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Suppressive or replacement doses of levothyroxine (LT4) are affected by the rate and extent of the active ingredient absorbed, as well as by the lean body mass. Obesity has reached epidemic proportions worldwide and is related with many comorbidities. The aim of this study was to determine the pharmacokinetic parameters of LT4 in severely obese individuals and compared them with similar data in lean control subjects.We studied 62 euthyroid subjects who had negative tests for anti-thyroid peroxidise antibodies (Ab-TPO). Thirty eight of these subjects were severely obese but otherwise healthy (severe obese subjects [SOS] group). Twenty-four were healthy control subjects (control group), with a body mass index of 23.3 ± 1.7 kg/m(2). Subjects received 600 μg oral sodium LT4 after an overnight fast. Serum triiodothyronine (T3), T4, and thyroid-stimulating hormone were measured at baseline. Serum T4 and T3 was measured 0.5, 1, 1.5, 2, 2.5, 3, and 4 hours after LT4 administration.Baseline serum T4 and thyroid-stimulating hormone concentrations were higher in the SOS group than in the control group; serum T3 was similar in the two groups. The corrected area under the curve and the maximum T4 concentration after LT4 administration were lower, whereas the time to maximum concentration from the baseline was higher in SOS than in the control group. The estimated plasma volume was higher in the SOS than in the control group. Mean serum T3 levels increased gradually during the four hours after LT4 administration in the control group. In contrast, they decreased gradually in the SOS group.Severely obese individuals may need higher LT4 suppressive or replacement doses than normal-weight individuals due, among other factors, to impaired LT4 pharmacokinetic parameters. The latter could be attributed to their higher plasma volume and/or to delayed gastrointestinal LT4 absorption. T4 conversion to T3 might be defective in severe obesity.

The aim of this study was to evaluate the effects of intensive physical exercise and acute psychological stress during high level athletic competition as reflected on the levels of salivary cortisol in elite artistic gymnasts (AGs).The study included 239 AGs (142 females-97 males) who participated in the European Championship of Gymnastics in 2006 and 81 adolescents (40 females-41 males), matched for age, as controls. All athletes participated voluntarily in all or parts of the study, providing samples or data for each of the variables measured. Height, weight, body fat, lean body mass (LBM), bone age and Tanner stage of puberty were assessed and data concerning the time of thelarche, adrenarche and menarche as well as, the onset and the intensity (hours per week) of training were obtained.Saliva samples were collected, the morning before training and in the afternoon shortly after the competition. From controls, the saliva samples were collected in the morning. Cortisol concentrations were measured using a chemiluminescence method. Acute stress was assessed using a questionnaire designed for the study.No difference was found between morning and afternoon salivary cortisol levels in both male and female AGs (females: AM: 15.45±7.45nmol/l vs PM: 15.73±9.38nmol/l; males: AM: 10.21±5.52nmol/l vs PM: 9.93±13.8nmol/l, p0.05). Female AGs presented higher levels of morning salivary cortisol than female controls (p0.05). Both male and female AGs had higher degree of psychological stress in comparison with controls (p0.001, p0.013, respectively). Female AGs had higher morning and afternoon salivary cortisol levels (p0.01, p0.01, respectively) and higher degree of stress (p0.003) than males.In elite AGs the diurnal rhythm of salivary cortisol has been abolished, probably due to the strenuous training and competition conditions. Female AGs presented higher levels of morning salivary cortisol and psychological stress compared to both male AGs and female controls. The long term consequences of these modifications of the HPA axis remain to be elucidated.

ObjectiveRelative corticosteroid insufficiency may be common in critically ill patients and is associated with a poor outcome; however, the response of the hypothalamic–pituitary–adrenal (HPA) axis in nursed patients is not known. Our aim was to evaluate the response of HPA axis to the severity of illness in non-critically ill nursed (NCIN) patients and the clinical outcome.Subjects and methodsFifty-six nursed patients who were divided into four groups (stroke, mild disease, sepsis and severe sepsis) as well as a control group (n=15) were studied. At admission (day 1), cortisol and ACTH were measured and a low-dose (1 μg) corticotrophin test was performed, followed 2 h later by a standard-dose (250 μg) corticotrophin test. Diurnal variation of cortisol was obtained on day 2. A second identical set of low-dose and standard-dose corticotrophin tests were performed on day 5 or 6 (recovery phase).ResultsIn patients with stroke and severe sepsis, cortisol had the highest values and its diurnal variation was abolished. Dissociation of ACTH and cortisol was found in all patients.The Δmax of cortisol after the 1-μg corticotrophin test did not differ among the groups, while after the 250-μg corticotrophin test, it was borderline higher in controls. The ratio of responders (Δmax of cortisol ≥9 μg/dl) to non-responders after 1- or 250-μg corticotrophin test did not differ among patients and controls. All patients had a good outcome without glucocorticoid treatment.ConclusionsDepending on the severity of illness, mild alterations in the HPA axis occurred. However, relative corticosteroid insufficiency was not confirmed in NCIN patients.

Nontoxic nodular goiter (NTNG) is common in endemic goiter regions. Thyroxine (T4) is often used to treat NTNG. There is little information regarding T4 treatment in regions that have recently become iodine sufficient. We studied the effect of T4 treatment on thyroid function tests in southwestern Greece (SWG), a recently iodine-sufficient area.We studied 827 residents of SWG (group A) to determine goiter prevalence, thyroid function, and urinary iodine concentration (UIC). Group B: 385 consecutive patients with thyroid dysfunction. Of these, 89 had NTNG and followed for 10 years on T4 treatment, and 296 had hyperthyroidism. Group C: 29 patients with NTNG, treated with triiodothyronine (T3) 50 mug/day and followed for 6 months. Measurements included serum T4 and 24-hour radioactive iodine uptake (RAIU) before and at the end of T3 administration.The median UIC in group A was 114 microg/L. In group B (89 patients), the incidence of newly diagnosed hyperthyroidism was 5-7% per year with a cumulative percentage of 33% at the 10th year. The initial thyrotropin (TSH) was lower (0.78 +/- 0.51 mIU/L) in those who developed thyrotoxicosis compared to those who remained euthyroid (1.17 +/- 0.74 mIU/L) (p0.05). In 296 thyrotoxic patients, the incidence of autoimmune hyperthyroidism and toxic multi-nodular goiter (TMNG) was similar. In group C, 10/29 patients remained euthyroid and the 24-hour RAIU decreased by 49% during T3 treatment. Similarly, serum T4 decreased by 49%. In the remaining patients who developed hyperthyroidism, 24-hour RAIU and T4 were decreased by 19% and 22%, respectively.In SWG, a recently iodine-sufficient region, the risk of developing hyperthyroidism in patients with NTNG after administration of 100-150 microg T4 is relatively high in those whose serum TSH before T4 treatment is in the lower normal range. Therefore, T4 treatment should be avoided in these patients.

Transient hyperglycemia is commonly observed in non-diabetic subjects during surgery. We undertook this study to investigate (1) insulin secretion pattern and glucose levels during elective surgery, and (2) the role of pre-operative fasting in the development of surgery-induced hyperglycemia.We examined 21 severely obese normal glucose tolerant patients, who underwent bariatric surgery. From the 21 operated subjects, 14 remained fasted while seven patients received 75 g glucose the preoperative night. They sampled at baseline and from the onset of operation frequently for 9 h thereafter, for measuring serum insulin and glucose.Hyperglycemia developed within 1 h from the onset of operation and lasted 9 h. The administration of 75 g glucose the preoperative night prevented surgery-induced hyperglycemia. Insulin profile analyzed by deconvolution analysis was similar between fasted patients and those who received 75 g glucose. Serum insulin was suppressed at the beginning of the surgery and reached baseline values 4 h thereafter.Hyperglycemia occurred within 1 h from the beginning of surgery and sustained for at least 9 h while insulin levels are suppressed or unaltered compared to baseline values in euglycemia. The administration of 75 g glucose the preoperative night prevents surgery-induced hyperglycemia without altering the profile of insulin secretion.

Morbidly obese subjects may present with abnormal thyroid function tests but the reported data are scarce. Therefore, we studied the thyroid parameters in 144 morbidly obese patients, 110 females and 34 males, to assess the prevalence of hypothyroidism. Eleven percent (11.8%) carried the diagnosis of hypothyroidism and were undergoing levothyroxine (LT4) replacement therapy, 7.7% had newly diagnosed subclinical hypothyroidism, 0.7% had subclinical hyperthyroidism and 7.7% were euthyroid with positive antibodies (anti-thyroid peroxidase antibodies [TPOAb]). From the 144 subjects, we selected a cohort of 78 euthyroid subjects with negative TPOAb, who did not receive LT4 replacement or suppression therapy (the experimental group) and compared them to 77 normal-weight euthyroid subjects, TPOA-negative, matched for age and gender who served as controls. The experimental group had higher serum levels of triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), and thyrotropin (TSH) compared to the control group. Serum TSH concentration was associated with fasting serum insulin levels and insulin resistance but not with serum leptin levels, body mass index (BMI), fat mass, and lean body mass. In conclusion, in morbidly obese individuals, the prevalence of overt and subclinical hypothyroidism was high (19.5%). The morbidly obese subjects have higher levels of T3, FT3, T4, and TSH, probably the result of the reset of their central thyrostat at higher level.

We investigated erythropoietin (Epo) response in a cohort of diabetic patients with various types of anemia to approach the pathogenesis of some cases of "unexplained" anemia encountered among diabetics. Serum Epo levels were determined totally in 747 evaluable subjects with normal renal and hepatic function, of whom 694 had anemia. Among anemic patients, 237 were diabetics, while among the 53 nonanemic persons, there were also 21 diabetics. Diabetic and nondiabetic subjects were uniformly balanced in relation to their demographic features and were categorized according to the etiology of their anemia. Hemoglobin (Hb) did not differ between diabetic and nondiabetic subjects in all the etiological groups and in the whole population. Diabetic patients had significantly lower serum Epo levels as compared to nondiabetics (36.5+/-61 vs 69.4+/-191 IU/ml, p0.0001), and this was true for all etiologic groups of anemia with the exception of patients with myeloproliferative disorders and those with megaloblastic anemia. The natural logarithmic (ln)-EpoxHb component was used as an index of response to anemia and was found to be significantly decreased in almost all subgroups of diabetic patients. Serum Epo levels were also negatively correlated with the percentage of glycosylated Hb, HbA1(C) (r=-0.446), and the correlation was stronger with the ln of serum Epo (r=-0.638, p0.001). Inappropriately low serum Epo level is a uniform feature in patients with type II diabetes mellitus and may represent a constitutive blunted response to anemia or an altered metabolic rate of Epo, probably as a result of abnormal glycosylation of the cytokine.

Farnesoid X receptor (FXR) is a nuclear receptor involved in lipoprotein as well as glucose metabolism. Statins are widely used hypolipidemic agents with many pleiotropic actions. It is known that statins affect other nuclear hormone receptors, but no reports are available on the effect of these drugs on FXR. Employing an animal model (Syrian hamsters), we hereby present evidence to demonstrate that Simvastatin, a broadly prescribed statin, decreases the expression of FXR at both the RNA and protein levels and down-regulates its DNA-binding activity. This novel property may have important implications on the mode statins influence on lipoprotein and carbohydrate homeostasis in the organism.

Background Coronary calcium detected noninvasively is an attractive way to diagnose atherosclerosis before the development of symptoms. This study examines the prognostic value of coronary calcium in asymptomatic subjects with usual cardiovascular risk. Methods and Results In 425 asymptomatic subjects, 229 men (aged 45.1 ± 14 years) and 196 women (aged 42.7 ± 13 years), coronary calcium presence was studied by digital cinefluoroscopy. The majority (76%) had no or at most one risk factor. Subjects were followed up for 58.4 ± 12.7 months for cardiac events. Coronary calcium was present in 76 of 425 (17.9%) subjects. Cardiac events were observed in 21 subjects: 2 cardiac deaths, 7 acute myocardial infarctions, 3 coronary artery bypass grafts, 3 coronary angioplasty procedures, 3 events of unstable angina, and 10 events of stable angina pectoris. Survival curve analysis showed significant differences in all the studied end points between subjects with and those without calcium. Coronary calcium was an independent predictor of all events (3.6-fold increase, P < .008), cardiac death/myocardial infarction/revascularization (13.9-fold increase, P < .02), and stable angina (7.4-fold increase, P < .007). However, calcium did not independently predict cardiac death/myocardial infarction or acute coronary syndromes. Conclusions Coronary calcium in asymptomatic subjects with usual cardiovascular risk adds significant incremental information to risk factors information for the development of symptomatic coronary artery disease. (Am Heart J 2003;145:542-8.)

The aim of the present study was to examine the effects of chronic iodide administration in pharmacological doses on thyroid function in children with a history of transient congenital hypothyroidism (TCH). We hypothesized that such children may carry a previously undisclosed intrinsic intrathyroidal defect, rendering them susceptible to TCH. We administered for this 60-65 mg iodide daily for 60 d in 13 individuals with TCH (group A), 8 of their siblings (group B), 8 healthy controls (group C), and 11 normal adults (group D). Thyroid function was evaluated by measuring serum T(3), T(4), free T(3), free T(4), TSH, and thyroglobulin concentrations and autoantibodies against thyroid peroxidase and thyroglobulin at baseline at 15, 30, and 60 d during iodide administration, and 2 months after iodide withdrawal. Hyperthyrotropinemia greater than 4.2 mU/liter but not higher than 10 mU/liter with normal thyroid hormone concentrations was observed in one of the TCH group and in two of the group B siblings. During iodide administration, hyperthyrotropinemia was observed in 8 of 13 (62%) adolescents in group A, 4 of 7 (57%) in group B, and 6 of 8 (75%) in group C. None of the 11 adults (group D) developed hyperthyrotropinemia during iodide administration. Serum T(4) and free T(4) concentrations were decreased in all groups when compared with baseline values. The magnitude of the decrease of serum T(4) was identical in all groups (0.7-0.8 microg/dl). Thyroid enlargement was observed in all subjects and was more pronounced in children. There were no cases of subclinical and/or overt hyperthyroidism. After iodine withdrawal, serum TSH decreased in all groups and returned to baseline levels, as well as the thyroid volume. In conclusion, the hypothalamic-pituitary-thyroid axis of adolescents with TCH responds to pharmacological doses of iodide similarly to that observed in normal children. The hyperthyrotropinemia observed in the adolescents exposed to iodides may reflect incipient transient hypothyroidism or simply a brisk TSH response to a small serum T(4) decrease. Whatever the mechanism, chronic use of excessive quantities of iodide should be avoided until the end of puberty.

This study assessed the information needs of Greek cancer patients and examined whether awareness of diagnosis had any impact on patients. One hundred patients were interviewed about overall and specific information needs, satisfaction, emotional distress, and quality of life. Patients exhibited a great desire for information overall. The need to have more information was high especially regarding the aftermath of chemotherapy, prognosis, how chemotherapy worked, and diagnosis. Patients were more satisfied with care but less satisfied with the information received. Only 37% knew they had cancer, especially the younger, the better educated, and those with breast cancer. Awareness was not related to satisfaction, emotional distress, or quality of life. Our findings suggest that Greek cancer patients need more factual information about their condition and management. Greek oncologists may feel freer to inform their patients about the diagnosis and other issues following their judgement, rather than employing the policy of concealing the truth.

The two traditional methods for the assessment of iodine deficiency in a given area are the estimation of urinary excretion of iodine, and the prevalence of goiter. In field studies, the estimation of urinary iodine excretion (UIE) in random urine specimens provides an adequate assessment of a population's iodine nutrition. The recommended method is the classic one, based on Sandell-Kolthoff reaction (Method A). Recently, a new semi-quantitative method has been introduced (rapid urinary iodide test [RUIT]). We performed a field study in a developing country (Azerbaijan) in order to compare the classic Method A to RUIT. The study included 942 schoolchildren, to whom UIE was estimated by RUIT. Comparing the two methods, (n = 260), the sensitivity of RUIT using as gold standard Method A, was 96% and the specificity was 61%. The correlation between median values UIE estimated by RUIT and by Method A was excellent (r = 0.98, p < 0.001). An agreement in iodine deficiency classification according to the World Health Organization-United Nations Children's Fund-International Council for the Control of Iodine-Deficiency Disorders (WHO-UNICEF-ICCIDD) between the two methods was observed in eight of nine areas. In conclusion, RUIT is a suitable method for UIE estimation in field studies of suspected iodine deficiency. The test is relatively inexpensive, easy to perform, and does not require sophisticated instruments.

To evaluate right ventricular function in patients with beta-thalassaemia major and congestive heart failure. Background In patients with beta-thalassaemia major a high incidence of cardiac involvement still exists despite improved prognosis with chelation therapy. Development of severe right heart failure is common and has been attributed to pulmonary hypertension secondary to lung haemochromatosis. However, the possibility of direct right ventricular myocardial involvement in the absence of significant pulmonary hypertension has not been adequately investigated.Twenty-nine consecutively screened patients with beta-thalassaemia major and congestive heart failure were investigated by Doppler echocardiography, right ventricular first-pass radionuclide examination and cardiac catheterization. Haemodynamic data were obtained both before and after volume loading. A control group of 39 patients with beta-thalassaemia major, free from cardiac disease, and matched for age, gender, body surface area and heart rate was used for comparison. A subset of the control thalassaemic group (n=15) underwent both radionuclide and haemodynamic assessment.The majority of patients were on non-optimal chelation therapy. Only two of 29 patients were found to have cor pulmonale. One other patient suffered from constrictive pericarditis. A restrictive filling pattern in both ventricles and left ventricular systolic dysfunction were evident in the other 26 patients. Pulmonary artery pressure (systolic, 33+/-8 vs 27+/-5 mmHg, P0.05) and pulmonary vascular resistance (114+/-56 vs 65+/-29 dynes. s. cm(-5), P0.01) were only mildly elevated in the heart failure group. After volume challenge, cardiac output remained unchanged although the increments of ventricular filling pressures were significant (Deltaright atrial: 4.8+/-2.2 mmHg, P0.05; Deltapulmonary capillary wedge: 5.6+/-2.9 mmHg, P0.05) and correlated with each other (r=0.69;P0.001) in heart failure patients, suggesting pericardial constraint and ventricular interaction. In these patients compared with the control thalassaemic group, a lower right ventricular ejection fraction (29%+/-9 vs 59%+/-6, P0.0001) without correlation with pulmonary artery pressures was found. Haemodynamically significant right ventricular dysfunction defined as mean right atrial pressure10 mmHg and ratio of mean right atrial-to-capillary wedge pressure0.8 was evident in 15 of the 26 patients (58%), all with severe symptoms, representing three fourths of the patients in functional class III and IV. Simultaneous pressure recordings in six of these 15 patients showed equalization of ventricular end-diastolic pressures within 5 mmHg.The majority of patients with beta-thalassaemia major and severe congestive heart failure demonstrated a unique haemodynamic pattern similar to that described in predominant right ventricular infarction, indicating severe right ventricular cardiomyopathy in addition to left ventricular dysfunction. The incidence of cor pulmonale as a cause of right heart failure seems to be much lower than previously hypothesized.

The goal of this study was to assess the prevalence of iodine deficiency (ID) in Azerbaijan after the discontinuation of an iodine prophylaxis program by assessing the prevalence of goiter, iodine intake, and thyroid function. The study included 942 schoolchildren (475 boys and 467 girls) ages 8-14 years, from 13 distinct regions. The survey included the following: (1) clinical evaluation; (2) assessment of thyroid volume both by ultrasound and by palpation; (3) determination of iodide in a morning urine specimen using the classic Sandel-Kolthoff reaction in 347 schoolchildren; (4) determinations of thyrotropin (TSH), triiodothyronine (T3), thyroxine (T4), thyroglobulin (Tg), and anti-thyroid peroxidase (TPO) in serum (n = 165) and TSH in whole blood spotted on filter paper (n = 942). The prevalence of goiter for the whole country was determined by ultrasound (US) to be 86% and by palpation 66%, reaching 100% in the mountainous regions of Caucasus. The median urinary iodine excretion (UIE) was 54 microg/L, reaching level of 26 and 39 microg/L in the Caucasus region. In conclusion, according to the World Health Organization (WHO) classification, Azerbaijan now has mild to moderate ID (median UIE, 54 microg/L) and in the mountainous regions with severe ID. The high prevalence of goiter and the low UIE emphasizes the need for urgent medical reintervention. An iodination program is now implemented by our team in the mountainous regions under the auspice of the government of Azerbaijan.

The etiology of the prompt decline in serum T3 in patients with nonthyroidal illness syndrome has not been adequately explained. It has been attributed to various parameters, including test artifacts, inhibitors of T4 and T3 binding to proteins, decreased 5′-deiodinase activity, and circulating cytokines. Currently, much attention is centered on the role of IL-6 and TNFα in developing the nonthyroidal illness syndrome through an effect on the hypothalamus, pituitary, and possibly 5′-deiodinase activity. We therefore studied the relation of the endogenous serum IL-6 and TNFα rise early in the course of nonthyroidal illness syndrome to the early decline in serum T3 in 19 apparently healthy individuals, aged 43 ± 16 yr, who underwent elective abdominal surgery for cholelithiasis or gastroplasty. Serum T3, free T3, T4, free T4, rT3, TSH, IL-6, and TNFα were measured before and at various time intervals up to 42 h after skin incision. We observed a prompt decline in serum T3 30 min before skin incision, which continued to decline throughout the observational period. The magnitude of the decline reached 20% from the baseline value at 2 h. The early decline of T3 was attenuated and lasted from the 2–8 h, probably due to the sharp increase in serum TSH that started immediately after the entrance to the operating room and lasted for 2 h. In contrast, serum T4 and free T4 concentrations were increased soon after skin incision and remained elevated during the first postoperative day. Serum rT3 increased approximately 6 h after the initiation of surgery and remained elevated thereafter. Serum IL-6 remained essentially undetectable for 2 h after skin incision, whereas serum T3 was low. Two hours after skin incision, serum IL-6 increased sharply and remained elevated throughout the observational period. Serum TNFα remained essentially undetectable throughout the postoperative period. Serum cortisol increased rapidly upon entrance to the operating room and remained elevated throughout the postoperative period. We conclude that the decline in serum T3 early in the course of nonthyroidal illness syndrome is not due to increased serum IL-6 or TNFα levels. The brisk TSH secretion soon after the onset of the syndrome attenuates the decline in serum T3 due to T3 secretion from the thyroid. The early and brisk cortisol response to surgery may at least in part explain the early decrease in serum T3 in nonthyroidal illness syndrome.

An early diagnosis of sepsis in patients with diabetic ketoacidosis and hyperosmolar non-ketotic coma is crucial and could save lives. We studied serum C-reactive protein and interleukin-6 to find out how useful these might be for identifying sepsis.Sixty one diabetic patients with ketoacidosis or hyperosmolar non-ketotic coma were enrolled. Patients with signs and symptoms of systemic inflammatory response syndrome were identified. Acute-phase reactants, including C-reactive protein and interleukin-6, the main cytokine responsible for the induction of acute-phase proteins, were measured on admission and when patients had clinically improved and were euglycaemic.A total of 49 out of 61 patients with diabetic ketoacidosis or hyperosmosis had signs of systemic inflammatory response syndrome. Another 27 patients had systemic inflammatory response syndrome and no signs of infection and 22 patients had systemic inflammatory response syndrome due to proven infection. We detected a significant increase in serum C-reactive protein and interleukin-6 values in patients infected compared with patients not infected with systemic inflammatory response syndrome SIRS. Patients who finally died had much higher levels of these proteins, while there was a prompt reduction of serum C-reactive protein and interleukin-6 early during remission.Diabetic ketoacidosis and hyperosmolar non-ketotic coma can often cause a clinical syndrome resembling systemic inflammatory response syndrome. Determination of serum C-reactive protein and interleukin-6 levels is a useful way of excluding an underlying infection early on as well as confirming and monitoring sepsis.

Background Cardiac hemochromatosis remains the most frequent cause of death in β-thalassemia major. Previous studies suggest an important right ventricular (RV) contribution to cardiac morbidity and mortality. Studies with Doppler echocardiography have shown contradictory results regarding left ventricular (LV) filling, whereas the RV filling characteristics have not been studied yet. We prospectively studied the pattern of RV filling and investigated echocardiographic and clinical correlates during baseline and follow-up examinations in patients with β-thalassemia major. Methods and Results The study included 79 patients, aged 24.2 ± 8.0 years, with homozygous β-thalassemia major without symptoms of heart failure with normal LV function and 51 healthy control subjects, matched for age, sex, and body surface area. Doppler echocardiographic indexes of systolic and diastolic ventricular function were assessed. Hemodynamic measurements were obtained in 8 patients by right heart catheterization. An abnormal RV relaxation pattern was evident in the patient group. The LV filling characteristics indicated increased preload without abnormal alteration, whereas catheterization findings were consistent with a high cardiac output state. Short tricuspid deceleration time (DT) had the best predictive value for subsequent cardiac events. Repeat echocardiographic study in 35 asymptomatic patients at 19 ± 7 months demonstrated deterioration of LV systolic function, chamber enlargement, and shortening of DT of tricuspid and mitral inflow. Conclusions In patients with homozygous β-thalassemia major without cardiac disease, the pattern of RV filling is abnormally altered, indicating impaired relaxation. In contrast, the LV filling is compatible with increased preload, as in chronic anemia. Short DT of early tricuspid inflow carries important prognostic value. LV remodeling occurs over time along with transition toward a restrictive ventricular filling pattern. (Am Heart J 2001;141:428-34.)

OBJECTIVE: Patients with beta-thalassemia frequently develop primary hypothyroidism and other endocrine disorders due to iron overload. We studied whether administration of excess iodide to patients with apparently normal thyroid function could uncover an underlying thyroid disease. DESIGN AND METHODS: Twenty-five patients, 10 prepubertal (mean age 11+/-3 years) and 15 adults (mean age 23+/-5 years) with normal thyroid hormone and TSH levels, a normal response of TSH to TRH and negative thyroid peroxidase antibodies received 20mg iodide three times daily for three weeks, and thyroid hormone and TSH levels were measured weekly during, and for three weeks after, iodide administration and every 3 months thereafter for the next 5 years. RESULTS: During iodide administration there was a significant decrease in thyroid hormone concentrations which remained within normal levels, and a significant increase in TSH concentrations which in 14 out of 25 (56%) patients reached the hypothyroid level. Baseline TSH values were higher in those patients who developed subclinical hypothyroidism (2.31+/-0.71mU/l vs 1. 34+/-0.64mU/l, P=0.0016). Subclinical hypothyroidism developed in 70% of prepubertal and in 47% of adult patients. Serum ferritin was elevated in all patients. Nine of the fourteen patients (64.3%) who developed subclinical hypothyroidism during iodide administration developed hypothyroidism during the 5-year follow-up compared with only one of the eleven patients with a normal response to iodide (P=0.004). CONCLUSIONS: Patients with beta-thalassemia should not be exposed to excess iodide due to increased sensitivity to its inhibitory effects on thyroid function. The susceptible individuals frequently develop permanent hypothyroidism in the following years.

The presence of medial arterial calcification (MAC), often referred to as Moncheberg's sclerosis, was sought in patients with long-standing diabetes mellitus. One hundred patients aged 22-50 years were initially divided into two groups, those with neuropathy and those without. As expected, the incidence of MAC was significantly higher in the neuropathy group (40% vs 20%) . When the patients were divided into two groups, those with MAC and those without, it appeared that the incidence of MAC was very high in patients who had microalbuminuria (57% vs 13%) and particularly when microalbuminuria was combined with neuropathy (40% vs 7%). It is concluded that microalbuminuria is a strong predicting factor of medial arterial sclerosis independent of neuropathy.

The aim of our study was to determine the prevalence of thyroid dysfunction and autoimmune abnormalities in rheumatoid arthritis (RA) and to further investigate the possible association between D-penicillamine and autoimmune thyroiditis. For this purpose, one hundred and one unselected consecutive patients with RA and 70 age and sex matched controls were studied prospectively. Evaluation included a complete history and physical examination with special attention to symptoms suggestive of thyroid pathology, routine laboratory and serologic immune profile, plus determination of serum levels of thyroxine (T4), triiodothyronine (T3), thyroid stimulating hormone (TSH), antibodies to thyroid peroxidase (AbTPO) and TSH receptor antibodies (TRAB). Serum thyroxine binding globulin (TBG) was measured in all subjects with high thyroid hormone levels, whereas free T3 and T4 concentrations were determined in all individuals with abnormal T3, T4, TSH or TBG. Six patients with hyperhyroidism, 3 with hypothyroidism and 1 with the euthyroid hyperthyroxinemia (EH) syndrome were found, whereas four of the controls had hyperthyroidism. Thirteen patients and 6 controls had high AbTPO levels whereas no one had high TRAB. No association was detected between thyroid abnormalities and any serologic RA finding. Furthermore, no correlation between thyroid dysfunction and elevated AbTPO's was found. A relatively high prevalence of thyroid dysfunction (9,9%) and subclinical autoimmune thyroiditis (12,9%), the latter indicated by elevated AbTPO's, was found in our RA patients. These figures were higher than those in the control group (5,7% and 8,6% respectively), but the difference did not reach statistical significance. Of further interest may be our finding that, despite anecdotal reports blaming D-penicillamine for cases of autoimmune thyroiditis, the incidence of the latter was similar among recipients and nonrecipients of the drug. Similarly, TRAB were not detected in any patient treated with D-penicillamine.

Brief hyperventilation is occasionally accompanied by repolarization abnormalities in subjects without apparent heart disease. However, the effect of prolonged hyperventilation on repolarization abnormalities is not clearly defined. We analysed the repolarization abnormalities induced by prolonged hyperventilation, correlated with hyperventilation induced haemodynamic changes and exercise test results and assessed the effect on them of age, gender, smoking and hypertension. Prolonged hyperventilation (overbreathing at least 30 respirations/min for 5 min and 10 min recovery) was performed in 474 healthy volunteers (269 men, 205 women) 42.6 +/- 13.5 years old. The electrocardiogram was analysed for transient ST depression or T-wave inversion. Repolarization abnormalities were observed in 72 subjects, 47 men (17.5%) and 25 women (12.2%). Age, gender, smoking and hypertension did not influence the overall incidence of repolarization abnormalities. ST depression was more frequently observed in women (4.4 vs 0.7%, P < 0.01), while T wave inversion from negative to positive was more frequent in men (8.9 vs 2.4%, P < 0.006). All subjects with ST depression were non-smokers (4.1% of the non-smokers, P < 0.003 compared to smokers). Repolarization abnormalities occurred usually (80.5%), but not exclusively, within the first hyperventilation minute. Subjects with repolarization abnormalities developed higher heart rate change with hyperventilation than those without repolarization abnormalities (29.2 +/- 13.1 vs 24.2 +/- 12.7, P < 0.002). A positive exercise test was observed in 45.4% of subjects with hyperventilation induced ST depression but only in 13.1% of subjects with T-wave changes, P < 0.02. Repolarization abnormalities are not uncommon during prolonged hyperventilation. Hear rate change affects the occurrence of repolarization abnormalities, while gender and smoking influence the type of repolarization abnormalities. ST depression but not T-wave inversion during hyperventilation is associated with a positive exercise test. Increased understanding about hyperventilation-induced repolarization abnormalities could affect use of the method in the clinic, either as a provocation test or as a complement to the interpretation of the exercise test.

Hyperventilation is well known to affect the electrocardiogram (ECG) in subjects without heart disease and produce spasm in patients with variant angina. The autonomic nervous system is thought to play a significant role in these effects. However, the normal hemodynamic response to hyperventilation is not well defined. We subjected 369 healthy volunteers (200 men, 169 women) to prolonged hyperventilation (30 respirations for 5 min and 10 min recovery) under continuous ECG monitoring and to exercise testing. Heart rate (HR), systolic and diastolic blood pressures (SBP, DBP) and rate-pressure product were recorded. Hyperventilation resulted in an immediate (within the first min), significant increase in HR by 27.4%, a further small increase at min 2 of hyperventilation, and a subsequent small decrease in HR at mins 3-5. An immediate drop of HR by 20.1% was observed with discontinuation of hyperventilation. Apart from a slightly higher HR increase in men, a similar pattern of HR changes was found in both genders. On multivariate analysis, younger age, absence of smoking, and male gender were associated with a higher HR increase with hyperventilation (p < 0.0001, p < 0.0001, and p < 0.001, respectively). SBP and DBP increased with hyperventilation, with their highest value at min 5 of hyperventilation and a subsequent drop to baseline levels. Age and gender did not affect the degree and pattern of BP changes. Absence of smoking and the presence of hypertension were associated with a higher SBP with hyperventilation (p < 0.003 and p < 0.007). The rate-pressure product increased by 43.6% with hyperventilation, a change that was only 19.1% of the respective rate-pressure product observed with exercise. Hyperventilation results in significant HR and BP increases, changes that are influenced by age, gender, smoking, and hypertension. Our study could serve as a standard for comparison of the hyperventilation effects in different disease states.

The absorption of levothyroxine (LT4) is affected by many factors. Bariatric surgery is recommended in severely obese patients. The aim of this study was to determine the consequences of bariatric surgery on LT4 pharmacokinetic parameters, and to identify the regions of the gastrointestinal tract where LT4 is absorbed in patients with severe obesity before and after surgery.We studied 32 severely obese nonhypothyroid patients who underwent sleeve gastrectomy (SG; n=10), Roux-en-Y gastric bypass (RYGBP; n=7), or biliopancreatic diversion with long limbs (BPD-LL; n=15). Before surgery, from 8:00 a.m., blood samples were collected before and every 30 minutes after the oral administration of a solution of 600 μg of LT4. The same procedure was repeated 35 days after surgery. We estimated the pharmacokinetic parameters of LT4 before and after surgery, including the area under the curve (AUC), the peak thyroxine concentration (Cmax), and the time to peak thyroxine concentration (Tmax).Following surgery, in the SG group, the mean AUC was higher than it was before surgery (18.97±6.01 vs. 25.048±6.47 [μg/dL]·h; p0.01), whereas the values of Cmax and Tmax were similar to those before surgery. In the RYGBP group, mean AUC, Cmax, and Tmax were similar before and after surgery. In the BPD-LL group, mean AUC and Cmax were higher after surgery than before (14.18±5.64 vs. 25.51±9.1 [μg/dL]·h, p0.001; 5.62±1.34 vs. 8.16±2.57 μg/dL, p0.001, respectively), whereas Tmax was similar.The pharmacokinetic parameters of LT4 absorption are improved following SG and BPD-LL types of bariatric procedures. We conclude that the stomach, the duodenum, and the upper part of the jejunum are not sites for LT4 absorption, because in the above-mentioned bariatric procedures these are bypassed or removed.

BACKGROUND: Stimulated hyperinsulinaemia is observed in some patients with syndrome X, defined as angina, positive stress test and normal coronary arteriography, and may be involved in the pathogenesis of the syndrome. An increased sympathetic response to exercise may also be pathogenetically involved. However, the diagnostic value of hyperinsulinaemia as a marker of this syndrome has not been defined. METHODS: We determined blood glucose and immunoreactive insulin during fasting, at 60 and 120 min after a glucose load of 75g in 21 patients (eight men, 13 women, 53.9 +/- 7.1 years old) with syndrome X and in 21 healthy volunteers matched to the patients for age, sex and body mass index (eight men, 13 women, 51.6 +/- 9.3 years old). Insulin values were related to the rate-pressure product increase at first exercise stage. RESULTS: The glucose values as well as the insulin values during fasting were similar in syndrome X patients and in controls. However, significantly higher insulin values (mU/l) were observed at 60 (P < 0.01) and 120 min (P < 0.005) in syndrome X patients (median 75.5 and 52, range 43-290 and 6.1-212, respectively) than in controls (median 47.5 and 24.5, range 8-195.6 and 5.2-164, respectively). A considerable overlap of insulin values, however, was observed between the two groups, with abnormal values even during fasting. For a specificity of 95%, an abnormal insulin value had a sensitivity of between 19 and 24% and a diagnostic accuracy of 57-60%. A significant positive correlation was found between insulin levels after the glucose load and the rate-pressure product increment with exercise (60 min, r = 0.60; 120 min, r = 0.65). CONCLUSION: Hyperinsulinaemia may be pathogenetically involved in syndrome X patients, in close relation to the higher sympathetic drive that characterizes this syndrome. However, the wide range of insulin values, frequently overlapping with normal values, limits the usefulness of this abnormality as a marker of the syndrome.

Bone mass (BM) and skeletal size are similar in prepubertal girls and boys and double between the onset of puberty and early adult life. Sex steroids are responsible for the maturation in human skeleton, as well as for the sexual dimorphism, observed after the onset of puberty. Physical activity in childhood is critical for maximizing bone growth and thus for preventing osteoporosis during older age. Therefore, it constitutes the most effective prevention strategy available. In athletes, high-impact loading activities have been shown to improve BM, whereas in sports requiring a lean somatotype (therefore leading to a negative energy balance), the delay in skeletal maturation and pubertal development predisposes athletes to osteopenia and osteoporosis. Although the early onset of training, the continuous intensive exercise and its long duration attenuate bone acquisition, the excess mechanical load to which these athletes are exposed from a young age exerts beneficial effects on bone formation that lead to a positive net-effect on BM.

Genetic potential for growth can be fully expressed only under favorable environmental conditions. Although moderate physical activity has beneficial effects on growth, excessive physical training may negatively affect it. Sports favoring restricted energy availability, in the presence of high energy expenditure, are of particular concern. In gymnastics, a different pattern in skeletal maturation and linear growth was observed, resulting in an attenuation of growth potential in artistic gymnasts (AG), more pronounced in males than in females. In female rhythmic gymnasts (RG), the genetic predisposition to growth was preserved owing to a late catchup growth phenomenon. In all other sports not requiring strict dietary restrictions, no deterioration of growth has been documented so far. Intensive physical training and negative energy balance alter the hypothalamic pituitary set point at puberty, prolong the prepubertal stage, and delay pubertal development and menarche in a variety of sports. In elite RG and AG, prepubertal stage is prolonged and pubertal development is entirely shifted to a later age, following the bone maturation rather than the chronological age.

During illness, thyroid parameters undergo acute changes, which are known as non-thyroidal illness syndrome, the cause of which has not been elucidated. In vitro and in vivo data demonstrate that leptin regulates the expression of thyrotropin-releasing hormone (TRH)-mRNA in the paraventricular nucleus as well as the secretion of thyrotropin (TSH) in response to fasting in humans and animals. Moreover, in healthy adults, TSH and leptin have almost identical circadian rhythms. Our aim was to investigate the secretion of leptin and TSH, and their probable interaction, during the acute stress that is induced by surgery.We studied 18 severely obese but otherwise healthy men. All participants were admitted to the hospital in the morning after an overnight fast. On the following day, 14 of the participants underwent bariatric surgery at 0900. The remaining four participants did not undergo surgery and served as controls. Serum samples to measure the levels of TSH and leptin were collected from all participants, as follows: upon admission to the hospital (baseline values) and on the following day at 0900 and every 10 min, thereafter for 9 h.The serum TSH increased during the first hour after skin incision (si) and then decreased gradually throughout the rest of the observation period. In contrast, during the first hour after si, the leptin levels remained unaltered. The leptin levels then decreased and reached a nadir at 4 h and 10 min post si after which they remained constant for approximately 1 h. Thereafter, while TSH continued to decrease, leptin started to increase and reached baseline values at 9 h post si. In control subjects, the TSH and leptin profiles seemed parallel each other.During acute surgical stress, the secretion of TSH and leptin in severely obese men is asynchronous and causality could not be proven.

Iodine deficiency (ID) is still a major universal health problem. Iodine deficiency disorders (IDDs) affect people of all ages, among whom the most vulnerable are children and adolescents. The aim of the present study was to assess the long-term effects on growth and pubertal development of correcting severe ID in areas of Azerbaijan between 1999 and 2000.Iodized oil was administered orally to 293,000 children, aged 6-16 years. Among those, 364 children were randomly selected and were examined 1 year before the administration of iodized oil (Group I-neg, iodine negative) and 295 children (Group I-Rx, iodine treated) were examined 4 years (Group I-R x 4, iodine treated 4 years later; n = 173) or 5 years (Group I-R x 5, iodine treated 5 years later; n = 122) after the last dose of iodide.In Group I-neg the median urine iodine concentration (UIC) (mcg/L) was 36 (mean: 36.272 +/- 11.036) and increased significantly (p0.001) in Group I-R x 4: 188 (mean: 230.969 +/- 155.818) and in Group I-R x 5: 175 (mean: 201.176 +/- 130.369). The prevalence of goiter was 99% in Group I-neg and 2% in Group I-R x 4. Children in Group I-Rx had a greater standard deviation score (SDS) for height (-0.1364 +/- 1.279, n = 294) than children in Group I-neg (-0.5019 +/- 1.17, n = 363) (p0.001, t = -3.817), which was more significant for boys. SDS for weight was similar in both groups (Group I-neg: -0.17 +/- 0.78, n = 363; Group I-Rx: -0.115 +/- 0.917, n = 294). The rate of puberty development as judged by the development of breast and pubic hair was normalized in both sexes after the correction of ID.Our results demonstrate that long-term correction of severe ID leads to sustained improvement of linear growth accompanied by a normalization of the time of onset of pubertal development for both sexes.

Different attempts were made to identify the variables that may be involved in the clinical course of cerebrovascular ischemia. In the case of stroke with mild severity (SMS), the clinical significance of neuroendocrine changes as well as of post-stroke depression (PSD) remains unknown. We therefore evaluated the presence of neuroendocrine changes in the acute and post-acute phase of SMS, and their potential role during convalescence. Serum cortisol, T4, T3, FT4, FT3, TSH and PRL levels were measured in 17 euthyroid patients with stroke on admission (day 1), following morning (day 2), 7 days and 3 months later. TSH and PRL secretion after TRH test were measured. Stroke severity on admission was determined by Scandinavian Stroke Scale (SSS). Montgomery-Asberg Depression Rating Scale (Madrs) was used for assessment of post-stroke depression. On admission, TSH and T3, were within normal limits and were greater compared to values on day 2. Lower basal TSH and decreased TSH response to TRH on day 2, were associated with stroke of greater severity. Delta-PRL after TRH on day 2 was higher in patients who develop PSD. Changes in serum thyroid hormones in SMS, reflects those of non-thyroidal illness. A mild stimulation of hypothalamic-pituitary-adrenal axis was detected. We provide evidence that PRL response to TRH, in the acute phase of stroke may be used as an index for early detection of PSD.

Capecitabine is a tumor-activated oral fluoropyrimidine with established antitumor activity in breast and colorectal cancer. Hypertriglyceridemia associated with this drug has rarely been reported in the literature.This is a report of two patients who developed capecitabine-induced severe hypertriglyceridemia, together with an increase in total cholesterol levels. The first patient developed hyperlipidemia during long-term capecitabine treatment in combination with trastuzumab for metastatic breast carcinoma (triglycerides: from 219 mgldl to 1409 mg/dl, 543% increase; cholesterol: from 239 mg/dl to 363 mg/dl, 52% increase). The second patient developed abnormalities in the lipid profile after the second cycle of chemotherapy with capecitabine and oxaliplatin for metastatic colorectal cancer (triglycerides: from 101 mg/dl to 1510 mg/dl, 1395% increase; cholesterol: from 203 mg/dl to 310 mgldl, 52% increase). An analysis of the possible underlying pathogeneic mechanisms is provided.Physicians should be aware of the possibility of dyslipidemia, particularly hypertriglyceridemia, following treatment with capecitabine.

Parathyroid scintigraphy and high-resolution ultrasonography are frequently used as preoperative localization procedures in primary hyperparathyroidism. However, when thyroid disease coexists, their diagnostic accuracy is probably abated. DESIGN: 56 patients with primary hyperparathyroidism were prospectively evaluated with parathyroid scintigraphy (with either thallium or technetium-99m agents or both) and 44 of them were also evaluated with ultrasonography. RESULTS: 33 patients (59%) had coexistent thyroid disease. Upon operation, 48 patients were found to have a solitary parathyroid adenoma and were all cured. One patient had a carcinoma and 7 had multiglandular parathyroid disease. Regarding solitary lesions, the sensitivity of parathyroid scintigraphy with Tc-agents was 97% and thallium 78%, while that of ultrasonography was 74%. The false positive rate was 2.6%, 18% and 22%, respectively. Concomitant thyroid disease had a non-significant effect on the results of parathyroid scintigraphy and ultrasonography. The efficiency of both modalities in diagnosing multiglandular disease was low (only 3/7 patients, 43%). CONCLUSIONS: Parathyroid scintigraphy, in conjunction with Sestamibi or Tetrofosmin, constitutes the most sensitive localizing technique as regards solitary lesions. Ultrasonography is also useful in confirming scintigraphic findings, offers more precise anatomic information, and is valuable in the evaluation of concomitant thyroid disease. The complementary use of parathyroid scintigraphy and ultrasonography is beneficial and efficacious in areas with high prevalence of thyroid disease. The value of these modalities is considerably lower in multiglandular disease.

Gonadal dysfunction in adult long-term survivors of hematopoietic stem cell transplantation (HSCT) is an adverse effect of conditioning regimens consisting of chemotherapy and total body irradiation (TBI). The impact of conditioning regimens consisting of chemotherapy alone on the function of the hypothalamic-pituitary-gonadal (HPG) axis was evaluated in a series of 41 female and 31 male patients who had undergone either autologous or allogeneic bone marrow/peripheral blood stem cell transplantation; mean age at transplantation was 32.6 years and mean time interval from transplantation was 1.5 years (range 0.2-9.8 years). Provocative testing of the HPG axis by administration of luteinizing hormone-releasing hormone was included in the first endocrinological evaluation. The follow-up period extended to three consecutive years. Gonadal dysfunction was not reported by any of the patients prior to their underlying illness. Hypergonadotrophic hypogonadism was observed in 97% of female and 19% of male patients. Leydig cell strain (normal testosterone, high luteinizing hormone levels) was evident in 32% and spermatogenesis damage (high follicle-stimulating hormone levels) in 68% of the male population. At the conclusion of the study four women (10%) had regained spontaneous menses and all hypogonadal men had resumed normal testosterone levels. Our results indicate a high incidence of gonadal dysfunction due to target organ failure in HSCT recipients not treated by TBI.

Steroids determination in saliva offers several advantages. The collection of saliva is a noninvasive, less stressful technique than blood withdrawal and reflects the circulating unbound fractions. The suitability of saliva for 17-hydroxyprogesterone and cortisol determinations has been documented in healthy subjects as well as in diseases like Congenital Adrenal Hyperplasia and Cushing syndrome. The aim of the study was to compare the influence of different collection methods on the results of 17-hydroxyprogesterone measurement in saliva collected by different ways, using commercially available RIAs developed for plasma. 17-hydroxyprogesterone was determined in 64 healthy adult volunteers (30 males, 34 females) in serum (Group SE) and in saliva collected before meals at 8-10 p.m. by directly spitting into a plastic tube (Group SP), using a cotton swab (Group SA) and using a polyester swab Salivette (Group SB). We used a commercially available direct radioimmunoassay without separation technique. The 17-hydroxyprogesterone mean values (ng/ml) were 1.16+/-1.3 (Group SE), 0.056+/-0.046 (Group SP), 0.089+/-0.048 (Group SA) and 0.058+/-0.049 (Group SB). The detection limit was 0.010 ng/ml. The correlations between the values in serum (Group SE) and in saliva were: r=0.77, p0.05 (Group SP); r=0.62, p0.05 (Group SA); r=0.70, p0.05 (Group SB). The saliva values corresponding to the serum cut-off point of 3 ng/ml upper limit of normal values were in ng/ml 0.13 (Group SP), 0.16 (Group SA) and 0.11 (Group SB). In conclusion, 17-hydroxyprogesterone determinations in saliva using commercially available RIAs primarily developed for serum, is a reliable and easy to perform procedure. The three different methods of saliva collection showed 17-hydroxyprogesterone concentrations to have good agreement.

We studied 262 athletes who were 13-23 yr old. There were 93 male and 169 female artistic gymnasts (AG). This study is unique in character, because all variables were measured on the field of competition (24th European Championship). Male AG had a higher height SD score than female (P < 0.001), with a higher reported target height SD score (P < 0.001), a higher predicted final height (P = 0.007), a lower Delta height - target height (P < 0.001), a less delayed bone age (P < 0.001), a greater body mass index (BMI) (P < 0.001), a lower mean body fat (P

Physical exercise enhances bone acquisition during adolescence. The aim of the study was to evaluate the influence of intensive physical exercise on bone acquisition in adolescent elite artistic gymnasts. The study included 262 athletes (93 males and 169 females, aged 13-23 yr) participating in the 24th European Championship held in Greece. Bone age compared with chronological age was delayed by 2 yr for females (n = 120) and 1 yr for males (n = 68). For both sexes, the growth chart of bone mineral density (BMD) followed a normal pattern when estimated according to bone age rather than chronological age. For females, BMD was positively correlated with bone age, chronological age, height, body weight, body mass index, body fat, lean body mass, and with age of onset of training, and negatively with duration of exercise and intensity of training (P values range from0.05 to0.0001). Multiple regression analysis revealed that age of onset of training was the major parameter attenuating the effect of exercise on BMD (P0.001). The latter was related to the stage of puberty (P0.05). For males, BMD was correlated positively with bone age, height, body weight, and lean body mass (P values range from0.01 to 0.0001). Multiple regression analysis revealed that the more powerful factor influencing BMD was weight (P0.01). In conclusion, bone acquisition in adolescents under intensive physical training follows the normal pattern only when estimated according to bone age. The age of onset, the duration, and the intensity of exercise attenuate the bone acquisition, at least in female artistic gymnasts.

BACKGROUND: Somatic activating mutations of the thyrotropin (thyroid-stimulating hormone (TSH)) receptor (TSHR) and G(alphas) protein have been detected in solitary toxic adenomas and toxic multinodular goiters, but their role in the pathogenesis of autonomous nodules is debated. The frequency of mutations is highly variable among populations and is inversely proportional to iodine intake. DESIGN AND PATIENTS: We screened 28 clinically and histologically heterogeneous autonomous nodules from 24 Greek patients for the presence of TSHR and G(alphas) mutations. RESULTS: By direct sequencing of genomic DNA, we detected 11 somatic heterozygous gain-of-function mutations in TSHR and one in G(alphas). Forty-three percent (12 of 28) of all nodules and 57% (four of seven) of solitary toxic adenomas harbored an activating mutation. Typical adenomas and hyperplastic nodules did not differ in mutation frequency. Substitutions I568T and T632I were detected in both histological types of nodules. CONCLUSIONS: Our findings indicate that activating somatic mutations in the TSH signaling pathway are frequent in autonomous nodules in Greece. This may be due to earlier exposure of the population to iodine deficiency, which was corrected in Greece only over the past two decades. Gain-of-function mutations are shared by nodules with varying histological and clinical presentations. Thus, they may represent a common molecular mechanism underlying the pathogenesis of non-autoimmune thyroid autonomy.

Aims and Background The objective of the study was to assess the efficacy of surgical resection of solitary brain metastasis in patients with non-small-cell lung cancer. Methods and Study Design We report a retrospective analysis of 32 patients with single brain metastasis surgically excised at our hospital. All but one patient underwent postoperative whole brain radiation therapy. Results The median survival of patients was 12.5 months postoperatively (mean, 17 months), and the overall 1-year survival was 53%. Thirteen patients had recurrence of brain metastasis: 6 of 13 underwent reoperation for the recurrent lesion, and 1 of the 6 patients had a third craniotomy. Baseline characteristics, which significantly influenced survival, included age less than 60 years, tumor histology (ie, adenocarcinoma), and treatment of the primary lung cancer. The analysis did not yield any significant differences between treatment modalities. Conclusions Our findings correspond well with those reported in the literature and suggest that surgical resection of single brain metastasis in patients with non-small cell lung cancer can improve survival over conservative management. Furthermore, surgical treatment of the primary tumor and the single brain metastasis, combined or not with radiotherapy and chemotherapy, represents an approach that merits further investigation with more patients and a prospective longitudinal design.

The sympathetic nervous system participates in the regulation of the basal metabolic rate (BMR) and in the manifestation of the obesity-related metabolic syndrome. A deletion/insertion germline polymorphism of the alpha(2B) adrenergic receptor that is associated with reduced agonist-promoted desensitization has been linked to low BMR in obese subjects and to a predisposition to gain weight. This study investigated an association of the alpha(2B) polymorphism with the BMR and metabolic syndrome-related parameters of morbidly obese patients. Genotype frequencies were similar in patients and in a control group. The patients' BMR, adjusted for fat-free mass, fat mass, sex and age, did not differ between alpha(2B) genotypes. The polymorphism was also not associated with the patients' BMI, systolic and diastolic blood pressure, resting heart rate, total and HDL cholesterol, triglycerides, fasting glucose and uric acid levels. These findings do not support a major functional significance of the alpha(2B) adrenergic receptor polymorphism in the present sample of morbidly obese subjects.

The purpose of this study was to assess whether the administration of recombinant human erythropoietin (rHuEPO) would correct anemia and improve the quality of life (QOL) in cancer patients receiving chemotherapy. One hundred twenty-two patients with hemoglobin/=11.0 g/dl were randomized to receive rHuEPO 10,000 U three times weekly (n = 61) or no additional treatment (n = 61). Response was assessed by measuring changes in hemoglobin level and QOL. QOL was evaluated before each cycle of chemotherapy at baseline, Week 4, and Week 12 using two separate self-report questionnaires. The analyses indicated that the rHuEPO-treated patients experienced significantly less fatigue (P0.05) than their control group counterparts, and reported significantly higher scores on energy level (P0.05), ability to perform daily activities (P0.01), and overall QOL (P0.05). The overall change in hemoglobin level was significantly greater in the rHuEPO group than in the control group (1.7 g/dl versus 0.3 g/dl, P0.001). rHuEPO effectively corrects anemia and significantly improves QOL in patients with solid tumors receiving chemotherapy.

Insulin resistance and loss of glucose-stimulated acute insulin response (AIR) are the two major and earliest defects in the course of type 2 diabetes. We investigated whether weight loss after bariatric surgery in patients with morbid obesity and type 2 diabetes could restore euglycemia and normal AIR to an intravenous glucose tolerance test (IVGTT). We studied 25 morbidly obese patients—12 with type 2 diabetes, 5 with impaired glucose tolerance, and 8 with normal glucose tolerance (NGT)—before and after a biliopancreatic diversion (BPD) with Roux-en-Y gastric bypass (RYGBP). Twelve individuals with normal BMI served as control subjects. Twelve months after surgery, in the diabetes group, BMI decreased from 53.2 ± 2.0 to 29.2 ± 1.7 kg/m2, fasting glucose decreased from 9.5 ± 0.83 to 4.5 ± 0.13 mmol/l, and fasting insulin decreased from 168.4 ± 25.9 to 37.7 ± 4.4 pmol/l (mean ± SE; P < 0.001). AIR, the mean of insulin concentration at 2, 3, and 5 min over basal in the IVGTT, increased by 770 and 935% at 3 and 12 months after surgery, respectively (from 24.0 ± 22.7 to 209 ± 43.4 and 248 ± 33.1 pmol/l, respectively; P < 0,001). Conversely, in the NGT group, the AIR decreased by 40.5% (from 660 ± 60 to 393 ± 93 pmol/l; P = 0.027) 12 months after surgery. BPD with RYGBP performed in morbidly obese patients with type 2 diabetes leads to significant weight loss, euglycemia, and normal insulin sensitivity; but most importantly, it restores a normal β-cell AIR to glucose and a normal relationship of AIR to insulin sensitivity. This is the first study to demonstrate that the lost glucose-induced AIR in patients with type 2 diabetes of mild or moderate severity is a reversible abnormality.

Splenic infarction in patients with sickle cell trait is usually related to hypoxic conditions, while non-hypoxia-related infarcts are extremely rare. We report on a case of a 17-year-old male patient, living at sea level, who developed a severe left upper quadrant abdominal pain during the course of a febrile episode. On physical examination he had a mildly palpable but extremely painful spleen. A spleen scan revealed 2 areas of impaired radionucleide distribution. Hepatic enzymes were moderately increased and the IgM anti-EBV antibodies positive. Hemoglobin electrophoresis revealed the presence of 42% of hemoglobin S. A probable diagnosis of splenic infarction was established in a patient with sickle cell trait, during the course of infectious mononucleosis. The patient was treated symptomatically. The conditions of splenic congestion induced by the EBV infection and the high-grade fever may have contributed to splenic sequestration and subsequent infarcts.

[corrected] The aim of the study was to evaluate prospectively the analgesic efficacy, toxicity and acceptability of the transdermal fentanyl therapeutic system (TTS-F) in Greek cancer patients with moderate-to-severe pain.Forty-eight patients participated in the study: 34 were men and 14 women, mean age was 63, and all but 2 had advanced stage (IV) cancer. Patients received TTS-F for a period of 8 weeks. Doses ranged from 25 to 225 micrograms/h. Thirty-three patients completed the study.Data indicated statistically significant lower pain scores on both NRS and EORTC QLQ-C30 at all follow-ups compared to baseline. In addition, the vast majority of the patients found the transdermal system easy to use and reported as being satisfied or highly satisfied with it. The only observed side-effect was vomiting.In summary, transdermal fentanyl appeared an acceptable, safe and effective method of managing chronic pain induced by malignancies.

The aim of this prospective study was to evaluate the significance of sonographically detected thyroid calcifications in the diagnosis of thyroid cancer.One hundred eighty-eight patients with thyroid disease, including 37 with thyroid cancer, were included in the study. Each patient underwent preoperative, high-resolution sonography to evaluate the thyroid gland for the presence of calcifications.The highest incidence of calcification was found in thyroid cancer (54%), followed by multinodular goiter (40%), solitary nodular goiter (14%), and follicular adenomas (12%). The incidence of cancer was significantly higher in calcified nodules (29%) than in noncalcified nodules in the entire group (14%) (p = 0.019), with a relative risk of 2.5. In the group of solitary thyroid nodules, the incidence of cancer in the calcified nodules (55%) was higher than in the nodules without calcification (23%) (p = 0.016). Multiple noncalcified thyroid nodules harbored cancer in only 5% of cases. Compared with multiple noncalcified thyroid nodules, the solitary calcified nodules demonstrated a relative risk of 22.8. In both the solitary and multiple nodules, the relative risk in the presence of calcification was about the same, around 4. Patients younger than 40 years with calcified nodules constituted a high-risk group, with a relative risk of 3.8 versus 2.5 in patients older than 40 years with calcified nodules.The detection of thyroid calcifications by sonography is diagnostically valuable, especially in cases involving a solitary nodule or a young person. The presence of calcifications in these cases should raise the suspicion of malignancy. The low incidence of cancer in patients with multiple noncalcified thyroid nodules suggests that a more conservative approach may be appropriate in such cases.

Insulin resistance and hyperinsulinemia both in normal persons and those with non- insulin dependent diabetes mellitus (NIDDM) (type 2 diabetes) appears to be related to obesity. It seems also that insulin plays a role in modulating the obesity-related factors (eg, hyperinsulinemia, hyperglycemia, hypertension, hypertriglyceridemia, hypercholes terolemia, low concentrations of high-density lipoprotein cholesterol) and takes its place among the many risk factors for coronary artery disease (CAD) associated with obesity. Insulin resistance and hyperinsulinemia could play the same role in pathogenesis of CAD independently of obesity. The authors determined blood glucose and immunoreactive insulin and plasma triglyceride concentrations in the fasting state at 60 and 120 minutes after a glucose load of 75 g in 68 patients (54 men, 14 women) with angiographic evidence of CAD and in 65 healthy volunteers matched to the patients for age, gender, and body mass index (43 men and 22 women). Patients with CAD and the healthy volunteers were categorized as obese (body mass index ≥ 26 kg/m2) and nonobese (body mass index < 26 kg/m2) . Four groups of subjects were analyzed: Group A included 40 healthy (28 men and 12 women) nonobese volunteers; group B, 25 healthy (15 men and 10 women) obese volunteers; group C, 39 (30 men and 9 women) nonobese patients with CAD; and group D, 29 (24 men and 5 women) obese patients with CAD. Fasting and postchallenged 60- and 120-minute glucose values were similar in groups A and C. However, significantly higher insulin values (mU/L) were observed in group C than in group A during fasting (12.2 ±6.2 vs 91 ±3, p Significantly higher plasma triglyceride concentrations were observed in group C than in group A (149.0 ±64.1 vs 114.6 ±46.6, p < 0.01 ) and in group D compared with group B (229.4 ± 104. 7 vs 144.9 ±65.1, p < 0.001. Plasma triglyceride concentrations were similar in groups B and C. The authors conclude that patients with documented CAD are insulin resistant inde pendently of obesity.

Coronary artery calcium detected by digital fluoroscopy is closely associated with known risk factors of coronary artery disease in asymptomatic low-risk populations. Even in the absence of significant luminal narrowing, this may not be an innocent finding, and subjects with coronary calcium may be at greater risk for developing obstruction and clinical disease.

Growth hormone (hGH), insulin-like growth factor-I (IGF-I) and prolactin (PRL) were measured in the cord and venous blood of small for gestational age (SGA) neonates in order to evaluate their endocrine status during the first 3 days of life. Although there were SGA newborns with both high and normal levels of hGH, the mean ( ± SD) concentration of hGH in the cord blood of the SGA neonates was 72.1 ± 50.6 ng/ml, whereas in the appropriate for gestational age (AGA) newborns it was 37.0 ± 23.5 (p = 0.001). The IGF-I in the cord blood of the SGA and the AGA newborns was 194.2 ± 174.8 ng/ml and 77.3 ± 50.2, respectively (p = 0.013). The PRL in the SGA and AGA newborns was 184.8 ± 62.4 ng/ml and ± 60.5, respectively (p = 0.0005). On the 3rd day the hGH in the SGA babies was 50.7 ± 41.2, whereas in the AGA it was 24.3 ± 12.3 (p = 0.034). On the same day the IGF-I was ± 120.9 and 44.8 ± 31.6, respectively (p > 0.05). Similarly, the PRL was 157.1 ± 52.3 and 90.9 ± 52.5, respectively (p = 0.0008). All neonates with high hGH concentrations had low IGF-I levels, whereas of those with normal hGH half had high and half normal IGF-I levels. There was no difference in the hormone levels between symmetric and asymmetric intrauterine growth-retarded infants. The findings suggest that the SGA neonates are heterogeneous comprising three groups. The neonates with high hGH and low IGF-I may have resistance at the level of the hGH receptor or a defect in IGF-I synthesis, whereas those with normal hGH and high IGF-I may have a post-IGF-I receptor defect, with compensatory increase in IGF-I synthesis independent of hGH control.

Three cases of deep venous thrombosis following varicella infection are described which were successfully treated with bed rest and anticoagulants. Two of these patients had severe pulmonary manifestations of varicella and the third was complicated by pulmonary embolism. Deep vein thrombosis is an uncommon systemic manifestation of varicella, possibly associated with vascular endothelium wall damage caused by varicella zoster virus infection.

We have studied the effects of rifampicin on the overnight 1-mg dexamethasone suppression test usually employed to exclude suspected Cushing's syndrome. Previous observations indicate that in humans, rifampicin profoundly attenuates the biological effects of hydrocortisol and prednisolone, probably by increasing the metabolism of these drugs in the liver. The study was carried out in 16 normal volunteers. All subjects had a normal overnight 1-mg dexamethasone suppression test (468 +/- 86 vs. 32 +/- 21 nmol/L; mean +/- SD). In 8 subjects treated with rifampicin (600 mg) for 10 days, the inhibitory effect of dexamethasone on serum cortisol was completely prevented (575 +/- 114 vs. 434 +/- 82). In the remaining 8 rifampicin-treated subjects, the inhibitory effect of 1, 2, or 3 mg dexamethasone on serum cortisol was not observed. When 4 mg dexamethasone were administered, the serum cortisol level was 193 nmol/L, above the expected normal suppression value. The plasma dexamethasone concentration was very low after rifampicin treatment (range, 1.2-4.8 nmol/L). We conclude that when patients are treated with rifampicin, the standard overnight dexamethasone suppression test not only has no diagnostic value, but can be very misleading.

The role of nonprotein sulfhydryl groups (NPSH) in the decreased in vitro hepatic 3',3,5-triiodothyronine (T(3)) generation from thyroxine (T(4)) in the starved, hypothyroid, fetal and 1- to 4-d-old neonatal rat and dwarf mouse was assessed. NPSH were measured in fresh 25% liver homogenates prepared in 0.1 M PO(4)/10 mM EDTA buffer. As compared with values in adult male rats, NPSH concentration was decreased in the 2-d-starved (1.1+/-0.04 (mean+/-SE) vs. 2.2+/-0.15 mmol/250 g wet liver weight, P0.001), fetal (1.0+/-0.04 vs. 3.2+/-0.08, P0.001), 1-d-old neonatal (1.1+/-0.03 vs. 2.1+/-0.04, P0.001), and hypothyroid (thyroidectomized 60 d) (1.4+/-0.06 vs. 2.2+/-0.15 P0.001) rat. NPSH were also decreased in the hypothyroid, hypopituitary dwarf mouse as compared with values in their normal litter mates (1.3+/-0.03 vs. 2.0+/-0.2, P0.01). Chronic administration of T(3) (0.5 mug/100 g body wt per d) markedly increased hepatic T(3) generation from T(4) in the thyroidectomized rat and in the dwarf mouse to values similar to those observed in the normal rodent without affecting NPSH concentration. In contrast, T(3) administration to the starved rat did not alter either hepatic T(3) generation from T(4) or NPSH. Reduced glutathione concentration was also markedly decreased in the starved rat (fed; 1.05+/-0.075 mmol/250 g wet tissue vs. starved 0.38+/-0.02, P0.001). Dithiothreitol (DTT), a thiol reducing agent, increased hepatic T(3) generation from T(4) in the normal adult male rat by 45+/-5% in six experiments. When compared to DTT-stimulated control homogenates, the addition of DTT completely restored hepatic T(3) generation in starved rats, partially restored T(3) generation in 1- and 4-d-old neonates, but had little or no effect in the fetal and hypothyroid rat and dwarf mouse. Liver homogenates stored for 6 mo at -20 degrees C lost their capacity to generate T(3) from T(4). NPSH concentrations in the frozen homogenates decreased progressively with increasing storage and were absent by 6 mo. 5'-Deiodinase activity correlated with NPSH concentration in the stored homogenates (r = 0.95, P0.005). Addition of DTT partially restored hepatic T(3) generation in the frozen homogenate. It is concluded that NPSH are important for the action of the liver 5'-deiodinase. The decreased hepatic T(3) generation in the starved rat is associated with decreased NPSH but not with a decrease in the absolute quantity of 5'-deiodinase because provision of sulfhydryl groups restored hepatic T(3) generation to normal. In contrast, the decreased hepatic T(3) generation in the adult hypothyroid rodent and in the fetal rat is probably due to a decrease in the enzyme concentration per se. In the 1- and 4-d neonatal rat, the decrease in hepatic T(3) generation is secondary to a decrease in NPSH and the deiodinating enzyme.