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Biomedical subjects

Paul Simon

Publications and source records attributed to Paul Simon.

At least 19 recordsLinked to original sources
PubMed2007

Multicentered European study on safety and effectiveness of the On-X prosthetic heart valve: intermediate follow-up.

BACKGROUND: This study was performed to determine the safety and effectiveness of the On-X valve, a novel mechanical valve substitute. METHODS: Eleven centers participated in a European, multicentered, longitudinal, nonrandomized study of the On-X valve performance. Isolated aortic or mitral valve replacement with an On-X valve was studied in 301 patients. Aortic valve replacement was performed in 184 patients (average follow-up, 5.0 years), whereas mitral valve replacement was performed in 117 patients (average follow-up, 4.4 years). RESULTS: In patients with aortic valve replacement, mean transvalvular pressure gradients ranged from 8.3 to 4.7 mm Hg and effective orifice areas from 1.5 to 2.7 cm2, for 19-mm through 25-mm valves, respectively. After mitral valve replacement, mean gradient was 4.2 mm Hg and effective orifice area by pressure half-time was 2.6 cm2 regardless of valve size. Hemolysis was low, with postoperative serum lactate dehydrogenase at 225 +/- 41 IU (mean +/- standard deviation) or 253 +/- 65 IU, after aortic valve replacement or mitral valve replacement, respectively (upper normal value, 250 IU). At 1 year or greater postoperatively, 91.6% of patients after aortic valve replacement and 84.6% after mitral valve replacement were in New York Heart Association functional class I or II. Adverse event rates in percent per patient-year after aortic valve replacement or mitral valve replacement were thromboembolism, 0.88 or 1.76; thrombosis, 0.11 or 0.20; bleeding, 0.77 or 1.96, respectively. Late mortality was 1.97% or 2.55%, respectively. CONCLUSIONS: At the intermediate follow-up, the On-X valve exhibited improved hemodynamics, low hemolysis with in-range lactate dehydrogenase, and low adverse event rates, particularly in the aortic position.

Aged↗
PubMed2006

Granulocyte-based immune response against decellularized or glutaraldehyde cross-linked vascular tissue.

Supporting structures derived from biological tissue have been used in numerous tissue-engineering applications. This study focuses on the immune response of human leukocytes toward decellularized or glutaraldehyde (GA) cross-linked vascular tissue in vitro. Porcine and human pulmonary roots were sterilized with antibiotics, decellularized or cross-linked with GA. Proteins of the vascular tissue were extracted and the migratory response of human leukocytes toward protein extracts was examined using an in vitro migration chamber. Transmigrated leukocytes were counted and subsets (lymphocytes, monocytes, granulocytes) analyzed by flow cytometry. Decellularization significantly reduced the migration of monocytes compared to native porcine tissue. Although the proportion of transmigrating lymphocytes was much lower, decellularization again reduced the migratory response. Surprisingly, after decellularization granulocyte migration was still significantly higher than the negative control. Results comparable to those obtained with porcine material were found when human tissue was used for the experiments. Interestingly, migratory behavior toward extracts of GA-fixed porcine tissue was similar to that of decellularized specimens. We have shown that decellularization of vascular tissue reduces lymphocyte and monocyte recruitment comparable to cross-linking treatment. However, the migration of granulocytes, which are also known to be strongly involved in early inflammatory reactions, could be abolished neither by decellularization nor by fixation with GA.

Animals↗
PubMed2006

Human antibodies for immunotherapy development generated via a human B cell hybridoma technology.

Current strategies for the production of therapeutic mAbs include the use of mammalian cell systems to recombinantly produce Abs derived from mice bearing human Ig transgenes, humanization of rodent Abs, or phage libraries. Generation of hybridomas secreting human mAbs has been previously reported; however, this approach has not been fully exploited for immunotherapy development. We previously reported the use of transient regulation of cellular DNA mismatch repair processes to enhance traits (e.g., affinity and titers) of mAb-producing cell lines, including hybridomas. We reasoned that this process, named morphogenics, could be used to improve suboptimal hybridoma cells generated by means of ex vivo immunization and immortalization of antigen-specific human B cells for therapeutic Ab development. Here we present a platform process that combines hybridoma and morphogenics technologies for the generation of fully human mAbs specific for disease-associated human antigens. We were able to generate hybridoma lines secreting mAbs with high binding specificity and biological activity. One mAb with strong neutralizing activity against human granulocyte-macrophage colony-stimulating factor was identified that is now considered for preclinical development for autoimmune disease indications. Moreover, these hybridoma cells have proven suitable for genetic optimization using the morphogenics process and have shown potential for large-scale manufacturing.

Amino Acid Sequence↗
PubMed2006

A comparison of underlying cause and multiple causes of death: US vital statistics, 2000-2001.

BACKGROUND: Mortality statistics can be compiled using underlying cause-of-death data or multiple cause-of-death data, which include other contributing causes of death. METHODS: For the leading causes of death in the United States during 2000-2001, we compared underlying and multiple cause-of-death statistics. RESULTS: For some conditions, little difference was observed between the 2 estimates. For other conditions, up to 10 times more deaths were identified from multiple-cause data than from underlying-cause data. The 10 leading causes of death differed when using the 2 types of data. CONCLUSIONS: Whenever possible, underlying and multiple cause-of-death statistics should both be presented. Analyses that use only the underlying cause of death ignore additional information that is readily available from multiple-cause data, and the more limited data may underestimate the importance of several leading causes of death.

Cause of Death↗
PubMed2006

Decellularization does not eliminate thrombogenicity and inflammatory stimulation in tissue-engineered porcine heart valves.

BACKGROUND AND AIM OF THE STUDY: In tissue engineering of heart valves using decellularized xenogenic valves, it has been suggested that cell elimination would result in a biologically inert matrix. The aim of this in-vitro investigation was to evaluate different decellularization methods in regard to the completeness of cell removal, inflammatory response, and thrombocyte activation. METHODS: Decellularized porcine Synergraft valves were compared with porcine pulmonary conduits decellularized with Triton X-100, sodium deoxycholate, Igepal CA-630 and ribonuclease. Completeness of decellularization was evaluated with staining for nuclei and alpha-Gal epitope. Decellularized heart valves with and without seeding with endothelial cells (ECs) were incubated with human platelet-rich plasma and stained for CD41 and PAC-1 to evaluate thrombocyte activation. Samples were processed for laser scanning microscopy (LSM) and scanning electron microscopy (SEM). Migration of human monocytic cells towards extracted valve proteins was tested. RESULTS: In contrast to the Synergraft, complete cell removal and elimination of the alpha-gal epitope was achieved with the new decellularization method. Numerous adherent and activated platelets were found on the decellularized matrix. This was inhibited by seeding with ECs. Even in completely cell-free valve tissue extracellular matrix proteins attracted human monocytic cells as in early inflammation, depending on whether porcine or human tissue was used. CONCLUSION: Important differences were found in the decellularization efficacy of treatment methods. However, even complete elimination of cells and their remnants did not result in a biologically inert matrix. The decellularized porcine heart valve matrix has the potential to attract inflammatory cells and to induce platelet activation. These findings suggest that it will be important to control the different inflammation-stimulating factors if porcine tissues are to be used successfully in tissue engineering.

Animals↗
PubMed2005

Tissue engineering of heart valves: decellularized porcine and human valve scaffolds differ importantly in residual potential to attract monocytic cells.

BACKGROUND: Tissue-engineered or decellularized heart valves have already been implanted in humans or are currently approaching the clinical setting. The aim of this study was to examine the migratory response of human monocytic cells toward decellularized porcine and human heart valves, a pivotal step in the early immunologic reaction. METHODS AND RESULTS: Porcine and human pulmonary valve conduits were decellularized, and migration of U-937 monocytic cells toward extracted heart valve proteins was examined in a transmigration chamber in vitro. Homogenized tissue specimens were size fractionated by SDS-PAGE. The decellularization procedure effectively reduced the migration of human monocytes toward all heart valve tissue. However, only the antigen reduction of human pulmonary valves abolished the monocytic response (wall, 0.88+/-0.19% versus 30.20+/-3.93% migrated cells [mean+/-SEM]; cusps, 0.10+/-0.06% versus 10.24+/-1.83%) and was significantly lower (P<0.05) than that of the decellularized porcine equivalent (wall, 5.03+/-0.14% versus 24.31+/-2.38%; cusps, 3.18+/-0.38% versus 10.24+/-1.83%). SDS-PAGE of the pulmonary heart valve tissue revealed that considerable amounts of proteins with different molecular weights that were not detected in the human equivalent remain in the decellularized porcine heart valve. CONCLUSIONS: We describe for the first time that the remaining potential of decellularized pulmonary heart valves to attract monocytic cells depends strongly on whether porcine or human scaffolds were used. These findings will have an important impact on further investigations in the field of heart valve tissue engineering.

Animals↗
PubMed2005

Invited commentary.

Explore the source record for details and available documents.

Absorbable Implants↗
PubMed2005

Doppler echocardiographic assessment of valvular regurgitation severity by measurement of the vena contracta: an in vitro validation study.

BACKGROUND: Noninvasive quantitation of valvular regurgitation remains a difficult problem. Measurements of the vena contracta (VC) by color Doppler echocardiography have been proposed but limited data are available on the actual accuracy of this method. METHODS: To evaluate how closely the color Doppler VC reflects the true fluid dynamic VC and the anatomic regurgitant orifice and whether this measurement is affected by flow changes, various models of valvular regurgitation were studied in an in vitro flow circuit. The VC diameter was measured with color Doppler using two different ultrasound systems (Agilent Sonos 5500; Agilent Technologies Inc, Palo Alto, Calif and Vingmed CFM 800; GE Healthcare, Chalfront St Giles, UK). Optical planimetry of the anatomic regurgitant orifice was performed, the true VC diameter was determined by laser particle flow visualization. RESULTS: Because of flow contraction, the true VC diameter was consistently smaller than the anatomic regurgitant orifice diameter. Anatomic orifice and true VC only marginally changed with flow rate. The diameter of the color Doppler VC, however, not only overestimated the anatomic orifice diameter by 45% to 60% and the true VC diameter by 130% to 160%, but was also highly affected by the flow rate and the ultrasound system. Despite these limitations a color Doppler VC diameter of 0.77 cm or more (Agilent) and 0.89 cm or more (Vingmed) detected severe regurgitation with a sensitivity of 93% and 84% and a specificity of 96% and 79%, respectively. CONCLUSIONS: Color Doppler estimates of the VC markedly overestimate regurgitant orifice and true VC. In contrast to the true VC, Doppler measurements are significantly affected by flow rate and by the ultrasound system used. Nevertheless, they allow semiquantitative assessment of valvular regurgitation separating severe from nonsevere regurgitation with acceptable accuracy.

Aortic Valve Insufficiency↗
PubMed2005

A multiple cause-of-death analysis of asthma mortality in the United States, 1990-2001.

OBJECTIVES: Most analyses of asthma mortality in the United States have relied solely on underlying cause-of-death data, which may underestimate the magnitude of asthma-related mortality. We used multiple cause-of-death data to examine asthma-related mortality trends in the United States. METHODS: Data were selected from the United States Multiple Cause-of-Death Files, 1990-2001. Mortality rates and 95% confidence intervals were computed to examine differences in asthma mortality over time and by age, race/ethnicity, and gender. Location of death and seasonal variations in asthma mortality were also assessed, as well as the impact of seasonal respiratory infections. RESULTS: We identified 135,668 asthma-related deaths in the United States over the 12-year period, representing an age-adjusted mortality rate of 4.4 per 100,000. Only 45% of the asthma-related deaths had asthma recorded as the underlying cause. Whites and older adults were less likely to have asthma listed as the underlying cause. Asthma mortality rates mirrored underlying cause trends, increasing slightly between 1990 and 1995, declining between 1996 and 1998, and further declining after International Classification of Disease (ICD)-10 implementation in 1999. Mortality was highest among blacks and the elderly and was higher among females than males. Asthma-related deaths peaked in the winter months and were over four times more likely than non-asthma deaths to have acute upper respiratory infections, influenza, or acute bronchitis listed on the death record. The proportion of asthma-related deaths occurring outside a medical setting increased steadily over the period, from 23.3% in 1990 to 29.4% in 2001. CONCLUSIONS: The burden of asthma may be underestimated by relying solely on underlying cause-of-death data. Further research is needed to determine the reasons for the steady increase in out-of-hospital deaths and the continued demographic disparities in mortality.

Adolescent↗
PubMed2005

The decellularized porcine heart valve matrix in tissue engineering: platelet adhesion and activation.

An approach in tissue engineering of heart valves is the use of decellularized xenogeneic matrices to avoid immune response after implantation. The decellularization process must preserve the structural components of the extracellular matrix to provide a biomechanically stable scaffold. However, it is known that in vascular lesions platelet adhesion to extracellular matrix components occurs and platelet activation is induced. In the present study we examined the effects of a decellularized porcine heart valve matrix on thrombocyte activation and the influence of re-endothelialisation in vitro. Porcine pulmonary conduits were decellularized using Triton X-100, Na-deoxycholate and Igepal CA-630 followed by a ribonuclease digestion. Cryostat sections of decellularized heart valves with and without seeding with human umbilical vein endothelial cells (HUVEC) were incubated with platelet rich plasma. Samples were either stained with fluorescent antibodies for CD41 and PAC-I (recognizing the activated fibrinogen receptor) or fixed with glutaraldehyde. Thereafter, the samples were processed for laser scanning microscopy (LSM) or scanning electron microscopy (SEM). Examination by LSM showed numerous platelets with co-localized staining for CD41 and PAC-1 on the nonseeded decellularized heart valve matrix whereas after seeding with endothelial cells no platelet activation was detected. SEM revealed platelet adhesion and aggregate formation only on the surface of the non-seeded or partially denuded matrix specimens. We show in this study that the decellularized porcine matrix acts as a platelet-activating surface. Seeding with endothelial cells effectively abolishes the platelet adhesion and activation and therefore is necessary to eliminate thrombogenicity in tissue engineered heart valves.

Animals↗
PubMed2004

Racial disparities in subarachnoid hemorrhage mortality: Los Angeles County, California, 1985-1998.

We examined the racial distribution of subarachnoid hemorrhage (SAH) mortality in a unique multiracial community. Mortality rates for SAH among the residents of Los Angeles County were calculated from death certificate data (1985-1998). Residential postal zones were classified into three strata as a measure of socioeconomic status. The number of SAH deaths was 2,897. The age-adjusted SAH mortality rate was 1.9 in whites, 2.7 in Hispanics, 3.0 in Asians and 3.7 in blacks. In those younger than 70 years of age, the SAH mortality rate among blacks was 2.2 times that of whites and 1.8 times that of Hispanics and Asians. The SAH mortality rate declines after age 70 in blacks. The SAH mortality rate was higher in women than in men in all races and it was highest in elderly Asian women (23.5 per 100,000). An inverse relationship was observed between income and SAH mortality rates in all racial groups except whites.

Adolescent↗
PubMed2004

Relation between size of prosthesis and valve gradient: comparison of two aortic bioprosthesis.

OBJECTIVES: The outcome of patients undergoing aortic valve replacement (AVR) may be affected by the influence of prosthesis-patient mismatch on left ventricular mass regression. However, due to the discrepancies in labeled valve size, size of sizer and actual valve dimension, it is difficult to compare different valve types. In order to perform an objective comparison, this study was designed to compare the hemodynamics of the Edwards Lifescience pericardial (ELP) and the Medtronic Mosaic porcine (MM) bioprosthesis between patients receiving the same valve size and between patients with the same aortic annulus diameter. METHODS: This prospective, randomized study was performed on 81 hospital survivors out of 86 patients undergoing AVR with either the ELP (n=39) or the MM (n=42) bioprosthesis. Intra-operative randomization was performed after the surgeon had excised the aortic valve, measured the size of the aortic annulus with three different sizers (ELP, MM and a set of metric sizers), and decided which size he would implant for either of the valve types. All valves were implanted in supra-annular position with the same implantation technique. Echocardiographic follow-up was performed early postoperatively and 6 months thereafter. RESULTS: In 12 (31%) of the patients receiving the ELP-valve, as compared to 3 (7.1%) of the patients receiving the MM-valve, the labeled valve size was smaller than the aortic annulus diameter (P<0.05). Early postoperatively, mean (17.4+/-3.1 vs 20.3+/-3.6 mmHg) and peak gradients (30.1+/-4.8 vs 37.6+/-9.6 mmHg) for the 21 mm ELP-valve were lower than for the 21 mm MM-valve (P<0.05). All other hemodynamic parameters did not show significant differences at any time point. When the same aortic annulus diameter was taken as a reference, there were no significant hemodynamic differences between either valve type at any time point, regardless of the valve size implanted. CONCLUSIONS: This study demonstrates that the hemodynamic performance of the ELP and the MM bioprosthesis are comparable when the same aortic annulus diameter is taken as a reference. The significant variabilities between different valve types with regard to labeled valve size, valve-sizer size and actual valve size have to be taken into account, when hemodynamic comparisons are performed.

Aged↗
PubMed2004

Reverse cardiac remodelling in patients with primary pulmonary hypertension after isolated lung transplantation.

OBJECTIVE: Pulmonary hypertension eventually leads to severe distortion of the cardiac geometry with consequent impact on cardiac function. The purpose of this study was to prove reverse cardiac remodelling after isolated bilateral lung transplantation (LuTX) in patients with advanced primary pulmonary hypertension (PPH) and severe alterations of cardiac morphology and function. METHODS: In the period of 2000-2002 17 (10 female, seven male) patients with advanced PPH underwent isolated bilateral LuTX. Median age was 30 years (range 16-53). All patients were in NYHA III or IV, most of them with intractable ascites, established renal impairment, malnutrition and immobility, continuously deteriorating despite various forms of pharmacological treatment including i.v. and inhalative prostacyclin, diuretics, Ca-antagonists, bosentan and catecholamines. Echocardiography and Doppler echocardiography measurements were performed before and 3 months after transplantation. Left and right ventricular diameters and function were assessed and tricuspid valve regurgitation was determined. RESULTS: Mortality after 3 months was 17.5% (cerebral bleeding, multi-organ failure and diffuse myocardial infarction in one patient each). Three months after LuTX the 14 surviving patients were in NYHA I or II. Echocardiography showed normal left ventricular function and markedly improved right ventricular function with normal size of the RV. The leftward shifted flattened interventricular septum had returned in its physiological position and the high-grade tricuspid insufficiency had disappeared in all patients. CONCLUSIONS: Advanced alterations of cardiac morphology and function normalize completely and pre-existing tricuspid insufficiency disappears in PPH patients after isolated bilateral LuTX. Quality of life is excellent. Therefore, LuTX is preferred and safe in patients with advanced PPH even with severe cardiac dysfunction.

Adolescent↗
PubMed2004

Decellularization protocols of porcine heart valves differ importantly in efficiency of cell removal and susceptibility of the matrix to recellularization with human vascular cells.

OBJECTIVE: We compared 3 different decellularization protocols in porcine heart valves for efficiency of complete cell removal and potential for recellularization. METHODS: Porcine aortic and pulmonary roots were treated with trypsin, sodium-dodecyl-sulphate, or a new method using 0.25% tert-octylphenyl-polyoxyethylen in combination with sodium-deoxycholate. After a subsequent ribonuclease digestion, specimens were seeded with in vitro expanded human saphenous vein endothelial cells and myofibroblasts. RESULTS: After treatment with trypsin and subsequent ribonuclease digestion, endothelial attachment took place; however, xenogenic cells were still visible within the matrix. Unexpectedly, when human cells were seeded onto specimens that had been decellularized with sodium-dodecyl-sulphate, the matrices were surrounded by nonviable endothelial cell fragments, indicating a toxic influence of the ionic detergent; 0.25% tert-octylphenyl-polyoxyethylen together with sodium-deoxycholate completely removed porcine cells and enabled host recellularization. CONCLUSION: Compared with trypsin and sodium-dodecyl-sulphate involving decellularization procedures, reported to be effective in cell removal and susceptible to recellularization with human cells, only the porcine matrix treated with a new detergent-based decellularization method using 0.25% tert-octylphenyl-polyoxyethylen/sodium-deoxycholate followed by nuclease digestion presented an excellent scaffold for recellularization with human cells.

Aortic Valve↗