[Pharmacotherapy of hyperthyreosis--adverse drug reactions]

The antithyroid drugs mainly include thioimidazole (carbimazole, methimazole=thiamazole) and propylthiouracil. After absorption, carbimazole is rapidly metabolized to methimazole and thus switching between these two drugs should not be considered in case of side effects. Furthermore, in case of side effects, sometimes even cross reactions between thioimidazoles and propylthiouracil occur. Common and typical adverse reactions of antithyroid drugs include dose dependent hypothyroidism and thus thyroid function should be repeatedly checked while the patient is on antithyroid drugs. Furthermore, pruritus and rash may develop. In this case, one might try to switch from thioimidazoles to propylthiouracil or vice versa. Antithyroid drugs may cause mild dose dependent neutropenia or severe allergy-mediated agranulocytosis, which typically occurs during the first three months of treatment, has an incidence of 3 per 10,000 patients and cross reactivity between thioimidazoles to propylthiouracil may occur. Rarely, antithyroid drugs can cause aplastic anemia. Mainly propylthiouracil, but sometimes also methimazole may lead to an asymptomatic transient increase in liver enzymes or to severe, even lethal liver injury of cholestatic or hepatocellular pattern. Since propylthiouracil associated liver injury was observed increasingly among children and adolescent, it has been suggested to prefer thioimidazoles for these patients. Because of these potential serious adverse effects, physicians should advise patients to immediately seek medical help if they get a fever or sore throat or malaise, abdominal complaints or jaundice, respectively. Furthermore, arthralgias may develop in 1-5% of patients under both antithyroid drugs. Since arthralgias may be the first symptom of more serious immunologic side effects, it is recommended to stop the antithyroid drug in this case. Drug induced polyarthritis mainly develops during the first month of therapy, whereas ANCA-positive vasculitis is generally observed only after long term exposure to propylthiouracil or very rarely with the thioimidazoles. The teratogenic risk of the thioimidazoles is somewhat higher (Aplasia cutis congenita), that is why one generally recommends preferring propylthiouracil during pregnancy. During breast feeding both, thioimidazoles or propylthiouracil, may be administered. Nowadays, perchlorate is only used short term in case of latent hyperthyroidism before administering iodine-containing contrast agents. Therefore, the known side effects, which usually are only observed after long term treatment, are not an issue any more.

[Should we screen and treat subclinical hypothyroidism?]

Subclinical hypothyroidism, defined as an elevated thyroid stimulating hormone and normal thyroxine level, is common with aging, particularly after 65 years old. This condition is potentially associated with important consequences, such as cardiovascular diseases and cognitive disorders. So far, indications for screening and thyroxine replacement therapy are still controversial. In this review, we examine the data on those risks and the potential benefits of the treatment. We also present a large European randomized clinical trial that should clarify this controversy, in order to improve clinical care of patients with subclinical hypothyroidism and to give reliable data on maintaining good health among the elderly.

Endocrine changes and liver mRNA abundance of somatotropic axis and insulin system constituents during negative energy balance at different stages of lactation in dairy cows

The liver has an important role in metabolic regulation and control of the somatotropic axis to adapt successfully to physiological and environmental changes in dairy cows. The aim of this study was to investigate the adaptation to negative energy balance (NEB) at parturition and to a deliberately induced NEB by feed restriction at 100 days in milk. The hepatic gene expression and the endocrine system of the somatotropic axis and related parameters were compared between the early and late NEB period. Fifty multiparous cows were subjected to 3 periods (1=early lactation up to 12 wk postpartum, 2=feed restriction for 3 wk beginning at around 100 days in milk with a feed-restricted and a control group, and 3=subsequent realimentation period for the feed-restricted group for 8 wk). In period 1, plasma growth hormone reached a maximum in early lactation, whereas insulin-like growth factor-I (IGF-I), leptin, the thyroid hormones, insulin, and the revised quantitative insulin sensitivity check index increased gradually after a nadir in early lactation. Three days after parturition, hepatic mRNA abundance of growth hormone receptor 1A, IGF-I, IGF-I receptor and IGF-binding protein-3 (IGFBP-3) were decreased, whereas mRNA of IGFBP-1 and -2 and insulin receptor were upregulated as compared with wk 3 antepartum. During period 2, feed-restricted cows showed decreased plasma concentrations of IGF-I and leptin compared with those of control cows. The revised quantitative insulin sensitivity check index was lower for feed-restricted cows (period 2) than for control cows. Compared with the NEB in period 1, the changes due to the deliberately induced NEB (period 2) in hormones were less pronounced. At the end of the 3-wk feed restriction, the mRNA abundance of IGF-I, IGFBP-1, -2, -3, and insulin receptor was increased as compared with the control group. The different effects of energy deficiency at the 2 stages in lactation show that the endocrine regulation changes qualitatively and quantitatively during the course of lactation.

Tumor classification of six common cancer types based on proteomic profiling by MALDI imaging

In clinical diagnostics, it is of outmost importance to correctly identify the source of a metastatic tumor, especially if no apparent primary tumor is present. Tissue-based proteomics might allow correct tumor classification. As a result, we performed MALDI imaging to generate proteomic signatures for different tumors. These signatures were used to classify common cancer types. At first, a cohort comprised of tissue samples from six adenocarcinoma entities located at different organ sites (esophagus, breast, colon, liver, stomach, thyroid gland, n = 171) was classified using two algorithms for a training and test set. For the test set, Support Vector Machine and Random Forest yielded overall accuracies of 82.74 and 81.18%, respectively. Then, colon cancer liver metastasis samples (n = 19) were introduced into the classification. The liver metastasis samples could be discriminated with high accuracy from primary tumors of colon cancer and hepatocellular carcinoma. Additionally, colon cancer liver metastasis samples could be successfully classified by using colon cancer primary tumor samples for the training of the classifier. These findings demonstrate that MALDI imaging-derived proteomic classifiers can discriminate between different tumor types at different organ sites and in the same site.

Congenital hypothyroidism in a kitten resulting in decreased IGF-I concentration and abnormal liver function tests

A 7-month-old male kitten was presented with chronic constipation and retarded growth. Clinical examination revealed disproportional dwarfism with mild skeletal abnormalities and a palpable thyroid gland. The presumptive diagnosis of congenital hypothyroidism was confirmed by low serum total thyroxine (tT(4)) concentration prior to and after the administration of thyroid stimulation hormone (TSH), increased endogenous TSH concentration and abnormal thyroid scintigraphic scan. The kitten had abnormal liver function tests and decreased insulin-like growth factor 1 (IGF-1) concentration, both of which returned to normal in correspondence with an improvement of the clinical signs after 6 weeks of thyroxine therapy. Congenital hypothyroidism is a rare disease that may present with considerable variation in clinical manifestation. In cases in which clinical signs are ambiguous, disorders such as portosystemic shunt and hyposomatotropism have to be taken into account as differential diagnosis. As hypothyroidism may be associated with abnormal liver function tests and low IGF-1 concentrations, test results have to be interpreted carefully.

Mapping genetic variants associated with beta-adrenergic responses in inbred mice

β-blockers and β-agonists are primarily used to treat cardiovascular diseases. Inter-individual variability in response to both drug classes is well recognized, yet the identity and relative contribution of the genetic players involved are poorly understood. This work is the first genome-wide association study (GWAS) addressing the values and susceptibility of cardiovascular-related traits to a selective β(1)-blocker, Atenolol (ate), and a β-agonist, Isoproterenol (iso). The phenotypic dataset consisted of 27 highly heritable traits, each measured across 22 inbred mouse strains and four pharmacological conditions. The genotypic panel comprised 79922 informative SNPs of the mouse HapMap resource. Associations were mapped by Efficient Mixed Model Association (EMMA), a method that corrects for the population structure and genetic relatedness of the various strains. A total of 205 separate genome-wide scans were analyzed. The most significant hits include three candidate loci related to cardiac and body weight, three loci for electrocardiographic (ECG) values, two loci for the susceptibility of atrial weight index to iso, four loci for the susceptibility of systolic blood pressure (SBP) to perturbations of the β-adrenergic system, and one locus for the responsiveness of QTc (p<10(-8)). An additional 60 loci were suggestive for one or the other of the 27 traits, while 46 others were suggestive for one or the other drug effects (p<10(-6)). Most hits tagged unexpected regions, yet at least two loci for the susceptibility of SBP to β-adrenergic drugs pointed at members of the hypothalamic-pituitary-thyroid axis. Loci for cardiac-related traits were preferentially enriched in genes expressed in the heart, while 23% of the testable loci were replicated with datasets of the Mouse Phenome Database (MPD). Altogether these data and validation tests indicate that the mapped loci are relevant to the traits and responses studied.

[Inherited alopecia X in Pomeranians]

Four male Pomeranians that showed alopecia with an age of onset between five months and eight years were investigated.The aim of the investigation was to clarify whether the affected dogs had alopecia X and whether their symptoms might be due to a hereditary defect.The four affected dogs showed hairless patches at the root of the tail, at the back, at the limbs from the thigh to the tarsus and at the abdomen. Within the hairless patches some islets with sparse hair were present. In hairless patches the skin was dark pigmented. Besides the alopecia and hyperpigmentation no other symptoms were found according to anamnestic and clinical examination. History, clinical examinations, laboratory diagnostics, and histopathology of skin biopsies allowed the diagnosis of alopecia X in three affected male dogs.The last one of the affected dogs additionally had slightly reduced thyroid hormone levels. Based on identical symptoms and the close relatedness of all four animals, it was assumed that the fourth affected dog also had alopecia X.The available data possibly indicate a monogenic autosomal dominant inheritance, however a recessive inheritance can not be excluded at this time.

Insulin-like growth factor type-1 receptor down-regulation associated with dwarfism in Holstein calves

Perturbations in endocrine functions can impact normal growth. Endocrine traits were studied in three dwarf calves exhibiting retarded but proportionate growth and four phenotypically normal half-siblings, sired by the same bull, and four unrelated control calves. Plasma 3,5,3'-triiodothyronine and thyroxine concentrations in dwarfs and half-siblings were in the physiological range and responded normally to injected thyroid-releasing hormone. Plasma glucagon concentrations were different (dwarfs, controls>half-siblings; P<0.05). Plasma growth hormone (GH), insulin-like growth factor-1 (IGF-1) and insulin concentrations in the three groups during an 8-h period were similar, but integrated GH concentrations (areas under concentration curves) were different (dwarfs>controls, P<0.02; half-siblings>controls, P=0.08). Responses of GH to xylazine and to a GH-releasing-factor analogue were similar in dwarfs and half-siblings. Relative gene expression of IGF-1, IGF-2, GH receptor (GHR), insulin receptor, IGF-1 type-1 and -2 receptors (IGF-1R, IGF-2R), and IGF binding proteins were measured in liver and anconeus muscle. GHR mRNA levels were different in liver (dwarfs

Targeting CCK receptors in human cancers

Gut hormone receptors can be over-expressed in several human cancers and represent the basis for receptor-targeted tumor imaging and therapy. A promising receptor for such clinical applications is the cholecystokinin receptor. Cholecystokinin receptors are expressed in numerous neuroendocrine tumors, in particular medullary thyroid carcinomas and neuroendocrine gut tumors, as well as in stromal tumors. Moreover, several radiolabeled CCK or gastrin analogs have been developed allowing to detect these tumors and their metastases in patients using in vivo cholecystokinin receptor scintigraphy, proving the feasibility of targeting CCK receptors in human tumors in vivo.

Pretherapeutic staging of recurrent laryngeal carcinoma: clinical findings and imaging studies compared with histopathology

OBJECTIVE: To assess the accuracy of preoperative imaging studies and clinical and endoscopic examinations for recurrent laryngeal carcinoma evaluation. STUDY DESIGN AND SETTING: A retrospective comparative study was performed at a university department on 42 recurrent laryngeal carcinomas. Surgical specimens were cut into whole-organ slices. Histologic findings were compared with the findings of the different preoperative diagnostic modalities. RESULTS: The craniocaudal tumor spread was correctly evaluated by endoscopy and imaging studies in 52% and 24%, respectively, and the contralateral tumor spread in 50% and 52%, respectively. The sensitivity, specificity, and accuracy for detection of tumor infiltration of the thyroid was 48%, 88%, and 64% and of the cricoid 47%, 80%, and 67%. The accuracy of recurrent tumor classification (crT) was 50%; most tumors were underclassified. CONCLUSION: The inadequately evaluated tumor spread and the inadequately classified recurrent tumors were underestimated and underclassified in most cases, respectively.

Pseudodominant Inheritance of Goitrous Congenital Hypothyroidism Caused by TPO Mutations: Molecular and in Silico Studies

Context and Objective: Most cases of goitrous congenital hypothyroidism (CH) from thyroid dyshormonogenesis 1) follow a recessive mode of inheritance and 2) are due to mutations in the thyroid peroxidase gene (TPO). We report the genetic mechanism underlying the apparently dominant inheritance of goitrous CH in a nonconsanguineous family of French Canadian origin. Design, Setting, and Participants: Two brothers identified by newborn TSH screening had severe hypothyroidism and a goiter with increased (99m)Tc uptake. The mother was euthyroid, but the father and two paternal uncles had also been diagnosed with goitrous CH. After having excluded PAX8 gene mutations, we hypothesized that the underlying defect could be TPO mutations. Results: Both compound heterozygous siblings had inherited a mutant TPO allele carried by their mother (c.1496delC; p.Pro499Argfs2X), and from their father, one brother had inherited a missense mutation (c.1978C-->G; p.Gln660Glu) and the other an insertion (c.1955insT; p.Phe653Valfs15X). The thyroid gland of one uncle who is a compound heterozygote for TPO mutations (p.Phe653Valfs15X/p.Gln660Glu) was removed because of concurrent multiple endocrine neoplasia type 2A. Immunohistochemistry revealed normal TPO staining, implying that Gln660Glu TPO is expressed properly. Modeling of this mutant in silico suggests that its three-dimensional structure is conserved, whereas the electrostatic binding energy between the Gln660Glu TPO and its heme group becomes repulsive. Conclusion: We report a pedigree presenting with pseudodominant goitrous CH due to segregation of three different TPO mutations. Although goitrous CH generally follows a recessive mode of inheritance, the high frequency of TPO mutations carriers may lead to pseudodominant inheritance.

Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies

BACKGROUND: Excess bodyweight, expressed as increased body-mass index (BMI), is associated with the risk of some common adult cancers. We did a systematic review and meta-analysis to assess the strength of associations between BMI and different sites of cancer and to investigate differences in these associations between sex and ethnic groups. METHODS: We did electronic searches on Medline and Embase (1966 to November 2007), and searched reports to identify prospective studies of incident cases of 20 cancer types. We did random-effects meta-analyses and meta-regressions of study-specific incremental estimates to determine the risk of cancer associated with a 5 kg/m2 increase in BMI. FINDINGS: We analysed 221 datasets (141 articles), including 282,137 incident cases. In men, a 5 kg/m2 increase in BMI was strongly associated with oesophageal adenocarcinoma (RR 1.52, p<0.0001) and with thyroid (1.33, p=0.02), colon (1.24, p<0.0001), and renal (1.24, p <0.0001) cancers. In women, we recorded strong associations between a 5 kg/m2 increase in BMI and endometrial (1.59, p<0.0001), gallbladder (1.59, p=0.04), oesophageal adenocarcinoma (1.51, p<0.0001), and renal (1.34, p<0.0001) cancers. We noted weaker positive associations (RR <1.20) between increased BMI and rectal cancer and malignant melanoma in men; postmenopausal breast, pancreatic, thyroid, and colon cancers in women; and leukaemia, multiple myeloma, and non-Hodgkin lymphoma in both sexes. Associations were stronger in men than in women for colon (p<0.0001) cancer. Associations were generally similar in studies from North America, Europe and Australia, and the Asia-Pacific region, but we recorded stronger associations in Asia-Pacific populations between increased BMI and premenopausal (p=0.009) and postmenopausal (p=0.06) breast cancers. INTERPRETATION: Increased BMI is associated with increased risk of common and less common malignancies. For some cancer types, associations differ between sexes and populations of different ethnic origins. These epidemiological observations should inform the exploration of biological mechanisms that link obesity with cancer.

Radiation exposure to the surgeon during fluoroscopically assisted percutaneous vertebroplasty: a prospective study

STUDY DESIGN: A prospective case control study design was conducted. OBJECTIVES: The purpose of the current study was to determine the intraoperative radiation hazard to spine surgeons by occupational radiation exposure during percutaneous vertebroplasty and possible consequences with respect to radiation protection. SUMMARY OF BACKGROUND DATA: The development of minimally invasive surgery techniques has led to an increasing number of fluoroscopically guided procedures being done percutaneously such as vertebroplasty, which is the percutaneous cement augmentation of vertebral bodies. METHODS: Three months of occupational dose data for two spine surgeons was evaluated measuring the radiation doses to the thyroid gland, the upper extremities, and the eyes during vertebroplasty. RESULTS: The annual risk of developing a fatal cancer of the thyroid is 0.0025%, which means a very small to small risk. The annual morbidity (the risk of developing a cancer including nonfatal ones) is 0.025%, which already means a small to medium risk. The dose for the eye lens was about 8% of the threshold dose to develop a radiation induced cataract (150 mSv); therefore, the risk is very low but not negligible. The doses measured for the skin are 10% of the annual effective dose limit (500 mSv) recommended by the ICRP (International Commission on Radiologic Protection); therefore, the annual risk for developing a fatal skin cancer is very low. CONCLUSION: While performing percutaneous vertebroplasty, the surgeon is exposed to a significant amount of radiation. Proper surgical technique and shielding devices to decrease potentially high morbidity are mandatory. Training in radiation protection should be an integral part of the education for all surgeons using minimally invasive radiologic-guided interventional techniques.

[Endocrine crises]

Pituitary apoplexy, diabetes insipidus, thyroid storm, myxedema coma, parathyrotoxic crisis, hypocalcemia tetany, pheochromocytoma and Addison crisis, diabetic ketoacidosis, diabetic hyperosmolar nonketotic coma, hypoglycemia and carcinoid crisis are the most important endocrine crises. Some of them are common, others very rare. All physicians nevertheless need to have at least a basic knowledge of all of them, since symptoms and signs of endocrine crises overlap with those of other severe disease states, and the failure to recognise endocrine crises as such and to begin rapidly the specific therapy can have fatal consequences.

Urinary iodine concentration during pregnancy in an area of unstable dietary iodine intake in Switzerland

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.