Rituximab treatment in patients with active Graves' orbitopathy: effects on proinflammatory and humoral immune reactions.

In active Graves' orbitopathy (GO), proinflammatory cytokines predominate. Circulating thyroid stimulating hormone (TSH)-receptor antibodies (TRAb) have been correlated with GO clinical activity and severity. In preliminary studies rituximab (RTX), an anti-CD 20 monoclonal antibody, has induced clinical improvement of active GO without a change in serum anti-thyroid antibodies. We have studied whether RTX in GO acts by affecting proinflammatory cytokines and thyroid and orbital-directed antibodies. Ten patients with GO were treated with RTX, administered twice intravenously (i.v.) (1000 mg) at days 1 and 15, and 20 with methylprednisolone, administered weekly i.v. (500 mg), for 16 weeks. Patients were studied before treatment, at B cell depletion and at 4, 8, 16, 20, 30 and 50 weeks. Peripheral lymphocytes, serum interleukin (sIL)-6, sIL-6r, chemokine (C-X-C motif) ligand 10 (CXCL10), TRAb and stimulating antibodies (TSAb) and autoantibodies against orbital calsequestrin, collagen XIII and flavoprotein subunit of succinate dehydrogenase (FP-SDH) were measured at baseline and after treatment. Serum IL-6 and sIL-6R concentrations did not change after RTX [P = not significant (n.s.)]. Serum CXCL10 increased after RTX at B cell depletion and at 30 weeks (P < 0·003). Serum TSAb did not change in relation to TRAb, nor did antibodies against orbital antigens (P = n.s.). In conclusion, this study shows that RTX in GO does not affect humoral reactions. The observed increase of serum CXCL10 concentrations at B cell depletion may result from cell lysis. We suggest that RTX may exert its effect in GO by inhibiting B cell antigen presentation.

Graves' orbitopathy activation after radioactive iodine therapy with and without steroid prophylaxis.

CONTEXT: The reactivation of Graves' orbitopathy (GO) after radioiodine (RAI) for Graves' disease (GD) is a known effect, and its clinical relevance is controversial. Prevention of RAI-induced GO activation is possible in at-risk patients with oral glucocorticoids (OGC). OBJECTIVES: The aim of the study was to analyze the effects of RAI on GO with or without prophylactic steroids based on known risk factors and to compare the effectiveness of prophylaxis with iv glucocorticoids (IVGC) and OGC. DESIGN: We conducted a retrospective study in which patients were assessed before and 1-12 months after RAI. PATIENTS AND SETTING: A total of 113 patients were included in the study; 83 underwent RAI without prophylactic steroids for the absence of risk of activation, and 30 were treated with either OGC (n = 21) or IVGC (n = 9). MAIN OUTCOME MEASURES: We analyzed the prevalence of GO activation with or without steroid prophylaxis and the difference in the prevalence of GO activation after OGC or IVGC. RESULTS: GO activation was observed in 7.2% of patients without and 33.3% of patients with steroid prophylaxis (P < 0.0001), for an overall prevalence of 14.6%. GO activation occurred in 47.6% of patients treated with OGC but in none of the nine patients treated with IVGC (P = 0.0001). Disease activation was more prevalent in males (P < 0.02) and in older patients (P = 0.04) with a shorter duration of GD (P < 0.01) and time from GO onset (P < 0.01). CONCLUSIONS: GO may occur after RAI in approximately 15% of patients also in the absence of signs of active GO. Prophylactic OGC did not prevent GO activation in a large proportion of patients, compared to IVGC.

Side effects of anabolic androgenic steroids abuse.

Long-term side effects of high doses of anabolic androgenic steroids self-administration were evaluated in this study. Twenty male bodybuilders, voluntarily starting steroid self-administration, were followed every 6 months over 2 years. Physical examination, haematological, metabolic and endocrine variables, semen analysis, hepatic and prostate ultrasound and echocardiographic evaluations were performed. LH values (baseline 3.43 +/- 1.75) were suppressed at 18 (1.98 +/- 1.99) (p = 0.026) and 24 (2.43 +/- 2.17) (p = 0.026), and FSH (3.95 +/- 2.01) at 6 (3.01 +/- 2.16) (p = 0.031), 12 (2.45 +/- 2.54) (p = 0.029), 18 (2.02 +/- 2.29) (p = 0.032) and 24 (3.42 +/- 2.64) (p = 0.032) months and SHBG (34.11 +/- 10.88) values significantly lowered at 12 (24.81 +/- 12.49) (p < 0.05), 18 (21.28 +/- 11.15) (p < 0.01), 24 months (25.42 +/- 11.16) (p < 0.01). A significant decrease in spermatozoa count (p < 0.01), and fertility index (p = 0.01) occurred. HDL-cholesterol (baseline 56.94 +/- 13.54) was reduced at 18 (41.86 +/- 14.17) (p < 0.01) and 24 (43.82 +/- 18.67) (p < 0.05) months and Apo A-1 at 12 (p < 0.001), 18 (p = 0.05) and 24 (p = 0.05) months. The most important long-term adverse effects were lower fertility and the impairment of lipid profile associated with an increased cardiovascular risk.

Euthyroid women with autoimmune disease undergoing assisted reproduction technologies: the role of autoimmunity and thyroid function.

UNLABELLED: Thyroid dysfunction and the presence of thyroid antibodies increase the risk of infertility and miscarriage. The aim of the present study was to assess if patients with autoimmune thyroid disease undergoing assisted reproduction technologies (ART) are afflicted by poor pregnancy and/or delivery rate and if the outcome is conditioned by pre-ART thyroid status. The study was retrospective (from January 2000 to January 2005) and was carried out at the Division of Physiopathology of Human Reproduction. Women who underwent ART were tested for TSH, free T4 (FT4), thyroid peroxidase antibodies (TPOAb) before and during pregnancy. A total of 416 euthyroid women were selected; 42 (10.1%) were TPOAb (+). Women >35 yr were excluded. The endpoints were pregnancy and delivery rates. RESULTS: no differences in pregnancy and delivery rates were observed between women with and without antibodies. In TPOAb (+), women who failed to become pregnant or miscarried displayed higher TSH values before ART (2.8 mIU/l) compared to the ones who delivered (1.6 mIU/l; p=0.032) and compared to TPOAb (-) (1.1 mIU/l; p=0.018). CONCLUSIONS: in euthyroid women undergoing ART the pregnancy and delivery rates are not affected by the presence of TPOAb. In TPOAb (+) high-normal TSH values are associated with increased risk of unsuccessful pregnancy or subsequent miscarriage. Further studies are required to ascertain possible benefits of levo-T4 (L-T4) in such patients.

Pioglitazone reduces blood pressure in non-dipping diabetic patients.

AIM: The association between insulin resistance and hypertension is firmly established and has been extensively investigated. Thiazolidinediones (TZD), a class of oral hypoglycemic agents that act as insulin sensitizers have been demonstrated, in many in vivo and in vitro studies, to possess antihypertensive properties. Whether the ability of TZD to lower blood pressure (BP) should be ascribed to a reduction of insulin resistance, or to a direct vasodilating effect, is matter of debate. Since blunted BP nocturnal dipping precedes overt hypertension and is associated with an increased risk of adverse cardiovascular events, we evaluated the pioglitazone effects on BP in non-dipper type 2 diabetic patients. METHODS: Forty non-dipper diabetic patients were randomly assigned to metformin + placebo (M) or metformin + pioglitazone 30 mg (MP) and submitted to 24 hours blood pressure monitoring at the beginning and after 8 weeks. RESULTS: After 8 weeks of treatment in subjects on metformin + pioglitazone 30 mg (group MP1), we found a reduction of nocturnal blood pressure values (mean nocturnal systolic BP 128.05+/- 1.23 vs 122.8+/-2.3 mmHg; p<0.02; mean nocturnal diastolic BP 81.2+/-0.99 vs 75.65+/-0.93 mmHg; p<0.005). The observed improvements in BP were independent from changes in metabolic parameters. CONCLUSION: The obtained data show that pioglitazone was effective in reducing BP values in non-dipping diabetic patients. The reduction of BP values was independent from amelioration of the metabolic picture: that suggest the hypothesis that these ameliorations may be also due to a direct antihypertensive action exerted by pioglitazone.

The management of thyroid disease by GPs.

BACKGROUND: Good medical practice depends on a collaborative relationship between a GP and a targeted specialist. OBJECTIVE: The aim of the present study was to assess knowledge and management by GPs of common endocrine disorders such as thyroid diseases. METHODS: We submitted to all the GPs (622) of the Province of Lecce an anonymous questionnaire with 11 questions which aimed to evaluate methods of approach to (questions 1 and 2) and knowledge about (questions 3-11) thyroid diseases. RESULTS: (i) Most GPs (72.1%) evaluate thyroid function on the basis of a clinical suspicion and perform preliminary investigations before referring the patient to a specialist. (ii) The ratio between right and wrong answers was significantly higher for four questions, significantly lower for one question and distributed by chance for four questions. (iii) The degree of knowledge strictly corresponds to the GP's attitude to patient's management. CONCLUSIONS: For a thyropathic patient to be diagnosed rapidly and treated efficiently, it is necessary to disseminate knowledge of standardized protocols to ensure a better utilization by both the GP and the endocrinologist of their respective competences.

The control of blood glucose in the critical diabetic patient: a neuro-fuzzy method.

Conventional algorithms for regulating insulin infusion rates in those critical diabetic patients submitted to parenteral glucose and insulin infusions do not allow to approach near normal blood glucose (BG) levels since traditional control systems are not fully effective in complex nonlinear systems as BG control is. Thus, we applied fuzzy logic principles and neural network techniques to modify intravenous insulin administration rates during glucose infusion. Forty critically ill, fasted diabetic subjects submitted to glucose and potassium infusion entered the study. They were randomly assigned to two treatment regimes: in group A, insulin infusion rates were adjusted, every 4 h at any step between -1.5 and +1.5 U/h, according to a neuro-fuzzy nomogram; in control group B, insulin infusion rates were modified according to a conventional algorithm. In group A, BG was lowered below 10 mmol/l faster than in group B (8.2+/-0.7 vs. 13+/-1.8 h, P<.02). Mean BG was 7.8+/-0.2 in group A and 10.6+/-0.3 mmol/l in group B (P<.00001). BG values below 4.4 mmol/l were: A=5.8% and B=10.2%. BG values lower than 2.5 mmol/l had never been observed. In conclusion, the neuro-fuzzy control system is effective in improving the BG control in critical diabetic patients without increasing either the number of BG determinations or the risk of hypoglycemia.

[Evaluation of the treatment with L-thyroxine: lack of correspondence between objectives and results]. / Valutazione del trattamento con L-Tiroxina: mancata corrispondenza fra obiettivi e risultati.

BACKGROUND: Hypothyroidism and nodular goiter are two frequent endocrine diseases which respectively require substitutive and suppressive treatment with L-Thyroxine. Objective of this work was to evaluate the correspondence between expected and obtained TSH values in patients affected with hypothyroidism and nodular goiter submitted to L-Thyroxine treatment. SETTING AND SUBJECTS: a questionnaire addressed to patients on L-Thyroxine has been available in consulting rooms of 12 family doctors of Lecce County (Italy) for a 6 month period. A hundred-twelve patients answered the questionnaire: 44 were on suppressive treatment for uni/multinodular goiter (group 1) and 68 were on substitutive treatment for hypothyroidism (group 2). RESULTS: TSH dosage had been performed since less than 1 year in 91% of group 1 patients and in 87% of group 2 patients (p = ns), in group 1, 25% of TSH values were < 0.3 microU/ml, 68.2% between 0.3 and 4.5 microU/ml, 6.8% > 4.5 microU/ml (p < 0.001); in group 2, 25% of TSH values was < 0.3 microU/ml, 63.3% between 0.3 and 4.5 microU/ml, 11.8% > 4.5 microU/ml: (p < 0.001). The distribution of TSH values between the two groups was not significantly different. In patients on suppressive treatment TSH was suppressed in a number of patients significantly less in respect to the ones with not suppressed TSH value: 11 vs 33; p < 0.01; in patients on substitutive treatment the number of those ones with TSH values in between the normal range was not different from patients with TSH values above or below the normal range: 43 vs 25; p = ns. Considering the two groups together, in 52% of patients TSH was not correspondent to therapeutical objectives. CONCLUSIONS: Inspite of regular checks of thyroid function, proper TSH values were achieved only in half of patients.

Effects of alcohol consumption and accompanying diet on metabolic response to arginine in chronic alcoholics.

OBJECTIVE: To evaluate, in chronic alcoholics, the effects of accompanying diet on the release of insulin (IRI) and glucagon (IRG) and on the hepatic glucose production. METHOD: We evaluated variations of the response to the infusion of arginine into 16 male and 8 female chronic alcoholics divided into three groups of eight subjects each before and after three weeks of treatment with: (1) an isocaloric diet plus 200 g/day of ethanol; (2) an hypocaloric diet without alcohol (17.5 kcal/kg/day); and (3) an isocaloric diet (35 kcal/kg/day). Statistical evaluation was done by Kruskall-Wallis ANOVA and by Wilcoxon matched-pairs signed rank test. RESULTS: After isocaloric diet plus ethanol both IRI/IRG ratios and plasma glucose during arginine testing remained unmodified; after the hypocaloric diet IRI/IRG remained unmodified and the arginine-induced plasma glucose rise was slightly but significantly reduced; after the isocaloric diet there was a strong decrease of the arginine-induced plasma glucose rise because of a significant increase in the insulin/glucagon ratio. CONCLUSIONS: In chronic alcoholics the replacement of the usual hypocaloric diet with an isocaloric one while maintaining alcohol consumption does not modify the metabolic response to arginine administration; the hypocaloric diet without alcohol increases insulin and glucagon release and slightly decreases liver glycogenolysis; the replacement of the usual hypocaloric diet with an isocaloric one together with alcohol withdrawal stimulates insulin, inhibits glucagon release and lowers glycogenolysis much more than observed with hypocaloric diet alone.

Effects of maternal weight variations and gestational diabetes mellitus on neonatal birth weight.

We evaluated the effects of gestational weight gain on neonatal birthweight women in whom gestational diabetes mellitus (GDM) was diagnosed after the 32nd week of gestation. The prevalence of macrosomia, the birthweight differences from 50th percentile value of a reference population, and the relationships among plasma glucose values during oral glucose tolerance test and neonatal birthweight were evaluated in 60 newborns from mothers with gestational diabetes mellitus divided according to pregravid body-mass index. Serving as controls were 132 newborns of mothers with normal glucose tolerance. The prevalence of macrosomia was higher in the GDM group; the neonatal birthweight difference above 50th percentile value was higher in newborns of mothers with GDM; and a strong relationship between maternal gestational weight gain and neonatal birth weight was present in all pregnant women. In conclusion, (1) the gestational weight gain is a good predictor of neonatal birth weight in all pregnant women; (2) GDM enhances the increase in neonatal size induced by excessive gestational weight gain alone, and (3) a weight gain of more than 9 kg makes the relative risk of macrosomia twofold higher in GDM than in control mothers.