[Thyroid nodules: benign or malignant?]. / Le nodule thyroïdien: bénin ou malin?

A thyroid nodule is a frequent occurrence. Its prevalence in a general adult population is about 50% and can even reach 67% when a cervical echography is performed. Only 5% of these nodules are cancers, and it is therefore important to avoid an useless and riskful surgery. We review the clinical factors and diagnostic tools available to reach the best options. The patient history and clinical signs give some informations about potential risks. Thyroid tests shall evaluate thyroid functional status and a thyroid scintigraphy shall detect hot thyroid nodules. The thyroid echography is a key element before fine needle aspiration cytology. Some echographic criteria in the TIRADS (Thyroid Imaging Reporting and Data System), classification can reach a 88% sensitivity, a 49% specificity, a 49% positive predictive value, a 88% negative predictive value and a 94% diagnostic accuracy. The fine needle aspiration cytology performed with echography will be crucial to decide if the patient is to be eligible for surgery. In 70 to 80% of the cases, nodules can be classified as benign or malignant with a 92% negative predictive value for a benign diagnosis and a 100% positive predictive value for a diagnosis of cancer. The discovery of a follicular proliferation (cancer incidence of 20-30%) is a grey zone. Follicular proliferation and definite cancer lead of course to a surgical option. A decisional tree summarizes the different steps leading to a therapeutic decision. The type of surgery and its complications are described at the end.

Decreased basal and stimulated thyrotropin secretion in healthy elderly men.

To delineate the effects of aging on basal and stimulated TSH secretion, we studied the 24-h profile of plasma TSH levels and the TSH response to TRH stimulation (200 micrograms TRH, iv) in eight healthy elderly men, aged 67-84 yr, and eight normal young men, aged 20-27 yr. Subjects with thyroid antibodies against microsomal or thyroglobulin antigens were excluded. During the 24-h study, blood was sampled at 15-min intervals. TSH levels were measured by an ultrasensitive immunoradiometric assay. Sleep was polygraphically monitored, and circadian and pulsatile TSH variations were quantified using specifically designed computer algorithms. In older men, the 24-h mean TSH concentration was approximately 50% lower than that in young men (0.78 +/- 0.37 vs. 1.43 +/- 0.41 microU/mL; P less than 0.01), but basal T3 levels were only slightly lower (93 +/- 12 vs. 115 +/- 16 ng/dL; P less than 0.02), while basal T4 levels were normal. The normal diurnal variation of TSH levels, with a nocturnal acrophase and an afternoon nadir, as well as the pulsatile nature of TSH release were preserved in elderly men. When expressed in microunits per mL, the amplitude of these temporal variations was reduced in elderly men compared to that in younger subjects. However, when expressed in relation to the mean TSH levels, the amplitudes of diurnal and pulsatile variations were similar in both groups of subjects. TRH-induced TSH secretion was lower in old than in young men (area under the curve, 15.9 +/- 6.3 microU/mL.10 min in elderly men vs. 42.0 +/- 16.6 microU/mL.10 min in young men; P less than 0.002). However, the TRH-induced elevations of T3 and T4 were of similar magnitude in both groups. These results indicate that in healthy elderly men, the overall 24-h TSH secretion is decreased, and the pituitary is less responsive to stimulation by TRH. However, the chronobiological modulation is preserved. These alterations could reflect an adaptative mechanism to the reduced need for thyroid hormones in old age. The thyroid keeps an intact capacity to respond to acute increases in TSH concentrations.

Dipyridamole and vascular prostacyclin production.

The action of dipyridamole on the vascular production of prostacyclin (PGI2) has been investigated. Dipyridamole (1-100 microM) did not induce a significant stimulation of PGI2 release in any of the following experimental models: rings of rabbit aorta, cultured endothelial cells from bovine aorta or human umbilical vein, cultured explants of bovine aortic smooth muscle. The activity of known stimuli of PGI2 release (ADP, suloctidil, serotonin) and the capacity of dipyridamole to inhibit adenosine uptake into endothelial cells were carefully checked. Pretreatment of the rabbit aorta with dipyridamole (10-100 microM) prolonged the transient stimulation of PGI2 release induced by mechanical deendothelialization: this effect was probably due to a partial protection of the cyclooxygenase against oxidative self-inactivation. Our largely negative results are consistent with the current theory that the antiplatelet action of dipyridamole is mediated by adenosine and not by PGI2.

Stimulation of prostacyclin production in blood vessels by the antithrombotic drug suloctidil.

Suloctidil is a calcium antagonist with vascular relaxing activity and an antithrombotic agent: its antiplatelet action has been demonstrated in vivo, but is difficult to reproduce in vitro and the mechanism of this effect remains unknown. We have observed that suloctidil (10 microM) stimulated the release of prostacyclin (PGI2) from the rabbit aorta, the dog vena cava and the dog portal vein, in vitro. This effect could be explained by an increased mobilization of free arachidonic acid. Neither the inactive congener CP894S, nor the two calcium channel antagonists, verapamil and flunarizine, reproduced the stimulatory effect of suloctidil. Suloctidil acted selectively on the vascular endothelium: it stimulated the release of PGI2 from bovine aortic and human umbilical vein endothelial cells, but neither from the de-endothelialized rabbit aorta nor from the bovine aortic media. The stimulatory effect of suloctidil on the release of the platelet inhibitor PGI2 from the vascular endothelium might contribute to the known antiplatelet and antithrombotic activity of this drug.

Stimulation of vascular prostacyclin by SKF 525-A (proadifen) and related compounds.

SKF 525-A (proadifen), a well-known inhibitor of drug metabolism and cytochrome P-450 activity, stimulated the release of prostacyclin (PGI2) from the rabbit aorta in vitro. The threshold concentration producing a detectable effect was 20 microM; the time course of SKF 525-A action exhibited particular features--progressive onset, long duration and slow reversibility--distinct from those of other stimuli (ADP, ionophore A23187 f.i.). The PGI2-stimulating activity of SKF 525-A was characterized by specific structural requirements: activity was abolished by the deletion of the terminal propyl group and increased by its elongation into an isobutyl group; chlorination of the phenyl groups increased the potency. SKF 525-A increased the production of PGI2 by cultured endothelial cells from bovine aorta and human umbilical vein, but had no effect on cultured smooth muscle from the bovine aortic media. Stimulation of PGI2 release could be explained by an increased availability of free arachidonic acid, which was probably independent from cytochrome P-450 inhibition. In human platelets, SKF 525-A inhibited prostaglandin and thromboxane production induced by A23187, thrombin and ADP. Simultaneous stimulation of endothelial PGI2 and inhibition of platelet TxA2 represents an original pharmacological profile: SKF 525-A might thus constitute the prototype of a new class of antiplatelet drugs.

Dopaminergic control of prolactin mRNA accumulation in the pituitary of the male rat.

Dopaminergic control of the expression of the prolactin gene was investigated by administration of bromoergocryptine (CB154) to male rats. The effects of the drug on the following parameters were measured: (i) circulating levels of GH and PRL; (ii) synthesis of GH and PRl measured by pulse labeling pituitary fragments in vitro; (iii) GH and PRL mRNA activities; and (iv) content of PRL and mRNA. After 1 day of CB154 administration, serum PRL fell to undetectable levels whereas it took 3 days to observe a 50% reduction in PRL synthesis. This effect was accounted for by a parallel decrease in PRL mRNA activity and content. GH synthesis and GH mRNA were not affected by the treatment. Our results show that the dopaminergic inhibition of PRL production involves regulation at a pre-translational level.

Comparison of oral psoralen-UV-A with a portable tanning unit at home vs hospital-administered bath psoralen-UV-A in patients with chronic hand eczema: an open-label randomized controlled trial of efficacy.

OBJECTIVE: To study whether oral psoralen-UV-A (PUVA) with a portable tanning unit at home is as effective as hospital-administered bath PUVA in patients with chronic hand eczema. DESIGN: Open-label randomized controlled trial, with a 10-week treatment period and an 8-week follow-up period. SETTING: Two university hospital dermatology departments in the Netherlands, specializing in hand eczema. PATIENTS: One hundred fifty-eight patients with moderate to severe chronic hand eczema (more than 1 year in duration). INTERVENTIONS: Oral PUVA using methoxsalen capsules and a simple portable commercial facial tanning unit, or hospital-administered bath PUVA with trioxsalen. MAIN OUTCOME MEASURES: The primary outcome was clinical assessment by a hand eczema score (evaluation of desquamation, erythema, vesiculation, infiltration, fissures, itch, and pain, each on a 4-point scale) after 10 weeks of treatment. The secondary outcome was hand eczema score at 8 weeks of follow-up, after completion of treatment. The tertiary outcome was travel cost and time off work. RESULTS: Both groups showed a comparable and substantial decrease in hand eczema score (meaningful clinical improvement). This decrease was maintained during the follow-up period. Patients treated with oral PUVA at home had lower travel costs and less time off work. CONCLUSIONS: Oral PUVA at home has a clinically relevant efficacy, similar to that of hospital-administered bath PUVA. This effect was maintained during an 8-week follow-up period. It resulted in lower travel costs and less time off work.

Effect of chronic oral testosterone undecanoate administration on the pituitary-testicular axes of hemodialyzed male patients.

Testosterone undecanoate (TU) or placebo was administered orally (for 12 weeks) in a double blind study, to 19 patients with chronic renal insufficiency on hemodialysis in a daily dose of 240 mg. Effect on plasma testosterone (T), dihydrotestosterone (DHT), androstenedione (A), 110H androstenedione (110A), FSH, LH and PRL concentration and the pituitary responsiveness to LH-RH/TRH stimulation was studied. These hormone levels were determined before the study and after 6 and 12 weeks of treatment. There was a rise in plasma androgen concentration in all treated patients. Mean plasma DHT, A and 110A increased at 12 weeks from 0.3, 0.85 and 1.13 ng/ml to 1.13 (p less than 0.05), 1.4 (p less than 0.05) and 1.44 (p less than 0.05) respectively. There was no change in plasma T or free testosterone. However, basal LH, FSH fell progressively from 5.51 and 5.51 ng/ml to 2.13 and 1.84 ng/ml (p less than 0.05). The level of significance of these changes was confirmed when the response to LH-RH was considered. Basal plasma PRL also decreased from 376 microU/nl to 306 (p less than 0.05), but PRL response to TRH remained unchanged. In contrast, none of these modifications were observed in placebo-treated patients. We conclude that oral TU restored to normal the pituitary-testicular axis. This form of treatment should be preferentially chosen instead of intramuscular injections in these frequently heparinized patients on hemodialysis.

[Spontaneous blood blister formation swellings of the oral mucosa]. / Spontane bloedblaarvormende zwellingen van het mondslijmvlies.

An 88 year-old man was hospitalized because of bullous pemphigoid of the skin with detectable autoantibodies against type XVII collagen. During his stay in the hospital, he developed easily bleeding hemorrhagic bullous lesions of the oral mucosa, which were thought to be an oral manifestation of bullous pemphigoid. A thorough blood examination showed acquired haemophilia A, related to the development of autoantibodies against factor VIII.

Assessment of severity of hand eczema: discrepancies between patient- and physician-rated scores.

BACKGROUND: In clinical practice or trials on hand eczema the severity of this disease can be 'measured' in different ways: by means of a physician-rated clinical severity score, a patient-rated clinical severity score or by an indicator of the burden of disease. We assume that the patient-rated severity score corresponds more with the (change in) burden of disease than with the physician-rated severity score. OBJECTIVES: To demonstrate how physicians and patients differ in their assessment of the severity of hand eczema as seen in a physician-rated severity score, patient-rated severity score and a burden of disease questionnaire. METHODS: We used data from an open-label randomized controlled trial which was set up in two university hospital dermatology departments in the Netherlands, specializing in hand eczema. One hundred and fifty-eight patients with moderate to severe chronic hand eczema were included. The main outcome measures were the physician-rated severity score, based on five visible aspects of hand eczema (desquamation, erythema, vesicles, infiltration, fissures), the patient-rated severity score (a self-rating scale), a burden of disease questionnaire (the Dermatology Life Quality Index, DLQI) and the correlations between these parameters, both at inclusion and over time. RESULTS: Only desquamation and infiltration were significantly correlated with patient-rated severity score. Patient-rated severity score correlated with seven of 10 DLQI items, but it did not correlate with the items regarding influence on clothes worn, impairment of sporting activities, and problems associated with treatment of the skin. The majority of patients showed improvement in all parameters after treatment. However, the improvement in patient-rated severity score was not clearly correlated with changes in physician-rated severity score. Except for DLQI item 1 (itch, soreness, pain, stinging), none of the changes in burden of disease was correlated with changes in patient-rated severity score. For each DLQI item, change over time correlated weakly with decreases in several, but not all, components of the physician-rated severity score. CONCLUSIONS: Disease severity can be expressed by different scores; these scores are not clearly correlated, and measure different aspects. Patient satisfaction is not guaranteed when treatment is focused solely on the visible aspects of hand eczema. Instead, burden of disease has a greater impact.

Physiological concentrations of ADP stimulate the release of prostacyclin from bovine aortic endothelial cells.

ADP (0.2-200 microM) stimulated the synthesis of prostacyclin (PGI2), as reflected by the release of 6-keto-prostaglandin F1 alpha (6-K-PGF1 alpha), in endothelial cells cultured from bovine aorta. This effect of ADP was mimicked by ATP, whereas AMP and adenosine were completely inactive. The release of 6-K-PGF1 alpha triggered by ADP was rapid and onset (within 5 min), transient (10 min) and followed by a period of refractoriness to a new ADP challenge. Growing and confluent cells were equally responsive to ADP. ADP stimulated the release of free arachidonic acid from the endothelial cells. ADP could thus exert two opposite actions on platelet aggregation in vivo: a direct stimulation and an inhibition mediated by PGI2. This last action might contribute to limit thrombus formation to areas of endothelial cell damage.

Prostacyclin-stimulating drugs: new prospects.

SKF 525-A (proadifen), a well-known inhibitor of drug metabolism and cytochrome P-450 activity, stimulated the release of prostacyclin (PGI2) from the rabbit aorta in vitro. The PGI2-stimulating activity of SKF 525-A was characterized by specific structural requirements: activity was abolished by the deletion of the terminal propyl chain and increased by its elongation into an isobutyl chain; chlorination of the phenyl rings increased the potency. SKF 525-A increased the production of PGI2 by cultured endothelial cells from bovine aorta and human umbilical vein, but had no effect on cultured smooth muscle from the bovine aortic media. In human platelets, SKF 525-A inhibited prostaglandin and thromboxane production induced by A23187, thrombin and ADP. Simultaneous stimulation of endothelial PGI2 and inhibition of platelet TxA2 represents an original pharmacological profile: SKF 525-A might thus constitute the prototype of a new class of antiplatelet drugs.

Treatment of supraventricular tachyarrhythmias associated with hyperthyroidism by radioiodine, amiodarone and propylthiouracil.

Beta-blockers and calcium antagonists have been advocated for thyrotoxicosis induced tachyarrhythmias. Amiodarone is generally considered as contraindicated because of its high iodine content. Since amiodarone combined with propylthiouracil induced a greater fall in serum thyroid hormone concentrations than propylthiouracil alone, we treated 2 hyperthyroid patients with supraventricular arrhythmias by radioiodine (day 0) followed after 24 h by amiodarone and propylthiouracil. Serum T3 was normalized on day 2 (patient 1) and 3 (patient 2). Effective t1/2 of intrathyroidal 131I were 6.6 and 4.3 days (versus 5.9 days for 131I given alone). In patient 1, atrial fibrillation, reverted to sinus rhythm after verapamil and digoxin, and did not recur. In patient 2, conversion of atrial fibrillation to sinus rhythm occurred on day 11; from day 0 to day 11, ventricular rate decreased and was significantly correlated to T3 (r = 0.82; p < 0.05). In conclusion, amiodarone may be beneficial in thyrotoxicosis associated tachyarrhythmias, given with propylthiouracil 24 h after radioiodine, it did not decrease thyroid irradiation and rapidly decreased serum T3.

Stimulation of aortic smooth muscle prostacyclin by serotonin: role of distinct receptors in contractile and synthetic states.

It has been shown previously that serotonin stimulates the production of prostacyclin by bovine aortic smooth muscle cells in culture, via 5-HT2 receptors (Coughlin SR, Moskowitz MA, Antoniades HN, Levine L. Proc Natl Acad Sci USA 1981;78:7134-7138). These cells express a synthetic phenotype, whereas the majority of the smooth muscle cells in the media from adult arteries are in a contractile state. We have now compared 5-HT stimulated prostacyclin production in bovine aortic media explants, a preparation of contractile smooth muscle, with cultured smooth muscle cells derived from the explants. In the 1-10 microM range, serotonin stimulates the release of prostacyclin from the explants of bovine aortic media, cultured for a short period. In the presence of cocaine (30 microM), 1 microM was sufficient to produce a maximal effect. The stimulatory action of serotonin was sustained with time and did not induce a lasting desensitization. The effect of serotonin on the explants was inhibited only partially (+/- 30%) by ketanserin, a selective and potent 5-HT2 antagonist. It was mimicked by 5-carboxamido-tryptamine, a 5-HT1 agonist, but was only weakly inhibited by methiothepin, a 5-HT1 antagonist. As expected, in cultured smooth muscle cells, 5-carboxamido-tryptamine was only a weak agonist in stimulating prostacyclin production. In conclusion, it appears that the serotonin effect on prostacyclin production is mediated by different receptors in media explants from bovine aortic media and cultured cells obtained by outgrowth from these explants: a 5-HT2 receptor in the smooth muscle cells in culture and a receptor presenting some similarities with 5-HT1 receptors in the explants.

P2-purinergic receptors in vascular endothelial cells: from concept to reality.

ATP exerts at least 2 actions on arterial endothelial cells: it stimulates the release of endothelium-derived relaxing factor, a still unidentified vasodilator, and of prostacyclin, a potent inhibitor of platelet aggregation. A study of agonist specificity indicates that these responses are mediated by P2-purinergic receptors. We have now demonstrated that in these cells, the P2-receptors are coupled to a phospholipase C hydrolysing phosphatidylinositol-bisphosphate and that this coupling involves a pertussis toxin-sensitive GTP-binding regulatory protein.

Effects of adenine nucleotides on the proliferation of aortic endothelial cells.

The effects of adenine nucleotides and adenosine on DNA synthesis and cell growth have been studied in bovine aortic endothelial cells (BAECs). ATP produced a small but significant (+44%) increase of the fraction of BAECs whose nuclei are labeled by [3H]thymidine. This mitogenic effect was mimicked by ADP, the phosphorothioate analogues ATP gamma S and ADP beta S, and the nonhydrolyzable analogue adenosine 5'-(beta, gamma-imido)triphosphate (APPNP), whereas adenosine 5'-(alpha, beta-methylene)triphosphate (APCPP), a selective agonist of P2x-purinoceptors, had no effect at 10 microM and a small one at 100 microM; this profile is consistent with the involvement of P2y-receptors. Adenosine induced a mitogenic response of a magnitude similar to that of ATP. This effect was not reproduced by R-phenylisopropyl adenosine, by 5'-N-ethylcarboxamide adenosine, or by 2',5'-dideoxyadenosine, selective ligands of the A1- and A2-receptors and the P site, respectively, nor was it inhibited by 8-phenyltheophylline, an antagonist of both A1- and A2-receptors. The mechanism of this adenosine action thus remains unclear. ATP and ATP gamma S did not enhance the proliferation of BAECs cultured in the presence of fetal calf serum concentrations ranging from 0.5% to 10%. They inhibited the growth-promoting effect of basic fibroblast growth factor; among the various nucleotides tested, APCPP was the least effective to reproduce the action of ATP, suggesting the possible involvement of P2y-receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Contact allergens in shoe leather among patients with foot eczema.

Some patients with relapsing foot eczema and a shoe leather allergy, who fail to show positive results with standard series and shoe wear screening tray patch testing, do not respond to the use of hypoallergenic shoe leather. We assume that relevant allergens are present in hypoallergenic shoe leather. We described an experiment to demonstrate the presence of these allergens. Alcoholic extracts were made of green, black and undyed hypoallergenic shoe leather, and the extracts were fractioned by paper chromatography. The resulting chromatograms were cut into 16 equal paper disks and patch tests were performed with extracts and the paper chromatography fractions. Positive reactions were seen to all extracts and to fractions of all types of leather. From analysis of the pattern of positive patch tests we concluded that leather-related allergens (e.g. tanning agent) and dyes were present in hypoallergenic shoe leather. In these cases, alternatives to shoe leather should be sought, for instance wooden or plastic shoes.

Cushing's syndrome with intermittent ectopic ACTH production.

A case of ectopic ACTH syndrome with intermittent secretion in a 72-yr-old woman is described. Plasma and urinary cortisol levels were obtained at frequent intervals for a period of more than 10 months and varied erratically from the normal range to extremely high values. Nonsuppression by high doses of dexamethasone was documented during a period of hypersecretion. Normal circadian rhythmicity and normal responses to hypoglycemia were observed during an interval of dormance of the ectopic secretion. Hypokalemia did not develop. These findings, together with the occult nature of the primary tumor, resulted in unusual diagnostic difficulties. Liver masses were detected by echography and CT scan. Pathological examination of liver biopsies suggested a neuroendocrine tumor of foregut origin. While a multicentric primary apudoma secreting ACTH was a putative diagnosis, detailed and extensive microscopic post-mortem studies revealed a more likely primary tumor site in the pancreatic tail.