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SummaryMost rotamer libraries are generated from subsets of the PDB and do not fully represent the conformational scope of protein side chains. Previous attempts to rectify this sparse coverage of conformational space have involved application of weighting and smoothing functions. We resolve these limitations by using physics-based molecular dynamics simulations to determine more accurate frequencies of rotameric states. This work forms part of our Dynameomics initiative and uses a set of 807 proteins selected to represent 97% of known autonomous protein folds, thereby eliminating the bias toward common topologies found within the PDB. Our Dynameomics derived rotamer libraries encompass 4.8 × 109 rotamers, sampled from at least 51,000 occurrences of each of 93,642 residues. Here, we provide a backbone-dependent rotamer library, based on secondary structure ϕ/ψ regions, and an update to our 2011 backbone-independent library that addresses the doubling of our dataset since its original publication.

Purpose: This paper proposes a novel application of computer-aided diagnosis (CAD) to an everyday clinical dental challenge: the noninvasive differential diagnosis of periapical lesions between periapical cysts and granulomas. A histological biopsy is the most reliable method currently available for this differential diagnosis; however, this invasive procedure prevents the lesions from healing noninvasively despite a report that they may heal without surgical treatment. A CAD using cone-beam computed tomography (CBCT) offers an alternative noninvasive diagnostic tool which helps to avoid potentially unnecessary surgery and to investigate the unknown healing process and rate for the lesions. Methods: The proposed semiautomatic solution combines graph-based random walks segmentation with machine learning-based boosted classifiers and offers a robust clinical tool with minimal user interaction. As part of this CAD framework, the authors provide two novel technical contributions: (1) probabilistic extension of the random walks segmentation with likelihood ratio test and (2) LDA-AdaBoost: a new integration of weighted linear discriminant analysis to AdaBoost. Results: A dataset of 28 CBCT scans is used to validate the approach and compare it with other popular segmentation and classification methods. The results show the effectiveness of the proposed method with 94.1% correct classification rate and an improvement of themore » performance by comparison with the Simon’s state-of-the-art method by 17.6%. The authors also compare classification performances with two independent ground-truth sets from the histopathology and CBCT diagnoses provided by endodontic experts. Conclusions: Experimental results of the authors show that the proposed CAD system behaves in clearer agreement with the CBCT ground-truth than with histopathology, supporting the Simon’s conjecture that CBCT diagnosis can be as accurate as histopathology for differentiating the periapical lesions.« less

Protein function is intimately linked to protein structure and dynamics yet experimentally determined structures frequently omit regions within a protein due to indeterminate data, which is often due protein dynamics. We propose that atomistic molecular dynamics simulations provide a diverse sampling of biologically relevant structures for these missing segments (and beyond) to improve structural modeling and structure prediction. Here we make use of the Dynameomics data warehouse, which contains simulations of representatives of essentially all known protein folds. We developed novel computational methods to efficiently identify, rank and retrieve small peptide structures, or fragments, from this database. We also created a novel data model to analyze and compare large repositories of structural data, such as contained within the Protein Data Bank and the Dynameomics data warehouse. Our evaluation compares these structural repositories for improving loop predictions and analyzes the utility of our methods and models. Using a standard set of loop structures, containing 510 loops, 30 for each loop length from 4 to 20 residues, we find that the inclusion of Dynameomics structures in fragment-based methods improves the quality of the loop predictions without being dependent on sequence homology. Depending on loop length, ∼ 25-75% of the best predictions came from the Dynameomics set, resulting in lower main chain root-mean-square deviations for all fragment lengths using the combined fragment library. We also provide specific cases where Dynameomics fragments provide better predictions for NMR loop structures than fragments from crystal structures. Online access to these fragment libraries is available at http://www.dynameomics.org/fragments.

Integrative structural biology attempts to model the structures of protein complexes that are challenging or intractable by classical structural methods (due to size, dynamics, or heterogeneity) by combining computational structural modeling with data from experimental methods. One such experimental method is chemical crosslinking mass spectrometry (XL-MS), in which protein complexes are crosslinked and characterized using liquid chromatography-mass spectrometry to pinpoint specific amino acid residues in close structural proximity. The commonly used lysine-reactive N-hydroxysuccinimide ester reagents disuccinimidylsuberate (DSS) and bis(sulfosuccinimidyl)suberate (BS3) have a linker arm that is 11.4 A long when fully extended, allowing Cα (alpha carbon of protein backbone) atoms of crosslinked lysine residues to be up to ∼24 A apart. However, XL-MS studies on proteins of known structure frequently report crosslinks that exceed this distance. Typically, a tolerance of ∼3 A is added to the theoretical maximum to account for this observation, with limited justification for the chosen value. We used the Dynameomics database, a repository of high-quality molecular dynamics simulations of 807 proteins representative of diverse protein folds, to investigate the relationship between lysine–lysine distances in experimental starting structures and in simulation ensembles. We conclude that for DSS/BS3, a distance constraint of 26–30 A between Cα atoms is appropriate. This analysis provides a theoretical basis for the widespread practice of adding a tolerance to the crosslinker length when comparing XL-MS results to structures or in modeling. We also discuss the comparison of XL-MS results to MD simulations and known structures as a means to test and validate experimental XL-MS methods.

Summary: Modern scientific investigation is generating increasingly larger datasets, yet analyzing these data with current tools is challenging. DIVE is a software framework intended to facilitate big data analysis and reduce the time to scientific insight. Here, we present features of the framework and demonstrate DIVE’s application to the Dynameomics project, looking specifically at two proteins. Availability and implementation: Binaries and documentation are available at http://www.dynameomics.org/DIVE/DIVESetup.exe. Contact: daggett@uw.edu Supplementary information: Supplementary data are available at Bioinformatics online.

The dynamic behavior of proteins is important for an understanding of their function and folding. We have performed molecular dynamics simulations of the native state and unfolding pathways of over 2000 protein/peptide systems (approximately 11,000 independent simulations) representing the majority of folds in globular proteins. These data are stored and organized using an innovative database approach, which can be mined to obtain both general and specific information about the dynamics and folding/unfolding of proteins, relevant subsets thereof, and individual proteins. Here we describe the project in general terms and the type of information contained in the database. Then we provide examples of mining the database for information relevant to protein folding, structure building, the effect of single-nucleotide polymorphisms, and drug design. The native state simulation data and corresponding analyses for the 100 most populated metafolds, together with related resources, are publicly accessible through http://www.dynameomics.org.

This paper proposes a novel application of computer-aided diagnosis to a clinically significant dental problem: non-invasive differential diagnosis of periapical lesions using cone-beam computed tomography (CBCT). The proposed semi-automatic solution combines graph-theoretic random walks segmentation and machine learning-based LDA and AdaBoost classifiers. Our quantitative experiments show the effectiveness of the proposed method by demonstrating 94.1% correct classification rate. Furthermore, we compare classification performances with two independent ground-truth sets from the biopsy and CBCT diagnoses. ROC analysis reveals our method improves accuracy for both cases and behaves more in agreement with the CBCT diagnosis, supporting a hypothesis presented in a recent clinical report.

This paper proposes a novel approach to improve the segmentation quality of a 3D random walks algorithm using classifiability criteria. We produce a range of potential threshold values by extending the decision function of a random walks algorithm using a likelihood ratio test. Optimal threshold values are quantitatively isolated using two data-driven methods: maximum total accuracy and Bayesian cross validation criteria. The proposed methods are evaluated using a dataset of 28 dental lesions in 3D cone-beam CT scans. Both methods produce viable thresholds, the first corresponding to a conservative segmentation and the second a relaxed segmentation. We qualitatively compare the results to determine the best method.

This paper presents an experimental study for assessing the applicability of general-purpose 3D segmentation algorithms for analyzing dental periapical lesions in cone-beam computed tomography (CBCT) scans. In the field of Endodontics, clinical studies have been unable to determine if a periapical granuloma can heal with non-surgical methods. Addressing this issue, Simon et al. recently proposed a diagnostic technique which non-invasively classifies target lesions using CBCT. Manual segmentation exploited in their study, however, is too time consuming and unreliable for real world adoption. On the other hand, many technically advanced algorithms have been proposed to address segmentation problems in various biomedical and non-biomedical contexts, but they have not yet been applied to the field of dentistry. Presented in this paper is a novel application of such segmentation algorithms to the clinically-significant dental problem. This study evaluates three state-of-the-art graph-based algorithms: a normalized cut algorithm based on a generalized eigen-value problem, a graph cut algorithm implementing energy minimization techniques, and a random walks algorithm derived from discrete electrical potential theory. In this paper, we extend the original 2D formulation of the above algorithms to segment 3D images directly and apply the resulting algorithms to the dental CBCT images. We experimentally evaluate quality of the segmentation results for 3D CBCT images, as well as their 2D cross sections. The benefits and pitfalls of each algorithm are highlighted.

This study demonstrates that when vascular resistance is low, peak systolic velocity and peak flow volume increase with increasing blood pressure. We used ischemia with reactive hyperemia to create reproducible low resistance conditions in 32 volunteers. Ischemia resulted in sharp increases in systolic and diastolic velocities, while the difference between these velocities increased minimally. Spontaneous variations in subject's systolic blood pressure were positively correlated with peak systolic volume and peak flow volume (r = 0.40 and 0.59, respectively), but resistive index was not. We conclude that low resistance flow is blood pressure dependent. Because blood pressure increases with age, tumor velocity and frequency shift thresholds may need blood pressure correction if applied over wide age ranges. The resistive index was independent of blood pressure and thus may be preferable.

The evaluation of mechanical prosthetic heart valves would be aided by a more satisfactory animal model. For acute assessment, a variety of animals have been used, but for chronic studies, only larger animals (pigs, calves, baboons) have been employed, creating an expensive model with laboratory management difficulties. Previously, the use of dogs for chronic evaluation has been unsatisfactory because of the frequent occurrence of early sepsis and valve-related thrombotic deaths. We have modified our existing acute dog protocol to produce a successful chronic model. Our model employs perioperative systemic antibiotics, short cardiopulmonary bypass period (range 35–60 min), a minimum of perioperative intravenous lines, postoperative anticoagulation therapy, and strict postoperative antiseptic technique for blood sampling. To evaluate this model, 11 consecutive mongrel dogs underwent mitral valve replacement with either a standard Dacron sewing skirt or a newly devised carbon-coated Teflon sewing skirt No. 23 mm Bjork-Shiley Convexo Concave (CC) prosthetic valve. Nine animals (82%) survived and were evaluated after a predetermined observation interval of either 3 or 6 months for valve function, pannus formation, and possible carbon particle migration. At sacrifice, all animals had good hemodynamics and valve function, minimal pannus formation and no carbon washout. Consequently, this model provides a relatively inexpensive, reproducible method of chronic in vivo evaluation of prosthetic valve modifications.

Ablation of the kidney was attempted in 12 dogs by injecting 10-30 ml of heated (100 degrees C) contrast medium (Hypaque-60, diatrizoate meglumine) into the renal artery. Complete renal ablation without collateralization was demonstrated. Hot contrast medium is an effective embolic agent, and its use is associated with few of the drawbacks of presently used techniques.

Between May 1983 and October 1984, 51 patients who had 68 ureteral stones underwent treatment at the University of Minnesota. All 68 stones were removed successfully using percutaneous techniques. The 100% success rate is a great improvement over previous results at our institution. The primary factors appear to be the development of the retrograde-flush technique, familiarity with and access to a wider range of methods, and the increasing use of the retrograde ureterorenoscope to see stones in the lower ureter. The average patient was a 45-year-old man who had no other medical problems. The average hospital stay was 6.8 days. Experimental studies with dogs indicate that injection rates of up to 30 ml/sec of contrast material through a retrograde catheter in the ureter are safe if a vent is present in the upper collecting system.

The effect upon pancreatic blood flow of systemic hypoxia and hypercapnia was examined in 15 anesthetized puppies. Blood flow was measured by the 86 RbCl distribution technique. Reduction in arterial P O 2 and elevation of arterial P CO 2 were each found to effect significant mean reductions in pancreatic blood flow of 47 and 50%, respectively. Simultaneous measurements of duodenal blood flow showed no change from control levels.

A new vena caval filter that can be inserted percutaneously through an angiographic catheter is described. The filter is secured by controlled penetration of the caval wall and is designed for percutaneous retrieval. The filter was easily and safely placed and removed in 11 mongrel dogs, and in an in vitro study, the filter was shown to be highly effective and less dependent than the Greenfield filter on positioning. The authors believe that the filter will be suitable for prophylactic placement in patients at high risk for pulmonary thromboembolic disease.

Canine superficial extremity veins were examined grossly and microscopically in a double blind fashion for endothelial damage and phlebitis one hour and four days after the injection of ionic monomeric or dimeric, and non-ionic monomeric, 300 mg I/ml, contrast media. Superficial veins of all four extremities and the tail vein were injected with the same amounts of contrast medium after application of tourniquets for 20 minutes following the injections. Silver staining and prefixation of the veins were done in situ. The specimens were evaluated together with cross-sectioned, hematoxylin-eosin stained biopsies. On the basis of a randomized study of 77 dogs, endothelial damage or thrombosis caused by various contrast media as seen in man was not demonstrated. This may be due to species differences. It is postulated that canine endothelium may have a higher resistance to contrast medium injury than human endothelium.

To better determine the risks of transcatheter closure of a patent ductus arteriosus (PDA), a model of PDA was made in newborn piglets by using 5- to 7-mm angioplasty catheters to dilate the probe PDA. This maneuver resulted in a permanent PDA in most piglets. Four to 6 weeks later PDA closure was attempted using the Rashkind PDA occluder. Twelve such procedures were attempted, using clean but nonsterile technique. Nine of 12 PDAs were successfully closed. Two failures were the result of inability to successfully traverse the PDA. This problem was solved by using a long sheath to position the device properly. Four complications occurred, all related to device release: left pulmonary artery embolization in 1 case, femoral artery embolization in 1, torn pulmonic valve cusp in 1 and lodgment of a prosthesis on a pulmonic valve cusp. Two successfully implanted devices were infected at necropsy. This study demonstrates the value of a piglet model in testing transcatheter PDA occlusion devices, the importance of sterile technique in such procedures, the hazards of device retrieval through the right heart and the feasibility of transcatheter PDA closure.

Regional segmental wall motion analysis assumes a linear or radial grid system. In this study, motion patterns of points on the canine endocardium were evaluated. Radiopaque endocardial and epicardial markers were inserted along the anterior and posterior descending coronary arteries. Postoperative cine radiography showed that the endocardial markers did not move along either linear or radial grids. The endocardial and epicardial markers were shown to have different patterns of movement.

The new Amplatz retrievable filter was placed 15 times into the inferior vena cava (IVC) of 7 dogs. Retrieval of the filter was attempted in 11 cases after 1 week and in 3 cases after 2 weeks. The retrieval was successful and without complication in all 14 cases. The 15th placement resulted in thrombotic occlusion of the IVC, and no retrieval was attempted.

Angioplasty produces a persistent 20-fold increase in blood flow through mural vasa vasorum. To assess the role of prostaglandins in this phenomenon, vessel wall blood flow in experimentally dilated carotid arteries of aspirin treated dogs was measured. Aspirin (10 mg/kg, intravenously) significantly attenuated the increase in blood flow produced by dilation (+283 +/- 91% SE, n = 6) when compared to non-aspirin-treated controls (+2356 +/- 885% SE, n = 10). This suggests that aspirin, by interfering with arachidonate metabolism, may decrease local vasodilation after angioplasty. The effect of aspirin therapy on the long-term success of angioplasty requires further study.

Balloon dilatation of the ductus arteriosus was carried out in vivo in newborn pigs and on postmortem specimens from humans and piglets. The ductus was functionally closed in all newborn animals but patency resulted in all animals after balloon dilatation. Left-to-right shunts of 50% to 70% were found with anatomic lumen sizes of 3 to 5 mm. Patency was demonstrated up to 6 weeks after dilatation. Histologic examination showed splitting of the internal elastic layer and media, areas of hemorrhage confined to the media, and preservation of the adventitia. Mediastinal hemorrhage did not occur. This new technique is useful as an animal model of patent ductus arteriosus and could theoretically be used for palliative treatment of ductus-dependent congenital heart disease.

Diatrizoate (76%) contrast agent heated to 100 degrees C was injected into the veins of dogs and one human volunteer for the nonsurgical occlusion of the vessels. Follow-up venograms and histologic examinations, at intervals varying from one day to four weeks later, revealed thrombosis of the injected veins in all animals. Thrombosis occurred one to five days after injection of contrast agent. The authors conclude that hot contrast medium is a safe and convenient agent for inducing thrombosis. It is much easier to use than mechanical devices, tissue glues, and plastics, which involve complex procedures and specialized equipment. In contrast to other sclerosing agents, hot contrast agent is rapidly converted into a nonsclerosing agent by cooling. The new technique allows a more controlled thermal injury to the vascular wall and is under fluoroscopic control.

Interruption of flow in the vasa vasorum may lead to medial necrosis and aneurysm formation. The purpose of this study was to determine whether angioplasty produces significant alterations in the morphology or blood flow of the vasa vasorum of the dilated artery. The morphology of the canine vasa vasorum was studied before and after angioplasty; in a separate experiment vessel wall blood flow (VWBF) in canine carotid arteries was measured after angioplasty to determine whether physiologic regulation of the blood flow was disrupted by arterial dilation. No morphologic changes could be demonstrated in the vasa vasorum of the dilated artery; however, VWBF was increased by 1194 +/- 215% (mean +/- standard error, p less than 0.01) between 90 and 120 minutes after angioplasty. VWBF in the adjacent nondilated arterial segment was also increased (720 +/- 177% between 10-30 minutes, p less than 0.01) but returned toward normal after 60 minutes. Adenosine caused a "paradoxical" decrease in VWBF (p less than 0.05) of the dilated arterial segment while causing increased VWBF (p less than 0.05) in the thoracic aorta. Angioplasty appears to produce persistent hyperemia in the dilated arterial wall. A paradoxical response to adenosine suggests that vasa vasorum in the dilated arterial segment are maximally vasodilated. This may be due to mechanical disruption of vasomotor tone or to release of vasoactive substances.

Embolization of coils into the lungs has been reported following their use for the obliteration of large arteriovenous fistulas. So far, except for a recent report, they have not been used on the venous side of the circulation. Experimental studies at our institution demonstrated that the placement of coils on the venous side can result in embolization to the lungs, even when oversized coils are introduced. A simple, easy to perform modification of the standard stainless steel coils (Gianturco-Wallace-Chuang spring embolus and coilons) makes these devices safe embolic agents for used on the venous side of the circulation, as for example in the obliteration of spermatic veins.

Ivalon (polyvinyl alcohol sponge) shavings can be used as a permanent embolic material. When injected as a suspension with assorted particles of proper size, congenital arteriovenous malformations can be cured, eliminating the need for surgical excision.

A new technique for embolization with compressed Ivalon plugs is described. Fourteen arteries--six renal, three splenic, two pulmonary, one left gastric, and two abdominal aortas--were occluded in six dogs. In one case of renal artery embolization, three plugs were used, and in one case of abdominal aorta embolization, two were needed for total occlusion. In all other cases only one plug was used. Total occlusion was angiographically demonstrated up to five months following embolization in all but one case. In this case, recanalization was thought to have occurred because of overcompression of the Ivalon plug.

Obliteration of varicoceles in men with infertility has been shown to improve semen quality and increase fertility rates. Many current techniques involve complex procedures and specialized equipment and may be associated with adverse effects. Transcatheter thermal vessel occlusion was utilized for spermatic vein obliteration in dogs. Diatrizoate (76%) contrast medium at a temperature of 100 degrees C was injected into canine spermatic veins. Follow-up venography and histologic examination revealed thrombosis of the injected veins without damage to the surrounding tissues in all cases. Clinical and laboratory examination of the animals revealed no adverse systemic effects. It is concluded that transcatheter thermal venous occlusion is an effective technique for spermatic vein occlusion in a canine model.

A new type of endovascular prosthesis has been developed using a unique metal alloy (nitinol) with a heat-sensitive memory. Nitinol wire coil grafts were straightened in ice water and passed into the canine aorta via catheter, where they reformed into their original shapes. Follow-up aortograms demonstrated long-term patency with minimal thrombus formation. Nitinol endovascular coil grafts may eventually be used in the nonsurgical treatment of several forms of vascular disease.

(1) Posterior hypothalamic stimulation causes a 36% reduction in colonic perfusion in the puppy with a simultaneous rise in vascular resistance. Neither effect is seen in the presence of hypoxia. (2) Hypoxia alone produces a 17% increase in colonic perfusion with a 33% decrease in resistance. In the presence of PHS, hypoxia is associated with an 83% increase in perfusion and a 43% reduction in resistance. (3) The data suggest that sympathetic overactivity may play a role in the genesis of the ischemic lesion of neonatal necrotizing enterocolitis, while hypoxia may be operative in the development of the hemorrhagic lesions. This concept is discussed in relation to other hypotheses regarding the genesis of this disease.

Total and regional cortical blood flow was measured in dogs by the radioactive microsphere technique after renal damage of varying severity had been induced by combining selective injection of diatrizoate, iopamidol, or normal saline with a 10 min occlusion of the renal artery. There was extensive tubular and glomerular damage in the kidneys exposed to diatrizoate, but not in the kidneys exposed to saline. Iopamidol caused intermediate changes. Average cortical blood flow was reduced from baseline levels in all groups 5 min after perfusion was restored. After 1 hr the flow had returned to the baseline level. Analysis of variance did not show a statistically significant difference among the groups. A tendency for redistribution of flow from outer to inner cortical layers was seen, but this was present in all groups. The flow changes detected in this study cannot explain the varying severity of renal damage.

Balloon dilatation of the ductus arteriosus was carried out in vivo in eight piglets that were 12 to 16 days old. The ductus was functionally closed in all animals before dilatation. Long-term patency for periods of up to 6 months after the procedure was demonstrated in six animals by angiography, Doppler ultrasound examination, and at autopsy. The presence of hemodynamically significant shunts was indicated by clinical development of heart failure, pulmonary infections, and left ventricular hypertrophy. These results confirm the value of this laboratory preparation to create left-to-right shunts at the ductus level.

In an attempt to study the role of prostaglandins in the renal vascular response to contrast media in mongrel dogs, renal arterial injections of 6 ml of either the non-ionic contrast medium Iopamidol or the ionic medium diatrizoate meglumine/Na+ were performed, before and after intravenous injection of a buffered solution of acetylsalicylic acid (10 mg/kg) (ASA). Renal blood flow was recorded using non-occluding electromagnetic flow probes. The resting renal blood flow was significantly reduced after ASA. The usual biphasic response to contrast injection was observed both before and after ASA, and using either contrast medium. Analysis of the results failed to show any difference in degree of vasodilation or vasoconstriction after ASA. We conclude that prostaglandins may affect the resting level of renal blood flow but are not mediators of the instantaneous changes in response to contrast injection.

The authors describe an experimental model for the study of nephrotoxicity induced by contrast media, based on a standardized injection combined with occlusion of the renal artery so as to expose the kidney to a high concentration of contrast medium for ten minutes. Iopamidol, ioxaglate, and both isosmolar and hyperosmolar saline were well tolerated, but diatrizoate caused marked radiological and pathological changes. This model may be helpful in studies of the mechanisms underlying contrast medium nephrotoxicity and evaluating differences in toxicity between contrast agents.

During wedge hepatic venography, mechanical injection should be accomplished at the lowest possible rate in order to avoid hemorrhagic infarction. Small amounts of contrast material should be administered. Hepatic angiography may result in in an area of tumor blush at the site of a previous wedge injection.

Canine superficial extremity veins were examined grossly and microscopically in a double blind fashion for endothelial damage and phlebitis one hour and four days after the injection of ionic monomeric or dimeric, and non-ionic monomeric, 300 mg I/ml, contrast media. Superficial veins of all four extremities and the tail vein were injected with the same amounts of contrast medium after application of tourniquets for 20 minutes following the injections. Silver staining and prefixation of the veins were done in situ. The specimens were evaluated together with cross-sectioned, hematoxylin-eosin stained biopsies. On the basis of a randomized study of 77 dogs, endothelial damage or thrombosis caused by various contrast media as seen in man was not demonstrated. This may be due to species differences. It is postulated that canine endothelium may have a higher resistance to contrast medium injury than human endothelium.

A new technique for percutaneous arterial grafting was developed using a unique metal alloy (nitinol) with a heat dependent memory. Ten tightly wound nitinol coils (5-15 mm in diameter and 2-5 cm in length) were straightened in ice water and passed via catheter into the iliac artery or abdominal aorta of nine animals. Long term patency (15 weeks) was demonstrated in all but one graft. In one animal, an experimentally created abdominal aortic aneurysm was successfully treated by interposition of a nitinol graft. This new technique may be a valuable adjunct to conventional treatment of both obstructive and aneurysmal arterial disease in man.

To obtain consistent, reproducible postextrasystolic potentiation (PESP), a single closely coupled extrasystole (ES) must be introduced using transvenous pacing. We hypothesized that multiple ES (spontaneous or catheter induced) produce maximal PESP at all coupling intervals (CI). Differences in PESP between single and double ES were assessed in dogs at varying CI by two different methods [systolic time intervals--PEP/LVET, and endocardial markers--ejection fraction (EF)]. Single ES produced variable decreases in PEP/LVET (-8.6 +/- 2.7% (SE) to -22.9 +/- 4.0%) depending on the CI duration. Double ES produced maximal decreases (-26.0 +/- 1.2%) at all CI. A similar relationship was noted for EF following single ES (8.6 +/- 2.7% to 43.0 +/- 4.0%) and double ES (42.9 +/- 1.3%). Double ES produced maximal PESP at all CI. This finding may allow simple myocardial assessment during routine left ventricular catheterization without simultaneous right ventricular catheterization.

To determine the effects of dynamic exercise on ductal left to right shunting and skeletal and myocardial blood flow distribution, a persistent ductus arteriosus was created by balloon catheters in neonatal piglets. At 8-10 weeks of age, aortic, pulmonary artery, and left atrial catheters were placed and radiolabelled microspheres injected for measuring left ventricular output, organ blood flows, and ductus left to right shunting at rest and during treadmill exercise (1.6 mph). At rest, effective left ventricular output and myocardial and skeletal muscle blood flows were similar in the study group and controls. Exercise increased skeletal muscle and left ventricular blood flows similarly in the control and study group and did not accentuate the exercise induced small reduction in the left ventricular subendocardial to subepicardial blood flow ratio. This was due to a significant reduction in the ductus left to right shunt during exercise (mean(SD) 34(15) vs 18(7)%, p less than 0.02) and maintenance of effective left ventricular output in the study group (447(144) vs 446(98) ml.min-1.kg-1 in controls). The reduction in ductus shunting during exercise was due to a significant decrease in systemic vascular resistance and a small increase in pulmonary vascular and ductus resistance. Thus, reduced persistent ductus arteriosus shunting and maintenance of effective left ventricular output prevents myocardial perfusion abnormalities during dynamic exercise in swine with a persistent ductus and small to moderate left to right shunts.

Transcatheter gastric embolization using Ivalon shavings was performed on three groups of dogs. The left gastric artery and splenic branches (the short gastric and left gastroepiploic arteries) were embolized in Group I, the left gastric artery in Group II, and the splenic branches in Group III. Infarctions of the gastric mucosa occurred only in Group I. Ischemic ulcers developed in three of the five dogs in Group I and in one of the three dogs in Group II. The study suggests that embolization can only be performed safely if particles of 0.3 mm or larger are used.

Neural control of bone metabolism and growth has been suggested, although the identity of participating neurons and neurotransmitters effecting this control has not been established. Immunohistochemical studies demonstrated a system of vasoactive intestinal peptide (VIP)-immunoreactive nerve fibers that innervate periosteum and bone in several mammalian species. Thoracic sympathetic chain ganglionectomy resulted in an ipsilateral loss of VIP-immunoreactive fibers in the periosteum of ribs, whereas dorsal root ganglionectomy had no effect. Injection of fast blue into rib periosteum labeled a population of VIP-immunoreactive sympathetic postganglionic neurons. Thus, postganglionic sympathetic neurons may provide an important means by which VIP regulates bone mineralization.

The reliable and safe production of myocardial infarction in closed-chest animals is of paramount research interest. To date, the injection of particulate matter and the introduction of occlusive solid plugs have been described. Because of the limited size of the catheter, only small branches could be occluded, which resulted in a high incidence of mortality. A new simple technique is described that allows occlusion of a major coronary artery at a preselected site. An Ivalon (polyvinyl alcohol) plug compressed around the tip of an introducing wire is advanced through a selectively placed catheter into the coronary artery. It is felt in place for 5 minutes and assumes its original size upon contact with blood. Once the plug is re-expanded, the wire is withdrawn. The new technique was carried out successfully on nine dogs with no immediate fatality and myocardial infarction as demonstrated by cine ventriculography and histopathologic examination.

The abdominal aortas in eight dogs were successfully occluded with a combination of stainless steel coils and compressed Ivalon (polyvinyl alcohol). There was no evidence of recanalization up to six months later. This combination is useful for the embolization of large arteries and arteriovenous fistulas.