The Utah total artificial heart.
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Equipment Design↗
Biomedical subjects
C Hansen
Publications and source records attributed to C Hansen.
Stable isotopes for determining biokinetic parameters of tellurium in rabbits.
We have compared the use of stable and radioactive isotopes for determining the concentration of tellurium in body fluids of animals and man, specifically in the blood plasma of rabbits. Particular effort has been devoted to developing a sample-processing technique that allows the total amount of tellurium and isotope ratios to be measured by graphite furnace atomic absorption spectrometry (GFAAS) and secondary ion mass spectrometry (SIMS), respectively. The procedure employed in the SIMS analysis is discussed in detail. Investigations on the plasma clearance and the fractional intestinal absorption were carried out on four rabbits. Tracer solutions containing stable tellurium enriched in 124Te or 126Te and radioactive tellurium (121mTe or 123mTe) were administered by gavage and/or intravenously. Blood samples were drawn during the first 2 days after application. The activity of the separated plasma was measured by standard gamma ray spectrometry. After wet ashing and solvent extraction with MIBK the samples were analyzed for stable tellurium. A detection limit of 1 ng/mL of plasma could be achieved with GFAAS. For SIMS analysis the processed samples were deposited on high-purity graphite backings. Reliable isotope ratios could be determined with sample fractions containing 1 ng of tellurium or even less. The results obtained by applying stable isotopes were found to be in good agreement with the data achieved by using radioactive tracers. Studies on the intestinal absorption and the metabolic behavior of tellurium in human volunteers may thus be performed with stable isotopes.
Animals↗
Pharmacokinetics of stealth versus conventional liposomes: effect of dose.
Liposomes which substantially avoid uptake into the mononuclear phagocyte system (MPS), termed Stealth liposomes, have recently been formulated (Allen, T.M. and Chonn, A., (1987) FEBS Lett. 223, 42-46). The pharmacokinetics of stealth liposomes as a function of liposome dose and a comparison to conventional liposome pharmacokinetics, was the subject of the present study. We have examined the tissue distribution of two different formulations of stealth liposomes, i.e., sphingomyelin:egg phosphatidylcholine:cholesterol:monosialoganglioside GM1 (SM:PC:CHOL:GM1) 1:1:1:0.2 and SM:PC:CHOL:polyethylene glycol distearoylphosphatidylethanolamine (PEG(1990)-DSPE) 1:1:1:0.2, and compared them with the tissue distributions seen for a liposomal formulation which is avidly removed from circulation by the cells of the MP system (PC:CHOL, 2:1). Tissue distribution in mice was examined over a 100-fold concentration range (0.1 to 10 mumol phospholipid/mouse) and at several time points over a 48 h time period. Liposome size ranged from 92-123 nm in diameter for all compositions. Clearance from blood of PC:CHOL liposomes following intravenous administration showed a marked dose dependence (i.e., saturation-type or Michaelis-Menten kinetics), with MPS uptake decreasing and % of injected dose in blood increasing as dose increased, over the entire dosage range. Injection of stealth liposomes, on the other hand, resulted in % of injected doses of liposomes in MPS, blood and carcass which were dose-independent and log-linear (first order kinetics) over the entire dosage range. The doses of stealth liposomes containing PEG(1900)-DSPE required for MPS saturation was higher than 10 mumol phospholipid/mouse or 400 mumol/kg. The dosage-independence of the pharmacokinetics of stealth liposomes and their lack of MPS saturation within the therapeutic dose range are two more assets, in addition to the prolonged circulation half-lives, leading towards their eventual use as drug delivery systems in the clinic.
Animals↗
Liposomes containing synthetic lipid derivatives of poly(ethylene glycol) show prolonged circulation half-lives in vivo.
Novel synthetic lipid derivatives of poly(ethylene glycol) (PEG) have been synthesized and tested for their ability to decrease uptake of liposomes into the mononuclear phagocyte system (MPS, reticuloendothelial system) in mice and to prolong circulation half-lives of liposomes. A carbamate derivative of PEG-1900 with distearoylphosphatidylethanolamine (PEG-DSPE) had the greatest ability to decrease MPS uptake of liposomes, at optimum concentrations of 5-7 mol% in liposomes composed of sphingomyelin/egg phosphatidylcholine/cholesterol (SM/PC/Chol, 1:1:1, molar ratio). Results obtained with this compound were equivalent to results previously obtained with 10 mol% monosialoganglioside GM1 in liposomes of similar compositions (Allen, T.M. and Chonn, A. (1987) FEBS Lett. 223, 42-46). Non-derivatized methyl PEG or PEG-stearic acid (PEG-SA) were incapable of decreasing MPS uptake of liposomes. PEG-Chol and PEG-dipalmitoylglycerol (PEG-DPG) were intermediate in their effects on MPS uptake. Altering liposome size for liposomes containing PEG-DSPE resulted in only minor changes in blood levels of liposomes. Half-lives of 0.1 microns liposomes of SM/PC/Chol/PEG-DSPE (1:1:1:0.2, molar ratio) in circulation was in excess of 20 h following either i.v. or i.p. injection. Liver plus spleen liposome levels for these liposomes was below 15% of injected label at 48 h following i.v. liposome injection and below 10% following i.p. injection. The major site of liposome uptake was in carcass tissues, with over 50% of label remaining in vivo at 48 h post-injections, either i.v. or i.p., in the carcass.
Animals↗
Presence of follicular fluid in the porcine oviduct and its contribution to the acrosome reaction.
Two experiments were conducted to measure the quantity of follicular fluid entering the porcine oviduct following ovulation and to establish its influence on the sperm acrosome reaction in vivo. Prepubertal gilts treated with pregnant mare serum gonadotropin (PMSG) followed by human chorionic gonadotropin (hCG) were used in both experiments. In experiment 1, each of 64 gilts was assigned at random to one of four treatment groups (n = 16 per group): I (preovulatory), surgery 38 hr post-hCG; II (ovulatory), (surgery 42 hr post-hCG; III (postovulatory), surgery 46 hr post-hCG; IV (ovulation blocked), surgery 46 hr post-hCG but also treated with indomethacin (INDO) at 24 hr. At surgery, both follicular and oviductal fluid were collected for determination of volume and progesterone (P4) concentration. In experiment 2, sperm were recovered surgically from the uterine horn, isthmus, and ampulla of gilts at 46 hr post-hCG either 1) inseminated and non-INDO-treated controls (n = 5) or 2) inseminated and INDO-treated at 24 hr (n = 4). Using P4 as a marker, it was calculated that only 0.51% +/- 0.10% of the available follicular fluid was present in the oviduct near the time of ovulation and that this amount had decreased 10-12-fold 4 hr later. Mean sperm concentration at 46 hr post-hCG was higher in the uterine horn than in the other two regions (P less than 0.05) but the percentage of acrosome-reacted sperm was greater in the ampulla (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Acrosome↗
New thermal stress test to assess the viability of cryopreserved boar sperm.
A new, rapid, thermal stress test for assessing the viability of boar semen, requiring only 45 min of incubation at 42.5 degrees C, was developed and compared with a widely used stress test of 180 min incubation at 37 degrees C. The shorter procedure was found to have the same discriminatory ability as the standard test in assessing the effects of freezing conditions on the percentage of spermatozoa remaining motile. Neither test was able to show differences in the kinetic rating of motile sperm after freezing in relation to the glycerol concentration present during freezing. However, the new test had a greater ability to distinguish the effects of different concentrations of glycerol, over the range of 0 to 6%, and to reveal different degrees of acrosomal damage sustained during freezing. The longer procedure was unable to distinguish among glycerol concentrations from 0 to 4% with respect to acrosomal damage and produced an overall lower proportion of sperm having a normal apical ridge. The new thermal stress test thus has the advantages of greater sensitivity and more rapid execution over the test hitherto in widespread use.
Animals↗
Cloning the mouse homolog of the human cystic fibrosis transmembrane conductance regulator gene.
The cystic fibrosis transmembrane conductance regulator is encoded by the gene known to be mutated in patients with cystic fibrosis. This paper reports the cloning and sequencing of cDNAs for the murine homolog of the human cystic fibrosis transmembrane conductance regulator gene. A clone that, by analogy to the human sequence, extends 3' from exon 9 to the poly(A) tail was isolated from a mouse lung cDNA library. cDNA clones containing exons 4 and 6b were also isolated and sequenced, but the remainder of the mRNA proved difficult to obtain by conventional cDNA library screening. Sequences spanning exons 1-9 were cloned by PCR from mouse RNA. The deduced mouse protein sequence is 78% identical to the human cystic fibrosis transmembrane regulator, with higher conservation in the transmembrane and nucleotide-binding domains. Amino acid sequences in which known cystic fibrosis missense mutations occur are conserved between man and mouse; in particular, the predicted mouse protein has a phenylalanine residue corresponding to that deleted in the most common human cystic fibrosis mutation (delta F508), which should allow the use of transgenic strategies to introduce this mutation in attempts to create a "cystic fibrosis mouse".
Amino Acid Sequence↗
Assessment of iron availability using stable 54Fe.
This paper describes a method of quantitatively assaying the bioavailability of orally administered iron in order to promote haemoglobin synthesis in iron deficiency anaemia. The non-radioactive tracer substance 54Fe was employed. An experimental iron deficiency model was tested in 18 healthy male volunteers. The trial design made it possible to assess intestinal absorption and efficacy of iron substitution. The iron deficiency was experimentally induced by weekly phlebotomy. Two commercially available iron preparations with different rates of iron release were investigated at a dosage of 150 and 160 mg Fe2+ daily, respectively. In the first seven days of treatment, both preparations were administered in 54Fe-labelled form. Afterwards, iron substitution was given with the commercially available preparations. Measurements were made of erythrocyte utilization of 54Fe and plasma iron tolerance curves at the beginning of the periods in which the 54Fe-labelled product and the commercially available preparation were administered, and of haemoglobin and serum ferritin concentration curves over three months. The mean utilization of the iron administered was virtually identical for the two preparations (23 and 22%, respectively). Likewise, there was no difference with respect to the average daily increase in haemoglobin concentration in the blood (1.5 g 1-1). There was also no significant difference with respect to serum ferritin concentration curves. In contrast, the two preparations differed markedly with respect to the plasma iron tolerance curves. This suggests that evaluation of plasma iron tolerance curves alone is not suitable for comparative assessment of the therapeutic value of orally administered iron preparations.
Administration, Oral↗
Renal excretion of tellurium after peroral administration of tellurium in different forms to healthy human volunteers.
As tellurium ranks among the rare non-essential trace elements there is only little known of its intestinal absorption and its metabolic behaviour in humans. Data for risk evaluations needed for occupational medicine are based on animal experiments only. In order to investigate the metabolic behaviour of tellurium in man, tellurium in different forms was administered perorally to healthy male human volunteers. It was given as sodium tellurate, sodium tellurite, metallic colloid and intrinsically bound in cress. For the latter, cress was cultivated with tellurium-containing water in order to provide tellurium for ingestion in a form which is more equivalent to foodstuffs. After the administration the urinary excretion of tellurium was determined. Tellurium concentrations were measured in urine samples by means of graphite furnace atomic absorption spectroscopy (GFAAS) after wet ashing and a preconcentration of tellurium by solvent extraction with isobutyl methyl ketone (IBMK). From the cumulative tellurium excretion in the first four days after the administration, a percentage intestinal absorption of 25% +/- 10% for soluble tellurium salts can be calculated. The renal tellurium excretion is faster after administration of hexavalent tellurium than after ingestion of the tetravalent form. This can explain the higher toxicity of the tetravalent tellurium compounds found in animal experiments. The introduction of tellurium to cress lowered the intestinal absorption to approximately 15%. For metallic tellurium the fractional intestinal absorption was found to be about 10%.
Adult↗
Deregulation in trans or c-myc expression in immortalized human urothelial cells and in T24 bladder carcinoma cells.
The expression of a number of cellular oncogenes was investigated in human urothelial cell lines with different in vitro growth properties. Constitutively elevated levels of expression of c-myc RNA were found in Hu609, an immortalized, nontumorigenic cell line that was derived from normal urothelium, and in the bladder carcinoma cell line T24. Potential mechanisms that might underlie deregulation of c-myc expression in these cells were investigated. It was found that the c-myc gene was apparently intact and not amplified in Hu609 and T24. No increased stability of c-myc RNA was detected. A c-myc-CAT fusion construct containing 2.5 kb of normal c-myc 5' sequences showed levels of expression that paralleled the overexpression of the endogenous gene, indicating that the high constitutive levels of c-myc expression were due, at least in part, to alterations in the activities of cellular trans-acting transcriptional regulators.
Animals↗
Alcohol decreases serum osteocalcin in a dose-dependent way in normal subjects.
The acute effect of 25 and 50 g of alcohol on the variation in serum osteocalcin, a specific and sensitive marker of bone formation, and on serum cortisol and serum parathyroid hormone (PTH)(1-84) was calculated in 6 normal young adults. They were studied during three periods, each lasting from 4 p.m.-7:30 a.m. Alcohol was ingested between 4:15 and 5 p.m. during period two and three. Blood was taken at 4 p.m. and every 15 minutes from 4:30 til 6 p.m., followed by hourly sampling until 12 p.m. The last blood sample was taken after an overnight fast at 7:30 a.m. Initial and end values before and after alcohol ingestion did not differ significantly from control values. Repeated measures analysis of variance showed that 50 g of ethanol decreased serum osteocalcin significantly (P less than 0.02) and increased serum cortisol (P less than 0.05) during the 4-12 p.m. interval. The interaction of 50 g of ethanol on the variation in serum osteocalcin was already significant during the first 2 hours (P less than 0.02), where no significant effect on serum cortisol could be detected. Although insignificant, the same pattern was observed after 25 g of alcohol. There was no significant change in the variation of serum iPTH(1-84) during the 4-6 p.m. after alcohol intake. We conclude that 3-4 drinks of alcohol taken over 45 minutes decreases serum osteocalcin in a dose-dependent way. The time lag between changes in serum osteocalcin and cortisol indicates that the decrease in serum osteocalcin is not related to the increase in serum cortisol.
Adult↗
[Use of OKT-3 in treatment of rejection following kidney transplantation].
Application of OKT-3 as rescue therapy in steroid-resistant rejection was effective in 7 out of 9 patients early after cadaveric kidney transplantation. Under attention of instructions for use of OKT-3 the adverse first-dose reactions are rare. The problem of OKT-3 therapy is early use and its reuse.
Adult↗
[4-way immunosuppression in pre-sensitized recipients of allogenic cadaver kidney transplants].
As a result of introduction of quadruple immunosuppression using cyclosporine, antithymocyte globulin, azathioprine and prednisone in immunological high-risk patients with a presensitization greater than or equal to 80% and/or multiple grafts the rate of immediate graft function could significantly increased, the frequency of rejection and graft rupture was reduced and the patient survival rate could improved to 100%. The problem of vascular rejection should resolved by a more aggressive biopsy approach.
Antilymphocyte Serum↗
Liposomes with prolonged circulation times: factors affecting uptake by reticuloendothelial and other tissues.
Many of the applications of liposomes drug-delivery systems have been limited by their short circulation half-lives as a result of rapid uptake into the reticuloendothelial (mononuclear phagocyte) system. We have recently described liposomes formulations with long circulation half-lives in mice (Allen, T.M. and Chonn, A. (1987) FEBS Lett. 223, 42-46). A study of the principal factors important to the attainment of liposomes with prolonged circulation half-lives is presented in this manuscript. Liposomes with the longest circulation half-lives, in mice, had compositions which mimicked the outer leaflet of red blood cell membranes (egg phosphatidylcholine/sphingomyelin/cholesterol/ganglioside GM1, molar ratio 1:1:1:0.14). Several other gangliosides and glycolipids were examined, but none could substitute for GM1 in their ability to prolong circulation half-lives. However, other negatively charged lipids with bulky headgroups, i.e., sulfatides and phosphatidylinositol, had some effect in prolonging circulation half-lives, but GM1 was clearly superior in this regard. Bilayer rigidity, imparted by sphingomyelin or other high-phase-transition lipids, acted synergistically with the negatively charged components, especially GM1, in extending circulation times. Circulation half-lives of liposomes increased with decreasing size, but even larger (0.2-0.4 microns) liposomes of the optimum formulations had significantly prolonged half-lives in circulation. Uptake of liposomes into tissues other than liver and spleen increased with increasing circulation times of the liposomes for i.v. and for i.p. injections. Liposomes appeared to move from the circulation into the carcass between 6 and 24 h post-injection. Our ability to achieve significant prolongation in circulation times of liposomes makes possible a number of therapeutic applications of liposomes which, until now, have not been achievable.
Animals↗
cAMP-dependent binding of a trans-acting factor to the thyroglobulin promoter.
We have investigated the interaction of a nuclear factor(s) with the promoter region of the thyroglobulin (Tg) gene, which is only expressed in differentiated thyroid cells under the positive control of the pituitary hormone thyrotropin (TSH) via a cAMP-dependent pathway. Using the mobility shift assay, we first demonstrated that a thyroid nuclear factor interacts with a short segment of 60 bp (-136 - -77) which is conserved among species in the regulatory region of the Tg gene. A specific binding site was then localized in a subfragment of 20 bp located between -126 bp and -107 bp relative to the transcription initiation site. The corresponding nuclear factor is absent in a tissue which does not express the Tg gene. This factor differs from previously identified factors shown to mediate a direct cAMP response since the observed binding is neither competed out by the cAMP responsive element (CRE) nor by the activator protein 2 (AP2) binding site. This trans-acting factor represents a new candidate intermediate in the regulation of transcription by a cAMP dependent mechanism.
Animals↗
Global increase in response latencies by early middle age: complexity effects in individual performances.
Ten young women (age 20 to 22 years) and 10 middle-aged women (age 36 to 44 years) served as subjects in choice reaction time, letter classification, and abstract matching-to-sample tasks. In each of seven conditions, the older group responded more slowly than the younger group. Age differences showed a complexity effect. That is, differences between the latencies of young and old subjects increased as the latency of the young subjects increased. Both linear and power functions accurately described the relation between the latencies of the middle-aged and young adult groups. This was true not only for the relation between average latencies but also for the relation between corresponding quartiles of latency distributions. Similar results were observed at the individual level: All middle-aged subjects showed complexity effects, and, for each middle-aged subject, the relation between her latencies and those of the average young adult was well described by linear and power functions. These findings indicate that age-related slowing is apparent by age 40, and that complexity effects are observable in individual performances. This slowing is global and not specific to particular tasks, as indicated by the fact that the latencies of older adults can be predicted directly from those of younger adults without regard to the nature of the task.
Adult↗
[Personal experiences with kidney transplantation in the elderly].
From January 1987 to December 1988 226 cadaveric renal allotransplants were performed in the Kidney Transplant Center of the Friedrichshain Hospital. 38 of the recipients (17%) were older than 50 years. The results of transplantation are comparable with younger recipients, except a higher frequency of age-related urological complications of benign prostatic hyperplasia.
Adolescent↗
Thyroid-specific and cAMP-dependent hypersensitive regions in thyroglobulin gene chromatin.
Two regions hypersensitive to DNase I digestion were found in a 7-kb segment of thyroglobulin gene 5'-flanking sequences in the chromatin from bovine thyroid. The most upstream site (-2000 to -1600 bp relative to the transcriptional start) was found in thyroid chromatin only, but independently of actual expression of the gene. It therefore represents a tissue-specific characteristic which may be associated with the commitment of the thyroglobulin gene to transcriptional activity. The very 5' end of the gene and the proximal promoter sequences (-100 to +60 bp relative to transcriptional start), constitute the second site, the hypersensitive character of which could be directly correlated with transcriptional activity. The structural changes occurring in this region of the chromatin were dependent on cAMP stimulation of the thyroid cells.
Animals↗