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Biomedical subjects

P Hahn

Publications and source records attributed to P Hahn.

At least 91 records · Page 5Linked to original sources
PubMed1990

X-ray induction of methotrexate resistance due to dhfr gene amplification.

The effect of ionizing radiation on methotrexate (MTX) resistance and gene amplification in cultured mammalian cells was investigated. X-irradiation of mouse EMT-6 cells induced cell killing and MTX resistance due to amplification of dihydrofolate reductase (dhfr) gene in a dose-dependent manner. The highest yields of mutant cells were obtained at approximately D37 (the dose at which 37% of the cells survive), where the frequency of MTX-resistant cells was four- to eightfold over that of the unirradiated population. The proportion of MTX-resistant cells among the survivors increased logarithmically with dose, up to a 1000-fold increase over unirradiated cells at 1000 cGy, the highest dose tested. The induced frequency of MTX resistance after X-irradiation was greater than the induced frequency of 8-azaguanine resistance, which indicates deletion of the hypoxanthine phosphoribosyltransferase gene. Inhibition of poly(ADP-ribose) polymerase by the addition of 3-aminobenzamide before irradiation increased both cell killing and MTX resistance. Metaphase spreads of chromosomes from EMT-6 cells that had been irradiated and subjected to stepwise increases in MTX concentration showed numerous double minutes. Pulsed-field gel electrophoresis of the DNA from cells containing radiation-induced double minutes showed that many copies of the dhfr gene were present on circular DNA molecules of 10(6), 2 x 10(6), and 3 x 10(6) base pairs. These results suggest a relationship between the induction of chromosome aberrations and the induction of gene amplification.

Animals↗
PubMed1990

Treatment planning for protocol-based radiation therapy.

Many protocol studies are conducted in which patients are assigned to alternative treatment regimens. Typically the dosimetric specifications will define the maximal and minimal target doses and maximal doses to specified critical normal structures, and the success of the study will depend upon the consistency and reliability with which these dose specifications are applied. We have investigated the use of dose-area histograms to ensure complete adherence to protocol dose specifications. A dose prescription is prepared that defines upper and lower target doses as well as normal tissue dose tolerance levels for all organs of interest. In addition, dose-volume histograms are derived which provide quantitative measures of the extent to which each dose limit has been met. This technique can be used during treatment planning to prevent protocol violations of pre-defined severity, or for retroactive correlation of local tumor recurrence and treatment-related morbidity with dose levels in the target and normal tissues. An example is presented for a protocol study of ca prostate, stages A and B, in which seven treatments were evaluated at the mid-plane for protocol violations.

Clinical Trials as Topic↗
PubMed1990

Studies on prostaglandin and luteolysis in the pseudopregnant rabbit.

The ability of pulsatile infusion of prostaglandin F2 alpha (PGF2 alpha) or 13, 14-dihydro prostaglandin F2 alpha to induce corpus luteum regression was examined in the pseudopregnant rabbit. Each prostaglandin was infused in 5, 1-hour pulses (1 per 6 hours) during a 25-hour period starting day 9 or 10 of pseudopregnancy. Although both prostaglandins were capable of inhibiting progesterone secretion, pulse administration was no more effective than continuous infusion. To determine if PGF2 alpha was released into the systemic circulation during spontaneous luteolysis, starting day 12 of pseudopregnancy serial blood samples were collected every 90 minutes from the jugular vein. Prostaglandin F levels remained steady (1-2 ng/ml over the collection period with no apparent increase associated with functional luteolysis. Although prostaglandins may be involved in luteolysis in the rabbit, the present results suggest that it is unlikely that PGF2 alpha by itself is responsible for the sustained fall in progesterone secretion at the end of the pseudopregnancy.

Animals↗
PubMed1990

Comparison of breast-feeding and formula feeding on intestinal and hepatic cholesterol metabolism in neonatal pigs.

Infant formulas (IFs) contain reduced cholesterol concentrations compared with breast milk (SM); how neonatal cholesterol metabolism responds to this difference is largely unknown. The effect of exclusive feeding of SM vs low-cholesterol IF on intestinal and hepatic cholesterol concentrations and synthesis during early postnatal development were compared in piglets. Animals were killed at birth or on days 5, 10, 15, or 25 postpartum. Plasma cholesterol concentrations were higher in SM-fed than in IF-fed piglets on days 15 and 25. In intestine both HMG-CoA reductase activity and 3H2O incorporation rates into cholesterol were similar for both groups or reduced in the IF-fed group at days 15 and 25. In liver, HMG-CoA reductase activity was higher in IF-fed than in SM-fed piglets on days 5, 10, and 15. Results indicate that during the early postpartum period, response to lower cholesterol intakes with IF occurs by increasing hepatic sterol synthesis whereas intestinal synthesis is largely unaffected.

Animals↗
PubMed1990

Diet and metabolic development.

For many years, investigators have been concerned with mechanisms that control and alter genetically regulated development. An intriguing aspect of these mechanisms is the ability of environmental factors to induce certain metabolic processes. Animal studies have shown that dietary manipulation of cholesterol and fatty acid metabolism during development can have persistent and permanent effects. In addition, there appears to be a critical period when changes in the diet can have lasting consequences. The changes in the control exerted by nutritional factors on metabolic development coincide with three phases of development: prenatal, suckling, and weaning. The effects of diet on cholesterol and fatty acid metabolism throughout these three phases of development will be addressed in this review.

Animals↗
PubMed1990

Development of cholesterol metabolism: the effect of diet composition at weaning.

Wistar rats were weaned on day 18 to a high fat (HF), high carbohydrate (HG) or high cholesterol (HCO 2%) diet. The activities of 3-hydroxy-3-methylglutaryl-CoA-reductase (HMGR), 7 alpha-hydroxylase (7-OHase) and acyl-CoA-cholesterol-acyltransferase (ACAT) were assayed in the liver and small intestinal mucosa on days 21, 25 and 30 and in adult animals. An HF diet raises hepatic ACAT and HMGR activities in young rats but has the opposite effect in the gut. The cholesterol diet also raises hepatic ACAT activity, but less so than the HF diet. In the gut, however, the HCO diet invokes the greatest rise in ACAT of all the diets tested. Except in adult rats, the HG diet always raises hepatic ACAT activity more than the HCO diet or the Purina Chow. In the gut, however, activity is very low for the HG diet, much lower than for the HCO diet. Early feeding of the HCO diet for 12 days (from day 18 to 30) and refeeding the same diet from day 48 to 50 resulted in a subsequent response to the HCO diet. It is concluded that early weaning results in changes in enzyme activities that depend on the composition of the diet fed at weaning and that this may also effect the later response to the same and perhaps other diets.

Acetyl-CoA C-Acyltransferase↗
PubMed1989

Cholesterol metabolism in infant rats, effect of 6-hydroxydopamine and guanfacine.

Infant rats (10-16 days) and weaned animals (older than 18 days) were treated with drugs inhibiting beta-adrenergic activity and were sacrificed 4 days later. 6-Hydroxydopamine acts on postsympathetic nerve fibres, and guanfacine stimulates alpha 2-receptors. Both drugs caused a rise in plasma cholesterol and a decrease in hepatic 3-hydroxy-3-methylglutaryl CoA reductase activity in infant but not in weaned animals. The activity of acylcholesterol acyl CoA transferase, on the other hand, was decreased after drug administration. Thus, both antihypertensive drugs may cause changes in cholesterol metabolism, especially in infant animals.

Adipose Tissue, Brown↗
PubMed1988

The objective evaluation of alternative treatment plans: I. Images of regret.

An innovative approach to treatment planning is described in which a planned dose distribution is evaluated in terms of prescribed limits of acceptability, and any discrepancies (referred to as "regions of regret") are displayed in the form of a contour diagram in which colors are used to represent different types and degrees of regret. A commercial treatment planning system has been modified to display images of regret in addition to conventional isodose plots, and is used for the comparison of alternative plans in terms of adequate target coverage and minimal irradiation of sensitive organs. Required tumor dose levels and organ-specific tolerance doses are prepared in advance by the clinician for each site and stored in a prescription file for use in the planning process. The method is found to expedite the optimization procedure, is objective and reproducible, and provides clear documentation of the selection process.

Computer Graphics↗
PubMed1988

Pyruvate carboxylase, phosphate-dependent glutaminase and glutamate dehydrogenase in the developing rat small intestinal mucosa.

The activities of glutaminase and glutamate dehydrogenase in the small intestinal mucosa of infant rats were found to increase at the time of weaning. Pyruvate carboxylase activity, on the other hand, was very high during the suckling period and decreased to negligible values at weaning. It is suggested that gluconeogenesis in the infant mucosa occurs primarily via oxaloacetate and not via alpha-ketoglutarate.

Aging↗
PubMed1988

Development of intestinal carnitine transport in rats.

The intestinal transport of carnitine in suckling rats (12 and 16 days old) and weaned rats (28 and 75 days old) was studied in vitro using everted small intestinal sacs. The sacs were incubated in a mucosal medium without carnitine or with added carnitine at a 200-microM concentration. The release of endogenous carnitine and its esters into the serosal medium was greatest in the 12-day-old pups and lowest in the postweaning period. In contrast, the transport of carnitine from the mucosal to the serosal compartment was lowest in the 12-day-old pups and higher in the older groups. The present study suggests that the transfer of carnitine from the mucosal to the serosal compartment is influenced by the presence of endogenous carnitine in the intestinal mucosa, which in turn is determined by the age of the animals.

Aging↗
PubMed1987

Ketone formation in the intestinal mucosa of infant rats.

The intestinal mucosa of infant rats was found to produce ketones when incubated in Krebs-Ringer-Bicarbonate solution. No production was found in weaned rats. Ketogenesis could be inhibited by D-carnitine or tetradecylglycidic acid (TDGA) an inhibitor of long-chain acylcarnitine transferase, suggesting that ketone production is due to a large extent to break-down of long-chain fatty acids. It is considered possible that both ketones and glucose (also produced by the infant mucosa) serve as substrates for the muscular part of the intestine.

Animals↗
PubMed1987

Does carnitine have a role in fat absorption?

The effect of D-carnitine and tetradecylglycidic acid (TDGA), an inhibitor of carnitine palmitoyltransferase, on intestinal absorption of palmitic acid was determined. The proximal intestinal segment was ligated in adult male rats and filled with 0.5 microCi of 14C-palmitic acid alone or with either D-carnitine or TDGA. Thirty minutes later the radioactivity was determined in the intestinal lumen, intestinal wall and plasma. The absorption of palmitic acid was decreased in the presence of D-carnitine (10 mg/ml) as evidenced by significantly lower levels of radioactivity in the gut wall and the plasma and by significantly greater residual radioactivity in the lumenal contents. L-carnitine had no effect on plasma radioactivity but if D- and L-carnitine were given together the effect of D-carnitine was still in evidence. TDGA also inhibited intestinal absorption of palmitic acid.

Animals↗
PubMed1987

The role of acentric chromosome fragments in gene amplification.

We assessed the role of acentric chromosome fragments in gene amplification by using cell fusion techniques to introduce the fragmented chromosomes of a donor Chinese hamster ovary (CHO) cell line that contained the dihydrofolate reductase (dhfr) gene(s) into a CHO cell line deficient for dhfr. Chromosome fragments were successfully integrated into cells at a frequency of approximately 3%. Methotrexate-resistant variants arose much more frequently in two cell lines derived from these successful cell fusions than in wild-type CHO cells. The hybrid cell lines also amplified their dhfr genes more readily than did the CHO cell line used as dhfr donor.

Animals↗
PubMed1987

Establishment and characterization of two human cell lines with amplified dihydrofolate reductase genes.

Two SV40-transformed human cell lines, GM637, derived from a normal human subject, and GM5849, derived from a patient with ataxia-telangiectasia (A-T), were grown in increasing concentrations of the cytotoxic agent methotrexate (MTX). The GM637 line was naturally more resistant to methotrexate than was GM5849 and, over a 5-month period, became resistant even to very high concentrations (up to 100 microM). The GM5849 line became resistant to 500 nM methotrexate during the same period. However, dot blot and Southern blot analyses showed that both cell lines had amplified their dihydrofolate reductase (dhfr) genes to about the same extent, approx. 50-fold. Using the GM5849 line with amplified dhfr, we attempted to determine if interruption of DNA synthesis by hydroxyurea would cause DNA to be replicated twice within a single cell cycle, as has been reported for Chinese hamster ovary cells. No evidence for such a phenomenon was obtained.

Cell Line↗
PubMed1987

L-carnitine treatment in the hyperlipidemic rabbit.

A study was designed to examine the hypolipidemic effect of L-carnitine treatment (4 weeks, 170 mg/kg/d) in rabbits fed a high fat diet (5% corn oil/0.5% cholesterol, w/w). Eight weeks of exposure to the high fat diet significantly increased plasma total cholesterol and triglycerides. VLDL associated triglycerides, cholesterol, apo-B, and total protein were also significantly increased with the diet. There was no change in HDL-cholesterol levels. Plasma concentration of carnitine (free, acyl, and total) all increased significantly with the high fat diet. The content of free, short-chain, and total carnitine were decreased in the liver whereas the content of long-chain acylcarnitines was increased. The diet generated a significant steatosis within the livers of these animals. Four weeks of treatment of L-carnitine reduced the extent of the liver steatosis and significantly decreased plasma total cholesterol, triglycerides, VLDL associated triglycerides, cholesterol, and total protein. HDL-cholesterol levels were unaffected by the treatment. All plasma fractions of carnitine (free, acetyl, acyl, and total) were significantly increased above those levels seen after 8 weeks of the high fat diet alone. The content of liver carnitine and its esters was normalized following treatment. The high fat diet decreased liver HMG-CoA reductase activity and increased the activities of 7-alpha-hydroxylase and acylcholesterol acyltransferase (ACAT). L-Carnitine treatment blunted the magnitude of the diet induced increase in 7 alpha-hydroxylase activity, yet overall the activity still remained elevated relative to controls. ACAT activity increased (1.5 times) with the high fat diet and increased further (4.5 times) following carnitine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗