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Biomedical subjects

Timothy J Gardner

Publications and source records attributed to Timothy J Gardner.

At least 19 recordsLinked to original sources
PubMed2006

Effect of blinded peer review on abstract acceptance.

CONTEXT: Peer review should evaluate the merit and quality of abstracts but may be biased by geographic location or institutional prestige. The effectiveness of blinded peer review at reducing bias is unknown. OBJECTIVE: To evaluate the effect of blinded review on the association between abstract characteristics and likelihood of abstract acceptance at a national research meeting. DESIGN AND SETTING: All abstracts submitted to the American Heart Association's annual Scientific Sessions research meeting from 2000-2004. Abstract review included the author's name and institution (open review) from 2000-2001, and this information was concealed (blinded review) from 2002-2004. Abstracts were categorized by country, primary language, institution prestige, author sex, and government and industry status. MAIN OUTCOME MEASURE: Likelihood of abstract acceptance during open and blinded review, by abstract characteristics. RESULTS: The mean number of abstracts submitted each year for evaluation was 13,455 and 28.5% were accepted. During open review, 40.8% of US and 22.6% of non-US abstracts were accepted (relative risk [RR], 1.81; 95% confidence interval [CI], 1.75-1.88), whereas during blinded review, 33.4% of US and 23.7% of non-US abstracts were accepted (RR, 1.41; 95% CI, 1.37-1.45; P<.001 for comparison between peer review periods). Among non-US abstracts, during open review, 31.1% from English- speaking countries and 20.9% from non-English-speaking countries were accepted (RR, 1.49; 95% CI, 1.39-1.59), whereas during blinded review, 28.8% and 22.8% of abstracts were accepted, respectively (RR, 1.26; 95% CI, 1.19-1.34; P<.001). Among abstracts from US academic institutions, during open review, 51.3% from highly prestigious and 32.6% from nonprestigious institutions were accepted (RR, 1.57; 95% CI, 1.48-1.67), whereas during blinded review, 38.8% and 29.0% of abstracts were accepted, respectively (RR, 1.34; 95% CI, 1.26-1.41; P<.001). CONCLUSIONS: This study provides evidence of bias in the open review of abstracts, favoring authors from the United States, English-speaking countries outside the United States, and prestigious academic institutions. Moreover, blinded review at least partially reduced reviewer bias.

Abstracting and Indexing↗
PubMed2006

Sparse time-frequency representations.

Auditory neurons preserve exquisite temporal information about sound features, but we do not know how the brain uses this information to process the rapidly changing sounds of the natural world. Simple arguments for effective use of temporal information led us to consider the reassignment class of time-frequency representations as a model of auditory processing. Reassigned time-frequency representations can track isolated simple signals with accuracy unlimited by the time-frequency uncertainty principle, but lack of a general theory has hampered their application to complex sounds. We describe the reassigned representations for white noise and show that even spectrally dense signals produce sparse reassignments: the representation collapses onto a thin set of lines arranged in a froth-like pattern. Preserving phase information allows reconstruction of the original signal. We define a notion of "consensus," based on stability of reassignment to time-scale changes, which produces sharp spectral estimates for a wide class of complex mixed signals. As the only currently known class of time-frequency representations that is always "in focus" this methodology has general utility in signal analysis. It may also help explain the remarkable acuity of auditory perception. Many details of complex sounds that are virtually undetectable in standard sonograms are readily perceptible and visible in reassignment.

Animals↗
PubMed2006

Fructose 1,6-diphosphate administration attenuates post-ischemic ventricular dysfunction.

BACKGROUND: Cardiomyocyte energy production during ischemia depends upon anaerobic glycolysis inefficiently yielding two ATP per glucose. Substrate augmentation with fructose 1,6-diphosphate (FDP) bypasses the ATP consuming steps of glucokinase and phosphofructokinase thus yielding four ATP per FDP. This study evaluated the impact of FDP administration on myocardial function after acute ischemia. METHODS: Male Wistar rats, 250-300 g, underwent 30 min occlusion of the left anterior descending coronary artery followed by 30 min reperfusion. Immediately prior to both ischemia and reperfusion, animals received an intravenous bolus of FDP or saline control. After 30 min reperfusion, myocardial function was evaluated with a left ventricular intracavitary pressure/volume conductance microcatheter. For bioenergetics studies, myocardium was isolated at 5 min of ischemia and assayed for ATP levels. RESULTS: Compared to controls (n=8), FDP animals (n=8) demonstrated significantly improved maximal left ventricular pressure (100.5+/-5.4 mmHg versus 69.1+/-1.9 mmHg; p<0.0005), dP/dt (5296+/-531 mmHg/s versus 2940+/-175 mmHg/s; p<0.0028), ejection fraction (29.1+/-1.7% versus 20.4+/-1.4%; p<0.0017), and preload adjusted maximal power (59.3+/-5.0 mW/microL(2) versus 44.4+/-4.6 mW/microL(2); p<0.0477). Additionally, significantly enhanced ATP levels were observed in FDP animals (n=5) compared to controls (n=5) (535+/-156 nmol/g ischemic tissue versus 160+/-9.0 nmol/g ischemic tissue; p<0.0369). CONCLUSIONS: The administration of the glycolytic intermediate, FDP, by intravenous injection, resulted in significantly improved myocardial function after ischemia and improved bioenergetics during ischemia.

Adenosine Triphosphate↗
PubMed2006

Mesenchymal stem cell injection after myocardial infarction improves myocardial compliance.

Cellular therapy for myocardial injury has improved ventricular function in both animal and clinical studies, though the mechanism of benefit is unclear. This study was undertaken to examine the effects of cellular injection after infarction on myocardial elasticity. Coronary artery ligation of Lewis rats was followed by direct injection of human mesenchymal stem cells (MSCs) into the acutely ischemic myocardium. Two weeks postinfarct, myocardial elasticity was mapped by atomic force microscopy. MSC-injected hearts near the infarct region were twofold stiffer than myocardium from noninfarcted animals but softer than myocardium from vehicle-treated infarcted animals. After 8 wk, the following variables were evaluated: MSC engraftment and left ventricular geometry by histological methods, cardiac function with a pressure-volume conductance catheter, myocardial fibrosis by Masson Trichrome staining, vascularity by immunohistochemistry, and apoptosis by TdT-mediated dUTP nick-end labeling assay. The human cells engrafted and expressed a cardiomyocyte protein but stopped short of full differentiation and did not stimulate significant angiogenesis. MSC-injected hearts showed significantly less fibrosis than controls, as well as less left ventricular dilation, reduced apoptosis, increased myocardial thickness, and preservation of systolic and diastolic cardiac function. In summary, MSC injection after myocardial infarction did not regenerate contracting cardiomyocytes but reduced the stiffness of the subsequent scar and attenuated postinfarction remodeling, preserving some cardiac function. Improving scarred heart muscle compliance could be a functional benefit of cellular cardiomyoplasty.

Animals↗
PubMed2006

Safety and efficacy of left ventricular assist device support in postmyocardial infarction cardiogenic shock.

BACKGROUND: Cardiogenic shock secondary to acute myocardial infarction (CS-AMI) is the leading cause of death in all acute coronary syndromes. Experience with the use of left ventricular assist devices (LVADs) in patients with CS-AMI is limited. One of the surgical dilemmas when implanting an LVAD into a patient with an acute anterior wall myocardial infarction is the safety of apical cannulation. We present a decade of experience with the use of LVAD with apical cannulation in patients with CS-AMI. METHODS: A retrospective review of the ventricular assist device (VAD) database at the Hospital of the University of Pennsylvania was instituted. RESULTS: From April 1995 to February 2005, 49 patients received LVAD support for CS-AMI (group I). The majority of these patients suffered anterior wall myocardial infarctions. This group of patients was compared with a separate cohort of 61 patients with chronic ischemic cardiomyopathy who received LVAD support (group II). The VAD support successfully bridged 38 (74%) group I patients and 37 (61%) group II patients to heart transplantation. Of the 38 patients transplanted in group I, 33 (87%) were discharged from the hospital. In group II, 36 of the 37 patients transplanted (97%) survived to hospital discharge. The overall in-hospital mortality rates for the series were 33% for group I patients, and 41% for group II patients. CONCLUSIONS: Left ventricular assist device support in patients with CS-AMI is a safe and effective therapy which should be incorporated into the standard treatment paradigm for appropriate patients presenting with this lethal disease.

Female↗
PubMed2006

Neovasculogenic therapy to augment perfusion and preserve viability in ischemic cardiomyopathy.

BACKGROUND: Ischemic cardiomyopathy is a global health concern with limited therapy. We recently described endogenous revascularization utilizing granulocyte-macrophage colony stimulating factor (GMCSF) to induce endothelial progenitor cell (EPC) production and intramyocardial stromal cell-derived factor-1alpha (SDF) as a specific EPC chemokine. The EPC-mediated neovascularization and enhancement of myocardial function was observed. In this study we examined the regional biologic mechanisms underlying this therapy. METHODS: Lewis rats underwent left anterior descending coronary artery (LAD) ligation and developed ischemic cardiomyopathy over 6 weeks. Three weeks after ligation, the animals received either subcutaneous GMCSF and intramyocardial SDF injections or saline injections as control. Six weeks after LAD ligation circulating EPC density was studied by flow cytometry. Quadruple immunofluorescent vessel staining for mature, proliferating vasculature was performed. Confocal angiography was utilized to identify fluorescein lectin-lined vessels to assess perfusion. Ischemia reversal was studied by measuring myocardial adenosine triphosphate (ATP) levels. Myocardial viability was assayed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling detection of apoptosis and quantitation of myofilament density. RESULTS: The GMCSF/SDF therapy enhanced circulating leukocyte (13.1 +/- 4.5 x 10(6) vs 3.1 +/- 0.5 x 10(6)/cc, p = 0.001, n = 6) and EPC (14.2 +/- 6.6 vs 2.2 +/- 2.1/cc, p = 0.001, n = 6) concentrations. Tetraimmunofluorescent labeling demonstrated enhanced stable vasculature with this therapy (39.2 +/- 8.1 vs 25.4 +/- 5.1%, p = 0.006, n = 7). Enhanced perfusion was shown by confocal microangiography of borderzone lectin-labeled vessels (28.2 +/- 5.4 vs 11.5 +/- 3.0 vessels/high power field [hpf], p = 0.00001, n = 10). Ischemia reversal was demonstrated by enhanced cellular ATP levels in the GMCSF/SDF borderzone myocardium (102.5 +/- 31.0 vs 26.9 +/- 4.1 nmol/g, p = 0.008, n = 5). Borderzone cardiomyocyte viability was noted by decreased apoptosis (3.2 +/- 1.4% vs 5.4 +/- 1.0%, p = 0.004, n = 10) and enhanced cardiomyocyte density (40.0 +/- 5.6 vs 27.0 +/- 6 myofilaments/hpf, p = 0.01, n=10). CONCLUSIONS: Endogenous revascularization for ischemic cardiomyopathy utilizing GMCSF EPC upregulation and SDF EPC chemokinesis upregulates circulating EPCs, enhances vascular stability, and augments myocardial function by enhancing perfusion, reversing cellular ischemia, and increasing cardiomyocyte viability.

Animals↗
PubMed2005

Recommendations of the National Heart, Lung, and Blood Institute Working Group on Future Direction in Cardiac Surgery.

New surgical procedures, imaging modalities, and medical devices have improved therapy for many patients and made treatment possible for others who have had few options in the past. In February 2004, the National Heart, Lung, and Blood Institute's (NHLBI) Advisory Council proposed that the institute evaluate the status and future directions in cardiac surgery. In response to this recommendation, the NHLBI convened a working group of cardiac surgeons on May 7 and 8, 2004, to assess the state of cardiac surgery research, identify critical gaps in current knowledge, determine areas of opportunity, and obtain specific recommendations for future research activities. The working group discussed surgical revascularization, novel surgical approaches, valvular research directions, biotechnology and cell-based therapy, heart failure, imaging modalities, and barriers to clinical research and presents its recommendations here.

Cardiac Surgical Procedures↗
PubMed2005

Comparing on-pump and off-pump coronary artery bypass grafting: numerous studies but few conclusions: a scientific statement from the American Heart Association council on cardiovascular surgery and anesthesia in collaboration with the interdisciplinary working group on quality of care and outcomes research.

One of the most hotly debated and polarizing issues in cardiac surgery has been whether coronary artery bypass grafting (CABG) without the use of cardiopulmonary bypass or cardioplegia (off-pump CABG, or OPCAB) is superior to that performed with the heart-lung machine and the heart's being chemically arrested (standard CABG). Various clinical trials are reviewed comparing the 2 surgical strategies, including several large retrospective analyses, meta-analyses, and the randomized trials that address different aspects of standard CABG and OPCAB. Although definitive conclusions about the relative merits of standard CABG and OPCAB are difficult to reach from these varied randomized and nonrandomized studies, several generalizations may be possible. Patients may achieve an excellent outcome with either type of procedure, and individuals' outcomes likely depend more on factors other than whether they underwent standard CABG or OPCAB. Nevertheless, there appear to be trends in most studies. These trends include less blood loss and need for transfusion after OPCAB, less myocardial enzyme release after OPCAB up to 24 hours, less early neurocognitive dysfunction after OPCAB, and less renal insufficiency after OPCAB. Fewer grafts tend to be performed with OPCAB than with standard CABG. Length of hospital stay, mortality rate, and long-term neurological function and cardiac outcome appear to be similar in the 2 groups. To definitively answer the remaining questions of whether either strategy is superior and in which patients, a large-scale prospective randomized trial is required.

American Heart Association↗
PubMed2005

Freedom and rules: the acquisition and reprogramming of a bird's learned song.

Canary song is hierarchically structured: Short stereotyped syllables are repeated to form phrases, which in turn are arranged to form songs. This structure occurs even in the songs of young isolates, which suggests that innate rules govern canary song development. However, juveniles that had never heard normal song imitated abnormal synthetic songs with great accuracy, even when the tutor songs lacked phrasing. As the birds matured, imitated songs were reprogrammed to form typical canary phrasing. Thus, imitation and innate song constraints are separate processes that can be segregated in time: freedom in youth, rules in adulthood.

Aging↗
PubMed2005

Emergent mechanical support in the community: improvement with early transplant center referral.

Emergent mechanical support for the failing ventricle, with eventual transfer for definitive care, is often required at non-transplant centers. Transfer for definitive care, in terms of bridge to transplant, may require ventricular assist device (VAD) placement at the primary institution or at the transplant center. Review of consecutive single transplant center referrals was conducted to decipher optimal management. From January 1997 to December 2000, 104 patients were transferred to the University of Pennsylvania Heart Failure/Transplant Service. Most were transferred from active cardiac surgical programs, with 56 patients having post-cardiotomy failure at the primary site. A VAD was placed in procedures done at the outside hospital (OSH) in 28 patients, most commonly (60%) an Abiomed device. Of the 76 patients that received a VAD at the transplant center (TxpC), 86% received a TCI or Thoratec device. Biventricular support was required in 34 patients. Overall survival was 57%, with 54 patients bridged to transplantation and 5 patients undergoing recovery. Patients having a VAD placed at the OSH had a 32% (9 of 28) survival, whereas at the TxpC survival was 65% (45 of 76) (p < 0.05). Mid-term follow-up showed that all 5 patients weaned are presently alive, and 52 patients are alive at >1-year post-transplant. The most common cause of death was multi-system organ failure (19 of 45), followed by major neurologic event (15 of 45). Infection was the cause of death in only 6 patients. Left ventricular failure can be treated by emergent VAD placement. Overall survival is substantial if these patients are referred to a transplant center with multiple options. In contrast to previous reports, survival rates may be improved by earlier referral, before VAD placement at non-transplant centers and use of a VAD with longer-term capability.

Acute Disease↗
PubMed2005

Ethyl pyruvate enhances ATP levels, reduces oxidative stress and preserves cardiac function in a rat model of off-pump coronary bypass.

BACKGROUND: Off-pump coronary artery bypass grafting is associated with transient periods of myocardial ischemia during revascularization resulting in myocardial contractile dysfunction and oxidative injury. The purpose of this study was to investigate the efficacy of ethyl pyruvate as a myocardial protective agent in a rat model of off-pump coronary artery bypass grafting associated with transient myocardial dysfunction without infarction. METHODS: Wistar rats were subjected to transient ischemia via 10 min occlusion of the LAD coronary artery followed by 10 min of reperfusion. Animals received an IV bolus of Ringer's solution as a control (n=10) or Ringer's ethyl pyruvate (n=10) immediately before the initiation of ischemia and reperfusion. Myocardial ATP and lipid peroxidation levels were quantified for an estimation of energetics and oxidative stress, respectively. In vivo cardiac function was assessed throughout the ischemia and reperfusion periods. RESULTS: Ethyl pyruvate significantly increased myocardial ATP levels compared to controls (2650+/-759 nmol/g versus 892+/-276 nmol/g, p=0.04). Myocardial oxidative stress was significantly reduced in animals treated with ethyl pyruvate compared to controls (70.4+/-2.6 nmol/g versus 81.8+/-2.4 nmol/g, p=0.04). dP/dt max and cardiac output were significantly greater in the ethyl pyruvate group compared to controls during ischemia and reperfusion. CONCLUSIONS: Ethyl pyruvate enhances myocardial ATP levels, reduces oxidative stress, and preserves myocardial function in a model of transient ischemia/reperfusion injury not subject to myocardial infarction.

Adenosine Triphosphate↗
PubMed2005

Stromal cell-derived factor and granulocyte-monocyte colony-stimulating factor form a combined neovasculogenic therapy for ischemic cardiomyopathy.

OBJECTIVE: Ischemic heart failure is an increasingly prevalent global health concern with major morbidity and mortality. Currently, therapies are limited, and novel revascularization methods might have a role. This study examined enhancing endogenous myocardial revascularization by expanding bone marrow-derived endothelial progenitor cells with the marrow stimulant granulocyte-monocyte colony-stimulating factor and recruiting the endothelial progenitor cells with intramyocardial administration of the potent endothelial progenitor cell chemokine stromal cell-derived factor. METHODS: Ischemic cardiomyopathy was induced in Lewis rats (n = 40) through left anterior descending coronary artery ligation. After 3 weeks, animals were randomized into 4 groups: saline control, granulocyte-monocyte colony-stimulating factor only (GM-CSF only), stromal cell-derived factor only (SDF only), and combined stromal cell-derived factor/granulocyte-monocyte colony-stimulating factor (SDF/GM-CSF) (n = 10 each). After another 3 weeks, hearts were analyzed for endothelial progenitor cell density by endothelial progenitor cell marker colocalization immunohistochemistry, vasculogenesis by von Willebrand immunohistochemistry, ventricular geometry by hematoxylin-and-eosin microscopy, and in vivo myocardial function with an intracavitary pressure-volume conductance microcatheter. RESULTS: The saline control, GM-CSF only, and SDF only groups were equivalent. Compared with the saline control group, animals in the SDF/GM-CSF group exhibited increased endothelial progenitor cell density (21.7 +/- 3.2 vs 9.6 +/- 3.1 CD34 + /vascular endothelial growth factor receptor 2-positive cells per high-power field, P = .01). There was enhanced vascularity (44.1 +/- 5.5 versus 23.8 +/- 2.2 von Willebrand factor-positive vessels per high-power field, P = .007). SDF/GM-CSF group animals experienced less adverse ventricular remodeling, as manifested by less cavitary dilatation (9.8 +/- 0.1 mm vs 10.1 +/- 0.1 mm [control], P = .04) and increased border-zone wall thickness (1.78 +/- 0.19 vs 1.41 +/- 0.16 mm [control], P = .03). (SDF/GM-CSF group animals had improved cardiac function compared with animals in the saline control group (maximum pressure: 93.9 +/- 3.2 vs 71.7 +/- 3.1 mm Hg, P < .001; maximum dP/dt: 3513 +/- 303 vs 2602 +/- 201 mm Hg/s, P < .05; cardiac output: 21.3 +/- 2.7 vs 13.3 +/- 1.3 mL/min, P < .01; end-systolic pressure-volume relationship slope: 1.7 +/- 0.4 vs 0.5 +/- 0.2 mm Hg/microL, P < .01.) CONCLUSION: This novel revascularization strategy of bone marrow stimulation and intramyocardial delivery of the endothelial progenitor cell chemokine stromal cell-derived factor yielded significantly enhanced myocardial endothelial progenitor cell density, vasculogenesis, geometric preservation, and contractility in a model of ischemic cardiomyopathy.

Angiogenesis Inducing Agents↗
PubMed2004

Juvenile zebra finches can use multiple strategies to learn the same song.

Does the ontogeny of vocal imitation follow a set program that, given a target sound, unfolds in a predictable manner, or is it more like problem solving, with many possible solutions? We report that juvenile male zebra finches, Taeniopygia guttata, can master their imitation of the same song in various ways; these developmental trajectories are sensitive to the social setting in which the bird grows up. A variety of vocal developmental trajectories have also been described in infants. Are these many ways to learn unique to the vocal domain or a hallmark of advanced brain function?

Animal Communication↗
PubMed2004

Apelin has in vivo inotropic effects on normal and failing hearts.

BACKGROUND: Apelin has been shown ex vivo to be a potent cardiac inotrope. This study was undertaken to evaluate the in vivo effects of apelin on cardiac function in native and ischemic cardiomyopathic rat hearts using a novel combination of a perivascular flow probe and a conductance catheter. METHODS AND RESULTS: Native rats (n =32) and rats in heart failure 6 weeks after left anterior descending coronary artery ligation (n =22) underwent median sternotomy with placement of a perivascular flow probe around the ascending aorta and a pressure volume conductance catheter into the left ventricle. Compared with sham-operated rats, the ligated rats had significantly decreased baseline Pmax and max dP/dt. Continuous infusion of apelin at a rate of 0.01 microg/min for 20 minutes significantly increased Pmax and max dP/dt compared with infusion of vehicle alone in both native and failing hearts. Apelin infusion increased cardiac contractility, indicated by a significant increase in stroke volume (SV) without a change in left ventricular end diastolic volume (102+/-16% change from initial SV versus 26+/-20% for native animals, and 110+/-30% versus 26+/-11% for ligated animals), as well as an increase in preload recruitable stroke work (180+/-24 mm Hg versus 107+/-9 mm Hg for native animals). CONCLUSIONS: The present study is the first to show that apelin has positive inotropic effects in vivo in both normal rat hearts and rat hearts in failure after myocardial infarction. Apelin may have use as an acute inotropic agent in patients with ischemic heart failure.

Animals↗
PubMed2004

Inhibition of matrix metalloproteinase activity by TIMP-1 gene transfer effectively treats ischemic cardiomyopathy.

BACKGROUND: Enhanced activity of matrix metalloproteinases (MMPs) has been associated with extracellular matrix degradation and ischemic heart failure in animal models and human patients. This study evaluated the effects of MMP inhibition by gene transfer of TIMP-1 in a rat model of ischemic cardiomyopathy. METHODS AND RESULTS: Rats underwent ligation of the left anterior descending coronary artery with direct intramyocardial injection of replication-deficient adenovirus encoding TIMP-1 (n=8) or null virus as control vector (n=8), and animals were analyzed after 6 weeks. Both systolic and diastolic cardiac function was significantly preserved in the TIMP-1 group compared with control animals (maximum left ventricular [LV] pressure: TIMP-1 70+/-10 versus control 56+/-12 mmHg, P<0.05; maximum dP/dt 2697+/-842 versus 1622+/-527 mmHg/sec, P<0.01; minimum dP/dt -2900+/-917 versus -1195+/-593, P<0.001). Ventricular geometry was significantly preserved in the TIMP-1 group (LV diameter 13.0+/-0.7 versus control 14.4+/-0.4 mm, P<0.001; border-zone wall thickness 1.59+/-0.11 versus control 1.28+/-0.19 mm, P<0.05), and this was associated with a reduction in myocardial fibrosis (2.36+/-0.87 versus control 3.89+/-1.79 microg hydroxyproline/mg tissue, P<0.05). MMP activity was reduced in the TIMP-1 animals (1.5+/-0.9 versus control 43.1+/-14.9 ng of MMP-1 activity, P<0.05). CONCLUSIONS: TIMP-1 gene transfer inhibits MMP activity and preserves cardiac function and geometry in ischemic cardiomyopathy. The reduction in myocardial fibrosis may be primarily responsible for the improved diastolic function in treated animals. TIMP-1 overexpression is a promising therapeutic target for continued investigation.

Adenoviridae↗