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At least 145 records · Page 8Linked to original sources
PubMed1993

Ab-interno erbium (Er):YAG laser sclerostomy with iridotomy in Dutch cross rabbits.

An ab-interno technique using a pigmented rabbit model has been developed that uses a pulsed erbium:YAG laser to create an iridotomy with a sclerostomy through the same corneal incision. Laser energy was delivered with an articulated arm terminating in side-firing (850 or 650 microns OD) or end-firing (850 or 400 microns OD) fiber optic endoprobes, which allowed iridotomies and sclerostomies, respectively, to be created. Initially, sclerostomies (8-10, 8 mJ/300 microseconds pulses) and basal iridotomies (1-3, 4 mJ/200 microseconds pulses) were created with the larger probes. Problems encountered with this technique included corneal decompensation and rapid formation of peripheral anterior synechiae with occlusion of sclerostomies. The smaller endoprobes were then used to create mid-peripheral iridotomies and sclerostomies utilizing the same energy parameters. Sclerostomies created in this manner remained patent in the first postoperative week until the animals were sacrificed to obtain material for histologic study.

Animals↗
PubMed1998

A test of the relationship between sequence and structure in proteins: excision of the heme binding site in apocytochrome b5.

The water-soluble domain of rat hepatic holocytochrome b5 is an alphabeta protein containing elements of secondary structure in the sequence beta1-alpha1-beta4-beta3-alpha2-alpha3-beta5- alpha4-alpha5-beta2-alpha6. The heme group is enclosed by four helices, a2, a3, a4, and a5. To test the hypothesis that a small b hemoprotein can be constructed in two parts, one forming the heme site, the other an organizing scaffold, a protein fragment corresponding to beta1-alpha1-beta4-beta3-lambda-beta2-alpha6 was prepared, where lambda is a seven-residue linker bypassing the heme binding site. The fragment ("abridged b5") was found to contain alpha and beta secondary structure by circular dichroism spectroscopy and tertiary structure by Trp fluorescence emission spectroscopy. NMR data revealed a species with spectral properties similar to those of the full-length apoprotein. This folded form is in slow equilibrium on the chemical shift time scale with other less folded species. Thermal denaturation, as monitored by circular dichroism, absorption, and fluorescence spectroscopy, as well as size-exclusion chromatography-fast protein liquid chromatography (SEC-FPLC), confirmed the coexistence of at least two distinct conformational ensembles. It was concluded that the protein fragment is capable of adopting a specific fold likely related to that of cytochrome b5, but does not achieve high thermodynamic stability and cooperativity. Abridged b5 demonstrates that the spliced sequence contains the information necessary to fold the protein. It suggests that the dominating influence to restrict the conformational space searched by the chain is structural propensities at a local level rather than internal packing. The sequence also holds the properties necessary to generate a barrier to unfolding.

Amino Acid Sequence↗
PubMed2004

On the functional significance of electron density protein structure alignments.

Electron density protein alignments are analyzed in terms of their underlying similarity measure, the density overlap. These alignments are conceptually unrelated to biochemical structural elements and, therefore, are appropriate in structure-only similarity studies. The analysis is focused on the low sequence similarity subset of protein domains. A remarkable association is found between simple, density overlap measures and the expert designed Structural Classification of Proteins (SCOP) for which functional and evolutive analogies prevail. The association found validates the functional significance of electron density alignments.

Cluster Analysis↗
PubMed1996

Incorporating Monte Carlo simulation into physiologically based pharmacokinetic models using advanced continuous simulation language (ACSL): a computational method.

Biologically based models with physiological parameters are becoming more popular as a tool to estimate target tissue doses from chemical exposures. However, the majority of current physiologically based pharmacokinetic (PBPK) models do not take into account the uncertainty and/or variability within the various model parameters. Consideration of uncertainty is important to evaluate the predictive ability and complexity of a model as well as identification of parameters which contribute disproportionately to variability in model output. In order to estimate the uncertainty in PBPK model output, a versatile and simple computational method is presented which can be readily incorporated into the majority of PBPK models without extensive additions to model computer code. In this paper, a separate computer program for Monte Carlo simulation is furnished that randomly samples values for model parameters and writes them into a run-time language (command file) format which can then be utilized to execute individual PBPK models. Modifications to the PBPK model allow the desired output to be written to a data file for statistical analysis. The method presented in this paper is applied to a simple PBPK model for benzene disposition.

Algorithms↗
PubMed1996

Physiologically based pharmacodynamic modeling of an interaction threshold between trichloroethylene and 1,1-dichloroethylene in Fischer 344 rats.

Physiologically based pharmacokinetic modeling (PBPK) and gas uptake experiments have been used by researchers to demonstrate the competitive inhibition mechanism between trichloroethylene (TCE) and 1,1-dichloroethylene (DCE). Expanding on their work, we showed that this pharmacokinetic interaction was absent at levels of 100 ppm or less of either chemical in gas uptake systems. In this study, we further illustrate the presence of such an interaction threshold at the pharmacodynamic level by examining the interaction effect of either chemical on the other's ability to bind and deplete hepatic glutathione (GSH) in Fischer 344 rats. However, at this end point, the pharmacodynamic interaction is complicated by the ability of the liver to resynthesize GSH in response to its depletion. To quantitatively resolve the interaction effects on GSH content from the resynthesis effects, physiologically based pharmacodynamic (PBPD) modeling is applied. Initially, the PBPD model description of hepatic GSH kinetics was calibrated against previously published data and by gas uptake experiments conducted in our laboratory. Then, the model was used to determine the duration of the gas uptake exposure experiments by identifying the critical time point at which hepatic GSH is at a minimum in response to both chemicals. Subsequently, gas uptake experiments were designed following the PBPK/PD model predictions. In these model-directed experiments, DCE was the only chemical capable of significantly depleting hepatic GSH. The application of TCE to the rats at concentrations higher than 100 ppm obstructed the ability of DCE to deplete hepatic GSH. Since the metabolites of DCE bind to hepatic GSH, this obstruction signaled the presence of metabolic inhibition by TCE. However, TCE, at concentrations less than 100 ppm, was not effective in inhibiting DCE from significantly depleting hepatic GSH. The same observations were made when the ability of DCE to cause hepatic injury, as measured by aspartate aminotransferase serum activity, was assessed. Both conclusions validated the previous findings of the presence of the interaction threshold at the pharmacokinetic level.

Animals↗
PubMed1999

Metabolism of chloroform by cytochrome P450 2E1 is required for induction of toxicity in the liver, kidney, and nose of male mice.

Chloroform is a nongenotoxic-cytotoxic liver and kidney carcinogen and nasal toxicant in some strains and sexes of rodents. Substantial evidence indicates that tumor induction is secondary to events associated with cytolethality and regenerative cell proliferation. Therefore, pathways leading to toxicity, such as metabolic activation, become critical information in mechanism-based risk assessments. The purpose of this study was to determine the degree to which chloroform-induced cytotoxicity is dependent on the cytochromes P450 in general and P450 2E1 in particular. Male B6C3F(1), Sv/129 wild-type (Cyp2e1+/+), and Sv/129 CYP2E1 knockout (Cyp2e1-/- or Cyp2e1-null) mice were exposed 6 h/day for 4 consecutive days to 90 ppm chloroform by inhalation. Parallel control and treated groups, excluding Cyp2e1-null mice, also received an i.p. injection (150 mg/kg) of the irreversible cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) twice on the day before exposures began and 1 h before every exposure. Cells in S-phase were labeled by infusion of BrdU via an implanted osmotic pump for 3.5 days prior to necropsy, and the labeling index was quantified immunohistochemically. B6C3F(1) and Sv/129 wild-type mice exposed to chloroform alone had extensive hepatic and renal necrosis with significant regenerative cell proliferation. These animals had minimal toxicity in the nasal turbinates with focal periosteal cell proliferation. Administration of ABT completely protected against the hepatic, renal, and nasal toxic effects of chloroform. Induced pathological changes and regenerative cell proliferation were absent in these target sites in Cyp2e1-/- mice exposed to 90 ppm chloroform. These findings indicate that metabolism is obligatory for the development of chloroform-induced hepatic, renal, and nasal toxicity and that cytochrome P450 2E1 appears to be the only enzyme responsible for this cytotoxic-related metabolic conversion under these exposure conditions.

Administration, Inhalation↗
PubMed1992

A new polymorphism of thyroxin-binding globulin in three African groups (Mali) with endemic nodular goitre.

The thyroxin-binding globulin (TBG) polymorphism was investigated in three African groups: two belonged to the Bwa villages of Mali, and the third was a Dogon group living in the same area. The Bwa groups were characterized by the occurrence of nodular goitres, whereas the Dogon population did not show similar pathological symptoms. Females were more affected by goitre than males in the affected villages. The TBG polymorphism enabled us to demonstrate the presence of an undescribed allele (TBG C1) in these populations. The frequency of the TBG S allele was also higher than previously published in other African groups. We observed a disequilibrium in the distribution of the C and S alleles in the population, with an excess of homozygous TBG S individuals. No clear relationship between the TBG polymorphism and the number of nodules can be drawn.

Alleles↗
PubMed1993

Affinity differences for vitamin D metabolites associated with the genetic isoforms of the human serum carrier protein (DBP).

Human vitamin D binding protein (DBP) displays considerable polymorphism with 120 described alleles. Among these, three alleles are frequently observed, Gc 1F (pI 4.94-4.84), Gc 1S (pI 4.95-4.85) and Gc 2 (pI 5.1). Differences between these genetic forms of the protein in affinity for vitamin D metabolites have been detected by electrophoretic methods. The constant affinity (Ka) values determined in this study confirm these differences. The affinities of six rare variants were also examine. Those of the DBP genetic forms to the vitamin D derivatives 25-OH-D3 and 1,25-(OH)2-D3 seem to be related to the isoelectric point of the proteins: a high affinity corresponding to a low isoelectric point. The Gc 1A9 and 1A11 mutants were associated with higher affinity for the vitamin D derivatives and the Gc 1C1 and 1C21 mutants were deficient.

Calcifediol↗
PubMed1989

BamHI and SacI RFLPs of the human immunoglobulin IGHG genes with reference to the Gm polymorphism in African people. Evidence for a major polymorphism.

In this paper, we extend the study of the IGHG gene RFLPs in black African persons and in some other individuals characterized by a Negroid admixture. We demonstrate a polymorphism that is much more important in black Africans, than in Caucasoids, mainly for the IGHG3 and G1 genes, the most 5' members of the IGHG multigene family. These genes encode for the IgG3 and IgG1 subclasses, which are of crucial biological importance.

Alleles↗
PubMed1978

Analysis of the Gc polymorphism in human populations by isoelectrofocusing on polyacrylamide gels. Demonstration of subtypes of the Gc allele and of additional Gc variants.

For the study of the group-specific component (Gc) system, serum samples were examined by polyacrylamide gel electrophoresis and by a newly developed immunofixation isoelectrofocusing procedure. Thereby, a greater extent of polymorphic variation was revealed than was known previously. The allele Gc1 could be subdivided into the alleles Gc1F and Gc1S. The distribution of Gc1 subtypes was very different in three populations (Pygmies, Amerindians, and Pyreneans) examined. New variants of the Gc1 and Gc2 genes were also described in the Amerindians and in the Pygmy population, respectively.

Alleles↗
PubMed1981

Gc revisited: six further Gc-phenotypes delineated by isoelectric focusing and by polyacrylamide gel electrophoresis.

Six newly observed Gc variants are described. The variants Gc 1A10, 1A11, 1A12, 1A13, and 1C11 have double band patterns. The anodal bands of these variants are susceptible to neuraminidase treatment. Gc 2A7 is a single band variant which is not altered by neuraminidase incubation. Polyacrylamide gel isoelectrofocusing with immunofixation and polyarcylamide gel electrophoresis appear to be efficient methods for the analysis of the Gc system.

Alpha-Globulins↗
PubMed1983

A deficiency mutant of the Gc system.

In the course of a paternity investigation an apparent mother-child incompatibility was observed in the Gc system. An extensive family study was undertaken to test the hypothesis of a silent gene or null allele responsible for the contrary phenotypes: the mother had the type Gc 2, the son was GC 1. The apparent incompatibility was due to a "pseudo" silent allele, called Gc * 1, which controlled a group-specific component with extremely reduced serum concentrations. This double-band mutant could be differentiated from the Gc 1S bands by two-dimensional electrophoresis: isoelectric focusing (IEF)/6 M urea IEF. The allele Gc * 1 was found in 12 persons from this family, it was not associated with any apparent disease state. Also present in this family was the variant Gc 1C1. Pedigree analysis revealed a possible (not significant) distorted segregation ratio for the allele Gc * 1C1, which was found in 22 of 33 offspring from marriages with one parent heterozygous for Gc * 1C1.

Adult↗
PubMed1983

The polymorphism of the vitamin D-binding protein (Gc); isoelectric focusing in 3 M urea as additional method for identification of genetic variants.

Since the last report numerous new DBP (Gc) variants have been observed; at present a total of 84 different mutants can be distinguished. Several of them have similar electrophoretic mobilities and/or isoelectric points of conventional isoelectric focusing (IEF). IEF in polyacrylamide gels in the presence of 3 M urea is a convenient and efficient method for the detection of hidden variation.

Carrier Proteins↗
PubMed1985

Unusual sialilation of three different rare genetic variants of serum DBP: Gc1A17, Gc1A16, and Gc1A11.

The proteins of three anodal Gc1 variants, Gc1A16, 1A11, and 1A17, are characterized by the most acidic isoelectric points observed so far among the different Gc mutants. Stepwise removal of N-acetylneuraminic acid (NANA) by treatment with neuraminidase was performed to estimate the degree of sialilation of these Gc variants. The results indicate that both proteins, the anodal and the cathodal component of these Gc1 mutants, carry sialic acid residues. This observation is remarkable in so far as usually only the anodal component of the Gc1 protein contains NANA and only a single residue. From the experiments carried out it can be deduced that Gc1A16 has two NANA residues in the anodal and one NANA residue in the cathodal component. Gc1A16 was found in four members of three generations in a Danish family; the variant segregated as a Mendelian trait. More difficult to interpret are the results obtained with the variants Gc1A11 and Gc1A17. Gc1A11 probably has three NANA residues in the anodal and two NANA residues in the cathodal component. Gc1A11 has been observed in two mother-child pairs and is presumably also a simple genetic trait. Gc1A17 has also several NANA residues in both Gc proteins; it is suggested that the anodal component has either three or four NANA residues and the cathodal component either two or three NANA residues. Family information on this variant is not yet available.

Alleles↗
PubMed1982

Polymorphism of the haptoglobin peptides by isoelectric focusing electrophoresis and isoelectric point determinations.

In this investigation, the authors developed two new procedures: a micromethod for haptoglobin purification and the isoelectric focusing electrophoresis on slab polyacrylamide gel for peptide subtyping. These technics are adapted to the study of large sample series for population genetic surveys. The improvements obtained enabled us to disclose in an easy and highly reproducible way the Hp alpha and alpha 2 peptide chains. Electrophoretic separation of the alpha 2 FS, SS, and FF chains were greatly improved. Their frequencies estimated in a sample already investigated by the conventional PAGE presented higher values than previously described. New Hp alpha and alpha 2 mutants were also detected. For the first time, isoelectric points of the Hp peptides were determined; the values obtained are discussed with regard to their known amino acid structure.

Electrophoresis, Polyacrylamide Gel↗
PubMed1980

A new procedure for the determination of transferrin C (Tf C) subtypes by isoelectric focusing. Existence of two additional alleles, Tf C4 and Tf C5.

Isoelectric focusing (IEF) is widely used for the determination of serum protein polymorphisms in forensic investigations. Because of non-genetic heterogeneity of some proteins and of protein-ligand dissociation observed after IEF standardization of procedures is necessary. In this article the authors point out the main difficulties encountered in studying the transferrin subtype polymorphism and describe a new and sensitive method. Two new Tf C subtypes were observed: Tf C4 in North American, Bolivian and Brazilian Indians, Tf C5 in Black Americans, both with polymorphic allele frequencies. In a Pyrenean population the allele frequencies for Tf C1, Tf C2 and Tf C3 were quite similar to those observed in a German population sample.

Alleles↗