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Biomedical subjects

K M Moser

Publications and source records attributed to K M Moser.

At least 55 records · Page 3Linked to original sources
PubMed1994

Effect of chronic thromboembolism on the pulmonary artery pressure-flow relationship in dogs.

To understand the hemodynamic alterations associated with chronic thromboembolic pulmonary hypertension, the large pulmonary arteries of mongrel dogs were chronically obstructed with lysis-resistant thrombi. Pulmonary hemodynamics were experimentally measured and described by multipoint pulmonary arterial pressure (PAP) vs. flow plots. In nine anesthetized chronically embolized dogs, but not in six control dogs, the PAP-flow line shifted significantly upward in a parallel fashion by 4.2 +/- 0.7 mmHg. The postembolic pulmonary circulation was further characterized by predictions from a morphometric-based elastic tube and sheet flow model of the canine pulmonary circulation. After model validation with the preembolic PAP-flow data, the derived postembolic PAP matched the in vivo results to within 1 mmHg. A detailed analysis of the model-derived PAP drop revealed that the PAP-flow line shift can be accounted for by a novel fixed resistor in the largest obstructed pulmonary artery.

Animals↗
PubMed1994

Expression of type 1 plasminogen activator inhibitor in chronic pulmonary thromboemboli.

BACKGROUND: Chronic thromboembolic pulmonary hypertension is the result of nonresolving pulmonary emboli that lead to chronic obstruction of the central pulmonary arteries. METHODS AND RESULTS: To determine if the failure to lyse pulmonary thromboemboli is caused by the local expression of the primary inhibitor of tissue-type plasminogen activator (type 1 plasminogen activator inhibitor, PAI-1), levels of PAI-1 antigen and mRNA were analyzed by immunohistochemistry and in situ hybridization in specimens harvested from a series of patients during pulmonary thromboendarterectomies. Red, fibrin-rich thrombi within the thromboendarterectomy specimens were lined with a single layer of endothelial cells exhibiting high levels of PAI-1 antigen. Quantitation of the in situ hybridization signal revealed that a significant increase in PAI-1 mRNA was present in the endothelial cells lining the fresh thrombi in comparison to the signal present in the endothelial cells from noninvolved areas of patients' pulmonary arteries (n = 16, P < .001). In contrast, tissue-type plasminogen activator antigen levels were low in all samples. Yellowish-white thrombi were composed of smooth muscle cells and endothelial cells in numerous vessels that stained prominently for PAI-1 antigen. Both types of cells within the highly organized tissues also exhibited elevated PAI-1 mRNA levels in comparison to patient pulmonary artery specimens that were free of thrombus (n = 16, P < .02). CONCLUSIONS: The prevalence of PAI-1 expression within pulmonary thromboemboli suggests that this inhibitory may play a role in the stabilization of vascular thrombi.

Adult↗
PubMed1994

Parallel analysis of tissue-type plasminogen activator and type 1 plasminogen activator inhibitor in plasma and endothelial cells derived from patients with chronic pulmonary thromboemboli.

BACKGROUND: Chronic thromboembolic pulmonary hypertension is the result of nonresolving pulmonary emboli that lead to chronic obstruction of the central pulmonary arteries. METHODS AND RESULTS: To determine if the failure to lyse pulmonary thromboemboli is caused by an abnormality in the endothelial cell (EC)-associated fibrinolytic system, conditions were established to culture ECs from patient main pulmonary arteries during surgical pulmonary thromboendarterectomies and to analyze the conditioned media for levels of tissue-type plasminogen activator (TPA) and type 1 plasminogen activator inhibitor (PAI-1). Our data indicate that the levels of TPA antigen and PAI-1 activity in media conditioned by primary ECs harvested from areas free of thrombus were not significantly different between patients with chronic thromboemboli and organ donors. In 13 consecutive patients, no correlation was obtained in either the TPA antigen or PAI-1 activity level in a patient's plasma and the respective levels in media conditioned by the patient's pulmonary ECs. Moreover, patient pulmonary arterial ECs were observed to increase the secretion of TPA and PAI-1 in response to thrombin in a fashion similar to donor pulmonary artery ECs. CONCLUSIONS: The data suggest that an inherent EC-mediated fibrinolytic imbalance is not a generalized phenomenon observed in pulmonary arteries of patients with chronic pulmonary thromboemboli.

Adult↗
PubMed1994

Suppression of thrombolysis in a canine model of pulmonary embolism.

BACKGROUND: The brisk fibrinolytic response of canines has impaired efforts to develop a canine model of chronic thromboembolic pulmonary hypertension. Difficulties in retaining chronic embolic residuals were partially overcome by administration of tranexamic acid (TXA) (Circulation. 1991;83:1272-1279.). In this study, we used type 1 plasminogen activator inhibitor (PAI-1), a major inhibitor of the endogenous fibrinolytic system, to determine its efficacy in the suppression of thrombolysis in canines. METHODS AND RESULTS: Thrombus was induced in the inferior vena cava of anesthetized mongrel dogs with thrombin and a special double-balloon catheter; 2 hours later, the thrombus was embolized. In one group of dogs, activated type 1 plasminogen activator inhibitor (PAI-1) (130 micrograms) was delivered directly into the forming thrombus; in another, TXA (110 mg/kg) was given intravenously before thrombus formation; in controls, thrombus was induced without inhibitors. Cross-linked fibrin degradation product (D-dimer) appeared in the blood of control animals within 1 hour of thrombus induction (176 +/- 62.5 versus 1.02 +/- 0.39 ng/mL baseline; mean +/- SEM), was maximal by 4 hours (413 +/- 110 ng/mL) and remained elevated at 24 hours (90.8 +/- 19.5 ng/mL). Compared with controls, PAI-1 and TXA suppressed D-dimer release by 80% and 85%, respectively, over the first 24 hours. One week later, animals were killed, and residual emboli were harvested. Perfusion scan defects persisted in all animals at this time, but there were no scan defect differences among groups. However, emboli recovered from animals receiving PAI-1 still harbored immunoreactive PAI-1 and were, on average, more than twofold greater in mass (393 +/- 56 mg) than emboli recovered from either controls (183 +/- 76 mg) or animals receiving TXA (180 +/- 80 mg). CONCLUSIONS: Intravenous TXA and intrathrombus PAI-1 effectively suppress thrombolysis for 24 hours in canines. Thromboemboli enriched with PAI-1 appear to resist lysis for longer periods of time (up to 1 week). These findings are consistent with the hypothesis that PAI-1 remains associated with the embolus, where it continues to inhibit lysis, whereas TXA eventually diffuses out of the embolus, allowing lysis to ensue.

Animals↗
PubMed1994

Inhaled nitric oxide reverses hypoxic pulmonary vasoconstriction in dogs. A practical nitric oxide delivery and monitoring system.

Nitric oxide (NO) is a potent dilator of vascular smooth muscle that likely represents an important endothelium-dependent relaxing factor. Recent interest has focused on inhaled NO as a pulmonary vasodilator. The purpose of this study was to design a reliable NO delivery system with on-line monitoring of NO and nitrogen dioxide (NO2) concentrations, and to test the effects of inhaled NO in a dog model of acute hypoxic pulmonary vasoconstriction (HPV). Six canines were studied. Marked HPV was induced using a hypoxic gas mixture. Using a standard blender. NO was delivered through a volume-cycled ventilator. We were able to rapidly adjust the delivered NO concentration using this system. An on-line chemoluminescence analyzer was used to continuously measure NO and NO2 concentrations. Inhaled NO at 40 and 80 ppm for 30 min rapidly reversed HPV in all animals (PVR 502 +/- 154 dynes.s.cm-5 with hypoxia, 244 +/- 52 with 40 ppm NO, 227 +/- 47 with 80 ppm NO). No significant NO2 or methemoglobin production was noted during the study. We conclude that inhaled NO can be easily delivered through a ventilator and the dose rapidly adjusted, NO and NO2 concentrations can be monitored continuously on-line, inhaled NO rapidly reverses HPV in dogs, and with short-term NO inhalation, there is no significant NO2 or methemoglobin formation. Inhaled NO may, therefore, have a future clinical role as a new agent in the diagnosis and treatment of other forms of pulmonary hypertension.

Administration, Inhalation↗
PubMed1993

Sensitive identification of bluetongue virus serogroup by a colorimetric dual oligonucleotide sorbent assay of amplified viral nucleic acid.

A polymerase chain reaction (PCR) procedure coupled to an enzyme-linked oligonucleotide sorbent assay (ELOSA; a PCR-ELOSA) identified all 24 serotypic variants of bluetongue virus (BTV) without identifying any of six viruses belonging to the related epizootic hemorrhagic disease virus serogroup. The PCR-ELOSA detected 0.01 50% cell culture infectious doses of each serotype of BTV. The sensitivity and serogroup-wide specificity of the PCR-ELOSA may enable it to replace the more expensive, time-consuming, and biohazardous methods used in the identification of BTV.

Base Sequence↗
PubMed1993

Factors contributing to increased vascular fibrinolytic activity in mongrel dogs.

BACKGROUND: Numerous investigators have observed that pulmonary emboli are rapidly lysed in a canine model system. This study was undertaken to delineate the unique mechanism that accounts for the rapid dissolution of pulmonary emboli in mongrel dogs. METHODS AND RESULTS: Canine plasminogen activator (PA) activity (2.6 +/- 1.1 IU/mL acidified platelet-poor plasma [PPP], < 0.3 IU/mL acidified whole blood serum [WBS], mean +/- SD; n = 6) and PA inhibitor activity (6.1 +/- 2.6 U/mL PPP, 35.4 +/- 7.8 U/mL WBS; n = 6) were determined in standard plasminogen-based chromogenic assays. Analysis of canine PPP, WBS, platelet lysates, and primary canine endothelial cell (EC) cultures by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fibrin autography revealed a plasminogen-dependent lytic zone at 45-kd relative molecular mass that was shown to be related to urokinase-type PA (u-PA) by its selective inhibition through amiloride. Analysis of canine platelets on standard 125I fibrin plate assays revealed a net fibrinolytic activity. In a clot lysis assay system, canine platelets were able to stimulate fibrinolysis when layered on the outside of fibrin clots containing autologous PPP. Moreover, net fibrinolytic activity of primary canine pulmonary artery endothelial cells was higher than the activities expressed by canine aortic or carotid artery endothelial cells. CONCLUSIONS: Rapid lysis of pulmonary emboli in mongrel dogs appears to be a result of 1) the high u-PA activity in canine PPP and 2) the predominant association of u-PA activity with canine platelets and canine pulmonary artery endothelial cells.

Animals↗
PubMed1993

Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension.

The status of small pulmonary arteries may influence diagnosis, surgical selection and postoperative outcome of patients with chronic major vessel thromboembolic pulmonary hypertension (CTEPH). Therefore, in patients with the established diagnosis of CTEPH, lung tissue was obtained by biopsy (15 patients) or at autopsy (16 patients) to assess the histopathologic composition of small pulmonary arteries. Pathologic examination disclosed the full range of pulmonary hypertensive lesions in the small arteries, including plexogenic lesions. The type and extent of hypertensive lesions did not relate to preoperative hemodynamic values, to patient age, or to symptom duration. The findings indicate that primary pulmonary hypertension cannot be differentiated from potentially correctable CTEPH on the basis of histopathologic findings in small pulmonary arteries. Furthermore, none of the histologic findings preclude a positive hemodynamic and clinical result from pulmonary thromboendarterectomy. However, development of these hypertensive changes may explain the deterioration which these patients experience preoperatively over time.

Adolescent↗
PubMed1993

Resolution of vascular steal after pulmonary thromboendarterectomy.

Patients who undergo thromboendarterectomy for relief of chronic, major-vessel thromboembolic pulmonary hypertension (CT-E PH) offer a unique opportunity to evaluate potential resolution of hypertensive lesions in the small, nonelastic pulmonary arteries. Prior studies have demonstrated that, postoperatively, these patients commonly develop new perfusion scan defects. This "vascular steal" phenomenon occurs almost exclusively in lung segments which, preoperatively, were normally perfused by lung scan, were served by segmental arteries normal by pulmonary angiography, and, at surgery, were uninvolved with thrombi by direct inspection. In this study, we explored whether this intriguing "steal" phenomenon resolves over time. Twenty-nine patients who returned at 11 or more months following thromboendarterectomy were reevaluated by perfusion lung scan, repeated right heart catheterization (26 patients), and pulmonary angiography (25 patients). "Steal" of one or more lung segments occurred in 79 percent of patients in postoperative, predischarge perfusion scans. All demonstrated postoperative improvement in pulmonary hemodynamics, which persisted at follow-up. Postoperative "steal" improved in 96 percent of patients and 86 percent of the "stolen" segments. The results suggest that, in CT-E PH, hypertensive lesions in the small, nonelastic pulmonary arteries are responsible for "steal," and that, with relief of pulmonary hypertension, these lesions can resolve. The study also indicates that postoperative "steal" does not connote either new thromboembolic events or a poor hemodynamic result.

Endarterectomy↗
PubMed1993

Colorimetric diagnosis of prolonged bluetongue viremia in sheep, using an enzyme-linked oligonucleotide sorbent assay of amplified viral nucleic acids.

Each of 5 US-origin serotypes of bluetongue virus (BTV) was inoculated into a separate pair of sheep. The duration of each animal's ensuing viremia was monitored, using a BTV serogroup-specific nested polymerase chain reaction (PCR) method and an embryonating chicken egg (ECE) inoculation procedure. Mean duration of viremia was 100 and 38 days for the PCR and ECE methods, respectively. This difference was significant (P < 0.001) and documents a more prolonged viremia in virus-exposed sheep than has been reported. A dual internal oligonucleotide solution hybridization procedure was developed for the rapid (2 hours) colorimetric detection and identification of BTV-specific PCR products. This enzyme-linked oligonucleotide sorbent assay (ELOSA) relied on annealing of separate biotinylated and fluoresceinated probes to the amplified BTV nucleic acid; these complexes were captured on streptavidin-coated microtitration wells and were detected, using a horseradish peroxidase-labeled antifluorescein antibody conjugate. End-point dilution analyses of PCR products indicated that the ELOSA was more sensitive than gel electrophoretic or comparable colorimetric slot-blot hybridization techniques. The BTV PCR-ELOSA system represents a more sensitive and expeditious means of diagnosing BTV-induced viremia than does the ECE procedure currently used. The combination of ELOSA with PCR should facilitate practical application of nucleic acid technology to diagnostic veterinary medicine.

Animals↗
PubMed1993

Experience and results with 150 pulmonary thromboendarterectomy operations over a 29-month period.

A program to alleviate chronic, major vessel thromboembolic pulmonary hypertension by pulmonary thromboendarterectomy was initiated at this institution in 1970. Multiple evolutionary changes in the diagnostic evaluation, surgical approach, and postoperative management have been implemented over the series of 323 thromboendarterectomies performed through March 1992. A sequence of five surgeons at the University of California at San Diego have performed these procedures, with the last 150 having been performed by one surgeon. We report here the changes in surgical approach developed over the last 150 cases and the results obtained. The operation involves a median sternotomy incision, the institution of cardiopulmonary bypass, and deep hypothermia with circulatory arrest periods. Incisions are made in both pulmonary arteries into the lower lobe branches. Pulmonary thromboendarterectomy is always bilateral, with removal of both organized thrombus and an endarterectomy plane from all involved vessels. The right atrium is routinely explored for atrial septal defects. Current techniques appear to allow more thorough revascularization and shorter circulatory arrest times. The surgical mortality of 8.7% over this span is below that previously reported from this and other institutions. Among survivors, the hemodynamic and functional results have been excellent. Surgically correctable chronic thromboembolic pulmonary hypertension likely remains underdiagnosed. The diagnostic, surgical, and postoperative management evolution provided by the coordinated team involved at this institution has established that pulmonary thromboendarterectomy can be performed with an acceptable risk and good hemodynamic and symptomatic results.

Adolescent↗
PubMed1992

Presence of active and latent type 1 plasminogen activator inhibitor associated with porcine platelets.

Data from a number of laboratories indicate that human platelets contain type I plasminogen activator inhibitor (PAI-1) primarily in a latent form; however, one report (Biochemistry 28:5773, 1989) indicated that it is predominantly the active form of PAI-1 that is present in and can be purified from an ammonium sulfate precipitate of porcine platelets. To clarify this situation, we investigated and compared the status of PAI-1 in porcine and human platelets. Immunologic analysis of the ability of PAI-1 to form complexes with immobilized t-PA indicated that porcine and human platelets contained 3.7 +/- 0.4 and 1.7 +/- 0.3 U of PAI activity per 10(8) platelets (n = 6; +/- SD), respectively; sodium dodecyl sulfate (SDS)-activation of the lysates increased PAI-1 activity to 10.8 +/- 3.0 and 3.8 +/- 0.5 U per 10(8) platelets. Platelet lysates were also treated with an excess of soluble t-PA, which formed complexes with active PAI-1, whereas the latent form was detected by SDS-polyacrylamide gel electrophoresis and reverse fibrin autography. Furthermore, immobilized t-PA was able to deplete active PAI-1 from the platelet extracts, and the latent form remaining in the absorbed extract could be quantitated by activation with 4 mol/L guanidine. To investigate the differences between our observations and the published data, porcine platelets were extracted, and PAI-1 was partially purified as described in the literature. For quantitative analysis, porcine platelet PAI-1 was also purified to homogeneity using standard chromatographic procedures optimized in our laboratory for endothelial PAI-1, and the purified protein was used to develop an enzyme-linked immunoabsorbent assay for porcine PAI-1 antigen. Our results indicate that: (1) latent PAI-1 in concentrated ammonium sulfate precipitates of porcine platelet lysates cannot be detected unless the precipitates are diluted before treatment with denaturants; and (2) active and latent porcine platelet PAI-1 can be separated by gel filtration over molecular sieving columns. In summary, this report documents that PAI-1 in porcine platelets is present in both an active and a latent form.

Animals↗
PubMed1992

Chronic major-vessel thromboembolic pulmonary artery obstruction: appearance at angiography.

The pulmonary angiograms of 250 patients evaluated for chronic thromboembolic pulmonary hypertension were reviewed. Pulmonary thromboendarterectomy was performed in each of these individuals, and the surgical findings were correlated with abnormal angiographic patterns. The pulmonary angiographic findings suggestive of chronic thromboembolic disease included "pouching" defects, webs or bands, intimal irregularities, abrupt vascular narrowing, and complete vascular obstruction. Pouching is reported by the authors to be a previously undescribed angiographic feature of this disease. Carefully obtained and properly interpreted pulmonary angiograms are necessary to confirm the diagnosis of operable chronic thromboembolic disease. Differential diagnostic possibilities should be considered prior to a decision to perform surgical correction.

Adolescent↗
PubMed1992

Endogenous fibrinolytic system in chronic large-vessel thromboembolic pulmonary hypertension.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a disorder characterized by pulmonary arterial hypertension as a consequence of organized thrombotic material in the central pulmonary arteries. Incomplete resolution of acute pulmonary emboli is believed to be pathogenically important; however, the mechanism for poor thrombus dissolution remains to be explained. We undertook this study to assess the major determinants of plasma fibrinolysis in patients with CTEPH (n = 32). METHODS AND RESULTS: Immunological and functional levels of tissue-type plasminogen activator (t-PA) and type 1 plasminogen activator inhibitor (PAI-1) were quantified in platelet-poor plasma (PPP) from patients with CTEPH as well as age-matched controls. Although basal PPP t-PA antigen levels (CTEPH mean, 29.5 ng/ml; control mean, 2.7 ng/ml) and PAI-1 antigen levels (CTEPH mean, 55.8 ng/ml; control mean, 21.0 ng/ml) were higher in the CTEPH group, no between-group differences were detected in the enzymatic activities of these two molecules. The CTEPH group demonstrated a greater rise in t-PA antigen (CTEPH mean rise, 53.0 ng/ml; control mean rise, 5.6 ng/ml) and PA activity (CTEPH mean rise, 10.5 IU/ml; control mean rise, 1.2 IU/ml) than controls in response to an experimentally induced venous occlusion. Immunoprecipitation and fibrin autography of PPP from two patients with markedly elevated basal t-PA antigen levels demonstrate that the t-PA antigen was present in PPP primarily in complex with PAI-1. CONCLUSIONS: Although abnormalities of the fibrinolytic system were detected, neither a high resting plasma PAI-1 activity nor a blunted response of t-PA to venous occlusion can be invoked as an etiology for CTEPH:

Adolescent↗
PubMed1992

Lack of utility of bronchial brush biopsy in patients infected with the human immunodeficiency virus.

While bronchoalveolar lavage has been shown to be more sensitive than brush biopsy (BB) for the diagnosis of Pneumocystis carinii pneumonia in AIDS patients, some have reported that BB occasionally is positive in spite of a negative BAL. Many bronchoscopists, therefore, continue to perform routine BB when doing bronchoscopy on AIDS patients. We performed a retrospective study of all fiberoptic bronchoscopies done on human immunodeficiency virus-infected patients over a one-year period at our institution to determine if the use of BB added to the diagnostic yield of bronchoscopy over that of BAL alone. Of 84 bronchoscopies in which BB was performed in addition to BAL, BB yielded no diagnoses that were not obtained by BAL. Brush biopsy added approximately $400 to the cost of bronchoscopy. We conclude that BB should not be routinely done when performing bronchoscopy on HIV-infected patients.

Biopsy↗
PubMed1992

Chronic thromboembolic pulmonary hypertension: clinical picture and surgical treatment.

Chronic, major vessel thromboembolic pulmonary hypertension (CTEPH), is an uncommon condition which, in the past, was an autopsy curiosity. Advances in diagnostic approaches, surgical techniques and postoperative management have transformed this disorder into a potentially curable form of pulmonary hypertension. The predominant symptom is unexplained dyspnoea on exertion. In patients with this complaint, CTEPH should be considered. Numerous pitfalls exist along the diagnostic path. Perfusion lung scans point toward the diagnosis, but often underestimate the extent of central arterial obstruction. Pulmonary angiography is the key diagnostic procedure, but the many patterns of thrombus organization-recanalization require a base of experience for proper interpretation. Criteria for selection of patients for surgery are evolving, but assurance of thrombus accessibility to surgery is critical. Surgical thromboendarterectomy bears no resemblance to acute pulmonary embolectomy. Recognition of thrombus (versus normal intima), meticulous dissection and a bloodless surgical field are essential for adequate restoration of pulmonary vascular patency. Multiple complications may arise postoperatively, and detailed attention to these is required for patient survival. With a co-ordinated, multi-specialty team effort, however, haemodynamic and clinical outcomes have been rewarding and persist long-term. Surgical mortality should steadily decline with such a co-ordinated effort, as well as earlier diagnosis and advances in surgical and postoperative management techniques.

Angiography↗