The hemodynamic effects of the diphosphonate terminus of a new infarct-avid magnetic resonance (MR) imaging agent, gadolinium-DTPA (diethylenetriamine-pentaacetic acid) HPDP (1-hydroxo-3-aminopropane-1,1-diphosphonate), and HEDP (hydroxyethyl-1,1-diphosphonate) (a simple diphosphonate terminus model) have been evaluated at MR imaging doses in both isolated and intact rabbit hearts. Rapid injections of the sodium salt of the diphosphonates reversibly depressed left ventricular developed pressure and its first derivative (dP/dt) but did not affect the in vivo heart rate. Hemodynamic depression was prevented by the co-administration of two equivalents of calcium ion per diphosphonate terminus in the isolated heart and by either slow infusion or co-administration of one equivalent of calcium ion per diphosphonate terminus in the in vivo heart. Therefore, if these agents are to be used in MR imaging of acute myocardial infarction, appropriate measures should be taken to prevent negative inotropic effects.

Animals↗

PubMedDate not supplied

Myocardial uptake of thallium 201 and technetium 99m-labeled sestamibi after ischemia and reperfusion: comparison by quantitative dual-tracer autoradiography in rabbits.

BACKGROUND: Myocardial scintigraphy with 99mTc-labeled sestamibi (99mTc-sestamibi) or 201Tl is used to assess regional perfusion in acute coronary syndromes associated with metabolic or functional abnormalities, such as acute coronary thrombosis with reperfusion and ischemia at rest. However, the initial uptake of these agents may be affected by a recent ischemic insult because the myocardial retention of these tracers depends on cellular metabolism. METHODS AND RESULTS: Accordingly, 99mTc-sestamibi and 201Tl were injected simultaneously in rabbits after transient brief (10 to 15 minutes, group I) or prolonged (45 to 60 minutes, group II) coronary occlusion. Accumulated subendocardial and subepicardial 99mTc-sestamibi and corresponding 201Tl activity were determined from autoradiographs of 30 microns short-axis slices comounted with serial tissue standards. Circumferential 99mTc-sestamibi and 201Tl activity profiles closely overlapped in both groups. The initial global and segmental myocardial activity per unit blood flow within the ischemic zone did not differ from unity for either tracer regardless of the duration of the ischemic insult. The initial myocardial uptake of both 99mTc-sestamibi and 201Tl after an acute ischemic insult reflected predominantly coronary blood flow, independent of myocardial viability. CONCLUSIONS: Thus this study supports the use of both 99mTc-sestamibi and 201Tl as perfusion probes in acute coronary syndromes characterized by acute occlusion and reperfusion.

Animals↗

PubMedDate not supplied

A method of simultaneous dual-radionuclide cardiac imaging with technetium 99m and thallium 201. I: Analysis of interradionuclide crossover and validation in phantoms.

BACKGROUND: Simultaneous dual-radionuclide technetium 99m/thallium 201 scintigraphy can potentially produce perfectly aligned stress and rest images in less time than conventional protocols. However, interradionuclide crossover limits diagnostic accuracy. Accordingly, we evaluated 99mTc and 201Tl crossover in line and heart phantoms. METHODS AND RESULTS: 99mTc crossover in the 201Tl imaging window constituted as much as one half of the counts in the 99mTc window, varied significantly with attenuation, and was spatially incoherent. 201Tl crossover was relatively small, less variable, and spatially similar to the primary image. Based on these findings, the following simultaneous dual-radionuclide 99mTc/201Tl method was developed, and validated in line and heart phantoms. The 99mTc source is imaged first into dual 201Tl/99mTc windows, followed by 201Tl administration and dual-radionuclide imaging. The single-radionuclide 99mTc image in the 201Tl window is count-normalized for acquisition time and then subtracted from the dual-radionuclide 201Tl image to specifically correct for 99mTc crossover. Image quality of the corrected dual-radionuclide 201Tl images approached their single-radionuclide counterparts. Correction for 201Tl crossover was relatively unimportant. CONCLUSION: Simultaneous dual-radionuclide 99mTc/201Tl myocardial scintigraphy is feasible with 99mTc crossover correction specific to each acquisition. The proposed dual-radionuclide 99mTc/201Tl method and the principles on which it is based can be applied to a broad range of dual-radionuclide pairs.

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PubMedDate not supplied

Schematic representation of residue-based protein context-dependent data: an application to transmembrane proteins.

An algorithmic method for drawing residue-based schematic diagrams of proteins on a 2D page is presented and illustrated. The method allows the creation of rendering engines dedicated to a given family of sequences, or fold. The initial implementation provides an engine that can produce a 2D diagram representing secondary structure for any transmembrane protein sequence. We present the details of the strategy for automating the drawing of these diagrams. The most important part of this strategy is the development of an algorithm for laying out residues of a loop that connects to arbitrary points of a 2D plane. As implemented, this algorithm is suitable for real-time modification of the loop layout. This work is of interest for the representation and analysis of data from (1) protein databases, (2) mutagenesis results, or (3) various kinds of protein context-dependent annotations or data.

Algorithms↗

PubMedDate not supplied

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Dental Equipment↗

PubMedDate not supplied

On the structural and mechanistic basis of function, classification, and ligand design for 5-HT receptors.

We review our results from the first computational simulations of a mechanism by which ligands can activate a 5-HT1A receptor, and relate the findings to information on the structure and function of the authentic receptor. The computational exploration of the recognition and activation mechanisms is carried out inside a protein selected as a model for the receptor based on cognate physicochemical and experimental data. A similar approach is applied to the 5-HT2 receptor. The interaction mechanisms at the two 5-HT receptor subtypes differ in the nature of the forces determining ligand-receptor interactions and the types of receptor activation mechanisms they entail. The main molecular property related to recognition at 5-HT1A receptors was shown to be the directional character of the electrostatic potential generated by the ligands in the molecular region corresponding to the indole in 5-HT. The corresponding recognition site was shown to have properties of a positively-charged (imidazolium) form of the side chain of a His residue. The mechanism of recognition at the 5-HT1A receptor was shown to be electrostatic, and conducive to a triggering of the receptor response through the change in the electronic structure of the imidazolium recognition site when it interacts with an activating ligand (agonist). This effect was shown to induce a proton transfer from the ring to a neighboring residue to which it can be hydrogen-bonded in the resting state. We show how this model for recognition and activation defines in molecular terms the mechanisms underlying the classical pharmacologic properties of agonists, partial agonists, and antagonists. The molecular correlates of pharmacologic efficacy emerge from the calculations of the effect of the ligands on the barriers for proton transfer, and on the energy drive for the proton transfer reaction. A different model is proposed for selective recognition at the 5-HT2 receptors, based on structural details of 5-HT-binding peptides. The recognition site is considered to consist of two aromatic residues separated by a hydrophilic residue. In contrast to the model for 5-HT1A, the recognition is based on the interaction of neutral molecules and the stabilization is provided by dispersion forces. The resulting activation mechanism is based on a structural rearrangement. These detailed descriptions of elements in the ligand-receptor interactions at the two receptor subtypes lead to a new basis for rational design of receptor-selective compounds with predetermined efficacy.

Animals↗

PubMedDate not supplied

Analysis of the molecular electrostatic potential for the prediction of N-oxidation and biological activity of substituted pyridines.

Comparative studies on the reactivity of the heterocyclic nitrogen were carried out for pyridine and its three monosubstituted derivatives 2-aminopyridine (2-AP), 3-aminopyridine (3-AP), and 4-aminopyridine (4-AP) to reveal the structural basis for the differences in their susceptibility to N-oxidation. Molecular orbital calculations were performed to obtain the wave functions for the calculation of the molecular electrostatic potentials (MEP) generated by the molecules. The comparison of the reactivity of the cyclic nitrogen, evaluated from the depth and accessibility of the minimum in the MEP, indicates that the nitrogen in 4-AP will be most susceptible to protonation and will be the most protected from N-oxidation at physiological pH values. The MEP map for 2-AP reveals the smallest minimum in the series of compounds and a considerable reduction in the accessibility of the region near the cyclic nitrogen caused by the proximal substitution. On this basis, 3-AP becomes the most likely derivative to form the ring N-oxide. Comparison of the conclusions from the MEP analysis with available data from bioassays suggests that the mechanism responsible for the genotoxic effects of the chemicals, where only 3-AP is active, is very different from the mechanism for systemic toxicity where 3-AP is the least active, and 4-AP is most active probably due to its channel blocking properties. As the mechanisms for the biological activities of the N-oxide metabolites become clear, reliable predictions of the toxicity of the pyridines should become possible based on such reactivity characteristics.

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PubMedDate not supplied

Long-term survival in Hodgkin's disease relative impact of mortality, second tumors, infection, and cardiovascular disease.

PURPOSE: Despite dramatic improvements in the survival of patients with Hodgkin's disease attributable to advances in treatment over the past 30 years, concern for the risk of treatment-related deaths has led to a number of trials to evaluate reduction of therapy. The consequences of these trials on recurrence, development of long-term complications, and survival remain unknown. We determined the causes of death in a group of patients with pathologically staged and intensively treated Hodgkin's disease who were followed for long intervals. MATERIALS AND METHODS: Between April 1969 and December 1988, 794 patients with laparotomy-staged IA to IIIB Hodgkin's disease were treated with radiation therapy alone or combined radiation therapy and chemotherapy. There were 8700 person-years of follow-up (average, 10.95 person-years/ patient). Causes of mortality were grouped into the categories Hodgkin's disease, second malignant tumors, cardiovascular, infection, and miscellaneous. Age- and gender-specific incidence rates were multiplied by corresponding person-years of observation to obtain expected numbers of events. Observed-to-expected results were calculated by type of treatment, age at treatment, sex, and time after Hodgkin's disease. Absolute (excess) risk was expressed as number of excess cases per 10,000 person-years. RESULTS: Of 124 patients who died, 56 died of Hodgkin's disease, 36 of second malignant neoplasms, 15 of cardiac causes, 9 of infection, and 8 of miscellaneous causes. The 20-year actuarial survival rate for all patients in this study is 73%. Age 40 years or older, mixed cellularity/lymphocyte-depleted histologic type, and stage-III disease were adverse independent predictors of survival. The largest differences were seen by age. The 20-year actuarial rates of survival were 78%, 78%, and 46%, respectively, for patients aged 16 or less, 17 to 39, and 40 years or older at diagnosis. Hodgkin's disease diagnosed at age 40 or older was a significant risk factor for all causes of death. The use of combined chemotherapy/ radiotherapy was a significant risk factor for second tumor and infection-related mortality. The excess risk of death from all causes, including Hodgkin's disease, remained constant with time from treatment and was approximately 1.2% per year over the first 20 years. Deaths from Hodgkin's disease decreased with time from treatment, with no patients dying after 15 years. This decrease, combined with an increased excess mortality risk with time from other causes, especially second tumors, accounted for the constant excess mortality with time after Hodgkin's disease. CONCLUSIONS: Hodgkin's disease followed by second tumors, cardiac events, and infections remain the major causes of death after treatment of Hodgkin's disease. Our findings suggest the importance of both maintaining a high disease-free survival and reducing long-term complications in designing treatments of Hodgkin's disease.

Adolescent↗