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Biomedical subjects

G Baumann

Publications and source records attributed to G Baumann.

At least 253 records · Page 14Linked to original sources
PubMed1991

Metabolism of growth hormone (GH) and different molecular forms of GH in biological fluids.

Human growth hormone (GH) consists of a number of molecular variants which derive from 2 genes, several alternative mRNA splicing mechanisms, and post-translational modifications such as deamidation, acylation, glycosylation, and oligomerization. After secretion, GH binds to two (or possibly more) circulating GH-binding proteins, one of which is a truncated GH receptor. The resulting mixture of GH moieties in plasma is enormously complex, consisting of over 100 molecular states. The various GH forms undergo differential clearance, receptor binding, and complexing with binding proteins, each exhibiting distinct kinetics. The net effect on bioactivity is correspondingly complex, and measurements by immunoassay or receptor assays are complicated by the lack of a homogeneous analyte. GH is best seen as a family of proteins, many of which fulfill as yet unknown functions in biology.

Body Fluids↗
PubMed1991

Growth hormone heterogeneity: genes, isohormones, variants, and binding proteins.

Human GH represents a family of proteins rather than a single hormone. The circulation contains a bewildering array of GH forms, including several monomeric variants, their homo- and heteropolymers, fragments, and complexes with at least two BPs. The net biological activity of this mixture is difficult to predict, as the various molecular forms interact as partial agonists and/or antagonists at the receptor level. The number of GH forms that can be counted in plasma exceeds 100. Table 5 attempts to illustrate what is known and provide estimates for circulating variants. It does not include GH-V and its variants, which have to be added in pregnancy. Of note, what is commonly understood as "plasma GH," i.e. free monomeric 22K, represents only 21% of total immunoreactivity in plasma. In view of this complicated picture, it should be no surprise that different assays of plasma GH yield different results (107, 108, 290). While immunoassays are relatively unaffected by the BPs (291), receptor assays are seriously affected by the high affinity BP (261). Immunoassays, particularly of the monoclonal variety, are vulnerable to differential recognition of molecular variants depending on the unique epitope specificity of the antibody used. Polyclonal assays are more robust in this regard because of "epitope averaging" among the wide spectrum of epitope specificities present in the antibody population. Future work should aim at developing antibodies that are specific for individual GH variants. Such molecular probes will be helpful not only in standardizing immunoassays, but also in delineating the biological role of the various GH forms. The physiological significance of the numerous GH forms (or of the BPs) is still largely unknown. Progress in this area has been hampered, on the one hand, by the unavailability of pure GH variants in quantities sufficient for biological studies, and, on the other, by a certain lack of interest stemming from suspicions about artifacts. The recent resurgence of interest in GH and in its receptor and BPs should also refocus attention on the various molecular forms. Thus far, this interest has been largely confined to monomeric 22K, which is certainly effective for its original intended purpose, namely growth promotion. Whether 22K is sufficient for optimal growth and development, or whether it can fulfill all the functions of the GH family is unknown. It can be argued that evolutionarily conserved GH variants probably have biological importance.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1991

Effects of growth hormone-binding proteins on serum growth hormone measurements.

GH-binding proteins (GH-BPs) in human blood theoretically may interfere with measurements of immunoreactive GH by forming complexes with GH and competing with antibody reagents for ligand. Indeed, results of serum GH obtained by immunoassays are known to differ markedly depending on the assay employed. To assess the potential role of circulating GH-BPs in this phenomenon, we systematically examined their effect on GH measurement in four RIAs and two immunoradiometric assays. In all except one RIA, the effect of the BPs on tracer binding to antibody was mildly inhibitory. In both immunoradiometric assays, BPs increased the nonspecific association of the tracer with the solid phase reagent. However, these effects were minor at the BP concentrations realistically encountered in practice. Furthermore, the impact of BPs on GH standard curves and final results was negligible because BP effects fall into the category of nonspecific or zero dose counts, which are subtracted during data reduction. We conclude that GH-BPs are only a minor disturbance in GH immunoassays, which is completely compensated for by conventional assay design. Disparities among results yielded by different assays are probably not due to BP interference.

Binding, Competitive↗
PubMed1991

Short stature and decreased serum growth hormone-binding protein in the Mountain Ok people of Papua New Guinea.

Two circulating GH-binding proteins (GH-BP), one of which is related to the GH receptor, have been described. To assess their possible role in or link with determining statural growth, we measured their activity/level in the serum of 25 adult subjects from a short-statured population from the highlands of Papua New Guinea (Mountain Ok people, similar in stature to African pygmies) and in 25 normal-statured North American control subjects. The Mountain Ok people have normal levels of GH, insulin-like growth factor-I (IGF-I), IGF-II, and serum albumin and prealbumin in association with short stature, making them a unique study population. Levels of the high affinity (GH receptor-related) GH-BP were significantly lower in the Mountain Ok subjects than in the taller controls (5.2 +/- 3.0% vs. 10.6 +/- 3.9% GH bound/160 microL, respectively; mean +/- SD; P less than 0.001). In contrast, the low affinity GH-BP was comparable in Mountain Ok and control subjects. Because of the structural similarity between the GH receptor and GH-BP, these data suggest that a limitation in GH receptor/GH-BP endowment may be associated with short stature despite normal circulating IGF-I levels. Alternatively, it is possible that the GH-BP itself plays an important role in growth promotion. Thus, the GH receptor (and/or GH-BP) complement may be a determinant of the genetically programmed height achieved.

Adult↗
PubMed1991

Growth hormone-binding protein activity is inversely related to 24-hour growth hormone release in normal boys.

To investigate the physiological relationship between serum GH-binding proteins and 24-h GH release, we compared the 24-h GH pulse attributes in serum samples obtained at 20-min intervals to the serum GH-binding protein activity (GH-BP) from 38 normal boys between 7 5/12 and 18 4/12 yr of age. GH-BP was determined in a serum sample from each study (containing less than 1.0 micrograms/L GH) using a standardized GH-BP assay. GH-BP results are expressed as the percentage of [125I]human GH bound to the high affinity GH-BP complex (peak II) per 160 microL serum. There were significant inverse relationships between the high affinity (receptor-related) GH-BP and several characteristics of 24-h GH release. Specifically, GH-BP was significantly (P less than 0.005 for all), but negatively, correlated with mean 24-h GH concentration (r = -0.62), sum of the GH pulse amplitudes (r = -0.57), sum of the GH pulse areas (r = -0.55), interpulse mean GH concentration (r = -0.53), and number of GH pulses per 24 h (r = -0.53). In addition, GH-BP correlated positively with the mean time interval between pulses (r = 0.59). There was also a significant positive correlation (r = 0.75; P less than 0.001) between GH-BP and the subject's age-adjusted body mass index SD score (BMI-SDS). Each characteristic of 24-h GH release correlating inversely with GH-BP also correlated inversely with BMI-SDS (P less than 0.01 for all comparisons). GH-BP did not, however, correlate with plasma insulin-like growth factor-I levels, serum testosterone concentrations, or height SDS. Binding to the low affinity GH-BP (peak I) did not correlate significantly with any of the examined GH pulse attributes, BMI-SDS, or the degree of binding to the high affinity GH-BP (peak II). We conclude that an inverse relationship exists between the high affinity serum GH-BP and 24-h GH release in boys under normal physiological conditions. We speculate that abnormalities in this relationship probably also exist and may underlie some disorders of growth.

Adolescent↗
PubMed1991

Plasma growth hormone (GH)-binding proteins: effect on GH binding to receptors and GH action.

GH-binding proteins (GH-BP) have recently been discovered in human plasma, but their biological function is unknown. The high affinity GH-BP is related to the GH receptor and may modulate the interaction of GH with tissue receptors, whereas the low affinity GH-BP should be inert in this regard. Modulation of receptor binding probably results in modulation of GH bioactivity. To address these issues, we examined the effects of purified GH-BPs as well as whole plasma on GH binding to receptors in human, rabbit, and female rat liver and in rat adipocytes. High affinity BP inhibited binding of GH to receptors in a dose-dependent fashion. Substantial inhibition was observed within the physiological range of BP concentrations; human liver and rat adipocytes were the most sensitive in this regard. In contrast, the low affinity BP had no effect on receptor binding of GH. Whole human plasma also inhibited GH binding to receptors. This effect could be attributed to its content of GH-BP, since removal or primary absence of the BP from plasma abolished its inhibitory effect. Purified high affinity BP also inhibited GH-dependent insulin-like growth factor-I production by cultured human fibroblasts to a degree comparable to receptor inhibition. We conclude that the circulating high affinity GH-BP, by sequestering GH, substantially interferes with binding of GH to its receptor, and that the well known inhibitory effect of plasma in RRAs for GH is largely due to this BP. GH action in human fibroblasts in vitro is similarly inhibited by this BP.

Adipose Tissue↗
PubMed1991

Binding of human growth hormone (GH)-variant (placental GH) to GH-binding proteins in human plasma.

Human GH-variant (hGH-V) is a natural GH analog arising from the hGH-V gene. It is expressed in the placenta and secreted into the maternal circulation during the second half of pregnancy. To gain information about its bioactivity in man, we examined the interaction of hGH-V with the high affinity GH-binding protein/receptor (GH-BP) in human plasma. hGH-V was equipotent with pituitary hGH (hGH-N) as a ligand for the GH-BP. hGH-N/hGH-V chimeric proteins, where the sequences encoded by exon 3 (amino acid residues 32-71, thought to be exposed on the molecule's surface and involved in receptor binding) were exchanged, also bound with similarly high affinities. A corresponding hGH-N/rat PRL chimeric protein had 25-fold reduced affinity for the GH-BP. We conclude that hGH-V is a potent somatogen in man, and that some of the manifestations of late pregnancy, such as increased insulin-like growth factor-I levels and coarsening of features, are probably related to the high circulating levels of hGH-V. GH-BP measurements in pregnancy must take into account BP saturation by endogenous hGH-V.

Binding, Competitive↗
PubMed1991

Acute effects of beta-adrenergic stimulation with dobutamine on the plasma levels of atrial natriuretic peptide and cyclic guanosine monophosphate in patients with chronic heart failure.

In eight patients (63 +/- 7.9 years) with angiographically documented dilated cardiomyopathy, we studied the acute effects of a beta-adrenergic stimulation with dobutamine on the plasma levels of atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP). For this purpose, a four-point dose-response curve was prepared for dobutamine starting with an initial dose of 2.5 micrograms kg-1 min-1, which was increased by 2.5 micrograms kg-1 min-1 at a time up to altogether 10 micrograms kg-1 min-1. Each stage lasted 15 min. ANP and cGMP were determined from the mixed venous blood before the start (t0), at 5 micrograms kg-1 min-1 after 30 min (t1), at 10 micrograms kg-1 min-1 after 60 min (t2) and after subsidence of the drug effect after 90 min (t3). ANP dropped from 380 +/- 151 pg ml-1 (normal range up to 55 pg ml-1) by 38% to 235 +/- 90 pg ml-1 after 30 min and by another 17% to 171 +/- 45 pg ml-1 after 60 min. After the effect of dobutamine had subsided, an increase by 41% to 325 +/- 139 was reached. There was a parallel drop of the mean cGMP level from 5.4 +/- 1.4 pmol.ml-1 by 28% to 3.89 +/- 1.4 pmol.ml-1 (30 min) and by another 14% to 3.2 +/- 0.7 pmol.ml-1 (60 min). After 90 min it was 18% below the initial value, being 4.4 +/- 1.3 pmol.ml-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1991

Cyclosporin A and FK-506 both affect DNA binding of regulatory nuclear proteins to the human interleukin-2 promoter.

The structurally unrelated immunosuppressive drugs cyclosporin A (Sandimmun) and FK-506 both interfere with the process of T-cell proliferation by blocking the transcription of the T-cell growth factor interleukin-2 (IL-2). Here we demonstrate that the transcriptional activation of this gene requires the binding of regulatory nuclear proteins to a promoter element with sequence similarity to the consensus binding site for NF-kappa B-related transcription factors. We present evidence that the binding by regulatory nuclear proteins to the kappa B element of the IL-2 promoter is affected negatively by cyclosporin A and FK-506 at concentrations paralleling their immunosuppressive activity in vivo. The decrease in DNA-protein complex formation induced by the immunosuppressive drugs correlates with a decrease in IL-2 production. FK-506 is 10 to 100 times more potent than cyclosporin A in its ability to inhibit sequence-specific DNA binding and IL-2 production. Our findings suggest that the actions of both drugs converge at the level of DNA-protein interaction.

Anti-Bacterial Agents↗
PubMed1991

Is the efficacy of positive inotropic drugs limited to symptomatic improvement?

It has been postulated that positive inotropic drugs accelerate the loss of myocardial function by increasing oxygen demands in the face of energy deficiency, especially in coronary artery disease. On the other hand subendocardial perfusion may be improved, mainly by decreasing filling pressures. Exercise tolerance, which in itself is a factor closely linked to prognosis, can be improved, and as newer compounds show, even endogenous catecholamine concentrations can be decreased. Especially the effects on peripheral vascular resistance, which many of these compounds also have, and the decrease in endogenous catecholamine concentrations might exert positive effects on mortality in congestive heart failure. The value of positive inotropic drugs in bridging therapy for heart transplantation is generally acknowledged, while the value of these compounds in chronic heart failure, especially in improvement of prognosis, has not been documented thus far.

Cardiotonic Agents↗
PubMed1991

Growth hormone binding proteins: biochemical characterization and assays.

Circulating growth hormone binding proteins have recently been recognized in man and certain animals. In man, two specific growth hormone binding proteins have been described, one with high affinity and another with low affinity. The high affinity binding protein corresponds to the extracellular portion of the hepatic growth hormone receptor, whereas the low affinity binding protein appears unrelated to the receptor. Both binding proteins bind one molecule of growth hormone to form complexes of 85 kD (high affinity) and 125 kD (low affinity). The isoelectric points of the two binding proteins are about 5.0 and 7.1, respectively. Most of the complexed growth hormone in plasma is associated with the high affinity binding protein. The binding proteins can be assayed by their specific ability to bind human growth hormone. Generally, plasma is incubated with radiolabelled human growth hormone under standardized conditions, and bound growth hormone is then separated from free growth hormone by size exclusion or ion exchange chromatography, or by charcoal adsorption. Several technical modifications of these fundamental assay designs exist.

Amino Acid Sequence↗
PubMed1990

The 20,000 Da variant of human growth hormone does not bind to growth hormone receptors in human liver.

The 20,000 Da variant of human growth hormone (hGH) (20K) exhibited no specific binding to hGH receptors in human liver plasma membranes. This contrasts with the 22,000 Da form of human growth hormone (22K), which bound with high affinity to the same hepatic receptor preparation. Since the liver is considered a major target organ for the somatogenic pathway of growth hormone action, this finding implies that in humans the 20K form plays little role in that pathway. The homologous hormone-receptor system examined here yielded results that differ from heterologous receptor binding experiments in animals. The differences are likely explained by the presence in non-primate mammals of more than one type of growth hormone receptor with varied specificities. In man, the 20K form of growth hormone may have a biological role distinct from that of the main 22K form of growth hormone.

Binding, Competitive↗
PubMed1990

Usefulness of dopexamine hydrochloride versus dobutamine in chronic congestive heart failure and effects on hemodynamics and urine output.

The hemodynamic effects of dopexamine hydrochloride and dobutamine were compared during dose-response infusions of dopexamine (1.0 to 4.0 micrograms/kg/min) and dobutamine (2.5 to 10.0 micrograms/kg/min) and during 48-hr infusions at doses producing initial matched increases in cardiac output. Thirty-three patients with severe, stable, chronic congestive heart failure (CHF) (New York Heart Association class III to IV) participated. Both drugs produced an increase in cardiac index, brought about by increased stroke volume index and heart rate, and systemic vasodilatation. The relative contribution of these mechanisms differed, dopexamine proving the more potent vasodilator. The effects of dopexamine were maintained without variation during the 48-hr infusion, apart from a reduction in the increase in heart rate. The effects of dobutamine, while remaining above control at most time-points during the 48-hr infusion, attenuated toward control values. Dopexamine also appeared to promote increased urine output and creatinine clearance during the 48-hr infusion. Both drugs were well tolerated. Dopexamine elicited larger peak hemodynamic effects at dosages that had equivalent effects on cardiac output, and favorable renal responses, and demonstrated no long-term attenuation of effect.

Adrenergic beta-Agonists↗
PubMed1990

Systemic anaphylaxis--separation of cardiac reactions from respiratory and peripheral vascular events.

An anaphylactic reaction in the isolated perfused heart is characterized by a drastic coronary constriction, arrhythmias, and an impairment of contractility. In vivo anaphylaxis is associated with respiratory distress and cardiovascular failure. The present investigation was designed to ascertain the electrocardiographic and cardiovascular changes during systemic hypersensitivity reactions. In addition, an attempt was made to differentiate cardiac from respiratory events. In guinea pigs, sensitization was produced by s.c. administration of ovalbumin together with Freund's adjuvant solution. Fourteen days after sensitization, the effects of an i.v. infusion of ovalbumin were tested in the anesthetized guinea pigs, which were ventilated with room air or 100% oxygen. A second administration of the antigen induced the development of cardiovascular collapse, leading to death within 12 min. Within 3 min, cardiac output decreased by 90% and end-diastolic left ventricular pressure increased significantly, indicating left ventricular pump failure. In the same time range, ECG recordings uniformly showed signs of acute myocardial ischemia. In addition, arrhythmias occurred in the form of atrioventricular block. Left ventricular contractility declined continuously within the first 4 min. Finally, after 4 min, blood pressure steadily decreased. During ventilation with room air, severe hypoxia developed, with arterial PO2 decreasing from 94 mmHg to 14 mmHg after 3 min. However, under ventilation with 100% oxygen, a dissociation between cardiac damage and respiratory distress occurred. Myocardial ischemia and signs of cardiac failure preceded the development of hypoxia by a significant time interval. It is to be concluded that cardiac damage is a primary event in anaphylactic shock. Furthermore, the electrocardiographic signs of ischemia are interpreted as a result of coronary artery spasm.

Anaphylaxis↗
PubMed1990

Long-term treatment with piroximone in patients with chronic heart failure.

The safety and efficacy of long-term oral piroximone therapy was assessed in 12 patients with chronic heart failure. Of these 12 patients, two died suddenly, and a further two were withdrawn because of worsening heart failure within 6 months while 8 completed the 1-year follow-up period. In 7 of these 8 patients, clinical evaluations showed sustained benefit, as demonstrated by significant increases in exercise tolerance. The remaining patient experienced a recurrence of severe heart failure at the end of follow-up. Twenty-four hour ambulatory electrocardiograms were compared in 9 patients before and during piroximone therapy. Aggravation of existing arrhythmias was observed in 3 patients, an amelioration in one with no change in the remaining 5. In the 5 patients in whom the hemodynamic effects of a single oral dose of 25 mg of piroximone were studied, the first dose resulted in a 20% increase in mean cardiac index and a 30% decrease in mean pulmonary capillary wedge pressure. This responsiveness to single-dose administration was maintained after 1-year follow-up. Likewise, comparison of the hemodynamic effects of four intravenous doses of piroximone revealed no significant difference in the response (n = 7), although the effects tended to be less marked at the end of follow-up. The present results suggesting that piroximone is effective and safe as adjunctive therapy in the management of patients with chronic heart failure will need to be confirmed in longer controlled trials.

Adult↗