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Biomedical subjects

K Bauer

Publications and source records attributed to K Bauer.

At least 127 records · Page 7Linked to original sources
PubMed1994

Cellular and molecular characterization of the role of the flk-2/flt-3 receptor tyrosine kinase in hematopoietic stem cells.

The flk-2/flt-3 receptor tyrosine kinase was cloned from a hematopoietic stem cell population and is considered to play a potential role in the developmental fate of the stem cell. Using antibodies derived against the extracellular domain of the receptor, we show that stem cells from both murine fetal liver and bone marrow can express flk-2/flt-3. However, in both these tissues, there are stem cell populations that do not express the receptor. Cell cycle analysis shows that stem cells that do not express the receptor have a greater percentage of the population in G0 when compared with the flk-2/flt-3-positive population. Development of agonist antibodies to the receptor shows a proliferative role for the receptor in stem cell populations. Stimulation with an agonist antibody gives rise to an expansion of both myeloid and lymphoid cells and this effect is enhanced by the addition of kit ligand. These studies serve to further illustrate the importance of the flk-2/flt-3 receptor in the regulation of the hematopoietic stem cell.

Animals↗
PubMed1994

Cloning of a cDNA encoding an ectoenzyme that degrades thyrotropin-releasing hormone.

Thyrotropin-releasing hormone (TRH) is an important extracellular signal substance that acts as a hypothalamic-releasing factor, which stimulates the release of adenohypophyseal hormones and functions as a neurotransmitter/neuromodulator in the central and peripheral nervous system. The inactivation of TRH after its release is catalyzed by an ectoenzyme localized preferentially on neuronal cells in the brain and on lactotrophic pituitary cells. This enzyme exhibits a very high degree of substrate specificity as well as other unusual properties. The activity of the adenohypophyseal enzyme is stringently controlled by estradiol and thyroid hormones, indicating that this enzyme itself may serve regulatory functions. Fragments of the enzyme isolated from rat or pig brain were generated by enzymatic digestion or cyanogen bromide cleavage, purified by reverse-phase HPLC, and sequenced. PCR amplification and screening of cDNA libraries from rat brain and pituitary led to the identification and isolation of a cDNA that encodes a protein of 1025 amino acids. The analysis of the deduced amino acid sequence was consistent with the identification of the enzyme as a glycosylated, membrane-anchored Zn metallopeptidase. Furthermore, Northern blot analysis demonstrated that the mRNA levels paralleled the tissue distribution of the enzyme and that in pituitary tissue the transcript levels rapidly increased when the animals were treated with triiodothyronine. Finally, transient transfection of COS-7 cells with this cDNA led to the expression of an active ectopeptidase that displayed the characteristics of the TRH-degrading ectoenzyme.

Amino Acid Sequence↗
PubMed1994

Purification and characterization of the thyrotropin-releasing-hormone-degrading ectoenzyme.

The membrane-bound enzyme which catalyzes the degradation of thyrotropin-releasing hormone (TRH; Glp-His-Pro-NH2) could be released from membranes of rat and pig brain by treatment with trypsin under very mild incubation conditions. The solubilized enzyme was purified 200,000-fold, with an overall yield of 20%, by conventional chromatographic methods. The enzyme preparation appeared to be electrophoretically homogenous since SDS/PAGE analysis revealed a single band with a molecular mass of 116,000 Da. By gel-filtration chromatography, a molecular mass of 230,000 Da was estimated, suggesting that the enzyme consists of two identical subunits. The enzyme could be identified as a glycoprotein by lectin-binding analysis and by the reduction of the molecular mass to 97,000 Da upon treatment of the denatured enzyme with endoglycosidase-F/N-glycosidase F. In its native form, however, the enzyme was only partially deglycosylated and retained full enzymatic activity. In addition to TRH, the enzyme also hydrolyzed L-5-oxoprolyl-beta-naphthylamide, and thus a convenient fluorimetric assay could be established to determine high enzyme activities. The hydrolysis of both substrates was found to obey Michaelis-Menten kinetics, but considerable differences in the respective Km and Vmax values were noticed.

Aminopeptidases↗
PubMed1994

Molecular genetic analyses of the Tyrolean Ice Man.

An approximately 5000-year-old mummified human body was recently found in the Tyrolean Alps. The DNA from tissue samples of this Late Neolithic individual, the so-called "Ice Man," has been extracted and analyzed. The number of DNA molecules surviving in the tissue was on the order of 10 genome equivalents per gram of tissue, which meant the only multi-copy sequences could be analyzed. The degradation of the DNA made the enzymatic amplification of mitochondrial DNA fragments of more than 100 to 200 base pairs difficult. One DNA sequence of a hypervariable segment of the mitochondrial control region was determined independently in two different laboratories from internal samples of the body. This sequence showed that the mitochondrial type of the Ice Man fits into the genetic variation of contemporary Europeans and that it was most closely related to mitochondrial types determined from central and northern European populations.

Animals↗
PubMed1994

Biosynthesis of carnosine and related peptides by skeletal muscle cells in primary culture.

Synthesis of carnosine (beta-alanyl-L-histidine) and related dipeptides could be demonstrated in primary muscle cell cultures derived from embryonic chick pectoral muscle. After incubation with radiolabeled beta-alanine or gamma-aminobutyric acid, the radiolabeled dipeptides were isolated from the cell extracts and also in small amounts from the culture medium. The kinetics of dipeptide formation indicated that anserine (beta-alanyl-1-methylhistidine) is not formed directly by these cells but as a secondary product via the methylation of carnosine. Coinciding with the morphological differentiation of the mononucleated myoblast to form multi-nucleated myotubes, a rapid increase in beta-alanine uptake and also in dipeptide synthesis could be observed. These results demonstrate that carnosine and related peptides are not merely deposited in skeletal muscles but that they are actively synthesized by muscle cells in culture.

Alanine↗
PubMed1994

Osmotic release oral drug delivery system of metoprolol in hypertensive asthmatic patients. Pharmacodynamic effects on beta 2-adrenergic receptors.

This study investigated the effects of an osmotic release oral drug delivery system of metoprolol on the changes induced by cumulative doses of inhaled salbutamol on bronchomotor tone, skeletal muscle, and the circulatory system after single (day 1) and multiple (day 7) dosing in 18 hypertensive asthmatic patients (forced expiratory volume in 1 second > 50% predicted; diastolic blood pressure > 90 mm Hg). The patients were given 14/190 mg metoprolol, 100 mg atenolol, and placebo once daily for a 7-day period each in a randomized, double-blind, crossover design. At the estimated time of peak plasma concentrations, cumulative doses of salbutamol (12.5, 37.5, 112.5, 412.5, 812.5, and 1612.5 micrograms) were applied every 20 minutes. Specific airway conductance, finger tremor amplitude, heart rate, and blood pressure were registered at baseline and at each dose increment. The slopes of the salbutamol dose-response curves of specific airway conductance did not differ on day 1 (P > .05). On day 7, atenolol caused a shift of the dose-response curves of specific airway conductance to the right (P < .05), whereas metoprolol was indistinguishable from placebo (P > .05). The median cumulative salbutamol concentrations causing a 50% increase in specific airway conductance were 416 and 384 micrograms (days 1 and 7, respectively) for placebo, 594 and 444 micrograms for metoprolol, and 562 and 1419 micrograms for atenolol. The median cumulative salbutamol concentrations causing a 35% increase in tremor were 732 and 706 micrograms for placebo, 812 and 1213 micrograms for metoprolol, and 797 and 1323 micrograms for atenolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1994

[The value of sequential CD 34 measurement for carrying out stem cell pheresis].

The recent significant improvement in disease-free survival in patients with certain haematological malignancies is due to high-dose chemotherapy and subsequent autologous bone marrow and/or stem cell transplantation. The proliferation and egression of stem cells into the peripheral blood must first be stimulated by defined chemotherapy and/or by administration of cytokines. However, the increase of circulating stem cells in peripheral blood is limited to only a few days. By immunologically analysing white blood cells for the expression of the surface antigen CD 34 it is possible to calculate the numbers of haematopoietic progenitor cells. Thus, besides monitoring haematopoietic recovery, the estimation of CD34+ cells in the peripheral blood can be used to indicate the optimal time point for stem cell collection. Two to four stem cell pheresis (one per day) may then yield sufficient stem cells to enable the safe and rapid reconstitution of haematopoiesis following supralethal chemotherapy.

Antigens, CD↗
PubMed1994

[Immunophenotyping of leukemia: overview].

Leukaemias that cannot be classified properly by morphological/cytochemical parameters may be diagnosed clearly by immunophenotyping. In this way, the neoplastic cells can be designated to either the myeloid or the lymphatic line of blood cells. Furthermore, myeloid leukaemias can be subtyped immunophenotypically in cases of type M0, M6, and M7, leukaemias, as well as in cases of mixed lineage or undifferentiated leukaemias. In patients with non-Hodgkin-lymphomas the cells can be characterized as being of B- or T-cell origin, and their activational or proliferative state can be assessed. Notably with acute lymphatic leukaemias, the prodigious therapeutical progress over the past years must be attributed to the refined definition of subtypes by immunophenotyping.

Antibodies, Monoclonal↗
PubMed1993

Identification of the thyrotropin-releasing-hormone-degrading ectoenzyme as a metallopeptidase.

A time-dependent inhibition of the thyrotropin-releasing-hormone (TRH)-degrading ectoenzyme (EC 3.4.19.-) from rat brain by the metal-complexing agents imidazole, NaCN, EDTA and 1,10-phenanthroline could be demonstrated. In contrast, the inhibition by the non-chelating analogues 4,7- and 1,7-phenanthroline was not time-dependent. At a concentration of 100 microM EDTA the enzymic activity decreased by 50% only after pretreatment for 6 h. It could be restored by addition of Zn2+, Ni2+ and Co2+ but not by other transition metal ions and also not by Ca2+ and Mg2+. Without pretreatment, the enzyme was activated by Co2+ and inhibited by Cu2+, Cd2+ and Hg2+ in a time-dependent manner, but remained unaffected by Ni2+ and Mn2+, as well as by Ca2+ and Mg2+. Compatible with the His-Glu-Xaa-Xaa-His consensus sequence of most zinc-containing metallopeptidases, chemical modification studies with carbodiimide revealed the presence of an essential acidic amino acid residue, probably located at the active site of the enzyme. The catalytically active metal ion could be exchanged for 65Zn and the enzyme could be effectively inhibited by L-pyroglutamyl hydroxamic acid, the chelating derivative of the TRH cleavage product pyroglutamic acid. The TRH-degrading ectoenzyme thus classifies as a member of the zinc-dependent metallopeptidase family.

Aminopeptidases↗
PubMed1993

[meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]- dichloroplatinum(II), a new drug not only parenterally but also orally active in the therapy of breast and prostate cancer.

The platinum complex [meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)- ethylenediamine]dichloroplatinum(II),K, was tested for its antitumor activity on hormone-sensitive tumor models under peroral administration. The resorption from the gastrointestinal tract was proved by determining the estrogenic effect of K in a dose/activity study using the immature-mouse uterine weight test. In comparison to the subcutaneous injection, a tenfold peroral dose was administered to achieve identical effects. By peroral treatment of the hormone-sensitive MXT(M3.2) mammary carcinoma of the mouse with K an almost complete inhibition of the tumor growth was obtained. This effect was superior to that of subcutaneously applied cisplatin and significantly better than that obtained by perorally administered ligand L at an equimolar dose, indicating that the antitumor effect is caused by the intact complex K and not by the liberated ligand L. The strong antitumor activity of perorally applied K was also demonstrated on the hormone-sensitive Noble Nb-R prostatic carcinoma of the rat. Histological examinations showed that the platinum complex K did not cause cisplatin-like kidney damage or irritations of gastric or intestinal mucosa when given perorally.

Administration, Oral↗
PubMed1993

Effect of intrauterine growth retardation on postnatal weight change in preterm infants.

To investigate the cause or causes of early postnatal weight change, we measured total body water and fluid and energy balances in 14 preterm infants who were appropriate in size for gestational age (AGA) and in 5 weight-matched, preterm, small-for-gestational-age (SGA) infants. On the first day of life, AGA and SGA infants had the same weight and total body water content. At 6 +/- 2 days (mean +/- SD), AGA infants had had significant weight loss (94 +/- 45 gm) and body water loss (67 +/- 80 ml), whereas weight and total body water content in the SGA infants at the same age (5 +/- 1 days) did not differ from the values at birth. Loss of weight and total body water in AGA infants was accompanied by a greater diuresis than in SGA infants at the same amount of fluid intake. At the end of week 1, AGA and SGA infants had the same total energy expenditure (184 +/- 33 vs 171 +/- 17 kJ.kg-1 x day-1); energy intake, which had exceeded total energy expenditure from the third day of life and beyond, already provided 188 +/- 46 (AGA) or 209 +/- 109 kJ.kg-1 x day-1 (SGA), respectively, for energy storage. Nitrogen balance was positive. Subsequent weight gain occurred at the same rate in AGA and SGA infants; both total body water and solids increased. Energy intake, total energy expenditure, and the amount of energy stored (measured during stable weight gain on a regimen of full enteral feedings) had significantly increased compared with week 1, but both groups maintained similar energy storage.(ABSTRACT TRUNCATED AT 250 WORDS)

Body Composition↗
PubMed1993

Pharmacodynamic effects of inhaled dry powder formulations of fenoterol and colforsin in asthma.

The airway and tremor response and cardiovascular and hypokalemic effects of single doses of inhalative fenoterol dry powder capsules (0.4 mg) were compared with the fenoterol metered dose inhaler (0.4 mg) and colforsin (forskolin) dry powder capsules (10.0 mg), a direct activator of the adenylate cyclase system, in 16 patients with asthma. Subjects (FEV1 < or = 60% predicted) were investigated in a randomized, double-masked, placebo-controlled, four-period, crossover trial for a 120 minute period. All active drugs caused a significant increase in specific airway conductance (p < 0.05); the order of potency (mean +/- SEM maximum increase from baseline) was fenoterol metered dose inhaler (0.51 +/- 0.06 sec-1 x kPa-1), fenoterol dry powder capsules (0.49 +/- 0.07), and colforsin dry powder capsules (0.30 +/- 0.03). A marked increase in finger tremor amplitude resulted after fenoterol metered dose inhaler only (62.93% +/- 10.21%; p < 0.05) in contrast to fenoterol dry powder capsules (15.84% +/- 4.35%; p < 0.05) and colforsin dry powder capsules (12.87% +/- 10.44%; p > 0.05). A decrease in plasma potassium was found after fenoterol (metered dose inhaler > dry powder capsules; p < 0.05). In conclusion, fenoterol dry powder capsules caused less tremor response and hypokalemic effects than the metered dose inhaler, although the bronchodilator capacity was similar. Colforsin dry powder capsules resulted in a measurable bronchodilatation in patients with asthma.

Administration, Inhalation↗
PubMed1993

Assessment of beta-adrenergic receptor blockade after isamoltane, a 5-HT1-receptor active compound, in healthy volunteers.

This study investigated the effects of isamoltane on the changes induced by cumulative doses of inhaled albuterol (salbutamol) on bronchomotor tone, skeletal muscle, circulatory system, and metabolism after single (day 1) and multiple dosing (day 7) in 15 healthy subjects. The volunteers were given placebo, 4 mg isamoltane, 10 mg isamoltane, or 20 mg propranolol over a 7-day period in a randomized, double-blind, crossover design. The greatest attenuation in albuterol-induced beta-adrenergic receptor responses occurred with propranolol. The median provocative dose of albuterol causing a 50% increase in specific airway conductance was 337 and 315 micrograms (day 1 and day 7, respectively) for placebo, 336 and 322 micrograms for 4 mg isamoltane, 344 and 389 micrograms for 10 mg isamoltane, and 667 and 652 micrograms for propranolol. The provocative dose of albuterol producing a 35% increase in tremor was 464 and 539 micrograms (day 1 and day 7, respectively) for placebo, 1122 and 1270 micrograms for 4 mg isamoltane, 1612 and > 1612 micrograms for 10 mg isamoltane, and > 1612 and > 1612 micrograms for propranolol. On day 5 of each period an exercise test was performed. Propranolol reduced exercise heart rate by 11% (compared with placebo), 10 mg isamoltane reduced heart rate by 5%, and 4 mg isamoltane reduced heart rate by 1%. In conclusion, low-dose isamoltane caused measurable systemic effects on both beta 2- and beta 1-adrenergic receptors, and the dose-dependent blockade on beta 2-receptors of skeletal muscle was more clear than the attenuation of exercise heart rate.

Adrenergic beta-Antagonists↗
PubMed1993

Short-term effects of blood transfusion on blood volume and resting peripheral blood flow in preterm infants.

The effects of blood transfusion on cardiac output and blood pressure are variable, but resting peripheral blood flow (RPBF) may be a sensitive indicator of changes in blood volume. The purpose of this investigation was to study the effects of red cell transfusion on blood volume (Evans blue), blood pressure, RPBF in the leg (strain-gauge plethysmography) and blood viscosity (cone-plate viscometer) in preterm infants during the first week after birth. Fourteen infants with mean +/- SD birth weight of 1658 +/- 429 g, gestational age 33 +/- 3 weeks and postnatal age 64 +/- 40 h received 18 +/- 4 ml/kg of packed red cells (red cells 11 +/- 2 ml/kg, plasma 7 +/- 1 ml/kg) because their hematocrit was less than 0.45 l/1. Mean blood volume before transfusion was 88 +/- 15 ml/kg. The increase in blood volume (9 +/- 4 ml/kg) measured 4 to 6 h after transfusion was smaller than the transfused volume (18 +/- 4 ml/kg), due to a shift of plasma to the extravascular space. The plasma shift increased with increasing pretransfusion blood volume (r = 0.70; p = 0.007). Red cell transfusion caused an increase in RPBF by 25% (p < 0.01), whereas systolic blood pressure (BP) increased by only 12%. Peripheral resistance (R = BP/RPBF) decreased by 9% (p < 0.01). Blood viscosity (eta) increased by 21% (p < 0.001) and vascular hindrance (R/eta) decreased by 24% (p < 0.001), indicating vasodilatation of limb arteries. The increase in RPBF and the decrease in hindrance were particularly pronounced in infants with high pretransfusion blood volume.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Pressure↗
PubMed1993

Systolic blood pressure and blood volume in preterm infants.

Blood volume and systolic blood pressure (SBP) were measured in 43 preterm infants. Mean (SD) blood volume was 83 (19) ml/kg (range 48-119) and SBP 50 (9) mm Hg (range 34-69), showing a significant overall relationship. Blood volume in infants with SBP > 60 mm Hg (110 (6) ml/kg) was significantly higher than in infants with SBP 40-60 mm Hg (78 (16) ml/kg) and in infants with SBP < 40 mm Hg (75 (10) ml/kg). In conclusion, SBP is of limited value in detecting hypovolaemia in very low birthweight infants.

Blood Pressure↗