Medicine (RMH) - Research Publications

Permanent URI for this collection

Search Results

Now showing 1 - 7 of 7
  • Item
    Thumbnail Image
    Deletion of guanine nucleotide binding protein αz subunit in mice induces a gene dose dependent tolerance to morphine
    Leck, KJ ; Bartlett, SE ; Smith, MT ; Megirian, D ; Holgate, J ; Powell, KL ; Matthaei, KI ; Hendry, IA (PERGAMON-ELSEVIER SCIENCE LTD, 2004-05)
    The mechanism underlying the development of tolerance to morphine is still incompletely understood. Morphine binds to opioid receptors, which in turn activates downstream second messenger cascades through heterotrimeric guanine nucleotide binding proteins (G proteins). In this paper, we show that G(z), a member of the inhibitory G protein family, plays an important role in mediating the analgesic and lethality effects of morphine after tolerance development. We blocked signaling through the G(z) second messenger cascade by genetic ablation of the alpha subunit of the G protein in mice. The Galpha(z) knockout mouse develops significantly increased tolerance to morphine, which depends on Galpha(z) gene dosage. Further experiments demonstrate that the enhanced morphine tolerance is not caused by pharmacokinetic and behavioural learning mechanisms. The results suggest that G(z) signaling pathways are involved in transducing the analgesic and lethality effects of morphine following chronic morphine treatment.
  • Item
    Thumbnail Image
    Current position of phenobarbital in epilepsy and its future
    Brodie, Martin ; KWAN, PATRICK ( 2012)
  • Item
    Thumbnail Image
    Outcome of ischemic stroke patients with serious post-thrombolysis neurological deficits
    Strbian, D ; Atula, S ; Meretoja, A ; Kaste, M ; Tatlisumak, T (WILEY, 2013-04)
    OBJECTIVES: To identify factors associated with favorable outcome in ischemic stroke patients having considerable post-thrombolytic neurological deficits but without endovascular treatment. MATERIALS AND METHODS: We registered 1427 consecutive thrombolysis-treated ischemic stroke patients, of which 473 (33%) had ≥8 NIH Stroke Scale (NIHSS) points after thrombolysis but did not undergo any further rescue intervention. We dichotomized them based on 3-month modified Rankin Scale (mRS) to those with favorable (mRS 0-2, n = 126, 27%) and unfavorable (mRS 3-6, n = 347) outcome. Univariate and multivariable methods tested associations of baseline and post-thrombolysis parameters with outcome. RESULTS: Lower post-thrombolysis NIHSS score and younger age had strongest association with favorable outcome. Most of patients with post-thrombolytic NIHSS score ≥11 achieved unfavorable outcome. In contrast, half of patients with favorable outcome had post-thrombolytic NIHSS≤10, and 62% of patients younger than 75 years and having post-thrombolytic NIHSS 8-9 achieved favorable outcome. Weaker independent association was observed for blood glucose level and baseline diastolic blood pressure. CONCLUSIONS: As expected, NIHSS score and patient age showed the strongest association with final outcome in a subpopulation of patients having considerable post-thrombolytic neurological deficit. A relatively high proportion of patients with post-thrombolytic NIHSS 8-9 (10) achieved a favorable 3-month outcome without any further intervention.
  • Item
    Thumbnail Image
    Ethosuximide reduces epileptogenesis and behavioral comorbidity in the GAERS model of genetic generalized epilepsy
    Dezsi, G ; Ozturk, E ; Stanic, D ; Powell, KL ; Blumenfeld, H ; O'Brien, TJ ; Jones, NC (WILEY, 2013-04)
    PURPOSE: Ethosuximide (ESX) is a drug of choice for the symptomatic treatment of absence seizures. Chronic treatment with ESX has been reported to have disease-modifying antiepileptogenic activity in the WAG/Rij rat model of genetic generalized epilepsy (GGE) with absence seizures. Here we examined whether chronic treatment with ESX (1) possesses antiepileptogenic effects in the genetic absence epilepsy rats from Strasbourg (GAERS) model of GGE, (2) is associated with a mitigation of behavioral comorbidities, and (3) influences gene expression in the somatosensory cortex region where seizures are thought to originate. METHODS: GAERS and nonepileptic control (NEC) rats were chronically treated with ESX (in drinking water) or control (tap water) from 3 to 22 weeks of age. Subsequently, all animals received tap water only for another 12 weeks to assess enduring effects of treatment. Seizure frequency and anxiety-like behaviors were serially assessed throughout the experimental paradigm. Treatment effects on the expression of key components of the epigenetic molecular machinery, the DNA methyltransferase enzymes, were assessed using quantitative polymerase chain reaction (qPCR). KEY FINDINGS: ESX treatment significantly reduced seizures in GAERS during the treatment phase, and this effect was maintained during the 12-week posttreatment phase (p < 0.05). Furthermore, the anxiety-like behaviors present in GAERS were reduced by ESX treatment (p < 0.05). Molecular analysis revealed that ESX treatment was associated with increased expression of DNA methyltransferase enzyme messenger RNA (mRNA) in cortex. SIGNIFICANCE: Chronic ESX treatment has disease-modifying effects in the GAERS model of GGE, with antiepileptogenic effects against absence seizures and mitigation of behavioral comorbidities. The cellular mechanism for these effects may involve epigenetic modifications.
  • Item
    Thumbnail Image
    Endovascular Therapy after Intravenous t-PA versus t-PA Alone for Stroke
    Broderick, JP ; Palesch, YY ; Demchuk, AM ; Yeatts, SD ; Khatri, P ; Hill, MD ; Jauch, EC ; Jovin, TG ; Yan, B ; Silver, FL ; von Kummer, R ; Molina, CA ; Demaerschalk, BM ; Budzik, R ; Clark, WM ; Zaidat, OO ; Malisch, TW ; Goyal, M ; Schonewille, WJ ; Mazighi, M ; Engelter, ST ; Anderson, C ; Spilker, J ; Carrozzella, J ; Ryckborst, KJ ; Janis, LS ; Martin, RH ; Foster, LD ; Tomsick, TA (MASSACHUSETTS MEDICAL SOC, 2013-03-07)
    BACKGROUND: Endovascular therapy is increasingly used after the administration of intravenous tissue plasminogen activator (t-PA) for patients with moderate-to-severe acute ischemic stroke, but whether a combined approach is more effective than intravenous t-PA alone is uncertain. METHODS: We randomly assigned eligible patients who had received intravenous t-PA within 3 hours after symptom onset to receive additional endovascular therapy or intravenous t-PA alone, in a 2:1 ratio. The primary outcome measure was a modified Rankin scale score of 2 or less (indicating functional independence) at 90 days (scores range from 0 to 6, with higher scores indicating greater disability). RESULTS: The study was stopped early because of futility after 656 participants had undergone randomization (434 patients to endovascular therapy and 222 to intravenous t-PA alone). The proportion of participants with a modified Rankin score of 2 or less at 90 days did not differ significantly according to treatment (40.8% with endovascular therapy and 38.7% with intravenous t-PA; absolute adjusted difference, 1.5 percentage points; 95% confidence interval [CI], -6.1 to 9.1, with adjustment for the National Institutes of Health Stroke Scale [NIHSS] score [8-19, indicating moderately severe stroke, or ≥20, indicating severe stroke]), nor were there significant differences for the predefined subgroups of patients with an NIHSS score of 20 or higher (6.8 percentage points; 95% CI, -4.4 to 18.1) and those with a score of 19 or lower (-1.0 percentage point; 95% CI, -10.8 to 8.8). Findings in the endovascular-therapy and intravenous t-PA groups were similar for mortality at 90 days (19.1% and 21.6%, respectively; P=0.52) and the proportion of patients with symptomatic intracerebral hemorrhage within 30 hours after initiation of t-PA (6.2% and 5.9%, respectively; P=0.83). CONCLUSIONS: The trial showed similar safety outcomes and no significant difference in functional independence with endovascular therapy after intravenous t-PA, as compared with intravenous t-PA alone. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00359424.).
  • Item
    Thumbnail Image
    Pre- and in-hospital intersection of stroke care
    Meretoja, A ; Kaste, M ; DelZoppo, GJ ; Alexandrov, AV (BLACKWELL SCIENCE PUBL, 2012)
    Acute ischemic stroke is a time-critical emergency for which thrombolytic therapy is the only medical treatment. Many patients who would benefit from this treatment are deprived of it due to delays. Failure to call for help rapidly is the main obstacle, but even when the call is made in time, the prehospital evaluation, transportation, and emergency department (ED) diagnostics often take too long to treat the patient with thrombolysis. Interventions to reduce pre- and in-hospital delays have been described; although no single intervention is likely to make a major difference, a whole set of interventions needs to be implemented. The intersection of the pre- and in-hospital care is of special importance. With successful protocols and good communication between the emergency medical service and ED, delays can be significantly reduced. On the basis of our experience, 94% of patients can be treated within 60 min of arrival, based largely on using the prehospital time effectively.
  • Item