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Obstetrician & Gynecologist (OB/GYN)
31 years of experience
Accepting new patients
Video profile

Credentials

Education ?

Medical School Score Rankings
University of Minnesota, Twin Cities (1981)
Family Medicine
  •  
Top 25%

Awards & Distinctions ?

Awards  
Selected for best doctors in america:southeastern edition 1995
Castle Connolly's Top Doctors™ (2012 - 2013)
Appointments
University Of South Florida College Of Medicine
ASSOCIATE PROFESSOR OF OBSTETRICS & GYNECOLOGY
University Of South Florida College Of M
ASSOCIATE PROFESSOR OF OBSTETRICS & GYNECOLOGY
Associations
American Board of Obstetrics and Gynecology

Affiliations ?

Dr. Williams is affiliated with 12 hospitals.

Hospital Affiliations

Score

Rankings

  • Southwest Florida Regional Medical Center
    2727 Winkler Ave, Fort Myers, FL 33901
    •  
    Top 25%
  • Gulf Coast Hospital
    Obstetrician & Gynecologist
    13681 Doctors Way, Fort Myers, FL 33912
    •  
    Top 25%
  • Cape Coral Hospital
    636 Del Prado Blvd S, Cape Coral, FL 33990
    •  
    Top 25%
  • HealthPark Medical Center-Lee Memorial
    Obstetrician & Gynecologist
    2776 Cleveland Ave, Fort Myers, FL 33901
    •  
    Top 25%
  • NCH Downtown Naples Hospital
    350 7th St N, Naples, FL 34102
    •  
    Top 25%
  • Lee Memorial Hospital
    2776 Cleveland Ave, Fort Myers, FL 33901
    •  
    Top 25%
  • The Tampa General Hospital
    2 Columbia Dr, Tampa, FL 33606
    •  
    Top 50%
  • Lee Memorial Hospital-Healthpark
  • Peace River Regional Medical Center
    2500 Harbor Blvd, Port Charlotte, FL 33952
  • HealthPark Medical Center
    9981 S Healthpark Dr, Fort Myers, FL 33908
  • Gulf Coast Endoscopy Center-South
  • Physicians Regional Medical Center
    6101 Pine Ridge Rd, Naples, FL 34119
  • Publications & Research

    Dr. Williams has contributed to 118 publications.
    Title Higher Harmonic Anisotropic Flow Measurements of Charged Particles in Pb-pb Collisions at Sqrt(s(nn)) = 2.76  tev.
    Date December 2011
    Journal Physical Review Letters
    Excerpt

    We report on the first measurement of the triangular v3, quadrangular v4, and pentagonal v5 charged particle flow in Pb-Pb collisions at sqrt(s(NN)) = 2.76  TeV measured with the ALICE detector at the CERN Large Hadron Collider. We show that the triangular flow can be described in terms of the initial spatial anisotropy and its fluctuations, which provides strong constraints on its origin. In the most central events, where the elliptic flow v2 and v3 have similar magnitude, a double peaked structure in the two-particle azimuthal correlations is observed, which is often interpreted as a Mach cone response to fast partons. We show that this structure can be naturally explained from the measured anisotropic flow Fourier coefficients.

    Title Cardiac and Coronary Ct Comprehensive Imaging Approach in the Assessment of Coronary Heart Disease.
    Date November 2011
    Journal Heart (british Cardiac Society)
    Excerpt

    Cardiac CT is a rapidly advancing technology. Non-invasive CT coronary angiography is an established technique for assessing coronary heart disease with accuracy similar to invasive coronary angiography. CT myocardial perfusion imaging can now identify perfusion defects in animal models and humans. MRI is the current 'gold standard' for the assessment of myocardial viability, but it is now also possible to assess delayed enhancement by CT. This has led to the possibility of a 'one-stop shop' for cardiovascular imaging that would provide information on anatomy, function, perfusion and viability in one rapid diagnostic test at a radiation dose equivalent to contemporary nuclear medicine imaging. This review discusses the current status of 'one-stop shop' cardiac CT assessment, clinical utility and directions for future research.

    Title Paired Mutations Abolish and Restore the Balanced Annealing and Melting Activities of Orf1p That Are Required for Line-1 Retrotransposition.
    Date October 2011
    Journal Nucleic Acids Research
    Excerpt

    Retrotransposition amplifies LINE-1 (L1) to high copy number in mammalian genomes. The L1 protein encoded by ORF1 (ORF1p) is required for retrotransposition. This dependence on ORF1p was investigated by mutating three highly conserved residues, R238, R284 and Y318 to alanine, thereby inactivating retrotransposition. R284A and Y318A were rescued by further substituting the alanine with the appropriate conservative amino acid, e.g. lysine or phenylalanine, respectively, whereas R238K remained inactive. Quantification of the steady-state levels of L1 RNA and ORF1p failed to discriminate active from inactive variants, indicating loss of L1 retrotransposition resulted from loss of function rather than reduced expression. The two biochemical properties known for ORF1p are high-affinity RNA binding and nucleic acid chaperone activity. Only R238A/K exhibited significantly reduced RNA affinities. The nucleic acid chaperone activities of the remaining paired mutants were assessed by single-molecule DNA stretching and found to mirror retrotransposition activity. To further examine ORF1p chaperone function, their energetic barriers to DNA annealing and melting were derived from kinetic work. When plotted against each other, the ratio of these two activities distinguished functional from non-functional ORF1p variants. These findings enhance our understanding of the requirements for ORF1p in LINE-1 retrotransposition and, more generally, nucleic acid chaperone function.

    Title Centrality Dependence of the Charged-particle Multiplicity Density at Midrapidity in Pb-pb Collisions at Sqrt[s(nn)] = 2.76 Tev.
    Date July 2011
    Journal Physical Review Letters
    Excerpt

    The centrality dependence of the charged-particle multiplicity density at midrapidity in Pb-Pb collisions at sqrt[s_{NN}]=2.76  TeV is presented. The charged-particle density normalized per participating nucleon pair increases by about a factor of 2 from peripheral (70%-80%) to central (0%-5%) collisions. The centrality dependence is found to be similar to that observed at lower collision energies. The data are compared with models based on different mechanisms for particle production in nuclear collisions.

    Title Charged-particle Multiplicity Density at Midrapidity in Central Pb-pb Collisions at Sqrt[s(nn)] = 2.76 Tev.
    Date April 2011
    Journal Physical Review Letters
    Excerpt

    The first measurement of the charged-particle multiplicity density at midrapidity in Pb-Pb collisions at a center-of-mass energy per nucleon pair √ S NN = 2.76 TeV is presented. For an event sample corresponding to the most central 5% of the hadronic cross section, the pseudorapidity density of primary charged particles at midrapidity is 1584 ± 4(stat) ± 76(syst), which corresponds to 8.3 ± 0.4(syst) per participating nucleon pair. This represents an increase of about a factor 1.9 relative to pp collisions at similar collision energies, and about a factor 2.2 to central Au-Au collisions at √ S NN = 2.76 TeV. This measurement provides the first experimental constraint for models of nucleus-nucleus collisions at LHC energies.

    Title Midrapidity Antiproton-to-proton Ratio in Pp Collisons at Sqrt[s]=0.9 and 7 Tev Measured by the Alice Experiment.
    Date January 2011
    Journal Physical Review Letters
    Excerpt

    The ratio of the yields of antiprotons to protons in pp collisions has been measured by the ALICE experiment at sqrt[s]=0.9 and 7 TeV during the initial running periods of the Large Hadron Collider. The measurement covers the transverse momentum interval 0.45<p_{t}<1.05  GeV/c and rapidity |y|<0.5. The ratio is measured to be R_{|y|<0.5}=0.957±0.006(stat)±0.014(syst) at 0.9 TeV and R_{|y|<0.5}=0.991±0.005(stat)±0.014(syst) at 7 TeV and it is independent of both rapidity and transverse momentum. The results are consistent with the conventional model of baryon-number transport and set stringent limits on any additional contributions to baryon-number transfer over very large rapidity intervals in pp collisions.

    Title Molecular Dynamics Study of the Melt Morphology of Polyethylene Chains with Different Branching Characteristics Adjacent to a Clay Surface.
    Date May 2010
    Journal Langmuir : the Acs Journal of Surfaces and Colloids
    Excerpt

    Conformations of model high-density polyethylene (HDPE) and linear low-density polyethylene (LLDPE) chains with different intramolecular branch distributions adsorbed on a relaxed octahedral surface of kaolinite, a major clay mineral, at 463 K (190 degrees C) were studied by using classical molecular dynamics (MD) simulation. Prior to the MD simulations, first-principle density functional theory (DFT) calculations were carried out to relax the inorganic surface that was created by cleaving the corresponding kaolinite crystal structure. The high-temperature MD simulation results showed that an ordered polyethylene region with a thickness of about one to three layers of chain segments developed rapidly near the clay surface. On the other hand, chain segments in the far field slowly evolved into another ordered region with a higher degree of order than the one adjacent to the surface. It was observed that the melt morphology in the far field depends on the architecture of the chains. Also, in between the two ordered regions, a region that contained no apparent order formed. The above observation is attributed to the fact that the mobility of chain segments adjacent to the surface was greatly reduced as a result of their strong affinity for the surface, while those in the far field were not. Despite the fact that the results are for the melt state, they suggest that nucleation and lamellar growth of polymer chains nearby an inorganic surface may proceed from the chain segments in the ordered region in the far field rather than from the organic/inorganic interface. This is because chain segments in the three described regions, upon cooling, should not have sufficient thermal energy to reorient themselves drastically to form a single lamella under normal crystallization conditions. However, it should be noted that the above speculation is made based on a rather short equilibration time (approximately 10 ns) used in the simulations.

    Title Epigenetic Mechanisms Modulate Thyroid Transcription Factor 1-mediated Transcription of the Surfactant Protein B Gene.
    Date February 2010
    Journal The Journal of Biological Chemistry
    Excerpt

    Epigenetic regulation of transcription plays an important role in cell-specific gene expression by altering chromatin structure and access of transcriptional regulators to DNA binding sites. Surfactant protein B (Sftpb) is a developmentally regulated lung epithelial gene critical for lung function. Thyroid transcription factor 1 (Nkx2-1) regulates Sftpb gene expression in various species. We show that Nkx2-1 binds to the mouse Sftpb (mSftpb) promoter in the lung. In a mouse lung epithelial cell line (MLE-15), Nkx2-1 knockdown reduces Sftpb expression, and mutation of Nkx2-1 cis-elements significantly reduces mSftpb promoter activity. Whether chromatin structure modulates Nkx2-1 regulation of Sftpb transcription is unknown. We found that DNA methylation of the mSftpb promoter inversely correlates with known patterns of Sftpb expression in vivo. The mSftpb promoter activity can be manipulated by altering its cytosine methylation status in vitro. Nkx2-1 activation of the mSftpb promoter is impaired by DNA methylation. The unmethylated Sftpb promoter shows an active chromatin structure enriched in the histone modification H3K4me3 (histone 3-lysine 4 trimethylated). The ATP-dependent chromatin remodeling protein Brg1 is recruited to the Sftpb promoter in Sftpb-expressing, but not in non-expressing tissues and cell lines. Brg1 knockdown in MLE-15 cells greatly decreases H3K4me3 levels at the Sftpb promoter region and expression of the Sftpb gene. Brg1 can be co-immunoprecipitated with Nkx2-1 protein. Last, Nkx2-1 and Brg1 with intact ATPase activity are required for mSftpb promoter activation in vitro. Our findings suggest that DNA methylation and chromatin modifications cooperate with Nkx2-1 to regulate Sftpb gene cell specific expression.

    Title Reactions to Prayer at Governmental Meetings.
    Date November 2009
    Journal Psychological Reports
    Excerpt

    An interaction of mean ratings of support and intent to vote for officials between scenarios in which the religion of a government official offering a prayer was experimentally manipulated, and the reported reaction of the community, was related to 64 college women's support and intention to vote for the official. Importance of religion to the participants contributed significant variance as a covariate.

    Title Increased Pea3/e1af and Decreased Net/elk-3, Both Ets Proteins, Characterize Human Nsclc Progression and Regulate Caveolin-1 Transcription in Calu-1 and Nci-h23 Nsclc Cell Lines.
    Date August 2009
    Journal Carcinogenesis
    Excerpt

    Caveolin-1 protein has been called a 'conditional tumor suppressor' because it can either suppress or enhance tumor progression depending on cellular context. Caveolin-1 levels are dynamic in non-small-cell lung cancer, with increased levels in metastatic tumor cells. We have shown previously that transactivation of an erythroblastosis virus-transforming sequence (ETS) cis-element enhances caveolin-1 expression in a murine lung epithelial cell line. Based on high sequence homology between the murine and human caveolin-1 promoters, we proposed that ETS proteins might regulate caveolin-1 expression in human lung tumorigenesis. We confirm that caveolin-1 is not detected in well-differentiated primary lung tumors. Polyoma virus enhancer activator 3 (PEA3), a pro-metastatic ETS protein in breast cancer, is expressed at low levels in well-differentiated tumors and high levels in poorly differentiated tumors. Conversely, Net, a known ETS repressor, is expressed at high levels in the nucleus of well-differentiated primary tumor cells. In tumor cells in metastatic lymph node sites, caveolin-1 and PEA3 are highly expressed, whereas Net is now expressed in the cytoplasm. We studied transcriptional regulation of caveolin-1 in two human lung cancer cell lines, Calu-1 (high caveolin-1 expressing) and NCI-H23 (low caveolin-1 expressing). Chromatin immunoprecipitation-binding assays and small interfering RNA experiments show that PEA3 is a transcriptional activator in Calu-1 cells and that Net is a transcriptional repressor in NCI-H23 cells. These results suggest that Net may suppress caveolin-1 transcription in primary lung tumors and that PEA3 may activate caveolin-1 transcription in metastatic lymph nodes.

    Title Hmgb Binding to Dna: Single and Double Box Motifs.
    Date March 2008
    Journal Journal of Molecular Biology
    Excerpt

    High mobility group (HMG) proteins are nuclear proteins believed to significantly affect DNA interactions by altering nucleic acid flexibility. Group B (HMGB) proteins contain HMG box domains known to bind to the DNA minor groove without sequence specificity, slightly intercalating base pairs and inducing a strong bend in the DNA helical axis. A dual-beam optical tweezers system is used to extend double-stranded DNA (dsDNA) in the absence as well as presence of a single box derivative of human HMGB2 [HMGB2(box A)] and a double box derivative of rat HMGB1 [HMGB1(box A+box B)]. The single box domain is observed to reduce the persistence length of the double helix, generating sharp DNA bends with an average bending angle of 99+/-9 degrees and, at very high concentrations, stabilizing dsDNA against denaturation. The double box protein contains two consecutive HMG box domains joined by a flexible tether. This protein also reduces the DNA persistence length, induces an average bending angle of 77+/-7 degrees , and stabilizes dsDNA at significantly lower concentrations. These results suggest that single and double box proteins increase DNA flexibility and stability, albeit both effects are achieved at much lower protein concentrations for the double box. In addition, at low concentrations, the single box protein can alter DNA flexibility without stabilizing dsDNA, whereas stabilization at higher concentrations is likely achieved through a cooperative binding mode.

    Title Deaminase-independent Inhibition of Hiv-1 Reverse Transcription by Apobec3g.
    Date January 2008
    Journal Nucleic Acids Research
    Excerpt

    APOBEC3G (A3G), a host protein that inhibits HIV-1 reverse transcription and replication in the absence of Vif, displays cytidine deaminase and single-stranded (ss) nucleic acid binding activities. HIV-1 nucleocapsid protein (NC) also binds nucleic acids and has a unique property, nucleic acid chaperone activity, which is crucial for efficient reverse transcription. Here we report the interplay between A3G, NC and reverse transcriptase (RT) and the effect of highly purified A3G on individual reactions that occur during reverse transcription. We find that A3G did not affect the kinetics of NC-mediated annealing reactions, nor did it inhibit RNase H cleavage. In sharp contrast, A3G significantly inhibited all RT-catalyzed DNA elongation reactions with or without NC. In the case of (-) strong-stop DNA synthesis, the inhibition was independent of A3G's catalytic activity. Fluorescence anisotropy and single molecule DNA stretching analyses indicated that NC has a higher nucleic acid binding affinity than A3G, but more importantly, displays faster association/disassociation kinetics. RT binds to ssDNA with a much lower affinity than either NC or A3G. These data support a novel mechanism for deaminase-independent inhibition of reverse transcription that is determined by critical differences in the nucleic acid binding properties of A3G, NC and RT.

    Title Erm is Expressed by Alveolar Epithelial Cells in Adult Mouse Lung and Regulates Caveolin-1 Transcription in Mouse Lung Epithelial Cell Lines.
    Date November 2007
    Journal Journal of Cellular Biochemistry
    Excerpt

    We previously identified an Ets cis-element in the mouse caveolin-1 promoter that is selectively activated in lung epithelial (E10), but not lung endothelial murine lung endothelial cell line (MFLM-4), cell lines and therefore appears important for differential, cell-specific caveolin-1 transcription. In the present study, we demonstrate that immunostaining of adult mouse lung detects the ETS protein Ets-related molecule (ERM PEA3) in distal lung epithelium in alveolar type I and II cells, but not in bronchial epithelium or lung endothelial cells. We tested ERM and polyomavirus enhancer activator 3 (PEA3) for their ability to increase endogenous caveolin-1 transcripts and to activate caveolin-1 promoter fragments containing the -865 Ets cis-element. Chromatin immunoprecipitation (ChIP) assays show that both ERM and PEA3 bind to the caveolin-1 promoter in murine E10, but not MFLM-4, cells. Normalized luciferase activities show that only ERM activates the caveolin-1 promoter in E10 cells, but neither protein enhances promoter activity in MFLM-4 cells. Mutation of the Ets site blocks ERM-mediated promoter activation in E10 cells. Furthermore, overexpression of ERM increases the cellular content of caveolin-1 mRNA and protein, in E10, but not MFLM-4, cells. The effects of PEA3 on the cellular content of endogenous caveolin-1 expression are variable. These results demonstrate that ERM is involved in caveolin-1 regulation in a murine lung epithelial, but not lung endothelial cell line. We conclude that transcriptional regulation of caveolin-1 differs markedly between lung epithelial and endothelial cell lines, perhaps explaining why the onset of caveolin-1 expression differs in epithelial and endothelial cells during lung development.

    Title Angiotensin Converting Enzyme 2 is Primarily Epithelial and is Developmentally Regulated in the Mouse Lung.
    Date October 2007
    Journal Journal of Cellular Biochemistry
    Excerpt

    Angiotensin converting enzyme (ACE) 2 is a carboxypeptidase that shares 42% amino acid homology with ACE. Little is known about the regulation or pattern of expression of ACE2 in the mouse lung, including its definitive cellular distribution or developmental changes. Based on Northern blot and RT-PCR data, we report two distinct transcripts of ACE2 in the mouse lung and kidney and describe a 5' exon 1a previously unidentified in the mouse. Western blots show multiple isoforms of ACE2, with predominance of a 75-80 kDa protein in the mouse lung versus a 120 kDa form in the mouse kidney. Immunohistochemistry localizes ACE2 protein to Clara cells, type II cells, and endothelium and smooth muscle of small and medium vessels in the mouse lung. ACE2 mRNA levels peak at embryonic day 18.5 in the mouse lung, and immunostaining demonstrates protein primarily in the bronchiolar epithelium at that developmental time point. In murine cell lines ACE2 is strongly expressed in the Clara cell line mtCC, as opposed to the low mRNA expression detected in E10 (type I-like alveolar epithelial cell line), MLE-15 (type II alveolar epithelial cell line), MFLM-4 (fetal pulmonary vasculature cell line), and BUMPT-7 (renal proximal tubule cell line). In summary, murine pulmonary ACE2 appears to be primarily epithelial, is developmentally regulated, and has two transcripts that include a previously undescribed exon.

    Title Key Developmental Regulators Change During Hyperoxia-induced Injury and Recovery in Adult Mouse Lung.
    Date July 2007
    Journal Journal of Cellular Biochemistry
    Excerpt

    Developmentally important genes have recently been linked to tissue regeneration and epithelial cell repair in neonatal and adult animals in several organs, including liver, skin, prostate, and musculature. We hypothesized that developmentally important genes play roles in lung injury repair in adult mice. Although there is considerable information known about these processes, the specific molecular pathways that mediate injury and regulate tissue repair are not fully elucidated. Using a hyperoxic injury model to study these mechanisms of lung injury and tissue repair, we selected the following genes based upon their known or putative roles in lung development and organogenesis: TTF-1, FGF9, FGF10, BMP4, PDGF-A, VEGF, Ptc, Shh, Sca-1, BCRP, CD45, and Cyclin-D2. Our findings demonstrate that several developmentally important genes (Sca-1, Shh, PDGF-A, VEGF, BCRP, CD45, BMP4, and Cyclin-D2) change during hyperoxic injury and normoxic recovery in mice, suggesting that adult lung may reactivate key developmental regulatory pathways for tissue repair. The mRNA for one gene (TTF-1), unchanged during hyperoxia, was upregulated late in recovery phase. These novel findings provide the basis for testing the efficacy of post-injury lung repair in animals genetically modified to inactivate or express individual molecules.

    Title The Fema Gras Assessment of Aromatic Substituted Secondary Alcohols, Ketones, and Related Esters Used As Flavor Ingredients.
    Date March 2007
    Journal Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association
    Excerpt

    This publication is the 11th in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. The list of GRAS substances has now grown to more than 2100 substances. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. In this monograph, a detailed interpretation is presented on the renal carcinogenic potential of the aromatic secondary alcohol alpha-methylbenzyl alcohol, aromatic ketone benzophenone, and corresponding alcohol benzhydrol. The relevance of these effects to the flavor use of these substances is also discussed. The group of aromatic substituted secondary alcohols, ketones, and related esters was reaffirmed as GRAS (GRASr) based, in part, on their rapid absorption, metabolic detoxication, and excretion in humans and other animals; their low level of flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic and chronic studies and the lack of significant genotoxic and mutagenic potential.

    Title Single Dna Molecule Stretching Measures the Activity of Chemicals That Target the Hiv-1 Nucleocapsid Protein.
    Date December 2006
    Journal Analytical Biochemistry
    Excerpt

    We develop a biophysical method for investigating chemical compounds that target the nucleic acid chaperone activity of HIV-1 nucleocapsid protein (NCp7). We used an optical tweezers instrument to stretch single lambda-DNA molecules through the helix-coil transition in the presence of NCp7 and various chemical compounds. The change in the helix-coil transition width induced by wild-type NCp7 and its zinc finger variants correlates with in vitro nucleic acid chaperone activity measurements and in vivo assays. The compound-NC interaction measured here reduces NCp7's capability to alter the transition width. Purified compounds from the NCI Diversity set, 119889, 119911, and 119913 reduce the chaperone activity of 5 nM NC in aqueous solution at 10, 25, and 100 nM concentrations respectively. Similarly, gallein reduced the activity of 4 nM NC at 100 nM concentration. Further analysis allows us to dissect the impact of each compound on both sequence-specific and non-sequence-specific DNA binding of NC, two of the main components of NC's nucleic acid chaperone activity. These results suggest that DNA stretching experiments can be used to screen chemical compounds targeting NC proteins and to further explore the mechanisms by which these compounds interact with NC and alter its nucleic acid chaperone activity.

    Title Nucleic Acid Binding and Chaperone Properties of Hiv-1 Gag and Nucleocapsid Proteins.
    Date February 2006
    Journal Nucleic Acids Research
    Excerpt

    The Gag polyprotein of HIV-1 is essential for retroviral replication and packaging. The nucleocapsid (NC) protein is the primary region for the interaction of Gag with nucleic acids. In this study, we examine the interactions of Gag and its NC cleavage products (NCp15, NCp9 and NCp7) with nucleic acids using solution and single molecule experiments. The NC cleavage products bound DNA with comparable affinity and strongly destabilized the DNA duplex. In contrast, the binding constant of Gag to DNA was found to be approximately 10-fold higher than that of the NC proteins, and its destabilizing effect on dsDNA was negligible. These findings are consistent with the primary function of Gag as a nucleic acid binding and packaging protein and the primary function of the NC proteins as nucleic acid chaperones. Also, our results suggest that NCp7's capability for fast sequence-nonspecific nucleic acid duplex destabilization, as well as its ability to facilitate nucleic acid strand annealing by inducing electrostatic attraction between strands, likely optimize the fully processed NC protein to facilitate complex nucleic acid secondary structure rearrangements. In contrast, Gag's stronger DNA binding and aggregation capabilities likely make it an effective chaperone for processes that do not require significant duplex destabilization.

    Title Ultrastructural Evaluation of the Apical Seal in Roots Filled with a Polycaprolactone-based Root Canal Filling Material.
    Date October 2005
    Journal Journal of Endodontics
    Excerpt

    This in vitro study compared the ultrastructural quality of the apical seal achieved with Resilon/Epiphany and gutta-percha/AH Plus. Single-rooted extracted human teeth were prepared using a crown-down technique, debrided with NaOCl and EDTA, and obturated with either Resilon/Epiphany or gutta-percha/AH Plus. They were examined for gaps along canal walls using SEM, and for apical leakage using a transmission electron microscopy (TEM). SEM revealed both gap-free regions, and gap-containing regions in canals filled with both materials. TEM revealed the presence of silver deposits along the sealer-hybrid layer interface in Resilon/Epiphany, and between the sealer and gutta-percha in the controls. It is concluded that a complete hermetic apical seal cannot be achieved with either root filling materials.

    Title Susceptibility of a Polycaprolactone-based Root Canal Filling Material to Degradation. I. Alkaline Hydrolysis.
    Date September 2005
    Journal Journal of Endodontics
    Excerpt

    Polycaprolactone, a thermoplastic aliphatic polyester, is reportedly susceptible to both alkaline and enzymatic hydrolyzes. This screening study examined the susceptibility of Resilon, a polycaprolactone-based root filling composite, to alkaline hydrolysis. There were 15-mm diameter disks of Resilon and Obtura gutta-percha prepared by compressive molding and immersed in 20% sodium ethoxide for 20 or 60 min. Control disks were immersed in ethanol for 60 min. These disks were examined using field-emission scanning electron microscopy and energy dispersive X-ray analysis. For Resilon, the surface resinous component was hydrolyzed after 20 min of sodium ethoxide immersion, exposing the spherulitic polymer structure and subsurface glass and bismuth oxychloride fillers. More severe erosion occurred after 60 min of sodium ethoxide treatment. Gutta-percha was unaffected after immersion in sodium ethoxide. As Resilon is susceptible to alkaline hydrolysis, it is possible that enzymatic hydrolysis may occur. Biodegradation of Resilon by bacterial/salivary enzymes and endodontically relevant bacteria warrants further investigation.

    Title Transplant Data: Sources, Collection, and Caveats.
    Date August 2004
    Journal American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
    Excerpt

    By examining the sources, quality and organization of transplant data available, as well as making observations about data reporting patterns and accuracy, we hope to improve understanding of existing results, help researchers with study design and stimulate new exploratory initiatives. The primary data source, collected by the OPTN, has benefited from extensive recent technological advances. Transplant professionals now report patient and donor data more easily, quickly, and accurately, improving data timeliness and precision. Secondary sources may be incorporated, improving the accuracy and expanding the scope of analyses. For example, auxiliary mortality data allows more accurate survival analysis and conclusions regarding the completeness of center-reported post-transplant follow-up. Furthermore, such sources enable examination of outcomes not reported by centers, such as mortality after waiting list removal, providing more appropriate comparisons of waiting list and post-transplant mortality. Complex collection and reporting processes require specific analytical methods and may lead to potential pitfalls. Patterns in the timing of reporting adverse events differ from those for 'positive' events, yielding the need for care in choosing cohorts and censor dates to avoid bias. These choices are further complicated by the use of multiple sources of data, with different time lags and reporting patterns.

    Title Transcription of the Caveolin-1 Gene is Differentially Regulated in Lung Type I Epithelial and Endothelial Cell Lines. A Role for Ets Proteins in Epithelial Cell Expression.
    Date August 2004
    Journal The Journal of Biological Chemistry
    Excerpt

    In the lung, caveolin-1 is expressed in both type I alveolar epithelial and endothelial cells where it is hypothesized to modulate molecular signaling activities and progression of tumorigenesis. Developmentally, caveolin-1alpha is expressed in fetal lung endothelial, but not epithelial, cells; in adult lung, both cell types express caveolin-1alpha. To test the hypothesis that caveolin-1 transcription is differentially regulated in type I and endothelial cells, we characterized the proximal promoter of the mouse caveolin-1 gene in lung cell lines to identify factors that control its cell-specific expression. We show that caveolin-1 expression is regulated by an Ets cis-element in a lung epithelial cell line, but not a lung endothelial cell line, and that three ETS family members, ETS-1, PEA3, and ERM, recognize and bind the Ets site in the epithelial cell line. Based on these findings, we have identified the Ets cis-element as a region that accounts for differential transcriptional regulation of caveolin-1 in lung epithelial and endothelial cells.

    Title The Organ Center of the United Network for Organ Sharing and Twenty Years of Organ Sharing in the United States.
    Date April 2004
    Journal Transplantation
    Excerpt

    The increasing size of the transplant waiting list and the increasing use of expanded criteria donors places a premium on efficient use of recovered organs. Maximal organ utilization often necessitates organ sharing between transplant organizations. Optimal organ sharing requires rapid, integrated communication of donor information combined with expedited organ transportation. For more than 20 years, the United Network for Organ Sharing's Organ Center has fulfilled this task for the United States transplant community. This overview details a brief history of United States organ sharing and the role played by the Organ Center. The current scope and modes of Organ Center operations are detailed.

    Title T1alpha, a Lung Type I Cell Differentiation Gene, is Required for Normal Lung Cell Proliferation and Alveolus Formation at Birth.
    Date May 2003
    Journal Developmental Biology
    Excerpt

    T1alpha, a differentiation gene of lung alveolar epithelial type I cells, is developmentally regulated and encodes an apical membrane protein of unknown function. Morphological differentiation of type I cells to form the air-blood barrier starts in the last few days of gestation and continues postnatally. Although T1alpha is expressed in the foregut endoderm before the lung buds, T1alpha mRNA and protein levels increase substantially in late fetuses when expression is restricted to alveolar type I cells. We generated T1alpha null mutant mice to study the role of T1alpha in lung development and differentiation and to gain insight into its potential function. Homozygous null mice die at birth of respiratory failure, and their lungs cannot be inflated to normal volumes. Distal lung morphology is altered. In the absence of T1alpha protein, type I cell differentiation is blocked, as indicated by smaller airspaces, many fewer attenuated type I cells, and reduced levels of aquaporin-5 mRNA and protein, a type I cell water channel. Abundant secreted surfactant in the narrowed airspaces, normal levels of surfactant protein mRNAs, and normal patterns and numbers of cells expressing surfactant protein-B suggest that differentiation of type II cells, also alveolar epithelial cells, is normal. Anomalous proliferation of the mesenchyme and epithelium at birth with unchanged numbers of apoptotic cells suggests that loss of T1alpha and/or abnormal morphogenesis of type I cells alter the proliferation rate of distal lung cells, probably by disruption of epithelial-mesenchymal signaling.

    Title Dose Variation That is Associated with Approximated One-quarter Tablet Doses of Misoprostol.
    Date October 2002
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: The purpose of this study was to evaluate dose variation in approximated one-quarter tablet misoprostol fragments. STUDY DESIGN: Misoprostol 100 microg tablets were weighed, separated into two lots, and quartered with a razor blade or a pill cutter. Fragments were reweighed, and the misoprostol content was determined by high-performance liquid chromatography mass spectroscopy. RESULTS: Fragment weights varied more when a pill cutter was used (P <.0001). Fewer pill-cutter fragments than razor-cut fragments weighed within 10% of expected (24% vs 65%, P <.0001). Misoprostol content among the fragments that were determined by high-performance liquid chromatography mass spectroscopy was 103% +/- 12% of expected (range, 73%-124%). Tablet fragments that weighed >or=27.5 mg contained misoprostol in excess of 110% of expected in seven of eight fragments, although none from fragments that weighed <or=26.5 mg did. Misoprostol was evenly distributed in all fragments that were assayed. CONCLUSION: Misoprostol is evenly distributed among tablet fragments. Accurate low-dose misoprostol cervical ripening is possible if the tablet fragments are individually weighed.

    Title Mycobacterium Tuberculosis: an Emerging Disease of Free-ranging Wildlife.
    Date July 2002
    Journal Emerging Infectious Diseases
    Excerpt

    Expansion of ecotourism-based industries, changes in land-use practices, and escalating competition for resources have increased contact between free-ranging wildlife and humans. Although human presence in wildlife areas may provide an important economic benefit through ecotourism, exposure to human pathogens may represent a health risk for wildlife. This report is the first to document introduction of a primary human pathogen into free-ranging wildlife. We describe outbreaks of Mycobacterium tuberculosis, a human pathogen, in free-ranging banded mongooses (Mungos mungo) in Botswana and suricates (Suricata suricatta) in South Africa. Wildlife managers and scientists must address the potential threat that humans pose to the health of free-ranging wildlife.

    Title Bone Marrow-derived Cells As Progenitors of Lung Alveolar Epithelium.
    Date February 2002
    Journal Development (cambridge, England)
    Excerpt

    We assessed the capacity of plastic-adherent cultured bone marrow cells to serve as precursors of differentiated parenchymal cells of the lung. By intravenously delivering lacZ-labeled cells into wild-type recipient mice after bleomycin-induced lung injury, we detected marrow-derived cells engrafted in recipient lung parenchyma as cells with the morphological and molecular phenotype of type I pneumocytes of the alveolar epithelium. At no time after marrow cell injection, did we detect any engraftment as type II pneumocytes. In addition, we found that cultured and fresh aspirates of bone marrow cells can express the type I pneumocyte markers, T1alpha and aquaporin-5. These observations challenge the current belief that adult alveolar type I epithelial cells invariably arise from local precursor cells and raise the possibility of using injected marrow-derived cells for therapy of lung diseases characterized by extensive alveolar damage.

    Title Fetal Abdominal Circumference Measurements of 35 and 38 Cm As Predictors of Macrosomia. A Risk Factor for Shoulder Dystocia.
    Date February 2001
    Journal The Journal of Reproductive Medicine
    Excerpt

    To determine if ultrasound measurements of fetal abdominal circumference (AC) can be used to predict macrosomic infants.

    Title Histologic Chorioamnionitis is Associated with Fetal Growth Restriction in Term and Preterm Infants.
    Date December 2000
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Our aim was to evaluate associations between chorioamnionitis and fetal growth restriction in infants enrolled in the Collaborative Perinatal Project. STUDY DESIGN: A total of 2579 nonanomalous, singleton infants delivered at 28 to 44 weeks' gestation with chorioamnionitis were matched 1:3 for ethnicity, gestational age, parity, and maternal cigarette use (all of which were correlated with both chorioamnionitis and markers of fetal growth restriction) with 7732 control infants. Moderate or marked leukocytic infiltrates of the placenta defined chorioamnionitis. Birth weight, length, head circumference, weight/length ratio, ponderal index, and birth weight/head circumference ratio in the lowest 5th percentile were markers of fetal growth restriction. Placental weight and the birth weight/placental weight ratio were also evaluated. RESULTS: Compared with data on matched control infants, histologic chorioamnionitis was associated with all markers of fetal growth restriction and with low birth weight/placental weight ratios (odds ratios, 1.3-1.7). The strongest associations were found at 28 to 32 weeks' gestation (odds ratios, 2.2-11). Attributable risks for several markers of fetal growth restriction exceeded 50% in infants born at <33 weeks' gestation. CONCLUSION: Histologic chorioamnionitis is associated with multiple markers of fetal growth restriction, with stronger associations noted in prematurity.

    Title Hormonal Modulation of Ishikawa Cells During Three-dimensional Growth in Vitro.
    Date October 1998
    Journal Journal of the Society for Gynecologic Investigation
    Excerpt

    The Ishikawa endometrial cancer cell line is hormonally responsive, expressing estrogen and progesterone receptors (ER, PR) when grown in traditional monolayer culture. The purpose of this paper is to demonstrate a three-dimensional spheroid culture system for cancer cells. We used this system to determine the response of the Ishikawa cell line to estradiol-17 beta (E), tamoxifen (T), megestrol acetate (MA), and progesterone (P).

    Title Modulation of T1alpha Expression with Alveolar Epithelial Cell Phenotype in Vitro.
    Date August 1998
    Journal The American Journal of Physiology
    Excerpt

    T1alpha is a recently identified gene expressed in the adult rat lung by alveolar type I (AT1) epithelial cells but not by alveolar type II (AT2) epithelial cells. We evaluated the effects of modulating alveolar epithelial cell (AEC) phenotype in vitro on T1alpha expression using either soluble factors or changes in cell shape to influence phenotype. For studies on the effects of soluble factors on T1alpha expression, rat AT2 cells were grown on polycarbonate filters in serum-free medium (MDSF) or in MDSF supplemented with either bovine serum (BS, 10%), rat serum (RS, 5%), or keratinocyte growth factor (KGF, 10 ng/ml) from either day 0 or day 4 through day 8 in culture. For studies on the effects of cell shape on T1alpha expression, AT2 cells were plated on thick collagen gels in MDSF supplemented with BS. Gels were detached on either day 1 (DG1) or day 4 (DG4) or were left attached until day 8. RNA and protein were harvested at intervals between days 1 and 8 in culture, and T1alpha expression was quantified by Northern and Western blotting, respectively. Expression of T1alpha progressively increases in AEC grown in MDSF +/- BS between day 1 and day 8 in culture, consistent with transition toward an AT1 cell phenotype. Exposure to RS or KGF from day 0 prevents the increase in T1alpha expression on day 8, whereas addition of either factor from day 4 through day 8 reverses the increase. AEC cultured on attached gels express high levels of T1alpha on days 4 and 8. T1alpha expression is markedly inhibited in both DG1 and DG4 cultures, consistent with both inhibition and reversal of the transition toward the AT1 cell phenotype. These results demonstrate that both soluble factors and alterations in cell shape modulate T1alpha expression in parallel with AEC phenotype and provide further support for the concept that transdifferentiation between AT2 and AT1 cell phenotypes is at least partially reversible.

    Title Low Weight/length Ratio to Assess Risk of Cerebral Palsy and Perinatal Mortality in Twins.
    Date June 1998
    Journal American Journal of Perinatology
    Excerpt

    The etiology of increased rates of cerebral palsy (CP) in twins is unclear, but likely is associated with growth retardation, which occurs more often in twins. Asymmetric growth restriction, a form of growth retardation, has been found associated with increased rates of perinatal morbidity in infants with normal centile birthweights, and occurs more often in twins. Data from 55,457 infants were evaluated. Associations between twinning, CP, and neonatal mortality were evaluated. Influences of confounding factors, such as prematurity, perinatal depression, and asymmetric growth were assessed. Although twinning was a significant univariate correlate of both CP and neonatal mortality, low weight/length ratio (a marker of asymmetric growth) was a better correlate of both outcomes, and twinning was not significantly associated with either outcome after logistic adjustment for factors such as prematurity, perinatal depression, and low weight/length ratio. Low weight/length ratio occurred more often in twins of advancing gestational age, supporting a hypothesis of competition for nutritional resources as the cause for increased rates of low weight/length ratio in twins as compared with singletons. Asymmetric growth restriction is an important correlate of neonatal morbidity in twins, and should be considered when these factors are assessed in infants from multiple gestations.

    Title Persistent Pulmonary Hypertension of the Neonate and Asymmetric Growth Restriction.
    Date March 1998
    Journal Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: To evaluate the possible associations between persistent pulmonary hypertension of the neonate, need for extra-corporeal membranous oxygenation, small for gestational age (SGA), and low ponderal index for gestational age in infants with persistent pulmonary hypertension of the neonate and in matched controls. METHODS: Eighty-six infants with persistent pulmonary hypertension of the neonate delivered from 1991 to 1994 at our hospital were matched with 430 contemporaneous control singleton neonates. Birth weight and ponderal indices (100 x weight/length3) less than the tenth percentile for gestational age and gender were defined as SGA and low ponderal index, respectively. We assessed associations between these markers, the presence of persistent pulmonary hypertension of the neonate, and the need for extracorporeal membranous oxygenation. RESULTS: Low ponderal index was associated with persistent pulmonary hypertension of the neonate (odds ratio [OR] 5.4), whereas SGA was not. Low ponderal index (OR 4.0) was an independent correlate of persistent pulmonary hypertension of the neonate after adjustment with logistic regression for 5-minute Apgar scores less than 7, umbilical arterial pH less than 7.10, and presence of meconium. Low ponderal index was associated with need for extracorporeal membranous oxygenation in neonates with persistent pulmonary hypertension (P < .001). CONCLUSION: Fetal developmental events may significantly affect neonatal pulmonary status. Diminished neonatal nutritional status, as measured by low ponderal index for gestational age, is associated with increased risk of persistent pulmonary hypertension of the neonate and severity of the disease process.

    Title Twins, Asymmetric Growth Restriction, and Perinatal Morbidity.
    Date March 1998
    Journal Journal of Perinatology : Official Journal of the California Perinatal Association
    Excerpt

    OBJECTIVE: Our objective in this study was to evaluate decreased weight/length ratio as a correlate of perinatal morbidity in twins. STUDY DESIGN: Rates of weight/length ratio less than 10% (low WL) were compared in 986 neonates from twin gestations and 4929 matched singletons. Low WL was compared with birth weight less than 10% (SGA) and 25% birth weight discordance as a marker for perinatal depression and neonatal mortality. RESULTS: Both SGA (42% vs 8%) and low WL (38% vs 8%) occurred more commonly in twins. Low WL was a better correlate of depression and mortality than SGA or 25% birth weight discordance. After adjustment for major anomalies, prematurity, and low WL, perinatal morbidity in twins and singletons did not differ. CONCLUSIONS: Low WL, a marker of asymmetric growth restriction, is a better marker for perinatal morbidity in twins than SGA or 25% discordance. Twins and singletons have similar rates of perinatal morbidity and mortality after adjustment for anomalies, prematurity, and growth restriction.

    Title Modulators of Prostaglandin E2 Synthesis in Human Amnion.
    Date February 1998
    Journal Journal of the Society for Gynecologic Investigation
    Excerpt

    OBJECTIVE: The purpose of these studies was to determine the effects of the essential fatty acid, linoleic acid, and the commonly used non-steroidal anti-inflammatory agents, aspirin and acetaminophen, on the rate of prostaglandin (PG) biosynthesis by human amnion cells. METHODS: Amnion cells were isolated from term, normal pregnancies and grown to confluence. Cells were incubated with control or medium containing 100 mumol/L linoleic acid. Cells were also incubated with control medium or medium containing 10 or 100 micrograms/mL aspirin or acetaminophen. RESULTS: Following an initial delay, amnion cells exposed to linoleic acid exhibited a significant increase in PGE synthesis. Both aspirin and acetaminophen in clinically relevant concentrations had a significant inhibitory effect on amnion cell PGE synthesis. CONCLUSIONS: Linoleic acid has a stimulatory effect and aspirin and acetaminophen have an inhibitory effect on PGE synthesis in human amnion cells in culture. We speculate that dietary habits, supplement ingestion, and over-the-counter drug use may affect amnion cell PG production. In view of the potential importance of intrauterine PG production in normal and abnormal labor, further study in this area is indicated.

    Title A Comparison of Birth Weight and Weight/length Ratio for Gestation As Correlates of Perinatal Morbidity.
    Date December 1997
    Journal Journal of Perinatology : Official Journal of the California Perinatal Association
    Excerpt

    OBJECTIVE: The purpose was to evaluate a low weight to length ratio as a correlate of perinatal morbidity and mortality. STUDY DESIGN: Data from the Collaborative Perinatal Project for infants of 34 weeks' gestation or more were evaluated. Associations between the weight to length ratio of < 10% (low weight to length) and birth weight of < 10% (small for gestational age) by gestational age and gender, perinatal depression, dysmaturity, cerebral palsy, and neonatal mortality were evaluated. RESULTS: A low weight to length ratio and small for gestational age status were associated with most markers of perinatal morbidity and mortality in term and preterm infants. In infants not small for gestational age, a low weight to length ratio was associated with increased morbidity and mortality (relative risk of 1.9 to 4.2) in term infants, and with perinatal depression (relative risk of 2.9) in preterm infants. Logistic regression found low weight to length ratio was a better independent correlate than small for gestational age status for all markers assessed and found low weight to length ratio was significantly associated with all morbidity and mortality markers in infants not small for gestational age. CONCLUSION: Low weight to length ratio, a marker for asymmetric growth restriction, is correlated with perinatal morbidity, even in infants not small for gestational age.

    Title The Value of the Cervical Score in Predicting Successful Outcome of Labor Induction.
    Date November 1997
    Journal Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: To compare cervical dilation and the Bishop score as correlates of successful labor induction and vaginal delivery and to determine whether the prognosis of post-ripening cervical characteristics varies with the method of ripening used. METHODS: Four hundred forty-three women with Bishop scores less than 9 who required induction of labor were assigned randomly to cervical ripening with prostaglandin E2 gel or hygroscopic dilation. The Bishop score and its component characteristics were evaluated as univariate correlates of successful induction of labor and vaginal delivery and then were assessed using logistic regression to adjust for other maternal and fetal factors. The differences in the association between method of ripening and successful labor induction were evaluated relative to pre-ripening and post-ripening cervical examination characteristics. RESULTS: Cervical dilation was a better correlate of successful labor induction and vaginal delivery than was the Bishop score, even after exclusion of patients with initial Bishop scores greater than 6 and dilation greater than 3.0. Both ripening methods yielded similar success in labor induction and vaginal delivery, but when categorized by post-ripening cervical examinations, patients undergoing hygroscopic ripening had lower rates of successful labor induction and vaginal delivery. CONCLUSION: Cervical dilation is a better predictor of successful labor induction and vaginal delivery than either the Bishop score or any other Bishop score component characteristic. The likelihood of successful labor induction and vaginal delivery based on post-ripening cervical characteristics varies by the ripening method used.

    Title Cerebral Palsy in Infants with Asymmetric Growth Restriction.
    Date September 1997
    Journal American Journal of Perinatology
    Excerpt

    The relationship between low ponderal index and cerebral palsy was evaluated. National Collaborative Perinatal Project and University of California Child Health and Development Study data were analyzed. Associations between low ponderal index (ponderal index < 5% for gestational age) were evaluated in the combined population, in term and preterm infants, and in non-SGA infants (with birth weights > 5% for gestational age and gender). Data from 55,571 infants, including 232 cases of cerebral palsy, were evaluated. Low ponderal index was significantly associated with CP in the delivery population (Relative risk 2.2) and in non-SGA infants (RR 1.9). Low ponderal index was a significant independent correlate of cerebral palsy (RR 1.9) in non-SGA infants after using logistic regression to correct for effects of prematurity and gender. Low ponderal index is associated with increased risk of CP, even in non-SGA infants. Assessment of the neonatal ponderal index provides an additional method of documenting prior abnormal fetal growth and development.

    Title Simultaneous in Situ Hybridization and Tunel to Identify Cells Undergoing Apoptosis.
    Date September 1997
    Journal The Histochemical Journal
    Excerpt

    Apoptotic cells in tissue sections can be localized by in situ labelling of partly degraded DNA. In a heterogeneous population of cells, however, the specific identity of cell types undergoing apoptosis often cannot be reliably achieved at the light microscope level because of the marked alterations in cellular morphology that characterize apoptosis. In order to clearly specify cell types undergoing apoptosis, in situ end labelling has been coupled to immunohistochemistry. This method is limited by the availability of antibodies that bind to cell-specific protein markers in tissue sections. In contrast, we describe a method that combines in situ end labellin with in situ hybridization, a technique that specifies cell types based on mRNA expression. Taking advantage of the specific expression of surfactant protein C mRNA in type II alveolar epithelial cells, we demonstrate that this technique has the ability to localize alveolar type II cells undergoing apoptosis in vivo after the intratracheal instillation of an antibody that activates the cell surface Fas protein. The wide availability of cell-specific gene markers suggests that this method can be adapted to define cell types that undergo apoptosis during various physiological and pathological states in vivo.

    Title Fas Expression in Pulmonary Alveolar Type Ii Cells.
    Date September 1997
    Journal The American Journal of Physiology
    Excerpt

    Fas, a type I membrane receptor protein, transduces a signal culminating in apoptosis after binding to the Fas ligand. Information regarding the expression of Fas in nonlymphoid tissues, although limited, suggests a role for Fas in epithelial progenitor cell populations. In this paper, we provide several lines of evidence indicating that the progenitor cell of the alveolus, the type II cell, displays restricted expression of Fas. We found 1) Fas gene expression in RNA derived from fresh isolates of primary rat type II cells; 2) restriction of Fas expression to a subset of alveolar type II cells by in situ hybridization and immunohistochemistry of the normal mouse lung; 3) induction of apoptosis in a mouse lung type II epithelial cell line (MLE) after activation of Fas; and 4) induction of apoptosis in a subpopulation of type II cells after the intratracheal instillation of an activating anti-Fas antibody in mice. These findings suggest that Fas-dependent apoptosis is involved in regulating turnover of the alveolar epithelium.

    Title Factorial Structure of the Wisconsin Card Sorting Test.
    Date August 1997
    Journal The British Journal of Clinical Psychology / the British Psychological Society
    Excerpt

    This study examined the factorial structure of the Wisconsin Card Sorting Test (WCST) in normal university students (N = 135) and a mixed clinical sample (N = 139). Two highly stable orthogonal factors were observed accounting for 70 and 21 per cent of the variance, respectively. Factor I was interpreted as reflecting undifferentiated executive function while Factor II may measure cognitive abilities associated with attentional function. This work can serve as the basis for further examination of the construct validity of the WCST and has implications for its use.

    Title Retinoic Acid Alters the Expression of Pattern-related Genes in the Developing Rat Lung.
    Date May 1997
    Journal Developmental Dynamics : an Official Publication of the American Association of Anatomists
    Excerpt

    Exogenous retinoids alter pattern formation and differentiation in many developing systems, such as limb, vertebrae, and central nervous system. Many of these effects are mediated by changes in expression of patterning genes such as Hox genes and Sonic hedgehog. We have previously shown that exogenous retinoic acid, administered to the embryonic rat lung in culture alters the structural pattern of the developing lung, suppressing formation of distal lung and favoring growth of proximal tubules. To determine whether these retinoic acid-induced changes in lung development were linked to alterations in pattern-related genes, we characterized the expression of Hoxa-2, Hoxb-6, and Sonic hedgehog mRNAs in vivo and in vitro, with or without 10(-5)M retinoic acid, by in situ hybridization and quantitative polymerase chain reaction. Each of these genes demonstrated unique timing and distribution of expression that was similar in vivo and in control cultured embryonic lungs. Hoxb-6 and Sonic hedgehog mRNAs both decreased during lung development in vivo or in vitro. From the patterns of mRNA expression we propose that Hoxb-6 is involved in distal airway branching while Hoxa-2 is involved in differentiation of proximal mesenchymal derivatives and vasculogenesis in the lung. RA upregulated all three genes, changing their developmental pattern of distribution and preventing the developmental decrease in Sonic hedgehog expression. We propose that RA acts to maintain high levels of expression of these and likely other pattern-related genes in a fashion that is characteristic of the immature lung, promoting continued formation of proximal lung structures and preventing formation of typical distal lung structures of the mature lung.

    Title Stem Cells in Lung Development, Disease, and Therapy.
    Date April 1997
    Journal American Journal of Respiratory Cell and Molecular Biology
    Title Type I Receptor Serine-threonine Kinase Preferentially Expressed in Pulmonary Blood Vessels.
    Date November 1996
    Journal The American Journal of Physiology
    Excerpt

    Type II and type I receptor serine-threonine kinases (RSTK) are important components of the transmembrane signaling machinery that allow cells to respond to the transforming growth factor-beta (TGF-beta) superfamily of cytokines. We have cloned from rat lung and report here a 3,935-base pair (bp) cDNA encoding a type I RSTK previously identified as R-3 (rat) or ALK-1 (human). Northern blot analysis reveals that the R-3 mRNA is more abundant in lung than in other adult rat tissues. With the use of in situ hybridization, the R-3 transcripts are found exclusively in the pulmonary vessels of all sizes, as well as in aorta, vena cava, and certain blood vessels of kidney, spleen, heart and intestine. In most blood vessels, a higher level of gene expression is found in endothelium than in adjacent smooth muscle. The R-3 transcripts are also found in splenic macrophages, as well as within cells of marginal zone of the splenic lymphoid tissue. In fetal rat lung, the expression of R-3 transcripts differs from the expression patterns of two other type 1 RSTK. The R-3 is expressed in vessels; the activin type IB receptor (R-2) is preferentially expressed in putative developing airways, whereas the TGF-beta type I receptor (R-4) transcripts appear to be ubiquitous. Our data suggest that in vivo R-3 may propagate signaling of TGF-beta in selected cell types. The differential expression of multiple type I receptors within different cell lineages may therefore define cell specific responses to TGF-beta.

    Title Epithelial Marker Genes Are Expressed in Cultured Embryonic Rat Lung and in Vivo with Similar Spatial and Temporal Patterns.
    Date November 1996
    Journal The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society
    Excerpt

    Explants of embryonic lung are often used to characterize lung growth, bronchial tree pattern, and cell differentiation. Most investigators culture lungs for 3-7 days in defined media lacking, e.g., added growth factors or hormones. If growth and differentiation are comparable to that in vivo, these cultures show considerable promise for identifying developmental regulatory molecules and target genes, and for elucidating molecular responses. We used in situ hybridization and RT-PCR to compare times and sites of expression of mRNAs of six epithelial genes in cultured and uncultured fetal rat lungs. These genes, expressed in distal lung of adult rats, are surfactant proteins (SP) A, B, and C; LAR, a receptor-type tyrosine phosphatase; Clara cell secretory protein (CC10, CCSP); and T1alpha. SP-A, SF-B, LAR, and CC10 are expressed by both Clara and Type II cells in adult animals. SP-C and T1alpha are unique markers for Type II and Type I cells, respectively. SP-C, LAR, and T1alpha are expressed before the lung is explanted (Day 13.5); SP-A, -B, and CC10 mRNAs are first detected later. The onset of expression is similar in vivo and in vitro. Although the patterns of expression differ for each mRNA, their sites of expression in culture match those in vivo relative to the bronchial tree. The explanted embryonic lung appears to be an excellent experimental model.

    Title On a Failure to Replicate: Methodologically Close, but Not Close Enough. A Response to Hogben Et Al.
    Date October 1996
    Journal Vision Research
    Excerpt

    Williams, Brannan and Lartigue (1987) (Clinical Vision Science, 1, 367-371) reported that poor readers took significantly longer to search letter arrays for a target than did good readers. In addition, they reported that blurring the letter arrays leads to faster search times for poor readers and a loss of the significant differences between the groups seen with unblurred displays. In a recent attempt to replicate these findings, Hogben et al. (1996) (Vision Research, 36, 1503-1507) found no differences in search rates between good and poor readers using unblurred arrays, and no differences in search rate between the groups when blurred arrays were used. In the present article, we have compared these two research efforts, and a third paper on the same topic, with regard to methodological factors in an attempt to understand how these two different results could occur. It is our belief that the letter spacing employed in the two studies may account for the difference and should be the focus of future studies of the original effect.

    Title Cerebral Palsy, Perinatal Depression and Low Ponderal Index.
    Date September 1996
    Journal Developmental Medicine and Child Neurology
    Excerpt

    To determine whether asymmetric growth restriction, abnormally lean body morphology, is associated with cerebral palsy (CP) in infants born with perinatal depression, perinatally depressed Collaborative Perinatal Project infants were assessed. Rates of ponderal index less than 5% for gestational age and race (low PI), a marker for asymmetric growth, were compared in infants either neurologically normal or having CP at 7 years of age. Low PI was associated with CP in infants with Apgar scores of 0 to 3 at 10, 15 or 20 minutes in both of these groups, after exclusion of small-for-gestational-age infants, and was a significant individual correlate of cerebral palsy with multiple logistic regression. The attributable risk of cerebral palsy related to low Pl was 12.4%.

    Title Two Closely Related Receptor-type Tyrosine Phosphatases Are Differentially Expressed During Rat Lung Development.
    Date March 1996
    Journal Developmental Dynamics : an Official Publication of the American Association of Anatomists
    Excerpt

    Transmembrane protein tyrosine phosphatases (PTPases) comprise a newly identified class of receptor-like molecules. In most cases their ligands and the substrates they dephosphorylate are not known. In order to begin to explore the functions of the PTPases in cell physiology and in mammalian development, we examined the expression patterns of two closely related receptor-type tyrosine phosphatase genes, namely LAR and PTP delta, in fetal rat lung and in selected adult rat tissues. In the lung, in situ hybridization and immunohistochemistry show that the LAR mRNA and protein are expressed exclusively in the epithelium. In the early embryonic or fetal lung (day 13 to 18) LAR is expressed by all of the epithelial cells of the forming bronchial tree. This widespread pattern of expression is lost later in fetal life (day 21) as the lung matures and acquires the morphologic and biochemical features of the adult organ. LAR gene expression is then confined to two epithelial progenitor cells of the distal airways, namely the bronchiolar Clara cell and the alveolar type II cell. The LAR gene products were also found abundantly expressed in epithelial progenitor cells of adult esophagus, skin, and small intestine, all of which are continuously renewing epithelia. The rat PTP delta gene, on the other hand, is specifically expressed in the mesenchyme of the developing lung. The level of the PTP delta mRNA decreases as the lung matures. These results suggest that the two closely related receptor-type tyrosine phosphatases are differentially expressed in a tissue-specific fashion. They are expressed mostly in proliferating cells or in cells which have potential to proliferate.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Expression of Insulin-like Growth Factor Receptors 1 and 2 in the Developing Lung and Their Relation to Epithelial Cell Differentiation.
    Date October 1995
    Journal American Journal of Respiratory Cell and Molecular Biology
    Excerpt

    Insulin-like growth factors (IGFs) and their receptors have been implicated as regulators of cell differentiation and cell proliferation in a number of systems and have been shown to play an important role in embryonic development. In this study we examined expression of mRNA for IGF-I and IGF-II, IGF binding protein 2 (IGFBP-2), and IGF receptors 1 (IGFR-1) and 2 (IGFR-2) during fetal lung development and in early postnatal and adult lungs by the polymerase chain reaction (PCR). IGF-I mRNA was found in embryonic and postnatal lungs at all ages as was IGFBP-2, whereas IGF-II mRNA was present only in prenatal lungs. IGFR-1 was present in all but the adult lungs. Lung epithelial cells expressed IGFR-1 at 14 days' gestation but not at 18 days' gestation as measured by PCR and in situ hybridization. Alveolar epithelial cells re-expressed IGFR-1 mRNA in the early postnatal period but not in the adult lung. IGFR-2 was expressed by PCR and in situ hybridization in 14-day embryonic epithelium, was not present at 18 days or at birth, but was re-expressed at high levels in the early postnatal alveolar wall. Immunocytochemical localization of IGFR-2 confirmed its absence in the late fetal and newborn lung. It reappeared in alveoli, exclusively in type 1 cells, in early postnatal and adult lungs. These studies demonstrate the stage- and cell-specific appearance of IGF receptors in the developing and postnatal lung. They also establish IGFR-2 as a marker of the mature alveolar type 1 cell.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title The Effect of Sample Preparation and Storage on Maternal Triple-marker Screening.
    Date July 1995
    Journal Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: To evaluate the effect of different sample collection, storage, and preparation techniques on serum alpha-fetoprotein (AFP), beta-hCG, and unconjugated estriol (E3) concentrations. METHODS: A solution containing known concentrations of AFP, hCG, and unconjugated E3 was diluted in blood samples obtained from seven healthy male volunteers. Serum from each blood sample was removed immediately, and either assayed or frozen at -70C. Portions of the remaining blood were handled as follows: centrifuged and refrigerated, centrifuged and left at room temperature, not centrifuged and refrigerated, or not centrifuged and left at room temperature. Serum was removed from these samples for triple-marker analysis at 24, 48, 96, and 168 hours after the initial sample collection. RESULTS: Immediate freezing of serum and subsequent thawing resulted in a significant increase in beta-hCG and unconjugated E3 levels, but no change in AFP levels. There was a significant effect over time on AFP, hCG, and unconjugated E3 concentrations. The change in AFP levels was influenced by centrifugation status, whereas all three analytes were influenced by refrigeration status. CONCLUSION: Different sample collection, storage, and preparation techniques may affect maternal triple-marker screening.

    Title Retinoic Acid Induces Changes in the Pattern of Airway Branching and Alters Epithelial Cell Differentiation in the Developing Lung in Vitro.
    Date June 1995
    Journal American Journal of Respiratory Cell and Molecular Biology
    Excerpt

    Retinoids have been shown to influence pattern formation during development and regeneration in numerous systems such as limbs, vertebrae, and neural tube although there is little information about the effects of retinoids on pattern formation in visceral organs. We investigated the effects of exogenous retinoic acid on the in vitro pattern of airway branching and on lung epithelial cell differentiation. Histology, [3H]thymidine autoradiographies and reverse transcriptase/polymerase chain reaction (RT/PCR) amplification were used to assess the effects of retinoids and the expression of lung epithelial markers of differentiation. We found that retinoic acid interferes, in a dose-dependent fashion, with the expression of epithelial genes that are found in distal segments of the fetal lung (surfactant-associated proteins SP-A, SP-B, and SP-C). At high concentrations, retinoic acid (RA) dramatically altered the developmental pattern of the lung, favoring growth of structures that resemble proximal airways and concomitantly suppressing distal epithelial buds. We hypothesize that this in vitro "proximalizing" effect on the developing lung may be related to alterations in the expression of pattern-related genes.

    Title Pre-induction Cervical Ripening: a Randomized Comparison of Two Methods.
    Date April 1995
    Journal Obstetrics and Gynecology
    Excerpt

    OBJECTIVES: To compare two methods of pre-induction cervical ripening in a randomized clinical trial. METHODS: A single intracervical prostaglandin E2 (PGE2) gel application was compared with a single insertion of hygroscopic dilators in 441 women at term with unfavorable cervical scores. Induction success was defined as entry into active labor within 6 hours of oxytocin infusion. RESULTS: There was no statistical difference in pre- or post-ripening cervical scores. In the group receiving hygroscopic dilators, only 28% entered the active phase of labor within 6 hours of oxytocin infusion compared with 45% (P < .001) in the PGE2 group. Thus, in this study, a change in cervical score did not directly predict induction success. There was a higher rate of postpartum endometritis (24 versus 14%; P = .007) and suspected neonatal infection (10 versus 5%; P = .03) in the dilator group. CONCLUSIONS: Pre-induction ripening by hygroscopic dilators and intracervical PGE2 was equivalent as measured by changes in the cervical score. The change in cervical score, however, was not predictive of successful induction, and PGE2 was more frequently associated with induction success. Hygroscopic dilators were associated with a higher incidence of postpartum maternal and neonatal infection because of a longer duration of labor. Hospital charges for intracervical PGE2 gel totaled $522 compared with $91 for the insertion of three dilators.

    Title Cloning, Characterization, and Development Expression of a Rat Lung Alveolar Type I Cell Gene in Embryonic Endodermal and Neural Derivatives.
    Date March 1995
    Journal Developmental Biology
    Excerpt

    We report here the identification and characterization of a novel gene, T1 alpha, expressed in high abundance in adult rat lung, fetal lung, and early fetal brain. T1 alpha was identified by a monoclonal antibody previously shown to be specific for an antigen expressed by alveolar epithelial type I cells. The cDNA for T1 alpha is 1.85 kb and identifies a single mRNA species of the same size on Northern blots of adult rat lung. The longest open reading frame of the cDNA is 498 bases which would encode a protein of approximately 18 kDa. The protein has a putative membrane spanning domain near the C-terminus but lacks consensus sequences for N-glycosylation. Northern blots and RT-PCR show high expression of T1 alpha in adult lung, with marginally detectable expression in adult brain, intestine, and kidney. RT-PCR analysis shows expression of T1 alpha in freshly isolated type I cells (50-60% purity) but not in highly purified type II cells or other lung cells. We believe therefore that T1 alpha is primarily if not uniquely expressed in alveolar type I cells in the adult rat. Polyclonal antisera against a 16-amino-acid peptide identified in the deduced sequence reacts with the apical membranes of adult type I cells in lung tissue sections but does not label other cell types. The above antiserum as well as the original monoclonal antibody recognize a single approximately 18-kDa protein derived from bacterial expression of a construct containing the T1 alpha open reading frame. By RT-PCR T1 alpha is detected in rat lung from Day 13.5 onward, but is detected by in situ hybridization earlier in lung, brain and neural derivatives, and foregut. Expression is down-regulated in all but lung tissues as development proceeds.

    Title The Effects of Spatial Filtering and Contrast Reduction on Visual Search Times in Good and Poor Readers.
    Date February 1995
    Journal Vision Research
    Excerpt

    Recent experiments with reading disabled children have shown that image blurring (produced with frosted acetate overlays) results in an immediate benefit in search performance, eye movement pattern and reading comprehension. This suggests that the contrast and spatial frequency content of visual stimuli are important factors for these children. In the present experiment, spatial frequency filtering and contrast reduction were employed to determine whether either of these factors contributes to the beneficial effects observed. Letter arrays were spatially filtered to produce low pass (< 3.5 c/deg) and high pass (> 7.0 c/deg) images. In addition, a low contrast control image was generated to match the low contrast of the high pass image. Children classified as good reader controls (CON), specific reading disabled (SRD), attention deficit disordered (ADD) or comorbid SRD/ADD (COM) were asked to perform a visual search task with each type of image. With high contrast, unfiltered arrays, the search times for the CON and ADD groups were much shorter than those of the SRD and COM groups. While both high pass and low pass filter conditions improved the search speed for the COM group, improvement for the SRD group was only obtained with low contrast stimuli. These results support the notion that the beneficial results of image blurring with SRDs derives from the contrast reduction produced by such manipulations.

    Title Sonographic Diagnosis of a Large Umbilical Cord Pseudocyst.
    Date October 1994
    Journal Journal of Ultrasound in Medicine : Official Journal of the American Institute of Ultrasound in Medicine
    Title Premature Luteinization in Controlled Ovarian Hyperstimulation Has No Adverse Effect on Oocyte and Embryo Quality.
    Date November 1993
    Journal Fertility and Sterility
    Excerpt

    OBJECTIVE: To determine if premature luteinization has an adverse effect on oocyte and, hence, embryo quality. DESIGN: Retrospective evaluation of anonymous ovum donors/oocyte recipients. SETTING: A large oocyte donation program. PATIENTS, PARTICIPANTS: Sixty-eight women undergoing controlled ovarian hyperstimulation (COH) as ovum donors were matched to 68 women with ovarian failure as ovum recipients who had endometrial maturation exogenously controlled by an identical hormone replacement protocol. INTERVENTIONS: Serum was collected for E2 and P in donors and recipients. MAIN OUTCOME MEASURES: The incidence of premature luteinization was determined in donors. Cycle characteristics were compared between donors with and without premature luteinization, with emphasis on oocyte and embryo quality. Implantation rates per embryo and delivery rates per transfer were measured in recipients. RESULTS: Twenty-one (31%) of the donors demonstrated premature luteinization. Serum P was higher on day before hCG, day of hCG, and day after hCG in women demonstrating premature luteinization. However, there were no differences between donor cycles with or without premature luteinization as determined by donor age, ampules of gonadotropins used, day of hCG administration, peak E2, total number of oocytes, and number of mature oocytes retrieved. Ovum recipients were of similar age and had similar E2 exposure (area under the E2 curve) before P administration. Similar fertilization rates, incidence of polyspermia, number of embryos transferred of similar embryo grade, and similar implantation rates and deliveries per transfer were observed in women receiving oocytes from donors with and without premature luteinization, respectively. CONCLUSIONS: Similar oocyte quality, fertilization, and polyspermia rates, embryo quality, implantation, and delivery rates suggest that any negative impact of premature luteinization on pregnancy rates in COH cycles from young women is not due to an adverse effect of PL on oocyte and hence embryo quality, but rather on the endometrial environment.

    Title Obstetric Correlates of Neonatal Retinal Hemorrhage.
    Date May 1993
    Journal Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: To determine whether maternal or fetal factors, other than vacuum-assisted delivery, play a role in neonatal retinal hemorrhage, and whether correlates are similar in retinal hemorrhage after spontaneous vaginal delivery. METHODS: A cross-section of assisted deliveries at an urban hospital (n = 156) over 7 months were compared with contemporaneous spontaneous vaginal deliveries (n = 122). A subset of assisted deliveries (n = 87) was prospectively randomized to forceps or vacuum-assisted delivery by sealed envelope. Maternal and neonatal biometric data were collected, and Apgar scores, umbilical artery blood gas analysis, and neonatal ophthalmologic evaluations were performed. RESULTS: Moderate to severe retinal hemorrhage was found in 18% of spontaneous, 13% of forceps, 28% of vacuum-assisted, and 50% of sequential vacuum and forceps-assisted deliveries. Fetal distress (P < .008), vacuum-assisted delivery (P < .02), decreased birth weight for gestation (P < .004), umbilical artery pH less than 7.20 (P < .004), and second stage of labor less than 30 minutes (P < .05) were most closely associated with increased degrees of retinal hemorrhage. Maternal parity, preeclampsia, length of labor, and head circumference were not correlated with retinal hemorrhage. Vacuum-assisted delivery among low birth weight infants (P < .0001), short second stage of labor (P < .006), fetal acidosis (P < .045), and sequential use of vacuum and forceps for assisted delivery (P < .005) formed a logistic model that correctly predicted 81% of moderate to severe retinal hemorrhage cases. Logistic analysis of the randomized assisted deliveries gave similar results. CONCLUSIONS: Maternal and fetal factors other than vacuum-assisted delivery are significant correlates of moderate to severe retinal hemorrhage. Vacuum-assisted delivery among small for gestational age infants is closely correlated with moderate to severe retinal hemorrhage.

    Title Effects of Surfactant Apolipoproteins on Liposome Structure: Implications for Tubular Myelin Formation.
    Date July 1992
    Journal The American Journal of Physiology
    Excerpt

    Tubular myelin is one of several forms of lung surfactant and may play an important role in its surface activity. To determine possible mechanisms of tubular myelin formation, we studied the effects of purified surfactant proteins (SP-A, SP-B, and SP-C) on large unilamellar dipalmitoylphosphatidylcholine-egg phosphatidylglycerol (7/3; wt/wt) liposomes. We studied different types of membrane interaction induced by the apolipoproteins and correlated these with the observed changes in ultrastructure. Aggregation was assessed by measurement of light absorbance, lysis, and fusion by measurement of the fluorescence emitted by water-soluble and lipid-soluble probes, respectively. Mixtures of the apolipoproteins and liposomes were examined in ultrastructural studies by negative staining and by thin sectioning. We found that each protein had a pronounced and distinct effect on liposome structure. SP-A caused aggregation, whereas SP-B and SP-C also caused extensive leakage of liposome contents (lysis) and some degree of lipid mixing (fusion). The disruptive effects of SP-B and to a lesser extent those of SP-C were correlated by negative staining with the appearance of bilayer disks, which tended to aggregate into large sheets. There was a marked synergy between SP-A and SP-B in the process of membrane fusion in the presence of calcium, which correlated with an early (10 min) and extensive rearrangement of the structures seen by electron microscopy followed by a delayed (24 h) appearance of small amounts of tubular myelin.

    Title Pulmonary Alveolar Epithelial Cell Differentiation.
    Date May 1992
    Journal Annual Review of Physiology
    Title A Randomized Comparison of Assisted Vaginal Delivery by Obstetric Forceps and Polyethylene Vacuum Cup.
    Date November 1991
    Journal Obstetrics and Gynecology
    Excerpt

    The assisted vaginal delivery methods of rigid obstetric forceps and polyethylene vacuum cup extraction were compared in a prospective, randomized study. The 99 women studied had all completed 35 full weeks' gestation, required attempted assisted vaginal delivery, and were randomly assigned to either attempted forceps or vacuum-assisted delivery. All presentations were cephalic, with stations ranging from +1 to +4. Neonates were evaluated at 24 hours by neonatal staff. The infants underwent intracranial ultrasound screening during the first 24 hours of life and ophthalmologic examination within 48 hours. Vaginal delivery was successful with the intended method in 83% of vacuum-assisted deliveries and in 78% of forceps deliveries (not statistically significant). Neonatal retinal hemorrhage was found in 17 and 38% (P less than .043) of the randomized forceps and vacuum deliveries, respectively. No intraventricular hemorrhage was found. Apart from associations between vacuum-assisted delivery and mild hyperbilirubinemia and neonatal retinal hemorrhage (of uncertain clinical significance), and between assisted forceps delivery and an increased potential for facial injury, neonatal outcomes did not differ significantly. Maternal outcomes also did not differ significantly. No significant differences in safety or efficacy were found between polyethylene cup vacuum extraction and rigid obstetric forceps-assisted vaginal delivery in this population of predominantly low-pelvic assisted deliveries. Patients delivered by sequential use of forceps after vacuum or by vacuum after failed forceps application did not suffer significantly increased morbidity relative to those delivered by forceps or vacuum alone. Use of alternate or sequential methods allowed an overall cesarean rate of 3% in this population.

    Title Regulation of Atp-dependent Surfactant Secretion and Activation of Second-messenger Systems in Alveolar Type Ii Cells.
    Date November 1991
    Journal The American Journal of Physiology
    Excerpt

    Several different classes of agonists are known to stimulate exocytosis in type II cells. These agonists cause increases in second messengers, such as adenosine 3',5'-cyclic monophosphate (cAMP) or cytosolic Ca2+, and/or stimulate protein kinase C. We studied generation of cAMP and phosphoinositide (PI) turnover in monolayer cultures of type II cells and measured [Ca2+]i in single cultured cells. ATP [10(-4) M], which stimulates secretion of phosphatidylcholine (PC) and increases cellular cAMP, also stimulated PI turnover and increased [Ca2+]i. 12-O-tetradecanoylphorbol-13-acetate (TPA), which stimulates PC secretion and activates protein kinase C, did not increase [Ca2+]i. Pretreatment of type II cells with the calmodulin antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) inhibited the PC secretion induced by ATP and TPA and blocked the increase in PI turnover caused by ATP. ATP-dependent surfactant secretion and stimulation of PI turnover could also be inhibited by pretreatment of the cells with pertussis toxin. We used the fluorescent probe indo-1 to measure [Ca2+]i in single cultured type II cells. ATP produced rapid transient increases in [Ca2+]i, which could be prevented by pretreatment of the cells with either TPA or W-7. Our data suggest that pertussis toxin-sensitive G protein(s) are involved in ATP-dependent activation of PI turnover and in secretion of surfactant in type II cells. Activation of protein kinase C blocks the ATP-stimulated increase in [Ca2+]i. Finally, calmodulin may be involved in the regulation of ATP-dependent increase in [Ca2+]i, the activation of PI turnover, and the secretion of surfactant in type II cells.

    Title Changes in Lipid Structure Produced by Surfactant Proteins Sp-a, Sp-b, and Sp-c.
    Date September 1991
    Journal American Journal of Respiratory Cell and Molecular Biology
    Excerpt

    Pulmonary surfactant phospholipids may assume several different structures including tubular myelin, unilamellar and multilamellar vesicles, and others. These populations of materials appear to have similar phospholipid compositions but may differ in their association with surfactant proteins SP-A, SP-B, or SP-C. We have used electron microscopy to determine the changes in structure of simple lipid mixtures (phosphatidylglycerol, dipalmitoylphosphatidylcholine) produced by adding one or combinations of the three proteins. Adding SP-A to lipids generated multilamellar structures composed of membranes with fuzzy or particulate surfaces. In contrast, SP-B or SP-C generated discoidal particles and structures that appeared to be sheets of membrane formed by associated particles. Used together, SP-A and SP-B reorganized some of the lipid into tubular myelin, a structure that was not observed in SP-A, SP-C recombinants. These observations confirm the in vitro formation of tubular myelin reported by others and support the possibility that surfactant materials with defined structure can be produced in vitro for analyses of their molecular organizations.

    Title Sequential Outpatient Application of Intravaginal Prostaglandin E2 Gel in the Management of Postdates Pregnancies.
    Date July 1991
    Journal Obstetrics and Gynecology
    Excerpt

    A randomized blinded investigation was undertaken to determine the efficacy and safety of sequentially applied intravaginal prostaglandin E2 (PGE2) gel for accelerating cervical ripening in an outpatient setting in low-risk prolonged pregnancies. Fifty women with uncomplicated pregnancies at or beyond 41 weeks' gestation and Bishop scores below 9 received twice-weekly outpatient administration of gel containing 2.0 mg of PGE2 or placebo. Thirty nulliparas and 20 multiparas were enrolled. The PGE2 gel failed to improve cervical ripening over placebo, as judged by Bishop scores. There was no difference between the groups in gestational age on admission to the labor and delivery suite, number of gel applications, requirement for oxytocin, incidence of cesarean delivery, or neonatal outcome. Only two patients (4%) experienced regular uterine contractions after gel insertion; these subsided spontaneously in both. None of the subjects experienced labor, tetanic contractions, evidence of fetal distress, or any other side effects related to gel insertion. We conclude that PGE2 gel in this dosage may be used safely in an outpatient setting, but more frequent application or earlier initiation may be required to produce a clinical effect.

    Title Eye Movement Indices of Mental Workload.
    Date January 1991
    Journal Acta Psychologica
    Excerpt

    Four investigations were carried out to assess the feasibility of using eye movement measures as indices of mental workload. In the first experiment, saccadic extent was measured during free viewing while subjects performed low, moderate and high complexity, auditory tone counting as the workload tasks. The range of saccadic extent decreased significantly as tone counting complexity (workload) was increased. In the second experiment the range of spontaneous saccades was measured under three levels of counting complexity with a visual task that did not require fixation or tracking. The results indicated that the extent of saccadic eye movements was significantly restricted as counting complexity increased. In the third experiment, the effects of practice were examined and decreased saccadic range under high tone counting complexity was observed even when significant increases in performance occurred with practice. Finally, in experiment 4, the first experiment was repeated with additional optokinetic stimulation and the saccadic range was again observed to decrease with tone counting complexity. The results indicated that the extent of spontaneous and elicited eye movements was significantly restricted as counting complexity increased. We conclude that this measure may provide a valuable index of mental workload.

    Title The Effect of Magnesium Sulfate Infusion on Systemic and Renal Prostacyclin Production.
    Date January 1991
    Journal Prostaglandins
    Excerpt

    Recent in vitro studies have suggested that magnesium sulfate (MgSO4) infusions may increase prostacyclin production. We studied the effect of MgSO4 infusion on prostacyclin (PGI2) metabolite excretion in women with either pregnancy induced hypertension or preterm labor. Excretion of renal and systemic metabolites of PGI2 was measured prior to and following the start of MgSO4 infusion in the two groups. An increased in renal PGI2 metabolite preterm labor excretion was noted in the hypertension group but no change was noted in systemic PGI2 excretion in either group. These data fail to support a generalized, short term increase in endothelial cell PGI2 production as the basis for the beneficial effect of MgSO4.

    Title Expression of Cell-specific Markers for Alveolar Epithelium in Fetal Rat Lung.
    Date July 1990
    Journal American Journal of Respiratory Cell and Molecular Biology
    Excerpt

    In adults, the alveolar epithelium is composed of types I and II cells which differ structurally and functionally although they appear to belong to the same cell lineage. Using cell-specific markers (type I cells, monoclonal antibody; type II cells, Maclura pomifera lectin [MPA]), we have determined when and in what pattern their binding sites occur during development of the fetal rat lung. Rather than first appearing on days 19 to 20, when morphogenesis of type I cells occurs and lamellar bodies provide positive identification of type II cells, the markers appeared on day 15 (for type I cell marker) and day 16 (for type II cell marker). The type I cell marker was widespread by day 17 and was sufficiently abundant to be detected on a Western blot. MPA binding appeared more gradually and was often found on isolated cells. On serial sections of day 20 lung, the markers appeared to be localized to the same cells. The early appearance of cell-specific markers suggests an early onset of the developmental program that leads to full differentiation of types I and II cells. Co-expression of both cell-specific markers suggest that fetal cell lineage may differ from the scheme proposed by others that type II cells serve as type I cell precursors during development.

    Title Interferon-gamma and Synthesis of Surfactant Components by Cultured Human Fetal Lung.
    Date April 1990
    Journal American Journal of Respiratory Cell and Molecular Biology
    Excerpt

    We examined the effects of interferon-gamma (IFN-gamma) on development of the surfactant system in alveolar epithelial cells of fetal lung. Explants of second-trimester human fetal lung were cultured for 1 to 6 days in serum-free medium containing recombinant human IFN-gamma (0.03 to 30 ng/ml) and/or dexamethasone (10 or 100 nM). Treatment for 3 days with IFN-gamma alone, dexamethasone alone, and IFN plus dexamethasone increased the content of surfactant protein A (SP-A, 28 to 36 kD) by approximately 3-, 2.5-, and 10-fold, respectively. The biphasic response pattern of SP-A to dexamethasone (stimulation initially and inhibition with continued culture) was not altered by the presence of IFN-gamma. IFN-gamma also stimulated accumulation of SP-A mRNA (2.7-fold at 24 h) but did not affect the levels of mRNAs for surfactant protein B (18 kD) and surfactant protein C (5 kD). To assess the effect of IFN-gamma on synthesis of surfactant lipids, we determined the content of phosphatidylcholine, the rate of labeled choline incorporation into phosphatidylcholine, saturation of newly synthesized phosphatidylcholine, and the activity of fatty acid synthetase, a glucocorticoid-inducible enzyme. Treatment of explants for 5 days with IFN-gamma had no effect on these parameters. Studies by light and electron microscopy revealed little difference between control and IFN-treated explants with regard to cell viability and epithelial cell differentiation. We conclude that IFN-gamma has a selective stimulatory effect on SP-A among surfactant components.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title The Fetal Board.
    Date July 1989
    Journal Journal of Perinatology : Official Journal of the California Perinatal Association
    Excerpt

    The fetal board is a multidisciplinary approach to complex perinatal clinical problems. It has a model in the tumor board, which has been used in many institutions to plan and coordinate care for patients with a malignancy. The pregnancy with a known or suspected abnormal fetus represents a clinical setting in which consultants from several disciplines have a potential role in the ultimate outcome. Therefore, a fetal board provides prospective opportunities for clinical diagnosis, counseling, and comprehensive care of the maternal patient and her fetus before, during, and after delivery. The fetal board's purpose is to incorporate the expertise of various specialties and subspecialties to provide optimum care for the abnormal fetus. The board also provides educational opportunities to all involved in patient care, including perinatologists, obstetricians, neonatologists, pediatricians, nursing staff, social service providers, and other health professionals.

    Title Off and Running: a Progress Report from the Ajrcmb.
    Date January 1989
    Journal The American Review of Respiratory Disease
    Title Temporal Order Judgements in Good and Poor Readers.
    Date January 1989
    Journal Neuropsychologia
    Excerpt

    The amount of time required to make accurate (75% correct) temporal order judgements was measured in groups of 3rd and 4th grade children who were selected on the basis of reading ability. The stimuli, two words (Box and Fox), were tachistoscopically presented to the left and right or above and below a fixation point. Subjects were asked to say which word came first under one condition, or which position contained the stimulus that occurred first under another condition. The stimulus onset asynchrony (SOA) was varied in half octave steps until threshold was determined. The results indicate that good readers required significantly longer SOAs to achieve 75% correct than adults, but significantly shorter SOAs than poor readers. There was not a significant difference in thresholds for the word and position conditions for adults or good readers, but poor readers required significantly more time to achieve criterion for the word condition. The word thresholds were highly correlated (-0.77) with reading level, but the correlation between position threshold and reading level was not significant. The implications of a temporal order deficit are discussed.

    Title Monoclonal Antibodies Specific to Apical Surfaces of Rat Alveolar Type I Cells Bind to Surfaces of Cultured, but Not Freshly Isolated, Type Ii Cells.
    Date August 1988
    Journal Biochimica Et Biophysica Acta
    Excerpt

    The alveolar surface of the lung is lined by two classes of epithelial cells, type I and type II cells. Type I cells cover more than 97% of the alveolar surface. Although this cell type is felt to be essential for normal gas exchange, neither unique identifying characteristics nor functions have been described for the type I cell. We have produced monoclonal antibodies to (a) component(s) of molecular weight 40,000 and 42,000 of the apical surface of rat alveolar type I cells. The antibodies are specific to the lung in Western blots of organ homogenates. In immunocytochemical studies of frozen lung at the level of both light and electron microscopy, the monoclonal antibodies appear to react specifically with the apical plasma membrane of type I cells. Airway, vascular, interstitial cells, type II cells and macrophages are not immunoreactive. Western blots of isolated type I cells (approx. 70% pure) also demonstrate immunoreactivity at molecular weights of 40,000 and 42,000. When the lung is injured, type I cells may be damaged and sloughed from the alveolar surface. Alveolar repair occurs when the second type of alveolar cell, the type II cell, divides. Cell progeny may retain type II cell morphology or may differentiate into type I cells. Western blots of freshly isolated type II cells (approx. 85% pure) do not display immunoreactivity with our monoclonal antibodies. However, type II cells maintained in culture acquire immunoreactivity to monoclonal antibodies, demonstrating that type II cells in vitro have the capacity to develop a characteristic associated with type I cells in situ. The availability of markers for a specific membrane component of type I cells should facilitate the study of many questions on alveolar functions, development and response to injury.

    Title Divalent Cation and Hydrogen Ion Effects on the Structure and Surface Activity of Pulmonary Surfactant.
    Date March 1988
    Journal Biochemistry
    Excerpt

    The structure and surface activity of the extracellular fraction of pulmonary surfactant known as tubular myelin are Ca2+ dependent. Previous studies have demonstrated surfactant-specific proteins with monomeric molecular weights of 28,000-36,000 (SP28-36) are associated with this fraction. In reassembled lipoprotein mixtures, SP28-36 promotes the Ca2+-induced aggregation and surface activity of surfactant lipids, but the detailed interactions between Ca2+, SP28-36, and surfactant lipids have not been established. In this study, we investigated the effect of various cations on the aggregation of surfactant lipid liposomes in the presence of SP28-36. SP28-36 reduced the threshold ion concentration for liposome aggregation from greater than 10 to 0.5 mM for Ca2+, Ba2+, and Sr2+ but not Mg2+ or Mn2+. The liposome aggregation was reversed by ethylenediaminetetraacetic acid and not associated with leakage of carboxyfluorescein. SP28-36 promoted similar liposome aggregation at pH less than 5 in the absence of divalent cations. Surfactant lipids adsorbed slowly to an air-fluid interface in all ionic conditions unless SP28-36 was present. Both Ca2+ and H+ induced rapid lipid adsorption in the presence of SP28-36. The surface activity of native surfactant had a similar ion dependence. Electron micrographs of native surfactant showed typical tubular myelin structures at pH 7.4 only in the presence of Ca2+. At pH 4.4 in the absence of Ca2+, similar but not identical structures were seen. In the reconstituted system, SP28-36 in the presence of Ca2+ induced the formation of larger multilayered structures including parallel bilayers and small areas of squares and triangles with dimensions similar to structures found in the native material.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Transfer of Perceptual-motor Training and the Space Adaptation Syndrome.
    Date November 1987
    Journal Aviation, Space, and Environmental Medicine
    Excerpt

    Perceptual cue conflict may be the basis for the symptoms which are experienced by space travelers in microgravity conditions. Recovery has been suggested to take place after perceptual modification or reinterpretation. To elucidate this process, 10 subjects who repeatedly experienced a visual/vestibular conflict (Purkinje) over trials and days, were then tested in a similar but not identical perceptual situation (pseudo-Coriolis) to determine whether any savings in perceptual adaptation had occurred as compared to an unpracticed control group (N = 10). The practiced subjects experienced lessening dizziness and ataxia within and over sessions. Their response to the new perceptual situation was markedly less than the control group (p less than 0.001). Assessment of "adaptability," in addition to the provocative vestibular tests now in use, may improve prediction of susceptibility to the space adaptation syndrome. An adaptability trait may exist in humans which, properly measured, could be used to predict who would adapt more readily to visual/vestibular conflict and perhaps to environmental stressors in general.

    Title An Improved Method for Isolating Type Ii Cells in High Yield and Purity.
    Date August 1986
    Journal The American Review of Respiratory Disease
    Excerpt

    A method has been developed for isolating alveolar type II cells by digesting lung tissue with elastase and "panning" the resultant cell suspension on plates coated with IgG. This method provides both high yield and purity of type II cells. In 50 experiments with rats, we obtained 35 +/- 11 X 10(6) cells/rat, 89 +/- 4% of which were type II cells (mean +/- SD). Type II cells isolated by "panning" adhered more rapidly and completely in tissue culture than did cells isolated by centrifugation over discontinuous density gradients of metrizamide. The "panning" method is superior to other methods for isolating type II cells in that it provides a population of type II cells of both high yield and high purity. The method is fast, reproducible, and easily adaptable to isolating type II cells from species other than rats.

    Title Changes in Biochemical Characteristics and Pattern of Lectin Binding of Alveolar Type Ii Cells with Time in Culture.
    Date September 1985
    Journal Biochimica Et Biophysica Acta
    Excerpt

    When cultured on plastic culture dishes for several days, alveolar type II cells gradually lose both their morphologic and biochemical identifying characteristics. Although type II cells cultured on a matrix derived from corneal endothelial cells have previously been reported to retain lamellar bodies for 7-10 days in culture, the ability of type II cells cultured on matrix to synthesize surfactant lipids has not been previously studied. We therefore measured the phospholipid content and the distribution of [14C]acetate into classes of lipids by type II cells maintained in culture. We found no differences between cells cultured on plastic or on matrix. We then studied the binding to type II cells in culture of Maclura pomifera and Ricinus communis I, lectins specific in vivo for type II and type I cells, respectively. We found that the cells progressively bind less M. pomifera and more R. communis I. The change in pattern of lectin binding occurs whether cells are cultured on plastic or matrix, whether lectins are conjugated with fluorescein, rhodamine or ferritin, or whether cells are cultured in the presence or absence of serum. We conclude that type II cells cultured on either tissue culture plastic or matrix derived from corneal endothelial cells lose the ability to synthesize and contain surfactant phospholipids, and, at least in their pattern of lectin binding, become similar to type I cells.

    Title Intoxication in Cattle, Chicks and Hamsters from Seed of the Palo Santo Tree (bulnesia Sarmientii).
    Date March 1985
    Journal The Veterinary Record
    Excerpt

    A case of intoxication in cattle in Paraguay from seed of the palo santo tree is discussed. Visible toxic signs and lesions observed at necropsy are described. The seed contained 3.5 per cent or more crude saponin. Laboratory studies established that aqueous extracts and crude saponin from the seeds were toxic to one-week-old chicks and adult hamsters.

    Title Protein Composition of Rabbit Alveolar Surfactant Subfractions.
    Date February 1985
    Journal Biochimica Et Biophysica Acta
    Excerpt

    The goal of this investigation was to characterize the proteins in subfractions of alveolar surfactant obtained by lung lavage and separated by differential centrifugation. It was previously demonstrated that the material in the more sedimentable fraction, which was enriched in tubular-myelin and was surface-active may be a precursor to the less sedimentable, vesicular, inactive material [1]. Separation of the proteins by polyacrylamide gel electrophoresis showed that the more sedimentable subfractions and rabbit surfactant isolated by conventional methods contained proteins with molecular weights comparable to those previously reported for alveolar surface active material (approximately 36 000 and 10 000). The less sedimentable subfractions contained less of these proteins. Immunoblots with anti-dog surfactant apoprotein antibodies, which cross-react with rabbit proteins, supported these observations. Immunoblots also showed that all of the subfractions contained serum proteins and secretory IgA, with the less sedimentable subfractions containing more secretory IgA. These results suggested that changes in protein composition may accompany functional changes in surfactant in the alveoli.

    Title Role of Apoprotein and Calcium Ions in Surfactant Function.
    Date November 1984
    Journal Experimental Lung Research
    Excerpt

    Pulmonary surfactant isolated in the presence of calcium ions contains substantial amounts of the morphologic structure, tubular myelin. Chelation of these calcium ions results in disruption of this structure and attendant loss of surface adsorption. Reassembly studies indicate that ability of the lipids to rapidly form surface films is dependent on the presence of a specific surfactant protein in addition to the calcium ions. The formation of this surface-active complex (apoprotein-lipid-calcium ions) is accompanied by aggregation of the lipid. This increase in aggregation may have important implications in the mechanism of surfactant function.

    Title Detection of an Abnormal Lipoprotein in a Large Colony of Pedigreed Baboons Using High-performance Gel Exclusion Chromatography.
    Date September 1984
    Journal Journal of Chromatography
    Excerpt

    High-performance gel exclusion chromatography was used to detect an abnormal lipoprotein in a large colony of baboons. Serum obtained from fasting baboons was adjusted to density 1.21 g/ml and ultracentrifuged to obtain lipoproteins. A small fraction (equivalent to 50 microliter serum) was separated using a gel filtration column (TSK 4000 SW) or a combination of TSK 4000 PW and TSK 3000 PW columns. The unusual lipoprotein was detected either as a distinct peak between low- and high-density lipoproteins or as a distinct shoulder to the high-density lipoprotein peak. In some baboons the unusual lipoprotein was present on both chow and atherogenic diet, but in most cases it was induced by feeding an atherogenic diet.

    Title Role of Calcium Ions the Structure and Function of Pulmonary Surfactant.
    Date May 1984
    Journal Biochimica Et Biophysica Acta
    Excerpt

    Pulmonary surfactant isolated by centrifugation in buffers containing ions contains at least three different morphologic structures. The presence of one of these, tubular myelin, is dependent on calcium ions, since chelation of the calcium ions causes disruption of this structure. Addition of EDTA also decreases the ability of the surfactant to absorb rapidly to air-water interfaces and lower surface tension. Titration with calcium ions (2.5 or 5 mM) restores rapid surface adsorption and restores the tubular myelin structural forms. Magnesium ions cannot substitute for calcium ions in these processes. The reversibility of structure and function induced by calcium ions and EDTA is also accompanied by reversible isopycnic density shifts probably related to aggregation and disaggregation of the lipid-protein complex with calcium ions and EDTA, respectively.

    Title Toxicity of Seeds of Three Aesculus Spp to Chicks and Hamsters.
    Date April 1984
    Journal American Journal of Veterinary Research
    Excerpt

    Seeds of horse chestnut (Aesculus hippocastanum), Ohio buckeye (A glabra), and yellow buckeye (A octandra) were tested for toxicity to 2-week-old Leghorn chicks and adult female Syrian hamsters. The LD50 of the water soluble portion of alcoholic extracts of horse-chestnut seeds (for hamsters and chicks) and of dried, powdered seeds (chicks only) was determined. The LD50 for a single dose of extract from horse-chestnut seeds was 10.6 mg/g of body weight for chicks and 10.7 mg/g of body weight for hamsters. The LD50 for chicks given 2 consecutive daily doses of horse-chestnut seed was 6.5 mg/g. Toxic signs included depression, muscular incoordination, paralysis, coma, and death. Extracts of seeds of Ohio buckeye were nontoxic to chicks and hamsters when fed at 80 mg/g. One of 5 hamsters died after dosing for 5 days with 80 mg/g of extract of seeds of yellow buckeye/g.

    Title Transepithelial Transport by Pulmonary Alveolar Type Ii Cells in Primary Culture.
    Date October 1983
    Journal Proceedings of the National Academy of Sciences of the United States of America
    Excerpt

    Fluid and electrolyte transport by epithelial cells in vitro can be recognized by the ability of cultured cells to form domes and by the electrical properties of monolayer cultures. Pulmonary alveolar epithelial cells are thought to be partially responsible for fluid movement in the fetal lung, but their role in electrolyte transport in the adult lung is not known. We isolated alveolar type II cells from adult rat lung and maintained them on plastic culture dishes alone, on plastic culture dishes coated with an extracellular matrix, and on collagen-coated Millipore filters. Numerous large domes were formed on culture dishes coated with the extracellular matrix; smaller domes were formed on uncoated plastic culture dishes. Sodium butyrate (3 mM) stimulated dome formation. Transmission electron microscopy showed that the epithelial cells had flattened but still retained lamellar inclusions and that the cells were polarized with microvilli on the apical surface facing the culture medium. The electrical properties of the monolayers maintained on collagen-coated Millipore filters were tested in two laboratories. The transepithelial potential differences were 0.7 +/- 0.1 mV (24 filters, seven experiments) and 1.3 +/- 0.1 mV (13 filters, two experiments) apical side negative, and the corresponding resistances were 217 +/- 11 ohm X cm2 and 233 +/- 12 ohm X cm2. Terbutaline (10 microM) produced a biphasic response with a transient decrease and then a sustained increase in potential difference. Amiloride (0.1 mM) completely abolished the potential difference when it was added to the apical side but not when it was added to the basal side, whereas 1 mM ouabain inhibited the potential difference more effectively from the basal side. Thus, type II cells form a polarized epithelium in culture, and these cells actively transport electrolytes in vitro.

    Title The Pharmacokinetics and Metabolism of Ethinyl Estradiol and Its Three Sulfates in the Baboon.
    Date June 1983
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    Ethinyl estradiol sulfates are major circulating metabolites of ethinyl estradiol (EE2); this is a relationship analogous to that of endogenous estrone and estrone sulfate. Because of the wide use of contraceptives containing EE2, the pharmacokinetics of its sulfate conjugates are of some importance. In previous studies of the intermediate metabolism of ethinyl estrogens we have shown that the baboon is an appropriate animal model. Accordingly, oral and/or intravenous doses of EE2 or each of its three sulfates were administered to castrate female baboons, and plasma levels of EE2 and its sulfates were studied by specific radioimmunoassay or radioisotope counting. After intravenous administration of EE2, the 3-sulfate and the 3,17-disulfate are the major circulating metabolites. After oral dosage administration, the 3-glucuronide and, in some cases, the 3,17-diglucuronide also become important. After intravenous administration, about twice as much of the drug exists in the sulfate as in the free form, as reflected by the areas under the plasma level curves. The bioavailability of orally administered EE2 was about 60%, confirming the presence of a substantial first-pass effect. Hydrolysis at the 17-position occurs when EE2-17-sulfate is administered orally but appears not to occur with intravenous administration. EE2 and the three sulfates, given intravenously, exhibited two-compartment open-model kinetics. The elimination phase half-lives of all four compounds were similar, ranging from 8.8 to 11.2 hours. The area under the plasma level curve of EE2 resulting from the intravenous administration of the 3-sulfate was approximately 8% of the total area under the plasma level curve of both EE2 and EE2 sulfates. The ratio of the area under the plasma level curve of sulfates resulting from 3-sulfate administration compared to the other two sulfates was approximately 0.3, reflecting the existence of other metabolic pathways for its disposition.

    Title Subfractionation of Lung Surfactant. Implications for Metabolism and Surface Activity.
    Date April 1983
    Journal Biochimica Et Biophysica Acta
    Excerpt

    Because previous studies have suggested that lung surfactant is not a simple compartment of homogeneous material, we subfractionated lamellar bodies and components of alveolar lavage from male New Zealand white rabbits, according to differences in sedimentability. We recovered two lamellar body populations at different densities in discontinuous sucrose density gradients; we separated six subfractions of alveolar lavage by differential centrifugation. To determine whether or not precursor-product relationships existed among the subfractions, we injected radioactive palmitate intravenously, killed the rabbits 1-72 h later, and measured phospholipid specific activities. The two populations of lamellar bodies had similar phospholipid composition, fatty acyl composition of phosphatidylcholine and phosphatidylglycerol, and surface activity. Light lamellar bodies had a higher ratio of phospholipid to protein, and labelled with tracer later in time than dense ones. For alveolar lavage subfractions, later labelling with tracer, lower adsorption rate and lower total protein and phosphatidylglycerol content seemed to correlate with decreasing average density and particle size as well as with the disappearance of tubular myelin structure and appearance of predominantly vesicular structure. The subfractions appear to be in a metabolic sequence in which heavier, more dense material is a precursor to lighter, less dense material. The results suggest that subfractions of surfactant are extensively recycled.

    Title Secretion of Surfactant by Primary Cultures of Alveolar Type Ii Cells Isolated from Rats.
    Date January 1983
    Journal Biochimica Et Biophysica Acta
    Excerpt

    Pulmonary surfactant conventionally is prepared from material obtained by endobronchial lavage. Although it has been assumed that the components of surfactant are secreted by alveolar type II cells, direct proof of this assumption has not been available. Furthermore, it is possible that the final material obtained by lavage has been modified after secretion or altered during the isolation procedure. It has been shown previously that type II cells, after 1 day in primary culture, secrete saturated phosphatidylcholine, one of the lipid components of surfactant. Because saturated phosphatidylcholine is not unique to surfactant and because type II cells in culture lose differentiated characteristics over the first several days in culture, it has not previously been established how closely the secretory products of cultures of type II cells resemble surfactant as obtained by endobronchial lavage. We therefore studied the morphologic, physical and chemical characteristics of the material that type II cells secrete under basal conditions and after stimulation with terbutaline or 12-O-tetradecanoyl-13-phorbol acetate. The secreted material resembled surfactant obtained by lavage; it was similar morphologically to the lamellar material and tubular myelin seen in the fluid-filled alveoli of fetal rats, it lowered surface tension to 5 mN per meter, and it contained the 72000 dalton apolipoprotein of surfactant (as measured by the 'rocket' immunoelectrophoresis technique). When cells were incubated for 22 h with [1-(14)C]acetate, the distribution of radioactivity in the secreted material was very similar to the phospholipid composition of rat surfactant. We conclude that the material secreted by alveolar type II cells after 1 day in primary culture is similar to surfactant obtained by endobronchial lavage.

    Title Problems in the Measurement of Putative Serum Immune Complexes by the Method of Beaumont.
    Date October 1982
    Journal American Journal of Reproductive Immunology : Ajri : Official Journal of the American Society for the Immunology of Reproduction and the International Coordination Committee for Immunology of Reproduction
    Excerpt

    A methodological investigation of the procedure used by Beaumont et al for measuring a "serum immune complex" precipitated by 25% ammonium sulfate and alleged to contain an ethynyl-estradiol binding immunoglobulin has found major problems with reproducibility and with the correlation of total protein as measured by the Lowry method and the IgG content as determined by a specific nephelometric procedure.

    Title Relative Rates of 2- and 4-hydroxyestrogen Synthesis Are Dependent on Both Substrate and Tissue.
    Date June 1982
    Journal Febs Letters
    Title Immunocytochemical Localization and Identification of the Major Surfactant Protein in Adult Rat Lung.
    Date September 1981
    Journal The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society
    Excerpt

    We investigated the cellular and subcellular sites of metabolism of the 72,000 dalton protein of pulmonary surfactant in order to provide insights into mechanisms of synthesis, intracellular assembly, and intraalveolar metabolism of this phospholipid-rich secretory product. Surfactant (approximately 90% lipid, 10% protein by weight) was purified by density gradient centrifugation of material obtained by lavaging rat lungs. The purified material was used to generate an antiserum from which a specific antibody was obtained by affinity chromatography. A horseradish peroxidase-labeled Fab was used to localize the antigen in rat lung. The antibody labeled the rough endoplasmic reticulum and Golgi apparatus of type II cells only. Some multivesicular bodies in type II cells were also labeled, but whether the antigen was present in lamellar bodies was uncertain. Phagosomes of alveolar macrophages were labeled as were similar inclusions in type I cells. Using indirect immunocytochemistry we determined that the labeling of alveolar cell surfaces does not represent the presence of a continuous layer of secreted surfactant. These results suggest that only the type II cell synthesizes surfactant protein and than mainly alveolar macrophages participate in its catabolism. The initial intracellular site of the association of protein with lipid may be multivesicular bodies as suggested previously by others.

    Title Unilamellar Liposomes Made with the French Pressure Cell: a Simple Preparative and Semiquantitative Technique.
    Date April 1981
    Journal Journal of Lipid Research
    Excerpt

    A simple, rapid, and almost quantitative technique is described for the preparation of 1-40 ml of homogeneous unilamellar liposomes from dilute or concentrated aqueous suspensions of egg phosphatidylcholine. Aqueous suspensions of lipid are placed with the chamber of a French pressure cell at room temperature and rapidly extruded at 20,000 psi through the small orifice. A single pass transforms more than 70% of the extruded lipid into a homogeneous population of single-wall bilayer vesicles; more than 90% is transformed by recycling the lipid through the French pressure cell. About 95% of these liposomes range between 150-300 A in diameter (mean 200 A). The liposomes are stable for days to months when stored under nitrogen at 0.4 degrees C and can be prepared at 0 degrees, 25 degrees, or 37 degrees C. The liposomes appeared unaltered by repeated passages through the French pressure cell and no degradation of the phospholipid was detected after ten consecutive cycles at 20,000 psi in the absence of a nitrogen atmosphere. The method is especially useful for trapping small molecular weight substances because the concentration of both lipid and solute can be made quite high. Cholesterol up to 45 mole % can be incorporated into larger liposomes of egg phosphatidylcholine (mean diameter 315 A). Other phospholipids and different lipid mixtures can also be transformed into unilamellar vesicles with this method which has the advantage that additional steps of ultracentrifugation, column chromatography, dialysis, and concentrating procedures are usually unnecessary. Multilayered liposomes of small size (980 A mean diameter; > 95% between 500-1,500 A) are produced at lower pressure (3,000 psi). The latter are separated by gel permeation chromatography from a second population of homogeneous vesicles of even smaller size (580 A mean diameter; > 95% between 300-900 A) that contain two bilayer shells.

    Title Asymmetry in the Brightness and Darkness Broca-sulzer Effects.
    Date February 1981
    Journal Vision Research
    Title Chromatographic Patterns of Urinary Ethynyl Estrogen Metabolites in Various Populations.
    Date January 1981
    Journal Steroids
    Excerpt

    Radioactive mestranol (ME) and/or ethynylestradiol (EE) were administered to women in Nigeria, Sri Lanka, and the USA, and the types and patterns of radioactive urinary conjugates examined by Sephadex LH-20 chromatography. There are no differences in the total excretion of urinary radioactivity over 3 days. Consistent geographic differences appear to be present in the proportion of 3-, 17-, and 3,17-glucuronides. If confirmed on larger population samples, these observations may indicate significant geographic differences in the hepatic metabolism of ethynyl estrogens. High performance liquid chromatographic patterns of the urinary aglycone metabolites of ME and EE were examined in a number of women. The separation was accomplished on a Chromegaprep Diol column with a gradient of isopropanol in heptane. Ethynyl estrogen metabolism shows considerable individual variation. EE is usually the principal compound escreted following ME or EE administration. Unmetabolized ME is present in the ME profiles. The profiles of EE and ME are similar, with EE demonstrating a more complex pattern. Oxidative metabolism occurs chiefly at positions 2, 6 and 16 and is fairly extensive in the USA subjects. The Sri Lankan women generally show less of the oxidative products and the Nigerian group display a notable lack of oxidative metabolism. There is no difference in the metabolic patterns of long-term oral contraceptive users vs. non-users. Using silver sulfoethylcellulose column chromatography, from 14.1 to 34.7% of the excreted radiolabeled aglycones are non-ethynyl (i.e., either D-homo or de-ethynylated estrogens).

    Title Metabolic Properties and Ultrastructure of Alveolar Type Ii Cells Isolated with Elastase.
    Date October 1980
    Journal Biochimica Et Biophysica Acta
    Excerpt

    We used porcine pancreatic elastase to isolate type II cells from the lungs of rats; the yield and purity of the type II cells was better than that obtained by methods using trypsin. In 102 experiments we obtained 82 +/- 23 . 10(6) cells/rat, 68 +/- 11% (mean +/- S.D.) of which type II cells. This preparation of cells, when centrifuged over a discontinuous density gradient, yielded 25 +/- 10 . 10(6) cells/rat, 80 +/- 13% of which were type II cells (n = 102). The cells, after density gradient centrifugation, could be futher purified by centrifugal elutriation (94 +/- 3% type II cells, n = 22) or adherence in primary culture (94 +/- 2% type II cells, n = 34). Type II cells isolated with elastase are similar morphologically and biochemically to type II cells isolated from rats with trypsin. The preparations of cells appeared healthy by several different criteria: ultrastructure, exclusion of vital dye, lack of stimulation of oxygen consumption by exogenous sodium succinate, and linear rates of oxidation of [1-14C]palmitic acid and of incorporation of [1-14C]acetate into fatty acids. Type II cells consumed 75 +/- 20 nmol O2/10(6) cell per h, oxidized [1-14C]palmitic acid at a rate of 0.4 nmol/10(6) cells per h, and incorporated [1-14C]acetate into fatty acids at a rate of 7.5 nmol/10(6) cells per h.

    Title Metabolites of Estradiol-17 Beta in Bovine Liver: Identification of the 17-beta-d-glucopyranoside of Estradiol-17 Alpha.
    Date February 1980
    Journal Journal of Steroid Biochemistry
    Title The Ultrastructure of Bronchial Macrophages and Lymphocytes in Sarcoidosis.
    Date May 1979
    Journal Human Pathology
    Excerpt

    A physical interaction between macrophages and lymphocytes was observed more frequently in bronchial lavage fluid obtained from patients with sarcoidosis than from normal volunteers, irrespective of their history of smoking. In this spontaneous interaction more than two lymphocytes were commonly seen adhering to a macrophage without evidence of cytoplasmic bridging or membrane fusion. To a greater extent than in normal volunteers, macrophages from patients with sarcoidosis were characterized by the appearance of a more highly irregular cell surface, more membrane bound inclusions, however, was positively correlated with the smoking history of the individual, and the number of surface projections (microvilli) of macrophages from smokers appeared to be reduced. Significant differences were not apparent in the nuclear or cellular diameters of macrophages from sarcoid and normal individuals.

    Title Synthesis of 17beta-d-glucopyranosiduronic Acid of 17alpha-ethynylestradiol.
    Date July 1978
    Journal Journal of Steroid Biochemistry
    Title Alveolar Type Ii Cells.
    Date January 1978
    Journal Federation Proceedings
    Title Sarcoidosis: Analysis of Cells Obtained by Bronchial Lavage.
    Date December 1977
    Journal The American Review of Respiratory Disease
    Excerpt

    The cellular content of bronchial lavage was studied in 14 patients with sarcoidosis and 20 normal volunteers. There was no alteration in the total number of cells recovered, except for the expected increase in cellularity in smokers. Nonsmoking patients with sarcoidosis had 19.6 per cent lymphocytes, compared to 8.1 per cent lymphocytes in nonsmoking control subjects. The percentage of alveolar macrophages showing spontaneous adherence of one or more bronchial lymphocytes were, respectively, 10.8 and 8.4 in nonsmoking and smoking patients with sarcoidosis, compared to 1.8 and 2.1, respectively, in nonsmoking and smoking control subjects.

    Title Corticosteroid Induction of Phosphatidic Acid Phosphatase in Fetal Rabbit Lung.
    Date October 1977
    Journal Biochemical and Biophysical Research Communications
    Title Inhibition of Hela Cell Messenger Rna Translation by 7-methylguanosine 5'-monophosphate.
    Date November 1976
    Journal The Journal of Biological Chemistry
    Excerpt

    Translation of HeLa cell RNA containing poly(A) in a wheat germ cell-free system is markedly but incompletely inhibited by 7-methylguanosine 5'-monophosphate (m7G5'p). We have analyzed the translation products synthesized in the presence of different concentrations of m7G5'p and find that translation of all mRNAs is equally inhibited. To demonstrate the specificity of the inhibitor for RNAs with 5'-terminal m7G5' ppp... we show that specific translation products of satellite tobacco necrosis virus RNA, which does not have this 5' terminus, are synthesized in the presence of m7G5' p. Protein synthesis programmed by endogenous mRNA in a HeLa cell-free system is inhibited after a 10-min lag by m7G5' p. Other guanosine nucleotides without the 7-methyl group or with the phosphate in a different position are not inhibitor. We show that translation of all mRNAs is inhibited to a similar extent by m7G5'p in the HeLa cell-free system, by synthesizing 35S-labeled proteins in the presence of different inhibitory concentrations of this nucleotide and analyzing the translation products by electrophoresis and autoradiography. Translation of encephalomyocarditis virus RNA added to the HeLa cell-free system is not inhibited by m7"g5p; this viral RNA does not have this nucleotide at the 5' terminus. This indicates that m7G5'p specifically inhibits translation of mRNAs with the 5' terminus m7G5'ppp... and suggests that initiation of translation of picornavirus RNA may proceed via a mechanism different from that of cellular mRNAs.

    Title Discoidal Bilayer Structure of Nascent High Density Lipoproteins from Perfused Rat Liver.
    Date October 1976
    Journal The Journal of Clinical Investigation
    Excerpt

    Rat livers were perfused for 6 h without added plasma proteins using washed erythrocytes and buffer in a recirculating system. An inhibitor to the enzyme lecithin-cholesterol acyltransferase (5,5'-dithionitrobenzoic acid) was added in some experiments to prevent modification of substrate-lipids contained in secreted lipoproteins. The inhibitor did not detectably alter hepatic ultrastructure or gas exchange, but it inhibited the secreted lecithin-cholesterol acyltransferase by more than 85%. Very low density lipoproteins in perfusate were unaltered but the high density lipoproteins obtained from livers perfused with the inhibitor appeared disk-shaped in negative stain by electron microscopy with a mean edge thickness of 46 +/- 5 A and a mean diameter of 190 +/- 25 A. The high density lipoproteins were composed predominantly of polar lipids and protein with only small amounts of cholesteryl esters and triglycerides. The major apoprotein of these discoidal fractions had the same electrophoretic mobility as the arginine-rich apoprotein, whereas plasma high density lipoproteins contained mainly the A-I approtein. In all these respects the discoidal perfusate high density lipoproteins closely resemble those found in human plasma which is deficient in lecithin-cholesterol acyltransferase. Perfusate high density lipoproteins obtained in the absence of the enzyme inhibitor more closely resembled plasma high density lipoproteins in chemical composition (content of cholesteryl esters and apoproteins) and in electron microscopic appearance. Purified lecithin-cholesterol acyltransferase synthesized cholesteryl esters at a substantially faster rate from substrate lipids of perfusate high density lipoproteins than those from plasma. The discoidal high density lipoproteins were the best substrate for this reaction. Thin sections of plasma high density lipoproteins indicated a spherical particle whereas discoidal high density lipoproteins stained with the characteristic trilaminar image of membranes. These observations suggest that the liver secretes disk-shaped lipid bilayer particles which represent both the nascent form of high density lipoproteins and preferred substrate for lecithin-cholesterol acyltransferase.

    Title Human Urinary and Liver Conjugates of 17alpha-ethnylestradiol.
    Date September 1976
    Journal Steroids
    Excerpt

    Chromatographic profiles of the conjugates of 17alpha-ethynylestradiol (EE2) were obtained from the urine of castrate and normal women given tritium labeled EE2 orally. Five distinct radioactive peaks were observed, with considerable quantitative variation between individuals. Glucosiduronate fractions comprised the dominant excreted radioactivity. In vitro incubation of normal human liver also produced five conjugate types. Simultaneous intravenous/oral (14C/3H) administration of EE2 demonstrated conversion to identical urinary conjugate and free steroid products, with a greater excretion of the intravenous material. Authentic 3-glucuronide of EE2 was synthesized and its position in the chromatographic system relative to the urinary conjugate peaks demonstrated.

    Title The Urinary Metabolites of 17alpha-ethynylestradiol-9alpha,11xi-3h in Women. Chromatographic Profiling and Indentification of Ethynyl and Non-ethynyl Compounds.
    Date June 1975
    Journal Steroids
    Excerpt

    Metabolites of 17alpha-ethynylestradiol (EE2) were obtained from human urine following ingestion of tritium-labeled EE2. Over 95% of the recovered activity was found as conjugated steroids and these were separated into four groups by chromatography of the urine extract on Sephadex LH-20 with chloroform-methanol (1/1) + 0.01M NaCl. The two major conjugate fractions appeared to be almost exclusively glucosiduronates. Enzymatic hydrolysis liberated at least ten different EE2 metabolites as shown by chromatography on Sephadex LH-20 with benzene-methanol (85/15). After additional separation and purification of these metabolites, positive identification was obtained for nine radioactive compounds by either gas liquid chromatography-mass spectrometry or reverse-isotope recrystallization. Five were ethynyl compounds: EE2, 2-MeO EE2, 16beta-OH EE2, 2-OH EE2 and 6alpha-OH EE2. The other four were de-ethynylated estrogens: estrone, estradiol-17beta, estriol, and 2-Me-O-estradiol-17beta.

    Title Urinary Testosterone Glucuronide As a Measure of Endogenous Testosterone Production.
    Date July 1971
    Journal Acta Endocrinologica
    Title The Reaction of a Species of Colobus Monkey to Inoculation with Yellow Fever Virus.
    Date September 1969
    Journal Annals of Tropical Medicine and Parasitology
    Title Congo Virus: a Hitherto Undescribed Virus Occurring in Africa. Ii. Identification Studies.
    Date November 1967
    Journal East African Medical Journal
    Title The Isolation in Mice of Strains of Herpes Virus from Burkitt Tumours.
    Date May 1967
    Journal European Journal of Cancer
    Title Attempts to Transmit Reovirus Type 3 by the Bite of Aedes (stegomyia) Aegypti Linnaeus.
    Date May 1966
    Journal East African Medical Journal
    Title Search for Strange Baryonium States in P-bard Interactions at 8.9 Gev/c.
    Date
    Journal Physical Review D: Particles and Fields
    Title Measurement of the Total Hadronic Cross Section in Virtual Photon-photon Interactions.
    Date
    Journal Physical Review Letters
    Title Measurements of R and a Search for Heavy-quark Production in E+e- Annihilation at Sqrt S =50 and 52 Gev.
    Date
    Journal Physical Review Letters
    Title Search for Isolated Leptons in Low-thrust E+e- Annihilation Events at Sqrt S =50 and 52 Gev.
    Date
    Journal Physical Review Letters
    Title Experimental Evidence for the Non-abelian Nature of Qcd from a Study of Multijet Events Produced in E+e- Annihilation.
    Date
    Journal Physical Review Letters
    Title Search for Unstable Heavy Neutral Leptons in E+e- Annihilations at Sqrt S from 50 to 60.8 Gev.
    Date
    Journal Physical Review Letters
    Title Comparison of Quark and Gluon Jets Produced in High-energy E+e- Annihilations.
    Date
    Journal Physical Review Letters
    Title Search for a Fourth-generation Charge -(1/3 Quark.
    Date
    Journal Physical Review Letters
    Title Measurement of E+e--->bb-bar Forward-backward Charge Asymmetry Between Sqrt S =52 and 57 Gev.
    Date
    Journal Physical Review Letters
    Title Resident Cellular Components of the Human Lung: Current Knowledge and Goals for Research on Cell Phenotyping and Function.
    Date
    Journal Proceedings of the American Thoracic Society
    Excerpt

    The purpose of the workshop was to identify still obscure or novel cellular components of the lung, to determine cell function in lung development and in health that impacts on disease, and to decide promising avenues for future research to extract and phenotype these cells. Since robust technologies are now available to identify, sort, purify, culture, and phenotype cells, progress is now within sight to unravel the origins and functional capabilities of lung cells in developmental stages and in disease. The Workshop's agenda was to first discuss the lung's embryologic development, including progenitor and stem cells, and then assess the functional and structural cells in three main compartments of the lung: (1) airway cells in bronchial and bronchiolar epithelium and bronchial glands (basal, secretory, ciliated, Clara, and neuroendocrine cells); (2) alveolar unit cells (Type 1 cells, Type 2 cells, and fibroblasts in the interstitium); and (3) pulmonary vascular cells (endothelial cells from different vascular structures, smooth muscle cells, and adventitial fibroblasts). The main recommendations were to: (1) characterize with better cell markers, both surface and nonsurface, the various cells within the lung, including progenitor cells and stem cells; (2) obtain more knowledge about gene expression in specific cell types in health and disease, which will provide insights into biological and pathologic processes; (3) develop more methodologies for cell culture, isolation, sorting, co-culture, and immortalization; and (4) promote tissue banks to facilitate the procurement of tissue from normal and from diseased lung for analysis at all levels.

    Title Knowns and Unknowns of the Alveolus.
    Date
    Journal Proceedings of the American Thoracic Society
    Excerpt

    Our current alveolar paradigm includes three highly specialized cell populations. Alveolar type I cells are flat, elongated cells that presumably enable gas exchange. Alveolar type II cells are small, cuboidal cells with metabolic, secretory, progenitor, and immunologic functions. Alveolar fibroblasts secrete extracellular matrix proteins that support alveolar structure. These cells work together to facilitate respiration. Many years of high-quality research have defined our understanding of alveolar biology. However, there is much to be determined about the factors controlling cellular phenotypes and crosstalk. Moreover, specific questions remain regarding origin, repopulation, and previously unrecognized functions of each cell. This article summarizes the current data for each cell type and highlights areas that would benefit from further investigation.

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