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Biomedical subjects

D K Hansen

Publications and source records attributed to D K Hansen.

At least 19 recordsLinked to original sources
PubMed2006

Changes in gait associated with acute stage II posterior tibial tendon dysfunction.

The purpose of this study was to examine differences in gait mechanics between patients with acute stage II PTTD and healthy volunteers. Hindfoot and midfoot kinematics, plantar foot pressures and electromyographic (EMG) activity of the posterior tibialis, gastrocnemius, anterior tibialis and the peroneals were measured in five patients with acute stage II PTTD. Kinematics and kinetics were compared to a database of 20 healthy volunteers. EMG and plantar pressure data were obtained from five healthy volunteers. Hindfoot moments and powers were also calculated. The center of pressure excursion index (CPEI) was calculated from the plantar pressures. Significant differences were observed between the two groups, which confirmed clinical observations. Limited hindfoot eversion and increased midfoot external rotation occurred during the first and third rockers. The EMG data suggested that tendon dysfunction in the posterior tibialis is associated with compensatory activity, not only in its antagonists (the peroneals), but also in the anterior tibialis and the gastrocnemius. These data suggest that non-operative treatment of patients with PTTD should consider minimizing the activity of the posterior tibialis as well as the peroneals, the anterior tibialis and the gastrocnemius.

Adult↗
PubMed2002

Comparison of in vitro BBMEC permeability and in vivo CNS uptake by microdialysis sampling.

The studies presented in this report were designed to assess the correlation of the bovine brain microvessel endothelial cell (BBMEC) apparent permeability coefficient (P(app)) and in vivo BBB penetration using microdialysis sampling. A mathematical model was developed to describe the relationship of brain extracellular fluid (ECF) concentration to free drug in plasma. The compounds studied have a broad range of physico-chemical characteristics and have widely varying in vitro and in vivo permeability across the blood-brain barrier (BBB). BBMEC permeability coefficients vary in magnitude from a low of 0.9 x 10(-5) cm/s to a high value of 7.5 x 10(-5) cm/s. Corresponding in vivo measurements of BBB permeability are represented by clearance (CL(in)) into the brain ECF and range from a low of 0.023 microl/min/g to a high of 12.9 microl/min/g. While it is apparent that in vitro data from the BBMEC model can be predictive of the in vivo permeability of a compound across the BBB, there are numerous factors both prior to and following entry into the brain which impact the ultimate uptake of a compound. Even in the presence of high BBB permeability, factors such as high plasma protein binding, active efflux across the BBB, and metabolism within the CNS can greatly limit the ultimate concentrations achieved. In addition, concentrations in the intracellular space may not be the same as concentrations in the extracellular space. While these data show that the BBMEC permeability is predictive of the in vivo BBB permeability, the complexity of the living system makes prediction of brain concentrations difficult, based solely on the in vitro measurement.

Animals↗
PubMed2001

Isolation and characterization of a folate receptor mRNA-binding trans-factor from human placenta. Evidence favoring identity with heterogeneous nuclear ribonucleoprotein E1.

The interaction of an 18-base cis-element in the 5'-untranslated region of human folate receptor (FR)-alpha mRNA with a cytosolic trans-factor protein is critical for the translation of FR (Sun, X.-L., and Antony, A. C. (1996) J. Biol. Chem. 271, 25539-25547). This trans-factor was isolated to apparent homogeneity as a 43- and 38-kDa doublet from human placenta using poly(U)-Sepharose, followed by preparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis and electro-elution as major purification steps. Amino acid microsequencing of two cyanogen bromide-generated peptide fragments of the 43-kDa trans-factor revealed complete identity with 43-kDa heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1). Purified specific rabbit anti-hnRNP E1 peptide antibodies (generated against a synthetic oligopeptide that was not represented in microsequenced peptides of the trans-factor) also recognized the purified trans-factor on Western blots. Conversely, the 18-base FR RNA cis-element also bound hnRNP E1 protein on Northwestern blots. Moreover, a 19-base RNA cis-element in the 3'-untranslated region of 15-lipoxygenase mRNA that is known to bind hnRNP E1 also interacted with placental 43-kDa trans-factor. In addition, several murine tissues containing a hnRNP E1-related protein (also known as alphaCP-1) readily interacted with the 18-base FR RNA cis-element. Finally, anti-hnRNP E1 antibodies specifically inhibited translation of FR in vitro in a dose-dependent manner, and the antibody effect could be reversed in a dose-dependent manner by either purified trans-factor or hnRNP E1. Collectively, the data favor identity of the FR mRNA-binding trans-factor and hnRNP E1, confirm its critical role in the translation of FR, and highlight yet another role of multifunctional hnRNP E1 in eukaryotic mRNA regulation.

Amino Acid Sequence↗
PubMed2001

Minimal effects from developmental exposure to St. John's wort (Hypericum perforatum) in Sprague-Dawley rats.

Increasing widespread use of St. John's Wort (SJW, Hypericum perforatum) has led to concerns about its use in pregnant women. Behavioral and physiological alterations resulting from developmental treatment were investigated in Sprague-Dawley rats exposed to diets containing 0, 180, 900, 1800 or 4500ppm SJW beginning on gestational day 3 and ending at offspring weaning on postnatal day (PND) 21. These dietary doses span 1-25 times the recommended human dose. Post-weaning behavioral assessments of male and female offspring included: open field activity, acoustic startle, performance of complex and Morris water mazes, and activity in an elevated plus-maze. There were no SJW effects on maternal weight gain or duration of gestation; offspring body weights were similar to controls from PND 2 through PND 56 after which, some treated groups weighed significantly less than the controls. There were no SJW-related behavioral alterations on any measure. Whole and regional brain weights of offspring at adulthood indicated no significant effects of SJW. These results indicate that there are few neurobehavioral alterations resulting from developmental SJW treatment in rats.

Animals↗
PubMed2001

An overview of rodent toxicities: liver and kidney effects of fumonisins and Fusarium moniliforme.

Fumonisins are produced by Fusarium moniliforme F. verticillioides) and other Fusarium that grow on corn worldwide. They cause fatal toxicoses of horses and swine. Their effects in humans are unclear, but epidemiologic evidence suggests that consumption of fumonisin-contaminated corn contributes to human esophageal cancer in southern Africa and China. Much has been learned from rodent studies about fumonisin B1(FB1), the most common homologue. FB1 is poorly absorbed and rapidly eliminated in feces. Minor amounts are retained in liver and kidneys. Unlike other mycotoxins, fumonisins cause the same liver cancer promotion and subchronic (studies (3/4) 90 days) liver and kidney effects as (italic)F. moniliforme. FB 1 induces apoptosis of hepatocytes and of proximal tubule epithelial cells. More advanced lesions in both organs are characterized by simultaneous cell loss (apoptosis and necrosis) and proliferation (mitosis). Microscopic and other findings suggest that an imbalance between cell loss and replacement develops, a condition favorable for carcinogenesis. On the molecular level, fumonisins inhibit ceramide synthase, and disrupt sphingolipid metabolism and, theoretically, sphingolipid-mediated regulatory processes that influence apoptosis and mitosis. Liver sphingolipid effects and toxicity are correlated, and ceramide synthase inhibition occurs in liver and kidney at doses below their respective no-observed-effect levels. FB1 does not cross the placenta and is not teratogenic in vivoin rats, mice, or rabbits, but is embryotoxic at high, maternally toxic doses. These data have contributed to preliminary risk evaluation and to protocol development for carcinogenicity and chronic toxicity studies of FB1 in rats and mice.

Animals↗
PubMed2000

Hypothesis: folate-responsive neural tube defects and neurocristopathies.

BACKGROUND: What accounts for the wide spectrum of folate-responsive dysmorphogeneses? Both embryonic and fetal cells are entirely dependent on maternal folate to support their requirement for precisely timed proliferative bursts during gestation. Folate receptors (FRs) mediate transport into cells and are central to transplacental maternal-to-fetal folate transport. FRs are also critical for neural tube and neural crest development because recent murine "knock-out" and "knock-down" of FRs results in a high percentage of folate-responsive neural tube defects (NTDs) and neurocristopathies. HYPOTHESIS: Central to our hypothesis is the fact that folate deficiency is accompanied by a reduction in the proliferative capacity of highly mitotic neural tube or neural crest cells. Therefore, depending on when in pregnancy various cohorts of highly proliferative cells are deprived of folate, and the origin of the affected cells will determine the type of developmental dysmorphogenesis. Thus, selective folate deficiency in early pregnancy of only highly proliferative neural tube or neural crest cells predisposes to NTDs or gross dysmorphogenesis, respectively. Folate deficiency that compromises placental development will predispose to small-for-date babies due to an overall nutrient deficiency, and the development of folate insufficiency later in pregnancy could predispose to more subtle midline birth defects involving atresia of neural crest cell-derived structures. Finally, a congenital folate transport defect would only be corrected by suprapharmacological doses of folate, which ensures passive diffusion. CONCLUSION: This hypothesis can explain the results of several earlier and more recent clinical trials on folate supplementation in pregnancy, but it also raises the possibility that there may be several as yet undiscovered neurocristopathies that are folate responsive. Teratology 62:42-50, 2000. Published 2000 Wiley-Liss, Inc.

Animals↗
PubMed1999

Food and Drug Administration proposed testing guidelines for reproduction studies. Revision Committee. FDA Guidelines for Developmental Toxicity and Reproduction, Food and Drug Administration.

In the United States, the Food and Drug Administration (FDA) is the agency responsible for ensuring that the direct food additives and color additives used in food are safe for all consumers. In order to determine the safety of these additives for consumption, appropriate information and results from a series of tests must be made available to the agency. In 1982, in an effort to provide guidance to the food industry concerning the appropriate tests for the determination of safety, the FDA issued the Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Foods, commonly referred to as the Redbook. In 1993, based on the expansion of technology and the use of food additives, as well as the refinement of the scientific criteria for establishing safety, the FDA updated its guidelines and issued the draft Redbook II. Since Redbook II was issued, additional refinements have been made in the procedures for the multigeneration reproduction study and for the assessment of effects on male reproduction. The latest proposed guidelines for multigeneration studies are provided here.

Animals↗
PubMed1999

Food and Drug Administration proposed testing guidelines for developmental toxicity studies. Revision Committee. FDA Guidelines for Developmental Toxicity and Reproduction, Food and Drug Administration.

The Food and Drug Administration (FDA) is the agency responsible for ensuring that the direct food additives and color additives used in food in the United States are safe for all consumers. In 1982, in an effort to provide guidance concerning appropriate tests, the FDA issued Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food, commonly known as the Redbook. The Redbook included detailed guidelines for testing the effects of direct and indirect food and color additives on mothers and their developing fetuses. Based on refinements in safety assessment and risk evaluation as well as expansion of knowledge concerning the metabolism and pharmacokinetics of food and color additives, the need to revise and update the 1982 document became apparent. In 1993, Redbook II in draft form was made available for public comment. Since then, test end points and developmental landmarks have been refined. The latest proposed guidelines for developmental toxicity studies are provided here.

Animals↗
PubMed1999

Pharmacokinetic considerations of dexamethasone-induced developmental toxicity in rats.

Dexamethasone (DEX) has been shown to elicit growth stunting and cleft palate in rat fetuses. This investigation characterized DEX dosimetry as various pharmacokinetic parameters and evaluated their impact on developmental toxicity endpoints. DEX pharmacokinetics was evaluated as a single dose on either gestation day (GD) 9 or 14, as well as on GD 14 after multiple daily dosing from GD 9 to GD 14. An additional set of pregnant rats was dosed with DEX on GD 9 through GD 14, pharmacokinetic evaluation was conducted on GD 14 through GD 16, and teratological evaluation was conducted following sacrifice on GD 20. For all pharmacokinetic evaluations, a subcutaneous (sc) injection of 0.8 mg DEX/kg body weight together with 50 microCi 3H-DEX was administered to Sprague-Dawley rats. Blood, urine, and feces were collected for 24 or 48 h. At GD 20 sacrifice, maternal tissues as well as fetal brain and liver samples were collected as part of the laparotomy. All samples were assayed using scintillation spectrometry. DEX pharmacokinetic parameters remained similar whether dosing occurred early (GD 9) or late (GD 14) in organogenesis, or dosing occurred on multiple sequential days (GD 9-14). DEX produced maternal and fetal weight loss, fetal lethality, and cleft palate. DEX a-half-life was positively correlated with the percentage of implants affected [(number of non-live + number with cleft palate)/number of implants]/litter. Neither the area under the concentration-time curve (AUC), the maximum maternal plasma concentration (Cmax), nor the terminal phase beta-half-life correlated with any fetal outcome parameters. The correlation between the percentage of the litter that was affected and half-life was improved if AUC was added in a stepwise multiple regression. These data suggest that the length of time that DEX is present in the maternal plasma at a sufficiently high concentration (i.e., slower tissue distribution of DEX) appears to be important in determining the risk of an adverse outcome in the offspring.

Abnormalities, Drug-Induced↗
PubMed1998

Effects of fumonisin B1 in pregnant rats.

Fumonisin B1 (FB1), the major mycotoxin from Fusarium moniliforme, has been implicated as a causative agent in several animal and human diseases. Despite animal toxicity studies and human epidemiological studies of FB1, knowledge of its reproductive effects is scarce. In this study, one of a series of proposed studies that will allow extrapolation to humans, pregnant rats were given oral doses of 0, 1.875, 3.75, 7.5 or 15 mg FB1/kg on gestation days 3 16. Caesarean sections were performed on day 17 or 20, and maternal condition, implantation efficiency, foetal viability and foetal development were measured. Dose-related decreases in overall feed consumption and body weight gain were seen, but only the feed consumption decrease at 15 mg/kg, and the decreased body weight gain at 15 mg/kg on days 0-17 were statistically significant. Foetal body weights at day 17 were similar in control and treated groups; but in day-20 foetuses, female weight and crown-rump length were significantly decreased at 15 mg/kg. FB1 was not teratogenic at the doses tested, and no dose-related effects were seen in either skeletal or soft-tissue development. In day-17 animals, maternal and foetal brain, liver and kidney tissues, and maternal serum were preserved to study the levels of sphinganine (Sa), sphingosine (So), and the Sa/So ratios. Dose-related increases were seen in Sa/So ratios in maternal livers, kidneys and serum. Sa/So ratios of maternal brains were not affected, nor were those of foetal kidneys, livers or brains.

Abnormalities, Drug-Induced↗
PubMed1998

Effects of fumonisin B1 in pregnant rats. Part 2.

The developmental toxicity of purified fumonisin B1 (FB1), a mycotoxin from the common corn fungus Fusarium moniliforme, was examined in Charles River rats. Pregnant rats were dosed orally on gestation days 3-16 at 0, 6.25, 12.5, 25 or 50 mg FB1/kg body weight/day. FB1 was not teratogenic at the doses tested. At 50 mg/kg, maternal toxicity (inappetence, emaciation, lethargy, death, resorption of entire litters) and foetal toxicity (increased number of late deaths, decreased foetal body weight, decreased crown rump length, increased incidence of hydrocephalus, increased incidence of skeletal anomalies) were seen. The foetal toxicity observed at 50 mg/kg may be related to maternal toxicity. Histopathological evaluation of tissues from dams of control and all treated groups revealed dose-related toxic changes in kidney and liver tissues. Acute toxic tubular nephrosis was seen in kidneys from all treated groups. Hepatocellular cytoplasmic alteration and individual cellular necrosis of the liver was seen in the two high-dose groups. Sphinganine (Sa) and sphingosine (So) were measured in day-17 adult and foetal tissues. Dose related increases in Sa/So ratios were seen in maternal liver, kidney, serum and brain, but there was no effect on foetal liver, kidney and brain. These data suggest that FB1 does not cross the placenta and further suggest that the observed foetal toxicity is a secondary response to maternal toxicity.

Animals↗
PubMed1997

Determination of kynurenic acid by capillary electrophoresis with laser-induced fluorescence detection.

Kynurenic acid (KA) is an excitatory amino acid receptor antagonist that is believed to play an important role in a host of diseases of the neuropsychiatric and central nervous system. A method for the determination of KA in microdialysate samples using capillary electrophoresis (CE) separation with laser-induced fluorescence (LIF) detection is described. CE is advantageous for the analysis of microdialysis samples due to its short analysis times and small sample volume requirements. Three complexation approaches were evaluated in an attempt to achieve the best limit of detection. The best approach was found to be pre-column complexation with inclusion of Zn(II) in the background electrolyte. After optimization of the zinc acetate concentration and pH, a limit of detection of 1 nM KA was achieved. However, when KA was present in the dialysate, the limit of detection increased 50-fold. Even though the endogenous levels of KA in rat brain are below this limit of detection, this methodology could be used to monitor the increase of KA levels in rat brain following dosing with its precursors, tryptophan and kynurenine.

Animals↗
PubMed1997

Antenna excited state decay kinetics establish primary electron transfer in reaction centers as heterogeneous.

The decay of the excited primary electron donor P* in bacterial photosynthetic reaction centers (both membrane-bound and detergent-isolated) has been observed to be nonexponential on a time scale of some tens of picoseconds. Although the multipicosecond nonexponentiality of P* has been ascribed to heterogeneity in teh rate of primary electron transfer (PET), the decay kinetics can be interpreted equally well using homogeneous models. To address this ambiguity, we studied the decay of excited bacteriochlorophyll (Bchl) in the membrane-bound core antenna/reaction center complexes of wild-type and mutant reaction center strains of Rhodobacter capsulatus. Reaction centers isolated from these same strains display a range of multiexponentiality in primary charge separation. The mutant strains carry substitutions of amino acids residing near the monomeric Bchl on the active and/or inactive sides of the reaction center. Transient absorption measurements monitoring the Qy bleach of antenna Bchls require at least two exponential components to fit all decays. The wild type was fitted with equal-amplitude components whose lifetimes are 24 and 65 ps. The shortest-lived component is relatively insensitive to mutation, in contrast to the longer-lived component(s) whose amplitude and magnitude were dramatically perturbed by amino acid substitutions. Unlike the situation with isolated reaction centers, here the only kinetic models consistent with the data are those in which the primary electron-transfer rate constant is heterogeneous, suggesting at least two structural populations of RCs. PET in the population with the shortest-lived antenna decay causes the kinetics to be transfer-to-trap-limited, whereas the kinetics in the other population(s)--having longer-lived antenna decays--are limited by the rate of PET. Observation of both types of kinetic limitation within a single light-harvesting system is unexpected and complicates any discussion of the rate-limiting step of light energy utilization in photosynthesis.

Bacterial Proteins↗
PubMed1997

Lack of embryotoxicity of fumonisin B1 in New Zealand white rabbits.

Fumonisin B1 (FB1) is one of a number of mycotoxins produced by fungi, especially Fusarium sp. As a contaminant of many maize-derived products, this toxin is associated with a variety of animal diseases, including esophageal cancer and possibly neural tube defects in humans. We have investigated the embryotoxic potential of this compound in New Zealand White rabbits. Animals were dosed by gavage daily on GD 3-19 with purified FB1 at 0.10, 0.50, or 1.00 mg/kg/day. Maternal lethality occurred at the 0.50 and 1.00 mg/kg/day doses. When examined on GD 29, there were no differences in maternal body weight, maternal weight gain, maternal organ weights, number of nonlive implantations, and number of malformations. Fetal weight was decreased at 0.50 and 1.00 mg/kg/day (13 and 16%, respectively); this was true for male and female pups. Fetal liver and kidney weights were also decreased at these doses. Analysis of embryonic sphinganine to sphingosine ratios demonstrated no differences between control and treated embryos on GD 20, although these ratios were increased in maternal urine, serum, and kidney when compared to control animals. These data suggest that FB1 did not cross the placenta and that the observed decreased fetal weight was probably the result of maternal toxicity, rather than any developmental toxicity produced by FB1.

Acyltransferases↗
PubMed1996

In vitro embryotoxicity of carbamazepine and carbamazepine-10, 11-epoxide.

Carbamazepine (Tegretol, CBZ) is an anticonvulsant drug that is very effective in the treatment of tonic-clonic seizures and is gaining acceptance as a treatment for various psychiatric disorders. The drug is embryotoxic in rodents and has been reported to produce neural tube defects in approximated 1% of prenatally exposed human offspring. It is metabolized by the cytochrome P-450 system to a stable, pharmacologically active epoxide intermediate, carbamazepine-10, 11-epoxide. It is currently unknown whether the parent compound, the epoxide intermediate or some other metabolite is the embryotoxic agent. The present study was designed to determine the embryotoxicity of CBZ and its epoxide intermediate (CBZ-E) in a rodent whole embryo culture system. Rat embryos were cultured beginning on day 9 of gestation (GD 9), and mouse embryos were cultured beginning in GD 8. All embryos were cultured for 48 hr in medium containing various concentrations of either CBZ or CBZ-E. Mice were more sensitive to the effects of CBZ than were rats. The parent compound was embryotoxic to mouse embryos at concentrations as low as 12 micrograms, but it was only embryotoxic at 60 micrograms/ml to rat embryos. CBZ-E was not embryotoxic to either species at concentrations as high as 48 micrograms/ml. These results suggest that the parent compound is the embryotoxic agent and that the epoxide intermediate plays no role in the drug's embryotoxic mechanism.

Animals↗
PubMed1996

Leukoencephalomalacia and hemorrhage in the brain of rabbits gavaged with mycotoxin fumonisin B1.

Two of five pregnant rabbits gavaged with purified fumonisin B1 at 1.75 mg/kg/day died, one after 9 and one after 13 doses. Microscopic examination revealed focal small hemorrhages in cerebral white matter in both animals, with malacia and hemorrhage also present in the hippocampus of one. The lesions were bilateral. Both animals also had marked degeneration of renal tubule epithelium and of hepatocytes. Apoptosis was the dominant degenerative change in kidney and liver. Fumonisin is known to cause leukoencephalomalacia and hemorrhage in equines, but CNS changes associated with exposure to fumonisins apparently have not been reported in other species. This preliminary observation in rabbits is reported to alert other investigators of a potential model of the disease in equines, as well as for investigation of potential mechanisms of toxicity to the CNS.

Animals↗
PubMed1995

Effect of supplemental folic acid on valproic acid-induced embryotoxicity and tissue zinc levels in vivo.

Valproic acid (VPA) is an anti-convulsant drug known to cause spina bifida in humans. Administration of the vitamin, folic acid, has been shown to decrease the recurrence and possibly also the occurrence of neural tube defects, primarily spina bifida, in humans. Additionally, treatment with a derivative (folinic acid) of folic acid has been reported to decrease the frequency of VPA-induced exencephaly in mice treated with the drug in vivo. A protective effect by folinic acid has not been observed in vitro. The purpose of this investigation was to reexamine the ability of folinic acid to decrease the incidence of VPA-induced neural tube defects in vivo. We also examined the effect of increased intake of folic acid on zinc levels in various maternal and embryonic tissues. Folinic acid, whether administered by intraperitoneal injection or in osmotic mini-pumps, did not decrease the number of mouse fetuses with VPA-induced exencephaly. Dietary supplementation with 10-20 times the daily required intake of folic acid in rodents also failed to decrease the embryotoxicity of VPA. Such dietary supplementation had no effect on zinc levels in maternal liver, brain, or kidney, nor in embryonic tissues. These results indicate that folic acid is not able to reverse the embryotoxicity induced by the anticonvulsant, that there is no apparent effect of high dietary folate intake on maternal or embryonic zinc levels and suggest that folate is probably not involved in the mechanism of VPA-induced embryotoxicity.

Animals↗