Biomedical subjects

H L Müller

Publications and source records attributed to H L Müller.

At least 19 recordsLinked to original sources

PubMed2003

Volumetric bone mineral density in patients with childhood craniopharyngioma.

As the overall survival rate is high in patients with craniopharyngioma, the prognosis in survivors depends mainly on late effects. Late effects such as hypogonadism, growth hormone deficiency, glucocorticoid overreplacement and obesity have a strong impact on volumetric bone mineral density (vBMD). We analyzed vBMD and possible risk factors for reduced vBMD in 61 patients with childhood craniopharyngioma (29 f; 32 m) and in 14 weight, age, and sex-matched controls. VBMD was quantified by peripheral quantitative computed tomography (pQCT). Endocrine status, hormonal substitution therapy and calcium phosphate metabolism were evaluated. VBMD was in the lower normal range in 61 craniopharyngioma patients (total radial z-scores: median - 1.5; range - 3.1 to 1.4; trabecular z-scores: median - 0.4; - 2.4 to 2.3). 23 severely obese patients (body mass index [BMI] > 4 SD) had a higher total radial (p < 0.05) and trabecular (p < 0.05) vBMD when compared with 38 non-severely obese patients and 7 weight-matched controls. Although there was no gender difference in terms of obesity, endocrine substitution therapy or calcium phosphate metabolism, male patients had lower total radial (p < 0.01) and trabecular (p < 0.05) vBMD. Only in male patients' vBMD z-scores showed a positive correlation with BMI standard deviation score (SDS) (total radial z-score: Spearman r = 0.38, p = 0.03; trabecular z-score: Spearman r = 0.35, p = 0.04). We conclude that obesity has a major impact on vBMD in patients with craniopharyngioma. Lean male patients are at special risk for a lower vBMD, whereas female gender and severe obesity seem to have a protective effect regarding vBMD.

Adolescent↗

PubMed2003

Perioperative dexamethasone treatment in childhood craniopharyngioma--influence on short-term and long-term weight gain.

The substitution of dexamethasone during and after surgery of childhood craniopharyngioma is necessary in order to treat and/or prevent brain edema and adrenal insufficiency. Early post-operative weight gain is a predictor for severe obesity during long-term follow-up. In a retrospective analysis of 60 patients with childhood craniopharyngioma we inquired whether dose and duration of perioperative dexamethasone therapy (n = 68) had influence on short-term post-operative weight gain and long-term development of severe obesity. The median follow-up period was 4.2 years, ranging from 1 to 9 years. 24 patients (14 f/10 m) developed severe obesity (BMI > 3 SD). 28 patients (10 f/18 m) retained normal weight (BMI < 2 SD). Eight patients presented with a BMI between 2 and 3 SD at the final visit. Differences in terms of age at surgery or follow-up period were non-detectable between the analyzed groups of craniopharyngioma patients. Duration and cumulative dexamethasone doses (mg/m2 BSA) for perioperative dexamethasone therapy were similar for severely obese patients (duration: 8.7 d; 4.5 - 17 d, cumulative dose: 74; 42 - 177 mg/m2 BSA) and normal weight patients (duration: 10.0 d; 1 - 41 d; dose: 76; 9 - 390 mg/m2 BSA). Whereas cumulative dexamethasone doses positively (p < 0.01; rho: 0.424) correlated with weight gain during the first year following surgery, long-term development of severe obesity was not influenced by dose and duration of perioperative dexamethasone treatment. Patients who developed severe obesity during follow-up had a higher (p < 0.001) BMI already at the time of diagnosis. We conclude that dose and duration of perioperative dexamethasone treatment had short-term effects on post-operative weight gain, but not on the development of long-term severe obesity. The results of our retrospective analysis are currently tested in a prospective surveillance study Kraniopharyngeom 2000 (www.kraniopharyngeom.com).

Adolescent↗

PubMed2001

Prospective study on plasma clotting parameters in diabetic children--no evidence for specific changes in coagulation system.

In a prospective study, clotting parameters of 37 children and adolescents with insulin-dependent diabetes mellitus (type 1 diabetes) were compared with those of a healthy control group. In a longitudinal follow-up over two years we found no statistical difference for most of the coagulation parameters investigated, including single factor analysis and coagulation inhibitors. The duration of type 1 diabetes was of no influence on these parameters. The only difference we found between patients and healthy controls was an elevation of PAI-1 in diabetics: median for PAI-1: 2.12 IU/ml in diabetics (range 0.50-8.40 IU/ml) and 0.84 IU/ml in normal controls (range 0.50-1.78 IU/ml). This difference was of statistic significance (p < 0.002) and also found in newly diagnosed patients. During observation time, none of our patients developed thrombosis or signs of vascular disease. In conclusion, we could not confirm the development of a hyper-coagulable state in pediatric diabetics, as it is described for adults with type 1 diabetes mellitus.

Adolescent↗

PubMed2000

Radical surgery in a neonate with craniopharyngioma. report of a case.

Ultrasonography revealed a suprasellar tumor in a fetus at 28 weeks of gestation. The male newborn, delivered 10 weeks later, was operated at the age of 17 days, and a craniopharyngioma was completely removed. Intraoperatively, inappropriate secretion of antidiuretic hormone occurred and was followed by diabetes insipidus causing imbalance of fluid and electrolytes. The tumor recurred and was totally removed 1 year later. Further development was uneventful and, at the age of 8 years, the boy is in generally good mental and physical condition except for a left-sided hemiparesis. In contrast to the poor outcome of neonatal craniopharyngioma reviewed in the literature, this case may encourage radical surgery even in the very young.

Brain Neoplasms↗

PubMed2000

Asp361Val Mutant of alkaline phosphatase found in patients with dominantly inherited hypophosphatasia inhibits the activity of the wild-type enzyme.

Hypophosphatasia is characterized by the hypomineralization of bone associated with the mutation of the tissue-nonspecific alkaline phosphatase (TNSALP) gene. Although the disease is usually autosomal recessive, an autosomal dominant form is also recognized. Approximately 50 mutations have been found in the TNSALP gene in patients with hypophosphatasia. However, the mutations identified to date do not seem to account for the dominantly inherited form of the disease. We have examined a German family in which the father and all 4 children were affected with hypophosphatasia, whereas the mother was healthy. The affected members of this family showed premature loss of deciduous teeth at or shortly before 2 yr of age and low levels of serum ALP with elevated levels of urinary phosphoethanolamine. DNA analysis by direct sequencing revealed a heterozygous missense mutation that caused the conversion of amino acid Asp to Val at position 361 (D361V) in the patients. Another substitution was detected in exon 12 (Val to Ala conversion at codon 505: V505A) in 1 allele of the mother and 3 children, indicating no association of the substitution with the disease. Reconstruction experiments demonstrated that the D361V mutant protein lost its enzymatic activity and that it inhibited the function of wild-type enzyme when coexpressed in COS-7 cells. On the other hand, the V505A mutant exhibited enzymatic activities equal to those of the wild-type ALP. It is likely that the mutant D361V protein forms dimers with the wild-type protein, and the protein-protein interaction contributes to the dominant effect of the mutant D361V. The mutation that causes D361V is the first one proven to be associated with the dominant form of hypophosphatasia.

Adult↗

PubMed1998

[Energy utilization of retrograded starch by sows].

A total metabolism trial was conducted in eight adult sows to compare the energetic utilization, nitrogen balance, and passage rate of retrograded starch (RGS) with that of pregelatinized wheat starch (PWS). The starch was added at levels of 12 and 24 g/kg W0.75 to a basal ration that covered the maintenance requirement. Each animal received all four treatment combinations in a change-over design. At the start and end of the trial all sows were fed the basal ration alone. Feeding took place twice daily. During each 3-week metabolism period a complete balance measurement was performed for all animals, with 6 daily collections of feces and urine and a 48-h gas exchange measurement in a respiration chamber. The sows' heat production and energy retention were calculated by the carbon-nitrogen balance method and the RQ method. Digestibility and metabolizability of energy and energy retention were lower in the basal ration with RGS supplement than in the PWS supplemented ration. With regard to N exchange, sows supplemented with RGS excreted more N in the feces and less N in the urine, whereas N retention was equal with both rations. The production of CH4 was higher with RGS than after feeding pregelatinized wheat starch. When compared with the nonsupplemented basal ration, the fecal volume was unchanged with PWS but significantly increased with RGS. The feed passage, measured as the mean retention time of a marker in the digestive tract, was 86 h on the basal diet, falling to 75 h with PWS supplementation and 65 h with RGS. The utilization of the supplemented energy was 12% lower for RGS compared with PWS. This difference was due to a reduction in the digestibility and intermediate utilization of the energy. The amount of metabolizable energy was calculated as 16 kJ/g and the net energy as 12.5 kJ/g RGS. The results of the trial underline the importance of retrograded starch as a fiber type nutrient and the associated advantages for the bowel function. The energetic utilization on the other hand is only slightly lower than that of non-resistant starch; unlike pure fibrous feed materials, RGS can therefore not be regarded as a "low energy" substance.

Animals↗

PubMed1998

A possible role for somatostatin receptor scintigraphy in the diagnosis and follow-up of children with medulloblastoma.

The surgical resection of medulloblastoma (MB), the most frequent malignant brain tumor in children, often remains subtotal. To estimate the response to further treatment the residual tumor is monitored by CT or MRI. The interpretation of both imaging techniques is complicated by disturbances resulting from surgery and radiation. Our study searched for alternative imaging techniques and asked the following questions. 1) Do MB express somatostatin receptors (SSTR), 2) is SSTR scintigraphy a sensitive imaging technique for the follow-up and the detection of vital tumor tissue in children with MB, and 3) do the results of SSTR scintigraphy correlate with the in vitro analysis of MB tissue by SSTR autoradiography. We analyzed the SSTR status in 20 children with MB, aged 1 to 15 years. Sixteen SSTR scintigraphies using Indium-111-DTPA-D-Phel-pentetreotide were performed in 14 children. MB tissue of 14 children was analyzed by SSTR autoradiography using Iodine-125-Tyr3-octreotide. In 8 cases SSTR were measured by both methods in vivo and in vitro. In comparison with conventional imaging, results of SSTR scintigraphy were true positive in 7 of 7 patients, true negative in 9 of 9 patients, including one patient with false positive findings in MRI, false negative in only one patient with small spinal metastases (diameter < 3 mm) and false positive in none of the analyzed patients. In all cases with residual tumor (n = 3) and suspected relapse (n = 4) the diagnosis could be confirmed (n = 4) or excluded (n = 3), consistent with the results of MRI and tumor histology. All MB tissues analyzed by SSTR autoradiography (n = 14) showed an extremely high density of SSTR ranging from 4047 to 15526 dpm/mg MB tissue. MB (n = 8) which were analyzed by SSTR scintigraphy and autoradiography demonstrated consistent results in evaluation by both methods. In cases where the integrity of the blood-brain barrier was tested by Tc-99m-DTPA scintigraphy (n = 10), the SSTR-to-brain scintigraphy index confirmed the tumor specificity of radionuclide uptake. We conclude that 1) MB tissue expresses a particularly high density of SSTR, 2) the high density of SSTR in autoradiography correlates with a sensitive imaging of these tumors by SSTR scintigraphy, 3) SSTR scintigraphy might be a valuable imaging method for detection of vital MB tissue in patients with residual tumor or relapse.

Adolescent↗

PubMed1998

Final height and weight of long-term survivors of childhood malignancies.

The aim of this study was to investigate growth and final height in young adults after therapy for malignant diseases. Final height and weight was studied in 50 long-term survivors (LTS) of childhood cancer (aged 17-31 years; 30 men, 20 women) 3-18 years after treatment for malignant diseases (7 acute lymphoblastic leukemia, 20 lymphoma, 8 sarcoma, 15 malignant central nervous system [CNS] tumours). None of the LTS had been treated with growth hormone (GH). A decrease in final height SDS (Standard deviation score) occurred in both LTS of malignant CNS tumours (median height SDS at diagnosis, 0.3; range, -0.9 to 2.2; median final height SDS, -1.3; range, -3.9 to 1.9; p < 0.01) and LTS of lymphoma (p < 0.05) or leukemia (p < 0.05). However, only LTS who received cranial (p < 0.05) or craniospinal (p < 0.001) irradiation (XRT) exhibited reduced final heights. LTS who had received XRT not involving the CNS or had received no XRT at all presented no reduction in final height. LTS of CNS tumours treated with high craniospinal XRT doses (24 to 56 Gy) reached lower (p < 0.01) final heights when compared with LTS of leukemia who received lower cranial XRT doses (18 to 24 Gy). Final height SDS correlated with chronological age at initiation of therapy (p < 0.05). No correlation was found between the cumulative doses of applied chemotherapeutic agents and the final height of LTS. During follow-up LTS developed an increase in weight for height index (WFH) which occurred independent of XRT. In conclusion, cranial and craniospinal XRT especially in young children with malignancies resulted in a decrease in final height SDS. As 6 of 15 LTS of malignant CNS tumours exhibited a final height SDS below -2 SD, analysis of pituitary function and substitution of GH after diagnosis of GH deficiency should be considered for these patients at a young age. Others factors not directly related to XRT are responsible for the increased risk for obesity in LTS of childhood cancer.

Adolescent↗

PubMed1996

Gonadal function of young adults after therapy of malignancies during childhood or adolescence.

UNLABELLED: As the survival rate of children with malignancies has increased over past decades, the follow up of adult long-term survivors (LTS) of childhood cancer should focus on late effects of disease and treatment. Gonadal function was therefore studied in 54 LTS (aged 17-29 years; 33 male, 21 female) 2-18 years after treatment for malignancies during childhood or adolescence. To analyse the sensitivity of different diagnostic methods, tests of endocrine function (n = 52), spermiograms (n = 14), gynaecological status (n = 20) and ultrasonography of the gonads (n = 53) were compared with the results of equivalent tests in 23 age-matched normal controls (12 male, 11 female). There were no differences between male and female LTS concerning age at diagnosis, gonadal dose of irradiation (XRT) and doses of applied chemotherapeutic agents. Whereas male LTS had elevated levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) before (P < 0.05; P < 0.001) and after (P < 0.01; P < 0.001) stimulation with gonadotropin releasing hormone, female LTS exhibited normal endocrine function. Accordingly, male patients exhibited lower testicular volumes than normal controls, as measured with a Prader orchidometer (P < 0.01) or by ultrasonography (P < 0.001). Gynaecological status and ultrasonography of the gonads were normal in female LTS and controls. Whereas all spermiograms of normal controls (n = 8) showed a normal sperm cell density (SCD), only 2 of 14 male LTS exhibited a normal SCD (P < 0.001). Azoospermic LTS (n = 9) had been treated more often with alkylating agents and had received higher (P < 0.05) gonadal doses of XRT. All male LTS with testicular volumes below the normal range (< 13 ml) and basal FSH levels above the normal range (> 10 IU/l) exhibited azoospermia, whereas LTS with normal values for testicular volume and basal FSH had a normal SCD. CONCLUSION: A sex-specific susceptibility for gonadal damage after treatment for malignancies might be responsible, in part, for the impaired gonadal function of male LTS. Therapy with alkylating agents and/or high gonadal doses of XRT were important risk factors for azoospermia. A simple method to estimate potential fertility in individual LTS is to measure testicular volume, using a Prader orchidometer, and basal FSH serum levels.

Adolescent↗

PubMed1996

[Feed intake and performance of dairy cows during feeding of fodder beets supplementing grass silage].

In a feeding experiment 3 x 12 dairy cows (German Simmental x Red Holstein Friesian) were used to investigate the influence of different amounts of fodder beets on feed intake, milk yield and milk composition. The fodder beets (variety Kyros) were fed in exchange for concentrate. The amounts of fodder beets were either 22 kg cow-1 d-1 or 44 kg cow-1 d-1 or zero (control group). All groups received 4 kg hay cow-1 d-1, grass silage ad libitum, and concentrate corresponding to the milk yield. In order to balance the rations the concentrate was either rich in protein or rich in energy. Feeding 22 kg or 44 kg fodder beets increased forage intake (including fodder beets) significantly. However, the total feed intake diminished on average from 18.3 kg DM cow-1 d-1 (control group) to 17.2 kg DM cow-1 d-1 (fodder beet groups). In each treatment the intake of hay was 3.3 kg DM cow-1 d-1. However, the intake of grass silage offered ad libitum was significantly suppressed by the fodder beets. Considering the different amounts of concentrate the quantity of suppression of grass silage by feeding fodder beets was calculated at -0.8 kg DM of grass silage per kg DM of fodder beet intake. The milk yield decreased linearly with increasing fodder beets on average up to 4 kg cow-1 d-1. However, the milk composition was scarcely influenced. The fat content increased a little, the mean alterations of the protein and lactose content were below 0.1 percentage points. Therefore, the change in daily excretion of milk fat, protein or lactose were similar to the change in milk yield. In conclusion, feeding fodder beets in combination to grass silage causes a positive effect on forage intake (including fodder beets). However, the amount of concentrate should not be reduced equivalently to the energy contents of the added fodder beets.

Animal Feed↗

PubMed1996

Effect of Hay's separation principle on the energy metabolism.

A cross-over experiment was conducted with 8 adult, nonpregnant sows in order to test whether feeding according to the principle of Hay's separation diet exerts a stimulant effect on thermogenesis. The protein part of the daily ration was offered at the morning feeding, the other ration components in equal amounts at two further feedings. The control group received the daily ration in three equal portions. The levels of all nutrients in the rations matched the maintenance requirement based on the initial weight of the sows and remained unchanged throughout the experiment. In both 3-week metabolism periods a complete balance was undertaken for each animal using the collection technique (feed, feces, urine) and 48-hour measurement of the gas exchange in a respiration chamber. The body weight of the sows fed the separation diet was 178.3 kg and that of the control 178.6 kg. Oxygen and carbon dioxide were reduced by 1.5% with separation. The respiratory quotient remained unchanged. The experimental treatment had no effect on energy digestibility and metabolizability. Heat production of the animals on the separation diet was 20.6 versus 20.1 MJ/day on the control diet. The result was reversed for energy retention, namely 0.6 versus 0.0 MJ/day. The daily energy exchange profile, represented by thermogenesis plotted at 5-min intervals, showed slightly lower values than the control after the protein meal and only random differences between the two treatments for the remainder of the day. It can be concluded from the results that separation of the protein and carbohydrates in the diet within 1 day, rather than stimulating thermogenesis, is more likely to reduce it.

Animal Nutritional Physiological Phenomena↗

PubMed1995

Transforming growth factor-beta-induced cell growth inhibition in human breast cancer cells is mediated through insulin-like growth factor-binding protein-3 action.

Most estrogen receptor-negative breast cancer cells, including Hs578T cells, express mRNAs encoding insulin-like growth factor-binding protein (IGFBP)-3, as well as transforming growth factor (TGF)-beta receptors. Our previous studies (Oh, Y., Muller, H. L., Lamson, G., and Rosenfeld, R. G. (1993) J. Biol. Chem. 268, 14964-14971; Oh, Y., Muller, H. L., Pham, H. M., and Rosenfeld, R. G. (1993) J. Biol. Chem. 268, 26045-26048) have demonstrated a significant inhibitory effect of exogenous IGFBP-3 on Hs578T cell growth and existence of IGFBP-3-specific receptors that may mediate those direct inhibitory effect of IGFBP-3. TGF-beta is also a potent growth inhibitor in human breast cancer cells in vitro and regulates IGFBP-3 production in different cell systems, suggesting that IGFBP-3 is a major anti-proliferative factor and a key element for TGF-beta-induced growth inhibition in human breast cancer cells. In support of this hypothesis, we have demonstrated using Hs578T cells that: 1) TGF-beta stimulates IGFBP-3 gene expression and production prior to its inhibition of cell growth, 2) treatment with an IGFBP-3 antisense oligodeoxynucleotide selectively inhibits TGF-beta-induced IGFBP-3 synthesis and cell growth inhibition, and 3) treatment with IGF-II and IGF-II analogs diminish TGF-beta effects by blocking TGF-beta-induced binding of IGFBP-3 to the cell surface. These findings suggest that IGFBP-3 is a major anti-proliferative factor and a key element in TGF-beta-induced growth inhibition in human breast cancer cells.

Amino Acid Sequence↗

PubMed1995

[Thermogenesis in overfeeding with administration of olive oil and fish oil in a swine model study].

A trial on total metabolism was conducted in eight nonpregnant, nonlactating sows over eight periods, each of 16 days duration, to measure potential fatty acid induced thermogenesis. During the first and last experimental periods, the animals received a basal ration which just covered the energy maintenance requirement. In the second to seventh periods supplements of olive oil, fish oil, or puffed wheat starch as reference nutrient were added to the diet in random sequence at two levels up to 50% above the maintenance requirement. All rations were calculated with reference to the sows' initial weight and remained quantitatively unchanged throughout the experiment. The animals were fed twice daily. During each metabolism period a complete energy balance was assessed for all sows by means of collection technique (feed, feces, urine), and 48-h measurements of the gas exchange in a respiration chamber. The sows' body mass increased linearly during the course of the experiment by 5.8 kg per period. The three supplement types had no influence on the animals' final body weight, wich averaged 205.5 kg with the starch supplement, 204.8 kg with olive oil, and 205.8 kg with fish oil. Energy digestibility (DE/GE) was 100% for all three supplements, and metabolizability of energy (ME/GE) one percentage point less. Carbon and energy depositions showed a pronounced linear relationship to the level of supplementation and were also influenced by the type of supplement. Heat production was 20.9 MJ/d after feeding the basal ration alone and, taking the average of the two supplementation levels, 21.6 MJ for the starch supplement, 21.0 MJ for olive oil, and 20.6 MJ for fish oil.(ABSTRACT TRUNCATED AT 250 WORDS)

Animal Feed↗

PubMed1995

[Thermogenesis and energy utilization of olive oil and fish oil in a model study with sows].

An animal model experiment was conducted with nine adult sows to study the effect of olive oil and fish oil (40% polyunsaturated fatty acids) on thermogenesis compared to wheat starch as control. The treatments were given to each animal according to a latin square design. The basal diet (20 g DM/kg W0.75) was mainly based on barley and soybean meal, and matched 60% of the ME requirements with all the other nutrients meeting maintenance requirements. The isoenergetic supplements amounted to 176 kJ gross energy per kg W0.75 and day. During each experimental period a complete energy balance was recorded for each animal using indirect calorimetry technique (RQ-method) as well as the carbon-nitrogen-balance technique. The treatments did not influence the digestibility of the rations. Digestibility of energy and of carbon averaged 83.4% and 83.3%, respectively. All three supplements were nearly completely digested as calculated by the difference method. Fish oil increased urine energy and decreased CH4 production, the shifts, however, were in absolute terms very small. The mean O2 consumption was 1,002 l/d showing no significant treatment effects. CO2 production was lowered with olive oil by 10%, and with fish oil by 13% compared to the starch diet. The daily heat production was 20.95, 20.72, and 20.04 MJ when starch, olive oil or fish oil was given. Corrected for equal energy retention the difference of thermogenesis between olive oil and starch was -0.4 MJ/d, and between fish oil and starch -1.2 MJ/d. These differences corresponded to a relation of starch:olive oil:fish oil = 1:0.95:0.86. The relation between starch and olive oil reflected exactly the theoretical expectation, calculated from the ATP regeneration by oxidation of both nutrients. When fish oil was added, the daily heat production was lower than theoretically calculated, which might be interpreted as an effect on the metabolic rate in general rather than especially on the efficiency of ATP formation from fish oil oxidation. In any case, there was no hint of a facultative thermogenesis induced by the oils.

Adenosine Triphosphate↗

PubMed1995

Antiproliferative actions of insulin-like growth factor binding protein (IGFBP)-3 in human breast cancer cells.

A number of lines of evidence suggest that IGFs are important mitogens in human breast cancer: (1) IGFs are the most potent growth factor in human breast cancer cells; (2) estrogen stimulates expression of IGF-II and the type 1 IGF receptor; and (3) stromal cells express IGFs, which may act in a paracrine manner. Numerous studies have demonstrated that IGFBPs modulate the mitogenic effects of IGFs in the local environment. In particular, we have recently demonstrated that IGFBP-3 inhibits the growth of Hs578T and MDA-MB-231 human breast cancer cells in an IGF-independent manner. Further studies revealed the existence of cell surface-associated IGFBP-3 receptors. Receptor binding and the subsequent antiproliferative action of IGFBP-3 was inhibited by IGFs, owing to the formation of an IGF-IGFBP-3 complex that prevents the binding of IGFBP-3 to its receptors. In addition, exogeneously added soluble heparin or heparan sulfate inhibited the binding of IGFBP-3 to the cell surface in a dose-dependent manner. However, when heparin and heparan sulfate linkages of glycosaminoglycans on the cell surface were enzymatically remove, IGFBP-3 binding was only minimally affected. These data suggest that soluble heparin or heparan sulfate forms a complex with IGFBP-3, thereby inhibiting receptor binding of IGFBP-3, rather than competing with cell-surface glycosaminoglycans for binding of IGFBP-3. Additionally, the role of IGFBP-3 in the antiproliferative effects of transforming growth factor (TGF)-beta and retinoic acid (RA) is supported by our observations that: (1) inhibition of IGFBP-3 gene expression using an IGFNBP-3 antisense oligodeoxynucleotide not only blocks TGF-beta and RA simulation of IGFBP-3 production by up to 90%m but also inhibits their antiproliferative effects by 40-60%; and (2) treatment with IGF-II and IGF-II analogs diminish TGF-beta effects by blocking TGF-beta induced binding of IGFBP-3 to the cell surface. Taken together, our results support the hypothesis that IGFBP-3 is an important antiproliferative factor in human breast cancer, acting in an IGF-independent manner in addition to its ability to modulate the binding of IGF peptides to IGF receptors.

Breast Neoplasms↗

PubMed1994

[Effect of isoenergetic replacement of starch by olive oil and fish oil concentrations of lipids in plasma and lipoprotein fractions in swine].

Two experiments with sows were performed to investigate the effect of isoenergetic replacement of starch by fish oil or olive oil on concentrations of lipids in plasma and lipoproteins. The first experiment was based on a cross-over design with three periods, each lasting 16 days. Each sow was fed during one of the periods a basal ration with isoenergetic addition of (1) starch (495 g/d), (2) olive oil (221 g/d), or (3) fish oil (223 g/d) based on energetic requirement for maintainance. The second experiment was based on a cross-over design with eight periods, each lasting 16 days. In the first and in the last periods, each sow was fed the basal ration. In the other six periods, each sow was fed the basal ration with addition of two different amounts of (1) starch (284/568 g/d), (2) olive oil (140/281 g/d), or (3) fish oil (141/282 g/d). The two different amounts of addition were selected to exceed the energetic requirement for maintainance by 25% or 50%. In both experiments blood samples were taken before each change of the ration. In both experiments olive oil elevated the concentration of cholesterol in plasma in comparison with starch. This elevation was due to a large elevation in high-density lipoproteins (HDL), and a slight elevation in low-density lipoproteins (LDL) and very-low density lipoproteins (VLDL). The ratio between HDL and LDL cholesterol was increased by feeding olive oil. The effect of olive oil on concentrations of cholesterol in plasma and lipoproteins was dose-dependent. In both experiments none of the two dietary oils significantly changed concentrations of triglycerides in plasma and lipoproteins. Concentrations of phospholipids in plasma, HDL, and LDL were elevated by olive oil. In both experiments addition of fish oil elevated concentration of cholesterol in plasma due to elevated cholesterol concentration in LDL. Concentration of HDL cholesterol was not changed by fish oil. Thus, the ratio between HDL cholesterol and LDL cholesterol was lowered by fish oil. The effect of fish oil on concentration of cholesterol in plasma and lipoproteins was also dose-dependent. Fish oil had no significant effect on phospholipid concentrations in plasma and lipoproteins. In conclusion, in the present experiment olive oil caused antiatherogenic changes of the lipoprotein profile, whereas fish oil caused proatherogenic changes of the lipoprotein profile.

Animals↗

PubMed1994

Insulin-like growth factor binding protein-3 concentrations and insulin-like growth factor binding protein-3 protease activity in sera of patients with malignant solid tumors or leukemia.

IGF binding proteins (IGFBP) regulate the bioavailability and bioactivity of IGF. The major IGFBP in serum is IGFBP-3. We investigated whether sera from children with malignancies show alterations in levels of IGFBP-3 as measured by Western ligand blot analysis (WLB) and RIA with alpha IGFBP-3gl, a specific rabbit polyclonal antibody. Furthermore, IGFBP-3 proteolysis was quantified by densitometric analysis of [125I]IGFBP-3 protease assays, and IGFBP-3 fragments were visualized by Western immunoblot with alpha IGFBP-3gl. We examined sera from 21 children with solid tumors, five patients with sarcoma who had reached complete remission, and 13 children with acute leukemia. Serum samples were collected at diagnosis, before initiation of therapy. Sera of 10 healthy children served as normal controls. Children with solid tumor or leukemia had significantly higher (p < 0.001) IGFBP-3 protease activity in serum than did normal controls or patients with sarcoma in complete remission. Corresponding to this finding, densitometry of WLB showed lower IGFBP-3 levels in sera of children with malignancies in comparison with normal controls. The negative correlation (p < 0.001, r = -0.80) between IGFBP-3 proteolysis, as measured by [125I]IGFBP-3 protease assay, and IGFBP-3 band density on WLB indicates that proteolysis is the probable reason for reduction of IGFBP-3 on WLB. IGFBP-3 concentrations measured by RIA were in the normal range for most patients, further indicating that differences in serum IGFBP-3 levels measured by WLB reflect protease activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

PubMed1994

Insulin-like growth factor-binding protein-2 concentrations in cerebrospinal fluid and serum of children with malignant solid tumors or acute leukemia.

Many tumor cell lines express insulin-like growth factors (IGFs) as autocrine growth factors and IGF-binding protein-2 (IGFBP-2) as a major IGFBP, which, in turn, regulates the bioavailability and bioactivity of IGFs. The aim of our study was to investigate 1) whether children with malignancies have elevated IGFBP-2 levels in cerebrospinal fluid (CSF) and serum, and 2) whether IGFBP-2 levels in these biological fluids could be useful markers for the diagnosis and follow-up of certain tumor types. We, therefore, measured IGFBP-2 levels in the CSF and serum of children with malignancies by Western ligand blot analysis; RIA with alpha IGFBP-2, a polyclonal antibody for human IGFBP-2; and immunoprecipitation with alpha IGFBP-2 and alpha Hec-1a, a polyclonal antibody that recognizes IGFBP-2 and -3. Furthermore, the expression of IGFBP-2 messenger ribonucleic acid in tumor tissue from three central nervous system (CNS) tumor patients was analyzed by Northern blot analysis. We examined CSF from 21 children with malignant CNS tumors, 25 patients with acute leukemia, and 4 patients with peripheral solid tumors and compared the IGFBP-2 levels with those in CSF from 21 patients who received a lumbar puncture to exclude meningitis. Serum was obtained from 7 patients with solid tumor, 12 patients with malignant CNS tumor, and 16 patients with acute leukemia. The serum IGFBP-2 levels were compared to serum levels in 5 patients with sarcoma who had reached complete remission and 13 normal control children. CSF and serum were collected at the same time, before initiation of therapy. Patients with malignant CNS tumors showed elevated IGFBP-2 levels in CSF (P < 0.001), whereas patients with solid peripheral tumor or acute leukemia had normal IGFBP-2 levels in CSF. CNS tumor patients with microscopically detectable malignant cells in the CSF had the highest CSF IGFBP-2 levels. Serum IGFBP-2 levels were increased in patients with solid peripheral tumors (P < 0.05), whereas patients in complete remission had normal serum IGFBP-2 levels. In summary, IGFBP-2 was elevated specifically in CSF from patients with CNS tumor, whereas IGFBP-2 serum levels were elevated in children with various peripheral tumors. We conclude that IGFBP-2 in CSF could be a specific marker for malignant CNS tumors. We detected high IGFBP-2 messenger ribonucleic acid expression in 1 of 3 CNS tumor tissues analyzed.

Adolescent↗