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1.
Clin Radiol ; 77(6): 436-442, 2022 06.
Article in English | MEDLINE | ID: mdl-35410786

ABSTRACT

AIM: To determine whether the pathological response to preoperative chemotherapy for pancreatic ductal adenocarcinoma (PDAC) can be predicted using 2-[18F]-fluoro-2-deoxy-d-glucose positron-emission tomography (F-18 FDG-PET). MATERIALS AND METHODS: Twenty-eight patients with PDAC who underwent only neoadjuvant chemotherapy (NAC) before surgery were enrolled in the study. All patients had F-18 FDG-PET examinations before NAC. The resected specimen was pathologically evaluated according to the Classification of Pancreatic Carcinoma (7th edn). Patients were categorised into a non-response group and a response group based on the pathological findings. The non-response group (Grades 1a and 1b) showed ≤50% necrosis in the specimen, while the specimens of the response group (Grades 2-3) showed >50% necrosis. The maximum standardised uptake values (SUVmax) of the tumours on F-18 FDG-PET were measured. The mean values of SUVmax were compared between the two groups. The diagnostic performance of SUVmax in distinguishing the two groups was also evaluated using receiver operating characteristic analysis. RESULTS: The mean SUVmax of the response group was higher than that of the non-response group (9.00 ± 1.78 versus 4.26 ± 2.35; p<0.001). The optimal cut-off value of SUVmax was 9.28 for distinguishing the two groups. The sensitivity, specificity, and accuracy for the prediction in the response group were 80%, 95.7%, and 92.9%, respectively. CONCLUSIONS: SUVmax on F-18 FDG-PET may be useful as a biomarker to predict the pathological response to NAC in patients with PDAC.


Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Carcinoma, Pancreatic Ductal/diagnostic imaging , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/surgery , Fluorodeoxyglucose F18 , Glucose , Humans , Necrosis , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/surgery , Positron Emission Tomography Computed Tomography/methods , Positron-Emission Tomography , Radiopharmaceuticals , Pancreatic Neoplasms
2.
Phys Rev Lett ; 114(1): 017601, 2015 Jan 09.
Article in English | MEDLINE | ID: mdl-25615501

ABSTRACT

We report on the noise spectrum experienced by few nanometer deep nitrogen-vacancy centers in diamond as a function of depth, surface coating, magnetic field and temperature. Analysis reveals a double-Lorentzian noise spectrum consistent with a surface electronic spin bath in the low frequency regime, along with a faster noise source attributed to surface-modified phononic coupling. These results shed new light on the mechanisms responsible for surface noise affecting shallow spins at semiconductor interfaces, and suggests possible directions for further studies. We demonstrate dynamical decoupling from the surface noise, paving the way to applications ranging from nanoscale NMR to quantum networks.


Subject(s)
Diamond/chemistry , Models, Theoretical , Spectrum Analysis/methods , Electronics , Nanotechnology/methods , Nitrogen/chemistry , Signal-To-Noise Ratio
3.
Bone Marrow Transplant ; 49(9): 1155-61, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24978139

ABSTRACT

Hematopoietic cell transplantation (HCT) is used for treatment of hematopoietic diseases. Assessment of T- and B-cell reconstitution after HCT is crucial because poor immune recovery has a major effect on the clinical course. In this study, we retrospectively analyzed T-cell receptor excision circles (TRECs) as well as signal and coding joint kappa-deleting recombination excision circles (sjKRECs and cjKRECs, respectively) as markers of newly produced lymphocytes in 133 patients (56 primary immunodeficient and 77 malignant cases, median (range): 12 (0-62) years old). We analyzed the kinetics of TREC and KREC recovery and determined the factors that contributed to better immune recovery. KRECs became positive earlier than TRECs and increased thereafter. Younger recipient age had a favorable effect on recovery of sjKRECs and cjKRECs. Compared with BM and peripheral blood, our data suggested that cord blood (CB) provided rapid B-cell recovery. CB also provided better B-cell neogenesis in adult HCT recipients. Chronic GVHD was associated with low TRECs, but not increased sjKRECs/cjKRECs. Finally, positive sjKRECs 1 month after HCT were associated with fewer infectious episodes. Monitoring of TRECs and KRECs may serve as a useful tool for assessment of immune reconstitution post HCT.


Subject(s)
B-Lymphocytes/cytology , Fetal Blood/transplantation , Hematologic Diseases/therapy , Hematopoietic Stem Cell Transplantation/methods , Adolescent , Adult , B-Lymphocytes/immunology , Child , Child, Preschool , Female , Hematologic Diseases/immunology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Infant , Infant, Newborn , Male , Middle Aged , Receptors, Antigen, T-Cell/blood , Receptors, Antigen, T-Cell/immunology , Retrospective Studies , Transplantation Conditioning/methods , Young Adult
4.
J Funct Biomater ; 3(3): 601-14, 2012 Sep 05.
Article in English | MEDLINE | ID: mdl-24955635

ABSTRACT

Biopolymers are easily denatured by heating, a change in pH or chemical substances when they are immobilized on a substrate. To prevent denaturation of biopolymers, we developed a method to trap a polynucleotide on a substrate by hydrogen bonding using silica particles with surfaces modified by aminoalkyl chains ([A-AM silane]/SiO2). [A-AM silane]/SiO2 was synthesized by silane coupling reaction of N-2-(aminoethyl)-3-aminopropyltrimethoxysilane (A-AM silane) with SiO2 particles with a diameter of 5 µm at 100 °C for 20 min. The surface chemical structure of [A-AM silane]/SiO2 was characterized by Fourier transform infrared spectroscopy and molecular orbital calculations. The surface of the silica particles was modified with A-AM silane and primary amine groups were formed. [A-AM silane]/SiO2 was trapped with single-stranded nucleic acids [(Poly-X; X = A (adenine), G (guanine) and C (cytosine)] in PBS solution at 37 °C for 1 h. The single-stranded nucleic acids were trapped on the surface of the [A-AM silane]/SiO2 by hydrogen bonding to form conjugated materials. The resulting complexes were further conjugated by derivatives of acridine orange (AO) as fluorescent labels under the same conditions to form [AO:Poly-X:A-AM silane]/SiO2 complexes. Changes in the fluorescence intensity of these complexes originating from interactions between the single-stranded nucleic acid and aromatic compounds were also evaluated. The change in intensity displayed the order [AO: Poly-G: A-AM silane]/SiO2 > [AO:Poly-A:A-AM silane]/SiO2 >> [AO:Poly-C:A-AM silane]/SiO2. This suggests that the single-stranded nucleic acids conjugated with aminoalkyl chains on the surfaces of SiO2 particles and the change in fluorescence intensity reflected the molecular interaction between AO and the nucleic-acid base in a polynucleotide.

5.
J Periodontal Res ; 45(4): 550-6, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20412415

ABSTRACT

BACKGROUND AND OBJECTIVE: Inflammatory agents, such as lipopolysaccharide (LPS), in periodontal pockets may promote atherogenesis by activating leukocytes. In our previous study, we developed a microchannel chip to observe the cell adhesion process in a fluid system. The objective of this investigation was to examine the mechanism by which periodontopathic bacterial LPS enhances plaque-like formation on a microchannel chip. MATERIAL AND METHODS: To evaluate the effect of Aggregatibacter actinomycetemcomitans LPS on the expression of adhesion molecules, e.g. intercellular adhesion molecule 1 (ICAM-1), lymphocyte function-associated antigen 1 (LFA-1) and L-selectin, on the surface of murine macrophage RAW264.7 cells, the expression of each adhesion molecule was examined by flow cytometry and western blot analysis. Moreover, a flow test on the microchannel chip involving anti-adhesion molecule antibodies was conducted to clarify which adhesion molecule is related to plaque-like formation of RAW264.7 cells. RESULTS: The expressions of ICAM-1 and LFA-1 on the surface of RAW 264.7 cells increased following 12 h culture with LPS; L-selectin expression was unaffected. An increase in ICAM-1 expression was also confirmed by western blot analysis. The flow test revealed that anti-ICAM-1 antibody inhibited plaque-like formation of LPS-stimulated macrophages on the micropillars of the microchannel chip. CONCLUSION: These findings indicate that ICAM-1 plays an important role in plaque-like formation of LPS-stimulated macrophages. Our microchannel chip is a suitable tool for the investigation of etiological factors of atherosclerosis, including periodontitis, in vitro.


Subject(s)
Aggregatibacter actinomycetemcomitans/physiology , Intercellular Adhesion Molecule-1/drug effects , L-Selectin/drug effects , Lipopolysaccharides/pharmacology , Lymphocyte Function-Associated Antigen-1/drug effects , Macrophages/drug effects , Animals , Antibodies , Atherosclerosis/pathology , Blotting, Western , Cell Adhesion/drug effects , Cell Aggregation/drug effects , Cell Culture Techniques , Cell Line , Flow Cytometry , Intercellular Adhesion Molecule-1/analysis , L-Selectin/analysis , Lab-On-A-Chip Devices , Lymphocyte Function-Associated Antigen-1/analysis , Mice
6.
J Periodontal Res ; 44(5): 609-15, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19453861

ABSTRACT

BACKGROUND AND OBJECTIVE: In the present study, micro-channel arrays were fabricated on the surface of plastic-based disposable chips. The cell adhesion process and the detection of plaque-forming macrophages were observed. Further, we evaluated cell adhesion in a fluid system in vitro. MATERIAL AND METHODS: Features of the micro-channel (1.4 mm wide and 10 mm long) included twenty micro-pillars (with a projection of 200 microm diameter and 250 microm high) coated in a 50 microm thick silicon rubber layer, which were regularly arranged at the bottom of each channel. The efficiency of cell capture was expected to increase by arrangement of micro-pillars in a micro-channel. Mouse macrophage RAW264.7 cells, stimulated for 24 h with lipopolysaccharide (LPS) derived from periodontopathic bacteria, were circulated continuously for 2 h at room temperature by the pump in a chip. RESULTS: Control cells had not formed plaques on micro-pillars 20 min into the experiment. By contrast, LPS-activated macrophages produced plaques at the side walls of micro-pillars after 20 min. The plaques grew during the flow test, and image shading became clearer with increasing flow time for 120 min. The maximal adhesion rate per unit area appeared at 20% for control cells, whereas the peak was shifted to 30% for LPS-activated macrophages (n = 20). The average adhesion rate was 3.0 +/- 2.0% for control cells and 5.0 +/- 3.9% for LPS-activated macrophages (n = 100). CONCLUSION: These findings indicate that LPS-activated macrophages accumulate in micro-channel arrays, and suggest that macrophage plaque formation is a two-step procedure: (1) LPS-activated macrophages adhere physically to the silicon rubber layer on micro-pillars; and (2) consequently, the cells adhere to the activated macrophage layer.


Subject(s)
Aggregatibacter actinomycetemcomitans/physiology , Lipopolysaccharides/pharmacology , Macrophage Activation/drug effects , Macrophages/drug effects , Algorithms , Animals , Cell Adhesion/drug effects , Cell Line , Cell Movement , Equipment Design , Image Processing, Computer-Assisted , Lab-On-A-Chip Devices , Mice , Rheology , Silicone Elastomers , Surface Properties , Time Factors
7.
Bone Marrow Transplant ; 37(5): 469-77, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16435016

ABSTRACT

We retrospectively analyzed our results of 30 patients with three distinctive primary immunodeficiency diseases (PIDs)--severe combined immunodeficiency (SCID, n = 11), Wiskott-Aldrich syndrome (WAS, n = 11) and X-linked hyper-immunoglobulin M (IgM) syndrome (XHIM, n = 8)--who underwent hematopoietic SCT (HSCT) during the past 20 years. Until 1995, all donors were HLA-haploidentical relatives with T-cell depletion (TCD) (n = 8). Since 1996, the donors have been HLA-matched related donors (MRD) (n = 8), unrelated BM (UR-BM) (n = 7) and unrelated cord blood (UR-CB) (n = 7). Twenty-seven of 30 patients had various pre-existing infections with or without organ damages before HSCT. Conditioning regimen and GVHD prophylaxis were determined according to disease, donor and pretransplant status. Although one of eight patients transplanted with TCD is alive with full engraftment, the other seven died. On the other hand, 18 of 22 patients transplanted without TCD are alive and well, including six of eight transplanted from MRD, seven of seven from UR-BM and five of seven from UR-CB. All 19 survivors did not require Ig supplementation after HSCT. These results indicate that UR-CBT as well as UR-BMT provides good results for PID comparable to MRD-SCT, and that early diagnosis, HSCT at early stage, careful supportive therapy and monitoring for various pathogens are important for the successful HSCT.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Immunologic Deficiency Syndromes/therapy , Adolescent , Adult , Child , Child, Preschool , Disease-Free Survival , Hematopoietic Stem Cell Transplantation/mortality , Humans , Immunologic Deficiency Syndromes/complications , Immunologic Deficiency Syndromes/mortality , Infant , Infections , Lymphocyte Depletion , Male , Retrospective Studies , Survival Rate , Tissue Donors , Transplantation Conditioning/methods
8.
Proc Natl Acad Sci U S A ; 98(18): 10463-8, 2001 Aug 28.
Article in English | MEDLINE | ID: mdl-11517312

ABSTRACT

Nitroxyl anion (NO(-)) is the one-electron reduction product of nitric oxide (NO( small middle dot)) and is enzymatically generated by NO synthase in vitro. The physiologic activity and mechanism of action of NO(-) in vivo remains unknown. The NO(-) generator Angeli's salt (AS, Na(2)N(2)O(3)) was administered to conscious chronically instrumented dogs, and pressure-dimension analysis was used to discriminate contractile from peripheral vascular responses. AS rapidly enhanced left ventricular contractility and concomitantly lowered cardiac preload volume and diastolic pressure (venodilation) without a change in arterial resistance. There were no associated changes in arterial or venous plasma cGMP. The inotropic response was similar despite reflex blockade with hexamethonium or volume reexpansion, indicating its independence from baroreflex stimulation. However, reflex activation did play a major role in the selective venodilation observed under basal conditions. These data contrasted with the pure NO donor diethylamine/NO, which induced a negligible inotropic response and a more balanced veno/arterial dilation. AS-induced positive inotropy, but not systemic vasodilatation, was highly redox-sensitive, being virtually inhibited by coinfusion of N-acetyl-l-cysteine. Cardiac inotropic signaling by NO(-) was mediated by calcitonin gene-related peptide (CGRP), as treatment with the selective CGRP-receptor antagonist CGRP(8-37) prevented this effect but not systemic vasodilation. Thus, NO(-) is a redox-sensitive positive inotrope with selective venodilator action, whose cardiac effects are mediated by CGRP-receptor stimulation. This fact is evidence linking NO(-) to redox-sensitive cardiac contractile modulation by nonadrenergic/noncholinergic peptide signaling. Given its cardiac and vascular properties, NO(-) may prove useful for the treatment of cardiovascular diseases characterized by cardiac depression and elevated venous filling pressures.


Subject(s)
Calcitonin Gene-Related Peptide/physiology , Myocardial Contraction/drug effects , Myocardial Contraction/physiology , Nitrogen Oxides/pharmacology , Animals , Anions , Baroreflex/drug effects , Baroreflex/physiology , Calcitonin Gene-Related Peptide/pharmacology , Calcitonin Gene-Related Peptide Receptor Antagonists , Cyclic GMP/physiology , Dogs , Male , Nitrates/blood , Nitric Oxide/pharmacology , Nitrites/blood , Nitrites/pharmacology , Nitrogen Oxides/metabolism , Oxidation-Reduction , Peptide Fragments/pharmacology , Signal Transduction
9.
FASEB J ; 15(10): 1718-26, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11481219

ABSTRACT

Recent studies implicate increased cGMP synthesis as a postreceptor contributor to reduced cardiac sympathetic responsiveness. Here we provide the first evidence that modulation of this interaction by cGMP-specific phosphodiesterase PDE5A is also diminished in failing hearts, providing a novel mechanism for blunted beta-adrenergic signaling in this disorder. In normal conscious dogs chronically instrumented for left ventricular pressure-dimension analysis, PDE5A inhibition by EMD82639 had modest basal effects but markedly blunted dobutamine-enhanced systolic and diastolic function. In failing hearts (tachypacing model), however, EMD82639 had negligible effects on either basal or dobutamine-stimulated function. Whole myocardium from failing hearts had 50% lower PDE5A protein expression and 30% less total and EMD92639-inhibitable cGMP-PDE activity. Although corresponding myocyte protein and enzyme activity was similar among groups, the proportion of EMD82639-inhibitable activity was significantly lower in failure cells. Immunohistochemistry confirmed PDE5A expression in both the vasculature and myocytes of normal and failing hearts, but there was loss of z-band localization in failing myocytes that suggested altered intracellular localization. Thus, PDE5A regulation of cGMP in the heart can potently modulate beta-adrenergic stimulation, and alterations in enzyme localization and reduced synthesis may blunt this pathway in cardiac failure, contributing to dampening of the beta-adrenergic response.


Subject(s)
3',5'-Cyclic-GMP Phosphodiesterases/physiology , Cardiac Output, Low/enzymology , Receptors, Adrenergic, beta/physiology , Signal Transduction , 3',5'-Cyclic-GMP Phosphodiesterases/analysis , 3',5'-Cyclic-GMP Phosphodiesterases/antagonists & inhibitors , Adenylyl Cyclases/metabolism , Adrenergic beta-Agonists/pharmacology , Animals , Blood Pressure , Colforsin/pharmacology , Cyclic GMP/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 5 , Dobutamine/pharmacology , Dogs , Female , Heart/drug effects , Hemodynamics , Immunohistochemistry , Male , Myocardial Contraction/drug effects , Myocardium/enzymology , Phosphodiesterase Inhibitors/pharmacology , Piperazines/pharmacology , Purines , Purinones/pharmacology , Pyrazoles/pharmacology , Sildenafil Citrate , Sulfones
10.
Circulation ; 103(1): 119-24, 2001 Jan 02.
Article in English | MEDLINE | ID: mdl-11136696

ABSTRACT

BACKGROUND: In vitro studies support K(+)(Ca) channel-induced smooth muscle hyperpolarization as underlying acetylcholine-mediated (or bradykinin-mediated) vasodilation that persists despite combined nitric oxide (NO) and PGI(2) inhibition. We tested the hypothesis that these channels are activated by enhanced pulsatile perfusion in vivo and contribute substantially to vasodilation from this stimulus. METHODS AND RESULTS: The canine left descending coronary artery was perfused with whole blood at constant mean pressure, and physiological flow pulsatility was set at 40 or 100 mm Hg by computer servo-pump. Cyclooxygenase was inhibited by indomethacin. Mean flow increased +18+/-2% (P:<0.0001) with enhanced pulsatility. This response declined approximately 50% by blocking NO synthase (L-NMMA) or K(+)(Ca) [charybdotoxin (CbTX)+apamin (AP)]. Combining both inhibitors virtually eliminated the flow rise. Inhibiting either or both pathways minimally altered basal coronary flow, whereas agonist-stimulated flow was blocked. Bradykinin-induced dilation declined more with CbTX+AP than with L-NMMA (-66% versus -46%, P:=0.03) and was fully blocked by their combination. In contrast, acetylcholine-induced dilation was more blunted by L-NMMA than by CbTX+AP (-71% versus -44%, P:<0.002) and was not fully prevented by the combination. Substituting iberiotoxin (IbTX) for CbTX greatly diminished inhibition of pulse pressure and agonist flow responses (with or without NOS inhibition). Furthermore, blockade by IbTX+AP was identical to that by AP alone, supporting a minimal role of IbTX-sensitive large-conductance K(+)(Ca) channels. CONCLUSIONS: K(+)(Ca) activation and NO comodulate in vivo pulsatility-stimulated coronary flow, supporting an important role of a hyperpolarization pathway in enhanced mechanovascular signaling. Small- and intermediate-conductance K(+)(Ca) channels are the dominant species involved in modulating both pulse pressure- and bradykinin-induced in vivo coronary dilation.


Subject(s)
Coronary Vessels/metabolism , Nitric Oxide/metabolism , Potassium Channels/metabolism , Pulsatile Flow/physiology , Vasodilation/physiology , Acetylcholine/metabolism , Acetylcholine/pharmacology , Animals , Apamin/pharmacology , Blood Flow Velocity/drug effects , Blood Flow Velocity/physiology , Bradykinin/metabolism , Bradykinin/pharmacology , Calcium/metabolism , Charybdotoxin/pharmacology , Coronary Vessels/drug effects , Dogs , Enzyme Inhibitors/pharmacology , Nitric Oxide/pharmacology , Peptides/pharmacology , Potassium/metabolism , Potassium/pharmacology , Potassium Channel Blockers , Pulsatile Flow/drug effects , Signal Transduction/drug effects , Signal Transduction/physiology , Vasodilation/drug effects , omega-N-Methylarginine/pharmacology
11.
Am J Physiol Heart Circ Physiol ; 279(4): H1982-8, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11009488

ABSTRACT

Nitric oxide (NO) has concentration-dependent biphasic myocardial contractile effects. We tested the hypothesis, in isolated rat hearts, that NO cardiostimulation is primarily non-cGMP dependent. Infusion of 3-morpholinosydnonimine (SIN-1, 10(-5) M), which may participate in S-nitrosylation (S-NO) via peroxynitrite formation, increased the rate of left ventricular pressure rise (+dP/dt; 19 +/- 4%, P < 0.001, n = 11) without increasing effluent cGMP or cAMP. Superoxide dismutase (SOD; 150 U/ml) blocked SIN-1 cardiostimulation and led to cGMP elaboration. Sodium nitroprusside (10(-10)-10(-7) M), an iron nitrosyl compound, did not augment +dP/dt but increased cGMP approximately eightfold (P < 0.001), whereas diethylamine/NO (DEA/NO; 10(-7) M), a spontaneous NO. donor, increased +dP/dt (5 +/- 2%, P < 0.05, n = 6) without augmenting cGMP. SIN-1 and DEA/NO +dP/dt increase persisted despite guanylyl cyclase inhibition with 1H-(1,2,4)oxadiazolo-(4,3,-a)quinoxalin-1-one (10(-5) M, P < 0.05 for both donors), suggesting a cGMP-independent mechanism. Glutathione (5 x 10(-4) M, n = 15) prevented SIN-1 cardiostimulation, suggesting S-NO formation. SIN-1 also produced SOD-inhibitable cardiostimulation in vivo in mice. Thus peroxynitrite and NO donors can stimulate myocardial contractility independently of guanylyl cyclase activation, suggesting a role for S-NO reactions in NO/peroxynitrite-positive inotropic effects in intact hearts.


Subject(s)
Cyclic GMP/physiology , Molsidomine/analogs & derivatives , Myocardial Contraction/drug effects , Nitrates/pharmacology , Nitric Oxide Donors/pharmacology , Nitric Oxide/metabolism , Animals , Cyclic GMP/metabolism , Diethylamines/pharmacology , Drug Combinations , Enzyme Inhibitors/pharmacology , Glutathione/pharmacology , In Vitro Techniques , Male , Molsidomine/antagonists & inhibitors , Molsidomine/pharmacology , Nitric Oxide/pharmacology , Nitroprusside/pharmacology , Nucleotides, Cyclic/metabolism , Oxadiazoles/pharmacology , Oxidation-Reduction , Quinoxalines/pharmacology , Rats , Rats, Wistar , Superoxide Dismutase/pharmacology
12.
Circulation ; 101(9): 1040-8, 2000 Mar 07.
Article in English | MEDLINE | ID: mdl-10704173

ABSTRACT

BACKGROUND: Myofilament Ca(2+) sensitizers enhance contractility but can adversely alter diastolic function through sensitization to low intracellular Ca(2+) concentration. Concomitant phosphodiesterase III inhibition (PDE3I) may offset diastolic changes but limit the mechanoenergetic benefits. We tested whether selective Ca(2+) sensitization in vivo with the use of EMD-57033 enhances both systolic and diastolic function in failing hearts at minimal energetic cost. METHODS AND RESULTS: Pressure-dimension data were measured with sonomicrometry/micromanometry in conscious dogs before (CON, n=9) and after tachycardia-induced heart failure (HF, n=11). In contrast to blunted dobutamine (DOB) responses in HF, low-dose EMD-57033 (0.4 mg. kg(-1). min(-1) for 20 minutes) markedly enhanced contractility, doubling end-systolic elastance and raising fractional shortening similarly in CON-treated and HF hearts. EMD-57033 effects were achieved at a reduced heart rate, without vasodilation. EMD-57033 augmented blunted heart rate-dependent contractility responses in HF at a rate of twice that of DOB, despite matched basal inotropic responses. EMD-57033 also improved diastolic function, lowering left ventricular end-diastolic pressure and increasing the filling rate. At equipotent inotropic doses and matched preload, EMD-57033 lowered the oxygen cost of contractility by -11.4+/-5.8%, whereas it rose 64+/-18% with DOB (P=0.001) and 28+/-11% with milrinone. Doubling EMD-57033 dose further augmented positive inotropy in CON and HF, accompanied by vasodilation, increased heart rate, and other changes consistent with PDE3I coactivity, but the oxygen cost of contractility remained improved compared with the use of DOB. CONCLUSIONS: Selective Ca(2+) sensitization with minimal PDE3I in vivo is achieved with the use of EMD-57033, improving basal and rate-stimulated contractility and mechanoenergetics of HF without compromising diastolic function. Despite PDE3I activity at higher doses, energetic benefits persist.


Subject(s)
Calcium/physiology , Cardiac Output, Low/physiopathology , Cardiotonic Agents/pharmacology , Heart/drug effects , Heart/physiopathology , Quinolines/pharmacology , Thiadiazines/pharmacology , Animals , Blood Pressure/drug effects , Coronary Circulation/drug effects , Diastole , Dobutamine/pharmacology , Dogs , Female , Male , Myocardial Contraction/drug effects , Myocardium/metabolism , Oxygen Consumption/drug effects , Rest
13.
Cardiovasc Res ; 45(4): 1001-9, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10728426

ABSTRACT

OBJECTIVES: ATP-sensitive potassium channels (K+ATP) prominently contribute to basal coronary tone; however, flow reserve during exercise remains unchanged despite channel blockade with glibenclamide (GLI). We hypothesized that increasing perfusion pulsatility, as accompanies exercise, offsets vasoconstriction from K+ATP-channel blockade, and that this effect is blunted by nitric oxide synthase (NOS) inhibition. METHODS: In 31 anaesthetized dogs the left anterior descending artery was blood-perfused by computer-controlled servo-pump, with real-time arterial perfusion pulse pressure (PP) varied from 40 and 100 mm Hg at a constant mean pressure and cardiac workload. RESULTS: At control PP (40 mm Hg), GLI (50 micrograms/min/kg, i.c.) lowered mean regional coronary flow from 37 +/- 5 to 25 +/- 4 ml/min (P < 0.001). However, this was not observed at 100 mm Hg PP (41 +/- 2 vs. 45 +/- 4). NOS inhibition by NG-monomethyl-L-arginine (L-NMMA) did not alter basal flow at 40 mm Hg PP, but modestly lowered flow (-5%, P < 0.001) at higher PP (100 mm Hg), reducing PP-flow augmentation by -36%, and acetylcholine (ACh) induced flow elevation by -39%. Co-infusion of L-NMMA with GLI resulted in net vasoconstriction at both PP levels (-60% and -40% at 40 and 100 mm Hg PP, respectively). Unlike GLI, vasoconstriction by vasopressin (-43 +/- 3% flow reduction at 40 mm Hg PP) or quinacrine (-23 +/- 7%) was not offset at higher pulsatility (-44 +/- 4 and -23 +/- 6%, respectively). Neither of the latter agents inhibited ACh- or PP-induced flow responses, nor did they modify the effect of L-NMMA on these responses. CONCLUSIONS: Increased coronary flow pulsatility offsets vasoconstriction from K+ATP blockade by likely enhancing NO release. This mechanism may assist exercise-mediated dilation in settings where K+ATP opening is partially compromised.


Subject(s)
Coronary Vessels/drug effects , Glyburide/pharmacology , Hypoglycemic Agents/pharmacology , Nitric Oxide/physiology , Potassium Channel Blockers , Vasoconstrictor Agents/pharmacology , Acetylcholine/pharmacology , Adenosine/pharmacology , Animals , Arginine Vasopressin/pharmacology , Coronary Circulation/drug effects , Coronary Circulation/physiology , Coronary Vessels/physiology , Dogs , Enzyme Inhibitors/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Pulsatile Flow , Quinacrine/pharmacology , omega-N-Methylarginine/pharmacology
15.
J Physiol ; 520 Pt 1: 271-80, 1999 Oct 01.
Article in English | MEDLINE | ID: mdl-10517818

ABSTRACT

1. Coronary flow elevation from enhanced perfusion pulsatility is synergistically amplified by adenosine. This study determined the specificity of this interaction and its potential mechanisms. 2. Mean and phasic coronary flow responses to increasing pulsatile perfusion were assessed in anaesthetized dogs, with the anterior descending coronary artery servoperfused to regulate real-time physiological flow pulsatility at constant mean pressure. Pulsatility was varied between 40 and 100 mmHg. Hearts ejected into the native aorta whilst maintaining stable loading. 3. Increasing pulsatility elevated mean coronary flow +11.5 +/- 1.7 % under basal conditions. Co-infusion of adenosine sufficient to raise baseline flow 66 % markedly amplified this pulsatile perfusion response (+82. 6 +/- 14.3 % increase in mean flow above adenosine baseline), due to a leftward shift of the adenosine-coronary flow response curve at higher pulsatility. Flow augmentation with pulsatility was not linked to higher regional oxygen consumption, supporting direct rather than metabolically driven mechanisms. 4. Neither bradykinin, acetylcholine nor verapamil reproduced the synergistic amplification of mean flow by adenosine and higher pulsatility, despite being administered at doses matching basal flow change with adenosine. 5. ATP-sensitive potassium (KATP) activation (pinacidil) amplified the pulse-flow response 3-fold, although this remained significantly less than with adenosine. Co-administration of the phospholipase A2 inhibitor quinacrine virtually eliminated adenosine-induced vasodilatation, yet synergistic interaction between adenosine and pulse perfusion persisted, albeit at a reduced level. 6. Thus, adenosine and perfusion pulsatility specifically interact to enhance coronary flow. This synergy is partially explained by KATP agonist action and additional non-flow-dependent mechanisms, and may be important for modulating flow reserve during exercise or other high output states where increased flow demand and higher perfusion pulsatility typically co-exist.


Subject(s)
Adenosine/pharmacology , Coronary Circulation/physiology , Vasodilator Agents/pharmacology , Animals , Blood Pressure/physiology , Calcium Channel Blockers/pharmacology , Diastole/physiology , Dogs , Dose-Response Relationship, Drug , Hemodynamics/drug effects , Hemodynamics/physiology , Myocardium/metabolism , Oxygen Consumption/drug effects , Perfusion/instrumentation , Pinacidil/pharmacology , Quinacrine/pharmacology , Systole/physiology , Verapamil/pharmacology
16.
Eur J Pediatr Surg ; 9(1): 53-7, 1999 Feb.
Article in English | MEDLINE | ID: mdl-10207706

ABSTRACT

We have treated four prenatally diagnosed cases of extensive congenital cystic adenomatoid malformation (CCAM) of the lung. The first case in 1982 was associated with severe fetal hydrops. After thoracentesis at 31 weeks of gestation abruptio placentae occurred, and a female baby was delivered by cesarean section. She underwent a right lower lobectomy, but soon died. The second baby without hydrops, diagnosed as having CCAM at 26 weeks of gestation, was followed conservatively until full term. After birth, it was necessary to treat the baby boy with extracorporeal membrane oxygenation (ECMO), but he survived. The third baby with fetal hydrops had an indwelling drainage catheter inserted into the CCAM at 27 weeks of gestation. The hydrops subsided and the baby was delivered at 37 weeks of gestation. He was allowed to breathe spontaneously, but was intubated 16 hours after birth. A right lower lobectomy was successfully performed 24 hours after delivery. The fourth baby without fetal hydrops was followed conservatively until delivery. He underwent left lower lobectomy successfully on the 4th day of life. Although management of prenatally diagnosed CCAM varies among patients, insertion of an indwelling catheter into the cyst appears to be the treatment of choice if indicated; the catheter can be maintained for as long as 10 weeks, as shown in Case 3. Cases of CCAM without fetal hydrops should also be treated carefully, because persistent fetal circulation may occur postnatally.


Subject(s)
Cystic Adenomatoid Malformation of Lung, Congenital/diagnostic imaging , Cystic Adenomatoid Malformation of Lung, Congenital/therapy , Ultrasonography, Prenatal , Catheters, Indwelling , Drainage , Extracorporeal Membrane Oxygenation , Female , Humans , Infant, Newborn , Male , Pneumonectomy , Pregnancy
17.
Jpn Heart J ; 39(2): 243-6, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9687833

ABSTRACT

We report a rare case of hemolysis after coil occlusion of a patent ductus arteriosus (PDA), which was treated by surgical removal of the coil and closure of PDA. A 65-year-old woman was admitted to our hospital with congestive heart failure due to severe aortic regurgitation associated with PDA. Before undergoing open heart surgery she underwent closure of the PDA using a Jackson coil as an adjunct of treatment to improve her hemodynamic state. However, a small residual shunt resulted in severe hemolysis. Two weeks after the intervention she underwent aortic valve replacement and PDA closure after removal of the coil through the main pulmonary artery under moderate hypothermia and temporary circulatory arrest. Hemolysis is always secondary to a residual leak and several methods have been reported to manage this complication. Our report suggests that early surgical retrieval of the coil before the organized thrombus is formed, can be safely performed even in an elderly patient whose ductus is usually fragile.


Subject(s)
Aortic Valve Insufficiency/complications , Ductus Arteriosus, Patent/immunology , Embolization, Therapeutic/adverse effects , Hemolysis , Aged , Ductus Arteriosus, Patent/therapy , Female , Humans
18.
Biol Pharm Bull ; 20(9): 1024-5, 1997 Sep.
Article in English | MEDLINE | ID: mdl-9331991

ABSTRACT

The intestinal absorption of oligopeptides, peptidase-degradable tyrosylglycylglycine (TGG) and peptidase-resistant L-tyrosyl-D-arginine (D-kyotorphin, D-KTP) across Peyer's patches (PP) in rabbit intestine were studied using an Ussing-type chamber and in situ closed perfusion methods. The clearance for the serosal appearance of intact TGG across PP by the Ussing-type chamber method was a little higher than that across the jejunal epithelium (JE). Meanwhile, the in situ closed perfusion experiment showed that the clearance for the plasma appearance of intact TGG across PP was about 10 times that of JE. Furthermore, it was shown that the clearance for the plasma appearance of D-KTP in PP was about twice that in JE by the in situ closed perfusion method, indicating that the membrane permeability of PP was higher than that of JE. Therefore, these results indicate that PP had less metabolic peptidase activity than JE, and that the PP was a suitable site for the intestinal absorption of oligopeptides, especially peptidase-degradable peptides.


Subject(s)
Endorphins/pharmacokinetics , Intestinal Absorption/physiology , Intestinal Mucosa/metabolism , Jejunum/metabolism , Oligopeptides/pharmacokinetics , Peyer's Patches/metabolism , Animals , Intestinal Mucosa/pathology , Jejunum/pathology , Male , Rabbits
19.
Acta Paediatr Jpn ; 38(6): 695-8, 1996 Dec.
Article in English | MEDLINE | ID: mdl-9002313

ABSTRACT

Recently, it has come to be accepted that the result of the tilt test is specific to neurally mediated syncope (vasovagal syncope). Only rarely is a case of paroxysmal atrial fibrillation without any organic diseases in childhood reported. A case reported here of a 14-year-old boy with neurally mediated syncope; which was complicated by paroxysmal atrial fibrillation, and which was diagnosed by performing the tilt test. Atrial fibrillation can be induced by the extraordinary stimulation of the vagal nerve during syncope. In a child, neurally mediated syncope complicated with paroxysmal atrial fibrillation has not been previously reported.


Subject(s)
Atrial Fibrillation/complications , Syncope, Vasovagal/etiology , Adolescent , Atrial Fibrillation/diagnosis , Electrocardiography , Humans , Male , Tilt-Table Test , Vagus Nerve/physiopathology
20.
Ann Thorac Surg ; 61(3): 845-50, 1996 Mar.
Article in English | MEDLINE | ID: mdl-8619704

ABSTRACT

BACKGROUND: A bidirectional cavopulmonary shunt has been performed for the high-risk Fontan patient. It is well known that in the presence of the bidirectional cavopulmonary shunt alone to secure pulmonary blood flow, the central pulmonary artery size decreases over time. We have performed pulsatile bidirectional cavopulmonary shunt (PBCPS), keeping pulmonary blood flow from the ventricle through the stenotic pulmonary valve, or a Blalock-Taussig shunt in patients who do not meet the criteria for the Fontan operation. METHODS: Eleven patients who underwent PBCPS between 1989 and 1993 were reviewed. We compared the results of cardiac catheterization immediately before PBCPS and during the postoperative observation period (310 +/- 257 days). RESULTS: Pulmonary blood flow and arterial oxygen saturation increased significantly after PBCPS (p = 0.01). Pulmonary artery area index showed a tendency to increase (p = 0.11). The mean number of risk factors for the Fontan procedure decreased significantly for 1.8 +/- 1.1 to 0.7 +/- 0.8 after PBCPS (p < 0.05). Overall, 5 of the 11 patients (45.5%) met the criteria for the Fontan procedure, and a fenestrated Fontan procedure was carried out in 4 of them. CONCLUSIONS: The PBCPS is useful for high-risk Fontan patients not only in the staged Fontan operation, but also as definitive palliation.


Subject(s)
Fontan Procedure/methods , Child , Child, Preschool , Heart Diseases/surgery , Humans , Infant , Lung/blood supply , Oxygen/blood , Palliative Care , Pulmonary Artery , Regional Blood Flow , Retrospective Studies , Treatment Outcome , Vascular Resistance
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