Metabolic engineering of Saccharomyces cerevisiae for the de novo production of psilocybin and related tryptamine derivatives.

Psilocybin is a tryptamine-derived psychoactive alkaloid found mainly in the fungal genus Psilocybe, among others, and is the active ingredient in so-called "magic mushrooms". Although its notoriety originates from its psychotropic properties and popular use as a recreational drug, clinical trials have recently recognized psilocybin as a promising candidate for the treatment of various psychological and neurological afflictions. In this work, we demonstrate the de novo biosynthetic production of psilocybin and related tryptamine derivatives in Saccharomyces cerevisiae by expression of a heterologous biosynthesis pathway sourced from Psilocybe cubensis. Additionally, we achieve improved product titers by supplementing the pathway with a novel cytochrome P450 reductase from P. cubensis. Further rational engineering resulted in a final production strain producing 627 ± 140 mg/L of psilocybin and 580 ± 276 mg/L of the dephosphorylated degradation product psilocin in triplicate controlled fed-batch fermentations in minimal synthetic media. Pathway intermediates baeocystin, nor norbaeocystin as well the dephosphorylated baeocystin degradation product norpsilocin were also detected in strains engineered for psilocybin production. We also demonstrate the biosynthetic production of natural tryptamine derivative aeruginascin as well as the production of a new-to-nature tryptamine derivative N-acetyl-4-hydroxytryptamine. These results lay the foundation for the biotechnological production of psilocybin in a controlled environment for pharmaceutical applications, and provide a starting point for the biosynthetic production of other tryptamine derivatives of therapeutic relevance.

Association of mortality with out-of-hours admission in patients with perforated peptic ulcer.

BACKGROUND: Perforated peptic ulcer is a serious emergency surgical condition. The aim of the present nationwide cohort study was to evaluate the association between mortality and out-of-hours admission in patients surgically treated for perforated peptic ulcer. METHODS: All Danish patients surgically treated for benign gastric or duodenal perforated peptic ulcer in Denmark between September 1, 2011 and August 31, 2013 were included. Patients were identified through The Danish Clinical Register of Emergency Surgery. The association between 90-day mortality and time and day of admission and surgery was assessed by crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: A total of 726 patients were included. Median age was 69.5 years (range 18.2-101.7), and 569 of the 726 patients (78.4%) had at least one coexisting disease. Adjusted ORs and 95% CIs between 90-day mortality and admission in daytime vs. nighttime and weekday vs. weekend were 1.0 (0.7-1.5) and 1.2 (0.8-1.8), respectively. Adjusted ORs with 95% CI between surgery in daytime vs. nighttime and weekday vs. weekend were 0.9 (0.6-1.3) and 1.2 (0.8-1.8), respectively. Sensitivity analysis was consistent with the primary analysis. The overall 90-day mortality rate was 25.6% (186/726). CONCLUSION: No statistically significant adjusted association between 90-day mortality and out-of-hours admission was found in patients surgically treated for perforated peptic ulcer.

Evaluating iodine deficiency in pregnant women and young infants-complex physiology with a risk of misinterpretation.

OBJECTIVE: To review methods for evaluating iodine deficiency in pregnant women and young infants and to discuss factors to be considered in the interpretation of their results. DESIGN: Review of the literature regarding the various methods available for assessing iodine status. SETTING: Population surveys and research studies. SUBJECTS: Pregnant women and young infants. RESULTS: Several factors to consider when assessing iodine status in pregnant women and young infants include: 1) the urinary iodine (UI) concentration (microg l-1) is not interchangeable with 24 h UI excretion (microg per 24 h); 2) the concentration of iodine in a spot or casual urine sample cannot be used to diagnose iodine deficiency in an individual; 3) a moderate fall in the concentration of serum free T4 during pregnancy is not a sign of maternal iodine deficiency; 4) an increase in the concentration of serum thyroglobulin (Tg) during pregnancy is not a sign of maternal iodine deficiency; 5) a higher concentration of TSH and Tg in cord blood than in maternal blood is not a sign of iodine deficiency in the mother or neonate; and 6) thyroid function in a full-term foetus, a neonate or a small child is not more sensitive to a mild iodine deficiency than in the mother. CONCLUSIONS: If the iodine status of pregnant women and small children is not to be misjudged, the above six factors need to be taken into account.

Low socio-economic status and familial occurrence of goitre are associated with a high prevalence of goitre.

The occurrence of goitre is dependent on genetic and environmental factors, but the associations with socio-economic and life-style factors have only been examined briefly. A cohort of 4649 participants from the general population was examined with questionnaires, thyroid ultrasonography, clinical examination and blood tests. Data were analysed in linear models and logistic regression analysis. Thyroid volume and serum thyroglobulin were closely associated with educational level with higher values in the group with the lowest levels of education (p < 0.001). The same pattern applied to thyroid multinodularity at ultrasonography (p = 0.002) and palpable goitre (p = 0.01). Physical activity in leisure time was negatively associated with thyroid enlargement (p = 0.02) and serum thyroglobulin (p < 0.001). These associations diminished markedly if adjustment was made for smoking habits, alcohol consumption and iodine intake. Familial occurrence of goitre was associated with goitre prevalence (Odds Ratio 2.5, 95% CI: 1.6-3.9), but did not confound the socio-economic associations. In conclusion, social imbalances in the occurrence of goitre were identified. These imbalances could in part be explained by differences in smoking habits and iodine intake.

High occurrence of thyroid multinodularity and low occurrence of subclinical hypothyroidism among tobacco smokers in a large population study.

Tobacco smoking increases the risk of goitre and Graves' disease, but the association with thyroid nodularity and hypothyroidism has not been settled. We investigated 4649 subjects from the general population with questionnaires, thyroid ultrasonography and blood tests. The results were analysed in multivariate regression models. Tobacco smoking was associated with an increased prevalence of thyroid multinodularity (odds ratio (OR) 1.9; 95% confidence interval (CI) 1.4-2.5), but not with increased prevalence of solitary thyroid nodules. The tendency was for a stronger association in the area with the most pronounced iodine deficiency (P for interaction=0.08). Lower levels of serum TSH were found among tobacco smokers (P<0.001), but this association disappeared when adjustment was made for thyroid nodularity and thyroid Volume. The prevalence of elevated TSH levels was markedly reduced among smokers (OR 0.47; 95% CI 0.33-0.67). No association was found between smoking and hyperthyroidism. The observed associations seem to be explainable by the blocking of iodine uptake and organification in the thyroid by thiocyanate, a degradation product of cyanide in tobacco smoke.

TSH-receptor antibody measurement for differentiation of hyperthyroidism into Graves' disease and multinodular toxic goitre: a comparison of two competitive binding assays.

OBJECTIVES: Graves' disease is characterized by stimulating autoantibodies to the TSH-receptor (TRAb). The aim of this study was to compare the performance of a new TRAb assay based on competitive binding to recombinant human TSH-receptors (H-TRAb) with an assay employing purified porcine TSH-receptors (P-TRAb). Furthermore, to evaluate the applicability of the H-TRAb assay to discriminate between patients with hyperthyroidism due to Graves' disease (GD) and multinodular toxic goitre (MNTG). DESIGN AND MEASUREMENTS: H-TRAb and P-TRAb were measured in patients with newly diagnosed hyperthyroidism due to GD (n = 106) and MNTG (n = 94). For comparison, TRAb was measured in patients with primary autoimmune hypothyroidism, euthyroid subjects with an enlarged thyroid gland by ultrasound, and healthy controls (n = 100 for each group). Patients were consecutively included from a population survey. RESULTS: If the cut-off values recommended by the manufacturer for TSH-receptor antibody positivity were used for evaluation, the sensitivity of the H-TRAb assay vs. the P-TRAb assay in diagnosing GD was: 95.3/67.9% (P < 0.001). Specificity was (H/P-TRAb): 99/99%. The sensitivity of P-TRAb was increased if the upper 97.5% limit of measurements in controls was used as cut-off (H-TRAb vs. P-TRAb: 95.3/80.2%, P < 0.001). Specificity (H/P-TRAb): 98/98%. The difference between assay performance may partly be due to a better technical performance of the H-TRAb assay with more reliable results in the low range of measurements. However, even in GD patients with clearly measurable TRAb, 25% had a P-TRAb < 50% of the value expected from the H-TRAb measurement. This suggests that a subgroup of patients produce TRAb with a higher affinity for the human than the porcine TSH receptor. A relatively high proportion of patients with MNTG were TRAb positive (H-TRAb/P-TRAb: 17/9%). Characteristics of H-TRAb positive and negative MNTG patients were compared. There was no difference between size of thyroid gland and number of nodules by ultrasonography. H-TRAb positive patients had significantly higher serum T4 and T3 and a greater number were TPO-Ab positive. CONCLUSIONS: H-TRAb diagnosed Graves' disease with a high sensitivity and specificity than P-TRAb. The high occurrence of TRAb in multinodular toxic goitre might in part reflect an overlap between Graves' disease and multinodular toxic goitre in some patients.

Serum Tg--a sensitive marker of thyroid abnormalities and iodine deficiency in epidemiological studies.

Serum Tg is widely used in the control of thyroid cancer but also in the diagnosis of certain other thyroid diseases. Serum Tg may be useful in the characterization of the iodine status of a population, but little is known about determinants of serum Tg levels. We examined a random selection of 4,649 subjects from 2 regions in Denmark with different iodine status. Thyroid volume and structure were determined with ultrasonography, and thyroid function tests and Tg analysis were performed. The factor with the closest association with serum Tg levels was thyroid volume at ultrasonography (P < 0.001). Also thyroid nodularity (P < 0.001) and iodine excretion (P < 0.001) had close associations to serum Tg, even after adjusting for the influence of the other parameters. Thyroid dysfunction had a less pronounced but still highly significant association with serum Tg (P < 0.001), but no relation was found to serum TSH in general. The association with age seemed to rely on differences in the prevalence of thyroid abnormalities, and men had lower Tg levels than women of the same age. There was a marked difference in serum Tg between the two regions with slightly different iodine excretion also after adjusting for the other factors. In conclusion, serum Tg reflects thyroid abnormalities and thyroid function and is a sensitive marker of iodine deficiency in a population.

Alcohol consumption is associated with reduced prevalence of goitre and solitary thyroid nodules.

OBJECTIVE: Goitre prevalence is dependent on iodine intake and smoking habits, but further risk factors have only been examined briefly. We examined the association between alcohol consumption and the prevalence of thyroid enlargement and nodularity. DESIGN: Cross-sectional population study with ultrasonography of the thyroid gland and assessment of alcohol intake and smoking habits from questionnaires. SUBJECTS: Four thousand six-hundred and forty-nine men and women aged 18-65 years, randomly selected from the Danish Civil Registration System. MEASUREMENTS: Thyroid volume and prevalence of thyroid enlargement, multiple nodules or a solitary nodule in the thyroid. RESULTS: Abstainers and participants with a low alcohol consumption (< 7 drinks/week) had the same prevalence of thyroid enlargement and nodularity, but participants with moderate (8-28 drinks/week for women, 8-42 for men) or high (> 28/42 drinks/week) alcohol consumption had much lower prevalence of thyroid abnormalities. Possible confounding by sex, age, iodine status and smoking was considered in all models. Odds ratios compared to abstainers for thyroid enlargement were 0.74 [95% confidence interval (CI) 0.57-0.96] for moderate- and 0.44 (95% CI 0.22-0.88) for high alcohol consumption. Odds ratios compared to abstainers for a solitary nodule were 0.64 (95% CI 0.42-0.96) for moderate- and 0.41 (95% CI 0.12-1.37) for high alcohol consumption. Mean thyroid volume was 13.5 ml among abstainers compared to 10.9 ml among participants with high alcohol consumption (P < 0.001). Both wine- and beer consumption were associated to lower prevalence of thyroid abnormalities. CONCLUSIONS: Increasing levels of alcohol consumption were associated to lower prevalence of thyroid enlargement and to lower prevalence of a solitary nodule in the thyroid, and indications of a causal relationship were found.

Environmental iodine intake affects the type of nonmalignant thyroid disease.

The relationship between the iodine intake level of a population and the occurrence of thyroid diseases is U-shaped with an increase in risk from both low and high iodine intakes. Developmental brain disorders and endemic goiter caused by severe iodine deficiency may seriously deteriorate overall health status and economic performance of a population. Severe iodine deficiency with a median 24-hour urinary iodine excretion of the population below 25 microg needs immediate attention and correction. Less severe iodine deficiency with median urinary iodine excretion below 120 microg per 24 hours is associated with multinodular autonomous growth and function of the thyroid gland leading to goiter and hyperthyroidism in middle aged and elderly subjects. The lower the iodine intake, the earlier and more prominent are the abnormalities. At the other end of the spectrum, severely excessive iodine intake starting at median urinary iodine excretion levels around 800 microg per 24 hours is associated with a higher prevalence of thyroid hypofunction and goiter in children. A number of studies indicate that moderate and mild iodine excess (median urinary iodine >220 microg per 24 hours) are associated with a more frequent occurrence of hypothyroidism, especially in elderly subjects. The exact mechanism leading to this has not been clarified, and more studies are needed to define the limits of excessive iodine intake precisely. Due to the frequent occurrence of thyroid disorders, proper monitoring and control of the population iodine intake level is a cost-effective alternative to diagnosing, therapy and control of the many individual cases of thyroid diseases that might have been prevented.

Evaluation of a semi-quantitative food frequency questionnaire to estimate iodine intake.

OBJECTIVE: To evaluate a food frequency questionnaire (FFQ) used to assess the dietary intake of iodine. DESIGN: The iodine intake determined by the FFQ was compared with 4-day dietary records and with iodine excretion in 24 h urine samples in a subgroup of participants in a cross-sectional study of iodine intake and thyroid diseases in Denmark. Furthermore, the intake of fish determined from the FFQ was compared with the intake of fish from a simple record kept for 3 months. SUBJECTS: Women aged 25-30 y and 60-65 y. RESULTS: Median iodine intake was similar when determined from the FFQ and from dietary records and the correlation between these measures was 0.52 (P < 0.001). Iodine intake was higher than iodine excretion (P < 0.001). The cross-check questions in the FFQ (for example the question 'How often did you get any kind of fish?') underestimated the intake. In contrast, the intake of a specific fish tended to be overestimated by the FFQ when compared with the 3 month record of fish intake. CONCLUSION: The FFQ can be used to classify subjects into low and high iodine intake groups, but the level of iodine tends to be overestimated.

Thyroid disorders in mild iodine deficiency.

Comparative epidemiologic studies in areas with low and high iodine intake and controlled studies of iodine supplementation have demonstrated that the major consequence of mild-to-moderate iodine deficiency for the health of the population is an extraordinarily high occurrence of hyperthyroidism in elderly subjects, especially women, with risk of cardiac arrhythmias, osteoporosis, and muscle wasting. The hyperthyroidism is caused by autonomous nodular growth and function of the thyroid gland and it is accompanied by a high frequency of goiter. Pregnant women and small children are not immediately endangered but the consequences of severe iodine deficiency for brain development are grave and a considerable safety margin is advisable. Moreover, a shift toward less malignant types of thyroid cancer and a lower radiation dose to the thyroid in case of nuclear fallout support that mild-to-moderate iodine deficiency should be corrected. However, there is evidence that a high iodine intake may be associated with more autoimmune hypothyroidism, and that Graves' disease may manifest at a younger age and be more difficult to treat. Hence, the iodine intake should be brought to a level at which iodine deficiency disorders are avoided but not higher. Iodine supplementation programs should aim at relatively uniform iodine intake, avoiding deficient or excessive iodine intake in subpopulations. To adopt such a strategy, surveillance programs are needed.

Folate intake, lifestyle factors, and homocysteine concentrations in younger and older women.

BACKGROUND: An elevated total homocysteine (tHcy) concentration is considered to be an independent risk factor for cardiovascular diseases and has also been associated with an increased risk of neural tube defects. OBJECTIVE: The objective of this study was to investigate folate intake, folate status, and the association between folate intake, other dietary and lifestyle factors, and tHcy concentrations in young and older women. DESIGN: tHcy concentrations were measured in 290 young women aged 25-30 y and in 288 older women aged 60-65 y. All participants completed questionnaires about factors including lifestyle, health, and use of vitamin supplements. Red blood cell folate was measured in 204 of the participants. A subgroup of 258 participants completed dietary records. RESULTS: Median tHcy was 7.6 micromol/L (range: 6.5-8.9) in the younger women and 9.4 micromol/L (7.7-11.1) in the older women. Folate intake from diet was 283 (224-348) and 268 (210-326) microg/d, respectively, in the 2 age groups. Folic acid intake from supplements (P: < 0.001 for the younger women and P: = 0.026 for the older women) and total folate intake (P: = 0.024 and P: = 0.079) were inversely associated with log tHcy in multiple linear regression analyses. Smoking status, coffee consumption, systolic blood pressure, and body mass index were positively associated and estrogen replacement therapy and tea consumption were inversely associated with log tHcy in some of the models. CONCLUSIONS: According to the criteria used, between 1% and 36% of the women had suboptimal folate intake. Folic acid is a strong predictor of tHcy concentration; however, several dietary and other lifestyle factors seem to be important as well.

Review of thyroid cancer cases among patients with previous benign thyroid disorders.

A previous register linkage study showed an increased risk of thyroid cancer among patients previously discharged from a hospital with a diagnosis of a benign thyroid disorder. In this study, we have reviewed all available medical records, first to validate the earlier result and second to describe the symptomatology of patients with a history of benign thyroid disorder prior to the cancer diagnosis. The previous study identified 189 patients with a benign and subsequent malignant thyroid disorder. Medical records were obtainable for 156 of these patients and were reviewed. For 104 patients, benign and malignant thyroid diseases were metachronous (a clearly separated disease history of the benign and malignant diseases), and for 48 patients synchronous. In 4 cases, thyroid cancer could not be confirmed. Among patients with metachronous thyroid disorders, all major benign thyroid disorders were represented including hot nodules, diffuse and multinodular toxic and nontoxic goiter. Symptoms preceding diagnosis of thyroid cancer included growth of goiter/nodules, globulus, stridor, hoarseness, and metastasis. No major differences were found among patients with metachronous and synchronous benign and malignant thyroid disorder, apart from the fact that all metastases were found among metachronous cases. This study confirmed the conclusion that patients with a previous history of goiter or nodules have an increased risk of thyroid cancer. However, thyroid cancer still occurs too infrequently to warrant screening in all patients with a previous history of goiter or nodules.

Comparative study of thyroid function and types of thyroid dysfunction in two areas in Denmark with slightly different iodine status.

OBJECTIVE: The pattern of thyroid dysfunction seems to depend on the iodine status of the population. Prevalence of thyroid dysfunction could be a parameter to consider when evaluating iodine deficiency disorders in a population. DESIGN: Comparative cross-sectional investigation in two regions in Denmark with marginally different iodine excretion. METHODS: A random selection of 4649 participants from the Civil Registration System in Denmark in age groups between 18 and 65 years were examined. Thyroid dysfunction was evaluated from blood samples and questionnaires, and compared with results from ultrasonography. RESULTS: Median iodine excretion was 53 microg/l in Aalborg and 68 microg/l in Copenhagen. Previously diagnosed thyroid dysfunction was found with the same prevalence in the regions. Serum TSH was lower in Aalborg than in Copenhagen (P=0. 003) and declined with age in Aalborg, but not in Copenhagen. Not previously diagnosed hyperthyroidism was found with the same overall prevalence in the regions, but in age >40 years hyperthyroidism was more prevalent in Aalborg (1.3 vs 0.5%, P=0.017). Not previously diagnosed hypothyroidism was found more frequently in Aalborg (0.6 vs 0.2%, P=0.03). Hyperthyroidism was more often associated with macronodular thyroid structure at ultrasound in Aalborg and hypothyroidism was more often associated with patchy thyroid structure in Copenhagen. CONCLUSIONS: Significant differences in thyroid dysfunction were found between the regions with a minor difference in iodine excretion. The findings are in agreement with a higher prevalence of thyroid autonomy among the elderly in the most iodine-deficient region.

Goitre prevalence and thyroid abnormalities at ultrasonography: a comparative epidemiological study in two regions with slightly different iodine status.

OBJECTIVE: The association between severe iodine deficiency and endemic goitre is well established, but little information is available on the relation between milder degrees of iodine deficiency and goitre prevalence. SUBJECTS: In a comparative epidemiological study performed in two regions in Denmark, we examined 4649 subjects from the general population, women aged 18-65 years and men aged 60-65 years. METHODS: Ultrasonography and palpation of the thyroid was performed in all participants. Iodine excretion was measured in casual urine samples. Previous thyroid disease was detected by questionnaires, personal interviews and tracing of records. RESULTS: The median iodine excretion was 61 microg/l (mild iodine deficiency (ID)) and 45 microg/l (moderate ID) in the two regions. Median thyroid volume at ultrasonography was 11. 9 ml (mild ID) and 13.6 ml (moderate ID), P <0.001, and thyroid enlargement was found in 15.0% (mild ID) and 22.6% (moderate ID), P<0.001. Goitre prevalence increased in both regions with age to the age group 40-45 years, but not after that age. Subjects who had moved from the moderate ID to the mild ID area had the same prevalence of thyroid enlargement as the subjects staying permanently in the mild ID area. Thyroid nodules at ultrasonography were found in 30% in both regions, but nodules were larger and more often palpable in the moderate ID area. Palpable goitre was found in 9.8% (mild ID) and 14.6% (moderate ID), P<0.001. The greatest regional difference in thyroid abnormalities was found among men. CONCLUSION: Marked differences in the prevalence of thyroid abnormalities were found in these regions with modest differences in iodine excretion.

Age- and sex-adjusted iodine/creatinine ratio. A new standard in epidemiological surveys? Evaluation of three different estimates of iodine excretion based on casual urine samples and comparison to 24 h values.

OBJECTIVE: The most accurate way to measure urinary iodine excretion in epidemiological surveys is still debated. We propose a new principle of estimating iodine excretion based on casual urine samples. MATERIAL AND METHODS: A total of 123 24 h urine samples and corresponding casual urine samples were collected from 31 subjects. Iodine excretion was expressed as 24 h iodine excretion and three different estimates: iodine concentration in the casual sample, iodine/gram creatinine in the casual sample, and the new principle-iodine/creatinine ratio in the casual sample, adjusted for expected creatinine excretion of the individual. RESULTS: All three estimates based on casual urine samples correlated significantly to 24 h values with a r (Pearson) of 0.37 for iodine concentration, 0. 61 for iodine/creatinine ratio and 0.62 for the age- and sex-adjusted iodine/creatinine ratio. The median iodine excretion in the entire group was 143 microg/day in 24 h samples, 87 microg/l as iodine concentration, 77 microg/g creatinine as iodine/creatinine ratio and 126 microg/day as age- and sex-adjusted iodine/creatinine ratio. CONCLUSION: Age- and sex-adjusted iodine/creatinine ratio is a more accurate and unbiased estimate of iodine excretion in epidemiological surveys of adults than the two most frequently used estimated: iodine concentration and iodine/gram creatinine, as these two estimates may introduce a bias depending on the composition of the investigated group. The adjusted iodine/creatinine ratio is superior to the other estimates, especially when individual estimates of 24 h iodine excretion is required or cohorts of selected groups are investigated. SPONSORSHIP: This work was supported by grants from the Medical Research Foundation Region Greater Copenhagen, Faroe Islands and Greenland; the Wedell-Wedellsborg Foundation; Musikforlaeggerne Agnes and Knut Morks Foundation.

Thyroid structure and size and two-year follow-up of solitary cold thyroid nodules in an unselected population with borderline iodine deficiency.

OBJECTIVE: Multinodular goitre has been found with a high prevalence in iodine-deficient areas, but less frequently in iodine-replete areas; the iodine intake sufficient to prevent goitre has not been established, however. METHODS: We report data from an ultrasonic investigation of the thyroid glands of 2656 randomly selected subjects aged 41 to 71 years in an area with borderline iodine deficiency. RESULTS: Median iodine concentration in spot urine samples was 70microg/l. Multinodular thyroid structure was found in 23% of the population, increasing in women from 20 to 46% with increasing age, and in men from 7 to 23%. Solitary, scintigraphically cold, thyroid nodules >10mm were found in 2.4% of the population with the same prevalence in the different age and sex groups. Two years of follow-up of these cold nodules revealed no signs of malignancies. Median thyroid volume was 11.0ml. Thyroid enlargement (>18ml for women and >25ml for men) was found among 13. 1% of the women and 6.2% of the men, and the prevalence increased with age. The presence of thyroid nodules was related to positive anti-thyroperoxidase antibody (TPO Ab) titres, whereas thyroid enlargement was associated with iodine excretion <50microg/day. CONCLUSIONS: Thyroid enlargement was associated with low iodine excretion and median thyroid volume was slightly increased compared with iodine-replete areas. Multinodular thyroid structure was found with a high prevalence and was associated with TPO Ab >200kU/l. Cold thyroid nodules were moderately prevalent, with no cases of detected malignancies during 2 years of follow-up.

Sedation in the intensive care unit.

OBJECTIVE: To describe the goals of sedative use in the intensive care unit and review the pharmacology of commonly used sedative drugs as well as to review pertinent publications in the literature concerning the comparative pharmacology of these drugs, with emphasis on outcomes related to sedation and comparative pharmacoeconomics. DATA SOURCES: Publications in the scientific literature. DATA EXTRACTION: Computer search of the literature with selection of representative articles. SYNTHESIS: Proper choice and use of sedative drugs is based on knowledge of the pharmacology of commonly used agents and is an essential component of caring for patients in the intensive care unit. The large variability in pharmacokinetics and pharmacodynamics in the critically ill make it difficult to directly compare agents. Midazolam provides rapid and reliable amnesia, even when administered for low levels of sedation. Propofol may be useful when deeper levels of sedation and more rapid awakening are required. Lorazepam can be used for long-term sedation in more stable patients if rapidity of effect is not required. Further investigation in assessment of depth of sedation in the critically ill is needed. Continued study of costs, side effects, and appropriate dosing strategies of all sedative agents is needed to answer questions not sufficiently addressed in the current literature. CONCLUSION: An individualized approach to sedation based on knowledge of drug pharmacology is needed because of confounding variables including concurrent patient illness, depth of sedation, and concomitant use of analgesic agents. (Crit Care Med 2000; 28:854-866)

Validation of ultrasonography of the thyroid gland for epidemiological purposes.

Ultrasonography of the thyroid is often used in epidemiological surveys, thus thorough characterization of the interobserver variation of the different parameters obtained is important. Various methods have been used for measuring thyroid volume, and different formulas have been used for calculation of thyroid volume from the measured dimensions. In this article, two principles of thyroid volume measurement are described in detail: the wellknown method based on the three axes of each lobe and a new principle based on planimetry in two planes. The interobserver variation of the examination and the measuring procedure in itself were tested on 25 participants in a population study. A comparison of postmortem ultrasonography of the thyroid and results of an autopsy was performed. Good correlation and agreement between observers was found for thyroid volume (r = 0.98) and prevalence of thyroid nodules (kappa = 0.72), whereas echogenecity and echopattern showed little agreement. The correlation of thyroid volume by ultrasonography to autopsy results was satisfactory (r = 0.93), but the volume tended to be slightly underestimated even when using the formula pi/6(= 0.52)*length*width*depth. No major differences were found between the performance of the two principles of volume calculation. We conclude that when the measuring procedure is well defined, results of ultrasonography are comparable between observers for thyroid volume and prevalence of thyroid nodules, but not for echogenecity or echopattern. The formula of length*depth*width*pi/6 is suitable for thyroid volume measurement.

The prevalence of thyroid dysfunction in a population with borderline iodine deficiency.

OBJECTIVE: We lack information on the influence of borderline iodine deficiency on the occurrence of thyroid dysfunction. Iodine deficiency has been reported to facilitate the development of toxic nodular goitre, whereas a high iodine intake may increase the prevalence of autoimmune hypothyroidism. SUBJECTS AND METHODS: In a cross-sectional study of a random sample of the general population in our region with borderline iodine deficiency 2656 (65%) of 4073 men and women aged 41 to 71 years participated. Records were made of previous thyroidal illness. Blood samples were drawn for thyroid parameters and TPO Ab values. Iodine and creatinine was assessed in casual urine samples. RESULTS: Previous or present hyperthyroidism was reported by 1.4% of the participants whereas 0.6% had unknown biochemical hyperthyroidism. All cases of undiagnosed hyperthyroidism were among women. Previously diagnosed and treated hypothyroidism was reported by 1.0% and undiagnosed hypothyroidism was found in 0.4%. Subclinical hyperthyroidism was found in 1.3% and subclinical hypothyroidism in 0.7%. TPO Ab titres >200 kU/l were found in 16.9% of the women and 6.6% of the men, and 83% of participants with TSH >5 mU/l had TPO Ab titres >200 kU/l. Participants with TPO Ab titres between 100 and 200 kU/l had no increased frequency of thyroid dysfunction. The median iodine excretion rate was estimated as 103 microg/day. Serum TSH values were higher in women than in men and showed higher dispersion in women as well as in old age. Serum free T3 was found to be higher in women than in men and increased with age. Serum free T4 showed no sex difference but values increased with increasing age. CONCLUSION: In our region with borderline iodine deficiency more than 5% of the general population has clinical or subclinical thyroid dysfunction. We found a relatively high prevalence of hyperthyroidism, especially previously undiagnosed disease, but a low prevalence of hypothyroidism as would be expected in an area of iodine deficiency. Hypothyroidism was related to TPO Ab titres of >200 kU/l. Thyroid hormone levels varied with age and sex.