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N. Michajlovskij and P. Langer

ABSTRACT

Following the addition of thiocyanate (SCN) to human and rat serum of 80 mg SCN/ 100 ml (initial concentration before dialysis) a marked increase in serum free thyroxine (FT4) was found. The addition of equivalent doses of other antihyroid anions or permanganate showed a similar increase of FT4 in the order: BF4 < CIO4 = SCN < MnO4 . The increase in the rat serum was greater than that in human serum. After peroral administration of these anions to the rats in amounts equal to 30 mg SCN/rat the increase of FT4 was still higher.

The addition of increased doses of SCN to the human and rat sera (5-80 and up to 1600 mg SCN/100 ml) caused a linear increase of FT4. Similarly, after the administration of various doses of SCN to rats (5-30 mg SCN/rat) a linear dose-response of the FT4 level in serum was observed.

The time-course of the increase of % FT4 and absolute FT4 (AFT4) level after a single administration of SCN to rats coincided with the increase of the serum SCN level. However, after the disappearance of SCN from the serum the % FT4 returned to the initial value, while the AFT4 was decreased.

The effect of these anions probably consists in the competitive displacement of thyroxine from serum thyroxine-binding proteins. These and previous results suggested that thiocynate influences the plasma protein-thyroxine equilibrium and the possible role of an increased free thyroxine level on the action of thyroxine on various tissues and the hypothalamo-pituitary-thyroid feed-back is discussed.

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P. Langer and N. Michajlovskij

ABSTRACT

Rats were force fed a single dose of 20, 40, 80, 160, 320, 640, 1280 and 2560 μg L-5-vinyl-2-thiooxazolidone (VTO) and injected with 131I one hour later. The 131I uptake, biosynthesis of thyroid hormones and PB131I were measured 4 h after the administration of 131I. Under these conditions, a higher antithyroidal effect with VTO was found in rats fed a normal diet (ND) for 10 days before the experiment as compared with rats fed a low iodinediet (LID) for the same period. The results are described in detail.

Similar doses of VTO were force fed to groups of rats fed LID daily for 20 days. The animals received 1 μCi 125I per 15 ml of drinking water for 30 days before sacrifice. One hour after the last dose of VTO they were injected with μCi 131I and killed 4 h later. In addition to the parameters presented above the thyroid weight, total 125I in the thyroid and PB125I were measured. The inhibition of thyroid activity was in direct relation to the dose of VTO administered.

Finally, ethereal extracts of urine of rats kept in metabolic cages and force fed a single dose of 10 mg VTO were prepared and the dried extract was dissolved in methanol and applied to the chromatographic paper. In two chromatographic systems (1. water saturated chloroform, 2. n-butanol:acetic acid:water) two compounds were detected, one of which (Compound A) was chromatographically identical with VTO and the other (Compound B) was unknown. The Compound B was extracted from chromatograms, its UV-absorption spectrum was measured and its antithyroid activity was tested in rats. The 131I uptake was significantly inhibited following a single administration of 640 μg Compound B.

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A Wild, P Langer, I Celik, B Chaloupka and DK Bartsch

OBJECTIVE: A variety of human tumors frequently show allelic deletions of chromosome 22q, suggesting that inactivation of one or more tumor suppressor genes in this region is important for their tumorigenesis. METHODS: In this study, 23 patients with pancreatic endocrine tumors (PETs), including gastrinomas, VIPomas and non-functioning islet cell carcinomas, were analyzed for loss of heterozygosity (LOH) on chromosome 22q with 12 microsatellite and 7 sequence tagged site markers. RESULTS: LOH on chromosome 22q was identified in 22 of 23 (96%) PETs. Markers in the chromosomal region 22q12.1 revealed LOH rates up to 85%. Notably, one tumor revealed a homozygous deletion in a second region at 22q12.3. LOH at this locus occurred more frequently in tumors with distant metastases (10 of 11) compared with tumors without distant metastases (3 of 12; P=0.0057) and, overall, allelic loss of 22q is positively correlated with distant metastases (r=0.78; P<0.0001). CONCLUSIONS: These findings are suggestive for novel tumor suppressor gene loci at chromosome 22q that might contribute to the pathogenesis of PETs, especially to the development of distant metastases.

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M Tajtakova, P Langer, V Gonsorcikova, Bohov and D Hancinova

OBJECTIVE: To evaluate whether small iodine supplements decrease the incidence of adolescent thyroid hypertrophy in an iodine-sufficient population or whether such thyroid enlargement should be considered an inevitable physiological phenomenon. DESIGN: Beginning in September 1991 (after an initial examination in September 1990), 54 11-year-old children in Bardejov, Slovakia were given small iodine supplements (Thyrojod depot tablets containing 1530 microg iodide) every 2 weeks for 2 years followed by once weekly for 2 years. A second group of 63 children served as controls. In June 1995, there were still 52 treated and 60 control children in the study and these were examined; 44 treated and 48 control children remained in the study until June 1997. METHODS: In 1990, 1993, 1995, 1996 and 1997 the thyroid volume (ThV) was measured by ultrasound. Serum levels of TSH, thyroglobulin, total and free thyroxine and tri-iodothyronine and anti-thyroid peroxidase (anti-TPO), anti-thyroglobulin (anti-TG) and anti-TSH receptor (TSR) antibodies were estimated in 1990 and 1994, while only TSH, and anti-TPO and anti-TSR antibodies were measured in 1997. RESULTS: There was no difference between the groups at any interval in the serum levels of the hormones measured. Marginally increased TSH was found in two treated and two control children. Anti-TSR antibodies were negative in all children, while anti-TPO and anti-TG antibodies were found in one treated and four control children. At the age of 10 years (1990), 84% of all ThVs were less than 4 ml, indicating a previous life-long sufficient iodine intake. After the treatment was completed (June 1995), a significant difference in ThV (P < 0.04) was found between the whole treated (5.78 +/- 0.19 ml) and the whole control group (6.56 +/- 0.30 ml). However, there was already a marked difference in the 75th percentile (6.4 ml in treated vs 8.5 ml in controls) due to more rapid thyroid growth in certain children of the control group (ThV > 7.0 ml in 6/52 treated children vs 24/60 controls; P < 0.01). Since such differences were much higher in 1997, the children in each group whose ThV was in the range of the upper 25% in 1997 were retrospectively evaluated as arbitrary separate subgroups in all the time intervals and compared with the remaining 75% of children who showed moderate thyroid growth rate. Two years after the termination of treatment (June 1997), excessive thyroid growth continued in the upper quarter of 12 controls with the highest ThV (13.60 +/- 0.40 ml or 7.60 +/- 0.29 ml/m2; 12/12 with ThV > 11.0 ml), and a similar subgroup now also appeared in 11 previously treated children (10.79 +/- 0.51 ml or 6.19 +/- 0.30 ml/m2; 5/11 with ThV > 11.0 ml). At the same time, ThV in the remaining 75% of both control (8.12 +/- 0.38 ml or 4.82 +/- 0.17 ml/m2; 3/36 with ThV > 11.0 ml) and treated (7.20 +/- 0.30 ml or 4.39 +/- 0.17 ml/m2; 0/33 with ThV > 11.0 ml) children was significantly less (P < 0.01 to P < 0.001) than that in the appropriate rapidly growing subgroups. During the whole observation period (1990-1997), no difference was found between treated and control subgroups with moderate thyroid growth. CONCLUSIONS: Since iodine intake in Slovakia has been adequate for decades and sporadic iodine deficiency is highly unlikely, the observed excessive thyroid growth in certain adolescents may result from causes other than simple iodine deficiency (e.g. hereditary), which are nevertheless ameliorated by small iodine supplements. The question remains whether such a subgroup with rapidly growing thyroids should be included in the range of normal thyroid volumes in adolescents.

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S. Alagna, P.P. Rovasio, M. Langer, A. Masala and G. Madeddu

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P Langer, M Tajtakova, G Fodor, A Kocan, P Bohov, J Michalek and A Kreze

OBJECTIVE: To evaluate whether long-term exposure to heavy environmental pollution with polychlorinated biphenyls (PCBs) could result in impairment of thyroid status as evaluated by an epidemiological field survey. METHODS: Thyroid volume (ThV) was measured by ultrasound in 238 employees of a factory (EMP) which previously produced PCBs and 454 adolescents from the surrounding area polluted by PCBs. Controls (C) were 572 adults and 965 adolescents from much less polluted areas. In the 238 EMP and various numbers (shown in parentheses) of adult C the levels of thyroid-stimulating hormone (TSH) (n = 498), thyroxine (n = 498), thyroglobulin (n = 278) and thyroid antibodies (anti-peroxidase (TPO Ab), n= 517; anti-thyroglobulin (Tg Ab), n=455; anti-TSH receptor (TSHR Ab), n=238) were estimated in serum, while only TSH and TPO Ab were measured in 269 and 171 adolescents from polluted and control areas respectively. In several subjects in whom thyroid disease was suspected, total tri-iodothyronine or free thyroxine and tri-iodothyronine were measured. In a total of 362 adults and adolescents the urinary iodine was estimated. RESULTS: Using the Mann-Whitney test, ThV in EMP (mean+/-S.E. = 18.85+/-0.69 ml, median= 17.3 ml, upper quartile=22.9 ml, n=238) was significantly higher (P< 0.001) than that in C (13.47+/-0.48 ml, 11.5 ml, 15.3 ml, n = 486 respectively). Similarly, ThV in adolescents from the polluted area (9.37+/-0.17 ml, 8.9 ml, 11.0 ml, n = 454 respectively) was significantly higher (P< 0.001) than that in C (8.07+/-0.10 ml, 7.6 ml, 9.6 ml, n = 965 respectively). In adults, a significantly increased prevalence of TPO Ab (P<0.05) was found (using the chi-square test) in EMP women of all ages (54/190) vs C women (70/282), in EMP women aged 31-50 years (40/117 vs 70/282 respectively) and those aged 41- 50 years (28/77 vs 54/215 respectively). Compared with C, there was also a higher prevalence of Tg Ab in EMP women aged 31-60 years (36/169 vs 50/342 respectively) and of TSHR Ab (P< 0.001) in the group of EMP men and women (25/238) vs sex- and age-matched C (6/238). No difference between EMP and C was found in the level of thyroxine (mean+/-S.D = 116.1+/-31.2 nmol/l, n = 238 vs 112.2+/-37.0 nmol/l, n = 460 respectively), TSH in the range 0.1-4.5 mU/l(1.56+/-0.86 mUl/l, n = 219 vs 1.51+/-0.84 mU/l, n = 460 respectively), prevalence of TSH >4.5 (14/238 vs 28/498 respectively) and <0.1 mU/l(5/238 vs 10/498 respectively). The prevalence of individuals without any defined clinical or laboratory signs of thyroid disorders among EMP who had worked in the factory for 21-35 years (43/128, 33.6%) was significantly lower than that in twice as many matched C (118/256, 46.1%, P< 0.025) or in EMP who had worked for only 11-20 years (36/73, 49.3%, P< 0.05). In adolescents, no difference was found in the prevalence of TPO Ab or TSH >4.5 mU/l between the polluted (17/269, 6.3%, and 2/243, 0.8% respectively) and C areas (15/171, 8.5% and 4/140, 2.8% respectively). The median values of urinary iodine were in the optimal range (microg per dl/number of cases) and about the same in polluted (12.6/90 and 11.4/55) and C areas (14.1/80, 13.2/82 and 13.4/55). CONCLUSIONS: Since iodine intake in Slovakia is considered sufficient as a result of 45 years of well-monitored iodine prophylaxis, the increased ThVand prevalence of thyroid disorders in the polluted areas presumably results from long-term exposure to toxic substances rather than from a difference in life-long iodine intake. The increased prevalence of some thyroid antibodies may be related to the known immunomodulatory effects of PCBs.

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P H Kann, D Ivan, A Pfützner, Th Forst, P Langer and S Schaefer

Objective: Endoscopic ultrasound (EUS) is a highly reliable procedure to localize insulinomas preoperatively. It has been considered to be important in planning surgical strategy, especially considering a minimal invasive approach. However, even under ideal conditions experienced examiners miss about 10–20% of insulinomas by EUS imaging.

Design and methods: This retrospective study aimed to identify factors associated with negative EUS imaging. Twenty-nine consecutive patients (24 benign and 5 malignant) with sporadic pancreatic insulinomas confirmed by successful surgery and positive histopathology were included. All EUS examinations were performed by one single experienced examiner over a period of one decade.

Results: Three of the tumors were not detected by preoperative EUS as they were isoechoic to the surrounding healthy pancreatic tissue; 25 could be detected as hypoechoic lesions, (including all malignant tumors), and one lesion was hyperechoic. Low body mass index (P=0.053) and young age (P=0.037) were associated with negative EUS imaging. All patients with negative imaging were females. The position on the examiner’s learning curve, the diameter and location of insulinoma, and endocrine parameters (insulin concentrations and insulin–glucose ratios in the prolonged fasting test) had no influence on the success of EUS imaging.

Conclusions: Some insulinomas are missed by preoperative EUS imaging as they are completely isoechoic. A low body mass index, female gender, and young age might be risk factors for negative imaging.

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S Schaefer, M Shipotko, S Meyer, D Ivan, K J Klose, J Waldmann, P Langer and P H Kann

Objective

Adrenal lesion is one of the features of multiple endocrine neoplasia type 1 (MEN1). This study aimed to assess prevalence, natural course and clinical relevance of small adrenal lesions without clinical symptoms, endocrine activity, or mechanical problems and thus without clear indication for surgical therapy by endoscopic ultrasound (EUS).

Design and methods

Forty-nine patients with familial MEN1 were studied. Twenty-seven of these with adrenal lesions were detected by EUS and at least two performed EUS examinations were included into a subgroup where changes in adrenal morphology were studied by measuring changes in the largest diameter of the dominant adrenal tumour.

Results

EUS detected adrenal lesions in 36 (73%) patients: 6 (12%) plump adrenals, 17 (35%) nodular hyperplasia, 12 (24%) adenomas and 1 (2%) cyst. Bilateral adrenal lesions were detected in 17 patients and unilateral in 19 patients. A change in the largest tumour diameter was found to be for nodular hyperplasia −0.02±1.41% per month (range −2.56 to 4.58%) and for adenomas −0.61±1.95% per month (range −6.25 to 1.15%). One patient had an adrenal cyst with significant growth. There was no evidence of carcinoma or metastatic disease during the study.

Conclusions

The prevalence of adrenal lesions in MEN1 is higher than that reported earlier. Except one cystic lesion, no significant change in the tumour size was observed over a mean observation period of more than 2 years. In a typical situation, small adrenal lesions in MEN1 seem to be constant in their morphology.

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E P Slater, S M Diehl, P Langer, B Samans, A Ramaswamy, A Zielke and D K Bartsch

Objectives: Adrenocortical carcinoma (ACC) is a rare malignant neoplasm with extremely poor prognosis. The molecular mechanisms of adrenocortical tumorigenesis are still not well understood. The comparative analysis by cDNA microarrays of gene-expression patterns of benign and malignant adrenocortical tumors allows us to identify new tumor-suppressor genes and proto-oncogenes underlying adrenocortical tumorigenesis.

Design and methods: Total RNA from fresh-frozen tissue of 10 ACC and 10 benign adrenocortical adenomas was isolated after histologic confirmation of neoplastic cellularity of at least 85%. The reference consisted of pooled RNA of 10 normal adrenal cortex samples. Amplified RNA of tumor and reference was used to synthesize Cy3- and Cy5-fluorescently labeled cDNA in a flip-color technique. D-chips containing 11 540 DNA spots were hybridized and scanned and the images were analyzed by ImaGene 3.0 software.

Results: The comparative analysis of gene expression revealed many genes with more than fourfold expression difference between ACC and normal tissue (42 genes), cortical adenoma and normal tissue (11 genes), and ACC and cortical adenoma (21 genes) respectively. As confirmed by real-time PCR, the IGF2 gene was significantly upregulated in ACCs versus cortical adenomas and normal cortical tissue. Genes that were downregulated in adrenocortical tumors included chromogranin B and early growth response factor 1.

Conclusions: Comprehensive expression profiling of adrenocortical tumors by the cDNA microarray technique is a very powerful tool to elucidate the molecular steps associated with the tumorigenesis of these ill-defined neoplasms. To evaluate the role of identified genes, further detailed analyses, including correlation with clinical data, are required.