Publications by authors named "Eric Hamilton"

18 Publications

  • Page 1 of 1

Patterns and Outcomes Associated With Timeliness of Initial Crystalloid Resuscitation in a Prospective Sepsis and Septic Shock Cohort.

Crit Care Med 2017 Oct;45(10):1596-1606

1Department of Emergency Medicine, Hofstra-Northwell School of Medicine, Hempstead, NY. 2Emergency Medicine Service Line, Northwell Health, New Hyde Park, NY. 3Icahn School of Medicine at Mount Sinai, New York, NY. 4Department of Medicine, Northwell Health System, Hofstra-Northwell School of Medicine, Manhasset, NY. 5Department of Science Education, Hofstra-Northwell School of Medicine, Hempstead, NY. 6Kransoff Quality Mangement Institute, Northwell Health, New Hyde Park, NY. 7Division of Pulmonary, Critical Care, and Sleep Medicine, Northwell Health System, Hofstra-Northwell School of Medicine, Manhasset, NY.

Objectives: The objectives of this study were to 1) assess patterns of early crystalloid resuscitation provided to sepsis and septic shock patients at initial presentation and 2) determine the association between time to initial crystalloid resuscitation with hospital mortality, mechanical ventilation, ICU utilization, and length of stay.

Design: Consecutive-sample observational cohort.

Setting: Nine tertiary and community hospitals over 1.5 years.

Patients: Adult sepsis and septic shock patients captured in a prospective quality improvement database inclusion criteria: suspected or confirmed infection, greater than or equal to two systemic inflammatory response criteria, greater than or equal to one organ-dysfunction criteria.

Interventions: The primary exposure was crystalloid initiation within 30 minutes or lesser, 31-120 minutes, or more than 120 minutes from sepsis identification.

Measurements And Main Results: We identified 11,182 patients. Crystalloid initiation was faster for emergency department patients (β, -141 min; CI, -159 to -125; p < 0.001), baseline hypotension (β, -39 min; CI, -48 to -32; p < 0.001), fever, urinary or skin/soft-tissue source of infection. Initiation was slower with heart failure (β, 20 min; CI, 14-25; p < 0.001), and renal failure (β, 16 min; CI, 10-22; p < 0.001). Five thousand three hundred thirty-six patients (48%) had crystalloid initiated in 30 minutes or lesser versus 2,388 (21%) in 31-120 minutes, and 3,458 (31%) in more than 120 minutes. The patients receiving fluids within 30 minutes had lowest mortality (949 [17.8%]) versus 31-120 minutes (446 [18.7%]) and more than 120 minutes (846 [24.5%]). Compared with more than 120 minutes, the adjusted odds ratio for mortality was 0.76 (CI, 0.64-0.90; p = 0.002) for 30 minutes or lesser and 0.76 (CI, 0.62-0.92; p = 0.004) for 31-120 minutes. When assessed continuously, mortality odds increased by 1.09 with each hour to initiation (CI, 1.03-1.16; p = 0.002). We observed similar patterns for mechanical ventilation, ICU utilization, and length of stay. We did not observe significant interaction for mortality risk between initiation time and baseline heart failure, renal failure, hypotension, acute kidney injury, altered gas exchange, or emergency department (vs inpatient) presentation.

Conclusions: Crystalloid was initiated significantly later with comorbid heart failure and renal failure, with absence of fever or hypotension, and in inpatient-presenting sepsis. Earlier crystalloid initiation was associated with decreased mortality. Comorbidities and severity did not modify this effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CCM.0000000000002574DOI Listing
October 2017

The Tension-sensitive Ion Transport Activity of MSL8 is Critical for its Function in Pollen Hydration and Germination.

Plant Cell Physiol 2017 Jul;58(7):1222-1237

Department of Biology, Box 1137, Washington University in St. Louis, One Brookings Drive, Saint Louis, MO 63130, USA.

All cells respond to osmotic challenges, including those imposed during normal growth and development. Mechanosensitive (MS) ion channels provide a conserved mechanism for regulating osmotic forces by conducting ions in response to increased membrane tension. We previously demonstrated that the MS ion channel MscS-Like 8 (MSL8) is required for pollen to survive multiple osmotic challenges that occur during the normal process of fertilization, and that it can inhibit pollen germination. However, it remained unclear whether these physiological functions required ion flux through a mechanically gated channel provided by MSL8. We introduced two point mutations into the predicted pore-lining domain of MSL8 that disrupted normal channel function in different ways. The Ile711Ser mutation increased the tension threshold of the MSL8 channel while leaving conductance unchanged, and the Phe720Leu mutation severely disrupted the MSL8 channel. Both of these mutations impaired the ability of MSL8 to preserve pollen viability during hydration and to maintain the integrity of the pollen tube when expressed at endogenous levels. When overexpressed in an msl8-4 null background, MSL8I711S could partially rescue loss-of-function phenotypes, while MSL8F720L could not. When overexpressed in the wild-type Ler background, MSL8I711S suppressed pollen germination, similar to wild-type MSL8. In contrast, MSL8F720L failed to suppress pollen germination and increased pollen bursting, thereby phenocopying the msl8-4 mutant. Thus, an intact MSL8 channel is required for normal pollen function during hydration and germination. These data establish MSL8 as the first plant MS channel to fulfill previously established criteria for assignment as a mechanotransducer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/pcp/pcw230DOI Listing
July 2017

Survival Benefit and Cost Savings From Compliance With a Simplified 3-Hour Sepsis Bundle in a Series of Prospective, Multisite, Observational Cohorts.

Crit Care Med 2017 Mar;45(3):395-406

1Department of Emergency Medicine, Hofstra-Northwell School of Medicine, Hempstead, NY. 2Icahn School of Medicine at Mount Sinai, New York, NY. 3Department of Medicine, Hofstra-Northwell School of Medicine, Hempstead, NY. 4Department of Neurosurgery, Hofstra-Northwell School of Medicine, Hempstead, NY. 5Feinstein Institute for Medical Research, Manhasset, NY. 6Krasnoff Quality Management Institute, Northwell Health System, New Hyde Park, NY.

Objectives: To determine mortality and costs associated with adherence to an aggressive, 3-hour sepsis bundle versus noncompliance with greater than or equal to one bundle element for severe sepsis and septic shock patients.

Design: Prospective, multisite, observational study following three sequential, independent cohorts, from a single U.S. health system, through their hospitalization.

Setting: Cohort 1: five tertiary and six community hospitals. Cohort 2: single tertiary, academic medical center. Cohort 3: five tertiary and four community hospitals.

Patients: Consecutive sample of all severe sepsis and septic shock patients (defined: infection, ≥ 2 systemic inflammatory response syndrome, and hypoperfusive organ dysfunction) identified by a quality initiative. The exposure was full 3-hour bundle compliance. Bundle elements are as follows: 1) blood cultures before antibiotics; 2) parenteral antibiotics administered less than or equal to 180 minutes from greater than or equal to two systemic inflammatory response syndrome "and" lactate ordered, or less than or equal to 60 minutes from "time-zero," whichever occurs earlier; 3) lactate result available less than or equal to 90 minutes postorder; and 4) 30 mL/kg IV crystalloid bolus initiated less than or equal to 30 minutes from "time-zero." Main outcomes were in-hospital mortality (all cohorts) and total direct costs (cohorts 2 and 3).

Measurements And Main Results: Cohort 1: 5,819 total patients; 1,050 (18.0%) bundle compliant. Mortality: 604 (22.6%) versus 834 (26.5%); CI, 0.9-7.1%; adjusted odds ratio, 0.72; CI, 0.61-0.86; p value is less than 0.001. Cohort 2: 1,697 total patients; 739 (43.5%) bundle compliant. Mortality: 99 (13.4%) versus 171 (17.8%), CI, 1.0-7.9%; adjusted odds ratio, 0.60; CI, 0.44-0.80; p value is equal to 0.001. Mean costs: $14,845 versus $20,056; CI, -$4,798 to -5,624; adjusted β, -$2,851; CI, -$4,880 to -822; p value is equal to 0.006. Cohort 3: 7,239 total patients; 2,115 (29.2%) bundle compliant. Mortality: 383 (18.1%) versus 1,078 (21.0%); CI, 0.9-4.9%; adjusted odds ratio, 0.84; CI, 0.73-0.96; p value is equal to 0.013. Mean costs: $17,885 versus $22,108; CI, -$2,783 to -5,663; adjusted β, -$1,423; CI, -$2,574 to -272; p value is equal to 0.015.

Conclusions: In three independent cohorts, 3-hour bundle compliance was associated with improved survival and cost savings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CCM.0000000000002184DOI Listing
March 2017

Propofol for Treatment of Refractory Alcohol Withdrawal Syndrome: A Review of the Literature.

Pharmacotherapy 2016 Apr 1;36(4):433-42. Epub 2016 Apr 1.

University of Arkansas for Medical Sciences Medical Center, Little Rock, Arkansas.

The authors evaluated all available evidence on the use of propofol as an adjuvant for the treatment of resistant alcohol withdrawal syndrome (AWS) in comparison to other therapies. A comprehensive PubMed search (1966-December 2015) was conducted using the search terms propofol, alcohol withdrawal, and drug therapy. Articles were cross-referenced for other citations. Clinical studies, case series, and case reports published in the English language assessing the use of propofol in adult patients for treatment of AWS were reviewed for inclusion. Propofol is a sedative-hypnotic that exerts its actions through agonism of GABAA receptors at a different binding site than benzodiazepines and reduces glutamatergic activity through N-methyl-d-aspartase (NMDA) receptor blockade. Dosages from 5 to 100 μg/kg/minute reduced AWS symptoms with frequent development of hypotension and requirement for mechanical ventilation. Patients on propofol often experienced longer durations of mechanical ventilation and length of stay, which may be attributed to more-resistant cases of AWS. When propofol was compared with dexmedetomidine as adjuncts in AWS, both agents showed similar benzodiazepine- and haloperidol-sparing effects. Dexmedetomidine was associated with more numerical rates of bradycardia, while propofol was associated with more numerical instances of hypotension. Dexmedetomidine was used more frequently in nonintubated patients. The available data assessing the utility of propofol for AWS exhibited significant heterogeneity. Propofol may be useful in a specific population of patients with AWS, limited to those who are not clinically responding to first-line therapy with benzodiazepines. Specifically, propofol should be considered in patients who are refractory to or not candidates for other adjuvant therapies, patients already requiring mechanical ventilation, or those with seizure activity or refractory delirium tremens. In severe, refractory AWS, adjuvant therapy with propofol may be considered but requires further research to recommend its use either preferentially or as monotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/phar.1726DOI Listing
April 2016

Mechanosensitive channel MSL8 regulates osmotic forces during pollen hydration and germination.

Science 2015 Oct;350(6259):438-41

Department of Biology, Washington University in Saint Louis, Saint Louis, MO 63130, USA.

Pollen grains undergo dramatic changes in cellular water potential as they deliver the male germ line to female gametes, and it has been proposed that mechanosensitive ion channels may sense the resulting mechanical stress. Here, we identify and characterize MscS-like 8 (MSL8), a pollen-specific, membrane tension-gated ion channel required for pollen to survive the hypoosmotic shock of rehydration and for full male fertility. MSL8 negatively regulates pollen germination but is required for cellular integrity during germination and tube growth. MSL8 thus senses and responds to changes in membrane tension associated with pollen hydration and germination. These data further suggest that homologs of bacterial MscS have been repurposed in eukaryotes to function as mechanosensors in multiple developmental and environmental contexts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aac6014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764502PMC
October 2015

Reassess the t Test: Interact with All Your Data via ANOVA.

Plant Cell 2015 Aug 28;27(8):2088-94. Epub 2015 Jul 28.

DynaMo Center of Excellence, University of Copenhagen, DK-1871 Frederiksberg C, Denmark Department of Plant Sciences, University of California, Davis, California 95616

Plant biology is rapidly entering an era where we have the ability to conduct intricate studies that investigate how a plant interacts with the entirety of its environment. This requires complex, large studies to measure how plant genotypes simultaneously interact with a diverse array of environmental stimuli. Successful interpretation of the results from these studies requires us to transition away from the traditional standard of conducting an array of pairwise t tests toward more general linear modeling structures, such as those provided by the extendable ANOVA framework. In this Perspective, we present arguments for making this transition and illustrate how it will help to avoid incorrect conclusions in factorial interaction studies (genotype × genotype, genotype × treatment, and treatment × treatment, or higher levels of interaction) that are becoming more prevalent in this new era of plant biology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1105/tpc.15.00238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568503PMC
August 2015

United in diversity: mechanosensitive ion channels in plants.

Annu Rev Plant Biol 2015 8;66:113-37. Epub 2014 Dec 8.

Department of Biology, Washington University in Saint Louis, Saint Louis, Missouri 63130; email: , ,

Mechanosensitive (MS) ion channels are a common mechanism for perceiving and responding to mechanical force. This class of mechanoreceptors is capable of transducing membrane tension directly into ion flux. In plant systems, MS ion channels have been proposed to play a wide array of roles, from the perception of touch and gravity to the osmotic homeostasis of intracellular organelles. Three families of plant MS ion channels have been identified: the MscS-like (MSL), Mid1-complementing activity (MCA), and two-pore potassium (TPK) families. Channels from these families vary widely in structure and function, localize to multiple cellular compartments, and conduct chloride, calcium, and/or potassium ions. However, they are still likely to represent only a fraction of the MS ion channel diversity in plant systems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1146/annurev-arplant-043014-114700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4470482PMC
January 2016

4-Hydroxy-2(E)-nonenal (HNE) catabolism and formation of HNE adducts are modulated by β oxidation of fatty acids in the isolated rat heart.

Free Radic Biol Med 2013 May 15;58:35-44. Epub 2013 Jan 15.

Department of Nutrition, Case Western Reserve University, Cleveland, OH 44106, USA.

We previously reported that a novel metabolic pathway functionally catabolizes 4-hydroxy-2(E)-nonenal (HNE) via two parallel pathways, which rely heavily on β-oxidation pathways. The hypothesis driving this report is that perturbations of β oxidation will alter the catabolic disposal of HNE, favoring an increase in the concentrations of HNE and HNE-modified proteins that may further exacerbate pathology. This study employed Langendorff perfused hearts to investigate the impact of cardiac injury modeled by ischemia/reperfusion and, in a separate set of perfusions, the effects of elevated lipid (typically observed in obesity and type II diabetes) by perfusing with increased fatty acid concentrations (1mM octanoate). During ischemia, HNE concentrations doubled and the glutathione-HNE adduct and 4-hydroxynonanoyl-CoA were increased by 7- and 10-fold, respectively. Under conditions of increased fatty acid, oxidation to 4-hydroxynonenoic acid was sustained; however, further catabolism through β oxidation was nearly abolished. The inhibition of HNE catabolism was not compensated for by other disposal pathways of HNE, rather an increase in HNE-modified proteins was observed. Taken together, this study presents a mechanistic rationale for the accumulation of HNE and HNE-modified proteins in pathological conditions that involve alterations to β oxidation, such as myocardial ischemia, obesity, and high-fat diet-induced diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.freeradbiomed.2013.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723455PMC
May 2013

Influences of microbubble diameter and ultrasonic parameters on in vitro sonothrombolysis efficacy.

J Vasc Interv Radiol 2012 Dec 27;23(12):1677-1684.e1. Epub 2012 Oct 27.

Department of Radiology, University of Arkansas for Medical Sciences, 4301 West Markham Street Slot #556, Little Rock, AR 72205, USA.

Purpose: To quantify the effects of microbubble (MB) size, elasticity, and pulsed ultrasonic parameters on in vitro sonothrombolysis (ultrasound [US]-mediated thrombolysis) efficacy.

Materials And Methods: Monodispersive MBs with diameters of 1 μm or 3 μm were exposed to pulsed US (1 MHz or 3 MHz) to lyse rabbit blood clots. Sonothrombolysis efficacy (clot mass loss) was measured as functions of MB size and concentration, ultrasonic frequency and intensity, pulse duration (PD), pulse repeat frequency (PRF), and duty factor.

Results: Sonothrombolysis at 1 MHz was more effective using 3-μm MBs and at 3 MHz using 1-μm MBs. Sonothrombolysis was more effective at 1 MHz when≥75% of MBs remained intact, especially for 3-μm MBs; improving sonothrombolysis by increasing PRF from 100 Hz to 400 Hz at 3 MHz was associated with increasing 3-μm MB survival. However, 60% of 1-μm MBs were destroyed during maximal sonothrombolysis at 3 MHz, indicating that considerable MB collapse may be required for sonothrombolysis under these conditions.

Conclusions: The ability to control MB size and elasticity permits using a wide range of US parameters (eg, frequency, intensity) to produce desired levels of sonothrombolysis. Comparable, maximal sonothrombolysis efficacy was achieved at 20-fold lower intensity with 3-μm MBs (0.1W/cm(2)) than with 1-μm MBs (2.0W/cm(2)), a potential safety issue for in vivo sonothrombolysis. US parameters that maximized MB survival yielded maximal sonothrombolysis efficacy except with 1-μm MBs at 3MHz where most MBs were destroyed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jvir.2012.08.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3508303PMC
December 2012

Production of uniformly sized serum albumin and dextrose microbubbles.

Ultrason Sonochem 2012 Jan 27;19(1):198-208. Epub 2011 May 27.

Department of Radiology, University of Arkansas for Medical Sciences, 4301 West Markham Street Slot #556, Little Rock, AR 72205, USA.

Uniformly-sized preparations with average microbubble (MB) diameters from 1 to 7 μm were produced reliably by sonicating decafluorobutane-saturated solutions of serum albumin and dextrose. Detailed protocols for producing and size-separating the MBs are presented, along with the effects that changing each production parameter (serum albumin concentration, sonication power, sonication time, etc.) had on MB size distribution and acoustic stability. These protocols can be used to produce MBs for experimental applications or serve as templates for developing new protocols that yield MBs with physical and acoustic properties better suited to specific applications. Size stability and ultrasonic performance quality control tests were developed to assure that successive MB preparations perform identically and to distinguish the physical and acoustic properties of identically sized MBs produced with different serum albumin-dextrose formulations and sonication parameters. MBs can be stored at 5 °C for protracted periods (2 weeks to one year depending on formulation).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ultsonch.2011.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152625PMC
January 2012

Sex differences in behavior and expression of CGRP-related genes in a rodent model of chronic migraine.

Headache 2011 May;51(5):674-92

Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, University of Kansas Medical Center, Kansas City, KS, USA.

Objective: The objectives of this study were to develop a preclinical rodent model that produces migraine-like behaviors based on International Headache Society diagnostic criteria, to determine whether sex differences are present, and to determine whether expression of calcitonin gene-related peptide (CGRP) and the genes encoding its receptor in trigeminal ganglion or medulla correlates with those behaviors.

Background: Few animal studies of migraine have tested behaviors associated with migraine diagnostic criteria. In this study, changes in activity and in mechanical sensitivity of facial regions following application of inflammatory soup (IS) or vehicle (phosphate-buffered saline [PBS]) to the dura were measured to model changes in routine activity and allodynia. CGRP, an important mediator of migraine pathogenesis, and the 3 components of its receptor, calcitonin-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and receptor component protein (RCP) mRNAs were quantified in the trigeminal ganglion and medulla to identify baseline sex differences and changes associated with application of IS or PBS to the dura.

Methods: Male and female Sprague-Dawley rats were implanted with a dural cannula. Groups of rats were treated with 10 or 20 µL volumes of IS or PBS. Baseline behavioral testing was conducted prior to surgery and again at 7 days postsurgery, and dural application of IS or PBS was performed repeatedly for a total of 8 applications. Locomotor activity was assessed using force plate actimetry during and following application to provide information on distance traveled, bouts of low mobility, spatial confinement, and focused energy. Periorbital and perimasseter sensory testing was performed 20 minutes post-application to measure allodynia. The rats were sacrificed 30 minutes following the final dural treatment, tissue was dissected and total RNAs were isolated from ipsilateral trigeminal ganglia and ipsilateral medulla. Quantitative real-time polymerase chain reactions were used to measure the expression of amplified constructs using gene-specific primers for CGRP, RAMP1, CLR, and RCP.

Results: Both males and females showed behavioral effects of IS application, but there were pronounced sex differences. Females showed effects at the lower dose, and activity changes were present for a longer duration, but males required fewer applications of IS to exhibit behavioral changes. Females showed increased withdrawal responses for periorbital and perimasseter mechanical testing (10 µL IS groups), and males showed increased perimasseter withdrawal responses (20 µL IS group). In the trigeminal ganglion, there were no baseline sex differences in CGRP-encoding mRNA, but females had lower baseline expression of RAMP1, CLR, and RCP-encoding mRNAs. In the medulla, females had higher baseline levels of CGRP-encoding mRNAs and lower baseline levels of RAMP1, CLR, and RCP-encoding mRNAs than males. Both IS and PBS increased expression of mRNAs encoding CGRP, RAMP1, RCP, and CLR in the trigeminal ganglion in males, but in females, only CLR and RCP were increased. In the medulla both IS and PBS increased expression of CGRP, CLR in males and CLR and RCP in females. Thus, expression of CGRP-related genes did not mirror the behavioral differences between IS and PBS groups. Instead, CGRP-related genes were upregulated by both IS and PBS applications.

Conclusions: This study demonstrates significant changes in locomotor activity and facial allodynia associated with application of IS to the dura as well as significant sex differences, demonstrating that International Headache Society diagnostic criteria can be used to design a rodent behavioral model of migraine. In addition, there were prominent baseline sex differences in expression of CGRP and its receptor in both the trigeminal ganglion and medulla, but the majority of changes in expression of CGRP and its receptor were present in both the IS and PBS treated rats. This suggests that the CGRP pathway responds to changes in intracranial pressure or meningeal stretch, while migraine-like behaviors occur after meningeal inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1526-4610.2011.01882.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4079043PMC
May 2011

Microbubbles improve sonothrombolysis in vitro and decrease hemorrhage in vivo in a rabbit stroke model.

Invest Radiol 2011 Mar;46(3):202-7

Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

Introduction: Tissue plasminogen activator (tPA) is the thrombolytic standard of care for acute ischemic stroke, but intracerebral hemorrhage (ICH) remains a common and devastating complication. We investigated using ultrasound (US) and microbubble (MB) techniques to reduce required tPA doses and to decrease ICH.

Materials And Methods: Fresh blood clots (3-5 hours) were exposed in vitro to tPA (0.02 or 0.1 mg/mL) plus pulsed 1 MHz US (0.1 W/cm²), with or without 1.12 × 10⁸/mL MBs (Definity or albumin/dextrose MBs [adMB]). Clot mass loss was measured to quantify thrombolysis. New Zealand white rabbits (n = 120) received one 3- to 5-hour clot angiographically delivered into the internal carotid artery. All had transcutaneous pulsed 1 MHz US (0.8 W/cm²) for 60 minutes and intravenous tPA (0.1-0.9 mg/kg) with or without Definity MBs (0.16 mL/mg/kg). After killing the animals, the brains were removed for histology 24 hours later.

Results: In vitro, MBs (Definity or adMB) increased US-induced clot loss significantly, with or without tPA (P < 0.0001). At 0 and 0.02 mg/mL, tPA clot loss was greater with adMBs compared with Definity (P ≤ 0.05). With MB, the tPA dose was reduced 5-fold with good efficacy. In vivo, both Definity MB and tPA groups had less infarct volume compared with controls at P < 0.0183 and P = 0.0003, respectively. Definity MB+tPA reduces infarct volume compared with controls (P < 0.0001), and ICH incidence outside of strokes was significantly lower (P = 0.005) compared with no MB. However, infarct volume in Definity MB versus tPA was not different at P = 0.19.

Conclusion: Combining tPA and MB yielded effective loss of clot with very low dose or even no dose tPA, and infarct volumes and ICH were reduced in acute strokes in rabbits. The ability of MBs to reduce tPA requirements may lead to lower rates of hemorrhage in human stroke treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/RLI.0b013e318200757aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3845811PMC
March 2011

Impaired expression of neuroprotective molecules in the HIF-1alpha pathway following traumatic brain injury in aged mice.

J Neurotrauma 2009 Sep;26(9):1557-66

Steve Palermo Nerve Regeneration Laboratory, University of Kansas Medical Center, Kansas City, Kansas, USA.

Elderly traumatic brain injury (TBI) patients have higher rates of mortality and worse functional outcome than non-elderly TBI patients. The mechanisms involved in poor outcomes in the elderly are not well understood. Hypoxia-inducible factor-1 alpha (HIF-1alpha) is a basic helix-loop-helix transcription factor that modulates expression of key genes involved in neuroprotection. In this study, we studied the expression of HIF-1alpha and its target survival genes, heme oxygenase-1 (HO-1), vascular endothelial growth factor (VEGF), and erythropoietin (EPO) in the brains of adult versus aged mice following controlled cortical impact (CCI) injury. Adult (5-6 months) and aged (23-24 months) C57Bl/6 mice were injured using a CCI device. At 72 h post-injury, mice were sacrificed and the injured cortex was used for mRNA and protein analysis using real-time reverse transcription--polymerase chain reaction (RT-PCR) and Western blotting protocols. Following injury, HIF-1alpha, HO-1, and VEGF showed upregulation in both the young and aged mice, but in the aged animals the increase in HIF-1alpha and VEGF in response to injury was much lower than in the adult injured animals. EPO was upregulated in the adult injured brain, but not in the aged injured brain. These results support the hypothesis that reduced expression of genes in the HIF-1alpha neuroprotective pathway in aging may contribute to poor prognosis in the elderly following TBI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/neu.2008.0765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2822808PMC
September 2009

Benchmarking the effectiveness of psychotherapy treatment for adult depression in a managed care environment: a preliminary study.

J Consult Clin Psychol 2008 Feb;76(1):116-24

Department of Educational Psychology, University of Utah, Salt Lake City, UT 84112, USA.

This preliminary study evaluated the effectiveness of psychotherapy treatment for adult clinical depression provided in a natural setting by benchmarking the clinical outcomes in a managed care environment against effect size estimates observed in published clinical trials. Overall results suggest that effect size estimates of effectiveness in a managed care context were comparable to effect size estimates of efficacy observed in clinical trials. Relative to the 1-tailed 95th-percentile critical effect size estimates, effectiveness of treatment provided in this setting was observed to be between 80% (patients with comorbidity and without antidepressants) and 112% (patients without comorbidity concurrently on antidepressants) as compared to the benchmarks. Because the nature of the treatments delivered in the managed care environment were unknown, it was not possible to make conclusions about treatments. However, while replications are warranted, concerns that psychotherapy delivered in a naturalistic setting is inferior to treatments delivered in clinical trials appear unjustified.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1037/0022-006X.76.1.116DOI Listing
February 2008

Leg flow-mediated arterial dilation in elderly patients with heart failure and normal left ventricular ejection fraction.

Am J Physiol Heart Circ Physiol 2007 Mar 3;292(3):H1427-34. Epub 2006 Nov 3.

Department of Internal Medicine, Section on Cardiology, Wake Forest Univ School of Medicine, Bowman Gray Campus, Winston-Salem, NC 27157-1045, USA.

Background: flow-mediated arterial dilation (FMAD), an indicator of endothelial function, is reduced in patients with heart failure and reduced left ventricular ejection fraction (HFREF). Many elderly patients with heart failure exhibit a normal left ventricular ejection fraction (HFNEF). It is unknown whether FMAD is severely reduced in the elderly with HFNEF.

Methods And Results: 30 participants >60 yr of age, 11 healthy, 9 with HFNEF, and 10 with HFREF, underwent a cardiovascular magnetic resonance (CMR) assessment of FMAD in the superficial femoral artery followed within 48 h by symptom-limited exercise with expired gas analysis. Elderly patients with HFREF and HFNEF had severely reduced peak oxygen consumption (Vo(2 peak); 12 +/- 2 and 13 +/- 1 ml.kg(-1).min(-1), respectively) vs. their healthy age-matched contemporaries (20 +/- 3 ml.kg(-1).min(-1)). FMAD was 3.8 +/- 1.3% (0.85 +/- 0.22 mm(2)) in patients with HFREF; it was 12.1 +/- 3.6% (3.1 +/- 1.2 mm(2)) and 13.7 +/- 5.9% (3.9 +/- 1.7 mm(2)), respectively, in patients with HFNEF and age-matched healthy older individuals. After adjustment for age and gender, the association of FMAD with Vo(2) was high in healthy and HFREF subjects (P = 0.05 and 0.02, respectively) but less so in HFNEF participants (P = 0.58).

Conclusions: elderly patients with HFNEF do not exhibit marked reduction in leg FMAD. These data suggest that mechanisms other than impaired femoral arterial endothelial function contribute to the severe exercise intolerance experienced by these individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpheart.00567.2006DOI Listing
March 2007

Perfluorochemical liquids enhance delivery of superoxide dismutase to the lungs of juvenile rabbits.

Pediatr Res 2006 Jul 11;60(1):65-70. Epub 2006 May 11.

Division of Neonatology , Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

Previous studies suggest acute lung injury (ALI) in premature newborns is associated with relative deficiency of antioxidant enzymes that may be ameliorated by recombinant human superoxide dismutase (rhSOD). Perfluorochemicals (PFCs) are distributed homogeneously and support gas exchange in diseased lungs. We investigated whether PFCs could provide an effective delivery system for rhSOD. Juvenile rabbits were lung-lavaged, treated with surfactant, and randomized: group I: fluorescently labeled rhSOD (5 mg/kg in 2 mL/kg saline); group II: fluorescently labeled rhSOD (5 mg/kg in 18 mL/kg PFC). Animals were ventilated with oxygen for 4 h; the lungs were harvested for analysis of SOD distribution and oxidative injury. Cardiopulmonary indices remained stable and similar between groups. Qualitative assessment (QA) showed a more homogeneous lung SOD distribution in group II and a better histologic profile. QA of lung SOD distribution showed significant increase in SOD concentrations in group II (7.37 +/- 1.54 microg/mg protein) compared with group I (1.65 +/- 0.23 microg/mg protein). Oxidative injury as assessed by normalized protein carbonyl was 149.1 +/- 26.8% SEM in group II compared with 200.5 +/- 7.3% SEM in group I. Plasma SOD was significantly higher in group II. Administration of rhSOD with or without PFCs does not compromise cardiovascular function or impede lung recovery after ALI. PFCs enhance rhSOD delivery to the lungs by 400% while decreasing lung oxidative damage by 25% compared with rhSOD alone. These data suggest that PFCs optimize lung rhSOD delivery and might enhance the beneficial effects of rhSOD in preventing acute and chronic lung injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1203/01.pdr.0000219392.73509.70DOI Listing
July 2006