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Biomedical subjects

Michael Freeman

Publications and source records attributed to Michael Freeman.

At least 19 recordsLinked to original sources

Autophagy for cancer therapy through inhibition of pro-apoptotic proteins and mammalian target of rapamycin signaling.

Autophagy is an alternative cell death pathway that is induced by mammalian target of rapamycin (mTOR) inhibitors and up-regulated when apoptosis is defective. We investigated radiation-induced autophagy in the presence or absence of Bax/Bak with or without an mTOR inhibitor, Rad001. Two isogenic cell lines, wild type (WT) and Bak/Bak(-/-) mouse embryonic fibroblasts and tumor cell lines were used for this study. Irradiated Bak/Bak(-/-) cells had a decrease of Akt/mTOR signaling and a significant increase of pro-autophagic proteins ATG5-ATG12 COMPLEX and Beclin-1. These molecular events resulted in an up-regulation of autophagy. Bax/Bak(-/-) cells were defective in undergoing apoptosis but were more radiosensitive than the WT cells in autophagy. Both autophagy and sensitization of Bak/Bax(-/-) cells were further enhanced in the presence of Rad001. In contrast, inhibitors of autophagy rendered the Bak/Bax(-/-) cells radioresistant, whereas overexpression of ATG5 and Beclin-1 made the WT cells radiosensitive. When this novel concept of radiosensitization was tested in cancer models, small interfering RNAs against Bak/Bax also led to increased autophagy and sensitization of human breast and lung cancer cells to gamma radiation, which was further enhanced by Rad001. This is the first report to demonstrate that inhibition of pro-apoptotic proteins and induction of autophagy sensitizes cancer cells to therapy. Therapeutically targeting this novel pathway may yield significant benefits for cancer patients.

Animals↗

Myocardial perfusion imaging in diabetes mellitus.

Although myocardial perfusion imaging is an established, noninvasive method for assessing risk in patients with suspected or known coronary artery disease, its usefulness in assessing the asymptomatic patient with diabetes mellitus has not been established. In the published literature, 16% to 56% of asymptomatic diabetes mellitus patients have stress myocardial perfusion-induced abnormalities. In prospective, unbiased populations, the prevalence of perfusion abnormalities are between 15% and 30%. The prognostic value of perfusion imaging in asymptomatic diabetes mellitus has been demonstrated. In diabetic patients with a normal perfusion scan, the yearly cardiac event rate is 1.2% to 2%, compared with 1% in the nondiabetic population. In patients with an abnormal myocardial perfusion scan, the cardiac event risk is increased three- to eightfold compared with patients with a normal scan. The severity of the perfusion abnormality is related to outcome. Prospective, randomized studies are required to demonstrate the efficacy of a strategy of stress myocardial perfusion imaging in asymptomatic diabetes mellitus patients.

Coronary Artery Disease↗

Partial regeneration of the human hip via autologous bone marrow nucleated cell transfer: A case study.

HISTORY: This is a case report of a 64-year-old white male with a 20 year history of unilateral hip pain that had become debilitating over the last several years. On intake, Harris hip score was rated as: Pain subscale = 10, Function subscale = 32, Deformity subscale = 4, Motions subscale = 4.775 with a total score of 50.8 out of 100. MRI of the affected hip showed severe degeneration with spurring, decrease in joint space, and several large subchondral cysts. The patient had been evaluated by an orthopedic surgeon and told he was a candidate for bipolar hip replacement. METHOD: Two autologous nucleated cell collections were performed from bone marrow with subsequent isolation and transfers into the intra-articular hip using a hyaluronic acid and thrombin activated platelet rich plasma scaffold. Marrow samples were processed by centrifugation and lysis techniques to isolate nucleated cells. CONCLUSION: This report describes partial by articular surface regeneration 8 weeks after intraarticular bone marrow transfer. Post-op 3.0T FGRE MRI showed neocortex formation when compared to immediate pre-op MRI and objective improvements were noted that coincided with subjective reports of improvement.

Bone Marrow Transplantation↗

Clusterin as a therapeutic target for radiation sensitization in a lung cancer model.

PURPOSE: Clusterin plays important roles in cell survival and death. Inactivation of clusterin enhances the therapeutic efficacy of chemotherapy in lung cancer models. The purpose of this study was to determine whether inhibition of clusterin by an antisense-based investigative drug enhances radiation sensitization in a lung cancer model. METHODS AND MATERIALS: Cells were transfected with an antisense oligonucleotide (ASO) against clusterin (OGX-011). Apoptosis was determined by 7-aminoactinomycin D staining. Cell survival was examined by 3-(4, 5-methylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) and clonogenic assay. Xenograft model was used to demonstrate tumor growth and tumor blood flow. RESULTS: OGX-011 specifically attenuated the expression of secreted clusterin (prosurvival), with no apparent effect on the expression of nuclear clusterin (proapoptotic). Apoptosis was significantly increased when H460 lung cancer cells were treated with OGX-011 plus radiation. Inhibition of clusterin followed by radiation greatly decreased cell survival. H460 xenografts that were treated with OGX-011 plus radiotherapy demonstrated growth delay beyond 17 days. Doppler studies showed that tumor blood flow was compromised when mice bearing H460 xenografts were treated with OGX-011 and radiation. CONCLUSION: A combination of radiotherapy and OGX-011 improved control of tumor growth and vascular regression in the H460 lung cancer model.

Animals↗

Effects of senescence-induced alteration in cytokinin metabolism on source-sink relationships and ontogenic and stress-induced transitions in tobacco.

Senescence and reserve mobilization are integral components of plant development, are basic strategies in stress mitigation, and regulated at least in part by cytokinin. In the present study the effect of altered cytokinin metabolism caused by senescence-specific autoregulated expression of the Agrobacterium tumefaciens IPT gene under control of the P(SAG12) promoter (P(SAG12)-IPT) on seed germination and the response to a water-deficit stress was studied in tobacco (Nicotiana tabacum L.). Cytokinin levels, sugar content and composition of the leaf strata within the canopy of wild-type and P(SAG12)-IPT plants confirmed the reported altered source-sink relations. No measurable difference in sugar and pigment content of discs harvested from apical and basal leaves was evident 72 h after incubation with (+)-ABA or in darkness, indicating that expression of the transgene was not restricted to senescing leaves. No difference in quantum efficiency, photosynthetic activity, accumulation of ABA, and stomatal conductance was apparent in apical, middle and basal leaves of either wild-type or P(SAG12)-IPT plants after imposition of a mild water stress. However, compared to wild-type plants, P(SAG12)-IPT plants were slower to adjust biomass allocation. A stress-induced increase in root:shoot ratio and specific leaf area (SLA) occurred more rapidly in wild-type than in P(SAG12)-IPT plants reflecting delayed remobilization of leaf reserves to sink organs in the transformant. P(SAG12)-IPT seeds germinated more slowly even though abscisic acid (ABA) content was 50% that of the wild-type seeds confirming cytokinin-induced alterations in reserve remobilization. Thus, senescence is integral to plant growth and development and an increased endogenous cytokinin content impacts source-sink relations to delay ontogenic transitions wherein senescence in a necessary process.

Abscisic Acid↗

A review of the literature refuting the concept of minor impact soft tissue injury.

BACKGROUND: Minor impact soft tissue (MIST) is an insurance industry concept that seeks to identify late whiplash as a psychosocial phenomenon. However, the medical literature in this area has not been systematically reviewed since the Quebec Task Force's review in 1995. OBJECTIVE: To review the medical literature which claims that late whiplash is an organic phenomenon causing significant disability. METHODS: The medical literature was reviewed in a narrative format. RESULTS: There are a significant number of studies which refute the MIST concept. CONCLUSION: A review of the literature did not support the validity of MIST.

Concept Formation↗

Fluoroscopically guided cervical prolotherapy for instability with blinded pre and post radiographic reading.

BACKGROUND: Several authors have postulated that cervical instability is a major cause of traumatic spinal pain. OBJECTIVE: The purpose of this prospective case series study (n = 6) was to determine if proliferant injections have an effect on cervical translation as measured by a blinded reader. DESIGN: This study was a prospective case series. Study participants were selected from patients seen for the primary complaint of Motor Vehicle Collision related neck pain in a private sub-specialty pain clinic. METHODS: Flexion and extension views were obtained by standard radiographs taken with a C-Arm fluoroscope under Valium sedation. Patients with more than 2.7 mm of absolute cervical translation and at least 50% reduction of cervical and referred pain with a two day rigid cervical immobilization test were admitted into the study. Participants underwent 3 prolotherapy injections at all sites that demonstrated translation. The difference in means between pre-test and post-test measurements (flexion translation, extension translation, and pain VAS scores) were assessed by a Wilcoxon signed ranks test (alpha = 0.05). RESULTS: The mean post-test VAS score (M= 3.83, SD=2.3, t=2.889) was significantly less (p=0.04) than the mean pre-test VAS score (M=5.75, SD=1.94). The correlation between difference in mean extension at C2-3 and C5-6 and difference in mean extension was significant (rho=0.89, p=0.02 and rho=0.85, p=0.03 respectively). Difference in mean flexion at C3-4 and C4-5 was significantly correlated with difference in mean flexion (rho=0.88, p=0.02 and rho=0.941, p <0.01 respectively). CONCLUSIONS: The results of this study demonstrate statistically significant correlations between proliferant injections, a reduction of both cervical flexion and extension translation, as well as a reduction in pain VAS score. Since patients with traumatic cervical instability have few viable treatment options other than surgical fusion, cervical proliferant injections under C-Arm fluoroscope may be a viable treatment option.

Journal Article↗

Survivin as a therapeutic target for radiation sensitization in lung cancer.

Expression of survivin is elevated in most malignancies, especially in radiation-resistant cell lines. In this study, we investigated how radiation affects survivin expression in primary endothelial cells as well as in malignant cell lines. We found that 3 Gy significantly reduced survivin protein level in human umbilical vein endothelial cells (HUVECs) but not in tumor cell lines. Flow cytometry studies suggest that the down-regulation of survivin is independent of cell cycle. In addition, survivin mRNA level was also down-regulatable by irradiation. However, it was abrogated by actinomycin D-mediated inhibition of gene transcription. Luciferase reporter gene assays suggest that irradiation suppressed the survivin promoter. p53 overexpression reduced survivin expression, but overexpression of a p53 mutant failed to abolish the radiation-induced down-regulation in HUVECs. Alteration of p53 status in Val138 lung cancer cell line also failed to restore the radiation-inducible down-regulation. Overexpression of survivin in 293 cells prevented apoptosis induced by irradiation and increased cell viability after irradiation. The inhibition of survivin using antisense oligonucleotides caused a significant decrease in cell viability of irradiated H460 lung cancer cells. These data suggest that radiation transcriptionally down-regulates survivin in HUVECs. This regulatory mechanism is defective in malignancies and is not mediated by p53. Survivin overexpression may lead to resistance to radiotherapy by inhibiting apoptosis and enhancing cell viability. The inhibition of survivin results in sensitization of H460 lung cancer cells to radiation. These studies suggest that survivin may be a target for cancer therapy.

DNA Damage↗

A prospective study of the use of cryosurgery for the treatment of actinic keratoses.

BACKGROUND: Actinic keratoses are the most common actinic lesions on Caucasian skin. Cryosurgery with liquid nitrogen is commonly used to treat actinic keratoses, but there have been few studies examining the true rate of cure in everyday dermatologic practice. AIM: To determine prospectively the true efficacy of cryosurgery as a treatment for actinic keratoses in everyday dermatologic practice. METHODS: A prospective, multicentered study (a subsidiary study of a photodynamic therapy trial) was performed. Patients with untreated actinic keratoses greater than 5 mm in diameter on the face and scalp were recruited. Eligible lesions received a single freeze-thaw cycle with liquid nitrogen given via a spray device and were reviewed 3 months thereafter. Each center used their preferred freeze time. The only treatment criterion was complete freezing of actinic keratoses and a 1-mm rim of normal skin. Treated lesions were assessed as complete response or noncomplete response. The influence of the duration of freeze, cosmetic outcomes, and adverse events were examined. RESULTS: Ninety adult patients from the community with 421 eligible actinic keratoses were recruited. The overall individual complete response rate was 67.2%[SEM = +/-3.5%; 95% confidence interval (CI) = 60.4-74.1%]. Complete response was 39% for freeze times of less than 5 s, 69% for freeze times greater than 5 s, and 83% for freeze times greater than 20 s. Cosmetic outcomes were good to excellent in 94% of complete response lesions. The main adverse events were pain, stinging, and burning during treatment, and hypopigmentation after healing. CONCLUSIONS: Cryosurgery is an effective treatment for actinic keratoses. The true complete response rate is significantly lower than that previously reported. The freeze duration influences successful treatment. Adverse events are mild and well tolerated.

Adult↗

What really happens during the Lachman test? A dynamic MRI analysis of tibiofemoral motion.

BACKGROUND: The Lachman test is the most reliable clinical test for diagnosing rupture of the anterior cruciate ligament (ACL). It is generally believed that the lateral side contributes more than the medial side to anterior tibial translation, but this has never been convincingly proven. The MRI study presented in this article addresses this issue. HYPOTHESIS: The lateral side of the ACL-deficient knee contributes more than the medial side to anterior tibial translation. STUDY DESIGN: Prospective cohort study. METHODS: The Lachman test and the radiologic Lachman test were performed on 10 patients with isolated rupture of the ACL while the knee was scanned dynamically using open-access magnetic resonance imaging. The amount of movement in the midmedial and midlateral compartments of both the contralateral normal knee and the ACL-deficient knee was measured. RESULTS: In both normal and ACL-deficient knees, the lateral compartment contributes more than the medial to anterior translation of the tibia. Rupture of the ACL leads to increased laxity in both medial and lateral compartments with a statistically significant greater contribution from the lateral side. CONCLUSION: Rupture of the ACL leads to increased anterior tibial translation coupled with tibial internal rotation.

Adult↗

Tibiofemoral kinematics following successful anterior cruciate ligament reconstruction using dynamic multiple resonance imaging.

BACKGROUND: The aim of anterior cruciate ligament reconstruction is to reduce excess joint laxity, hoping to restore normal tibiofemoral kinematics and therefore improve joint stability. It remains unclear if successful ACL reconstruction restores normal tibiofemoral kinematics and whether it is this that is associated with a good result. STUDY: Case series. PURPOSE: To assess the kinematics of the anterior cruciate ligament-reconstructed knee using open-access MRI. METHODS: Tibiofemoral motion was assessed using open-access MRI, weightbearing through the arc of flexion from 0 degrees to 90 degrees in 10 patients with isolated reconstruction of the anterior cruciate ligament (hamstring autograft) in one knee and a normal contralateral knee. Midmedial and midlateral sagittal images were analyzed in all positions of flexion in both knees to assess the tibiofemoral relationship. Sagittal laxity was also assessed by performing the Lachman test while the knees were scanned dynamically using open-access MRI. RESULTS: The amount of excursion between the tibial and femoral joint surfaces was similar between the normal and reconstructed knees, but the relationship of tibia to femur was always different for each position of knee flexion assessed-the lateral tibia being about 5 mm more anterior in the anterior cruciate ligament-reconstructed knees. This anterior tibial position is statistically significantly different at 0 degrees (P <.0006), 20 degrees (P =.0004), 45 degrees (P =.002), and 90 degrees of flexion (P <.006). Anteroposterior laxity was similar between normal and anterior cruciate ligament-reconstructed knees. CONCLUSION: Anterior cruciate ligament reconstruction reduces sagittal laxity to within normal limits but does not restore normal tibiofemoral kinematics despite a successful outcome.

Adult↗

The effect of posterior cruciate ligament deficiency on knee kinematics.

BACKGROUND: Alteration of the kinematics of the PCL-deficient knee might be a factor in producing the articular damage. Very little is known about the in vivo weightbearing kinematics of the PCL-deficient knee. HYPOTHESIS: Isolated rupture of the posterior cruciate ligament alters knee kinematics, predisposing the patient to development of early osteoarthritis. STUDY DESIGN: Case series. METHODS: Tibiofemoral motion was assessed using open-access magnetic resonance imaging, weightbearing in a squat, through the arc of flexion from 0 degrees to 90 degrees in 6 patients with isolated rupture of the posterior cruciate ligament in one knee and a normal contralateral knee. Passive sagittal laxity was assessed by performing the posterior and anterior drawer tests while the knees were scanned, again using the same magnetic resonance imaging scanner. The tibiofemoral positions during this stress magnetic resonance imaging examination were measured from midmedial and midlateral sagittal images of the knees. RESULTS: Rupture of the posterior cruciate ligament leads to an increase in passive sagittal laxity in the medial compartment of the knee (P < .006). In the weightbearing scans, posterior cruciate ligament rupture alters the kinematics of the knee with persistent posterior subluxation of the medial tibia so that the femoral condyle rides up the anterior upslope of the medial tibial plateau. This fixed subluxation was observed throughout the extension-flexion arc and was statistically significant at all flexion angles (P < .018 at 0 degrees , P < .013 at 20 degrees , P < .014 at 45 degrees , P < .004 at 90 degrees ). The kinematics of the lateral compartment were not altered by posterior cruciate ligament rupture. The posterior drawer test showed increased laxity in the medial compartment. CONCLUSION: Posterior cruciate ligament rupture alters the kinematics of the medial compartment of the knee, resulting in "fixed" anterior subluxation of the medial femoral condyle (posterior subluxation of the medial tibial plateau). This study helps to explain the observation of increased incidence of osteoarthritis in the medial compartment, and specifically the femoral condyle, in posterior cruciate ligament-deficient knees.

Adult↗

Covered stents for injuries of subclavian and axillary arteries.

INTRODUCTION: Injury to the subclavian and axillary arteries is uncommon. Exposure of these vessels is associated with significant morbidity, and mortality ranges from 5% to 30%. Endovascular methods may offer an alternative approach to these technically challenging injuries. METHODS: We retrospectively studied patients with blunt or penetrating (including iatrogenic) injuries to the subclavian or axillary artery between January 1, 1996 and July 30, 2002. Demographic data, mechanism of injury, concomitant injuries, angiographic findings, and treatment method and outcome were recorded. RESULTS: Twenty-seven patients with injury to the subclavian or axillary artery were seen at our institution during the study. Twenty-three patients underwent interventions. Eleven patients required open repair; 12 patients had lesions amenable to endovascular repair. Depending on the preference of the surgeon, 5 patients with injuries amenable to endovascular repair underwent open repair, and 7 underwent endovascular repair. A Wallgraft endoprosthesis was used in all patients; two grafts were required in 1 patient. Endovascular repair was associated with shorter operative time (P =.04) and less blood loss (P =.01). One-year patency was similar between the two groups. CONCLUSION: Covered stents are a feasible alternative to open repair in properly selected patients with subclavian or axillary artery injury, resulting in shorter procedure time and less blood loss.

Adult↗

Short-term aerobic training and circulatory function in women: age and hormone-replacement therapy.

The physiological basis of training responses in women, and particularly older women, is not well understood. Short-term aerobic training (STAT) was used to probe the effects of age and hormone-replacement therapy (HRT) on women's ability to rapidly change peak uptake ( VO(2max)), plasma volume and cardiac function. A total of 39 females participated in the STAT programme: 15 younger (Y; aged 19-29 years), 12 postmenopausal women undergoing HRT and 12 non-medicating postmenopausal (PM) women (aged 60-75 years). Training consisted of ten sessions of cycling over a 2-week period, which progressed in duration from 20 to 60 min and in intensity from 60-75% of maximum heart rate. Plasma volume (PV; as determined by Evan's Blue dye dilution), VO(2max) (cycle ergometry) and cardiac function (radionuclide ventriculography) were analysed using analysis of covariance or repeated measures ANOVA. All groups demonstrated similar increase in VO(2max) (Y, 13%; PM, 17%; HRT, 13%), but without a significant change in left-ventricular ejection fraction and diastolic function or volumes during supine exercise. PV expansion was observed among the Y group (7%; P <0.05) but not the PM group (2%; P >0.05) or women undergoing HRT (1%; P >0.05). Age and hormone-replacement status did not affect the magnitude of VO(2max) change. This study suggests that STAT improves VO(2max), independent of central adaptations.

Adult↗

View of normal human skin in vivo as observed using fluorescent fiber-optic confocal microscopic imaging.

Fluorescence confocal scanning laser microscopy, using a miniaturized handheld scanner, was performed to visualize the microscopic architecture of normal human epidermis in vivo. Fluorescein sodium (approximately 20 microL of 0.2% wt/vol) was administered via intradermal injection to normal skin on the volar forearm of 22 patients. The skin was imaged continuously from 1 to 15 min after injection. Fluorescein was excited at 488 nm and the fluorescent emission was detected at > 505 nm. In each subject, a series of images was collected at increasing depth, from superficial stratum corneum to papillary dermis. Features observed in confocal images were compared to those seen in hematoxylin- and eosin-stained sections of skin. The confocal images demonstrated the architecture of superficial skin in the horizontal plane. There was a transition in keratinocyte size, shape, and morphology with progressive imaging into the deeper epidermal layers. Superficial dermis and microscopic capillaries with blood flow were easily observed. The morphologic patterns associated with the major cell types of the epidermis were consistent with those known from conventional histology. We report the ability of in vivo fluorescence point scanning laser confocal microscopy to produce real-time, high-resolution images of the microscopic architecture of normal human epidermis using a noninvasive imaging technology.

Adult↗

Left ventricular performance during acute rate control in atrial fibrillation: the importance of heart rate and agent used.

BACKGROUND: The relation between heart rate and left ventricular function during rate control in atrial fibrillation is incompletely understood. METHODS: Twenty-four patients (age 67 +/- 11 years) with symptomatic recent onset rapid atrial fibrillation and rapid ventricular rate (> 110 bpm) were randomly assigned to receive either intravenous digoxin (13 mcg/kg) or intravenous diltiazem (0.25 mg/kg bolus plus a maintenance infusion). A portable radionuclide detector was used to collect validated measures of relative left ventricular volumes, along with heart rate data, every 15 seconds for 6 hours. RESULTS: Heart rate decreased significantly at 15 minutes and 180 minutes in the diltiazem group (from 133 +/- 18 bpm to 111 +/- 26 bpm [P <.01] to 94 +/- 24 bpm [P <.001]) but not in the digoxin group (from 129 +/- 18 bpm to 126 +/- 17 bpm [P = NS] to 118 +/- 15 bpm [P = NS]). Left ventricular ejection fraction improved in both groups to a similar extent (from 39 +/- 10% to 50 +/- 8%, [P <.05] after diltiazem, and from 38 +/- 8% to 52 +/- 11% [P <.05] after digoxin at baseline vs 180 minutes, respectively). The ejection fraction vs heart rate slope was steeper in the digoxin group than in the diltiazem group (-0.34 +/- 0.18 vs -0.16 +/- 0.17, P =.048) indicating a more pronounced improvement in ejection fraction per unit decrease in heart rate. CONCLUSION: In patients with acute atrial fibrillation, digoxin led to similar improvements in ejection fraction compared to diltiazem despite a slower and less potent heart rate slowing.

Aged↗

Positron emission tomography and recovery following revascularization (PARR-1): the importance of scar and the development of a prediction rule for the degree of recovery of left ventricular function.

OBJECTIVES: The aim of this study was to determine whether the extent of viability or scar is important in the amount of recovery of left ventricular (LV) function, and to develop a model for predicting recovery after revascularization that could be tested in a randomized trial. BACKGROUND: F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) is used to define viable myocardium in patients with coronary artery disease (CAD) and severe LV dysfunction and to guide revascularization decisions. Whether this approach improves clinical outcomes has not been tested in a randomized trial. Before doing so, an objective model for prediction of recovery is required. METHODS: A total of 82 patients with CAD and an ejection fraction (EF) < or =35% had FDG PET perfusion imaging before revascularization. Complete follow-up was available on 70 patients (86%). Patients had radionuclide angiograms at baseline and three months post-revascularization. RESULTS: Diabetes (p = 0.029), time to operation (p = 0.008), and scar score (p = 0.001) were significant independent predictors of the change in EF. Previous coronary artery bypass graft confounded the effect of age. There was a significant interaction between the perfusion tracer used and mismatch score (p = 0.02). The multivariable prediction model incorporating PET and clinical variables had a goodness of fit with p = 0.001. Across tertiles of scar scores (I, small: 0% to 16%; II, moderate: 16% to 27.5%; III, large: 27.5% to 47%), the changes in EFs were 9.0 +/- 1.9%, 3.7 +/- 1.6%, and 1.3 +/- 1.5% (p = 0.003: I vs. III), respectively. CONCLUSIONS: In patients with severe LV dysfunction, the amount of scar was a significant independent predictor of LV function recovery after revascularization. A combination of PET and clinical parameters predicts the degree of recovery. This model is being applied in a large randomized controlled trial to determine the effectiveness of therapy guided by FDG PET.

Aged↗