Treatment of Obesity with Thyroid hormones in Europe. Data from the THESIS* Collaboration.

PURPOSE: The use of thyroid hormones (TH) to treat obesity is unsupported by evidence as reflected in international guidelines. We explored views about this practice, and associations with respondent characteristics among European thyroid specialists. METHODS: Specialists from 28 countries were invited to a survey via professional organisations. The relevant question was whether "Thyroid hormones may be indicated in biochemically euthyroid patients with obesity resistant to lifestyle interventions". RESULTS: Of 17,232 invitations 5695 responses were received (33% valid response rate; 65% women; 90% endocrinologists). Of these, 290 (5.1%) stated that TH may be indicated as treatment for obesity in euthyroid patients. This view was commoner among non-endocrinologists (8.7% vs. 4.7%, p < 0.01), private practice (6.5% vs. 4.5%, p < 0.01), and varied geographically (Eastern Europe, 7.3%; Southern Europe, 4.8%; Western Europe, 2.7%; and Northern Europe, 2.5%). Respondents from Northern and Western Europe were less likely to use TH than those from Eastern Europe (p < 0.01). Gross national income (GNI) correlated inversely with this view (OR 0.97, CI: 0.96-0.97; p < 0.001). Having national guidelines on hypothyroidism correlated negatively with treating obesity with TH (OR 0.71, CI: 0.55-0.91). CONCLUSIONS: Despite the lack of evidence, and contrary to guidelines' recommendations, about 5% of respondents stated that TH may be indicated as a treatment for obesity in euthyroid patients resistant to life-style interventions. This opinion was associated with (i) respondent characteristics: being non-endocrinologist, working in private practice, treating a small number of hypothyroid patients annually and (ii) national characteristics: prevalence of obesity, Eastern Europe, low GNI and lack of national hypothyroidism guidelines.

Synthesis of Some New Folic Acid-Based Heterocycles of Anticipated Biological Activity.

To date, no fused heterocycles have been formed on folic acid molecules; for this reason, and others, our target is to synthesize new derivatives of folic acid as isolated or fused systems. Folic acid 1 reacted with ethyl pyruvate, triethyl orthoformate, ethyl chloroformate, thioformic acid hydrazide, and aldehydes to give new derivatives of folic acid 2-6a,b. Moreover, It reacted with benzylidene malononitrile, acetylacetone, ninhydrin, ethyl acetoacetate, ethyl cyanoacetate, and ethyl chloroacetate to give the pteridine fused systems 10-15, respectively. Ethoxycarbonylamino derivate 5 reacted with some nucleophiles containing the NH2 group, such as aminoguanidinium hydrocarbonate, hydrazine hydrate, glycine, thioformic acid hydrazide, and sulfa drugs in different conditions to give the urea derivatives 16-20a,b. Compound 4 reacted with the same nucleophiles to give the methylidene amino derivatives 21-24a,b. The fused compound 10 reacted with thioglycolic acid carbon disulfide, malononitrile, and formamide to give the four cyclic fused systems 25-30, respectively. The biological activity of some synthesized showed moderate effect against bacteria, but no effect shown towards fungi.

Aortic stiffness and left ventricular function in patients with differentiated thyroid cancer.

OBJECTIVE: The aim of this study was to investigate aortic stiffness and left ventricular (LV) systolic and diastolic function in patients with differentiated thyroid cancer (DTC) on thyroxine (L-T4) therapy and after L-T4 withdrawal to assess the cardiovascular impact of long-term subclinical hyperthyroidism and short-term overt hypothyroidism. METHODS: Twenty-four patients who had had total thyroidectomy and radioiodine ablation for differentiated thyroid cancer were studied on two occasions: on TSH suppressive L-T4 therapy (sTSH 0.24 ± 0.11 mU/L), and 4 weeks after L-T4 withdrawal (sTSH 89.82 ± 29.36 mU/L). Echocardiography was performed and thyroid function, serum thyroglobulin, lipid parameters, homocystine, C-reactive protein, fibrinogen and von Willebrand factor activity (vWF) were measured. Twenty-two healthy volunteers matched for age and sex served as euthyroid controls. RESULTS: Aortic stiffness was increased both in hypothyroidism (6.04 ± 2.88 cm(2)/dyn/10(3), p < 0.05) and subclinical hyperthyroidism (9.27 ± 4.81 cm(2)/dyn/10(3), p < 0.05) vs. controls (3.92 ± 1.84 cm(2)/dyn/10(3)). Subclinical hyperthyroidism had a more marked effect (p < 0.05). LV dimensions and ejection fractions were similar before and after L-T4 withdrawal. The E'/A' was higher in euthyroid controls (1.34 ± 1.02) as compared to both subclinical hyperthyroidism (1.0 ± 0.14, p < 0.05) and overt hypothyroidism (1.13 ± 0.98, p < 0.05). Change of aortic stiffness correlated with change of free-thyroxine (fT4), vWF and fibrinogen levels in a positive manner. CONCLUSION: Long-term thyrotropin-suppression therapy has continuous adverse effects on the arterial wall. The degree of TSH suppression in patients with DTC should be kept at the possible minimum, based on individually determined potential benefits and risks of treatment, especially in patients with cardiovascular co-morbidities.

Effect of thyroid hormone status and concomitant medication on statin induced adverse effects in hyperlipidemic patients.

Statins are effective treatment for the prevention of cardiovascular diseases and used extensively worldwide. However, adverse effects induced by statins are the major barrier of maximalizing cardiovascular risk reduction. Hypothyroidism and administration of drugs metabolized on the same cytochrome P450 (CYPP450) pathways where statin biotransformation occurs represent a significant risk factor for statin induced adverse effects including myopathy. Simvastatin, atorvastatin and lovastatin are metabolized by CYP3A4, fluvastatin by CYP2C9, while rosuvastatin by CYP2C9 and 2C19. We investigated the levels of the free thyroid hormones and CYP metabolism of concomitant medication in 101 hyperlipidemic patients (age 61.3 +/- 9.9 ys) with statin induced adverse effects including myopathy (56 cases; 55.4%), hepatopathy (39 cases; 38.6%) and gastrointestinal adverse effects (24 cases; 23.8%). Abnormal thyroid hormone levels were found in 5 patients (4.95%); clinical hypothyroidism in 2 and hyperthyroidism in 3 cases. 11 patients had a positive history for hypothyroidism (10.9%). Myopathy occured in one patient with hypothyroidism and two patients with hyperthyroidism. There were no significant differences in the TSH, fT4 and fT3 levels between patients with statin induced myopathy and patients with other types of adverse effects. 78 patients (77.2%) were administered drugs metabolized by CYP isoforms also used by statins (3A4: 66 cases (65.3%); 2C9: 67 cases (66.3%); 2C19: 54 cases (53.5%)). Patients with myopathy took significantly more drugs metabolized by CYP3A4 compared to patients with other types of adverse effects (p < 0.05). More myopathy cases were found in patients on simvastatin treatment (52% vs. 38%, ns.), while significantly less patients with myopathy were on fluvastatin treatment (13% vs. 33%, p < 0.05) compared to patients with other types of statin induced adverse effects. Both abnormal thyroid hormone status and administration of drugs metabolized by CYP3A4, 2C9 and 2C19 are common in our patients with statin induced adverse effects. Normalizing the thyroid hormone status and optimizing of the concomitant medication may reduce the risk of statin induced adverse effects.

The c.-133A > G polymorphism in NPC1L1 gene influences the efficacy of ezetimibe monotherapy on apolipoprotein A1 in hyperlipidemic patients.

Niemann-Pick C1-like 1 protein (NPC1L1) plays a critical role in intestinal cholesterol absorption. Previous studies found that the NPC1L1 c.-133A > G SNP, but not other NPC1L1 SNPs, was associated with response to statin treatment and statin-ezetimibe combinations. To date effect of NPC1L1 c.-133A > G SNP on ezetimibe monotherapy has not been studied. Our objective was to examine whether SNP c.-133A > G at the NPC1L1 gene has effects on lipid levels and on the efficacy of 3, 6 and 12 months of 10 mg daily ezetimibe monotherapy in hyperlipidemic patients with statin induced adverse effects. One hundred and one type IIa and IIb hyperlipidemic patients (72 females, 29 males; age: 61.23 +/- 9.87 ys; BMI: 28.18 +/- 4.29 kg/m2) were enrolled. The genotype frequencies were conformed to Hardy-Weinberg equilibrium. We could not find significant differences in initial lipid levels between AA and AG + GG patients. While plasma levels of apolipoprotein A1 (ApoA1) did not significantly decrease after ezetimibe treatment (1.96; 3.39 and 2.74%) in AA patients, a significant elevation in ApoA1 levels has been found after treatment in AG + GG patients (9.15; 8.54 and 13.58%). The effect of NPC1L1 c.-133A > G on the ApoA1 levels was found significant (p < 0.05). Efficacy of treatment with ezetimibe on other plasma lipid parameters after 3, 6 or 12 months did not differ significantly. NPC1L1-133A > G SNP influences the ApoA1 response to ezetimibe monotherapy, therefore, may alter the effect of ezetimibe on the structure and function of the high-density lipoprotein particles.

Fertility of testicular cancer patients after anticancer treatment--experience of 11 years.

Testicular cancer affects men mostly in their reproductive age with a cure rate over 90%. Preserved fertility is one of the main concerns of the survivors. To further elucidate the question of fertility after anticancer treatment for testicular cancer, we performed a survey among patients who underwent sperm cryopreservation procedure in our department. A structured questionnaire was designed to collect data on demography, anticancer treatment, histological type of cancer, family planning intentions and fertility prior to and after treatment. During a period of 11 years 86 men underwent semen cryopreservation before starting chemo-or radiotherapy. Fifty-nine of them consented to participate in the study. The average length of follow up was 4.6 +/- 3.8 years. In case of 11.9% of the patients their banked sperm was used, which led to live birth in 57% of the couples. The partners of 6 patients became pregnant after in vitro fertilization (IVF) resulting in 4 live births and 2 miscarriages. The spontaneous pregnancy rate was 22%. Spontaneous pregnancy occurred in 13 partners resulting in 18 pregnancies followed by 12 live births, 2 artificial abortions and 4 miscarriages. We could not prove any association between preserved fertility and anticancer treatment or the histological type of the cancer. In conclusion, although spontaneous pregnancy rate is remarkably high after anticancer treatment for testicular cancer, the risk of infertility after receiving gonadotoxic treatment cannot be predicted. Cryopreservation is a safe and effective method to preserve fertility in these cases. As a result we strongly recommend discussing the advantages of semen cryopreservation with all patients awaiting treatment for testicular cancer.

Addition of chlorine during water purification reduces iodine content of drinking water and contributes to iodine deficiency.

Drinking water is the major natural source of iodine in many European countries. In the present study, we examined possible sites of iodine loss during the usual water purification process.Water samples from 6 sites during the technological process were taken and analyzed for iodine content. Under laboratory circumstances, prepared iodine in water solution has been used as a model to test the effect of the presence of chlorine. Samples from the purification sites revealed that in the presence of chlorine there is a progressive loss of iodine from the water. In the chlorine concentrations employed in the purification process, 24-h chlorine exposure eliminated more than 50% of iodine when the initial iodine concentration was 250 µg/l or less. Iodine was completely eliminated if the starting concentration was 16 µg/l.We conclude that chlorine used during water purification may be a major contributor to iodine deficiency in European communities.

Evaluation of the metabolic changes during hemodialysis by signal averaged ECG.

Cardiovascular diseases are frequent complications of end-stage kidney disease. The aim of the present study was to prove the arrhythmogenic effect of dialysis using signal averaged ECG. The ECG changes and laboratory parameters (sodium, potassium, urea and creatinine levels) were detected during hemodialysis treatment in 26 patients suffering from end-stage kidney disease. The tests and the ECG were performed four times, before (0. minute), during (at 15 and 90 min), and eventually after dialysis (at 240 min). The duration of the QRS complex, high-frequency low-amplitude signals (HFLA), and root-mean-square voltage of the terminal 40 ms of the filtered QRS (RMS) were determined. We considered test results to be positive when two of the three tested parameters were outside the normal range: QRS > 120 ms, RMS < 20 uV, HFLA > 39 ms. Signal averaged ECG was positive in two cases (8%) before and after the dialysis. The duration of the QRS-complex increased significantly during the dialysis (predialysis: 109 +/- 7.6 ms, postdialysis: 116 +/- 8.0 ms, p < 0.0001). Serum urea nitrogen (predialysis: 26.2 +/- 5.4, postdialysis: 11.4 +/- 3.3 mmol/l, p <0.0001) and serum creatinine levels (predialysis: 931 +/- 212, postdialysis: 434 +/- 120 micromol/I, p < 0.0001) decreased significantly during the treatment. Significant and continuous decrease in the potassium levels were detected (predialysis: 5.30 +/- 0.72, postdialysis: 3.91 +/- 0.42 mmol/I, p < 0.0001) during the dialysis. Serum sodium levels (predialysis: 139 +/- 2.7, postdialysis: 141.4 +/- 2.2 mmol/I) had not changed during the dialysis. A significant negative correlation was found between decreasing potassium levels and increasing QRS duration (r = - 0.48, p = 0.01). Our results support our primer assumption that the metabolic changes during dialysis treatment can lead to considerable risk of cardiac arrhythmias.

Evaluation of the thyroid function of healthy pregnant women by five different hormone assays.

A normal function of the thyroid gland during pregnancy is essential. Any change can affect both the pregnant woman and the fetus. Thyroid hormones play a crucial role in the brain development of the fetus, thus proper maternal free thyroid hormone levels are important especially during the first trimester. We compared the free thyroid hormone levels FT3 and FT4 in forty pregnant women with no thyroidal disease by five different assays available on the market. The blood samples were collected between the 8th and 22nd weeks of pregnancy. The correlation coefficient "r" between different assays was 0.908-0.975 for TSH, 0.676-0.892 for FT4 and 0.480-0.789 for FT3. These data show that the inter-assay results varied widely in the studied population. One reasonable explanation may be that during pregnancy the serum levels of the thyroid hormone binding proteins are altered and "free" hormone measurements by immunoassays are influenced by these alterations. Thus, the results may show higher or lower thyroid hormone values depending upon the assay used. Therefore, it is strongly suggested that every laboratory should establish its own pregnant reference ranges for the tests used for the evaluation of thyroid function, based on values of the population served.

Quadriceps protects the anterior cruciate ligament.

The aim of this study is to show that the quadriceps is the primary muscular restraint to anterior tibial translation during closed kinetic chain activities such as running, jumping, walking, and standing. It is my hypothesis that the quadriceps vector is directed superiorly during open kinetic chain knee extension and inferiorly during closed kinetic chain knee extension. My methods involve vector analysis based on a lateral radiograph of the normal human knee and muscle ultrasound. My results show that the quadriceps vector is directed superiorly for open kinetic chain knee extension and inferiorly for closed kinetic chain knee extension. The inferiorly directed quadriceps vector has an anterior femoral-tibial or posterior tibial-femoral component, which protects the anterior cruciate ligament (ACL) from anterior tibial-femoral shear. Therefore during closed kinetic chain activities, the quadriceps protects the ACL regardless of the activity of the hamstrings. Given that the quadriceps is much stronger than the hamstrings, has better leverage at low knee flexion angles, and a favorable vector with regard to the ACL during closed kinetic chain activities, and since most activities of daily living, sports, and non-contact ACL injuries occur with the foot on the ground, then it can be concluded that the quadriceps is the primary ACL protagonist. My findings have the following implications: (1) weak quadriceps are a risk factor for non-contact ACL injuries, (2) strong quadriceps are important for ACL injury prevention and rehabilitation, and (3) preservation of quadriceps strength is an important surgical goal.

Prevalence of cardiovascular risk factors of the smokers and non-smokers in the city of Debrecen, Hungary.

The aim of our study was to compare the major cardiovascular disease (CVD) risk factors of smokers and non-smokers. Risk screening of CVD was estimated by a questionnaire, via interview. Random samples of 20 000 inhabitants of Debrecen, Hungary, aged 30-65 y, took part in the study. 19 922 questionnaires were considered appropriate for further evaluation. 32.2% of the participants (n=6410) were smokers, whose data were compared to those of the 68.8% of non-smokers (n=13 512). There were more male smokers than female (39.3% vs 27.7%), (P<0.001). 36.5% of males and 58.9% of females had not previously smoked regularly (P<0.001). 24.2% of males and only 13.3% of females were able to stop smoking (P<0.001). 8.7% of the participants smoked more than 20 cigarettes per day (14.8% of males, 5.0% of females), (P<0.001). Smokers were younger, with a mean age of 43.4 y vs 47.1 y for non-smokers (P<0.01). The ex-smokers and non-smokers had a higher body mass index than light, moderate and heavy smokers (26. 75+/-4.1 kg/m2 and 26.09+/-4.3 kg/m2 vs 24.87+/-3.9 kg/m2 and 24. 89+/-4.2 kg/m2 and 25.32+/-4.3 kg/m2, respectively), (P<0.001). The results of the last measured blood pressures did not differ between the two groups. 94.8% of smokers and 93.6% of non-smokers did not perform any regular leisure time exercises (P<0.01). 39.8% of smokers regularly ate fatty food, in comparison to 28.0% of non-smokers (P<0.001). 30.6% of smokers vs 28.6% of non-smokers were factory workers while 69.4% of smokers vs 71.4% of non-smokers did sedentary jobs (P<0.001). 2.3% of smokers vs 0.9% of non-smokers admitted regular consumption of alcohol (P<0.001). Amongst the parents and brothers/sisters of smokers the prevalence of heart attack was higher 19.7% vs 18.7%, than for those of non-smokers (P<0. 05). We observed an accumulation of cardiovascular risk factors in the case of smokers, which indicates the higher susceptibility of smokers to CVD.

111-indium human antimyosin monoclonal antibody-fragment study on alcoholic (and diabetic) cardiomyopathic patients (ACM-DCM) with Centocor Europe Myoscint (Msc).

The criteria of Msc-positivity were: typical accumulation of hot spots in 2 directions of planar scan in the 24-48-hr measurements, while in atypical cases the hot spots were present only in the 48 hr picture. Twenty-one male volunteers were assessed. 18 of them had ACM (2 patients were studied repeatedly). The negative and positive control cases exhibited the expected Msc pattern. Seven ACM patients were regarded typically positive, in 5 cases atypical positivity was stated, and 6 patients were classified as Msc negatives. The heart lung activity ratio was 1.75 +/- 0.45 and 1.68 +/- 0.44 for typical and atypical positive cases, respectively. The control and DCM H/L ratios were 1.15 and 1.3 +/- 0.2, respectively, in AMI the H/L was 1.91, in DCM of dilatative phase it was 1.55 +/- 0.06 with serum myosin in the normal range. Heart dilation in the DCM groups: 5 dilated out of 7 typically positive cases while in atypically positive, and negative cases the dilation occurred in 2 out of 5 and 1 out of 6 cases, respectively. Low LV-EF (less than 45%) were found in ratios of 4/7, 2/5, and 1/6 in typically positive, atypically positive and negative cases, respectively. Elevated PCP similar ratios. In the same groups pathological ECG was seen in ratios of 5/7, 1/5, and 1/6, respectively. The g-GT activity was enhanced in all cases, there was, however, no evident correlation between the actual enzyme activity and intensity of hot accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)