Circadian rhythms of basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), cortisol, and melatonin in women with breast cancer.

BACKGROUND: Circadian rhythms in plasma concentrations of many hormones and cytokines determine their effects on target cells. METHODS: Circadian variations were studied in cortisol, melatonin, cytokines (basic fibroblast growth factor IbFGF], EGF, insulin-like growth factor-1 [IGF-1]), and a cytokine receptor (insulin-like growth factor binding protein-3 [IGFBP-3]) in the plasma of 28 patients with metastatic breast cancer. All patients followed a diurnal activity pattern. Blood was drawn at 3h intervals during waking hours and once during the night, at 03:00. The plasma levels obtained by enzyme-linked immunoassay (ELISA) or radioimmunoassay (RIA) were evaluated by population mean cosinor (using local midnight as the phase reference) and by one-way analysis of variance (ANOVA). RESULTS: Cortisol and melatonin showed a high-amplitude circadian rhythm and a superimposed 12h frequency. bFGF showed a circadian rhythm with an acrophase around 13:00 with a peak-to-trough interval (double amplitude) of 18.2% and a superimposed 12h frequency. EGF showed a circadian rhythm with an acrophase around 14:20, a peak-to-trough interval of 25.8%, and a superimposed 12h frequency. IGF-1 showed a high value in the morning, which is statistically different (t test) from the low value at 10:00, but a regular circadian or ultradian rhythm was not recognizable as a group phenomenon. IGFBP-3 showed a low-amplitude (peak-to-trough difference 8.4%) circadian rhythm with the acrophase around 11:00 and low values during the night. CONCLUSIONS: (1) Circadian periodicity is maintained in hospitalized patients with metastatic breast cancer. (2) Ultradian (12h) variations were superimposed on the circadian rhythms of the hormones and several of the cytokines measured. (3) Studies of hormones and cytokines in cancer patients have to take their biologic rhythms into consideration. (4) The circadian periodicity of tumor growth stimulating or restraining factors raises questions about circadian and/or ultradian variations in the pathophysiology of breast cancer.

The oculo-dento-digital syndrome: male-to-male transmission and variable expression in a family.

We report two siblings--a 5 1/2 year old female and her 4 1/2 year old brother, both presenting the classical clinical findings of oculo-dento-digital dysplasia (ODD). 1. Digital anomalies: bilateral complete cutaneous syndactyly of fingers IV-V (III-IV-V at the left hand of the boy) and camptodactyly IV. 2. Facial and ocular anomalies: microphtalamos-epicanthal folds, small midfacies, thin nose with hypoplastic alae nasi and small nares. 3. Dental anomalies with partial dental agenesis and enamel hypoplasia. Examination of the parents showed a bilateral cutaneous syndactyly IV-V in the father as the sole partial manifestation of ODD. The findings in the present family confirm the autosomal dominant inheritance of ODD with great variability in clinical expression. Moreover, the facial morphology (thin, hypoplastic nose) observed in several ODD patients suggests nosological overlap with the Hallerman-Streiff syndrome and could indicate that both syndromes are variable expressions of a contiguous gene deletion syndrome.

Stimulation of the secretion of dehydroepiandrosterone by melatonin in mouse adrenals in vitro.

Adrenals of young adult male mice kept on a LD 12:12 lighting regimen for three weeks prior to study and harvested at four different circadian stages were incubated for 2 hours with 0.4 IU synthetic ACTH in 2 ml Krebs-Ringer buffer (KR), or with 50, 150, and 450 microM of melatonin in KR containing 0.4 IU ACTH. The addition of melatonin to ACTH leads to a dose dependent stimulation of production and/or secretion of DHEA into the incubation medium irrespective of the circadian stage of harvesting of the adrenals. This relationship is of interest in view of the simultaneous decrease of dehydroepiandrosterone and melatonin in the course of aging, and the effects of these compounds upon aging related changes.

Effects of radioiodine therapy in hyperthyroidism (thyroid function, thyroid volume, Graves' ophtalmopathy, thyrotoxic heart disease).

The study group consisted of 135 hyperthyroid patients--128 with Graves' disease and 7 with toxic multinodular goiter. A single dose of radioiodine was given in 110 cases (81.48%), two doses in 22 patients (16.3%) and three doses in 3 patients (2.22%); mean total dose was 6.8 mCi (range = 3-24 mCi). The main goal of radio iodine therapy is to achieve euthyroidism; after radioiodine treatment, 61 patients (45.2%) were euthyroid, 60 patients (44.4%) with permanent hypothyroidism and 14 (10.36%) with PERSISTING HYPERTHYROIDISM--the mean duration of follow-up being 4.2 years. After radioiodine therapy, goiter became absent in 30 patients (28%); in those patients, goiter was moderately enlarged or large before therapy. Around 63% (12 cases) of the patients with thyrotoxic atrial fibrillation reverted to sinus rhythm. During the last four years (1990-1994) the patients with Graves' ophthalmopathy from the study group were treated with Prednisone after radioiodine therapy; this corticotherapy contributes to the lower percentage (1.5%) of worsening Graves' ophthalmopathy after radioiodine therapy.

Chronobiology of pituitary-thyroid functions.

One hundred ninety four children, 11 +/- 1.5 years of age and 166 elderly men and women, 77 +/- 8 years of age were studied over one or (in the case of some of the elderly subjects) over several (up to 4) 24-hours spans. All subjects were diurnally active and rested at night and followed their regular three meal pattern. The subjects were studied in subgroups of 20-25 during all four seasons of the year. During each study, blood was collected at 4 hour intervals over one 24-hour span (6 samples). Circadian and circannual variations were found and described by cosinor analysis in the children as well as in the elderly subjects. The children with endemic goiter (134) as compared to those without endemic goiter (60) showed a slight circadian phase advance in plasma total and free T3, a lower circadian amplitude of total T4 concentrations and the absence of a detectable circadian rhythm in free T4. The children with goiter showed a phase delay in serum TBG. There was no difference between the children with and without goiter in the circadian MESOR of any thyroid parameter or of TSH. The children with endemic goiter in the region of Dimbovita, Romania, are in clinical and biochemically euthyroid condition with some slight poral abnormalities of thyroid function. Seasonal variations in children and elderly patients showed the highest values of TSH during summer and fall, while the highest values in the plasma concentrations of thyroid hormones were found during the cold season of the years. Thyroglobulin in the children showed a circadian rhythm but no seasonal variation.

A 22-year old female with the 9p deletion syndrome.

A 22-year old female patient with psycho-motor retardation, statural hypotrophy and clinical picture characteristic of the 9p deletion syndrome, i.e., trigonocephalia (corrected surgically), epicanthus, hypertelorism, long filtrum, micrognathia, low inserted and malformed ears, filiform fingers, is presented.

Radioiodine treatment in recurrences of subacute thyroiditis.

The three cases of subacute thyroiditis treated by radioiodine were refractory to systemic corticoid therapy (2-3 recurrences in a mean duration of 7.6 mos) and to external antiinflammatory radiotherapy (relapses after 2 and 4 mos, respectively). No relapse after radioiodine administration has appeared (mean follow-up period: 3 yrs) and post-iodine hypothyroidism was mild.

Circadian and seasonal variations in iodine excretion in children with and without endemic goiter.

The urinary iodine excretion was measured in 193 children 11 +/- 1.5 years of age living in the endemic goiter area of Dîmbovita, Romania. One hundred and thirty four of the children showed some degree of endemic goiter, 59 showed none. All children followed a diurnal activity pattern with rest during the night. They received their usual iodine supplement of 1 gm potassium iodide once a week during the school year (which included the time of all measurements made). Urine was collected in six 4-hour samples over a 24-hour span. The examinations were conducted during the months of March, June, September and December. Iodine was determined by an automated ceric ion arsenic acid method using a Technicon Autoanalyzer. Circadian and seasonal variations of urine volume and iodine excretion were statistically verified by the cosinor technique and the seasonal variations also by one way analysis of variance using the circadian means as input. A comparable circadian rhythm of iodine excretion was found in the children with and without endemic goiter, with an acrophase during the evening (20:16 with a 95% C.I., from 19:32 to 21:04). The circadian rhythm in iodine excretion has to be taken into account whenever an estimate of the 24-hour excretion is attempted from a sample covering less than the entire 24-hour span. There was a statistically significant seasonal variation of the 24-hour iodine excretion in the boys with and without endemic goiter and in the group as a whole. The 24-hour iodine excretion during March was 102 +/- 6 mcg, during June 81 +/- 4 mcg, during September 79 +/- 3 mcg and during December 102 +/- 7 mcg. The average 24-hour iodine excretion pooled over all seasons was 91 +/- 3 mcg/24 hrs in the children with and 91 +/- 5 mcg/24 hrs in the children without endemic goiter. During March and December the iodine excretion indicates an iodine intake not usually associated with a high prevalence of endemic goiter. However, during the months of June and September (and presumably even more during the months of July and August when during summer vacation no iodine supplementation was given in school) the 24-hour iodine excretion indicates some degree of iodine deficiency. The seasonal variation in urinary iodine excretion thus points to a time when increased iodine prophylaxis may be of value.

Direct assay of 3-methoxy-4-hydroxy-phenylglycol (MHPG) in human saliva; a new approach in the assessment of noradrenergic function.

The present paper offers a simple, reliable and specific method for the evaluation of salivary level of conjugated MHPG in 16 children (5-16 years) selected as control group. In the chosen group, we established the urinary level of NA: 17.64 +/- 1.38 micrograms/24 h, of A: 5.87 +/- 0.44 micrograms/24 h, of MHPG: 1.62 +/- 0.14 mg/24 h, of VMA: 1.54 +/- 10.10 mg/24 h. In all patients we assayed salivary MHPG: 57 +/- 5.25 mg/ml; in only 6 patients we also determined salivary NA: 2.21 +/- 0.11 micrograms/l and A: 0.25 +/- 0.03 micrograms/l. The MHPG in saliva correlates with urinary MHPG but doesn't correlate with NA in saliva or in urine. The assay of salivary MHPG may represent a non-invasive procedure of evaluation of noradrenergic tonus in children.

Low level of urinary 5-hydroxyindole acetic acid (5 HIAA) in obese children having concomitantly high 3-methoxy-4-hydroxyphenyl glycol (MHPG) excretion.

Eighty six obese children and adolescents (44 males) were screened for urinary 5 HIAA and MHPG, noradrenaline (NA), and adrenaline (A) and the results compared with age- and sex-matched controls. Significantly lower amounts of 5 HIAA were found, by contrast to the significantly higher levels of MHPG. These findings cannot be easily explained but an alteration of the normal equilibrium between the adrenergic and the serotonergic tonus may be circumstantially invoked.

Thyroid hormone-induced reduction of urinary 5-hydroxyindole acetic acid (5 HIAA) in obese children. Comparison with hypothyroid patients of similar age having either pituitary dwarfism or congenital myxedema.

Urinary excretion of monoamine metabolites (noradrenaline-NA, adrenaline-A, 3-methoxy-4-hydroxyphenyl glycol-MHPG, homovanillic acid-HVA, 5-hydroxyindole acetic acid-5 HIAA) was studied in four groups of children as follows: Group I consisting of obese children subjected to caloric restriction and to a short term course of thyroid extract in "low" dosage (1-2 mg/kg bwt), Group II consisting of obese children subjected to diet alone, Group III consisting of children myxedema and subjected to a short term course of thyroid extract given in the "high" dosage (3-5 mg/kg bwt) and Group IV consisting of GH deficient short children having (many of them) thyrotropin deficiency and subjected to a short term course of thyroid extract in "very high" dosage (5-10 mg/bwt). In obese, calorie-restricted children, the previously low mean level of 5 HIAA excretion was further lowered by thyroid extract. In obese children subjected to calorie restriction alone no urinary abnormality was noted. The congenitally hypothyroid patients had low levels of basal 5 HIAA when compared to controls. The degrees of 5-hydroxy tryptamine (5 HT) deficiency in Group III was similar to the obese groups. The thyroid extract course did not influence, at least in short term administration, the low 5 HIAA levels in group III. In GH deficient, short children (group IV) thyroid extract had no significant effect on urinary pattern of monoamine metabolites. A central 5 HT deficiency may tentatively explain the mood disturbances and possibly the other psychic disorders in both the obese and myxedematous patients. The different effects of thyroid extract on 5 HIAA may also witness the differences in the food intake behaviour in these two conditions.

The serum osteocalcin levels in adult and aged hypothyroid patients.

Osteocalcin (OC) or the bone protein containing gamma-carboxyglutamic acid (BGP or Gla-P), is a specific and sensitive marker of bone turnover. A radioimmunoassay (RIA) system for human osteocalcin was developed with the sensitivity of 0.5 ng/ml. The osteocalcin was measured in sera from 33 hormonally and/or clinically hypothyroid patients: 12 adult and 21 aged patients. For comparison, blood samples were collected from 14 hormonally hyperthyroid adult patients in whom the OC levels were 16.23 +/- 7.57 ng/ml (mean +/- SD) and from hormonally euthyroid adult patients (previously treated hyperthyroid patients) having OC 9.76 +/- 5.32 ng/ml. Abnormal low OC levels were noted in the hypothyroid adult patients group: 1.04 +/- 0.23 ng/ml by comparison to the hypothyroid aged patients 3.76 +/- 2.38 ng/ml (p less than 0.001). Moreover, great variability of the OC serum levels was observed in the aged group, four patients hormonally eu- or hypothyroid having high OC levels in the range: 13.29-55.45 ng/ml and other three patients although hormonally euthyroid but clinically hypothyroid had low OC levels 0.88-2.27 ng/ml. The abnormalities of the OC levels in hypothyroid adult and aged patients are discussed.

The assessment of the dopaminergic tonus by urinary determinations of homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) in normal, obese and GH-deficient short children.

In order to assess the dopaminergic tonus, urinary determinations of HVA and DOPAC and also of noradrenaline (NA), adrenaline (A), and methoxyhydroxyphenylglycol (MHPG) were performed in 86 obese children, 11 growth hormone (GH)-deficient short children and also in 40 control children. Part of the obese patients were subjected to a low carbohydrate, low calorie diet and also to short-term (9-14 days) courses of diethylpropion (DEP) 50 mg/day, meclofenoxate (MEC) 100 mg/day and thyroid extract (THE) 1-2 mg/kg/day. The GH-deficient patients received only THE in substitutive (5-10 mg/kg/day) doses. Significative correlations between DOPAC and age, weight and height were found in controls. In the obese group a significantly increased mean level of HVA was found (1.45 +/- 0.09 mg/24 h vs 1.15 +/- 0.10 in controls). The excretion of DOPAC was slightly greater but far from significance. There was also a significant decrease of HVA but not DOPAC in the DEP-treated obese. The rest of the drugs and the diet alone were not effective in any way. Normal levels in all metabolites except NA and A were found in GH-deficient short children. The therapy with thyroid extract did not alter the excretion levels. These findings indicate that in infantile obesity the dopaminergic tonus is somewhat increased but its pathophysiological significance is doubtful. In GH-deficient short children of standard appearance the dopaminergic tonus seems to be undistinguishable from normal.

Leprechaunism: report of two cases and review.

Two new cases of leprechaunism are reported, one of which from consanguinous parents. Both cases show the clinical picture characteristic of this syndrome: severe pre- and postnatal growth failure, psychic backwardness, lack of adipose tissue, cutis laxa; elf-like face, large ears, globular eyes, hypertelorism, micrognathia and various degrees of external genitalia hypertrophy. Endocrinologically, one of the patients shows the syndrome of low T3. The role of the endocrine alterations in the etiology of the syndrome is discussed.

Protein content and thyroid hormone release in vitro by differentiated thyroid cancer cells in the presence of estradiol, dehydroepiandrosterone, polypeptidic hormones and pesticides.

The reactivity of thyroid cancer cells treated with estradiol (E) and dehydroepiandrosterone (DHA) in the presence of other hormones (TSH, STH, insulin), myopeptide and some pesticides (aminotriazole--ATA, atrazine--ATZ, prometryne--P and ATC) proved to be active in the culture medium. Protein synthesis in sclerosing folliculo-papillary cancer cells under the treatment applied is more markedly inhibited by DHA than by E in the culture medium is compared to the control lots. Tg1 and T3 release into the culture medium under the action of T4 and TSH decreases progressively going from the control to the treated lots, in the presence of E and DHA. STH inhibits Tg1 and T3 secretion in thyroid follicular carcinoma, whether or not E or DHA are present in the culture medium.

Free 3-methoxy-4-hydroxyphenylglycol (MHPG) in human urine: metabolic routes, biochemical and clinical significance in healthy and obese children.

Conjugated MHPG is an indicator of the adrenergic tonus having clinical use in the follow-up of affective disorders, arterial hypotension, anorexia nervosa and recently of obesity. Little is known about the significance of the unconjugated, free MHPG in various body fluids. Nineteen healthy and 38 obese children were studied as regards the urinary excretion of free MHPG (MHPGF), conjugated MHPG (MHPGC), total MHPG (MHPGT) and also free noradrenaline (NA) valnillyl mandelic acid (VMA) and metanephrines (MN). Part of the obese received a short-term course of drug therapy (diethyl-propion-DEP or thyroid extract) and were subjected to a low-carbohydrate diet containing 800-1000 calories a day. The same urinary determinations were made after diet alone or after diet and drug therapy. MHPGC and MHPGT were significantly higher in the obese children. The level of MHPGF was essentially the same in both groups and did not change significantly following any drug or after diet alone. It was concluded that esterification mechanisms are not involved in the pathological states expressing high or low levels of MHPGC. Suggestion is made that these mechanisms may not be saturated unless huge amounts of MHPG outflow from the brain into CSF.

The serum osteocalcin levels in patients with thyroid diseases.

The mechanism of bone, calcium, phosphorus and proteins abnormalities observed in hyperthyroidism is rather complex and as yet not wholly understood. Increased serum osteocalcin was recently reported in hyperthyroid patients and its decrease after 4-8 months of treatment. Osteocalcin was measured by RIA in the sera of 211 women and 18 men with thyroid diseases. The patients were divided into 3 groups according to diagnosis: I. polynodular goitre and subacute thyroiditis (59 women, 5 men); II. Graves' disease (70 women, 3 men) and III. thyroid cancer, after treatment by surgery and 131I (82 women, 10 men). The osteocalcin levels in the sera of these patients were: 2.97 +/- 2.63 ng/ml (mean +/- SD) for the women and 3.56 +/- 2.10 ng/ml for the men in the 1st group; 16.31 +/- 11.34 ng/ml for the women and 12.75 +/- 6.09 ng/ml for the man in the IInd group and, 1.01 +/- 0.60 ng/ml for the women and 0.78 +/- 0.46 ng/ml for the men in the IIIrd group. No differences were found between the osteocalcin concentrations in the hyperthyroid female patients treated with antithyroid drugs (no = 58) and the non-treated hyperthyroid women (no = 12): 16.22 +/- 11.40 ng/ml vs 16.74 +/- +/- 11.53 ng/ml. These data suggest that bone resorption stimulated by endogenous thyroid-hormones is a rather resistant processus, persisting even after 6-8 mos of associated anti-thyroid therapy. Further are analyzed the possible causes of the subnormal osteocalcin levels observed in patients with thyroid cancer treated by surgery and radioisotope, whose suppression therapy was discontinued 2-3 weeks before blood sampling.(ABSTRACT TRUNCATED AT 250 WORDS)

Significance of high levels of serum malonyl dialdehyde (MDA) and ceruloplasmin (CP) in hyper- and hypothyroidism.

The lipid peroxidation process is enhanced in both hyperoxygenated or underoxygenated tissues though its mechanism of production is different. Because in thyroid functional diseases there are severe disorders in tissue oxygenation we studied the lipid peroxidation process by using the serum level of malondialdehyde (MDA) as indicator. We also determined the serum ceruloplasmin (CP), an enzymatic protein belonging to the circulating system of antioxidative protection and also playing a role in the cell-mediated immunity. We also followed serum level of uric acid (UA). The determinations were performed on serum samples collected from three groups: 1, adult control subjects: 2. adult untreated hyperthyroid patients, and 3. adult hypothyroid thyroidectomized patients to whom replacement therapy was discontinued for at least 15 days. The mean MDA level was significantly higher in both hyperthyroid and hypothyroid patients by comparison to the control group. CP mean level was significantly lower than in controls. It was concluded that in post thyroidectomy hypothyroidism an enhancement of lipid peroxidation does exist and that its consequences are probably aggravated by the low serum CP level. The enhancement of the process occurs by other mechanisms than for hyperthyroid group. At hypothyroid patients there is an ADP excess which is degenerated to xanthine, the substrate of xanthine oxidase resulting in toxic anion superoxide and UA. In contrast with hyperthyroid group, in hypothyroid patients we observed significant higher values of UA in comparison to the controls. The excess of MDA found in hyperthyroid patients is statistically significant, but its consequences are probably less severe because the serum CP is higher than normal, a rather expected finding for an autoimmune disease.