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J C Rutledge

Publications and source records attributed to J C Rutledge.

At least 55 records · Page 3Linked to original sources
PubMed1993

Renal and biliary abnormalities in a new murine model of autosomal recessive polycystic kidney disease.

Current models of autosomal recessive polycystic kidney disease (ARPKD) fail to demonstrate biliary abnormalities in association with renal cysts. We therefore studied a new murine model of ARPKD in which dual renal tubular and biliary epithelial abnormalities are present. Affected homozygous animals typically die 1 month postnatally in renal failure with progressively enlarged kidneys. Renal cysts shift in site from inner cortical proximal tubules at birth to collecting tubules 20 days later, as determined by segment-specific lectin binding. Increased numbers of mitosis were demonstrated in proximal and collecting tubular cysts. In addition, epithelial hyperplasia was demonstrated morphometrically in the intra- and extrahepatic biliary tract of affected animals. The number of intrahepatic biliary epithelial cells was increased by 50% on postnatal day 5 and by 100% on postnatal day 25 (P < 0.01). Despite an increased frequency of "chaotic" portal areas in mice with renal cysts, no intrahepatic cysts or shape abnormalities of the biliary lumen were detected using biliary casts and morphometry. Additionally there was nonobstructive hyperplastic dilatation of the extrahepatic biliary tract which was linked in all animals to the presence of renal cysts. The hyperplastic abnormalities in both renal and biliary epithelium make this new mouse strain a good model for the study of the dual organ cellular pathophysiology of ARPKD.

Animals↗
PubMed1992

Bleomycin: female-specific dominant lethal effects in mice.

Limited comparative data in mice indicate that chemical mutagens that induce dominant lethal mutations in males are not necessarily effective in females, but those which are effective in females are generally equally or more effective in males. Recently, however, a few chemicals have been identified that are female-specific with respect to induction of dominant lethal mutations. The antitumor antibiotic adriamycin is among them. Another antitumor antibiotic, bleomycin was examined for its ability to induce dominant lethal mutations in the reproductive cells of male and female mice. No dominant lethal or cytotoxic effects were observed in males treated with bleomycin, even at a maximum tolerated dose. In females, on the other hand, a dose nearly 1/4 of that used in males induced not only a high level of dominant lethal mutations but also killed oocytes in certain stages of follicular development. The effectiveness of bleomycin in inducing dominant lethal mutations in mouse oocytes makes it a valuable tool for investigating whether gonadal transport, inherent differences in the configuration of chromatin in the germ cells of the two sexes or other factors are responsible for the differential susceptibility to bleomycin, which implies potential gender-specific genetic risk in cancer chemotherapy.

Animals↗
PubMed1992

Developmental anomalies derived from exposure of zygotes and first-cleavage embryos to mutagens.

Results of continuing studies indicate that the mouse zygote and two-cell embryo stages are a window of susceptibility in the experimental induction of congenital anomalies with certain mutagenic agents. The mechanisms by which the mutagens initiate the pathogenesis of these developmental defects are not known. However, in certain cases there is evidence that a nonconventional, perhaps epigenetic, mechanism is involved. Detailed characterization of the spectrum of anomalies induced and comparison of responses at the various stages exposed allowed classification of the mutagens generally into two groups. One group is characterized by being effective only in the early stages of zygote development and capable of producing a relatively high incidence of fetal death and hydrops. The other group affects all of the zygote stages studied as well as the two cell-embryo, but does not increase the incidence of fetal death and hydrops. Except for hydrops, chemicals in the two groups do not differ in terms of the types of anomalies present among malformed live fetuses, which bear a resemblance to a subset of common, sporadic human developmental anomalies that are of unknown etiology. This similarity raises the possibility that certain human developmental defects may have their origins in events that happen in the zygote and early pre-implantation stages.

Abnormalities, Drug-Induced↗
PubMed1992

Desmin positivity in primitive neuroectodermal tumors of childhood.

In this report, we describe two rosette-forming primitive neuroectodermal tumors that were found to contain desmin by both immunohistochemistry and Western blotting. Electron microscopy on both cases was consistent with primitive neuroectodermal tumors and revealed that the tumor cells contained cytoplasmic bundles of intermediate filaments. In both cases, studies for MyoD1 protein using immunohistochemistry and Western blotting were negative. Thus, the detection of desmin in a pediatric neoplasm does not absolutely exclude the diagnosis of primitive neuroectodermal tumor and should not be considered as prima facie evidence that a small-cell tumor is a rhabdomyosarcoma.

Abdominal Neoplasms↗
PubMed1992

Temperature and hydrostatic pressure-dependent pathways of low-density lipoprotein transport across microvascular barrier.

To further investigate the chemical and physical nature of low-density lipoprotein (LDL) transport pathways across intact microvessels, the effect of changes in temperature and microvessel hydrostatic pressure were measured in individually perfused postcapillary vessels within frog mesenteric vascular beds. LDL microvessel transport was measured at two microvessel temperature ranges (18-21 degrees C and 4-6 degrees C) and compared with transport of fluorescein, a small solute. Also, LDL transport was measured at a series of hydrostatic pressures (3-20 cmH2O) at microvessel temperatures of 18-21 degrees C and 4-6 degrees C to determine whether LDL transport was coupled to water flow, which would be evidence for hydraulic pathways of solute transport across the microvascular barrier. Quantitative fluorescence microscopy was employed to determine apparent solute permeability coefficients (Ps) under the various temperature and hydrostatic pressure conditions studied. The ratio of Ps fluorescein 18-21 degrees C/4-6 degrees C [1.6 +/- 0.3 (SD)] indicated that fluorescein was freely diffusible across the microvascular barrier through water-filled pathways as transport was inversely proportional to temperature-dependent changes in viscosity. The larger ratio for LDL (Ps LDL 18-21/4-6 degrees C = 9.5 +/- 8.1) than for fluorescein cannot be explained by LDL transport through fixed hydraulic pathways alone and suggests additional or alternate LDL transport mechanisms. In addition, Ps LDL increased as microvessel hydrostatic pressure increased at microvessel temperatures of 18-21 degrees C but not at 4-6 degrees C. Coupling of LDL transport to water flow at the high microvessel temperature range, but not at the low range, indicated the presence of a hydraulic transport pathway that was effectively absent when the microvessel was cooled. These results demonstrated a highly temperature and hydrostatic pressure-dependent LDL pathway that is consistent with a dynamic porous extracellular or transcellular mechanism of LDL transport.

Animals↗
PubMed1990

Extravascular distribution of low-density lipoprotein and dextran in a high-permeability state.

Previous studies from this laboratory indicated that in the early phase of a high-permeability state, low-density lipoprotein (LDL) crosses the microvascular barrier by porous pathways. To determine the extravascular distribution of LDL (3,500,000 MW) and a smaller reference macromolecule [20,000 MW dextran (D20)] image processing techniques were employed, and extravascular accumulation of solutes from different microvessels was compared to quantitative fluorescence microscopy. Frog mesenteric venular microvessels (n = 8) were cannulated and perfused with fluorescent-labeled LDL and D20 and extravascular distribution of both solutes was imaged at control and after permeability was increased with the calcium ionophore ionomycin (5 microM). At the peak increase in apparent permeability (2-4 min after ionophore), the processed images of the microvessels demonstrated that the extravascular distribution of fluorescent-labeled solute was not uniform and that D20 accumulated outside the microvessel wall in some areas where LDL did not accumulate. The patterns of extravascular accumulation of LDL and D20 in a high-permeability state imply a distribution of effective microvascular pore sizes and/or a distribution of resistances to solute flow in the pore or in the tissue surrounding the microvessel.

Abdomen↗
PubMed1990

Increased incidence of developmental anomalies among descendants of carriers of methylenebisacrylamide-induced balanced reciprocal translocations.

N,N'-Methylenebisacrylamide (MBA), a dimer of the monomeric acrylamide, was studied for induction of clastogenic effects in germ cells of male mice. It was found to be effective in inducing dominant-lethal mutations and heritable translocations in maturing sperm. The semisterile translocation carriers and their normal counterparts were used to determine the health impact of transmitted chromosomal rearrangements through anatomical analysis of their immediate descendants in utero. As expected, semisterility resulted primarily from embryonic death during the periimplantation stages presumably caused by sperm segregants with unbalanced chromosome complement fertilizing some of the eggs. Among conceptuses that survived to mid- and late-gestation stages, there was an increased incidence of developmental anomalies including fetal death and phenotypic defects. These anomalies are assumed to be caused by certain types of unbalanced segregants that are compatible with survival beyond the periimplantation period. This class of unbalanced segregants represent in humans a major health problem to the mother and her conceptus.

Acrylamides↗
PubMed1990

Molecular and genetic characterization of a radiation-induced structural rearrangement in mouse chromosome 2 causing mutations at the limb deformity and agouti loci.

Molecular characterization of mutations in the mouse, particularly those involving agent-induced major structural alterations, is proving to be useful for correlating the structure and expression of individual genes with their function in the whole organism. Here we present the characterization of a radiation-induced mutation that simultaneously generated distinct alleles of both the limb deformity (ld) and agouti (a) loci, two developmentally important regions of chromosome 2 normally separated by 20 centimorgans. Cytogenetic analysis revealed that an interstitial segment of chromosome 17 (17B- 17C; or, possibly, 17A2-17B) had been translocated into the distal end of chromosome 2, resulting in a smaller-than-normal chromosome 17 (designated 17del) and a larger form of chromosome 2 (designated 2(17). Additionally, a large interstitial segment of the 2(17) chromosome, immediately adjacent and proximal to the insertion site, did not match bands 2E4-2H1 at corresponding positions on a normal chromosome 2. Molecular analysis detected a DNA rearrangement in which a portion of the ld locus was joined to sequences normally tightly linked to the a locus. This result, along with the genetic and cytogenetic data, suggests that the alleles of ld and a in this radiation-induced mutation, designated ldIn2 and ajIn2, were associated with DNA breaks caused by an inversion of an interstitial segment in the 2(17) chromosome.

Abnormalities, Radiation-Induced↗
PubMed1990

Graded modulation of frog microvessel permeability to albumin using ionophore A23187.

We investigated the exchange of water and macromolecules across venular microvessels after permeability was increased. Quantitative fluorescence microscopy was used to measure albumin permeability coefficients in individually perfused microvessels of decerebrate frogs. Control permeability coefficient was 2.3 +/- 0.25 X 10(-7) cm/s. Solvent drag increased the apparent solute permeability coefficient (Ps) by 0.57 +/- 0.05 X 10(-7) cm/s for each cmH2O increase in microvessel pressure. The divalent cation ionophore A23187 (0.1-5 microM) produced a transient increase in Ps to a peak value (within 1-3 min), followed (after 4-8 min) by a sustained increase in permeability (16-34% of peak values). Peak values of Ps were 13 and 80 times control for 0.1 and 5 microM A23187, respectively. Both diffusion and solvent drag contributed to the sustained increase in Ps. The equivalent pore radius of the structures determining diffusion and solvent drag was less than or equal to 25 nm during the sustained increase in permeability, smaller than observed gaps between adjacent endothelial cells. The basement membrane and a fibrous matrix secreted by endothelial cells into the gaps may offer resistance to exchange in the high permeability state.

Animals↗
PubMed1990

Low density lipoprotein transport across a microvascular endothelial barrier after permeability is increased.

We investigated the pathways for low density lipoprotein (LDL) transport across an endothelial barrier in individually perfused microvessels before and after an increase in permeability. The divalent cation ionophore A23187 (5 microM) was used to increase microvessel permeability. LDL permeability coefficients (PsLDL) were measured using quantitative fluorescence microscopy. In the control state, PsLDL measured after 10-23 minutes of accumulation of fluorescent-labeled LDL outside the microvessel wall was 4.8 x 10(-8) cm/sec. The transvascular vesicular exchange of approximately 50 vesicles/sec would account for the measured flux. The flux of LDL across the microvessel wall increased as much as 170-fold at the peak of the permeability increase (2-4 minutes after ionophore infusion). Permeability returned toward control values 10 minutes after ionophore infusion but remained elevated for as long as ionophore was present in the perfusate. The effective PsLDL was similar in magnitude to the Ps for fluorescent-labeled dextran (MW 20,000) when permeability was increased. To investigate the nature of pathways for LDL in the high-permeability state, PsLDL was measured at a series of microvessel pressures. LDL transport increased as microvessel pressure increased, demonstrating coupling of LDL flux to transvascular water flow. Solvent drag accounted for more than 95% of the increased flux of LDL in the period 2-10 minutes after permeability increased. Our results conform to the hypothesis that porous pathways between adjacent endothelial cells contribute to LDL transport across an endothelial barrier when permeability is increased.

Animals↗
PubMed1989

Fetal pathology produced by ethylene oxide treatment of the murine zygote.

Exposure of female mice to ethylene oxide by inhalation 1 or 6 h after mating produced not only multitemporal death of conceptuses but also high rates of abnormalities among surviving fetuses. In contrast, only marginal effects were observed when females were exposed 9 or 25 h after mating. The abnormalities found among 17 day gestation live fetuses were predominated by hydrops and eye defects, which, together, constitute 54% of all anomalies. Most of the remaining anomalies were distributed among 5 other types: small size, cleft palate, and cardiac, abdominal wall, or extremity and/or tail defects. In a follow-up study, the fetuses of females treated 6 h postmating were examined at 11-15 days gestation and the progression of fetal death and of malformations was studied. Results indicate that the expression of most fetal anomalies does not become apparent until late in gestation. Several of these induced anomalies are similar to common human sporadic birth defects. This new class of experimentally induced fetal anomalies provides a new avenue for investigating zygotic biology and a system for studying the progression of aberrant development.

Animals↗
PubMed1989

Ovarian torsion and amputation resulting in partially calcified, pedunculated cystic mass.

Three children with torsion and amputation of the right ovary are presented. The detached ovary resulted in a cystic mass containing necrotic material and a solid, partially calcified mural node. The cysts were attached to the omentum, to the mesentery of the transverse colon, or to the lower edge of the liver by a long twisted pedicle containing thin-walled vascular spaces. The radiographic and sonographic findings were quite similar and clearly reflected the operative and pathologic changes.

Abdomen↗
PubMed1989

Fetal anomalies produced subsequent to treatment of zygotes with ethylene oxide or ethyl methanesulfonate are not likely due to the usual genetic causes.

Earlier studies in this laboratory revealed that ethylene oxide (EtO) or ethyl methanesulfonate (EMS) induced high frequencies of midgestation and late fetal deaths, and of malformations among some of the surviving fetuses, when female mice were exposed at the time of fertilization of their eggs or during the early pronuclear stage of the zygote. Effects of the two mutagens are virtually identical. Thus, in investigating the mechanisms responsible for the dramatic effects in the early pronuclear zygotes, the two compounds were used interchangeably in the experiments. First, a reciprocal zygote-transfer study was conducted in order to determine whether the effect is directly on the zygotes or indirectly through maternal toxicity. And second, cytogenetic analyses of pronuclear metaphases, early cleavage embryos, and midgestation fetuses were carried out. The zygote transplantation experiment rules out maternal toxicity as a factor in the fetal maldevelopment. Together with the strict stage specificity observed in the earlier studies, this result points to a genetic cause for the abnormalities. However, the cytogenetic studies failed to show structural or numerical chromosome aberrations. Since intragenic base changes and deletions may also be ruled out, it appears that the lesions in question induced in zygotes by the two mutagens are different from conventional ones and, therefore, could be a novel one in experimental mammalian mutagenesis. Alternatively, the mechanism could involve a non-mutational 'imprinting' process that caused changes in gene expression.

Abnormalities, Drug-Induced↗
PubMed1989

Pediatric specimen collection for chemical analysis.

Laboratory tests can be an important factor in patient care and health care costs. To maximize their utility and cost effectiveness, one must be aware of factors that can compromise their accuracy. The process from choice of tests to interpretation of results is complex, but it can be successfully completed if the variables discussed in this article are minimized. Note: Since submission of this manuscript, an article summarizing the neonatal experience at Columbus Children's Hospital and several surveyed pediatric hospitals has been published. This article reviews methods and provides numerous suggestions on improving technique.

Blood Specimen Collection↗
PubMed1989

Bilirubin and the laboratory. Advances in the 1980s, considerations for the 1990s.

The limitations of current methods of measuring bilirubin are well established and relate to the broad dynamic range and inability of the technique to determine different but structurally similar bilirubin species. New instrumentation and methodology circumvent these limitations, and clinical studies are beginning to reveal their increased diagnostic usefulness. Nevertheless, in several clinical situations, for example, the prediction of kernicterus, better bilirubin determinations may not eliminate the controversy surrounding appropriate therapeutic interventions.

Bilirubin↗
PubMed1989

Modulation of microvessel wall charge by plasma glycoprotein orosomucoid.

Haraldsson and Rippe suggested that the circulating glycoprotein orosomucoid (alpha 1-acid glycoprotein) contributes to the net charge on microvessel walls (Acta Physiol. Scand. 129: 127-135, 1987). We tested their hypothesis in individually perfused microvessels of frog mesentery by measuring solute permeability coefficients of two globular proteins (alpha-lactalbumin and ribonuclease) having approximately the same size (Stokes radius, 2 nm) but different charge (-11 and +3, respectively). In vessels perfused with orosomucoid (0.1 and 1 mg/ml) in a Ringer-albumin perfusate, the solute permeability coefficient of alpha-lactalbumin decreased to one-half [0.47 +/- 0.25 (SD)] the value in the absence of orosomucoid, and the solute permeability coefficient of ribonuclease was close to six times as large as alpha-lactalbumin permeability. Both results may be accounted for if orosomucoid increases the net negative charge on microvessel walls in frog mesentery from 11.2 to 28 meq/l. A similar change in microvessel charge would be more than sufficient to account for the decrease in albumin clearance in the presence of orosomucoid reported by Haraldsson and Rippe in rat muscle microvessels.

Animals↗
PubMed1989

Research advances in prenatal craniofacial development: report of a conference and review of topics.

Cell biology techniques are now being applied to classical embryology. Although many of us are afforded the opportunity to see developmental maladies in our practice, the fetal stage at which we examine these patients is often well past the time at which we could have applied the same tools to gain an understanding of the pathogenesis. We can, however, provide the end-stage correlations to naturally or artificially perturbed morphogenesis by directing our examinations to anatomic areas that correlate with those seen in experimental models or which are derived from similar, not necessarily regional, precursors or by similar developmental steps. More importantly, these experimental studies provide us a route (perhaps an escape route) from the blind-ending alleys of the current taxonomy of human malformations and place us squarely on the superhighway to understanding their pathogenesis. We are more likely to develop a greater understanding for the end-stage structure if we have had a glimpse of the blueprints for its design. I recommend the conference proceedings for an in-depth, illustrated treatise on craniofacial development.

Animals↗