Biomedical subjects

D M Meyer

Publications and source records attributed to D M Meyer.

At least 19 recordsLinked to original sources

PubMed2001

Load versus humoral activation in the genesis of early hypertensive heart disease.

BACKGROUND: The role of load versus angiotensin II (Ang II) and endothelin-1 (ET) in the pathogenesis of hypertensive heart disease is controversial. We sought to determine whether alterations in cardiac structure and function due to hypertension (HTN) were dependent on Ang II or ET activation. Methods and Results-- Bilateral renal wrapping to produce HTN (n=12) or sham surgery (n=6) was performed in adult dogs. Weekly blood pressure, plasma renin activity, Ang II, ET, and catecholamines were measured. Systolic (end-systolic elastance, Ees) and diastolic (tau) function were assessed in sham and HTN dogs at 5 (HTN-5wk) or 12 (HTN-12wk) weeks. Ang II and ET were assayed in the left ventricle (LV) and kidney. Mean arterial pressure was higher in renal wrap dogs at week 1 (*P<0.05 versus controls: 139+/-4* versus 123+/-4 mm Hg), week 5 (174+/-7* versus 124+/-4 mm Hg), and week 12 (181+/-12* versus 124+/-4 mm Hg). LV mass index was increased in HTN-5wk (22%*) and HTN-12wk (39%*). LV fibrosis was increased in HTN-12wk. Ees was preserved in HTN-5wk and HTN-12wk. tau was increased in HTN-5wk (50+/-3* ms) and HTN-12wk (62+/-10* ms) dogs compared with sham (41+/-2 ms). Plasma Ang II, ET, catecholamines, and plasma renin activity were unchanged during the progressive HTN. Ang II and ET in LV and kidney were not different from controls. CONCLUSIONS: Systemic HTN induces LV hypertrophy, myocardial fibrosis, and isolated diastolic dysfunction in the absence of local or systemic activation of Ang II or ET. These findings suggest that load is the prevailing stimulus for the structural and functional changes associated with early hypertensive heart disease.

Angiotensin II↗

PubMed2001

Indications for using video-assisted thoracoscopic surgery to diagnose diaphragmatic injuries after penetrating chest trauma.

BACKGROUND: Video-assisted thoracoscopic surgery (VATS) has been shown to be an accurate method for identifying diaphragmatic injuries (DIs). The purpose of this investigation was to establish specific indications for the use of VATS after penetrating chest trauma. METHODS: A retrospective review of all patients undergoing VATS after penetrating chest trauma at a level 1 trauma center over an 8-year period was performed. Logistic regression was used in an attempt to identify independent predictors of DI. RESULTS: One hundred seventy-one patients underwent VATS assessment of a hemidiaphragm, and 60 patients (35%) were found to have a DI. Five independent risk factors for DI were identified from analyzing the patient records: abnormal chest radiograph, associated intraabdominal injuries, high-velocity mechanism of injury, entrance wound inferior to the nipple line or scapula, and right-sided entrance wound. CONCLUSIONS: In the largest published series of patients undergoing VATS to exclude a DI, this review identifies five independent predictors of DI after penetrating chest trauma. A diagnostic algorithm incorporating these five factors was designed with the goal of reducing the number of unrecognized DIs after penetrating chest trauma by using VATS for patients at greatest risk for such injuries.

Adult↗

PubMed2001

Single vs bilateral, sequential lung transplantation for end-stage emphysema: influence of recipient age on survival and secondary end-points.

BACKGROUND: The appropriate age to perform bilateral, sequential lung transplants (BSLT) in patients with chronic obstructive pulmonary disease (COPD) remains controversial. Although single lung transplant (SLT) offers an advantage in terms of organ availability, the long-term survival may not warrant this strategy in all age groups. METHODS: We analyzed 2,260 lung transplant recipients (1835 SLT, 425 BSLT) with COPD recorded in the International Society for Heart and Lung Transplantation/United Network for Organ Sharing thoracic registry between January 1991 and December 1997. To assess mortality, we performed univariate (Kaplan-Meier method and the chi-square statistic) and multivariate analyses (proportional hazards method). Because of incomplete morbidity data in the international registry, only data from U.S. centers (n = 1778, 1467 SLT, 311 BSLT) were used in the morbidity analysis. RESULTS: Survival rates (%) computed using the Kaplan-Meier method at 30 days, 1 year, and 5 years for the patients aged < 50 years were 93.6, 80.2, and 43.6, respectively, for the SLT patients, and 94.9, 84.7, and 68.2, respectively, for the BSLT patients. For patients aged 50 to 60 years, survival rates (%) were 93.5, 79.4, and 39.8 for the SLT patients compared with 93.0, 79.7, and 60.5 for the BSLT patients. For those aged > 60 years, SLT survival (%) was 93.0, 72.9, and 36.4, compared with 77.8 and 66.0 for the BSLT group (a 5-year rate could not be completed in this group). The multivariate model showed a higher risk ratio for mortality in patients aged 40 to 57 years who received SLT vs BSLT. Recipient age and procedure type did not appear to affect the development of rejection, bronchiolitis obliterans, bronchial stricture, or lung infection. CONCLUSIONS: Single lung transplant may offer acceptable early survival for patients with end-stage respiratory failure. However, long-term survival data favors BSLT in recipients until approximately age 60 years. These data suggest that a BSLT approach offers a significant survival advantage to recipients younger than 60 years of age.

Adult↗

PubMed2001

Differential effects of natriuretic peptides and NO on LV function in heart failure and normal dogs.

beta-Adrenergic hyporesponsiveness in congestive heart failure (CHF) is mediated, in part, by nitric oxide (NO). NO and brain natriuretic peptide (BNP) share cGMP as a second messenger. Left ventricular (LV) function and inotropic response to intravenous dobutamine (Dob) were assessed during sequential intracoronary infusion of saline, HS-142-1 (a BNP receptor antagonist), and HS-142-1 + N(G)-monomethyl-L-arginine (L-NMMA) in anesthetized dogs with CHF due to rapid pacing and in normal dogs during intracoronary infusion of saline, exogenous BNP, and sodium nitroprusside (SNP). In CHF dogs, intracoronary HS-142-1 did not alter the inotropic response to Dob [percent change in first derivative of LV pressure (% Delta dP/dt) 47 +/- 4% saline vs. 54 +/- 7% HS-142-1, P = not significant]. Addition of intracoronary L-NMMA to HS-142-1 enhanced the response to Dob (% Delta dP/dt 73 +/- 8% L-NMMA + HS-142-1, P < 0.05 vs. H142-1). In normal dogs, intracoronary SNP blunted the inotropic response to Dob (% Delta dP/dt 93 +/- 6% saline vs. 71 +/- 5% SNP, P < 0.05), whereas intracoronary BNP had no effect. In CHF dogs, the time constant of LV pressure decay during isovolumic relaxation increased with intracoronary HS-142-1 (48 +/- 4 ms saline vs. 58 +/- 5 ms HS-142-1, P < 0.05) and further increased with intracoronary L-NMMA (56 +/- 6 ms HS-142-1 vs. 66 +/- 7 ms L-NMMA + HS-142-1, P < 0.05). Endogenous BNP and NO preserve diastolic function in CHF, whereas NO but not BNP inhibits beta-adrenergic responsiveness.

Adrenergic beta-Agonists↗

PubMed2000

Testing reminder and motivational telephone calls to increase screening mammography: a randomized study.

BACKGROUND: Prospective randomized trials have demonstrated that motivational telephone calls increase adherence to screening mammography. To better understand the effects of motivational calls and to maximize adherence, we conducted a randomized trial among women aged 50-79 years. METHODS: We created a stratified random sample of 5062 women due for mammograms within the Group Health Cooperative of Puget Sound, including 4099 women with prior mammography and 963 without it. We recruited and surveyed 3743 (74%) of the women before mailing a recommendation. After 2 months, 1765 (47%) of the 3743 women had not scheduled a mammogram and were randomly assigned to one of three intervention groups: a reminder post-card group (n = 590), a reminder telephone call group (n = 585), and a motivational telephone call addressing barriers group (n = 590). The telephone callers could schedule mammography. We used Cox proportional hazards models to estimate the hazard ratio (HR) and 95% confidence interval (CI) for documented mammography use by 1 year. RESULTS: Women who received reminder calls were more likely to get mammograms (HR = 1.9; 95% CI = 1.6-2.4) than women who were mailed postcards. The motivational and reminder calls (average length, 8.5 and 3.1 minutes, respectively) had equivalent effects (HR = 0.97; 95% CI = 0.8-1.2). After we controlled for the intervention effect, women with prior mammography (n = 1277) were much more likely to get a mammogram (HR = 3.4; 95% CI = 2.7-4.3) than women without prior use (n = 488). Higher income, but not race or more education, was associated with higher adherence. CONCLUSIONS: Reminding women to schedule an appointment was as efficacious as addressing barriers. Simple intervention groups should be included as comparison groups in randomized trials so that we better understand more complex intervention effects.

Affect↗

PubMed2000

Histologic evidence of the safety of endoscopic saphenous vein graft preparation.

BACKGROUND: Endoscopic methods of saphenous vein procurement have recently been introduced. These techniques have been successful in limiting pain and wound complications, but less information on assessing potential trauma to the harvested vein segment is available. METHODS: Fourteen male patients undergoing coronary artery bypass grafting were included in the study. Nine patients underwent endoscopic procurement of saphenous vein whereas 5 patients underwent procurement using standard open techniques. Histologic appearance and immunohistochemical studies (factor VIII:vWF [von Willebrand factor protein] and CD34) of the vein segments were reviewed in a blinded fashion. RESULTS: On histologic analysis, no differences in the intima, media, or adventitia were found between endoscopically and conventionally obtained vein segments. Immunohistochemical staining for factor VIII:vWF and CD34 showed no differences between veins harvested by the two techniques. CONCLUSIONS: Endoscopic saphenous vein harvesting does not appear to traumatize the vessel wall any more than open techniques. Longitudinal assessment is necessary to evaluate long-term patency in vein grafts procured using this method.

Aged↗

PubMed2000

Effects of storage and reperfusion oxygen content on substrate metabolism in the isolated rat lung.

BACKGROUND: Lung transplantation requires a period of storage and ischemia; we examined the largely unknown effects of that period on intermediary metabolism. METHODS: Two groups of isolated rat lung blocks (n = 16 each) were flushed with Euro-Collins solution and harvested. The lung blocks were immediately ventilated and either perfused for 30 minutes with an erythrocyte-based solution containing carbon 13 labeled substrates (group 1) or stored for 6 hours at 1 degree C and then reperfused (group 2). Half of each group was reperfused at a physiologic Po2 the other half at high Po2. Analysis of carbon 13 isotopomers was performed to determine substrate utilization through aerobic pathways in lung tissue. RESULTS: Lungs from both groups oxidized all major substrates. The contribution of fatty acids to acetylcoenzyme acid oxidized in the citric acid cycle was significantly higher in group 2 than in group 1 (31.3% +/- 2.2% versus 22.0% +/- 2.1%, p < 0.05). Perfusate Po2 did not affect substrate preference. Gas exchange was worse in stored lungs. CONCLUSIONS: After a period of hypothermic ischemia and storage, substrate preference in lung tissue exhibits a switch towards fatty acids. As fatty acid oxidation occurring after ischemia is deleterious in other organs, strategies to inhibit this process in stored lungs may warrant further investigation.

Animals↗

PubMed2000

Does human leukocyte antigen matching influence the outcome of lung transplantation? An analysis of 3,549 lung transplantations.

BACKGROUND AND OBJECTIVE: Human leukocyte antigen (HLA) compatibility has been shown to improve the outcome of renal and cardiac transplantation. However, its impact on outcome following lung transplantation is not clear, with several single-center studies reporting inconsistent results. We studied the influence of HLA matching on survival and the development of rejection and obliterative bronchiolitis after lung transplantation, using data from the United Network for Organ Sharing/International Society for Heart and Lung Transplantation registry. METHODS: The study population included adult patients who received cadaveric lung transplants between October 1987 and June 1997 for whom HLA data were available. Two cohorts were examined, depending on the era of transplantation: (1) October 1987 to June 1997 (n = 3,549): Differences in actuarial survival as stratified by either the total number of HLA mismatches or the number of mismatches at each HLA locus were determined using a log-rank test. Multivariate logistic regression models were developed to determine independent predictors of survival at 1, 3, and 5 years following lung transplantation. (2) April 1994 to June 1997 (n = 1,796): The association of HLA mismatching with acute rejection and obliterative bronchiolitis was determined using a chi-squared analysis. RESULTS: Only 164 patients (4.6%) received lung grafts with 2 or fewer HLA mismatches. Univariate analyses demonstrated a significant difference in post-transplant survival by mismatch level, with the total number of HLA mismatches (p = 0.0008) and mismatching at the HLA-A locus (p = 0.002) associated with worse survival. Multivariate logistic regression demonstrated that the number of mismatches at the HLA-A and HLA-DR loci predicted 1-year mortality (incremental odds ratios 1.18, p = 0.01, and 1.15, p = 0. 03, respectively). The total number of HLA mismatches predicted 3- and 5-year mortality (incremental odds ratios 1.13 at 3 years, p = 0. 0004, and 1.14 at 5 years, p = 0.0002). However, other covariates such as repeat transplantation, transplantation for congenital heart disease, advanced recipient age, and an early era of transplantation were stronger predictors of mortality. We found no significant association between HLA mismatching and the development of obliterative bronchiolitis, although there was an association between mismatching at the HLA-A locus and acute rejection episodes requiring hospital admission (p = 0.008). We also found no association between mismatching at the HLA-B locus and rejection episodes requiring either hospitalization or the alteration of anti-rejection medications (p = 0.034). CONCLUSION: Although the number of HLA mismatches at the HLA-A and HLA-DR loci predicted 1-year mortality and the total number of mismatches predicted 3- and 5-year mortality following lung transplantation, the effect of each covariate was small in this multicenter study of 3,549 patients. Further close follow-up of registry patients is necessary to determine the effect of HLA matching on long-term survival and freedom from obliterative bronchiolitis and rejection following lung transplantation. A prospective study of HLA matching for lung transplantation should not yet be considered in view of the small number of grafts with 2 or fewer mismatches and the modest effect of HLA matching on outcome.

Adult↗

PubMed2000

Effects of adrenomedullin on load and myocardial performance in normal and heart-failure dogs.

Myocardial actions of the vasodilator peptide adrenomedullin (ADM) in the intact animal are unknown. Negative and positive inotropic actions have been reported in ex vivo experiments. Myocardial and load-altering actions of ADM in dogs before and after development of heart failure were studied. With controlled heart rate (atrial pacing) and after beta-blockade, ADM was administered to five normal dogs in doses of 20 ng. kg(-1). min(-1) iv, 100 ng. kg(-1). min(-1) iv, and 200 ng. kg(-1). min(-1) into the left ventricle (LV). LV peak systolic pressure and end-systolic volume decreased with each dose of ADM. End-systolic pressure decreased with the two higher doses. At the highest dose, arterial elastance and the time constant of LV isovolumic relaxation (tau) decreased, and LV end-systolic elastance (E(es)) increased. LV end-diastolic pressure and volume were unchanged. In five additional normal dogs receiving only the highest dose of ADM (200 ng. kg(-1). min(-1) intra-LV), to control for increased heart rate and sympathetic activation observed with the cumulative infusion, ADM produced arterial vasodilation but no change in E(es) or tau. In four dogs with pacing-induced heart failure, ADM (200 ng. kg(-1). min(-1) intra-LV) was without effect on tau, E(es), and systolic or diastolic pressure and volume. In vivo, ADM appears to be a selective arterial dilator without inotropic or lusitropic effects. The vasodilatory actions are attenuated in heart failure.

Adrenomedullin↗

PubMed2000

Mechanically strained cells of the osteoblast lineage organize their extracellular matrix through unique sites of alphavbeta3-integrin expression.

Bone cells transduce mechanical signals into anabolic biochemical responses. However, the mechanisms of mechanotransduction are unknown. To address this issue, we performed studies in primary cells of the human osteoblast lineage grown on collagen/vitronectin-coated supports. We discovered that mechanical strain stimulated a redistribution of the alphavbeta3-integrin to irregular plaque-like areas at the cell-extracellular matrix surface. Proteins involved in integrin-matrix interactions in focal adhesions, vinculin and talin, did not localize to the plaque-like areas of alphavbeta3-expression, but signaling molecules such as focal adhesion kinase (FAK) did. Mechanical strain increased the number and size of the plaques defined by surface expression of alphavbeta3-integrin. Osteopontin was secreted as a cross-linked macromolecular complex, likely through the action of tissue transglutaminase that also was found in the plaques of alphavbeta3-integrin cell-matrix interaction. Mechanical strain increased mineralization of the extracellular matrix that developed in these plaques in alphavbeta3-integrin-dependent manner. Because the plaque-like areas of cell-matrix interaction exhibit macromolecular assembly and mineralization, we conclude that they may represent subcellular domains of bone formation and that alphavbeta3-integrin activation represents one mechanism by which mechanical strain stimulates bone formation.

Bone Marrow Cells↗

PubMed2000

Effect of donor age and ischemic time on intermediate survival and morbidity after lung transplantation.

BACKGROUND: Pressure to expand the donor pool has required the use of lungs from older donors or from more-distant procurement areas. The long-term consequences of this policy have not yet been fully addressed. The effect of donor age and donor ischemic time on intermediate survival and important secondary end points after lung transplantation was therefore examined. METHODS: A cohort of 1,800 lung transplant recipients with complete 2-year follow-up, operated on in the United States between April 1, 1993, and March 31, 1996, was studied to assess survival. For analysis of secondary end points, the cohort was limited to 1,450 patients. RESULTS: Donor age when analyzed independently did not significantly affect intermediate survival (p = 0.4). Secondary end points were also not affected by age, with the exception of the incidence of hospitalization for rejection in the univariate analysis (p = 0.02) and in the multivariate analysis (p = 0.04). Moreover, there was not a significant impact of donor age or ischemic time independently on survival in the multivariate analysis. Similarly, when the interaction between ischemic time and donor age was examined in all of the multivariate models, none of the secondary end points were found to be significantly influenced. However, the combined interaction between donor age and ischemia time demonstrated a significantly worse survival at 2 years (p = 0.02) with donor age of > 50 years and donor ischemic time > 7 h. CONCLUSIONS: Donor age and donor ischemic time did not independently influence survival or important secondary end points after lung transplantation. However, intermediate-term survival was affected by the use of older donors when combined with a prolonged ischemic time. The impact of this combination should be considered when attempting to expand the donor pool.

Actuarial Analysis↗

PubMed2000

Pharmacokinetics of bisphenol A released from a dental sealant.

BACKGROUND: Limited information is available regarding potentially estrogenic bisphenol A, or BPA, released from dental sealants. This study determined the rate- and time-course of BPA released from a dental sealant (Delton Opaque Light-cure Pit and Fissure Sealant, Preventive Care/Dentsply) when applied at a dosage of 8 milligrams (one tooth) or 32 mg (8 mg on each of four teeth) to 40 healthy adults. METHODS: The authors recruited 40 healthy subjects (18 men and 22 women, 20-55 years of age) who did not have histories of pit and fissure sealant placement or composite resin restorations. The authors collected saliva (30 milliliters) and blood (7 mL) specimens from all subjects immediately before sealant placement (baseline) and at one hour, three hours, one day, three days and five days after sealant placement. They used high-pressure liquid chromatography to determine BPA (detection sensitivity 5 parts per billion, or ppb) in all specimens. RESULTS: The authors detected BPA in some saliva specimens (5.8-105.6 ppb) collected at one hour and three hours. The BPA, however, was not detectable beyond three hours or in any of the serum specimens. For the one- and three-hour saliva samples, the BPA concentration in the high-dose (32 mg) group was significantly greater than in the low-dose (8 mg) group (P < .05, Wilcoxon signed rank test). In the high-dose group, there was a significant decrease in saliva BPA concentrations from one hour to three hours (P < .01, Wilcoxon signed rank test). CONCLUSION: This study showed that BPA released orally from a dental sealant may not be absorbed or may be present in nondetectable amounts in systemic circulation. The concern about potential estrogenicity of sealant may be unfounded.

Adult↗

PubMed2000

Peptidomimetic antagonists of alphavbeta3 inhibit bone resorption by inhibiting osteoclast bone resorptive activity, not osteoclast adhesion to bone.

Osteoclasts are actively motile on bone surfaces and undergo alternating cycles of migration and resorption. Osteoclast interaction with the extracellular matrix plays a key role in the osteoclast resorptive process and a substantial body of evidence suggests that integrin receptors are important in osteoclast function. These integrin receptors bind to the Arg-Gly-Asp (RGD) sequence found in a variety of extracellular matrix proteins and it is well established that the interaction of osteoclast alpha v beta 3 integrin with the RGD motif within bone matrix proteins is important in osteoclast-mediated bone resorption. In this study, we characterized the effects of two synthetic peptidomimetic antagonists of alpha v beta 3, SC-56631 and SC-65811, on rabbit osteoclast adhesion to purified matrix proteins and bone, and on bone resorption in vitro. SC-56631 and SC-65811 are potent inhibitors of vitronectin binding to purified alpha v beta 3. Both SC-56631 and SC-65811 inhibited osteoclast adhesion to osteopontin- and vitronectin-coated surfaces and time-lapse video microscopy showed that osteoclasts rapidly retract from osteopontin-coated surfaces when exposed to SC-56631 and SC-65811. SC-56631 and SC-65811 blocked osteoclast-mediated bone resorption in a dose-responsive manner. Further analysis showed that SC-65811 and SC-56631 reduced the number of resorption pits produced per osteoclast and the average pit size. SC-65811 was a more potent inhibitor of bone resorption and the combination of reduced pit number and size led to a 90% inhibition of bone resorption. Surprisingly, however, osteoclasts treated with SC-65811, SC-56631 or the disintegrin echistatin, at concentrations that inhibit bone resorption did not inhibit osteoclast adhesion to bone. These results suggest that alphavbeta3 antagonists inhibited bone resorption by decreasing osteoclast bone resorptive activity or efficiency but not by inhibiting osteoclast adhesion to bone per se.

Aniline Compounds↗

PubMed1999

Influence of graft ischemic time and donor age on survival after lung transplantation.

BACKGROUND: Increased graft ischemic time and donor age are risk factors for early death after heart transplantation, but the effect of these variables on survival after lung transplantation has not been determined in a large, multinational study. METHODS: All recipients of cadaveric lung transplantations performed between October 1, 1987 and June 30, 1997 which were reported to the United Network for Organ Sharing/International Society for Heart and Lung Transplantation (UNOS/ISHLT) Registry were analyzed. Patient survival rates were estimated using Kaplan-Meier methods. Multivariate logistic regression was used to determine the impact of donor and recipient characteristics on patient survival after transplantation. To examine whether the impact of donor age varied with ischemic time, interactions between the 2 terms were examined in a separate multivariate logistic regression model. RESULTS: Kaplan-Meier survival did not differ according to the total lung graft ischemia time, but recipient survival was significantly adversely affected by young (-10 years) or old (-51 years) donor age (p = 0.01). On multivariate analysis, neither donor age nor lung graft ischemic time per se were independent predictors of early survival after transplantation, except if quadratic terms of these variables were included in the model. The interaction between donor age and graft ischemia time, however, predicted 1 year mortality after lung transplantation (p = 0.005), especially if donor age was greater than 55 years and ischemic time was greater than 6 to 7 hours. CONCLUSIONS: Graft ischemia time alone is not a risk factor for early death after lung transplantation. Very young or old donor age was associated with decreased early survival, whereas the interaction between donor age and ischemic time was a significant predictor of 1 year mortality after transplantation. Cautious expansion of donor acceptance criteria (especially as regards ischemic time) is advisable, given the critical shortage of donor lung grafts.

Adolescent↗

PubMed1998

A peptidomimetic antagonist of the integrin alpha(v)beta3 inhibits Leydig cell tumor growth and the development of hypercalcemia of malignancy.

The integrin alpha(v)beta3 interacts with the arginine-glycine-aspartic acid (RGD) tripeptide recognition sequence of a variety of extracellular matrix proteins. Recent studies show that alpha(v)beta3 plays an important role in tumor-induced angiogenesis and tumor growth and that antagonists of alpha(v)beta3 inhibit angiogenic processes that include endothelial cell adhesion and migration. Consequently, we reasoned that an RGD-based peptidomimetic antagonist of alpha(v)beta3 might inhibit tumor angiogenesis and tumor growth in vivo. An RGD-peptidomimetic library was screened to identify antagonists of vitronectin binding to alpha(v)beta3, and the compounds chosen were modified to produce selective and potent inhibitors of alpha(v)beta3. One of these compounds, beta-[[2-2-[[[3-[(aminoiminomethyl)amino]-phenyl]carbonyl]amino]ac etyl]amino]-3,5-dichlorobenzenepropanoic acid (SC-68448), inhibited vitronectin binding to both alpha(v)beta3 and the closely related platelet receptor, alpha(IIb)beta3, in a dose-responsive manner. SC-68448 inhibited vitronectin binding to alpha(v)beta3 (IC50, 1 nM) and fibrinogen binding to the platelet receptor alpha(IIb)beta3 (IC50, >100 nM), demonstrating that SC-68448 was 100-fold more potent as an inhibitor of alpha(v)beta3 versus alpha(IIb)beta3. In cell-based studies, SC-68448 inhibited alpha(v)beta3-mediated endothelial cell proliferation in a dose-dependent manner but did not inhibit tumor cell proliferation, suggesting that effects on endothelial cell proliferation were not due to SC-68448-induced cytotoxicity. In accord with these results, SC-68448 inhibited angiogenesis in vivo in a basic fibroblast growth factor-induced rat corneal neovascularization model. A xenogeneic severe combined immune deficiency mouse/rat Leydig cell tumor model was developed for testing SC-68448 as an inhibitor of tumor growth in vivo. Rat Leydig cell tumors grew rapidly in severe combined immune deficiency mice and produced humoral hypercalcemia of malignancy. SC-68448 inhibited the growth of the tumors in mice by up to 80% and completely blocked the development of hypercalcemia. Together, these results demonstrate the feasibility of antitumor therapies based upon the development of nontoxic small molecule pharmacological antagonists of integrin alpha(v)beta3.

Animals↗

PubMed1998

A series of function blocking antibodies against the alpha v beta 3 integrin bind allosteric to the ligand binding site and induce ligand dissociation.

The alpha v beta 3 integrin plays a critical role in bone resorption, angiogenesis, and tumor cell invasion. A blockade of this receptor has therapeutic potential in osteoporosis, vascular restenosis, and cancer. In this report, we characterize the mechanism by which six monoclonal antibodies inhibit the function of alpha v beta 3. All six antibodies interact with a common site that is partially comprised of residues 164-202 within the beta 3 subunit. This domain is physically separate from the RGD binding site, and appears to regulate ligand binding allosterically. Thus, the blocking antibodies function, in part, by inducing the dissociation of ligand from alpha v beta 3. Although this family of antibodies is able to virtually abolish alpha v beta 3-mediated cell adhesion, they only block about one-half of soluble ligand binding to the integrin. This observation is consistent with the idea that two functionally distinct populations of alpha v beta 3 are present on the cell surface. The unique mechanism of action of these antibodies provides new insight in the structure-function relationships of alpha v beta 3, and also suggest that such antibodies are likely to behave differently than RGD mimetics if used as drugs.

Allosteric Site↗

PubMed1998

A prospective study of sealant application in navy recruits.

A 3-year prospective study was designed to evaluate sealants in preventing the formation and progression of caries in a young adult military population. United States Navy dentists performed dental examinations on recruits being in-processed at the Naval Training Center, San Diego, California. Contralateral molar pairs (same arch) without caries or restorations were selected. Occlusal decalcification and lesions limited to enamel were also eligible, but teeth with proximal decalcification were disqualified. The sample consisted of 860 molar pairs in 529 Navy recruits, each contributing one or two pairs. Required annual dental examinations provided follow-up data, with results being recorded on postcards that were mailed back to the investigator. Yearly response rates were as follows: 1 year, 62.2% (483 molar pairs); 2 year, 47.8% (378 molar pairs); and 3 year, 41.4% (317 molar pairs). The response rate for pairs having at least one observation during the 3-year follow-up was 72.6% (563 molar pairs), with a caries conversion rate of 1.2% (7 teeth) on sealed teeth and 5.3% (32 teeth) on control teeth, yielding 35 discordant molar pairs on 33 recruits (30 on control teeth and 5 on sealed teeth) (p < 0.0001). These results confirm the efficacy of sealants in significantly reducing the rate caries in a young adult military population.

Adult↗

PubMed1997

Results of extracorporeal membrane oxygenation in children with sepsis. The Extracorporeal Life Support Organization.

BACKGROUND: Despite good results in neonates, extracorporeal membrane oxygenation (ECMO) is less well accepted in pediatric patients. Older children frequently undergo ECMO for severe bacterial, viral, or aspiration pneumonia and many have coexisting systemic sepsis. We reviewed data from a national registry to study the influence of sepsis on survival from ECMO. METHODS: Six hundred fifty-five patients (aged 2 weeks to 17 years) with respiratory failure treated with ECMO were divided into two groups by the presence (n = 76) or absence (n = 579) of sepsis. Groups were compared by univariate analysis and by multivariate logistic regression that considered 10 additional pre-ECMO variables (age, sex, weight, arterial blood gas results, ventilator parameters, and renal failure). RESULTS: By univariate analysis, survival was lower in septic children (36.8% versus 51.6%; p < 0.02). However, by multivariate analysis, sepsis was not an independent survival predictor (odds ratio, 0.578; 95% confidence interval, 0.288-1.162; p = 0.12). The ECMO complications predicted by the presence of sepsis included (1) seizures, (2) other neurologic complications, and (3) infection at other sites (all p < 0.05). CONCLUSIONS: Systemic sepsis does not independently influence survival in pediatric ECMO. This therapy should not be withheld solely because of sepsis, although neurologic complications may occur more frequently.

Adolescent↗