Publications by authors named "John E Thompson"

33 Publications

Categorization in Mechanically Ventilated Pediatric Subjects: A Proposed Method to Improve Quality.

Respir Care 2016 Sep 14;61(9):1168-78. Epub 2016 Jun 14.

Department of Anesthesiology, Perioperative, and Pain Medicine, Division of Critical Care Medicine, Boston Children's Hospital and Pediatric Anesthesia, Harvard Medical School, Boston, Massachusetts.

Background: Thousands of children require mechanical ventilation each year. Although mechanical ventilation is lifesaving, it is also associated with adverse events if not properly managed. The systematic implementation of evidence-based practice through the use of guidelines and protocols has been shown to mitigate risk, yet variation in care remains prevalent. Advances in health-care technology provided the ability to stream data about mechanical ventilation and therapeutic response. Through these advances, a computer system was developed to enable the coupling of physiologic and ventilation data for real-time interpretation. Our aim was to assess the feasibility and utility of a newly developed patient categorization and scoring system to objectively measure compliance with standards of care.

Methods: We retrospectively categorized the ventilation and oxygenation statuses of subjects within our pediatric ICU utilizing 15 rules-based algorithms. Targets were predetermined based on generally accepted practices. All patient categories were calculated and presented as a percent score (0-100%) of acceptable ventilation, acceptable oxygenation, barotrauma-free, and volutrauma-free states.

Results: Two hundred twenty-two subjects were identified and analyzed encompassing 1,578 d of mechanical ventilation. Median age was 3 y, median ideal body weight was 14.7 kg, and 63% were male. The median acceptable ventilation score was 84.6%, and the median acceptable oxygenation score was 70.1% (100% being maximally acceptable). Potential for ventilator-induced lung injury was broken into 2 components: barotrauma and volutrauma. There was very little potential for barotrauma, with a median barotrauma-free state of 100%. Median potential for a volutrauma-free state was 56.1%.

Conclusions: We demonstrate the first patient categorization system utilizing a coordinated data-banking system and analytics to determine patient status and a surveillance of mechanical ventilation quality. Further research is needed to determine whether interventions such as visual display of variance from goal and patient categorization summaries can improve outcomes. (ClinicalTrials.gov registration NCT02184208.).
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http://dx.doi.org/10.4187/respcare.04723DOI Listing
September 2016

SNS01-T modulation of eIF5A inhibits B-cell cancer progression and synergizes with bortezomib and lenalidomide.

Mol Ther 2014 Sep 26;22(9):1643-52. Epub 2014 Feb 26.

1] Department of Biology, University of Waterloo, Waterloo, Ontario, Canada [2] Senesco Technologies, Bridgewater, New Jersey, USA.

The high rates of recurrence and low median survival in many B-cell cancers highlight a need for new targeted therapeutic modalities. In dividing cells, eukaryotic translation initiation factor 5A (eIF5A) is hypusinated and involved in regulation of protein synthesis and proliferation, whereas the non-hypusinated form of eIF5A is a potent inducer of cell death in malignant cells. Here, we demonstrate the potential of modulating eIF5A expression as a novel approach to treating B-cell cancers. SNS01-T is a nonviral polyethylenimine-based nanoparticle, designed to induce apoptosis selectively in B-cell cancers by small interfering RNA-mediated suppression of hypusinated eIF5A and plasmid-based overexpression of a non-hypusinable eIF5A mutant. In this study, we show that SNS01-T is preferentially taken up by malignant B cells, inhibits tumor growth in multiple animal models of B-cell cancers without damaging normal tissues, and synergizes with the current therapies bortezomib and lenalidomide to inhibit tumor progression. The results collectively demonstrate the potential of SNS01-T as a novel therapeutic for treatment of a diverse range of B-cell malignancies.
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http://dx.doi.org/10.1038/mt.2014.24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4435495PMC
September 2014

Challenges in the use of tests to diagnose tuberculosis infection.

Authors:
John E Thompson

N S W Public Health Bull 2013 Nov;24(2):92

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http://dx.doi.org/10.1071/NB13012aDOI Listing
November 2013

Role of p38 and JNK MAPK signaling pathways and tumor suppressor p53 on induction of apoptosis in response to Ad-eIF5A1 in A549 lung cancer cells.

Mol Cancer 2013 May 2;12:35. Epub 2013 May 2.

Department of Biology, University of Waterloo, 200 University Ave. W., Waterloo, ON N2L 3G1, Canada.

Background: The eukaryotic translation initiation factor 5A1 (eIF5A1) is a highly conserved protein involved in many cellular processes including cell division, translation, apoptosis, and inflammation. Induction of apoptosis is the only function of eIF5A1 that is known to be independent of post-translational hypusine modification. In the present study, we investigated the involvement of mitogen- and stress-activated protein kinases during apoptosis of A549 lung cancer cells infected with adenovirus expressing eIF5A1 or a mutant of eIF5A1 that cannot be hypusinated (eIF5A1K50A).

Methods: Using adenoviral-mediated transfection of human A549 lung cancer cells to over-express eIF5A1 and eIF5A1K50A, the mechanism by which unhypusinated eIF5A1 induces apoptosis was investigated by Western blotting, flow cytometry, and use of MAPK and p53 inhibitors.

Results: Phosphorylation of ERK, p38 MAPK, and JNK was observed in response to adenovirus-mediated over-expression of eIF5A1 or eIF5A1K50A, along with phosphorylation and stabilization of the p53 tumor suppressor protein. Synthetic inhibitors of p38 and JNK kinase activity, but not inhibitors of ERK1/2 or p53 activity, significantly inhibited apoptosis induced by Ad-eIF5A1. Importantly, normal lung cells were more resistant to apoptosis induced by eIF5A1 and eIF5A1K50A than A549 lung cancer cells.

Conclusions: Collectively these data indicate that p38 and JNK MAP kinase signaling are important for eIF5A1-induced cell death and that induction of apoptosis was not dependent on p53 activity.
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http://dx.doi.org/10.1186/1476-4598-12-35DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660295PMC
May 2013

Comparison of 2 lung recruitment strategies in children with acute lung injury.

Respir Care 2013 Aug 4;58(8):1280-90. Epub 2012 Dec 4.

Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

Background: Lung recruitment maneuvers are frequently used in the treatment of children with lung injury. Here we describe a pilot study to compare the acute effects of 2 commonly used lung recruitment maneuvers on lung volume, gas exchange, and hemodynamic profiles in children with acute lung injury.

Methods: In a prospective, non-randomized, crossover pilot study, 10 intubated pediatric subjects with lung injury sequentially underwent: a period of observation; a sustained inflation (SI) maneuver of 40 cm H2O for 40 seconds and open-lung ventilation; a staircase recruitment strategy (SRS) (which utilized 5 cm H2O increments in airway pressure, from a starting plateau pressure of 30 cm H2O and PEEP of 15 cm H2O); a downwards PEEP titration; and a 1 hour period of observation with PEEP set 2 cm H2O above closing PEEP.

Results: Arterial blood gases, lung mechanics, hemodynamics, and functional residual capacity were recorded following each step of the study and following each increment of the SRS. Both SI and SRS were effective in raising PaO2 and functional residual capacity. During the SRS maneuver we noted significant increases in dead-space ventilation, a decrease in carbon dioxide elimination, an increase in PaCO2, and a decrease in compliance of the respiratory system. Lung recruitment was not sustained following the decremental PEEP titration.

Conclusions: SRS is effective in opening the lung in children with early acute lung injury, and is hemodynamically well tolerated. However, attention must be paid to PaCO2 during the SRS. Even minutes following lung recruitment, lungs may derecruit when PEEP is lowered beyond the closing pressure.
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http://dx.doi.org/10.4187/respcare.01808DOI Listing
August 2013

Modulation of eIF5A expression using SNS01 nanoparticles inhibits NF-κB activity and tumor growth in murine models of multiple myeloma.

Mol Ther 2012 Jul 15;20(7):1305-14. Epub 2012 May 15.

Department of Biology, University of Waterloo, Waterloo, Ontario, Canada.

Despite recent advances in the first-line treatment of multiple myeloma, almost all patients eventually experience relapse with drug-resistant disease. New therapeutic modalities are needed, and to this end, SNS01, a therapeutic nanoparticle, is being investigated for treatment of multiple myeloma. The antitumoral activity of SNS01 is based upon modulation of eukaryotic translation initiation factor 5A (eIF5A), a highly conserved protein that is involved in many cellular processes including proliferation, apoptosis, differentiation and inflammation. eIF5A is regulated by post-translational hypusine modification, and overexpression of hypusination-resistant mutants of eIF5A induces apoptosis in many types of cancer cells. SNS01 is a polyethylenimine (PEI)-based nanoparticle that contains both a B-cell-specific expression plasmid expressing a non-hypusinable mutant of eIF5A and a small interfering RNA (siRNA) which depletes endogenous hypusinated eIF5A. Reducing hypusine-modified eIF5A levels was found to inhibit phosphorylation and activity of ERK MAPK and nuclear factor-κB (NF-κB), and thus sensitize myeloma cells to apoptosis resulting from transfection of a plasmid expressing eIF5A(K50R). SNS01 exhibited significant antitumoral activity in both KAS-6/1 (95% inhibition; P < 0.05) and RPMI 8226 (59% inhibition; P < 0.05) multiple myeloma xenograft models following systemic administration. These results highlight the potential of using this approach as a new therapeutic strategy for multiple myeloma.
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http://dx.doi.org/10.1038/mt.2012.94DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392975PMC
July 2012

The unique hypusine modification of eIF5A promotes islet beta cell inflammation and dysfunction in mice.

J Clin Invest 2010 Jun 24;120(6):2156-70. Epub 2010 May 24.

Department of Pediatrics and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.

In both type 1 and type 2 diabetes, pancreatic islet dysfunction results in part from cytokine-mediated inflammation. The ubiquitous eukaryotic translation initiation factor 5A (eIF5A), which is the only protein to contain the amino acid hypusine, contributes to the production of proinflammatory cytokines. We therefore investigated whether eIF5A participates in the inflammatory cascade leading to islet dysfunction during the development of diabetes. As described herein, we found that eIF5A regulates iNOS levels and that eIF5A depletion as well as the inhibition of hypusination protects against glucose intolerance in inflammatory mouse models of diabetes. We observed that following knockdown of eIF5A expression, mice were resistant to beta cell loss and the development of hyperglycemia in the low-dose streptozotocin model of diabetes. The depletion of eIF5A led to impaired translation of iNOS-encoding mRNA within the islet. A role for the hypusine residue of eIF5A in islet inflammatory responses was suggested by the observation that inhibition of hypusine synthesis reduced translation of iNOS-encoding mRNA in rodent beta cells and human islets and protected mice against the development of glucose intolerance the low-dose streptozotocin model of diabetes. Further analysis revealed that hypusine is required in part for nuclear export of iNOS-encoding mRNA, a process that involved the export protein exportin1. These observations identify the hypusine modification of eIF5A as a potential therapeutic target for preserving islet function under inflammatory conditions.
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http://dx.doi.org/10.1172/JCI38924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877928PMC
June 2010

Arabidopsis eIF5A3 influences growth and the response to osmotic and nutrient stress.

Plant Cell Environ 2010 Oct;33(10):1682-96

Department of Biology, University of Waterloo, Waterloo, Ontario, Canada.

AteIF5A3, one of three genes encoding eukaryotic translation initiation factor 5A (eIF5A) in Arabidopsis thaliana, and corresponding genes PdeIF5A3 from Populus deltoides (eastern cottonwood) and SleIF5A4 from Solanum lycopersicum (tomato) were constitutively over-expressed in A. thaliana. The resultant transgenic plants exhibited enhanced vegetative and reproductive growth. Indeed, the increase in seed yield relative to empty vector controls for the PdeIF5A3 over-expressing plants ranged from 50% to 300% depending on the line. The PdeIF5A3 over-expressing plants also exhibited enhanced fitness when exposed to osmotic and nutrient (N, P and K) stress. The spatial localization of AteIF5A3 was visualized by confocal microscopy using transgenic plants expressing P(AteIF5A3) :GFP-AteIF5A3. GFP fluorescence reflecting expression of AteIF5A3 was detectable in the phloem, particularly companion cells, of roots, stems and leaves, in the epidermal cells of the root tip, in the columella cells of the root cap and in the chalazal tissue of fertilized ovules, which all play a pivotal role in nutrient or hormone translocation. Thus, AteIF5A3 appears to be involved in supporting growth and to play a regulatory role in the response of plants to sub-lethal osmotic and nutrient stress.
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http://dx.doi.org/10.1111/j.1365-3040.2010.02173.xDOI Listing
October 2010

Apoptosis induction by eIF5A1 involves activation of the intrinsic mitochondrial pathway.

J Cell Physiol 2010 Jun;223(3):798-809

Department of Biology, University of Waterloo, Waterloo, Ontario, Canada.

The regulatory role of eukaryotic translation initiation factor 5A1 (eIF5A1) in apoptosis was examined using HT-29 and HeLa S3 cells. eIF5A is the only known protein to contain the unusual amino acid, hypusine, and eIF5A1 is one of two human eIF5A family members. Two observations indicated that eIF5A1 is involved in apoptosis. First, siRNA-mediated suppression of eIF5A1 resulted in inhibition of apoptosis induced by various apoptotic stimuli, and second, adenovirus-mediated over-expression of eIF5A1 strongly induced apoptotic cell death. A mutant of eIF5A1 incapable of being hypusinated also induced apoptosis when over-expressed indicating that unhypusinated eIF5A1 is the pro-apoptotic form of the protein. Over-expression of eIF5A1 or of the mutant resulted in loss of mitochondrial transmembrane potential, translocation of Bax to the mitochondria, release of cytochrome c, caspase activation, up-regulation of p53, and up-regulation of Bim, a pro-apoptotic BH3-only Bcl-2 family protein. In addition, Bim(L) and Bim(S), the pro-apoptotic alternative spliced forms of Bim, were induced in response to over-expression of eIF5A1. Thus eIF5A1 appears to induce apoptosis by activating the mitochondrial apoptotic pathway. Proteomic analyses indicated that, of 1,899 proteins detected, 131 showed significant changes in expression (P or=1.5) within 72 h of eIF5A1 up-regulation. Among these are proteins involved in translation and protein folding, transcription factors, proteins mediating proteolysis, and a variety of proteins known to be directly involved in apoptosis. These observations collectively indicate that unhypusinated eIF5A1 plays a central role in the regulation of apoptosis.
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http://dx.doi.org/10.1002/jcp.22100DOI Listing
June 2010

Respiratory distress associated with inadequate mechanical ventilator flow response in a neonate with congenital diaphragmatic hernia.

Respir Care 2010 Mar;55(3):342-5

Respiratory Care Department, Children's Hospital Boston, Boston, Massachusetts 02115, USA.

The incidence of congenital diaphragmatic hernia has been reported as 0.17-0.66 per 1,000 births. Despite advances in neonatal intensive care, congenital diaphragmatic hernia is associated with high mortality and morbidity. We report a neonate who was born with a left congenital diaphragmatic hernia and underwent surgical repair. The lack of ventilator flow response and flow cycling was identified via interpretation of the ventilator graphic and clinical assessment. Presumably, the ventilator failed to respond to the patient's peak inspiratory flow demand, despite the clinician's setting the highest peak flow available. A time-cycled pressure-limited mode with adjustable peak flow rate was the only option that met the infant's flow requirement, and alleviated the respiratory distress. This clinical finding follows bench research that raises the concern that so called "cradle-to-grave" ventilators may not optimally support all neonates.
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March 2010

Gas exchange and lung mechanics during high frequency ventilation in the perflubron-treated lung.

Pediatr Crit Care Med 2008 Nov;9(6):641-6

Division of Critical Care Medicine, Department of Anesthesia, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.

Objective: To identify the effect of perflubron on gas exchange and lung mechanics during high frequency oscillatory ventilation in an animal model.

Design: Prospective randomized animal trial.

Subjects: Eighteen Yorkshire swine.

Interventions: Three groups of six animals each were investigated: control (high frequency oscillatory ventilation alone), low dose perflubron (high frequency oscillatory ventilation plus perfluoro-octyl bromide [PFOB]-Lo, 1.5 mL/kg), and high dose perflubron (high frequency oscillatory ventilation plus PFOB-Hi, 3 mL/kg). Lung injury was induced with repeated saline lavage and amplified for 1 hr using large tidal volumes. Perflubron (Alliance, CA) or a sham dose (room air) was administered with bronchoscopic guidance. The animals were transitioned to high frequency oscillatory ventilation starting at a mean airway pressure of 15 cm H2O. Mean airway pressure was increased (inflation phase) by 5 cm H2O every 15 mins to a maximum mean airway pressure of 40 cm H2O. During the deflation phase, mean airway pressure was reduced by 5 cm H2O every 15 mins to a mean airway pressure of 15 cm H2O.

Measurements And Main Results: Oxygenation was improved and pulmonary shunt fraction was reduced for PFOB-Hi compared with the control group only at a mean airway pressure of 15 and 20 cm H2O. At a maximal mean airway pressure of 40 cm H2O, oxygenation was not different between the groups, but pulmonary artery pressures were elevated in both PFOB-groups compared with the control group. During the deflation phase, oxygenation, pulmonary shunt fraction, and pulmonary artery pressures were adversely affected by PFOB-Hi and PFOB-Lo.

Conclusions: Although PFOB-Hi compared with the control group improved oxygenation and reduced pulmonary shunt fraction only during the first pressure steps of a formal stepwise recruitment maneuver during high frequency oscillatory ventilation, this effect was not sustained during maximal recruitment. During the deflation phase, both PFOB groups were associated with worse gas exchange compared with the control group. PFOB also produced significant pulmonary hypertension in comparison with the control group.
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http://dx.doi.org/10.1097/PCC.0b013e31818d1742DOI Listing
November 2008

Eukaryotic translation initiation factor 5A is involved in pathogen-induced cell death and development of disease symptoms in Arabidopsis.

Plant Physiol 2008 Sep 16;148(1):479-89. Epub 2008 Jul 16.

Department of Biology, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1.

Eukaryotic translation initiation factor 5A (eIF5A) is a highly conserved protein found in all eukaryotic kingdoms. This study demonstrates that plant eIF5A is involved in the development of disease symptoms induced by a common necrotrophic bacterial phytopathogen. Specifically, AteIF5A-2, one of the three eIF5A genes in Arabidopsis (Arabidopsis thaliana), is shown to regulate programmed cell death caused by infection with virulent Pseudomonas syringae pv tomato DC3000 (Pst DC3000). Transgenic Arabidopsis plants with constitutively suppressed AteIF5A-2 exhibited marked resistance to programmed cell death induced by virulent Pst DC3000, and there was a corresponding reduction in pathogen growth and development of disease symptoms in the plant tissue. Constitutive overexpression of AteIF5A-2 circumvented the apparent posttranscriptional regulation of AteIF5A-2 protein expression characteristic of wild-type plants but did not increase susceptibility to virulent Pst DC3000 ingression. The transgenic plants with constitutive AteIF5A-2 overexpression did, however, display phenotypes consistent with precocious cell death. The results indicate that AteIF5A-2 is a key element of the signal transduction pathway resulting in plant programmed cell death.
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http://dx.doi.org/10.1104/pp.108.118869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2528091PMC
September 2008

Modulation of eIF5A1 expression alters xylem abundance in Arabidopsis thaliana.

J Exp Bot 2008 27;59(4):939-50. Epub 2008 Feb 27.

Department of Biology, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.

Eukaryotic translation initiation factor 5A (eIF5A) is thought to facilitate protein synthesis by participating in the nuclear export of specific mRNAs. In Arabidopsis, there are three isoforms of eIF5A. One of them, AteIF5A1, has been shown to be expressed in vascular tissue, specifically developing vessel members, using GUS as a reporter. In order to determine whether AteIF5A1 plays a role in xylem formation, its full-length cDNA was constitutively over-expressed in transgenic Arabidopsis plants. Microscopic analysis revealed that the cross-sectional area of the xylem in the main inflorescence stems of transgenic plants was 1.9-fold higher than those of corresponding inflorescence stems of wild-type plants. In wild-type stems, the primary xylem typically comprised six cell layers and was approximately 105 mum thick, but increased to 9-11 cell layers, 140-155 mum thick, in transgenic stems. Similarly, the secondary xylem increased from six cell layers, approximately 70 mum thick, in control stems to approximately 9 cell layers, 95-105 mum thick, in transgenic stems. Moreover, constitutive down-regulation of AteIF5A1 using antisense technology resulted in the major suppression of xylem formation compared with control plants, and the antisense transgenic plants were also stunted. These data collectively indicate that eIF5A1 plays a role in xylogenesis.
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http://dx.doi.org/10.1093/jxb/ern017DOI Listing
May 2008

Regulation and execution of molecular disassembly and catabolism during senescence.

New Phytol 2007 ;175(2):201-214

Department of Biology, University of Waterloo, Waterloo, ONT Canada N2L 3G1.

Senescence is a highly orchestrated developmental stage in the life cycle of plants. The onset of senescence is tightly controlled by signaling cascades that initiate changes in gene expression and the synthesis of new proteins. This complement of new proteins includes hydrolytic enzymes capable of executing catabolism of macromolecules, which in turn sets in motion disassembly of membrane molecular matrices, leading to loss of cell function and, ultimately, complete breakdown of cellular ultrastructure. A distinguishing feature of senescence that sets it apart from other types of programmed cell death is the recovery of carbon and nitrogen from the dying tissue and their translocation to growing parts of the plant such as developing seeds. For this to be accomplished, the initiation of senescence and its execution have to be meticulously regulated. For example, the initiation of membrane disassembly has to be intricately linked with the recruitment of nutrients because their ensuing translocation out of the senescing tissue requires functional membranes. Molecular mechanisms underlying this linkage and its integration with the catabolism of macromolecules in senescing tissues are addressed.
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http://dx.doi.org/10.1111/j.1469-8137.2007.02118.xDOI Listing
August 2007

Regional lung volume changes in children with acute respiratory distress syndrome during a derecruitment maneuver.

Crit Care Med 2007 Aug;35(8):1972-8

Division of Critical Care Medicine, Department of Anesthesia, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.

Objective: Regional differences in lung volume have been described in adults with acute respiratory distress syndrome, but it remains unclear to what extent they occur in children. To quantify regional alveolar collapse that occurred during mechanical ventilation during a standardized suctioning maneuver, we evaluated regional and global relative impedance changes (relative DeltaZ) in children with acute respiratory distress syndrome using electrical impedance tomography.

Design: Prospective observational trial.

Setting: A 30-bed pediatric intensive care unit.

Patients: Six children with acute respiratory distress syndrome.

Interventions: Standardized suctioning maneuver.

Measurements And Main Results: By comparing layers from nondependent (layers 1 and 2) to dependent lung areas (layers 3 and 4), it was demonstrated that the middle layers (2 and 3) had the greatest ventilation-induced change in relative DeltaZ; layer 4 showed the least ventilation-induced change in relative DeltaZ. During suctioning, layers 1, 2, and 3 showed a negative change in relative DeltaZ, whereas layer 4 showed no significant change in relative DeltaZ. The derecruitment-induced change in relative DeltaZ representing the lung-volume loss was -9.8 (-3.0 mL/kg) during the first suctioning maneuver, -16.1 (-5.4 mL/kg) during the second, and -21.7 (-7.4 mL/kg) during the third. The ventilation-induced change in relative DeltaZ during mechanical ventilation remained unchanged after suctioning (mean change in relative DeltaZ before vs. after suctioning, 40.1 +/- 9.1 vs. 41.4 +/- 10.8; p = .30). Dynamic compliance was 11.8 +/- 6.1 mL.cm H2O before and 11.8 +/- 6.9 mL.cm H2O after the suctioning sequence (p = .90).

Conclusions: Considerable regional heterogeneity was present during ventilation and a derecruitment maneuver. Significantly lower change in relative DeltaZ in the most dependent lung regions suggests alveolar collapse during ventilation before suctioning.
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http://dx.doi.org/10.1097/01.CCM.0000275390.71601.83DOI Listing
August 2007

Potential drug sequestration during extracorporeal membrane oxygenation: results from an ex vivo experiment.

Intensive Care Med 2007 Jun 3;33(6):1018-24. Epub 2007 Apr 3.

Children's Hospital, Farley 517, Division of Critical Care Medicine, 300 Longwood Avenue, Boston 02115, MA, USA.

Objective: Using an ex vivo simulation model we set out to estimate the amount of drug lost due to sequestration within the extracorporeal circuit over time.

Design: Simulated closed-loop extracorporeal membrane oxygenation (ECMO) circuits were prepared using a 1.5-m2 silicone membrane oxygenator. Group A consisted of heparin, dopamine, ampicillin, vancomycin, phenobarbital and fentanyl. Group B consisted of epinephrine, cefazolin, hydrocortisone, fosphenytoin and morphine. Drugs were tested in crystalloid and blood-primed circuits. After administration of a one-time dose of drugs in the priming fluid, baseline drug concentrations were obtained (P0). A simultaneous specimen was stored for stability testing at 24 h (P4). Serial post-membrane drug concentrations were then obtained at 30 min (P1), 3 h (P2) and 24 h (P3) from circuit fluid.

Measurements And Results: One hundred and one samples were analyzed. At the end of 24 h in crystalloid-primed circuits, 71.8% of ampicillin, 96.7% of epinephrine, 17.6% of fosphenytoin, 33.3% of heparin, 17.5% of morphine and 87% of fentanyl was lost. At the end of 24 h in blood-primed extracorporeal circuits, 15.4% of ampicillin, 21% of cefazolin, 71% of voriconazole, 31.4% of fosphenytoin, 53.3% of heparin and 100% of fentanyl was lost. There was a significant decrease in overall drug concentrations from 30 min to 24 h for both crystalloid-primed circuits (p = 0.023) and blood-primed circuits (p = 0.04).

Conclusions: Our ex vivo study demonstrates serial losses of several drugs commonly used during ECMO therapy. Therapeutic concentrations of fentanyl, voriconazole, antimicrobials and heparin cannot be guaranteed in patients on ECMO.
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http://dx.doi.org/10.1007/s00134-007-0606-2DOI Listing
June 2007

Characterization of a plastid triacylglycerol lipase from Arabidopsis.

Plant Physiol 2007 Mar 26;143(3):1372-84. Epub 2007 Jan 26.

Department of Biology, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1.

Full-length cDNA corresponding to Arabidopsis (Arabidopsis thaliana) gene At2g31690, which has been annotated in GenBank as a putative triacylglycerol (TAG) lipase, was obtained by reverse transcription-polymerase chain reaction using RNA from senescing rosette leaves of Arabidopsis as a template. The cognate protein was found to contain the lipase active site sequence, and corresponding recombinant protein proved capable of deesterifying TAG. In vitro chloroplast import assays indicated that the lipase is targeted to chloroplasts. This was confirmed by confocal microscopy of rosette leaf tissue treated with fluorescein isocyanate-labeled, lipase-specific antibody, which revealed that lipase protein colocalizes with plastoglobular neutral lipids. Western-blot analysis indicated that the lipase is expressed in roots, inflorescence stems, flowers, siliques, and leaves and that it is strongly up-regulated in senescing rosette leaf tissue. Transgenic plants with suppressed lipase protein levels were obtained by expressing At2g31690 cDNA in antisense orientation under the regulation of a constitutive promoter. Transgenic plants bolted and flowered at the same time as wild-type plants, but were severely stunted and exhibited delayed rosette senescence. Moreover, the stunted growth phenotype correlated with irregular chloroplast morphology. The chloroplasts of transgenic plants were structurally deformed, had reduced abundance of thylakoids that were abnormally stacked, and contained more plastoglobular neutral lipids than chloroplasts of wild-type plants. These observations collectively indicate that this TAG lipase plays a role in maintaining the structural integrity of chloroplasts, possibly by mobilizing the fatty acids of plastoglobular TAG.
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http://dx.doi.org/10.1104/pp.106.090811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1820909PMC
March 2007

Eukaryotic translation initiation factor 5A induces apoptosis in colon cancer cells and associates with the nucleus in response to tumour necrosis factor alpha signalling.

Exp Cell Res 2007 Feb 28;313(3):437-49. Epub 2006 Oct 28.

Department of Biology, University of Waterloo, 200 University Ave. W., Waterloo, Ontario, Canada N2L 3G1.

Eukaryotic translation initiation factor 5A (eIF5A) is thought to function as a nucleocytoplasmic shuttle protein. There are reports of its involvement in cell proliferation, and more recently it has also been implicated in the regulation of apoptosis. In the present study, we examined the effects of eIF5A over-expression on apoptosis and of siRNA-mediated suppression of eIF5A on expression of the tumour suppressor protein, p53. Over-expression of either eIF5A or a mutant of eIF5A incapable of being hypusinated was found to induce apoptosis in colon carcinoma cells. Our results also indicate that eIF5A is required for expression of p53 following the induction of apoptosis by treatment with Actinomycin D. Depiction of eIF5A localization by indirect immunofluorescence has indicated, for the first time, that the protein is rapidly translocated from the cytoplasm to the nucleus by death receptor activation or following treatment with Actinomycin D. These findings collectively indicate that unhypusinated eIF5A may have pro-apoptotic functions and that eIF5A is rapidly translocated to the nucleus following the induction of apoptotic cell death.
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http://dx.doi.org/10.1016/j.yexcr.2006.09.030DOI Listing
February 2007

Clinical trial design--effect of prone positioning on clinical outcomes in infants and children with acute respiratory distress syndrome.

J Crit Care 2006 Mar;21(1):23-32; discussion 32-7

Critical Care and Cardiovascular Nursing, Children's Hospital, Boston, MA 02115, USA.

Purpose: This paper describes the methodology of a clinical trial of prone positioning in pediatric patients with acute lung injury (ALI). Nonrandomized studies suggest that prone positioning improves oxygenation in patients with ALI/acute respiratory distress syndrome without the risk of serious iatrogenic injury. It is not known if these improvements in oxygenation result in improvements in clinical outcomes. A clinical trial was needed to answer this question.

Materials And Methods: The pediatric prone study is a multicenter, randomized, noncrossover, controlled clinical trial. The trial is designed to test the hypothesis that at the end of 28 days, children with ALI treated with prone positioning will have more ventilator-free days than children treated with supine positioning. Secondary end points include the time to recovery of lung injury, organ failure-free days, functional outcome, adverse events, and mortality from all causes. Pediatric patients, 42 weeks postconceptual age to 18 years of age, are enrolled within 48 hours of meeting ALI criteria. Patients randomized to the prone group are positioned prone within 4 hours of randomization and remain prone for 20 hours each day during the acute phase of their illness for a maximum of 7 days. Both groups are managed according to ventilator protocol, extubation readiness testing, and sedation protocols and hemodynamic, nutrition, and skin care guidelines.

Conclusions: This paper describes the process, multidisciplinary input, and procedures used to support the design of the clinical trial, as well as the challenges faced by the clinical scientists during the conduct of the clinical trial.
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http://dx.doi.org/10.1016/j.jcrc.2005.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1778462PMC
March 2006

Leaf-specific suppression of deoxyhypusine synthase in Arabidopsis thaliana enhances growth without negative pleiotropic effects.

J Plant Physiol 2007 Apr 5;164(4):408-20. Epub 2006 Apr 5.

Department of Biology, University of Waterloo, Waterloo, Ont, Canada.

Deoxyhypusine synthase (DHS) mediates the first of two enzymatic reactions required for the post-translational activation of eukaryotic translation initiation factor 5A (eIF5A), which in turn is thought to facilitate translation of specific mRNAs. Analyses of GUS activity in transgenic Arabidopsis plants expressing the GUS reporter gene under regulation of the promoter for AtDHS revealed that the expression of DHS changes both spatially and temporally as development progresses. In particular, DHS is expressed not only in rosette leaves, but also in the anthers of developing flowers. To determine the role of DHS in leaves, transgenic plants in which DHS was selectively suppressed in rosettes of Arabidopsis plants were prepared. This was achieved by expressing AtDHS 3'-UTR cDNA as a transgene under regulation of the promoter for AtRbcS2, a gene encoding the small subunit of Rubisco. The dominant phenotypic traits of the DHS-suppressed plants proved to be a dramatic enhancement of both vegetative and reproductive growth. As well, the onset of leaf senescence in the DHS-suppressed plants was delayed by approximately 1 week, but there was no change in the timing of bolting. In addition, there was no evidence for the negative pleiotropic effects, including stunted reproductive growth and reduced seed yield, noted previously for transgenic plants in which DHS was constitutively suppressed. The results indicate that DHS plays a pivotal role in both growth and senescence.
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http://dx.doi.org/10.1016/j.jplph.2006.02.001DOI Listing
April 2007

Effect of prone positioning on clinical outcomes in children with acute lung injury: a randomized controlled trial.

JAMA 2005 Jul;294(2):229-37

Children's Hospital Boston, Medical-Surgical Intensive Care Unit, 300 Longwood Ave, Boston, MA 02115, USA.

Context: In uncontrolled clinical studies, prone positioning appeared to be safe and to improve oxygenation in pediatric patients with acute lung injury. However, the effect of prone positioning on clinical outcomes in children is not known.

Objective: To test the hypothesis that at the end of 28 days infants and children with acute lung injury treated with prone positioning would have more ventilator-free days than those treated with supine positioning.

Design, Setting, And Patients: Multicenter, randomized, controlled clinical trial conducted from August 28, 2001, to April 23, 2004, of 102 pediatric patients from 7 US pediatric intensive care units aged 2 weeks to 18 years who were treated with supine vs prone positioning. Randomization was concealed and group assignment was not blinded.

Intervention: Patients were randomized to either supine or prone positioning within 48 hours of meeting acute lung injury criteria, with those patients in the prone group being positioned within 4 hours of randomization and remaining prone for 20 hours each day during the acute phase of their illness for a maximum of 7 days, after which they were positioned supine. Both groups were treated using lung protective ventilator and sedation protocols, extubation readiness testing, and hemodynamic, nutrition, and skin care guidelines.

Main Outcome Measure: Ventilator-free days to day 28.

Results: The trial was stopped at the planned interim analysis on the basis of the prespecified futility stopping rule. There were no differences in the number of ventilator-free days between the 2 groups (mean [SD], 15.8 [8.5] supine vs 15.6 [8.6] prone; mean difference, -0.2 days; 95% CI, -3.6 to 3.2; P = .91). After controlling for age, Pediatric Risk of Mortality III score, direct vs indirect acute lung injury, and mode of mechanical ventilation at enrollment, the adjusted difference in ventilator-free days was 0.3 days (95% CI, -3.0 to 3.5; P = .87). There were no differences in the secondary end points, including proportion alive and ventilator-free on day 28 (P = .45), mortality from all causes (P>.99), the time to recovery of lung injury (P = .78), organ-failure-free days (P = .88), and cognitive impairment (P = .16) or overall functional health (P = .12) at hospital discharge or on day 28.

Conclusion: Prone positioning does not significantly reduce ventilator-free days or improve other clinical outcomes in pediatric patients with acute lung injury.
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http://dx.doi.org/10.1001/jama.294.2.229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1237036PMC
July 2005

Antisense suppression of deoxyhypusine synthase in tomato delays fruit softening and alters growth and development.

Plant Physiol 2005 Jul 10;138(3):1372-82. Epub 2005 Jun 10.

Department of Biology, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1.

The effects of suppressing deoxyhypusine synthase (DHS) have been examined in tomato (Solanum lycopersicum cv UCT5). DHS mediates the first of two sequential enzymatic reactions that activate eukaryotic translation initiation factor-5A (eIF-5A) by converting a conserved Lys to the unusual amino acid, deoxyhypusine. DHS protein levels were suppressed in transgenic plants by expressing the 3'-untranslated region of tomato DHS under regulation of the constitutive cauliflower mosaic virus promoter. Fruit from the transgenic plants ripened normally, but exhibited delayed postharvest softening and senescence that correlated with suppression of DHS protein levels. Northern-blot analysis indicated that all four gene family members of tomato eIF-5A are expressed in fruit, and that three are up-regulated in parallel with enhancement of DHS mRNA as the fruit begin to senesce and soften. Transgenic plants in which DHS was more strongly suppressed were male sterile, did not produce fruit, and had larger, thicker leaves with enhanced levels of chlorophyll. The activity of PSII was 2 to 3 times higher in these transgenic leaves than in corresponding leaves of wild-type plants, and there was also enhanced deposition of starch in the stems. The data collectively indicate that suppression of DHS has pleiotropic effects on growth and development of tomato. This may, in turn, reflect the fact that there is a single DHS gene in tomato and that its cognate protein is involved in the activation of four distinct isoforms of eIF-5A.
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http://dx.doi.org/10.1104/pp.105.060194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1176410PMC
July 2005

The first use of live continuous glucose monitoring in patients on extracorporeal life support.

Diabetes Technol Ther 2005 Jun;7(3):431-9

Department of Surgery, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.

Background: Evidence suggests that glycemic control provides clinical benefit to critically ill patients. The Extracorporeal Glucose Monitoring System (EGMS), Medtronic Minimed, Northridge, CA) has been developed to measure real-time, continuous blood glucose concentrations in patients on extracorporeal bypass. This pilot study reports the first in vitro and in vivo evaluations of EGMS in an extracorporeal circuit.

Methods: In an in vitro study, three EGMS sensors were inserted in a neonatal extracorporeal circuit. Circuit blood glucose levels were altered by saline dilution and dextrose infusion. EGMS sensors were then inserted into the venous return limb of the extracorporeal circuit in a cohort of six critically ill infants on extracorporeal life support (ECLS). Continuous glucose measurements were compared with laboratory and bedside glucose values at predefined intervals. Linear regression analyses and the Clarke error grid were constructed to analyze device accuracy.

Results: All three in vitro EGMS sensors recorded real-time data without interruption for 48 h. EGMS glucose measurements closely correlated with reference levels (R (2) = 0.93). EGMS glucose values demonstrated an approximate 7-10 min lag while glucose concentrations were rapidly changing. Eight EGMS devices were inserted into six neonates on ECLS on day of life 6 +/- 3. EGMS correlated well with laboratory glucose (R2 = 0.61) and bedside glucose during a hyperinsulinemic euglycemic clamp (R2 = 0.78). On the Clarke error grid, 98% of readings were within zones A and B using laboratory glucose as reference, and 100% were within zones A and B using bedside glucose measurements. Blood glucose range during the in vitro study was 19-295 mg/dL and during the in vivo study was 80-257 mg/dL.

Conclusions: This pilot study suggests that EGMS is a reliable tool for measuring continuous blood glucose in critically ill patients connected to an extracorporeal circuit, although important limitations exist. Potential applications of this technology include intensive glucose monitoring in patients on ECLS, cardiopulmonary bypass, and renal replacement therapy.
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http://dx.doi.org/10.1089/dia.2005.7.431DOI Listing
June 2005

Capnographic waveforms in the mechanically ventilated patient.

Respir Care 2005 Jan;50(1):100-8; discussion 108-9

Respiratory Care Department, Children's Hospital, 300 Longwood Avenue, Boston MA 02115, USA.

A focus on patient safety has heightened the awareness of patient monitoring. The importance of clinical applications of capnography continues to grow, as reflected by the increasing number of medical societies recommending its use. Recognition of changes in the capnogram assists in clinical decision making and treatment and can increase patient safety by alerting the clinician to important situations and changes. This article describes the interpretation of capnograms and how capnogram interpretation influences airway management.
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January 2005

Effect of lung compliance and endotracheal tube leakage on measurement of tidal volume.

Crit Care 2004 Dec 6;8(6):R398-402. Epub 2004 Oct 6.

Pediatric pulmonary and Intensive Care, Dhahran Health Center, Saudi ARAMCO, Saudi Arabia.

Introduction: The objective of this laboratory study was to measure the effect of decreased lung compliance and endotracheal tube (ETT) leakage on measured exhaled tidal volume at the airway and at the ventilator, in a research study with a test lung.

Methods: The subjects were infant, adult and pediatric test lungs. In the test lung model, lung compliances were set to normal and to levels seen in acute respiratory distress syndrome. Set tidal volume was 6 ml/kg across a range of simulated weights and ETT sizes. Data were recorded from both the ventilator light-emitting diode display and the CO2SMO Plus monitor display by a single observer. Effective tidal volume was calculated from a standard equation.

Results: In all test lung models, exhaled tidal volume measured at the airway decreased markedly with decreasing lung compliance, but measurement at the ventilator showed minimal change. In the absence of a simulated ETT leak, calculation of the effective tidal volume led to measurements very similar to exhaled tidal volume measured at the ETT. With a simulated ETT tube leak, the effective tidal volume markedly overestimated tidal volume measured at the airway.

Conclusion: Previous investigators have emphasized the need to measure tidal volume at the ETT for all children. When ETT leakage is minimal, it seems from our simulated lung models that calculation of effective tidal volume would give similar readings to tidal volume measured at the airway, even in small patients. Future studies of tidal volume measurement accuracy in mechanically ventilated children should control for the degree of ETT leakage.
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http://dx.doi.org/10.1186/cc2954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1065056PMC
December 2004

Role of eIF5A in TNF-alpha-mediated apoptosis of lamina cribrosa cells.

Invest Ophthalmol Vis Sci 2004 Oct;45(10):3568-76

Department of Biology, University of Waterloo, Waterloo, Ontario, Canada.

Purpose: To determine the role of eukaryotic translation initiation factor 5A (eIF5A) in TNF-alpha-induced apoptosis of lamina cribrosa (LC) cells.

Methods: LC cells were isolated from optic nerve heads of eyes of two human donors. The cells were treated with TNF-alpha and camptothecin, a TNF synergist, and the incidence of apoptosis was scored by Hoechst staining. Expression of eIF5A protein in response to camptothecin or a combination of camptothecin and TNF-alpha was determined by Western blot analysis. The ability of small inhibitory (si)RNAs directed against eIF5A to protect LC cells from TNF-alpha-induced apoptosis was determined by Hoechst and TUNEL staining of transfected LC cells.

Results: TNF-alpha and camptothecin synergized to induce greater than two times more apoptosis in LC cells than when the cells were treated with TNF-alpha or camptothecin separately. Expression of eIF5A protein increased significantly after 8 hours of exposure to TNF-alpha and camptothecin, but not in response to camptothecin alone. siRNAs directed against eIF5A reduced apoptosis of LC cells in response to TNF-alpha and camptothecin by between 35% and 69%, as determined by Hoechst staining. An siRNA against glyceraldehyde-3-phosphate dehydrogenase (GAPDH) also reduced apoptosis of LC cells by 42%. TUNEL of transfected LC cells treated with TNF-alpha and camptothecin revealed an 80% reduction in apoptosis with siRNA against eIF5A.

Conclusions: TNF-alpha, in synergy with camptothecin, induces apoptosis in human LC cells. eIF5A is upregulated by LC cells in response to TNF-alpha, and siRNAs against eIF5A protect LC cells from apoptosis. Thus, eIF5A appears to be a novel proapoptotic protein in the TNF pathway and a possible target for treatment of glaucoma.
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http://dx.doi.org/10.1167/iovs.03-1367DOI Listing
October 2004

Regulation of senescence by eukaryotic translation initiation factor 5A: implications for plant growth and development.

Trends Plant Sci 2004 Apr;9(4):174-9

Department of Biology, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1.

Regulation of protein synthesis is increasingly being recognized as an important determinant of cell proliferation and senescence. In particular, recent evidence indicates that eukaryotic translation initiation factor 5A (eIF-A) plays a pivotal role in this determination. Separate isoforms of eIF-5A appear to facilitate the translation of mRNAs required for cell division and cell death. This raises the possibility that eIF-5A isoforms are elements of a biological switch that is in one position in dividing cells and in another position in dying cells. Changes in the position of this putative switch in response to physiological and environmental cues are likely to have a significant impact on plant growth and development.
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http://dx.doi.org/10.1016/j.tplants.2004.02.008DOI Listing
April 2004

Pleiotropic effects of suppressing deoxyhypusine synthase expression in Arabidopsis thaliana.

Plant Mol Biol 2003 Aug;52(6):1223-35

Department of Biology, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1.

A full-length cDNA clone encoding deoxyhypusine synthase (DHS) was isolated from a cDNA expression library prepared from senescing leaves of Arabidopsis thaliana. Southern blot analysis indicated that DHS is encoded by a single-copy gene in Arabidopsis. During leaf development, the abundance of DHS mRNA in the third pair of rosette leaves peaked at days 14 and 35 after emergence coincident with the initiation of bolting and the later stages of leaf senescence, respectively. These changes in DHS expression were paralleled by corresponding changes in transcript abundance for eIF-5A1, one of three isoforms of eIF-5A in Arabidopsis. Levels of DHS transcript also increased in detached leaves coincident with post-harvest senescence. DHS was suppressed in transgenic plants by introducing antisense full-length or 3'-untranslated Arabidopsis DHS cDNA under the regulation of the constitutive cauliflower mosaic virus (CaMV-35S) promoter. Plants expressing the antisense transgenes had reduced levels of leaf DHS protein and, depending on the level of DHS suppression, exhibited delayed natural leaf senescence, delayed bolting, increased rosette leaf and root biomass, and enhanced seed yield. Suppression of DHS also delayed premature leaf senescence induced by drought stress resulting in enhanced survival in comparison with wild-type plants. In addition, detached leaves from DHS-suppressed plants exhibited delayed post-harvest senescence. These pleiotropic effects of DHS suppression indicate that the protein plays a central role in plant development and senescence.
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http://dx.doi.org/10.1023/b:plan.0000004332.80792.4dDOI Listing
August 2003

Use of a plant-derived enzyme template for the production of the green-note volatile hexanal.

Biotechnol Bioeng 2003 Nov;84(3):265-73

Department of Biology, University of Waterloo, Waterloo, Ontario, Canada N2L 3G12.

Hexanal is a key organoleptic element of green-note that is found in both fragrances and flavors. We report a novel process for the production of hexanal using immobilized enzyme templates extracted from different plant sources in combination with hollow-fiber ultrafiltration for in situ separation. Enzyme templates, known to be responsible for the synthesis of hexanal from linoleic acid (18:2), were isolated from naturally enriched tissues including carnation petals, strawberry and tomato leaves. These templates were immobilized in an alginate matrix and used as a biocatalyst in a packed-bed bioreactor. Continuous product recovery was achieved using a hollow-fiber ultrafiltration unit. The effects of pH, reaction temperature, and substrate and enzyme concentrations were studied and their effects on hexanal generation identified and optimized. Utilizing optimized conditions, hexanal production 112-fold higher than endogenous steady-state levels in a corresponding amount of plant tissue could be achieved over a 30-minute period. Based on the reactor studies, product inhibition also appears to be an important factor for bioreactor-based hexanal production.
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http://dx.doi.org/10.1002/bit.10776DOI Listing
November 2003

Extended high-frequency partial liquid ventilation in lung injury: gas exchange, injury quantification, and vapor loss.

J Appl Physiol (1985) 2003 Sep 16;95(3):1248-58. Epub 2003 May 16.

Division of Pediatric Critical Care, University of Virginia, Charlottesville, VA 22908-0386, USA.

High-frequency oscillatory ventilation with perflubron (PFB) reportedly improves pulmonary mechanics and gas exchange and attenuates lung injury. We explored PFB evaporative loss kinetics, intrapulmonary PFB distribution, and dosing strategies during 15 h of high-frequency oscillation (HFO)-partial liquid ventilation (PLV). After saline lavage lung injury, 15 swine were rescued with high-frequency oscillatory ventilation (n = 5), or in addition received 10 ml/kg PFB delivered to dependent lung [n = 5, PLV-compartmented (PLV(C))] or 10 ml/kg distributed uniformly within the lung [n = 5, PLV(U)]. In the PLV(C) group, PFB vapor loss was replaced. ANOVA revealed an unsustained improvement in oxygenation index in the PLV(U) group (P = 0.04); the reduction in oxygenation index correlated with PFB losses. Although tissue myeloperoxidase activity was reduced globally by HFO-PLV (P < 0.01) and regional lung injury scores (lung injury scores) in dependent lung were improved (P = 0.05), global lung injury scores were improved by HFO-PLV (P < 0.05) only in atelectasis, edema, and alveolar distension but not in cumulative score. In our model, markers of inflammation and lung injury were attenuated by HFO-PLV, and it appears that uniform intrapulmonary PFB distribution optimized gas exchange during HFO-PLV; additionally, monitoring PFB evaporative loss appears necessary to stabilize intrapulmonary PFB volume.
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http://dx.doi.org/10.1152/japplphysiol.00598.2002DOI Listing
September 2003