Subacute thyroiditis: clinical characteristics and treatment outcome in fifty-six consecutive patients diagnosed between 1999 and 2005.

OBJECTIVE: To identify predictive factors of clinical outcome of subacute thyroiditis. DESIGN: Retrospective case series of 56 consecutive patients treated in 3 outpatient clinics between 1999 and 2005. Medical records were reviewed for demographic data, seasonal disease distribution, laboratory and clinical course, treatment, and short-term outcome. MAIN OUTCOME: Mean age was 48.6+/-12 yr; 70% were females. Twenty-five percent had antithyroid antibodies and 9% had recurrent disease. Differences in occurrence by season were not significant (p=0.28). Ultrasound, performed in 35 patients, revealed thyroid nodules in 25 (median size, 17 mm). Ten patients received no treatment, and 43 received either non-steroidal anti-inflammatory drugs (NSAID) (no.=25) or glucocorticoids (no.=18); data for 3 patients were missing. Median disease duration was 77 days; mean peak free T4 (FT4) level was 43.7+/-25.3 pmol/l. A hypothyroid phase was documented in 31 patients, and remained permanent in 6. Peak FT4 level, but not erythrocyte sedimentation rate or clinical score, was positively correlated with the highest TSH level and with disease duration. Untreated patients had less severe clinical disease than treated patients, but a similar outcome. Patients given glucocorticoids had a shorter overall disease duration (p=0.03), with no differences in duration of hyperthyroidism, peak FT4 or highest TSH levels, compared with patients given NSAID. CONCLUSION: Subacute thyroiditis follows an unpredictable clinical course that is hardly affected by its clinical features or treatment.

Symptomatic hyponatremia as a presenting sign of hypothalamic-pituitary disease: a syndrome of inappropriate secretion of antidiuretic hormone (SIADH)-like glucocorticosteroid responsive condition.

Hyponatremia associated with high urine osmolality is usually caused by inappropriate secretion of antidiuretic hormone. However, secondary hypoadrenalism is also accompanied by hyponatremia and with features indistinguishable from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). As secondary hypoadrenalism requires a specific treatment, a high index of suspicion and appropriate hormonal testing are required to differentiate between these two entities. We retrospectively studied 10 patients with a previously undiagnosed hypothalamic-pituitary disease who presented with an acute symptomatic hyponatremia. Mean age (+/-SD) was 65.1+/-8.4 yr. Mean serum sodium was 120.7+/-2.9 nmol/l and urinary osmolality, 453.9+/-74 mosmol/kg. Serum creatinine, urea and uric acid were low. Mean serum morning cortisol was low, 104.0+/-55.2 nmol/l. High-dose ACTH test showed adequate increment of serum cortisol in 3 out of 7 patients tested. Two of these 3 patients did not respond adequately to the low-dose ACTH test. Endocrine evaluation disclosed partial or complete hypopituitarism in all 10 patients. Six patients had pituitary macroadenomas, one had a craniopharyngioma, one patient had a large aneurysm of the internal carotid with sellar destruction and two others had empty sella. Treatment by fluid restriction did not affect serum sodium levels significantly. In contrast, all patients achieved normal sodium when treated by glucocorticosteroid. Central hypoadrenalism should be considered in any patient presenting with hyponatremia with high urine osmolality. Low-dose ACTH test should be performed and followed by appropriate endocrine and imaging studies. Hyponatremia in these patients is promptly corrected by glucocorticosteroid replacement.

Management of pituitary apoplexy: clinical experience with 40 patients.

BACKGROUND: Pituitary apoplexy is a rare major clinical event with neurological, neuro-ophthalmological, cardiovascular and hormonal consequences, resulting from an acute infarction of pituitary adenoma. We report our experience with a series of 40 patients presenting with pituitary apoplexy. PATIENTS: Forty patients (27 males, 13 females; mean age, 51.2 yr) were admitted to our medical center between years 1985-2002 with acute presentation of pituitary apoplexy. Visual field defects occurred in 61% and ocular paresis in 40% of subjects. Sixty-three percent of adenomas were nonfunctional, and prolactinomas comprised 31%. RESULTS: Thirty-four patients underwent transsphenoidal pituitary decompression. Visual fields and ophthalmoplegia improved in 81% and 71%, respectively. During follow-up (4.5+/-5.4 yr), 79% of patients developed hypogonadotrophic hypogonadism, central hypothyroidism appeared in 54% and hypocortisolism--in 40% of patients. Permanent diabetes insipidus was diagnosed in 8%. Serial sellar MRI showed disappearance of pituitary tumor in 63% of operated subjects. Six patients (3 with PRL-secreting and 3 nonfunctional adenomas) were treated medically (corticosteroids, dopamine agonists), two patients (out of three) with visual deficits improved, and tumor shrinkage was noted in four. CONCLUSIONS: We present a large series of patients with pituitary apoplexy. Most subjects were operated, but six were treated conservatively. Almost all patients improved clinically, including those who were not operated, but hormonal deficiencies are very common.

Pulmonary embolism-the initial manifestation of renal cell carcinoma in a young woman.

We report a case of massive pulmonary embolus demonstrated on CT in a young woman presenting with dyspnea, with no known risk factors for embolism. Abdominal CT on further investigation showed a renal tumor invading the left renal vein and the inferior vena cava as the cause of the pulmonary embolus. In a patient presenting with pulmonary artery embolism without venous thrombosis, the differential diagnosis should include an occult tumor as the cause of the embolus.

Mutation analysis of the MEN1 gene in Israeli patients with MEN1 and familial isolated hyperprolactinemia.

Multiple endocrine neoplasia type 1 (MEN-1) is characterized by hyperfunction and tumor formation of the parathyroids, anterior pituitary and endocrine pancreas. We carried out exon-specific, PCR-based DNA sequencing of the coding exons of the MEN1 gene in 8 Israeli MEN1 patients: 4 familial and 4 sporadic. We similarly analyzed Israeli families with a unique phenotype of isolated hyperprolactinemia (HPRL). Four mutations were detected in 4 MEN1 patients: C to T alteration at nucleotide 2608 resulting in R108X, and three intronic insertions/deletions (a 13 basepair (bp) deletion and a 1 bp insertion both in intron 1, and a 2 bp insertion in intron 3) leading to exonic frame shifts as they encompass the splice junctions. An additional patient exhibited a compound mutation: a G to T change at position 7614 resulting in E463X, and insertion/deletion of 9 bp at position 7622-7630 resulting in EAE466-468X. Haplotype analysis showed no segregation of phenotype with 11q13 markers in 4 familial HPRL, and no men 1 germline mutations were detected in three representative individuals, from 3 families. Our results confirm that men 1 gene germline mutations occur in the majority of patients with clinically diagnosed MEN1, and that familial HPRL is a genetically distinct disorder.

Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers.

Prolonged furosemide treatment is associated with urinary loss of thiamine and thiamine deficiency in some patients with congestive heart failure and low dietary thiamine intake. In the rat, diuretic-induced thiamine urinary loss is solely dependent on increased diuresis and is unrelated to the type of diuretic used. We studied the effects of single intravenous doses of furosemide (1, 3, and 10 mg) and of normal saline infusion (750 mL) on urinary thiamine excretion in 6 volunteers. Over a 6-hour period, furosemide induced dose-dependent increases in urine flow and sodium excretion rates (mean +/- SD), from 51 +/- 17 mL/h at baseline to 89 +/- 29 mL/h, 110 +/- 38 mL/h, and 183 +/- 58 mL/h (F = 10.4, P < .002) and from 5.1 +/- 2.3 mmol/h to 9.4 +/- 6.8 mmol/h, 12.1 +/- 2.6 mmol/h, and 20.9 +/- 10.6 mmol/h (F = 6.3, P < .005) for the three doses, respectively (104 +/- 35 mL/h and 13.0 +/- 6.2 mmol/h for the saline infusion). During this period the thiamine excretion rate doubled from baseline levels (mean of four 24-hour periods before the diuretic interventions) of 6.4 +/- 5.1 nmol/h to 11.6 +/- 8.2 nmol/h (F = 5.03, P < .01, for all four interventions, no difference being found between them), then returning over the following 18 hours to 6.1 +/- 3.9 nmol/h. The thiamine excretion rate was correlated with the urine flow rate (r = 0.54, P < .001), with no further effect of the type of intervention or sodium excretion rate. These findings complement our previous results in animals and indicate that sustained diuresis of >100 mL/h induces a nonspecific but significant increase in urinary loss of thiamine in human subjects. Thiamine supplements should be considered in patients undergoing sustained diuresis, when dietary deficiency may be present.

Urinary thiamine excretion in the rat: effects of furosemide, other diuretics, and volume load.

Long-term furosemide therapy is associated with increased urinary loss of thiamine. To examine the mechanism of furosemide-induced urinary thiamine loss, we measured urinary excretion of thiamine in rats in response to increasing doses of furosemide, acetazolamide, chlorothiazide, amiloride, mannitol, and extracellular fluid (ECF) volume loading by saline infusion. All animals were in normal thiamine balance as reflected by a thiamine pyrophosphate effect (TPPE) of 2.25% +/- 0.60% (mean +/- SEM), and all had normal renal function. Urinary flow increased in response to diuretic administration in a dose-dependent manner, reaching (mean) peak urinary flow rates of 283 to 402 microL/min. Fractional excretion of sodium (FE(Na)) exhibited the same pattern, reaching peak values of 12.3% to 23.2%. Urinary thiamine excretion increased in proportion to the incremental doses of diuretic agents, reaching (mean) maximal values of 7.44 to 9.34 pmol/min, with no significant difference (P = .11) between the various diuretics tested nor in response to saline loading. None of the diuretics tested differed in the effect on thiamine excretion, which was clearly flow dependent and only partially related to fractional sodium excretion. Urinary flow rate, being the single significant predictor, explained 78% (R2 = 0.78) of the variability in thiamine excretion rates. These findings indicate that urinary thiamine loss is caused by a nonspecific, flow-dependent mechanism common to all of the diuretics tested.

CD44 expression in normal adrenal tissue and adrenal tumours.

BACKGROUND: CD44 is a cell surface glycoprotein found on many normal cells, mainly lymphoid and epithelial. Normal cells usually express standard CD44 (CD44-S), whereas malignant tumours may express CD44 variant isoforms (CD44-V). CD44 expression has been described for neural crest derivatives. Characterisation of differences in CD44 expression may help in the diagnosis and differentiation of distinct adrenal tumours. AIMS: To examine CD44 expression in different layers of cortical cortex, in adrenal medulla, and in adrenal tumours. METHODS: CD44-S and CD44-V6 expression were studied in 12 cases of adrenal cortical adenoma, 3 of adrenal cortical carcinoma, 10 of pheochromocytoma, and 4 normal adrenal glands. RESULTS: CD44-V6 staining showed cytoplasmic expression in normal adrenal cortex and in cortical adenomas and carcinomas. Pheochromocytomas also showed CD44-V6 expression but in 5 of the 10 cases it was sparse, focal, and sometimes perinuclear. Strong membranous staining for CD44-S was observed in normal adrenal medulla. Analysis of CD44-S expression revealed differences between cortical adrenal tumours and pheochromocytomas. Ten of 12 cortical adenomas and 2 of 3 cortical carcinoma cells showed weak to moderate cytoplasmic staining, but all cases of pheochromocytoma had strong membranous staining. CONCLUSIONS: Membranous CD44-S staining may help to distinguish pheochromocytoma from adrenal cortical adenoma.

Growth hormone-releasing factor expression is discordantly regulated in the hypothalamus and testis of streptozotocin-diabetic rats.

Growth hormone-releasing factor (GRF) mRNA expression in male rats occurs predominantly in the hypothalamus (mainly in the arcuate nucleus), and among extraneural sites primarily in the testis. Hypothalamic GRF is the physiological tropic stimulus to growth hormone secretion. However, the role of GRF in the testis is unknown. We have shown previously that hypothalamic GRF mRNA expression is significantly reduced in streptozotocin (STZ)-diabetic rats. This reduction is confined to the arcuate nucleus and probably accounts for the suppression of growth hormone pulsatility. The present studies were performed to evaluate GRF expression in the testis of streptozotocin (STZ)-diabetic rats. Diabetes was induced by injection of STZ (100 mg/kg i.p.). Seventeen to twenty days later diabetic rats were hyperglycemic compared with vehicle-injected controls and demonstrated growth failure. Insulin treatment reduced the glycemia and increased body weight towards normal. Total RNA was extracted from the hypothalamus and testis, and GRF mRNA levels estimated by solution hybridization/nuclease protection assay. Levels of hypothalamic somatostatin mRNA were measured to serve as control values. GRF mRNA was significantly (P < 0.001) decreased in the hypothalamus of STZ-diabetic rats (0.2 +/- 0.07 mean relative densitometric units, n = 8) compared with controls (1.0 +/- 0.19, n = 8) with no change in somatostatin mRNA expression. In contrast, testicular GRF mRNA was increased 70% (P < 0.05) in STZ-diabetic rats. Insulin treatment resulted in normalization of hypothalamic GRF mRNA levels (1.1 +/- 0.17, n = 5) with no effect on testicular GRF mRNA expression. In conclusion GRF gene expression is discordantly regulated in tissues of male STZ-diabetic rats. While reduced GRF expression may account for the low growth hormone state in this model, increased testicular GRF mRNA (with the previously reported reduction of insulin-like growth factor-I mRNA) resembles the response seen in growth hormone-sensitive tissue (especially the hypothalamus) to this growth hormone-deficient state.

Chronic myeloid leukaemia following 131I treatment for thyroid carcinoma: a report of two cases and review of the literature.

Leukaemia is an uncommon late complication of exposure to the ionizing radiation of radioactive iodine (131I). Most cases reported have been of acute leukaemias developing after high doses of 131I. Only a few cases of chronic myeloid leukaemia (CML) have been reported in this setting to date. We report two new cases of CML after low dose radioactive iodine and review the literature. We present an analysis of the minimal relative risk of CML developing in thyroid cancer patients treated with 131I in Israel. Two male patients, 35 and 51 years old, developed CML following low dose 131I therapy for metastatic mixed papillary and follicular carcinoma of the thyroid. Both had undergone thyroidectomy and neck dissection and thyroid ablation with 131I (total dose: 56 and 130 mCi respectively). Four and 10 years later, respectively, a leucocytosis was noticed with typical blood smears, and CML was diagnosed either by Philadelphia translocation or bcr-abl gene rearrangement. Thyroid cancer at that time was in remission. Estimated minimal relative risk of CML after 131I therapy where the population considered at risk comprised all thyroid cancer patients detected during the years 1981-1991 in Israel was 8.95 (95% confidence limits 2.26-35.16). Literature review disclosed five additional similar cases. The mean radioiodine dose given to the seven CML patients was 11416MBq (range 1134-32130 MBq), considerably lower than the dose given to patients reported in the literature who subsequently developed acute leukaemias (mean 34965, range 3856-54810 MBq). We suggest that CML is a potential complication of low dose 131I therapy given for thyroid carcinoma even at the lower end of the dose range used for this indication. Leucocytosis appearing in these patients should raise the suspicion of secondary CML.

Primary psoas abscess due to methicillin-resistant Staphylococcus aureus concurrent with septic arthritis of the hip joint.

We report an unusual case of a primary psoas abscess due to community acquired methicillin-resistant Staphylococcus aureus in an immunocompetent man. The course of the disease was indolent, expressed as septic arthritis of the hip joint. When the diagnosis was made, 3 months after symptoms began, the patient was treated by surgical evacuation of the abscess and appropriate antibiotics. Full recovery and return to his usual activity followed total hip replacement.

Pituitary and hypothalamic insulin-like growth factor-I (IGF-I) and IGF-I receptor expression in food-deprived rats.

The present study was designed to evaluate a possible role for the insulin-like growth factor-I (IGF-I) system in mediating the suppression of growth hormone (GH) secretion observed in food-deprived rats by measuring IGF-I mRNA, receptor concentration and receptor mRNA in neuroendocrine tissues (hypothalamus and pituitary). Rats were deprived of food (food-deprived) for 72 h or had free access to food (fed). Tissues were processed for measurement of steady-state levels of: (a) IGF-I and IGF-I receptor mRNA (by solution hybridization/RNase protection assay); (b) IGF-I in serum and tissue extracts (by RIA) and (c) IGF-I displaceable [125I]IGF-I binding to plasma membrane preparations. Food deprivation resulted in decreased serum and liver levels of IGF-I. Kidney IGF-I mRNA levels were reduced 80% in food-deprived rats with a concomitant increase in IGF-I receptor concentration and mRNA levels. Refeeding of food-deprived rats fully normalized these perturbations. Pituitary IGF-I content was reduced 50% in food-deprived rats while IGF-I mRNA levels were unaffected. A modest increase was seen in pituitary IGF-I receptor concentration; however, IGF-I receptor mRNA levels were not changed. Hypothalamic IGF-I mRNA content was reduced in 72 h food-deprived rats while IGF-I receptor binding capacity and mRNA were unaffected. In conclusion, IGF-I mRNA levels are decreased in liver, kidney and hypothalamus together with a reduction in plasma IGF-I in food-deprived rats but is unaffected in anterior pituitary. IGF-I receptor gene expression and binding capacity are coordinately regulated in kidney and hypothalamus, but not in the pituitary.(ABSTRACT TRUNCATED AT 250 WORDS)

[Atrial septal defects and embolic stroke in young adults].

The mechanism of embolic stroke in young adults remains unidentified in about 35% of cases. In recent years defects in the atrial septum have been described as an important route for cerebral and retinal embolism. These include classical atrial septal defect and patent foramen ovale, as well as the less well-recognized entity of atrial septal aneurysm, with or without interatrial communication. The combined incidence of these defects in the general population is between 20-35%. The introduction of transesophageal echocardiography and the use of echogenic contrast have lead to significant improvement in identification. We describe 3 patients in whom atrial defects were identified as possible routes for cerebral embolism: The first presented with recurrent stroke and combined atrial septal aneurysm and patent foramen ovale. In the second, patent foramen ovale was found in a patient with 2 prosthetic values. The third was a soldier in whom patent foramen ovale was found following transient loss of consciousness. Based on our modest experience and review of the literature we believe that transesophageal and contrast echocardiography should be performed in every young patient with unexplained cerebral ischemia.

Pituitary insulin-like growth factor-I content and gene expression in the streptozotocin-diabetic rat: evidence for tissue-specific regulation.

Insulinopenic diabetes mellitus in the rat is associated with reduced circulating levels of insulin-like growth factor-I (IGF-I), resulting primarily from decreased IGF-I synthesis in liver and extrahepatic sites. Plasma GH levels in these animals are also suppressed, with loss of episodic secretion and decreased pituitary synthesis. Intrapituitary IGF-I has been postulated to exert local autocrine/paracrine negative feedback regulation on GH synthesis and secretion. The present studies were designed to examine regulation of pituitary IGF-I peptide content and gene expression in insulinopenic streptozotocin (STZ)-diabetic rats compared to that in liver and testis. Serum IGF-I levels were reduced by 86% in STZ-diabetic rats together with reduction of IGF-I content in liver (53%) and testis (74%; all P less than 0.001 vs. control). Concomitantly, liver and testicular IGF-I mRNA levels were reduced by 90% (P less than 0.001 vs. control). Insulin treatment restored IGF-I peptide levels in serum, liver, and testis toward normal, with a partial but significant increase in liver IGF-I mRNA. In contrast, pituitary IFG-I peptide content increased by 69% in STZ-diabetic rats (P less than 0.001 vs. control), with no change in IGF-I gene expression. Insulin treatment completely reversed the rise of pituitary IGF-I peptide content. These results demonstrate a novel discordance in the regulation of IGF-I gene expression and peptide content between pituitary and other tissues in STZ-induced diabetic rats. Elevated IGF-I levels in the pituitaries of these animals may partly explain the suppressed GH synthesis and secretion seen in STZ-diabetic rats and provide further evidence for a potential autocrine or paracrine role of pituitary IGF-I in GH regulation.

Influence of food deprivation in the rat on hypothalamic expression of growth hormone-releasing factor and somatostatin.

Food deprivation in the rat is associated with a reduction in serum GH levels characterized by suppression of high amplitude GH bursts and a decrease in the duration of secretory episodes. The mechanism(s) mediating this response is unknown. The present studies were designed to evaluate the role of hypothalamic factors potentially responsible for abnormal GH dynamics in food-deprived rats by measuring hypothalamic prepro-GH-releasing factor (GRF) and preprosomatostatin (SRIF) mRNA and peptide levels in adult male Sprague-Dawley rats after 72 h of food deprivation or free access to food. Hypothalamic prepro-GRF mRNA was reduced 80% in food-deprived rats compared to that in fed controls (P less than 0.001), while GRF content was unchanged. Levels of prepro-SRIF mRNA in food-deprived rats were similar to those in controls, as was hypothalamic SRIF content. The time course of hypothalamic prepro-GRF mRNA reduction was determined in groups of rats food-deprived for 24, 48, or 72 h and revealed a significant (30%) reduction of prepro-GRF mRNA (P less than 0.05 vs. fed) by 24 h, with maximal reduction (80%) by 48 h. Refeeding groups of animals for up to 72 h after they had been food-deprived for 72 h resulted in restoration of prepro-GRF mRNA levels to 50% of control levels by 24 h (P less than 0.05 vs. fed) and a return to control values by 48 h. These data suggest that decreased GRF gene expression and possibly GRF release play a major role in the loss of pulsatile GH secretion seen in this model of nutrient deprivation.

Increased hypothalamic content of preproneuropeptide-Y messenger ribonucleic acid in streptozotocin-diabetic rats.

Neuropeptide-Y (NPY) is a 36-amino acid C-terminally amidated peptide found within the hypothalamus that can potently stimulate carbohydrate feeding. Moreover, the hypothalamic content of NPY can be modulated by peripheral hetabolic status. To further evaluate the regulation of NPY synthesis in states of altered metabolic homeostasis, we measured the hypothalamic content of prepro-NPY mRNA in streptozocin (STZ)-diabetic, STZ-diabetic insulin-replaced, and control rats by both nuclease protection and in situ hybridization analyses. Adult male Sprague-Dawley rats received a single injection of STZ (100 mg/kg, ip) or citric acid (control). Beginning 72 h later one group of STZ-treated animals received daily injections of insulin (4 U Ultralente/day). All animals were killed 17-19 days after STZ or control treatment. STZ-treated animals were hyperglycernic and showed growth failure compared to control rats. Glycemic control was restored by insulin replacement, as was partial growth. Nuclease protection analysis revealed an approximately 3- to 4-fold increase in prepro-NPY mRNA levels in the samples from STZ-treated rats vs. control. This increase was returned to control values by insulin replacement. In situ hybridization analysis revealed the STZ-induced increase in hypothalamic prepro-NPY mRNA was detectable in the arcuate nucleus at levels that were in agreement with the nuclease protection results, but that NPY expression in other brain regions appeared to be either unaffected or decreased after STZ treatment. These data suggest that hypothalamic NPY expression is modulated by peripheral metabolic status and provide further explanation for the hyperphagia accompanying STZ-induced diabetes.