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Biomedical subjects

D M Meyer

Publications and source records attributed to D M Meyer.

At least 19 recordsLinked to original sources
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↗
PubMed1997

Early evacuation of traumatic retained hemothoraces using thoracoscopy: a prospective, randomized trial.

BACKGROUND: Failure to adequately evacuate blood from the pleural space after trauma may result in extended hospitalization and complications such as empyema. METHODS: Patients with retained hemothoraces were prospectively randomized to either a second tube thoracostomy (group 1, n = 24) or video-assisted thoracoscopy (VATS) (group 2, n = 15). Group 1 patients in whom additional tube drainage failed were subsequently randomized to either VATS or thoracotomy. Study end points included duration and costs of hospitalization. RESULTS: During a 4-year period, 39 patients were entered into the study. Patients in group 2 had shorter duration of tube drainage (2.53 +/- 1.36 versus 4.50 +/- 2.83 days, mean +/- standard deviation; p < 0.02), shorter hospital stay after the procedure (3.60 +/- 1.64 versus 7.21 +/- 5.30 days; p < 0.02), and shorter total hospital stay (5.40 +/- 2.16 versus 8.13 +/- 4.62 days; p < 0.02). Hospital costs were also less in this group ($7,689 +/- 3,278 versus $13,273 +/- 8,158; p < 0.02). There was no mortality in either group. No group 2 patient required conversion to thoracotomy. In 10 group 1 patients additional tube placement failed, and this subset was randomized to VATS (n = 5) or thoracotomy (n = 5). No significant difference in clinical outcome was found between these subgroups. CONCLUSIONS: In many patients treated only with additional tube drainage (group 1), this therapy fails, necessitating further intervention. Intent to treat with early VATS for retained hemothoraces decreases the duration of tube drainage, the length of hospital stay, and hospital cost. Early intervention with VATS may be a more efficient and economical strategy for managing retained hemothoraces after trauma.

Adolescent↗
PubMed1997

Voluntary programs: ADA Seal program and international implications.

For about 130 years the American Dental Association (ADA) has aided the profession and the public in selecting safe and effective dental products. Since 1930, dental products have been evaluated through the ADA Seal program. In accordance with the ADA's Bylaws, the Council on Scientific Affairs assesses information evaluating the safety, efficacy, appropriate use, and promotional claims of dental products. In doing so, the Council may award the ADA's Seal of Acceptance. In collaboration with interested parties, expert consultants, and Council members, the ADA produces guidelines suggesting appropriate methodologies and submission data to assist manufacturers in voluntarily earning the Seal of Acceptance. To date, numerous professional and consumer products have been evaluated, and about 1,300 of these products bear the Association's Seal of Acceptance. When a product is awarded the Seal it means that adequate data have been submitted and reviewed and, based on available information, the product meets ADA guidelines of safety and effectiveness. Dental health care professionals and consumers who use products that have the Seal can be confident that a product's properties and performance are consistent with current professional standards and manufacturers' claims. The ADA Seal program serves to help dentists and manufacturers meet their ethical obligations to the public by promoting safe and effective health care products.

American Dental Association↗
PubMed1996

A peptide isolated by phage display binds to ICAM-1 and inhibits binding to LFA-1.

A mixed phage library containing random peptides from four to eight residues in length flanked by cysteine residues was screened using a recombinant soluble, form of human ICAM-1, which included residues 1-453, (ICAM-1(1-453)). Phage bound to immobilized ICAM-1(1-453) were eluted by three methods: (1) soluble ICAM-1(1-453), (2) neutralizing murine monoclonal antibody, (anti-ICAM-1, M174F5B7), (3) acidic conditions. After three rounds of binding and elution, a single, unique ICAM-1 binding phage bearing the peptide EWCEYLGGYLRCYA was isolated; the identical phage was selected with each method of elution. Attempts to isolate phage from non-constrained (i.e., not containing cysteines) libraries did not yield a phage that bound to ICAM-1. Phage displaying EWCEYLGGYLRCYA bound to immobilized ICAM-1(1-453) and to ICAM-1(1-185), a recombinant ICAM-1, which contains only the two amino-terminal immunoglobulin domains residing within residues 1-185. This is the region of the ICAM-1 that is bound by LFA-1. The phage did not bind to proteins other than ICAM-1. The phage bound to two ICAM-1 mutants, which contained amino acid substitutions that dramatically decreased or eliminated the binding to LFA-1. Studies were also performed with the corresponding synthetic peptide. The linear form of the synthetic EWCEYLGGYLRCYA peptide was found to inhibit LFA-1 binding to immobilized ICAM-1(1-453) in a protein-protein binding assay. By contrast, the disulfide, cyclized, form of the peptide was inactive. The EWCEYL portion of the sequence is homologous to the EWPEYL sequence found within rhinovirus coat protein 14, a nonintegrin protein that binds to ICAM-1. Taken together, the results suggests that the EWCEYLGGYLRCYA sequence is capable to binding to immobilized ICAM-1. Phage display appears to represent a new approach for the identification of peptides that interfere with ICAM-1 binding to beta 2 integrins.

Bacteriophages↗
PubMed1996

Central venous pressure in space.

Gravity affects cardiac filling pressure and intravascular fluid distribution significantly. A major central fluid shift occurs when all hydrostatic gradients are abolished on entry into microgravity (microG). Understanding the dynamics of this shift requires continuous monitoring of cardiac filling pressure; central venous pressure (CVP) measurement is the only feasible means of accomplishing this. We directly measured CVP in three subjects: one aboard the Spacelab Life Sciences-1 space shuttle flight and two aboard the Spacelab Life Sciences-2 space shuttle flight. Continuous CVP measurements, with a 4-Fr catheter, began 4 h before launch and continued into microG. Mean CVP was 8.4 cmH2O seated before flight, 15.0 cmH2O in the supine legs-elevated posture in the shuttle, and 2.5 cmH2O after 10 min in microG. Although CVP decreased, the left ventricular end-diastolic dimension measured by echocardiography increased from a mean of 4.60 cm supine preflight to 4.97 cm within 48 h in microG. These data are consistent with increased cardiac filling early in microG despite a fall in CVP, suggesting that the relationship between CVP and actual transmural left ventricular filling pressure is altered in microG.

Adult↗
PubMed1996

Tobacco use habits of naval personnel during Desert Storm.

This study examined availability and usage of tobacco products, and their potential impact on the oral health of naval personnel deployed to Desert Storm. Of 4,200 surveys mailed to a randomly selected sample, 45.6% were returned (N = 1,915). The respondents included 55.9% who reported a present or former smoking habit, 34.1% who identified themselves as current smokers (SM), and 23.8% who were smokeless tobacco (ST) users. Tobacco products were easily and inexpensively accessible through ship stores, exchange, or military support organizations (USO). While in the Persian Gulf, 7.0% started SM and 9.3% started ST, resulting in an overall 4.7 and 6.1% increase in SM and ST, respectively. Of those who were already tobacco users, 29.2% reported more SM use and 19.0% used ST more often. Stress (35.1%) and boredom (21.4%) were the most frequently cited reasons to start or increase use. Although 30.5% of respondents reported military personnel have encouraged them to quit, 77.2% reported that anti-smoking efforts have been unsuccessful in influencing them to quit. Since the tobacco usage rate is higher in the military than in the civilian sector, greater emphasis on preventive efforts in warranted to promote health and wellness.

Adult↗
PubMed1996

The evaluation of a managed dental delivery concept.

Phased dentistry (PD) is a philosophy of managed oral health care that emphasizes an orderly approach to dental risk assessment, prevention, and disease management. PD is divided into two stages. Phase I (PH1) care is intended to eliminate all conditions that may produce a dental emergency within 12 months. PH1 care is directed primarily to recruits and apprentice training students. Phase 2 (PH2) care strives to attain and maintain optimal oral health for Navy and Marine Corps personnel after their initial training period and throughout their military career. The purpose of this study was to evaluate the feasibility of introducing PH1 into a recruit dental treatment facility. Data were obtained at Naval Dental Center (NDC), Orlando from 4,571 recruit dental patients who were in-processed and completed recruit training between May 27 and October 1, 1993. The incoming operational dental readiness (ODR) of recruits during the PD trial was 28.5%, whereas the ODR of graduating recruits was 85.8%. During this same period there was a 34% increase in completed dental treatments per provider full time equivalent. Although dramatic increases in ODR and productivity were noticed during PD, other variables may have contributed to these results.

Dentistry↗
PubMed1995

Characterization of intercellular adhesion molecule-1 ectodomain (sICAM-1) as an inhibitor of lymphocyte function-associated molecule-1 interaction with ICAM-1.

Intercellular adhesion molecule-1 (ICAM-1) is a member of the Ig superfamily, contains five Ig-like domains comprising the extracellular portion of the molecule, and interacts with lymphocyte function-associated molecule-1 (LFA-1), a member of the beta 2-integrin family. LFA-1/ICAM-1 interaction is important in a variety of cellular events including Ag-specific T cell activation and leukocyte transendothelial migration. Recently, a soluble circulating form of ICAM-1 has been detected in human serum that appears to result from the proteolytic cleavage of membrane ICAM-1. Native and recombinant soluble forms of ICAM-1 have been reported to inhibit LFA-1/ICAM-mediated adhesion in vitro, and it is conceivable that circulating forms of soluble ICAM-1 are regulators of LFA-1/ICAM-1-mediated cell-cell interaction in vivo. We have investigated the properties of the ICAM-1 ectodomain (sICAM453) as an inhibitor of LFA-1 interaction with ICAM-1 in cell- and molecule-based systems. The results show clearly that recombinant sICAM453 can inhibit LFA-1/ICAM-1 interaction. Soluble ICAM-1 inhibited LFA-1-mediated cell adhesion to immobilized sICAM453 and homotypic T-cell aggregation with IC50 in the 20 to 40 microM range. Definitive evidence that sICAM-1 can inhibit LFA-1 interaction with ICAM-1 was obtained by showing that the sICAM-1 inhibited the interaction between LFA-1 protein micelles and ICAM-1 immobilized on plastic. These results clearly show that sICAM453 can bind to LFA-1 and competitively inhibit ICAM-1/LFA-1-mediated cell-cell interaction, albeit at concentrations much greater than found in plasma. As a consequence, it is unlikely that sICAM-1 would antagonize ICAM-1/LFA-1-mediated cellular events in vivo.

Animals↗
PubMed1995

Interleukin 8 and mast cell-generated tumor necrosis factor-alpha in neutrophil recruitment.

In the reverse passive Arthus reaction in mouse skin and immune injury of mouse dermal basement membrane, neutrophil (PMN) infiltration in mast cell deficient WBB6F1-W/Wv (W/Wv) mice was only 40% of that in WBB6F1-(+)/+ (+/+) mice that had a normal mast cell repertoire. An anti-tumor necrosis factor-alpha (TNF-alpha) monoclonal antibody (mAb) decreased PMN infiltration by 35-80% in +/+ but not W/Wv mice. In addition, an anti-human interleukin-8 (IL-8) MAb, DM/C7, inhibited PMN infiltration of the skin induced by either intradermal administration of recombinant human IL-1 beta or immune complex deposition. In both models of immune complex injury, DM/C7 reduced PMN infiltration by 40-60% in +/+ mice but not W/Wv mice. PMN infiltration and the sensitivity of this infiltration to anti-TNF-alpha or DM/C7 MAb in W/Wv mice whose mast cell population had been restored was indistinguishable from the influx observed in +/+ mice. These data suggest that TNF-alpha, IL-8, and mast cells play a fundamental role in PMN recruitment following immune complex injury.

Animals↗
PubMed1995

Neonatal extracorporeal membrane oxygenation complicated by sepsis. Extracorporeal Life Support Organization.

The onset of sepsis in neonates while on extracorporeal membrane oxygenation (ECMO) may portend adverse results. Nevertheless, ECMO has been used as a therapy in the management of septic conditions. This study assessed morbidity and mortality in neonates in whom septic complications developed while they were on ECMO. Of 5,123 neonates in the Extracorporeal Life Support Organization Registry undergoing ECMO for nonseptic indications, 217 patients had development of septic complications. A multivariate logistic regression analysis that considered 15 pre-ECMO criteria was performed to evaluate outcome. Mortality was higher in the septic group (35% versus 17%; p < 0.002) and ECMO duration averaged 85 hours longer (p < 0.001). Septic neonates had a greater frequency of complications including seizures, gastrointestinal bleeding, renal dysfunction, and metabolic problems (all p < 0.05). Transfusion requirements were doubled. Oxygenator thrombi and hemofilter malfunction occurred more often in septic patients (p < 0.03). New strategies to prevent sepsis and associated thrombotic and metabolic complications may be indicated. A critical reappraisal of continued aggressive support may be warranted when septic complications develop in neonates during ECMO.

Analysis of Variance↗
PubMed1995

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

Use of extracorporeal membrane oxygenation for treatment of respiratory failure caused by sepsis is controversial because of concerns over survival benefit and hemorrhage-related complications. To evaluate the impact of the primary diagnosis of sepsis on outcome, we reviewed data from 6853 neonates in the Extracorporeal Life Support Organization Registry and defined two groups: group 1 (n = 1060), all patients undergoing extracorporeal membrane oxygenation with a primary diagnosis of sepsis; group 2 (n = 5793), those with any other primary diagnosis. A multivariate logistic regression analysis that considered 15 variables present before extracorporeal membrane oxygenation (including age, sex, birth weight, prior cardiopulmonary arrest, arterial blood gas results, and ventilator settings) was used to compare outcomes between groups. Survival was not different between the two groups (77%, group 1; 82%, group 2; p = 0.2480), although lung recovery was less frequent in the patients with sepsis (p = 0.0185). Group 1 had a higher incidence of complications including seizures (odds ratio 1.446, p = 0.0346), cerebral infarct or hemorrhage (2.310, p = 0.0001), need for dialysis (1.478, p = 0.0131), hypernatremia (2.089, p = 0.0019), hyperbilirubinemia (2.423, p = 0.0001), and dobutamine use (1.918, p = 0.0001). Neonates with sepsis are more likely to have neurologic, renal, and metabolic complications from extracorporeal membrane oxygenation but may still achieve a survival benefit equivalent to those without sepsis. From these data, extracorporeal membrane oxygenation should not be withheld from neonates solely on the basis of sepsis. Rather, management strategies should focus on limiting the incidence or severity of the common complications.

Extracorporeal Membrane Oxygenation↗
PubMed1995

Treatment of a crowded Class II malocclusion with significant maxillary incisor protrusion.

A case report of a 10-year-old girl with a skeletal and dental Class II, Division 1 malocclusion is presented. There was marked arch length deficiency in the mandibular arch and significant maxillary incisor protrusion. The patient was treated with maxillary premolar extractions and early maxillary treatment for incisor retraction. The treatment was completed nonsurgically with full treatment later and a single mandibular incisor extraction. The Class II malocclusion and crowding were resolved with Class II molar and Class I canine relationships and a positive profile change. [This case was presented to the American Board of Orthodontics in partial fulfillment of the requirements for the certification process conducted by the Board.]

Bicuspid↗
PubMed1995

Use of echocardiography to detect occult cardiac injury after penetrating thoracic trauma: a prospective study.

One hundred five hemodynamically stable patients with penetrating thoracic trauma were prospectively evaluated for occult cardiac injury. All patients underwent transthoracic echocardiography (ECHO) and subxiphoid exploration (SXE). Those with positive SXE underwent exploration. Results are calculated based on operative findings of significant injuries. For the entire group, SXE was more sensitive than ECHO (sensitivity, 100% vs. 56%; specificity, 92% vs. 93%; and accuracy, 92% vs. 90%, respectively). The SXE missed no injuries in this group. Eight of 17 patients, however, with positive SXEs had insignificant injuries at sternotomy. Seven patients had positive ECHO, but no significant injury. The ECHO missed four significant injuries. When comparing SXE with ECHO in patients without hemothorax, however, sensitivity (100% vs. 100%), specificity (89% vs. 91%), and accuracy (90% vs. 91%) were comparable between SXE and ECHO. We conclude that ECHO has significant limitations in identifying serious cardiac injuries in patients with hemothorax. For hemodynamically stable patients without hemothorax, ECHO missed no significant injuries and may be an acceptable diagnostic option for detecting significant cardiac trauma in patients with injuries in proximity to the heart.

Adolescent↗
PubMed1994

High-level expression of biologically active, soluble forms of ICAM-1 in a novel mammalian-cell expression system.

LFA-1/ICAM-1 interaction is important in facilitating a number of cellular events including antigen-specific T-cell activation and leukocyte transendothelial migration. We are interested in defining residues and contact sites that mediate ICAM-1 interaction with the integrin receptor, LFA-1. To provide sufficient material to facilitate study of the interaction of this ligand-receptor pair, we have developed a new high-level mammalian-cell expression system based on the use of the herpes simplex virus (HSV) VP16 transactivator and the HSV IE175 promoter to direct expression of foreign genes in BHK cells. In this system, the gene of interest is expressed as a fusion protein with a carboxyl terminal decapeptide tail to aid in identification, quantitation, and affinity purification of recombinant protein. This system allowed rapid generation of cell lines producing high levels of levels of soluble proteins corresponding to the full-length extracellular (sICAM453) and the amino terminal two immunoglobulin domains (sICAM185) of ICAM-1. Both sICAM453 and sICAM185 were biologically active and were purified in a single step from conditioned media by antibody affinity chromatography.

Amino Acid Sequence↗