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Biomedical subjects

R D Hesch

Publications and source records attributed to R D Hesch.

At least 55 records · Page 3Linked to original sources
PubMed1990

Circadian and pulsatile TSH secretion under physiological and pathophysiological conditions.

In addition to the well known circadian rhythm of TSH secretion a pulsatile pattern of release has been shown. Analysis of the pulsatile release by different computer-assisted methods revealed systematic differences in the number and distribution of TSH pulses. Using the same approximation of false positive pulses (less than 1%) in any of the 21 healthy male volunteers tested a lower number of pulses was found by the Pulsar method (mean 5.1 +/- 2.0/24 h) than by the Cluster (10.6 +/- 1.8) or the DESADE program (13.6 +/- 4.6). The results of the Cluster and Desade analysis fit well to that of Fourier transformation which revealed a dominant frequency at 160 min. In addition dominant frequencies in comparison to a noise series were found at 24 h and at 33 min. Analysis of the data in 8 h segments between 2000 and 0400 h, 0400 and 1200 h and 1200 and 2000 h by Desade and cluster revealed that app. 50% of pulses occurred between 2000 and 0400 h, suggesting an important role of pulsatile TSH release in the generation of the circadian TSH rhythm. In 3 patients with TSH-induced hyperthyroidism the circadian and pulsatile pattern of TSH secretion was similar to that in healthy controls. In contrast, in a patient with a TSH producing pituitary tumor the circadian variation of TSH secretion was abolished. Patients with a non-toxic goitre revealed a significantly lower mean TSH serum level as the control group of healthy subjects. The number of TSH pulses was slightly but significantly lower when analyzed by the DESADE program but not when analyzed with any other method.

Adult↗
PubMed1989

Thyroid hormone effect on rat heart mitochondrial proteins and affinity labeling with N-bromoacetyl-3,3',5-triiodo-L-thyronine. Lack of direct effect on the adenine nucleotide translocase.

N-bromoacetyl-3,3',5-tri[3'-125I]iodo-L-thyronine was used to label intact heart mitochondria from eu, hypo- and hyperthyroid rats in order to identify proteins involved in T3-regulated mitochondrial processes. The results show strong labeling, competed for by T3 and other analogues, of two proteins with a molecular mass of 48,000 and 49,200 Da. No labeling is seen of the adenine nucleotide translocase, a likely target, neither at 0 degree C, at room temperature, nor after preincubation with the substrates or specific inhibitors. No difference in labeling intensity or distribution is seen in mitochondria from eu-, hypo- or hyperthyroid rats, and the abundance of the adenine nucleotide translocase is unchanged, but five other proteins show differential abundance.

Affinity Labels↗
PubMed1989

Increase of vertebral density by combination therapy with pulsatile 1-38hPTH and sequential addition of calcitonin nasal spray in osteoporotic patients.

Combination therapy with the biologically active (1-38) human parathyroid hormone peptide and calcitonin using pulsatile and sequential activation of the skeleton for 14 months in patients with low-turnover osteoporosis resulted in an increase in trabecular bone mass. These favorable responses were observed without any significant changes in cortical (forearm) bone mass content.

Administration, Intranasal↗
PubMed1989

Physiological regulation of thyrotropin.

The pattern of TSH secretion in man in pulsatile in addition to the well known circadian variation. The mechanism triggering TSH pulses remains unclear to date. Infusions of somatostatin or dopamine rapidly lowering basal TSH levels without suppressing the pulsatile pattern suggest that an episodic disinhibition exerted by a physiological inhibitor is not a likely cause. On the same basis, thyroid hormones do not appear to be candidates, since they similarly inhibit basal TSH levels after a time lag of several hours but again do not suppress pulsatile release of the hormone. In contrast, bolus injections of dexamethasone completely abolish pulsatile release of TSH for several hours despite a normal sensitivity of the pituitary to exogenous TRH, suggesting a hypothalamic action of the drug. The hypothesis that pulsatile TSH release might be governed by a pulsatile mode of a hypothalamic stimulator is supported by the observation that an infusion of nifedipine, a calcium channel blocker, which in vitro selectively inhibits the TRH effect on TSH but not prolactin secretion, exerts a comparable effect when it is infused in vivo.

Dopamine↗
PubMed1989

Rapid effects of the flavonoid EMD 21388 on serum thyroid hormone binding and thyrotropin regulation in the rat.

Naturally occurring and synthetic flavonoids are potent inhibitors of thyroid hormone 5'-deiodination and binding to human serum transthyretin (TTR) in vitro. We now describe the inhibitory effect of the most potent flavonoid, 3-methyl-4',6-dihydroxy-3',5'-dibromo-flavone (EMD 21388), on the serum protein binding of T4 and T3 and subsequent alterations of pituitary-thyroid function in the rat. Eight to 10 mumol/liter EMD 21388 added to pooled rat serum completely displaced [125I]T4 or [125I]T3 binding from TTR, the major thyroid hormone-binding protein in the rat, and markedly increased the percentages of free T4 and T3, measured by equilibrium dialysis. One to 4 h after the ip administration of 2 mumol EMD 21388/100 g BW to euthyroid rats, [125I]T4 and [125I]T3 binding to TTR decreased, serum T4 and T3 concentrations decreased, and the percentages of free T4 and free T3 increased. No changes were observed in the free T4 and free T3 concentrations. Serum TSH concentrations decreased at 1 h and were very low thereafter. EMD 21388 administration did not affect the elevated serum TSH concentrations in hypothyroid rats, strongly suggesting that the flavonoid does not directly affect TSH secretion. No changes were observed in hepatic type I 5'-deiodinase in euthyroid rats and pituitary type I and type II 5'-deiodinase in euthyroid and hypothyroid rats after EMD 21388 administration. We conclude that the ip administration of EMD 21388 to euthyroid rats inhibits T4 and T3 binding to TTR, with subsequent increases in the percentages of free T4 and free T3 and decreased serum T4 and T3 concentrations. The decrease in the serum TSH concentration was possibly due to transcient increases in the serum free T4 and/or free T3 concentrations, resulting in increased pituitary thyroid hormone content.

Animals↗
PubMed1989

Pulse amplitude and frequency modulation of parathyroid hormone in plasma.

Inconclusive reports on pulsatile secretion of PTH in man have been published. In this study PTH was measured by intact and PTH-(44-68) assays. Central venous blood sampling was performed every 2 min in 10 healthy men between 6-9 h and in 3 male patients with osteoporosis for over 6 h. Pulsatile PTH secretion was identified for healthy men and controls. Narrow pulses and bursts of narrow pulses (broad pulse) could be distinguished. Six narrow pulses per h with 26 +/- 16 ng/L amplitude and 1 burst of narrow pulses/h were detected for the intact hormone. One narrow pulse/h with 25 +/- 12 ng/L amplitude and 1 burst of narrow pulses (broad pulse) every 2 h were found (Pulsar) for PTH-(44-68). Intact and PTH-(44-68) exhibit in part a concordant pattern. Results from 3 patients with osteoporosis show a decreased amplitude and frequency of pulsatile PTH secretion. The same decreased pattern was demonstrated in a postmenopausal osteoporotic woman. A constant decline in ionized calcium elicits major secretory episodes of PTH, and ionized calcium increases after major secretory episodes of PTH. We conclude that pulsatile secretion of PTH in healthy young men is the physiological mode of secretion. Low pulsatile secretion of PTH might be related to low turnover osteoporosis.

Activity Cycles↗
PubMed1989

The role of glucocorticoids in the regulation of thyrotropin.

The potentially inhibitory action of endogenous or exogenous synthetic glucocorticoids on TSH secretion was investigated. Pulsatile and circadian TSH and cortisol rhythms were measured in healthy subjects (12 rhythms), but no correlation between the hormones could be detected. Acute stimulation of endogenous cortisol secretion by CRH tests (1 microgram/kg of ovine CRH) at 20.00 h in 9 healthy volunteers did not significantly alter the nightly increase in TSH. Chronic elevation of endogenous cortisol serum levels in patients with Cushing's disease revealed a heterogeneous pattern. In 2 patients serum TSH and thyroid hormone levels showed a normal 24-h rhythm, whereas the other 2 patients had low TSH serum levels. Acute treatment of 9 healthy volunteers with 0.5, 1 or 2 mg dexamethasone po at 23.00 h resulted in a significant dose-dependent suppression of mean basal TSH levels 9h later. Treatment with 30 mg of prednisone for 1 week in 7 patients with Crohn's disease did not influence basal TSH. The TSH response to TRH was only temporarily suppressed on day 3, but not on day 7 of treatment. The results suggest than under physiological conditions glucocorticoids have no regulatory influence on pulsatile and circadian TSH secretion.

Adult↗
PubMed1988

Results of a stimulatory therapy of low bone metabolism in osteoporosis with (1-38)hPTH and diphosphonate EHDP. Protocol of study I, osteoporosis trial Hannover.

In contrast to prevention, the therapy of manifest osteoporosis remains a clinically significant problem. So far all therapeutic attempts have yielded unsatisfying results. For this reason we have tried to achieve a positive bone balance by sequential stimulation and inhibition of the osseous metabolism. The therapy consisted of six 14-day courses with 400 units (1-38)hPTH per day and, in addition, starting with the 2nd week of PTH therapy, EHDP 5 mg per kg body weight per day for a total of 2 weeks. Already the initial therapeutic course resulted in a stimulation of decreased bone metabolism which could be documented by an increase in the calcium-47 accretion rate (six patients). An increase of the alkaline phosphatase could be noted (four patients); this, however, did not correlate with the calcium accretion. A positive calcium balance could, nonetheless, only be attained in four of eight patients within this period, while neither the alkaline phosphatase nor the kinetics would allow a prediction of this effect. Changes of the balance coincided with equal changes in the net calcium absorption. The urinary calcium excretion increased temporarily during the therapeutic phase. We were not able to detect an influence on the vitamin D metabolites. Histomorphometric studies did not demonstrate an increase in bone mass in the iliac creast after six therapeutic courses. Nevertheless, progressive deformations of vertebral bodies did not occur. We conclude that already after 2 weeks this therapeutic concept can lead to a stimulation of bone metabolism.

Adult↗
PubMed1988

Flavonoid effects on transport, metabolism and action of thyroid hormones.

Flavonoids are potent non-toxic ITH deiodinase inhibitors in microsomal membranes, and intact rat hepatocytes. Flavonoids are specific high affinity competitors for L-T4-binding to human TBPA, weaker antagonists in the rT3-5'deiodinase reaction, and very poor inhibitors of T3 binding to the nuclear T3 receptor. Optimized flavonoid antagonists exhibit an ITH bio-isosteric structure and conformation. The T4-binding site of hTBPA is a useful "receptor model" for type I deiodinase in computer aided drug design of flavonoid antagonists with improved pharmacological characteristics, bio-availability, and target-specificity for ITH-binding sites. The optimized T4-antagonistic flavonoid EMD 21388 given for 4 days in a 10-fold dose compared to the euthyroid T4-substitution dose does not alter serum levels of T4, T3. and TSH in rats. However, this dose of EMD 21388 results in a "tissue hyperthyroidism" in rat liver, which is not reflected by serum hormone levels and not monitored by altered pituitary TSH secretion. Many questions arise from these studies: Does EMD 21388 alter a) T3 degradation in rat liver, b) ITH transport across the liver plasma membrane c) ITH compartmentalization in the liver? Are these effects dependent on dose, application form and duration of the treatment? EMD 21388 is a suitable model compound to address these questions in future experiments. These studies furthermore will both elucidate the role of ITH deiodination for tissue specific expression of thyroid hormone action and effect as well advance the knowledge of specific interaction of flavonoids with biomolecules involved in mammalian intermediary metabolism. The dual effect of EMD 21388 as inhibitor of intracellular ITH deiodinase and as competitor of T4 binding to the serum transport protein TBPA may allow the design of a potent antithyroidal agent with extra-thyroidal mechanism of action in the process of T4 bioactivation to the thyromimetically active T3.

Animals↗
PubMed1988

Flavonoids specifically inhibit iodothyronine-deiodinase in rat hepatocytes.

Functionally intact hepatocytes in suspension metabolize iodothyronines (T4, rT3) by 5'-deiodination. These ITH-5H-deiodination reactions are inhibited by flavonoids. The structure-activity relationships are similar to those found for the 5'-D reaction using microsomal membranes as enzyme source. Different effects of flavonoids on the 5'-deiodination reaction of T4 and rT3 point to additional effects, e.g. ITH cellular uptake, transport and binding. Estimation of gluconeogenesis from lactate by biochemically intact hepatocytes allows us to detect "cell toxic" flavonoid effects with higher sensitivity than estimation of viability by trypan blue exclusion. Gluconeogenesis per se is not affected by T4, T3, rT3 or T3 formed by T4-5'-D reaction.

Animals↗
PubMed1988

[Current problems in osteoporosis from the clinical and radiologic viewpoints].

Osteoporosis is a disease leading to enhanced fragility of bone in association with minimal trauma. This is because of thinning and rarefaction of spongy and cortical bone. Initially, osteoporosis is often only detectable in the spine; later, peripheral cortical bone is also affected. Osteoporosis mainly is a problem associated with postmenopausal bone loss (PMO). With the increasing use of technique evaluating bone density, non-PMO-associated osteoporosis can be increasingly detected. In early menopause, estrogen substitution prevents further bone loss; in severe cases strategies to increase bone mass are under investigation and are very effective in the patients tested so far. Radiological methods are of value to diagnose osteoporosis and monitor the efficacy of treatment. Density measurement of trabecular and cortical spinal bone with computed tomography seems to be the technique of choice. Peripheral measurements must still prove their value, however. The advantage of quantitative CT is its capacity, selectively and reproducibly, to determine distinct bone structures like cortical or trabecular bone. Normal lateral X-ray films of the spine are essential to assess vertebral deforming events and exclude further wedging during therapeutic trials.

Bone and Bones↗
PubMed1987

On antisense peptides: the parathyroid hormone as an experimental example and a critical theoretical view.

We followed an approach which predicts that translation of two complementary RNA strands into protein generates pairs of "antisense" peptides which bind each other with specific and high affinity (Bost et al. Proc. Natl. Acad. Sci. (1985) 82, 1372). We used human parathormone as an experimental example, and we analysed by computer homologies between antisense peptide sequences and their published receptor sequences. We conclude that there is no experimental indication that parathormone binds to a synthetic peptide, the sequence of which was derived from the antisense RNA sequence. Based on homology scores and antigenicity indexes (Hopp) the analysis shows that the peptide ligand itself, or a random artificial peptide, are as good candidates as the antisense peptide in producing antibodies, presumably recognizing the receptor. We therefore question the general applicability of this approach.

Amino Acid Sequence↗
PubMed1987

Atrial natriuretic peptide and blood pressure in a geographically defined population.

Plasma atrial natriuretic peptide (ANP) was measured in 717 subjects in a cross-sectional study of patients with hypertension (treated and untreated) and normotensive controls, representatives of a geographically defined population. ANP concentrations did not differ between the groups and there was no correlation with blood pressure. These results do not support the view that hypertensive and normotensive subjects have different ANP concentrations; they also call into question the role of ANP in the development of high blood pressure.

Adult↗
PubMed1987

[Morphologic changes in iliac crest trabecular bone in primary hyperparathyroidism and their significance for diagnosis].

Iliac crest bone biopsy specimens of 391 patients with surgically proven primary hyperparathyroidism were investigated. In 60 unselected cases quantitative analysis of trabecular bone changes was performed. The age of the patients ranged between 12 and 85 years. The observed morphological findings were divided into four stages. In a few cases no differences from normal bone tissue could be observed. In 46% occurrence of a nonspecific increase of osteoid seams, osteoblasts, and osteoclasts was observed. Of the cases 50% showed a specific, but very often mild endosteal fibrosis. Only in 4% was there a severe fibroosteoclasia with development of so-called brown tumors. The quantitative analysis showed an increase of trabecular bone mass as well as of remodeling surfaces. But there was an overlap of up to 25% with the normal controls. The results demonstrate the influence of parathyroid hormone peptides on bone morphology. However, the investigation of a bone biopsy specimen is not generally very useful for diagnostic purposes.

Adolescent↗