Treatment for acute lymphoblastic leukemia in children is associated with papillary carcinoma of thyroid, but not with thyroid disfunction.

AIM: The treatment of acute lymphoblastic leukemia (ALL) in children may cause sequelae, some appearing only at long-term follow-up. We investigated the thyroid gland morphology and the function of the pituitary-thyroid axis in a group of patients treated for ALL in childhood. METHODS: A cohort study was conducted at a tertiary medical center. Thirty-three children (22 males and 11 females; age: 11.9+/-3 years; range: 6 to 18 years) were studied. The mean age at the time of chemotherapy and prophylactic cranial irradiation (12-24 Gy) was 5.5+/-2.6 years (range: 1 to 14 years). The average length of the follow-up was 6.1+/-3 years (range: 2 to 12 years). Thyroid morphology (n=33) was evaluated by palpation and ultrasonography. Thyroid function (n=30) was evaluated measuring total T3 and T4, and by the thyrotrophin-releasing hormone (TRH) test. Prolactin secretion was assessed before and after injection of TRH to evaluate the diagnostic test accuracy. RESULTS: One out of the 33 children (3%) was found to have a papillary carcinoma of thyroid four years after ALL treatment. Thyroid function was normal in all the patients, however one case (3%) showed high TSH (9.2 microU/mL) and prolactin (37.5 ng/mL) basal levels, but normal responses to TRH (TSH = 17.8 microU/mL; prolactin = 82.3 ng/mL). These hormonal alteration were not confirmed at follow-up: TSH = 1.6 microU/mL and prolactin = 13.7 ng/mL. CONCLUSIONS: In this cohort of patients, the treatment of ALL was associated with one case of thyroid carcinoma, but it did not produce adverse effect on the thyroid function, at least after a follow-up lasted on average 6 years.

Growth hormone provocation tests and their prediction in the growth of children treated for acute lymphoblastic leukemia.

AIM: The aim of this study was to evaluate the positive predictive value of two growth hormone stimulation tests (insulin-induced hypoglycemia and clonidine) for stature below percentile 10 in patients treated for acute lymphoblastic leukemia in childhood. METHODS: The study population was a cohort of 30 patients (aged 14.1+/-2.9 years; 20 male) treated for acute lymphoblastic leukemia during childhood and then examined after insulin-induced hypoglycemia (30 patients) and clonidine (16 patients) tests. The follow-up time was 7.7+/-2.8 years since treatment and 2.3+/-1.3 years after administration of the tests. RESULTS: In the last evaluation, 12 patients (40%) were below and 18 (60%) were above percentile 10. The insulin-induced hypoglycemia test response was: 9 patients (30%) had growth hormone peak <5 ng/mL and 19 (63.3%) <7 ng/mL. The clonidine test response was: 7 patients had growth hormone peak <5 ng/mL and 8 (50%) <7 ng/mL. For stature below of the percentile 10, the positive predictive values of insulin-induced hypoglycemia test (33%) and clonidine (28%) were low when growth hormone peak <5 ng/mL was considered; however, when growth hormone peak <7 ng/mL was considered, the positive predictive values were 83% and 50% for the insulin-induced hypoglycemia and clonidine tests, respectively. CONCLUSIONS: In patients treated for acute lymphoblastic leukemia in childhood, the positive predictive values for statural deficit of both tests were low, except for the insulin-induced hypoglycemia test when a growth hormone peak <7 ng/mL was considered.

Shift work and autoimmune thyroid disorders.

Stress induces autoimmune disorders by affecting the immune response modulation. Recent studies have shown that shift work stress may enhance the onset of the autoimmune Graves hyperthyroidism. On the other hand, the possible association between occupational stress and autoimmune hypothyroidism has not yet been investigated. In order to detect the possible association between shift work and subclinical autoimmune hypothyroidism we investigated the prevalence of isolated anti-peroxidase thyroid (TPO) autoantibodies in 220 shift workers and in 422 day-time workers. Subclinical autoimmune hypothyroidism was diagnosed by the concomitant presence of high anti-TPO values and TSH levels higher than 2.51 mU/l. Anti TPO antibodies were measured by chemiluminescent technology (Advia Centaur) (a value above 60 IU/l was considered altered). Subclinical autoimmune hypothyroidism was diagnosed in 7.7 percent shift workers and in 3.8 percent day-time workers with a statistically significant difference: Odds Ratio (OR) 2.12, 95 percent Confidence Interval (CI) 1.05 to 4.29; p=0.03. The difference persisted after multivariate analysis taking into account age, sex, smoking habits, alcohol intake, familial history of autoimmune thyroid disease and exposure to radiation as possible confounders: OR. 2.24, 95 percent CI.1.01 to 4.94, p 0.05. Altered anti- TPO autoantibodies were found in 13.6 percent shift workers and in 8.6 percent day-time workers OR. 1.64, 95 percent CI.1.03 to 2.74, p=0.05. The significant difference was still detectable after multivariate analysis: OR. 1.95, 95 percent CI. 1.09 to 3.48, p=0.02. Our data show a significant association between shift work and autoimmune hypothyroidism. This finding may have implications in the health surveillance programs.

High eradication rates of Helicobacter pylori with a new sequential treatment.

BACKGROUND: Eradication rates of Helicobacter pylori with standard triple therapy are disappointing, and studies from several countries confirm this poor performance. AIM: To assess the eradication rate of a new sequential treatment regimen compared with conventional triple therapy for the eradication of H. pylori infection. METHODS: One thousand and forty-nine dyspeptic patients were studied prospectively. H. pylori-infected patients were randomized to receive 10-day sequential therapy [rabeprazole (40 mg daily) plus amoxicillin (1 g twice daily) for the first 5 days, followed by rabeprazole (20 mg), clarithromycin (500 mg) and tinidazole (500 mg) twice daily for the remaining 5 days] or standard 7-day therapy [corrected] [rabeprazole (20 mg), clarithromycin (500 mg) and amoxicillin (1 g) twice daily]. H. pylori status was assessed by histology, rapid urease test and 13C-urea breath test at baseline and 6 weeks or more after completion of treatment. RESULTS: Higher eradication rates were found with the sequential regimen compared to the standard regimen (intention-to-treat: 92% vs. 74%, P < 0.0001; per protocol: 95% vs. 77%, P < 0.0001). Higher eradication rates were also seen in patients with peptic ulcer disease and non-ulcer dyspepsia. In both treatments, compliance was similar (> 90%), as was the rate of side-effects, which were mild. CONCLUSIONS: This 10-day sequential treatment regimen achieves high eradication rates in peptic ulcer disease and non-ulcer dyspepsia.

Effect of substance P on basal and thyrotropin-releasing hormone-stimulated thyrotropin release in humans.

To test the possible effects of intravenous administration of substance P (SP) on basal and thyrotropin-releasing hormone (TRH)-stimulated thyrotropin (TSH) release, SP was infused alone (0.5 or 1.5 pmol/kg-1/min-1 for 60 minutes) or after TRH (20 or 400 micrograms in an intravenous bolus) in 21 normal male subjects (aged 26 to 36 years) and in 18 normal women (aged 25 to 32 years). Women were studied during follicular (day 6 to 8) and luteal (day 21 to 23) phases of following regular menstrual cycles. In addition, plasma cortisol levels during SP infusion were measured. In agreement with previous findings, significant increments in plasma cortisol levels were observed in men and women when the higher (1.5 pmol/kg-1/min-1) but not the lower (0.5 pmol/kg-1/min-1) amount of SP was administered. In contrast, in both men and women basal and TRH (20 or 400 mg)-induced TSH releases were not modified by SP at any tested amount. Results in the follicular and luteal phase were similar. These data suggest that in normal men and women plasma SP is not involved in the control of TSH release, at least not outside the blood-brain barrier.

Endogenous opioid mediation of the inhibitory effect of ethanol on the prolactin response to breast stimulation in normal women.

The effect of ethanol on the prolactin (PRL) response to breast stimulation was tested in normal women. The possible role of endogenous opioids in the control of the PRL response to breast stimulation and ethanol action was also examined. Eleven normal women were tested four times on the 22nd day of four consecutive regular menstrual cycles. All women underwent mechanical breast stimulation (for 10 min) with the concomitant administration of normal saline, naloxone (2 mg in an iv bolus plus 10 mg over 75 min. or 4 mg in an iv bolus plus 20 mg over 75 min.), ethanol (50 ml in 110 ml of whiskey p.o.) or the combination of ethanol and naloxone. Serum PRL levels rose significantly after breast stimulation, with a mean peak response (71.4% higher than baseline at 20 min). The PRL response to breast stimulation was not changed by the treatment with the lower (2 plus 10 mg) or the higher (4 plus 20 mg) dose of naloxone, whereas it was strikingly decreased by ethanol (mean peak was 25% higher than baseline). However, when ethanol was given together with naloxone, the peak rise induced by breast stimulation was only partially inhibited by ethanol (the mean PRL peak was 46.2% higher than baseline). At both doses naloxone produced similar effects. These data demonstrate that ethanol inhibits the PRL response to breast stimulation. Naloxone-sensitive endogenous opioids do not appear to be involved in the control of the PRL rise induced by breast stimulation. In contrast, since naloxone partially reversed the inhibiting effects of ethanol, a partial involvement of opioid peptides in ethanol action is supposed.

Role of GABA and opioids in the regulation of the vasopressin response to physical exercise in normal men.

The present study was undertaken in order to establish the possible involvement of GABAergic and/or opioid pathways in the mechanism underlying the arginine-vasopressin (AVP) response to physical exercise. After fasting overnight, seven subjects were tested on four mornings at least 1 week apart. Exercise was performed on a bicycle ergometer. The workload was gradually increased at 3 min intervals until exhaustion and lasted about 15 min in all subjects. Tests were carried out under administration of placebo, the opioid antagonist naloxone (10 mg as an i.v. bolus injection), the GABAergic agonist sodium valproate (600 mg in three divided doses orally) or naloxone plus sodium valproate. Plasma AVP levels rose 4-fold during exercise. The administration of naloxone did not modify, whereas sodium valproate completely abolished the plasma AVP rise during exercise. When naloxone was given together with sodium valproate, AVP rose 3-fold in response to exercise. These data suggest the involvement of a GABAergic mechanism in regulation of the AVP response to physical exercise in men. Furthermore, the data argue against a role of naloxone sensitive endogenous opioids in the control of AVP during exercise, whereas they suggest a partial opioid mediation of the GABAergic inhibitory action.

Inhibitory effect of dexamethasone on the oxytocin response to insulin-induced hypoglycemia in normal men.

Glucocorticoids are known to reduce both ACTH and arginine vasopressin responses to insulin-induced hypoglycemia in normal men. The present study was undertaken in order to establish whether glucocorticoids are capable of modifying the oxytocin (OT) response to hypoglycemia. For this purpose, 8 normal men (28-33 yr) were tested with insulin (0.15 IU/kg in an iv bolus) [insulin tolerance test (ITT)] with and without pretreatment with dexamethasone (2 or 4 mg in an iv bolus 10 min before insulin). Eight different subjects (29-35 yr) were tested with dexamethasone alone. The administration of dexamethasone (2 or 4 mg) alone changed neither ACTH nor OT concentrations in the plasma during the next hour. Insulin produced similar hypoglycemic responses, regardless of dexamethasone treatment. ACTH levels rose significantly in response to insulin-induced hypoglycemia, with a mean peak response at 45 min (p less than 0.01 vs baseline). Two and four mg dexamethasone produced similar significant reductions of the ACTH response to hypoglycemia (p less than 0.02 at 45 min, p less than 0.05 at 30 and 60 min vs ITT). In the ITT, OT levels rose significantly in response to hypoglycemia, with a mean peak response at 45 min (p less than 0.01 vs basal value). The pretreatment with 2 or 4 mg dexamethasone reduced in a similar manner the hypoglycemia-induced OT rise (p less than 0.05 at 30 and 45 min vs ITT). These findings show a partial inhibition by dexamethasone of the OT response to hypoglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Oxytocin does not modify the prolactin response to metoclopramide in normal women.

The present study was undertaken in order to establish whether oxytocin (OT) affects the dopaminergic control of PRL secretion in normal women during follicular, periovulatory and luteal phase of their menstrual cycle. For this purpose, 22 normal women were tested with a lower (1 mg) or higher (10 mg) dose of the dopaminergic antagonist metoclopramide (MCP) with or without the concurrent treatment with OT (2 IU injected plus 0.033 IU/min infused for 2 h). Since OT was found unable to modify the effect of either 1 or 10 mg MCP, in additional experiments the same doses of MCP and OT were administered after dopamine (0.04 micrograms/kg/min for 2 h) infusion. Also in these experimental conditions OT failed to modify the PRL response to MCP. These data argue against a role of OT in modulation of the dopaminergic control of PRL secretion in normal women.

Endogenous opioids modulate the oxytocin response to insulin-induced hypoglycaemia and partially mediate the inhibitory effect of ethanol in man.

Abstract The possible inhibition exerted by ethanol on the oxytocin (OT) response to insulin-induced hypoglycaemia was tested in man. Furthermore, the possibilities that endogenous opioids play a role in the control of hypoglycaemia and/or ethanol action on OT were examined. Insulin tolerance tests were performed in three groups of eight age- and weight-matched normal men treated with: 1) naloxone, group 1 1 mg bolus naloxone + 2.5 mg over 105 min, group 2 2 mg bolus naloxone + 5 mg over 105 min, group 3 4 mg bolus naloxone + 10 mg over 105 min; 2) ethanol (50 ml in 110ml of whiskey) to all the groups; 3) a combination of ethanol + naloxone; 4) normal saline. Furthermore, the effect of ethanol + naloxone (4+10mg) in the absence of insulin-induced hypoglycaemia was evaluated in seven additional subjects. During this latter test, the plasma levels of OT remained unchanged. Insulin-induced hypoglycaemia produced a 2.2-fold increment in plasma OT levels in the control experiments. This response was not changed by the treatment with the lowest dose of naloxone (1+2.5mg) in group 1, but it was significantly enhanced by administration of naloxone at higher doses (mean peak OT levels rose 2.8-fold in both group 2 and group 3). In all subjects the OT response to hypoglycaemia was completely abolished by ethanol. However, when ethanol was given together with naloxone, the hypoglycaemia-induced OT rise was only partially inhibited by ethanol. At all doses naloxone produced similar effects; in fact, in all groups OT rose 1.5-fold in response to hypoglycaemia during insulin tolerance test + ethanol + naloxone. Neither naloxone nor ethanol altered the basal secretion of OT, as tested during 45 min before the insulin tolerance test. These data demonstrate that the OT response to insulin-induced hypoglycaemia is inhibited by ethanol. Furthermore, the data indicate that endogenous opioids are involved in the control of hypoglycaemia-stimulated OT secretion and partially modulate ethanol inhibitory action.

Cardiac arrhythmias as correlated with the circadian rhythm of arterial pressure in hypertensive subjects with and without left ventricular hypertrophy.

To evaluate the relationship among supraventricular and ventricular arrhythmias with blood pressure and heart rate (HR) values, we studied 2 groups of 20 hypertensive men with (group I) and without (group II) left ventricular hypertrophy. Ambulatory electrocardiographic tracings were recorded continuously, together with ambulatory arterial pressure. Systolic (SBP) and diastolic (DBP) blood pressure values measured over 24 h showed no difference between the two groups, but we found greater variability in SBP in group I. The incidence of ventricular and supraventricular arrhythmias was significantly higher in patients of group I; moreover, we found a strong correlation between the incidence of ventricular extrasystoles (VPCs) and SBP, DBP, and HR values in group I, whereas in group II the incidence of supraventricular extrasystoles (APCs) was higher during peaks of SBP and HR values. The relationship between APCs and SBP observed in group II may be attributable to the pressure stimulus on a normal atrium, and the significant correlation between VPCs and SBP, DBP, and HR values may be due to episodes of subendocardial ischemia or to the influence of adrenergic stimulation on previously compromised myocardial tissue.