Publications by authors named "Amal Nadel"

7 Publications

  • Page 1 of 1

Hepatoprotection and lethality rescue by histone deacetylase inhibitor valproic acid in fatal hemorrhagic shock.

J Trauma 2008 Sep;65(3):554-65

Department of Surgery, Trauma Research and Readiness Institute for Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.

Background: Pharmacological histone deacetylase (HDAC) inhibitors, such as known anticonvulsant valproic acid (VPA), demonstrate cytoprotective effects and increase acetylation of nuclear histones, promoting transcriptional activation of deregulated genes. Therefore, we examined protective effects of VPA administration in lethal hemorrhage and analyzed the patterns of hepatic histone acetylation.

Methods: Male Wistar Kyoto rats were pretreated with VPA (n = 10) and 2-methyl-2-pentenoic acid (2M2P), structural VPA analog with limited HDAC inhibiting activity (2M2P; n = 8), at 300 mg/kg/dose, administered subcutaneously, 24 hour and immediately before lethal, if untreated, hemorrhage was induced by removing the 60% of total blood volume. Both drugs were dissolved in normal saline (NS) and rats pretreated with corresponding volume of NS served as control group (n = 8). Time to death, the degree of histone acetylation in liver, HDAC activity and markers of cytotoxicity (alpha-glutathione S-transferase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and lactate), and apoptosis were analyzed.

Results: VPA-pretreated animals demonstrated five-fold increase in survival duration. At 12 hours posthemorrhage, 70% (VPA) and 12% (2M2P) pretreated rats were alive versus 0% in NS group. Hyperacetylation of histones H2A, H3, and H4 indicated the presence of active genes and correlated with survival (VPA > 2M2P > NS). Hemorrhage-induced increases in lactate, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase were alleviated by VPA. Moreover, alpha-glutathione S-transferase release, indicative of liver damage, was completely abolished.

Conclusion: VPA offers considerable protection in severe hemorrhagic shock. The role of HDAC inhibition is suggested in mediating prosurvival actions of VPA.
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http://dx.doi.org/10.1097/TA.0b013e31818233efDOI Listing
September 2008

Valproic acid prevents hemorrhage-associated lethality and affects the acetylation pattern of cardiac histones.

Shock 2006 Apr;25(4):395-401

Department of Surgery, Trauma Research and Readiness Institute for Surgery, Uniformed Services University of the Health Sciences, Bethesda, , MD 20814, USA.

Pharmacological inhibitors of histone deacetylases (HDAC) demonstrate cytoprotective effects both in vitro and in vivo. In this study, we investigated whether valproic acid (VPA), a known mood stabilizer and anticonvulsant with HDAC-inhibiting activity, improves survival following otherwise lethal hemorrhage in rats. We found that preinsult injection of VPA (300 mg/kg, twice) prolonged the survival of severely hypotensive animals up to 5 times. VPA treatment increased the acetylation of nonhistone and histone proteins in the rat heart. The pattern of modifications of individual histones revealed hyperacetylation of histones H2A, H3, and H4, indicating the presence of active genes. Expression of HSP70 and superoxide dismutase, implicated in the modulation of vitality, was increased by VPA. Our results reveal that VPA offers considerable protection in the hemorrhagic shock model and suggest a role for HDAC inhibition in mediating VPA actions.
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http://dx.doi.org/10.1097/01.shk.0000209522.28120.c8DOI Listing
April 2006

Induction of profound hypothermia modulates the immune/inflammatory response in a swine model of lethal hemorrhage.

Resuscitation 2005 Aug 19;66(2):209-16. Epub 2005 Apr 19.

Trauma Research and Readiness Institute for Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.

Unlabelled: Profound hypothermic arrest ("suspended animation") is a new strategy to improve outcome following uncontrolled lethal hemorrhage (ULH). However, the impact of this approach on the immune/inflammatory response is unknown. This experiment was conducted to test the influence of profound hypothermia on markers of immune/inflammatory system.

Methods: ULH was induced in 32 female swine (80-120 lb) by creating an iliac artery and vein injury, followed 30 min later by laceration of the descending thoracic aorta. Through a left thoracotomy approach, total body hypothermic hyperkalemic metabolic arrest was induced by infusing organ preservation fluids into the aorta using a cardiopulmonary bypass machine (CPB). Experimental groups were (1) normothermic controls (no cooling, NC), or hypothermia induced at the following rates: (2) 0.5 degrees C/min (slow, SC), (3) 1 degrees C/min (medium, MC) and (4) 2 degrees C/min (fast, FC). Vascular injuries were repaired during 60 min of profound (10 degrees C) hypothermic arrest. Hyperkalemia was reversed by hypokalemic fluid exchange, and blood was infused for resuscitation during re-warming (0.5 degrees C/min). The surviving animals were monitored for 6 weeks. Levels of IL-1, TNFalpha, IL-6, IL-10, TGF-1 beta and heat shock protein (HSP-70) were measured by ELISA in serum samples collected serially during the experiment and post-operatively.

Results: Some of the immune markers were influenced by the use of CPB, independent of hypothermia (decrease in TGF-1 beta and increase in IL-1 beta). Hypothermia caused a significant decrease in IL-6, and an increase in HSP-70 expression compared to normothermic controls, independent of the cooling rate. An increase in IL-10 levels was noted which was influenced by the rate of cooling (p<0.05, MC versus NC).

Conclusions: Profound hypothermia modulates the post-shock immune/inflammatory system by attenuating the pro-inflammatory IL-6, increasing anti-inflammatory IL-10 and augmenting the protective heat shock responses.
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http://dx.doi.org/10.1016/j.resuscitation.2005.01.021DOI Listing
August 2005

Profound hypothermia protects neurons and astrocytes, and preserves cognitive functions in a Swine model of lethal hemorrhage.

J Surg Res 2005 Jun;126(2):172-81

Trauma Research and Readiness Institute for Surgery, Bethesda, Maryland, USA.

Background: Lethal injuries can be repaired under asanguineous hypothermic arrest (suspended animation) with excellent survival. This experiment was designed to test the impact of this strategy on neuronal and astroglial damage in a swine model of lethal hemorrhage. Furthermore, our goal was to correlate the histological changes in the brain with neurological outcome, and the levels of circulating brain specific markers.

Materials And Methods: Uncontrolled hemorrhage was induced in 32 female swine (80-120 lbs) by creating an iliac artery and vein injury, followed 30 min later by laceration of the thoracic aorta. Through a thoracotomy approach, organ preservation fluid was infused into the aorta using a roller pump. Experimental groups included normothermic controls (no cooling, NC), and groups where hypothermia was induced at three different rates: 0.5 degrees C/min (slow, SC), 1 degrees C/min (medium, MC), or 2 degrees C/min (fast, FC). Profound hypothermia (core temperature of 10 degrees C) was maintained for 60 min for repair of vascular injuries, after which the animals were re-warmed (0.5 degrees C/min) and resuscitated on cardiopulmonary bypass (CPB). Circulating levels of neuron specific enolase (NSE) and S-100beta were serially measured as markers of damage to neurons and astrocytes, respectively. Light microscopy and quantitative immunohistochemical techniques were used to evaluate hippocampal CA1 area and caudate putamen for neuronal injury and astrogliosis (astrocyte hyperplasia/hypertrophy). Surviving animals were observed for 6 weeks and neurological status was documented on an objective scale, and cognitive functions were evaluated using a technique based upon the concept of operant conditioning.

Results: Normothermic arrest resulted in clinical brain death in all of the animals. None of the surviving hypothermic animals displayed any neurological deficits or cognitive impairment. On histological examination, normothermic animals were found to have ischemic changes in the neurons and astrocytes (hypertrophy). In contrast, all of the hypothermic animals had histologically normal brains. The circulating levels of brain specific proteins did not correlate with the degree of brain damage. The changes in NSE levels were not statistically significant, whereas S-100beta increased in the circulation after CPB, largely independent of the temperature modulation.

Conclusions: Profound hypothermia can preserve viability of neurons and astrocytes during prolonged periods of cerebral hypoxia. This approach is associated with excellent cognitive and neurological outcome following severe shock. Circulating markers of central nervous system injury did not correlate with the actual degree of brain damage in this model.
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http://dx.doi.org/10.1016/j.jss.2005.01.019DOI Listing
June 2005

Endoscopic and Microscopic Extended Subfrontal Approach to the Clivus: A Comparative Anatomical Study.

Skull Base 2003 Aug;13(3):139-147

Department of Neurosurgery, University “Vita e Salute,” San Raffaele Hospital, Milan, Italy.

Ten cadaveric heads fixed and injected were dissected in the operative position. An enlarged subfrontal approach was adopted. The clival bone was drilled as much as possible under direct microscopic vision. Dissection in blind angles was avoided until the clival dura was exposed. The rigid 4-mm endoscope (angled 0 degrees and 30 degrees) was secured in a holder so the surgical cavity could be inspected. The residual bone was drilled under endoscopic visualization. The amount of bone removed was measured and compared with that removed under microscopic view. Blind angles in both microscopic and endoscopic views were recorded. The additional area of clival bone removed under endoscopic visualization compared with microscopic visualization was 467 mm(2) (range, 176 to 753 mm(2); standard deviation, 208.8 mm(2)).The amount of additional bone removed under endoscopy was inversely and significantly related to the minimal distance between the vertical segment of the two cavernous carotid arteries (p = 0.04). The endoscope is of great value in the removal of clival bone through the extended subfrontal approach. Its use improves the visualization of angles that are blind under the microscope.
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http://dx.doi.org/10.1055/s-2004-43324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1131843PMC
August 2003

The rate of induction of hypothermic arrest determines the outcome in a Swine model of lethal hemorrhage.

J Trauma 2004 Nov;57(5):961-9

Trauma Research and Readiness Institute for Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.

Background: Lethal injuries can be surgically repaired under asanguineous hypothermic condition (suspended animation) with excellent outcome. However, the optimal rate for the induction of hypothermic metabolic arrest following uncontrolled lethal hemorrhage (ULH) is unknown.

Methods: ULH was induced in 32 female swine (80-120 lbs) by creating an iliac artery and vein injury, followed 30 minutes later by laceration of the descending thoracic aorta. Through a left thoracotomy approach, total body hypothermic hyperkalemic metabolic arrest was induced by infusing organ preservation fluids into the aorta. Experimental groups were: normothermic controls (no cooling, NC), or hypothermia induced at a rate of 0.5 degrees C/min (slow, SC), 1 degrees C/min (medium, MC), or 2 degrees C/min (fast, FC). Vascular injuries were repaired during the 60 minutes of profound (10 degrees C) hypothermic arrest. Hyperkalemia was reversed by hypokalemic fluid exchange, and blood was infused for resuscitation during the re-warming (0.5 degrees C/ minute) period. The survivors were monitored for 6 weeks.

Results: The 6 week survival rates were 0% (NC), 37.5% (SC), 62.5% (MC), and 87.5% (FC) respectively (p < 0.05 MC&FC versus NC). All of the surviving hypothermic arrest animals were neurologically intact and displayed no long term organ dysfunction.

Conclusion: Hypothermic metabolic arrest can be used to maintain viability of key organs during repair of lethal injuries. Survival is influenced by the rate of cooling with the best outcome following rapid induction of hypothermia.
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http://dx.doi.org/10.1097/01.ta.0000149549.72389.3fDOI Listing
November 2004

Role of estrogen receptor-related antigen in initiating the growth of human glioma cells.

J Neurosurg 2004 May;100(5):923-30

Department of Neurological Surgery, George Washington University Medical Center, Washington, DC, USA.

Object: The expression of estrogen receptor-related antigen (ER-D5) has been demonstrated in many tumors, including those of the brain, but the actual role of ER-D5 in cell growth is unknown. The authors evaluated the role of ER-D5 in the growth of gliomas in vitro.

Methods: Human glioblastoma multiforme (GBM) cell lines A172, T98G, U87MG, and U118MG; rat C6 glioma and 9L gliosarcoma; AS human astrocytoma; GBM in primary culture and tumor tissues; and normal brain tissues were examined for ER-D5 by using immunohistochemical, Western immunoblot, flow cytometry, and enzyme-linked immunosorbent assays. The ER-D5 was detected in all tumor cell types of human origin, but not in rat cell lines and normal brain; the expression of ER-D5 was not related to cell cycle phase. Kinetic analysis of ER-D5 expression in cultured cell lines revealed that an enhanced and sharp accumulation of ER-D5 occurred during the first 24 hours of culture, followed by a sharp fall in the next 24 hours. Gradual decreases of ER-D5 during the subsequent days were demonstrated in all human cell lines, and in primary cultures of GBM. This accumulation pattern of ER-D5 was confirmed on Western blot analysis. The ER-D5 was also detected in cells cultured in serum-free medium. Culture cells were treated with D5 antibody against ER-D5 for 48 hours and the effects were evaluated using a monotetrazolium colorimetric assay; the result revealed that growth of cultured cells was inhibited in a dose-dependent manner, and that addition of a single median inhibitory concentration dose resulted in complete growth inhibition and arrest of cell growth at the G0/G1 phase at 96 hours posttreatment.

Conclusions: These findings indicated that synthesis and accumulation of ER-D5 is an essential event in the very early phase of in vitro growth of human gliomas.
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http://dx.doi.org/10.3171/jns.2004.100.5.0923DOI Listing
May 2004