecutive minutes 2) disposition to home or another hospital department or 3) decompensating respiratory status requiring bi-pap, c-pap or intubation. RESULTS: Seven hundred ninety four patients were screened. Thirty-five met all enrollment criteria and were assigned a de-identified patient number. Six patients were excluded from the final data analysis (5 for critical errors in ETCO2 data collection and 1 had AMS of non-intoxication etiology). Of the remaining 29 patients, 20 were male, 9 female. Ages ranged from 19-54 yrs. Alcohol was one of the intoxicants in almost half of patients. Other intoxicants included benzodiazepines, synthetic cannabinoids, cocaine, heroin and diet pills. Some patients had exposure to more than one intoxicant. ETCO2 values of > 45 mmHg were considered indicators of hypoventilatory state. There were a total of 19 episodes of hypoventilatory status as indicated by ETCO2 > 45 mmHg. Of the patients with multiple episodes (> 2) of hypoventilatory status, two had used heroin, one 62 mg lorazepam. Pulse oximetry reflected a normal oxygen saturation during at least 6 of the episodes. CONCLUSION: ETCO2 may detect hypoventilatory status before pulse oximetry and should be standard of care in patients presenting with intoxication associated with CNS depression.Item Isoflurane Preserves Viability of Highly Metabolic Renal Epithelial Cells Exposed to Anoxia(2016-04-01) Mantravadi, Vasudha; Kojima, Koji; Ambardekar, Aditee; Lin, Xihui; Gingrich, KevinBACKGROUND: Cells subjected to ischemia, whether in the context of hypoxia, hypovolemia, or circulatory collapse, undergo damage and death as a result of oxygen deprivation. Previous studies have shown that general anesthetics can protect cells from ischemic injury by lowering their aerobic metabolism and decreasing production of toxic metabolites, among other mechanisms (1, 2, 3). This very preliminary study investigated the potential protective effect of isoflurane on the survival of cells that have a fairly high baseline metabolic rate, human renal proximal tubular epithelial cells (HK-2) and human microvascular endothelial cells (HMEC), in an anoxic environment. METHODS: Cultured HK-2 and HMEC cells were incubated in a Forma Scientific Anaerobic System at 37C either in the absence (control) or presence (experimental) of 5% isoflurane for 0, 24, 48, 72, and 96 hours. Cell viability and metabolic activity were then assessed using live/dead fluorescence imaging and an MTT cell metabolism assay, respectively. RESULTS: In vitro exposure of cells to anoxia without isoflurane over a period of 96 hours, resulted in a reduction of viability of HK-2 cells from a baseline of 98%, to approximately 8-9%. Over the same period of time, viability of cells exposed to isoflurane and anoxia decreased to 35%. This represented a fourfold increase in survival of HK-2 cells exposed to isoflurane at 96 hours. At earlier time points, both cell death in anoxia, and the protective effect of isoflurane were less dramatic. HMECs did not undergo significant cell death upon exposure to either anoxia or anoxia with isoflurane, with 98% of the cells surviving the exposure to anoxia in both cases. The net metabolic activity, as assessed by absorbance using the MTT assay, decreased in HK-2 cells over increasing periods of anoxia, a trend that did not change with the addition of isoflurane. Metabolic activity of HMECs remained intact and relatively stable throughout the course of anoxic exposure. CONCLUSION: In this preliminary study, continuous exposure of HK-2 cells to 5% isoflurane during anoxic incubation had a protective effect on cell viability over a period of 96 hours. Whether this effect was also present in the less metabolically active HMECs, was not determined, as anoxia over the time period of the study had little effect on cell viability in either the experimental group or in the control group. The protective effect observed for HK-2 cells will likely vary with differences in metabolic requirements of different cell types, types and concentrations of anesthetic agents, and duration of anesthetic exposure. Anesthetic treatment may need to be tailored specifically to a cell type to confer the protective effects desired.Item The Mammalian Hypoxia Response Pathway: Regulation of HIF and HIF Prolyl Hydroxylases(2007-05-22) Ozer, Abdullah; Bruick, Richard K.Cells exposed to hypoxia -limited oxygen availability- initiate an adaptive response orchestrated by a transcription factor called Hypoxia Inducible Factor (HIF). HIF is composed of an oxygen-sensitive alpha -, and an oxygen-insensitive beta -subunit (ARNT). The stability and transcriptional activity of HIF alpha are controlled by two different Fe(II)- and 2- oxoglutarate-dependent dioxygenases that utilize molecular oxygen during hydroxylation of HIF alpha -subunit. When oxygen levels are sufficient (normoxia), HIF Prolyl Hydroxylases (HPH-1, -2, and -3) hydroxylate the Oxygen-dependent Degradation Domain (ODD) of HIF-alpha targeting it to ubiquitin-mediated proteosomal degradation. Factor Inhibiting HIF 1 (FIH-1, an asparaginyl hydroxylase), on the other hand, hydroxylates C-terminal Transactivation Domain (CTAD) thereby abolishing recruitment of transcriptional co-activators by HIF alpha. However, under hypoxic conditions, both hydroxylations are diminished allowing HIF alpha to escape degradation and induce transcription by associating with co-activators. Because of its critical role as an oxygen sensor, we studied HIF Prolyl Hydroxylase 2 (HPH-2) and focused on protein-protein interactions expecting that some of the interacting proteins might regulate its function. We characterized the function of a HPH-2 interacting protein identified in yeast two-hybrid screen; Inhibitor of Growth 4 (ING4) -a candidate tumor suppressor protein-, and showed that ING4 represses HIF transcriptional activity under hypoxia in a chromatindependent manner. Recruitment of ING4 to alter HIF transcriptional activity represents a novel function of HPH-2. To shed some light on the mechanism of this transcriptional repression, we purified ING4 containing co-repressor complex containing MYST2 and JADE3. Furthermore, we showed that ING4 and MYST2 targets not only HIF but also NF- κB transcription factor, a previously identified target of ING4, perhaps misregulation of which in the absence of functional ING4 protein contributes to tumor progression. Moreover, we identified additional HPH-2 interacting proteins and found that HPH enzymes can be modified by Protein Arginine Methyltransferase 1 (PRMT1) in vitro. Inhibition of methyltransferases in vivo further stabilized and activated HIF-1alpha suggesting a role for methyltransferases in regulation of HIF that might be mediated through HPH enzymes. Methylation of HPH enzymes, the first identified post-translational modification of these enzymes, adds another layer of complexity to the regulation of HIF alpha and it may serve as an interface between the hypoxia response pathway and other signaling pathways.Item [Southwestern News](2003-11-25) Shields, AmyItem [UT Southwestern Medical Center News](2008-02-29) Stafford, Erin Prather