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OBJECTIVE AND DESIGN: Iodide concentration (IC) in salt was cautiously increased in Switzerland (15 --> 20 ppm iodide). We evaluated the dynamics of the effect of this intervention on urinary iodine concentration (UIC, microg/l) and on thyroid parameters. SETTING: University Hospital in Bern, Switzerland. SUBJECTS: A cohort of 36 subjects (12 children, 11 women, 13 men) out of 44 were recruited. INTERVENTIONS: During the study periods PRE (May 1996-May 1998) and POST (October 1998-December 2000, subdivided into equal subperiods POST1 and POST2), that is, before and after the increase of IC in salt, subjects collected 6248 urine spots for analysis of UIC. Thyroid volumes (n=2/subject) and serum thyroid parameters (n=8/subject) were sequentially evaluated. METHODS: Average PRE-POST data were compared (multiple regression analysis). RESULTS: UIC increased overall by 5.1% (P=0.0003). Increase of UIC was highest in children (11.3%, P<0.0001), significant in women (8%, P=0.0016), but not significant in men (P=0.143). Comparison between periods POST1 and POST2 showed that UIC changed more gradually in women than in children. Thyroid volumes were normal, no nonphysiological change occurred. TSH indicated euthyroidism; it decreased in children (1.98 ==> 1.74 mU/l, P=0.04) and increased in men (1.65 ==> 1.91mU/l, P=0.025). FT3 decreased in children (P<0.004) and FT4 decreased in men (P=0.017), both within normal ranges. TSH, FT3 and FT4 were unchanged in women. FT3/FT4 ratios were stable. Anti-TPO-Ab titers were stable (P=0.9). Anti-Tg-Ab titers decreased (P=0.009). CONCLUSION: The significant UIC effects were of uncertain metabolic relevance. No pathological side effects occurred. Differential delays and penetrances of UIC increase in children and adults were hitherto unknown. The unspectacular stepwise policy seems to be safe. Our pilot results in a population with moderate iodine deficiency in women should be confirmed in population-based cluster studies. SPONSORSHIP: This work was supported by grants from the University Hospital in Bern, the Swiss Federal Office of Public Health (SFOPH), the 'Swiss National Foundation for Scientific Research' (32-49424.96), the 'Fondation Genevoise de Bienfaisance Valerie Rossi di Montelera', the 'Schweizerische Lebensversicherungs- und Rentenanstalt' and the 'Schüpbach Foundation of the University of Bern'.

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OBJECTIVE: To compare different possibilities of reporting the iodine supply in the same urine samples. Indeed, in field studies, urinary iodine concentration (I/L: micro g I/L, micro mol I/L, I/creatinine: micro g I/g creatanine, micro mol I/mol creatinine) is more readily available than excretion (I/24h micro g I/24 h, micro mol I/24h). However, confusion exists regarding the comparability of iodine supply based upon I/L, I/creatinine and I/24h, which for decades have been regarded as biochemically equivalent. DESIGN: We compared I/24h, I/L and I/creatinine in accurate 24 h collections of urine and I/L and I/creatinine in 47 spot urine samples. PATIENTS: A total of 13 subjects (Bern n=7, Brussels n=6) collected a total of 110 precise 24 h urine collections (Bern n=63, Brussels n=47). The subjects from Brussels also took a spot sample at the beginning of each 24 h collection. RESULTS: Iodine supply in both places was mildly deficient according to the criteria of WHO; all but one collection indicated an intake of >0.39 micro mol I/24h (>50 micro g I/24h). The same data presented as I/creatinine (or I/L) indicated an iodine intake of <0.39 (<50 micro g I/24h) in 5% (24%) of the samples in Bern and 23% (57%) in Brussels. Similar findings were observed for 47 spot samples. Whatever the cut-off selected, I/creatinine and I/L were systematically lower than I/24h (P<0.0002). Creatinine showed smaller CV than volume but did not perform better in defining iodine intake. CONCLUSION: Considering I/24h as a reference, both I/creatinine and I/L clearly underestimate the iodine intake in subjects with adequate proteoenergetic intake. The significant deviations observed illustrate the urgent need for establishing separate ranges for I/24h, I/creatinine and I/L. In population studies, these deviations might even be larger.

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We prospectively investigated urinary iodine concentration (UIC) in pregnant women and in female, non-pregnant controls in the canton of Berne, Switzerland, in 1992. Mean UIC of pregnant women [205 +/- 151 microg iodine/g creatinine (microg l/g Cr); no. = 153] steadily decreased from the first (236 +/- 180 microg l/g Cr; no. = 31) to the third trimester (183 +/- 111 microg l/g Cr, p < 0.0001; no. = 66) and differed significantly from that of the control group (91 +/- 37 microg l/g Cr, p < 0.0001; no. = 119). UIC increased 2.6-fold from levels indicating mild iodine deficiency in controls to the first trimester, demonstrating that high UIC during early gestation does not necessarily reflect a sufficient iodine supply to the overall population. Pregnancy is accompanied by important alterations in the regulation of thyroid function and iodine metabolism. Increased renal iodine clearance during pregnancy may explain increased UIC during early gestation, whereas increased thyroidal iodine clearance as well as the iodine shift from the maternal circulation to the growing fetal-placental unit, which both tend to lower the circulating serum levels of inorganic iodide, probably are the causes of the continuous decrease of UIC over the course of pregnancy. Mean UIC in our control group, as well as in one parallel and several consecutive investigations in the same region in the 1990s, was found to be below the actually recommended threshold, indicating a new tendency towards mild to moderate iodine deficiency. As salt is the main source of dietary iodine in Switzerland, its iodine concentration was therefore increased nationwide in 1998 for the fourth time, following increases in 1922, 1965 and 1980.

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OBJECTIVE: Because of known significant seasonal fluctuations of iodine concentration in cow's milk (ICM) in Switzerland (winter/summer (w/s) ICM ratio averages 5.6), we looked for seasonal variations and familial aspects in urinary iodine and sodium concentrations (UIC, UNaC). DESIGN: : Prospective sequential cohort investigation. SETTING: University hospital. SUBJECTS: Thirteen children (six girls, seven boys) aged 3-10 y and their parents (n=9) aged 30-47 y. INTERVENTIONS: The volunteers collected 1729 spot urine samples (5.1996-5.1998). UIC data from winter (UIC(w): December-February) and summer seasons (UIC(s): July-September) were compared with UNaC and average milk consumption. Iodine intakes from milk and salt were modelized. RESULTS: Highest seasonal fluctuations of UIC were found in six pre-school children (w/s UIC group average=1.56, significant), followed by seven school children (w/s UIC group average=1.24, N.S.); none existed in adults. UIC/UNaC showed corresponding seasonal fluctuations in children, but not in adults. Winter milk was an important iodine source for children, as proven indirectly by similar seasonal fluctuations of ICM, UIC, UIC/UNaC and an important part within UIC due to milk. CONCLUSIONS: Contribution to UIC from milk intake during winter was high in children (40-50%) and lower in adults (about 20%). Compared with children, dietary habits of adults are more complex and their iodine supply depends mainly on iodized salt and not on milk, so the effect of seasonal ICM variations on UIC is less marked. Because of significant seasonal UIC fluctuations in consumers of fresh milk products in Switzerland, results of future UIC studies conducted during summer and winter seasons should be compared cautiously, especially in young children. Furthermore, consumption of milk is to be promoted, since, besides calcium and vitamins, it is an essential source of iodine. UNaC determination should be included in epidemiologic studies if the dietary source of iodine is questioned.

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OBJECTIVES: To see whether a collection of portraits depicting inhabitants of a defined geographical region and covering several centuries is a useful source for studying the sociocultural significance and epidemiology of particular visible diseases, such as goitre, which is known to have been common in this region. DESIGN: Systematic review of portraits and description of visible signs of illness. SETTING: The Burgerbibliothek (archives of the burghers' community) in Berne, Switzerland. DATA SOURCES: 3615 portraits; 2989 of individuals whose identity is known and 626 of individuals whose identity is unknown. MAIN OUTCOME MEASURES: Visible signs of illness evaluated by means of a standardised visual assessment. RESULTS: Visible signs of illness in portraits were common and appeared in up to 82% (451/553) of paintings from the 17th and 18th centuries. The most common findings were signs of goitre in women and overweight in men. In only the portraits where the neck region could be evaluated, 41% of women with known identities (139/343) had goitre compared with 24% of men with known identities (21/86). The prevalence of goitre was even higher in sitters whose identities were unknown: 63% in men (5/8) and 68% in women (82/121). Overweight in people with known identities was more common in men than in women (30%, 346/1145 v 44%, 811/1844). Overweight was most common in sitters aged >40 than in those aged 40 or younger. Other conditions, such as missing teeth, amputated limbs, or osteoarthritic deformations were surprisingly rare in the portraits under evaluation. CONCLUSIONS: Goitre and other diseases are under-represented in the people depicted in these portraits. Artistic idealisation is a likely explanation for this observation: what was reproduced depended on what was considered pathological or shameful at the time, and therefore depended on age and sex. Stigmatising details may have been omitted. Further, artistic skills and contemporary fashion may have influenced the way in which people were reproduced. People depicted are possibly not representative of the general Bernese population as they constituted a socioeconomically advantaged group.

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OBJECTIVE: Before a scheduled increase of salt iodide content up to 20 p.p.m. in Switzerland, urinary iodine concentration (UIC, microg/l) of a randomly selected, area-covering, age-stratified population subgroup was sampled in spring 1997. In contrast to former published studies on UIC, we minimized biases by age, gender, rural/urban, socio-economic and cultural influences. METHODS: We contacted 750 households in the Bernese region using random telephone numbers. Per household, one proband selected by play dice collected a spot urine sample. We defined seven age categories: infants, children, adolescents, adults I-III and seniors, aged 0-5, 6-12, 13-20, 21-35, 36-50, 51-65 and >65 years respectively. Randomized UIC data were compared with WHO criteria of iodine deficiency (ID) and previous non-randomized, age-dependent Swiss UIC data. To recruit a perfect random group of volunteers proved difficult, as study participation of adolescent and male populations was somewhat lower than that of elder and female (P<0.005) populations respectively. Study participation of inhabitants of rural and suburban regions was comparable (P=0.139). Out of 413 obtained urine spots, 412 (55%) were analyzed statistically (58% women, 42% men, P<0.005). RESULTS: Ninety per cent of all UIC values ranged between 25 and 200 microg/l. Median UIC showed mild ID (94 microg/l). UIC varied significantly between age categories (P=0. 0006). Women had lower UIC than men (P=0.014). Infants had no ID. Women in child-bearing age (13-35 years), adults II, adults III and seniors had mild ID. Compared with recommended supplies of 150 and 200 microg I/day in children and male adolescents respectively, we consider their UIC (110 and 144 microg/l) as at least borderline deficient. Absolute UIC was lowest in seniors. Probands from rural/suburban households had similar UICs. Our UIC data were comparable to published ones. CONCLUSIONS: Despite long-term national efforts with iodized salt (15 p.p.m. in 1997), mild ID still prevailed in Bern in spring 1997, with rare extreme UIC values. Mild ID with women in child-bearing age (and probably also with children and male adolescents) was a serious concern, as goiter growth with puberty or pregnancy might be the consequence. Mild ID in adults and seniors might be due to restricted NaCl intake. Results of our randomly selected subgroup from a 650 000 population show that age- and gender-dependency are important when comparing our collected data with published UIC data. This fact must be considered with non-randomly selected population subgroups.

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Our overall aim is to monitor iodine supply in a prospective study before and after the September 1998 increase of salt iodide content in Switzerland. Because iodide is supplied by alimentation, we moreover wondered whether urinary iodine concentration (UI) is governed by circadian rhythmicity. Forty-two subjects (18 males and 24 females, including 13 children) collected 3023 urine spots between May 1996 and May 1998, at a rate of three to five samples per month, at any time of the day. The results show that circadian rhythmicity of UI in adults and children was found independent of the individual subject, age, gender, and season. Lowest UI levels were found between 8-11 h. A curve increasing progressively between 12 and 24 h was obtained. UI returned to base-line levels between 21 and 22 h in children only. UI peaks occurred 4-5 h after main meals; children's peaks occurred later than that of adults. Although the existence of a circadian rhythm of UI is probably universal, its profile, however, depends on alimentation. Because nadir of UI is represented by morning spots, this might seem an appropriate collecting period. In view of the significant circadian rhythmicity of UI, studies with restriction of sampling time to morning hours, for example, cannot be directly compared with studies in which urine is sampled all over the day.

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Neoplastic growth results from cell production that exceeds cell loss. We registered mitotic and apoptotic indices (MI and AI) in 97 immunohistochemically verified oncocytic (Hürthle cell) tumors of the thyroid (OT; 50 adenomas [OA], 20 atypical adenomas [aOA], and 27 carcinomas [OC]) and compared these kinetic data with histological diagnoses and other parameters. MI, although very low in all, was significantly higher in carcinomas than in adenomas. Conversely, AI did not differ as much among the 3 groups. This indicates that the magnitude of cell deletion did not play a prominent role in determining the disparate growth of the 3 types of oncocytic tumors. Cluster analysis with MI and AI per case as variables revealed the existence of 3 groups of neoplasms with highly distinct growth characteristics: (1) near-steady state (n = 78, all diagnostic categories represented); (2) progressive (n = 9, mostly carcinomas); and (3) regressive (n = 10, mostly adenomas). MI distinguished between histologically benign and malignant with the greatest discriminant power of the variables tested. Proliferative indices should thus be included in the differential diagnostic evaluation of oncocytic thyroid tumors. Our study also suggests that invasiveness and growth are 2 diverging properties of carcinomas.

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We report a case of a man presenting with a cervical malignant teratoma and a chondrosarcomatous rib metastasis. He was alive and free of recurrence five years and 10 months (= 70 months) after resection of the primary mass, followed by chemotherapy and subsequent resection of the rib tumor. This is the 35th patient reported in the literature and the first description in which an 'adjuvant' or primary chemotherapy was used. Previous patients with a cervical malignant teratoma, reported after lethal outcome, had survivals of one to 22 months (median nine months). In all patients with a preoperative clinical impression of an aggressive, differentiated or undifferentiated malignancy, the definite diagnosis of teratoma could only be made histologically. By analogy to germ cell tumors, the prognosis of malignant teratoma might be improved if complete excision is combined with new, adjuvant chemotherapy protocols for germ cell tumors. Lessons learned from this case are placed in the context of germ cell tumors in general and of non-gonadal malignant teratomas in particular.

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An inductively coupled mass spectrometric method was developed for the direct determination of iodine in urine. The application of isotope dilution analysis with added 129I offers new possibilities for automatic and accurate determinations. The sample preparation consists of dilution with an ammonia solution containing 129I. The validation was made by comparison with the results obtained in another laboratory by a spectrophotometric method based on the Sandell-Kolthoff reaction. Different regression models, including maximum likelihood estimation, were used to compare the methods. None of the models revealed analytical bias between the two methods. The urine samples analyzed for validation were from three persons previously exposed to an iodine bath and covered a concentration range of 0.2 to 2.8 micromol/L. A detection limit of 0.02 micromol/L, a within-run CV of 2.5%, and a between-run CV of 11.9% were estimated for the proposed method.

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Over the last 20 years, unifocal functionally autonomous nodes (UFA) of the thyroid have accounted for more than one third of all patients with hyperthyroidism in the former iodine-deficient and goiter-endemic region of Bern. This situation calls for a special diagnostic approach, i.e. etiologic diagnosis of any solitary nodule and careful consideration of therapy in contrast to regions with iodine excess where UFA is very rare, such as the USA. Therapy is recommended even where hyperthyroidism is still latent (blocked TRH test, normal TT3 and TT4) and reliably leads to subjective and objective improvement even in oligosymptomatic individuals. The safe and easy radioiodine therapy (RIT) is preferred in elderly patients with associated conditions. Surgical resection is recommended chiefly where malignancy is suspected or RIT is technically inappropriate. Both methods produce prompt eradication of the source of hyperthyroidism. The most frequent complication is hypothyroidism requiring lifelong follow-up.

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The regional excess of function and cell mass in potentially "toxic" thyroid areas with nonimmunogenic hyperthyroidism (NIH) (unifocal [UFA, previously "toxic adenoma"] and multifocal functional autonomies [MFA or "toxic goiter"]) are quantified by an enhanced diagnostic method: double isotope subtraction scintigraphy (Ssc) with radioiodine and 99mTc-MIBI. In 125 patients, a toxicity index T was derived from the Ssc (*J-*MIBI), and a cell density index Q from the *MIBI image. The median value of T, as an expression of the regional autonomous excess function (165 in UFA, 15 in MFA), by far exceeded the median value of Q (3.8 in UFA, 2.0 in MFA). The significant (p < 0.001) effects of radioiodine therapy (RIT) were monitored by the changes towards normalization of T and Q in 53 patients in follow-ups 3 and 9 months thereafter. Our aim was (a) to extend the conventional field of measurement of NIH-hyperthyroidism with the scintigraphically quantified function and morphology, and (b) to compare the return to euthyroid state with scintigraphic scarification of the functionally autonomous areas.

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Owing to the progressive iodination of salt in Switzerland (5, 10, 20 mg KI/kg in the years 1922, 1965, 1980), iodine deficiency in former endemic goiter regions had nearly disappeared. In several areas of the country, urinary iodine had increased from below 30 micrograms/24 h (1920) to > 100 micrograms/g creatinine (1981-1990). In 1991-1992, however, the 24-h-iodinuria in a subgroup of 160 examinations out of a total of 289 persons in Berne was again insufficient (norm > 150 micrograms J/24 h): mean 121 micrograms/24 h (82 micrograms/l), median 107.8 micrograms/24 h (67 micrograms/l). Follow-up of one proband in 1991-1992 (n = 9) and 1996 (n = 11) yielded average 24-h-iodinurias in the slightly deficient domain of (mean +/- SD) 104 +/- 57 micrograms/ 24 h (75 +/- 30 micrograms/l) and 103 +/- 27 micrograms/24 h (44 +/- 17 micrograms/l) respectively, with a wide range (45-258 micrograms l/24 h globally). Possible reasons for the decreasing iodide intake in recent years, resulting in the 1990s in a marginally deficient supply, are reduced intake of salt in recent decades, increased consumption of foodstuffs prepared with non-iodized salt, dietary diversification, and frequent meals away from the family table. Therefore, intake of non-iodized salt should be avoided in Switzerland.

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We describe a case of extramedullary hematopoiesis in a hyperplastic thyroid nodule from a patient with primary myelofibrosis. The presence of extensive extramedullary hematopoiesis in the thyroid gland was suspected as a result of fine-needle aspiration cytologic examination and was confirmed by histo- and immunomorphologic examination of the resected nodule. The diagnosis of myelofibrosis was established on the basis of clinical findings, hematologic laboratory results, and bone marrow morphologic characteristics.

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Regional autonomous cell mass (Q: cell density ratio) and function (T: toxicity index) were compared by double isotope parametric thyroid scintigraphy (Als et al., Nucl. Med. 1995; 34) in 53 patients with non-immunogenic hyperthyroidism before and after radioiodine therapy (aRIT) and showed a break-down (medians) of Q: 4.3-->1.0 (toxic adenomas: TA), 2-->1.1 (multifocal functional autonomies: MFA)(p < 0.0001) as of T: 96-->1.7 (TA), 15-->1.1 (MFA) (p < 0.001). Five functional aRIT patterns resulted: euthyroidism (n = 37, 70%), at half with scarred/non-scarred autonomous areas (low/higher T, respectively), primary hypothyroidism (n = 4), residual hyperthyroidism (n = 7), secondary hyperthyroidism (n = 5). The last two groups with persistent subnormal TSH values were clearly separated by divergent T, thyroxine and triiodothyronine levels. A resulting T > 1 may represent a clinically sub-critical mass of residual autonomous tissue. This new technique facilitates individual pretherapeutic evaluations and aRIT quality control.

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UNLABELLED: A new quantitative subtraction method of thyroid scans is proposed which shows that regional function (F) by far exceeds regional cellularity or cell density (C) in potentially toxic thyroidal areas of non-immunogenic hyperthyroidism (NIH). METHODS: A multistep processing of radioiodine and MIBI thyroid scans of patients with non-immunogenic hyperthyroidism led to normalized images of regional function excess and of perinodular enhancement. Two numeric factors were derived from regions of interest: Q (cell density ratio) comparing MIBI uptake in autonomous and suppressed areas and T (toxicity index): the maximal F/C contrast. RESULTS: Q never exceeded 61; T, however, expanded toxicity levels over a range of 6-8735 with toxic adenomas (median = 165) and with hot areas of multifocal functional autonomy (median = 15). T was weakly correlated to serum TT3 (r = 0.41), but not to autonomous tissue mass, ultrasonographic or cytologic criteria. CONCLUSIONS: T is governed by inherent features of autonomous tissue and the response of the imbedded thyroid tissue to TSH stimulation. This standardized technique consolidates experiences from visual analysis; the huge T range mirrors the natural evolution from compensated autonomy towards hyperthyroid, decompensated stages.

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