[Health--disease. Attempt at a presentation for a society whose life is significantly modified by information technology and molecular biology].
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Computer Simulation↗
Biomedical subjects
R D Hesch
Publications and source records attributed to R D Hesch.
[New views of an old disease].
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Estradiol Congeners↗
Parathyroid hormone stimulation of mitosis in rat thymic lymphocytes is independent of cyclic AMP.
The in vitro mitotic response of rat thymic lymphocytes to hPTH(1-34), hPTH (1-38), and 8,18 Nle hPTH(1-34) exhibits a dependency upon extracellular calcium. Removal of extracellular calcium or the addition of Verapamil (5 micrograms/ml) or trifluoroperazine (10 microM) abrogated the mitotic response. Mitogenic concentrations of 8,18 Nle hPTH(1-34) increased calcium 45 uptake from 4.49 +/- 0.25 to 8.23 +/- 0.75 pMol/10(6) cells/min. The intracellular calcium concentration, measured by Quin 2 fluorescence, also increased after addition of 8,18 Nle hPTH(1-34). Parathyroid hormone-induced activation could not be demonstrated in an otherwise responsive thymocyte membrane adenylate cyclase. In intact cells mitogenic levels of 8,18 Nle hPTH(1-34) decreased intracellular cyclic AMP content. This response was blocked by both 3-isobutyl 1-methyl xanthine and trifluoroperazine, and may indicate activation of calcium-dependent phosphodiesterase. We conclude that PTH stimulates thymic lymphocyte proliferation independently of cyclic AMP, and that changes in cellular calcium homeostasis are intimately involved in the action of PTH. In all of the assays employed, the hitherto antagonistic analogue 8,18 Nle 34 Tyr bPTH(3-34)amide proved to be an agonist. We postulate that the receptor utilized for this PTH action may not exhibit classical PTH structure-activity specificities.
Animals↗
[Surgical therapeutic concept of immune thyropathy].
73 patients with Graves' disease, surgically treated from 1975-1986, were investigated retrospectively. 43 patients, treated by subtotal thyroidectomy (Enderlen-Hotz) and a bilateral thyroid remnant of a total of about 8-12 g, were compared with 30 patients, treated by a modified subtotal thyroidectomy leaving a unilateral thyroid remnant of about 4-8 g, with respect to preoperative duration of disease, indications for surgical treatment, weight of resected specimens, operative complications and postoperative thyroid function. Surgical complications were similar in both groups. After subtotal thyroidectomy 14/43 patients (33%) displayed either recurrent hyperthyroidism (9/43, 21%) or local recurrence of Graves' goiter (3/43, 7%) or both (2/43, 5%). The modified subtotal resected group showed no recurrences of the disease. After subtotal thyroidectomy 11 patients were euthyroid without thyroid medication (26%) compared to only two patients (7%) after the modified procedure of subtotal thyroid resection. To prevent recurrences of goiter as well as hyperthyroidism and, on the other hand, to achieve euthyroid function postoperatively without need for thyroid replacement therapy, subtotal thyroidectomy with a small thyroid remnant of about 4-8 g is recommended for all patients with large goiter and a chronic recurrent course of the disease or with iodine induced thyrotoxicosis. Patients with non-recurrent Graves' disease but large goiter probably benefit from subtotal thyroidectomy with a larger thyroid remnant of about 8-12 g.
Adolescent↗
Metabolism of the thyroid hormones.
This review covers the current knowledge about the various metabolic pathways involved in the conversion of thyroid hormones to the thyromimetically active and inactive iodothyronines. The concerted mechanism of systemic and local production of iodothyronines by tissue-specific iodothyronine deiodinase isozymes will ultimately determine the expression of thyroid hormone action. This is exemplified for the regulation of synthesis and release of TSH by iodothyronines at the pituitary level. Iodothyronine metabolites, e.g. Triac, rT3 and T3 amine may modulate TSH secretion, and alterations of local pituitary deiodination (e.g. iopanoate inhibition) influence diurnal TSH secretion without changing TRH-dependent episodic TSH secretion pattern. A summary of structure-activity relationships of greater than 200 naturally occurring and synthetic ligands of rat liver type I iodothyronine deiodinase isozyme propylthiouracil-sensitive) in vitro allows the design of iodothyronine analogues which either serve as specific substrates or antagonists of iodothyronine binding and metabolizing proteins. Furthermore, a complete picture of the ligand-complementary active site of the type I isozyme can be derived. A synthetic 'structurally optimized' iodothyronine-analogue flavonoid inhibitor of the type I deiodinase is able to displace T4 from binding to thyroxine-binding prealbumin and leads to unexpected organ-specific alterations of thyroid hormone metabolism and expression of thyroid hormone actions in an animal model. Therefore, for a complete understanding of thyroid hormone metabolism and action, thyroid hormone transport, cellular compartmentalization, and alternate pathways also have to be considered.
Pituitary Gland↗
Circadian and pulsatile thyrotropin secretion in euthyroid man under the influence of thyroid hormone and glucocorticoid administration.
The inhibitory action of thyroid hormones (TH) and glucocorticoids on circadian and pulsatile TSH secretion was investigated in groups of five normal men by sampling blood every 10 min for 24 h (start, 1750 h). Serum TSH was measured by a sensitive immunoradiometric assay. Continuous infusion of 50 micrograms T3 or 250 micrograms T4 for 8 h (1900-0300 h) significantly suppressed serum TSH levels (T3, P less than 0.025; T4, P less than 0.05; by paired t test). Administration of 3 g sodium ipodate 7 h before TH infusion did not alter the TSH response to T3, but T4-dependent suppression was abolished. Pulsatile TSH secretion [basally, 5.8 +/- 1.3 (+/- SD) pulses/24 h, as analyzed by the PULSAR program; 6.8 +/- 1.9 by the Cluster program] was not significantly altered by any of the experimental conditions. The additional finding of blunting of the TSH response to TRH after TH alone or ipodate and T3 suggests a predominantly pituitary feedback action of TH exerted via conversion of T4 to T3. In contrast, bolus injections of 4 mg dexamethasone (dex) at 1900 and 2200 h abolished TSH pulses for at least 6 h (PULSAR, 6.6 +/- 1.6 pulses/24 h basally vs. 3.6 +/- 3.0 under dex; Cluster, 7.0 +/- 2.7 pulses/24 h basally vs. 1.6 +/- 1.6 under dex). Dex administration also resulted in a prompt, sustained, and significant suppression of basal TSH (P less than 0.0005). Together with a normal serum TSH response to TRH (in separate experiments 1, 9, and 19 h after dex administration), these data suggest that glucocorticoid feedback occurs at a suprapituitary level.
Adult↗
[Digital subtraction angiography and iodine 123 amphetamine scintigraphy (IMP-SPECT) in the diagnosis of acute and chronic inner-ear hearing loss].
Vascular lesions may play a role in the genesis of acute and chronic hearing loss. After exclusion of other causes the vascular status of 33 patients was examined using digital subtraction angiography (DSA) for the supra-aortic vessels, and the N-isopropyl-(I-123)p-iodoamphetamine (IMP-SPECT) technique to investigate cerebral blood flow. Not a single case of stenosis affecting the hemodynamics, of a vascular anomaly or of a cerebrovascular perfusion disorder was found.
Adult↗
Direct radioimmunoassay for human atrial natriuretic peptide (hANP) and its clinical evaluation.
A direct radioimmunoassay for the rapid and accurate detection of human ANP from unextracted plasma is described. The sensitivity was approximately 50 pg/ml, respectively 2.5 pg/tube, the intra-assay variation 4%, and the inter-assay variation less than 12%. Rat ANP (1-28, 5-25, 5-27 and 5-28), oxydized and reduced hANP as well as plasma samples from various patients run in parallel to the 1-28 hANP standard curve. These findings imply, that the antibody primarily recognizes the mid-region (amino acids 6-25) of the intact ANP, that the C-terminal portion further increases the immunoreactivity, and that circulating plasma hANP is reliably measured. Plasma hANP ranged from 50-166 pg/ml (mean +/- SD: 98.3 +/- 44.6) in healthy individuals, there was no significant difference between samples were drawn in upright or lying position, the apparent half-life of injected hANP was 5.65 minutes. Patients with liver cirrhosis revealed significantly higher hANP levels of 244.5 +/- 173.5 pg/ml. Patients with various forms of cardiac disease had hANP concentrations ranging from 50 to 1744 pg/ml, depending at least partially on the right atrial pressure. No difference was observed if the samples were drawn from either right or left intracardial locations. Our findings with this system demonstrate that hANP is reliably measured even without prior extraction.
Antibody Specificity↗
Inhibition of rat liver iodothyronine deiodinase. Interaction of aurones with the iodothyronine ligand-binding site.
We report that aurone derivatives of plant extracts produce potent, dose-dependent, and ultimately complete inhibition of three different metabolic monodeiodination pathways catalyzed by rat liver microsomal type I iodothyronine deiodinase. These data show that (3'),4',4,6-(tetra)trihydroxyaurones are the most potent naturally occurring plant-derived inhibitors of this deiodinase enzyme (IC50 V 0.5 microM). Lineweaver-Burk analysis using both L-thyroxine (T4) and 3',5',3-triiodothyronine as substrates suggests a cofactor competitive mechanism of inhibition for 4',4,6-trihydroxyaurone which also can displace 125I-L-T4 from binding to thyroxine-binding prealbumin with a potency comparable to its inhibition of T4-5'-deiodinase. Among type I deiodinase inhibitors, cofactor competition has been observed only for propylthiourea. Computer graphic modeling studies were also carried out to explore aurone conformations and to compare them with those of the thyroid hormones. This analysis shows that the aurones can adopt either a planar or an antiskewed conformation, such as observed for 3',5',3-triiodothyronine, the most potent natural deiodinase substrate inhibitor. The thyroxine-binding prealbumin complex was used to model the deiodinase ligand binding site because of the similarity observed between inhibitor binding affinity and enzyme inhibition characteristics. These studies show that the aurones which adopt an antiskewed conformation can interact favorably in the prealbumin binding site. This model of the deiodinase active site can be used to design other deiodinase inhibitors.
Animals↗
Rat liver iodothyronine monodeiodinase. Evaluation of the iodothyronine ligand-binding site.
Ligand binding characteristics of rat liver microsomal type I iodothyronine deiodinase were evaluated by measuring dose-response inhibition and apparent Michaelis-Menten or inhibitor constants of iodothyronine analogues to compete as substrates or inhibitors for the natural substrate L-thyroxine. These data show strong correlations with the binding requirements of hormone analogues to serum thyroxine-binding prealbumin since iodothyronine analogues with a negatively charged side chain, a negative charge or hydrogen bonding function in the 4'-position, tetraiodo ring substitution, and a skewed hormone conformation are structural features shared in common which markedly affect enzyme activity and protein binding affinity. 3,3',5'-Triiodo-L-thyronine is the most potent natural substrate (IC50 = 0.3 microM) and tetraiodothyroacetic acid is the most potent inhibitor (IC50 = 0.2 microM). Both thyroxine (T4)-5'- and T4-5-deiodination pathways are inhibited by these potent analogues, providing further evidence for a single enzyme catalyzing the rat liver microsomal deiodination reactions. These data also show that L-hormone analogues are preferentially deiodinated via the T4-5'-deiodination pathway, whereas D-analogues produce products via the T4-5-deiodination pathway. The thyroxine-binding prealbumin complex was used to model the interaction of thyroid hormones with the deiodinase active site. Computer graphic modeling of the prealbumin complex showed that only those analogues which are potent deiodinase inhibitors or substrates can be accommodated in the hormone binding site. This model suggests the design of functionally specific ligands which can modulate peripheral thyroid hormone metabolism and act as antithyroidal drugs.
Animals↗
Crystal structure of phlorizin and the iodothyronine deiodinase inhibitory activity of phloretin analogues.
Phloretin, a 7,8-dihydrochalcone of plant origin, and the high molecular weight (less than 15,000) polyphloretinphosphate (PPP) polymers are potent inhibitors of iodothyronine monodeiodinase activity from rat liver microsomal preparations, whereas phlorizin, the 2'-O-glucoside of phloretin, is inactive. The polymers, differing in degree of phosphorylation-dependent polymerization, exhibited a concentration-dependent, and ultimately complete, inhibition of deiodinase activity with an IC50 between 0.2 and 0.5 micrograms PPP/ml. Phloretin inhibition, on the other hand, was cofactor (DTE) competitive, with a Ki = 0.75 microM. 2',4',6',3,4- Pentahydroxychalcone, which has a substitution pattern in the A-ring identical to that of phloretin, was the only active inhibitor (IC50 = 8 microM) among several derivatives tested. The phloretin biodegradation products, phloretic acid and phloroglucinol, and its biosynthetic precursors, monomeric cinnamic acid and cinnamic acid derivatives, were inactive in concentrations up to 100 microM. The X-ray crystal structure analysis of phlorizin dihydrate showed that the molecule is planar and fully extended, similar to the conformation observed in chalcone structures that are characterized by an alpha, beta-unsaturated bond between phenol rings. Comparison of the planar phlorizin crystal structure with a skewed or antiskewed thyroid hormone conformation revealed that the beta-D-glucose moiety does not share any of the thyroid hormone's conformational space, and that the best structural homology is found with the antiskewed conformation of 3',5',3-triiodothyronine, the natural deiodinase substrate that also inhibits further deiodination.
Animals↗
[Mid C regional parathyroid hormone in the clinical workup: diagnostic value in extrarenal (primary) and renal (secondary) hyperparathyroidism].
The selective determination of mid-C-regional parathyroid hormone (mid-C-PTH) in combination with other laboratory parameters is a reliable tool for diagnosis and treatment of extra-renal (primary) and renal (secondary) hyperparathyroidism. Early stages, which show either high-to-normal serum calcium and elevated mid-C-PTH or increased serum calcium but normal mid-C-PTH, can be distinguished from overt hyperparathyroidism. Alkaline phosphatase (AP) activity and mid-C-regional PTH provide biochemical confirmation of histologically classified renal osteodystrophy. Since the index AP X PTH signifies osseous changes in dialysis patients at an early stage, therapeutic regimens may be altered without additional invasive procedures. After renal transplantation mid-C-PTH normalizes and serum creatinine decreases. Increased mid-C-PTH in patients with normal renal graft function reflects autonomous PTH secretion, which requires careful monitoring to prevent PTH-induced hypercalciuria.
Chronic Kidney Disease-Mineral and Bone Disorder↗
Pulsatile pattern of thyrotropin-release in normal men.
To evaluate the existence of a pulsatile secretion pattern of thyrotropin (TSH) the 24 h release profile of the hormone was investigated in 7 healthy male subjects by taking blood via an indwelling venous catheter at 10-min intervals. Thyrotropin levels were analysed with high precision by a recently developed immunoradiometric assay (IRMA) able to distinguish euthroid and hyperthyroid TSH-levels. Visual analysis (n = 10.4 peaks/24 h) and the computer assisted evaluation by the Santenprogramme (n = 9.9 peaks/24 h) as well as the Pulsar-programme (n = 7.7 peaks/24 h) revealed an episodic release pattern with a low amplitude of pulses. These preliminary results are highly suggestive of a pulsatile TSH secretion similar to other pituitary hormones.
Adult↗
Radioimmunoassay for human osteocalcin using an antibody raised against the synthetic human (h37-49) sequence.
Radioiodination of synthetic human 37-49 osteocalcin requires optimal labeling conditions in order to obtain a maximum of mono- and di-iodinated tracer with little contamination by tri- and tetra-iodinated products or "radio-damage." The antibody raised against osteocalcin(h37-49) had the highest affinity for the C-terminal peptide used for iodination and the larger peptide (h30-49). The intact bovine osteocalcin (b1-49) revealed less immunoreactivity. This C-terminal specific radioimmunoassay detected the intact human osteocalcin in HPLC purified plasma and peritoneal dialysate from patients with terminal renal insufficiency and in extracted human bone. Some quantities of osteocalcin peptides with a higher hydrophobicity were predominantly detected in uremic plasma. These peptides that had a higher molecular weight than the intact human molecule might represent aggregated forms of the intact bone-derived osteocalcin. Immunoreactivity in plasma samples from healthy individuals revealed a remarkable difference as to which substance was employed for anticoagulation. Compared to heparin, the addition of EDTA largely reduced the osteocalcin immunoreactivity, implying that conformational changes within the N-terminal portion (containing the Gla- and Cys-residues) are extended to the C-terminal portion.
Antibodies↗
Parathyroid hormone in coronary artery disease--results of a prospective study.
Parathyroid hormone (PTH) influences the calcium metabolism of many different mammalian cell types; indeed, hypertension due to changes in muscle tone is a frequent symptom of hypercalcemic hyperparathyroidism. In a blind study of 81 patients with various forms of heart disease undergoing coronary angiography, the plasma concentrations of the midcarboxyl regional PTH immunoreactivity were determined. PTH concentrations were elevated in 26 of the 56 patients exhibiting organic coronary artery disease (CAD). The plasma PTH levels were highest in those patients with CAD affecting three vessels and in patients with evidence of myocardial infarction. PTH levels were not influenced by previous drug treatments, and did not correlate to stress hormone levels. We propose that increased PTH levels may be a marker for initiation or potentiation of calcium-dependent changes in vascular smooth muscle behavior inducing coronary functional and anatomic lesions typical of CAD.
Adult↗
Type II PTH receptor-operated calcium channel and its importance for PTH peptide elevations in coronary artery disease.
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Calcium↗
Pulsatile gonadotropin-releasing hormone treatment in idiopathic delayed puberty.
Idiopathic delayed male puberty is defined as a delay of puberty beyond the age of 16, with prepubertal testosterone levels, normal gonadotropin responses to GnRH (excluding pituitary failure), and normal androgen responses to a single hCG injection (excluding testicular Leydig cell dysfunction), in absence of serious disease. Ten boys with this condition were evaluated as to their spontaneous LH, FSH, and PRL secretory patterns during a 24-h sampling period (20-min intervals). After this all patients were treated with pulsatile infusions of GnRH (25 ng/kg . pulse every 90 min for 10 days. Two groups could be distinguished by means of their pretreatment LH secretory pattern. Five patients had nighttime pulsatile elevation of LH levels, as usually occurs in early puberty. The other five patients did not have such a pattern (prepubertal type). The GnRH treatment resulted in increased LH and testosterone levels in both groups. All patients with pretreatment nighttime pulsatile LH secretion had steady pubertal development during the post-GnRH treatment observation period, whereas the other patients did not. In conclusion, among a number of tests, including chronic pulsatile GnRH treatment for 10 days, only the nocturnal LH secretory pattern differentiated delayed puberty from permanent hypothalamic hypogonadism in boys.
Adolescent↗
Multiple pre- and postreceptor defects in pseudohypoparathyroidism (a multicenter study with twenty four patients).
Three different pathophysiological mechanisms are probably responsible for hereditary pseudohypoparathyroidism: 1) a defect at the prereceptor-level, 2) a defective membrane N-protein accounting for diminished second messenger production, and 3) a defect in the cytosolic response to the hormone. In a cooperative, study 24 patients (mean age, 13 yr; range, 3-23 yr, 8 girls, 16 boys) receiving vitamin D metabolites (5,000-80,000 U/day) were examined and compared to a control group of 36 normal children. Immunoreactive N-terminal PTH (N-PTH), mid-C-regional PTH (mid-C-PTH), intact PTH and bio-PTH, vitamin D metabolites, and serum calcium and phosphate, alkaline phosphatase activity, and the N-protein activity of erythrocyte membranes were measured in each subject. By clinical and biochemical criteria three groups were differentiated. Eight patients had the completely expressed features of Albright's Hereditary Osteodystrophy (AHO+), including brachydactyly and/or sc calcifications, and increased N-PTH, mid-C-PTH, and alkaline phosphatase activity. Bio-PTH, intact PTH, and N-protein were normal. Nine additional patients with complete (AHO+) had elevated levels of bio-PTH, N-PTH, and mid-C PTH, normal hydroxylation of vitamin D, but decreased N-protein activity. Seven patients with pseudohypoparathyroidism had no features of AHO (AHO-), no increase of urinary cAMP excretion after exogenous PTH, normal PTH peptide levels and N-protein activity, but elevated 25-hydroxyvitamin D and decreased 1,25-dihydroxyvitamin D concentrations. In conclusion, we identified three subpopulations of PsHP: group a had a dissociation of N-PTH and bio-PTH suggesting a defective N-PTH causing renal resistance, whereas their bones respond to PTH. Group b had defective N-protein causing generalized PTH resistance. Group c was characterized by high 25-hydroxyvitamin D and relatively low 1,25-dihydroxyvitamin D levels, thus providing evidence for a defect in the cytosolic interaction of the two different second messengers for PTH, cAMP, and calcium.
Adolescent↗