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1.
Rev Sci Instrum ; 93(10): 105102, 2022 Oct 01.
Article in English | MEDLINE | ID: mdl-36319381

ABSTRACT

A platform has been developed to study laser-direct-drive energy coupling at the National Ignition Facility (NIF) using a plastic sphere target irradiated in a polar-direct-drive geometry to launch a spherically converging shock wave. To diagnose this system evolution, eight NIF laser beams are directed onto a curved Cu foil to generate Heα line emission at a photon energy of 8.4 keV. These x rays are collected by a 100-ps gated x-ray imager in the opposing port to produce temporally gated radiographs. The platform is capable of acquiring images during and after the laser drive launches the shock wave. A backlighter profile is fit to the radiographs, and the resulting transmission images are Abel inverted to infer radial density profiles of the shock front and to track its temporal evolution. The measurements provide experimental shock trajectories and radial density profiles that are compared to 2D radiation-hydrodynamic simulations using cross-beam energy transfer and nonlocal heat-transport models.

2.
Rev Sci Instrum ; 93(8): 083513, 2022 Aug 01.
Article in English | MEDLINE | ID: mdl-36050054

ABSTRACT

Recent progress at the National Ignition Facility (NIF), with neutron yields of order 1 × 1017, places new constraints on diagnostics used to characterize implosion performance. The Magnetic Recoil neutron Spectrometer (MRS), which is routinely used to measure yield, ion temperature (Tion), and down-scatter ratio (dsr), has been adapted to allow measurements of dsr up to 5 × 1017, and yield and Tion up to 2 × 1018 in the near term with new data processing techniques and conversion foil solutions. This paper presents a solution for extending MRS operation up to a yield of 2 × 1019 (60 MJ) by moving the spectrometer outside of the NIF shield wall. This will not only enhance the upper yield limit by 10× but also improve signal-to-background by 5×.

4.
Circulation ; 104(8): 881-6, 2001 Aug 21.
Article in English | MEDLINE | ID: mdl-11514373

ABSTRACT

BACKGROUND: Mechanical unloading of the failing human heart with a left ventricular assist device (LVAD) results in clinically documented reversal of chamber dilation and improvement of cardiac function. We tested the hypothesis that LVAD support normalizes the ability of cardiac muscle to respond to sympathetic nervous system stimulation by reversing the downregulation of beta-adrenergic receptors. METHODS AND RESULTS: Human LV tissue was obtained from nonfailing hearts of unmatched organ donors and failing hearts at the time of transplantation, with or without LVAD. Baseline contractile parameters and inotropic response to a beta-adrenergic agonist were measured in isolated trabecular muscles. beta-Adrenergic receptor density was quantified by radioligand binding. Results showed a significant increase in the response to beta-adrenergic stimulation after LVAD (developed tension increased by 0.76+/-0.09 g/mm(2) in nonfailing, 0.38+/-0.07 in failing, and 0.68+/-0.10 in failing+LVAD; P<0.01), accompanied by an increased density of beta-adrenergic receptors (58.7+/-9.6 fmol/mg protein in nonfailing, 26.2+/-3.8 in failing, and 63.0+/-8.3 in failing+LVAD; P<0.05). These changes were unrelated to the duration of support. CONCLUSIONS: Data demonstrate that mechanically supporting the failing human heart with an LVAD can reverse the downregulation of beta-adrenergic receptors and restore the ability of cardiac muscle to respond to inotropic stimulation by the sympathetic nervous system. This indicates that functional impairment of cardiac muscle in human heart failure is reversible.


Subject(s)
Down-Regulation , Heart Failure/physiopathology , Heart-Assist Devices , Heart/physiopathology , Receptors, Adrenergic, beta/metabolism , Adult , Aged , Binding, Competitive , Disease Progression , Female , Heart/drug effects , Heart/innervation , Heart Ventricles/drug effects , Heart Ventricles/innervation , Heart Ventricles/physiopathology , Humans , In Vitro Techniques , Isoproterenol/pharmacology , Male , Middle Aged , Myocardial Contraction/drug effects , Myocardium/metabolism , Myocardium/pathology , Recovery of Function , Sympathetic Nervous System
5.
J Mol Cell Cardiol ; 33(6): 1283-95, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11444930

ABSTRACT

Left ventricular hypertrophy may lead to heart failure. The transition between hypertrophy and heart failure is, however, incompletely understood. On the cellular level, human heart failure is characterized by alterations in Ca(2+)-cycling proteins and beta-adrenergic receptor density, but the hypertrophied human heart remains largely under studied. In this investigation, 21 donor hearts which could not be used for transplantation were studied. Ten of these hearts came from organ donors with documented left ventricular hypertrophy and normal cardiac function. Eleven of the hearts were non-failing, obtained from individuals with no evidence of cardiac disease. Nine failing hearts from transplant recipients were also studied. beta-adrenergic receptor density was determined by radioligand binding. mRNA for atrial natriuretic factor, calsequestrin, sarcoplasmic reticulum Ca(2+)-ATPase, and phospholamban was measured by Northern blot. Actin, calsequestrin, sarcoplasmic reticulum Ca(2+)-ATPase, and phospholamban proteins were quantified by Western blot. In both hypertrophied and failing ventricles, mRNA for atrial natriuretic factor was expressed, as compared to no expression in non-failing hearts. In failing hearts, beta -adrenergic receptor density and both mRNA and protein levels of the Ca(2+)-ATPase were significantly decreased v non-failing hearts. By comparison, hypertrophied hearts showed a reduction in mRNA expression for both the Ca(2+)-ATPase and phospholamban with no change in the corresponding protein levels, and no change in beta-receptors. These data suggest that the previously demonstrated reduction in beta-adrenergic receptors and Ca(2+)-cycling proteins in the failing human heart may be features of the decompensated state, but are not found in human hearts with left ventricular hypertrophy and preserved systolic function.


Subject(s)
Calcium-Binding Proteins/metabolism , Heart Failure/metabolism , Hypertrophy, Left Ventricular/metabolism , Receptors, Adrenergic, beta/metabolism , Aged , Atrial Natriuretic Factor/genetics , Atrial Natriuretic Factor/metabolism , Blotting, Northern , Calcium-Binding Proteins/genetics , Calcium-Transporting ATPases/genetics , Calcium-Transporting ATPases/metabolism , Calsequestrin/genetics , Calsequestrin/metabolism , Female , Humans , Male , Middle Aged , Radioligand Assay , Sarcoplasmic Reticulum Calcium-Transporting ATPases
6.
Circulation ; 103(14): 1912-9, 2001 Apr 10.
Article in English | MEDLINE | ID: mdl-11294812

ABSTRACT

BACKGROUND: Three-month studies of stent-delivered brachytherapy in the rabbit model show reduced neointimal growth. However, intimal healing is delayed, raising the possibility that intimal inhibition is merely delayed rather than prevented. The purpose of this study was to explore the long-term histological changes after placement of beta-emitting radioactive stents in normal rabbit iliac arteries. METHODS AND RESULTS: Three-millimeter beta-emitting (32)P stents (6, 24, and 48 microCi) were placed in normal rabbit iliac arteries with nonradioactive stents as controls. Animals were euthanatized at 6 and 12 months, and histological assessment, morphometry, and analysis of endothelialization were performed. Morphometric measurements demonstrated a >50% reduction in intimal growth and percent lumen stenosis within 24- and 48-microCi stents versus control nonradioactive stents at both 6 and 12 months. However, the 24- and 48-microCi stents also showed delayed healing of the intimal surface, characterized by persistent fibrin thrombus with nonconfluent areas of matrix, incomplete endothelialization, and increased intimal cellular proliferation. Stent edge stenosis was present at 12 months in the 24- and 48-microCi stent groups, characterized by both intimal thickening and negative arterial remodeling. CONCLUSIONS: Inhibition of intimal growth is maintained 6 and 12 months after (32)P beta-emitting stent placement. However, delayed arterial healing, incomplete endothelialization, and edge effects are present.


Subject(s)
Iliac Artery/radiation effects , Stents , Animals , Arteriosclerosis/pathology , Cell Division/radiation effects , Endothelium, Vascular/pathology , Endothelium, Vascular/radiation effects , Endothelium, Vascular/ultrastructure , Fibrin/metabolism , Fibrin/radiation effects , Iliac Artery/pathology , Male , Microscopy, Electron, Scanning , Phosphorus Radioisotopes/pharmacology , Rabbits , Time Factors , Tunica Intima/metabolism , Tunica Intima/pathology , Tunica Intima/radiation effects
7.
J Mol Cell Cardiol ; 33(3): 449-60, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11181014

ABSTRACT

Myocardial inflammation contributes to the development of dilated cardiomyopathy, as well as other cardiac diseases. We have previously shown decreased left ventricular function in mice with autoimmune myocarditis. To test the hypothesis that decreased function is mediated by changes in contractility and/or Ca2+ cycling, we isolated cardiac myocytes from mice with myocarditis and age-matched controls at two time points: day 18 (prior to cardiac dysfunction) and day 35 (during cardiac dysfunction). We measured cell shortening and the Ca2+ transient simultaneously at 28 degrees C and 0.3 Hz. We also quantified proteins which regulate contractility and [Ca2+](i), using Western blot analysis. Results showed no change in cell shortening or systolic Ca2+ on day 18, despite a significant reduction in diastolic Ca2+. By day 35, the decrease in diastolic Ca2+ was accompanied by significantly reduced cell shortening and a decrease in the systolic Ca2+ transient. Protein levels of the sarcoplasmic reticulum Ca2+ ATPase were unchanged at both time points, while phospholamban and the sodium/calcium exchanger were significantly reduced in myosin-immunized mice at both time points. Calsequestrin was unchanged at day 18, but was significantly reduced in the myosin-immunized mice on day 35. Results of this study suggest that decreased diastolic Ca2+, as well as protein levels of phospholamban and the sodium/calcium exchanger, may actually contribute to disease progression in autoimmune myocarditis, while changes in calsequestrin may be related to systolic dysfunction in this model.


Subject(s)
Autoimmune Diseases/metabolism , Calcium/metabolism , Heart Ventricles/metabolism , Myocarditis/metabolism , Animals , Autoimmune Diseases/chemically induced , Autoimmune Diseases/physiopathology , Calcium-Binding Proteins/metabolism , Calcium-Transporting ATPases/metabolism , Calsequestrin/metabolism , Cells, Cultured , Disease Models, Animal , Heart Ventricles/cytology , Heart Ventricles/physiopathology , Male , Mice , Myocarditis/chemically induced , Myocarditis/physiopathology , Sarcoplasmic Reticulum Calcium-Transporting ATPases , Sodium-Calcium Exchanger/metabolism
8.
Int J Radiat Oncol Biol Phys ; 48(3): 889-98, 2000 Oct 01.
Article in English | MEDLINE | ID: mdl-11020587

ABSTRACT

PURPOSE: Studies have shown a potential benefit of brachytherapy in preventing restenosis. However, the effects of intravascular radiation on arterial healing have not been well-established. The purpose of this study was to explore the histologic changes following placement of beta-emitting radioactive stents in arteries focusing on intimal responses and endothelialization. METHODS AND MATERIALS: 3.0-mm beta-emitting (32)P stents (6-microCi and 24-microCi) were placed in rabbit iliac arteries with nonradioactive stents serving as controls. Animals were euthanized at 3 months and histologic assessment, morphometry, and analysis of endothelialization were performed. RESULTS: The lumen areas of 24-microCi stents (4.24 +/- 0.22 mm(2), p < 0.0007) and 6-microCi stents (4.23 +/- 0.49 mm(2), p < 0.01) were larger than control stents (3.64 +/- 0.44 mm(2)). The mean lumen percent stenosis was 11. 4 +/- 3.0% in the 24-microCi stents (p < 0.007 vs. 6-microCi stents and p < 0.0001 vs. control stents), 18.7 +/- 6.4% in the 6-microCi stents (p < 0.02 vs. control stents), and 25.0 +/- 4.9% in control stents. Neointimal area was least in the 24-microCi stent (54.2% smaller than controls and 42.7% smaller than 6-microCi); the neointimal area of the 6-microCi stents was 20.0% less than controls. The control stent neointima consisted of smooth muscle cells in a proteoglycan and collagen matrix. In contrast, the intima of radioactive stents showed persistent fibrin thrombus with nonconfluent areas of matrix. Actin-positive intimal cell density was reduced with radioactive stenting, but intimal cell proliferation was increased. Evans blue staining, an indicator of increased endothelial permeability, was present on 86 +/- 9% of the stented segment of 6-microCi stents vs. 10 +/- 11% in controls (p < 0.0001). Scanning electron microscopy demonstrated endothelialization of 97 +/- 8% of the intimal surface of control stents; in contrast, the midportion of the 6-microCi stents remained nonendothelialized, and only 33 +/- 15% (p < 0.0001) of the entire stent surface was endothelialized. CONCLUSIONS: (32)P beta-emitting stents reduce neointimal growth, but healing is incomplete with poor endothelialization at 3 months. Longer-term studies with complete arterial healing are needed to determine whether there is sustained neointimal inhibition by stent-delivered brachytherapy.


Subject(s)
Phosphorus Radioisotopes/therapeutic use , Radiation Injuries, Experimental/physiopathology , Stents , Tunica Intima/radiation effects , Wound Healing/radiation effects , Animals , Cell Division/radiation effects , Endothelium, Vascular/physiology , Endothelium, Vascular/radiation effects , Iliac Artery/physiology , Iliac Artery/radiation effects , Male , Microscopy, Electron, Scanning , Rabbits , Radiobiology , Radiotherapy Dosage , Tunica Intima/physiology , Wound Healing/physiology
9.
Int J Radiat Oncol Biol Phys ; 46(4): 1019-24, 2000 Mar 01.
Article in English | MEDLINE | ID: mdl-10705025

ABSTRACT

PURPOSE: Long-term preclinical studies using continuous, low-dose-rate vascular brachytherapy with (32)P beta-emitting stents have yielded largely disappointing results. In contrast, a shorter half-life, higher dose-rate (90)Y beta-emitting stent more closely mimics the delivery dose rate characteristics of clinically effective beta- and gamma-wire and balloon brachytherapy devices. We evaluated the dose response characteristics of a (90)Y beta-emitting stent in the canine coronary injury model and hypothesized that this device would reduce neointimal formation. METHODS: Seventy-seven (90)Y beta-emitting coronary stents (15 mm BXTM, 3.0- and 3.5-mm diameter) were implanted in 26 normal dogs (20-25 kg) using a randomized, blinded study design. Stent activity included nonradioactive controls (n = 24), 4.5 microCi (n = 15), 8 microCi (n = 12), 16 microCi (n = 18), and 32 microCi (n = 8). Histologic endpoints were assessed at 3 months. RESULTS: Luminal stenosis and neointimal area were similar in control stents and low-activity (4.5 and 8 microCi) (90)Y stents. Higher activity stents (16 and 32 microCi) were associated with significant adverse effects. Frequent total occlusions (5 of 18 stents, 28%; p = 0.008) and a 40% increase in neointimal area (p = 0.024 vs. control) occurred in the 16 microCi group. Incomplete neointimal healing and a trend for reduced neointimal cell density were evident only in the 16- and 32-microCi group. CONCLUSION: Despite unique characteristics (2.7 day half-life and a higher dose rate) of (90)Y beta-emitting coronary stents, they have an adverse effect on neointimal formation, including frequent total occlusions at high activity levels. Incomplete healing, present 90 days (33 half-lives) after stent placement, indicates prolonged recovery from radiation injury.


Subject(s)
Brachytherapy/methods , Coronary Vessels/radiation effects , Stents , Tunica Intima/radiation effects , Yttrium Radioisotopes/therapeutic use , Animals , Brachytherapy/instrumentation , Coronary Vessels/injuries , Dogs , Dose-Response Relationship, Radiation , Double-Blind Method , Half-Life , Phosphorus Radioisotopes/therapeutic use , Random Allocation , Stents/adverse effects , Tunica Intima/injuries
10.
Cardiovasc Radiat Med ; 1(4): 327-35, 1999.
Article in English | MEDLINE | ID: mdl-10828562

ABSTRACT

BACKGROUND: Radioactive stents have been proposed as a means to prevent in-stent restenosis by inhibiting intimal proliferation with continuous low-dose irradiation. OBJECTIVES: The purpose of this study is to determine the effects of cumulative dose and dose-rate delivery on neointimal formation using 32P and 90Y beta-particle emitting radioactive stents in a porcine coronary model of restenosis. METHODS AND MATERIALS: We compared the late histologic results of 0.25 to 32.0 microCi 90Y (half-life 64 hours) (n = 64 stents) and 0.1 to 57.6 microCi 32P (half-life 14.3 days) (n = 55 stents) Beta-particle emitting radioactive stents with non-radioactive (n = 40) stents in a porcine coronary model of restenosis. A computer-based dosimetry modeling program was used to determine the 28 day cumulative dose and dose-rate delivery for the beta-particle emitting radioactive stents at a distance of 0.1 mm from the stent surface. RESULTS: Continuous low dose-rate (1 to 5 cGy/hr) radiation delivery for > 2 weeks via a 0.1 to 0.5 microCi 32P radioactive stent effectively reduced in-stent neointimal hyperplasia at 90 days. Cumulative doses of > 55 Gy induced severe adventitial fibrosis, microvascular damage and promoted the formation of a matrix-rich neointima. Delayed vascular repair was evident at focal regions within the body of radioactive stents that delivered cumulative doses of > or = 140 Gy at 28 days and cumulative doses of 1,100 Gy at 90 days. CONCLUSIONS: These data may be useful in predicting safe and effective dose and dose rate delivery for beta-particle emitting radioactive stents.


Subject(s)
Brachytherapy/methods , Coronary Disease/radiotherapy , Phosphorus Radioisotopes/therapeutic use , Stents , Yttrium Radioisotopes/therapeutic use , Animals , Dose-Response Relationship, Radiation , Radiotherapy Dosage , Swine
11.
Cardiovasc Radiat Med ; 1(4): 358-67, 1999.
Article in English | MEDLINE | ID: mdl-10828566

ABSTRACT

PURPOSE: To measure density of arterial plaque specimens for purposes of improving calculation of intravascular radiation dose. METHODS AND MATERIALS: In the described technique, the mass of the specimen submerged in water is compared with its mass in air. Thirty-three plaque specimens harvested from cadavers and subsequently histologically classified (18 coronary, 15 noncoronary) were subjected to density measurement, and were also assayed for calcium using inductively coupled plasma optical emission spectroscopy (ICPOES). A dose point kernel (DPK) computer model extended to heterogeneous media is used to determine delivered dose to tissues for stents labeled with 32P, 103Pd, and 131Cs, based on measured density values. RESULTS: Plaque specimens identified histologically as noncalcified (non-class VII) had an average density of 1.22 +/- 0.03 g/cm3 (n = 19). Plaque specimens identified as calcified (Class VII) had an average density of 1.45 +/- 0.06 g/cm3 (n = 13). Density of calcified portions of plaque may be even higher because plaque specimens are heterogeneous. Plaque density was found to be correlated with calcium weight percentage (R2 = 0.67) and histologic percent area calcification (R2 = 0.58). Significant variations in calculated dose were found according to isotope, plaque density, and plaque thickness. The assumption of an "all water density" dose model overestimates dose to tissues. For 1-mm thick calcified (class VII) plaque, computed dose to tissues (via DPK model) are decreased by 29%, 34%, and 15%, for 32P, 103Pd, and 131Cs stents, respectively, compared with an "all water density" assumption model, when density is taken into account. Similar decreases are expected for catheter-based brachytherapy systems using beta or low energy (< 100 keV) gamma sources. CONCLUSIONS: This work has importance for radioactive stents and catheter-based brachytherapy due to dependence of dose on density at distances between 0.1 mm and 3 mm away from the radiation source. This dependence is important for both beta- and gamma-based systems.


Subject(s)
Arteriosclerosis/pathology , Arteriosclerosis/radiotherapy , Brachytherapy/methods , Calcium/analysis , Aged , Cadaver , Catheterization , Female , Humans , Male , Radiation Dosage , Radiometry , Stents
13.
J Cutan Pathol ; 24(6): 356-63, 1997 Jul.
Article in English | MEDLINE | ID: mdl-9243363

ABSTRACT

This study used MIB-1 monoclonal antibody to quantify the proliferating keratinocytes and endothelial cells and their proliferation fractions in cases of normal skin, acute and established plaque psoriasis, and acute and chronic spongiotic dermatitis. The number and the proliferation fraction of MIB-1 positive cells were higher in psoriatic and chronic spongiotic lesions than in normal skin (p < 0.05). Established plaque psoriasis had a higher number of proliferating keratinocytes and a higher keratinocytic proliferation fraction than did acute psoriasis (p < 0.05). The number of proliferating endothelial cells decreased as acute psoriatic lesion became chronic, but the number in acute spongiotic lesion increased as it became chronic. The endothelial proliferation fraction was higher in acute psoriasis than in established plaque psoriasis (p < 0.05). The ratio of keratinocytic proliferation fraction to endothelial cell proliferation fraction of the psoriatic and spongiotic lesions suggested the presence of different reaction patterns to inflammation in psoriasis and spongiotic dermatitis.


Subject(s)
Dermatitis, Contact/pathology , Endothelium/pathology , Keratinocytes/pathology , Psoriasis/pathology , Adolescent , Adult , Aged , Antigens, Nuclear , Biomarkers/analysis , Biopsy , Cell Division , Dermatitis, Contact/metabolism , Female , Humans , Ki-67 Antigen , Male , Middle Aged , Nuclear Proteins/metabolism , Psoriasis/metabolism
14.
J Neurooncol ; 33(1-2): 19-26, 1997 May.
Article in English | MEDLINE | ID: mdl-9151220

ABSTRACT

The stable isotope 10B has a peculiarly marked avidity to capture slow neutrons whereupon it disintegrates into a lithium and a helium atom. These give up the 2.4 MeV of disintegration energy which they share within 5 and 9 microns of the 10B atom respectively. This means that the cell closest to the 10B atom bears the brunt of its atomic explosion. The objective of the tumor therapist is to find a carrier molecule for the boron atom which will concentrate in the tumor. Although a number of investigators saw the peculiar advantage of this selective tactic to achieve destruction of a species of unwanted cells, no success in animal studies was achieved until 1950. Sweet and colleagues found that the capillary blood-brain barrier keeps many substances out of the normal brain but that the gliomas had much less of such a barrier. He, Brownell, Soloway and Hatanaka in Boston together with Farr. Godwin, Robertson, Stickley. Konikowski and others at the Brookhaven. National Laboratory worked partially in collaboration and partly independently. We irradiated at 3 nuclear reactors several series of glioma patients with no long-term remission, much less a cure being achieved. Hatanaka on his return to Japan kept BNCT alive by treating a total of 140 patients with various brain tumors. Beginning in 1972, Mishima and colleagues have achieved useful concentrations of 10B-borono-phenylalanine, an analogue of the melanin precursor tyrosine, for BNCT of melanomas.


Subject(s)
Boron Neutron Capture Therapy , Brain Neoplasms/radiotherapy , Glioma/radiotherapy , Blood-Brain Barrier , Boron , Brain Neoplasms/physiopathology , Glioma/physiopathology , Humans , Isotopes , Nuclear Reactors
15.
Circ Res ; 79(6): 1064-76, 1996 Dec.
Article in English | MEDLINE | ID: mdl-8943945

ABSTRACT

Phospholamban ablation is associated with significant increases in the sarcoplasmic reticulum Ca(2+)-ATPase activity and the basal cardiac contractile parameters. To determine whether the observed phenotype is due to loss of phospholamban alone or to accompanying compensatory mechanisms, hearts from phospholamban-deficient and age-matched wild-type mice were characterized in parallel. There were no morphological alterations detected at the light microscope level. Assessment of the protein levels of the cardiac sarcoplasmic reticulum Ca(2+)-ATPase, calsequestrin, myosin, actin, troponin I, and troponin T revealed no significant differences between phospholamban-deficient and wild-type hearts. However, the ryanodine receptor protein levels were significantly decreased (25%) upon ablation of phospholamban, probably in an attempt to regulate the release of Ca2+ from the sarcoplasmic reticulum, which had a significantly higher diastolic Ca2+ content in phospholamban-deficient compared with wild-type hearts (16.0 +/- 2.2 versus 8.6 +/- 1.0 mmol Ca2+/kg dry wt, respectively). The increases in Ca2+ content were specific to junctional sarcoplasmic reticulum stores, as there were no alterations in the Ca2+ content of the mitochondria or A band. Assessment of ATP levels revealed no alterations, although oxygen consumption increased (1.6-fold) to meet the increased ATP utilization in the hyperdynamic phospholamban-deficient hearts. The increases in oxygen consumption were associated with increases (2.2-fold) in the active fraction of the mitochondrial pyruvate dehydrogenase, suggesting increased tricarboxylic acid cycle turnover and ATP synthesis. 31P nuclear magnetic resonance studies demonstrated decreases in phosphocreatine levels and increases in ADP and AMP levels in phospholamban-deficient compared with wild-type hearts. However, the creatine kinase activity and the creatine kinase reaction velocity were not different between phospholamban-deficient and wild-type hearts. These findings indicate that ablation of phospholamban is associated with downregulation of the ryanodine receptor to compensate for the increased Ca2+ content in the sarcoplasmic reticulum store and metabolic adaptations to establish a new energetic steady state to meet the increased ATP demand in the hyperdynamic phospholamban-deficient hearts.


Subject(s)
Calcium-Binding Proteins/deficiency , Calcium/metabolism , Heart/physiopathology , Myocardium/metabolism , Animals , Calcium-Transporting ATPases/metabolism , Immunoblotting , Magnetic Resonance Spectroscopy , Mice , Mice, Mutant Strains , Myocardial Contraction
16.
Circulation ; 94(4): 718-26, 1996 Aug 15.
Article in English | MEDLINE | ID: mdl-8772694

ABSTRACT

BACKGROUND: We recently demonstrated that Gh, which transfers the signal from the alpha 1-adrenergic receptor to the 69-kD phospholipase C, is the previously identified tissue-type transglutaminase (TGase II). The alpha 1-adrenergic receptor mediates actions of the sympathetic nervous system, including cardiac, arteriolar, and smooth muscle contractions. In human cardiac tissue, the expression of the alpha 1-adrenergic receptor is increased under pathophysiological conditions, but changes in the physiological response are small. Therefore, it has been suggested that the other components involved in the alpha 1-adrenergic receptor-mediated signaling pathway are probably altered. METHODS AND RESULTS: Immunological and biochemical studies with nonfailling and failing human heart tissues revealed that the GTP-binding and TGase activities of human heart TGase II (hhG alpha n) are downregulated in both ischemic and dilated cardiomyopathic human heart. In ischemic cardiomyopathy, the alpha 1-adrenergic receptor number increased twofold (27.0 fmol/mg) compared with the nonfailing (12.8 fmol/mg) and the dilated cardiomyopathic (15.6 fmol/mg) heart tissues, but the coupling of hhG alpha h with the alpha 1-adrenergic receptor did not increase. The intrinsic activity of hhG alpha h, was greatly decreased in membrane fractions, whereas the cytosolic TGase activity was not changed. In the dilated cardiomyopathic human heart, these intrinsic enzyme activities of hhG alpha h were also downregulated in the membrane fraction, whereas the amount of hhG alpha h protein was greatly increased (2.8-fold) compared with the nonfailing heart. CONCLUSIONS: The results of the present study clearly demonstrate that the alpha 1-adrenergic receptor in human heart couples with Gh (TGase II) and indicate that downregulation of hhG alpha h activity is associated with human cardiac failure but that the mechanism differs between ischemic and dilated cardiomyopathies.


Subject(s)
Cardiomyopathies/metabolism , Cardiomyopathy, Dilated/metabolism , GTP Phosphohydrolases/metabolism , Myocardial Ischemia/metabolism , Myocardium/metabolism , Receptors, Adrenergic, alpha-1/metabolism , Transglutaminases/metabolism , Adolescent , Adult , Aged , Analysis of Variance , Animals , Blotting, Western , Child , Female , GTP-Binding Proteins/metabolism , Guinea Pigs , Humans , Male , Middle Aged , Protein Glutamine gamma Glutamyltransferase 2 , Reference Values
17.
J Cutan Pathol ; 23(3): 247-53, 1996 Jun.
Article in English | MEDLINE | ID: mdl-8793660

ABSTRACT

We have quantified perivascular mast cells in cases of urticaria pigmentosa, urticaria, and dermal hypersensitivity reactions. To facilitate reproducibility, the mast cells were counted for a precisely defined vessel unit. These vessel units were divided arbitrarily into those < or = 55 microns and > 55 microns in largest diameters. Urticaria pigmentosa showed an average of 6.4 +/- 1.9 and 22.8 +/- 13.2 mast cells for vessel unit < or = 55 microns and > 55 microns, respectively. Urticaria yielded a lower number of mast cells: 1.5 +/- 0.2 and 2.9 +/- 0.9 for the same respective vessel units. Dermal hypersensitivity reactions revealed an average of 1.6 +/- 0.4 and 2.2 +/- 0.7 mast cells, and the normal skin showed 1.5 +/- 0.3 and 2.4 +/- 0.6 mast cells for each of the vessel units of < or = 55 microns and > 55 microns. The perivascular mast cell distributions of urticaria pigmentosa are statistically different from those of urticaria and dermal hypersensitivity reactions with p < 0.0001. No statistical difference was noted between urticaria, dermal hypersensitivity reactions, and normal skin. The percentages of vessel units < or = 55 microns with > or = 5 mast cells and vessel units > 55 microns with > or = 10 mast cells were determined for each case. The average percentage of vessel units for the former and latter in urticaria pigmentosa was 82.6% and 58.9%, respectively. Urticaria yielded 0% and 0.2%, respectively. None of vessel units in the dermal hypersensitivity reactions or normal skin contained more than 5 mast cells in vessel units < or = 55 microns and more than 10 mast cells in vessel units > 55 microns. Cases of urticaria pigmentosa can be distinguished from other cutaneous eruptions containing mast cells using a simple counting technique on Giemsa stained sections.


Subject(s)
Mast Cells/pathology , Skin/blood supply , Skin/pathology , Urticaria Pigmentosa/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged
18.
Circ Res ; 76(6): 1011-9, 1995 Jun.
Article in English | MEDLINE | ID: mdl-7758155

ABSTRACT

Recent evidence has suggested that arachidonic acid (AA) may be an important signaling molecule in cardiac excitation-contraction coupling. We previously showed that AA and endothelin-1 (ET) inhibit distinct K+ channels via protein kinase C-dependent pathways in rat ventricular myocytes. In addition, we demonstrated that Ca2+ transients in populations of fura 2-loaded myocytes were potentiated by AA and ET via activation of protein kinase C. In this study, we have used suspensions of [32P]orthophosphate (32Pi)-labeled rat ventricular myocytes to study the effects of AA and ET at the level of the myofilaments. After a 10-minute incubation of the labeled cells with phorbol 12-myristate 13-acetate (PMA), AA, or ET in the presence or absence of the protein kinase C inhibitor calphostin C, the myofibrillar proteins were separated by PAGE. Measurement of unloaded cell shortening using video edge detection in single electrically stimulated myocytes was also used to assess the effects of AA and ET on myocyte contractility. Incubation with either PMA, AA, or ET resulted in similar increases in 32Pi incorporation into troponin I (TnI) and myosin light chain 2 (MLC2), which was inhibited by preincubation with the protein kinase C antagonist calphostin C. In addition, the ability of these agonists to stimulate phosphorylation of TnI or MLC2 did not require extracellular Ca2+ or intact intracellular Ca2+ stores. The effects of AA and ET together on phosphorylation of TnI or MLC2 were not additive.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Arachidonic Acid/metabolism , Myocardium/metabolism , Myosins/metabolism , Troponin/metabolism , Actin Cytoskeleton/drug effects , Actin Cytoskeleton/metabolism , Animals , Arachidonic Acid/pharmacology , Blotting, Western , Calcium/metabolism , Endothelins/pharmacology , Enzyme Activation , Heart Ventricles/cytology , Heart Ventricles/drug effects , In Vitro Techniques , Marine Toxins , Myocardial Contraction , Myocardium/cytology , Myofibrils/drug effects , Myofibrils/metabolism , Myosins/analysis , Oxazoles/pharmacology , Phosphoprotein Phosphatases/antagonists & inhibitors , Phosphorylation , Protein Kinase C/metabolism , Rabbits , Rats , Tetradecanoylphorbol Acetate/pharmacology , Troponin/analysis , Troponin I
19.
Acta Neurochir Suppl ; 64: 83-7, 1995.
Article in English | MEDLINE | ID: mdl-8748590

ABSTRACT

In the last 5 years several remarkable methods for localizing precisely a wide range not only of specific motor and sensory functions but as well of more complex mental phenomena in the domain of cognitive functions have been demonstrated to evoke sharply localizable responses. In pain, positron emission tomography (PET) scanning has been used to show that the anterior gyrus cinguli is an integral component of the pain system. The PET technique suffers from a limitation of both spatial and temporal resolution, which permits only accurate center of mass coordinates of activated regions. Functional mapping of the brain by nuclear magnetic resonance has been achieved with techniques depicting specific brain areas in action during a mental process. These techniques open up an entirely new domain for study and treatment of many problems linked to cognition including many in whom pain is a central feature. The many cerebral cortical areas involved in pain make it unlikely that any ablative procedure will achieve long sustained pain relief. The dual objective of relief of both pain and suffering is probably going to be attained only by activation of pain suppressor mechanisms. This may well require the added knowledge accessible only by functional magnetic resonance imaging.


Subject(s)
Brain Mapping/methods , Pain/surgery , Psychosurgery/methods , Cerebral Cortex/physiopathology , Cerebral Cortex/surgery , Cognition/physiology , Gyrus Cinguli/physiopathology , Gyrus Cinguli/surgery , Humans , Magnetic Resonance Imaging , Mental Processes/physiology , Neural Pathways/physiopathology , Neural Pathways/surgery , Pain/physiopathology , Tomography, Emission-Computed , Treatment Outcome
20.
Pediatr Neurosurg ; 21 Suppl 1: 28-38, 1994.
Article in English | MEDLINE | ID: mdl-7841076

ABSTRACT

Craniopharyngiomas, although histologically benign, are usually so intimately associated with the hypothalamus that total extirpation of these tumors was generally followed by death from hypotension and gross endocrine deficiencies. During the first half of the present century, those recording their tribulations include the famous names of Grant, Bailey, Bucy, Peet, Kahn, Olivecrona, Norlen, Sjöqvist, Rougerie and Northfield. Matson and Sweet were the first to achieve major reductions in mortality by giving massive doses of cortisone plus meticulous dissection, which took advantage of the reactive glial envelope which surrounds the great majority of these tumors.


Subject(s)
Craniopharyngioma/history , Hypophysectomy/history , Pituitary Irradiation/history , Pituitary Neoplasms/history , Child , Europe , History, 20th Century , Humans , United States
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