Abnormal thyroid function is common in takotsubo syndrome and depends on two distinct mechanisms: results of a multicentre observational study.

BACKGROUND: Several reports have described Takotsubo syndrome (TTS) secondary to thyrotoxicosis. A complex interaction of central and peripheral catecholamines with thyroid homeostasis has been suggested. In this study, we analysed sequential thyroid hormone profiles during the acute phase of TTS. METHODS: Thyrotropin (TSH), free T4 (FT4) and free T3 (FT3) concentrations were analysed at predefined time points in 32 patients presenting with TTS or acute coronary syndrome (ACS, n = 16 in each group) in a 2-year period in two German university hospitals. Data were compared to age- and sex-matched controls (10 samples, each of 16 subjects), and an unsupervised machine learning (ML) algorithm identified patterns in the hormone signature. Subjects with thyroid disease and patients receiving amiodarone were excluded from follow-up. RESULTS: Among patients with TTS, FT4 concentrations were significantly higher when compared to controls or ACS. Four subjects (25%) suffered from subclinical or overt thyrotoxicosis. Two additional patients developed subclinical or overt thyrotoxicosis during stay in hospital. In four subjects (25%), FT4 concentrations were increased, despite nonsuppressed TSH concentration, representing an elevated set point of thyroid homeostasis. The thyroid hormone profile was normal in only six patients (38%) presenting with TTS. CONCLUSION: Abnormal thyroid function is frequent in patients with TTS. Primary hyperthyroidism and an elevated set point of thyroid homeostasis are common in TTS, suggesting a stress-dependent endocrine response or type 2 thyroid allostasis. Thyroid function may be a worthwhile target in treating or preventing TTS.

Profiling retrospective thyroid function data in complete thyroidectomy patients to investigate the HPT axis set point (PREDICT-IT).

BACKGROUND: The homeostatic euthyroid set point of the hypothalamus-pituitary-thyroid axis of any given individual is unique and oscillates narrowly within substantially broader normal population ranges of circulating free thyroxine (FT4) and thyroid-stimulating hormone (TSH), otherwise termed 'thyroid function test (TFT)'. We developed a mathematical algorithm codenamed Thyroid-SPOT that effectively reconstructs the personalized set point in open-loop situations and evaluated its performance in a retrospective patient sample. METHODS: We computed the set points of 101 patients who underwent total thyroidectomy for non-functioning thyroid disease using Thyroid-SPOT on each patient's own serial post-thyroidectomy TFT. Every predicted set point was compared against its respective healthy pre-operative euthyroid TFT per individual and their separation (i.e. predicted-observed TFT) quantified. RESULTS: Bland-Altman analysis to measure the agreement between each pair of an individual's predicted and actual set points revealed a mean difference in FT4 and TSH of + 3.03 pmol/L (95% CI 2.64, 3.43) and - 0.03 mIU/L (95% CI - 0.25, 0.19), respectively. These differences are small compared to the width of the reference intervals. Thyroid-SPOT can predict the euthyroid set point remarkably well, especially for TSH with a 10-16-fold spread in magnitude between population normal limits. CONCLUSION: Every individual's equilibrium euthyroid set point is unique. Thyroid-SPOT serves as an accurate, precise and reliable targeting system for optimal personalized restoration of euthyroidism. This algorithm can guide clinicians in L-thyroxine dose titrations to resolve persistent dysthyroid symptoms among challenging cases harbouring "normal TFT" within the laboratory ranges but differing significantly from their actual euthyroid set points.

Bridge Technology with TSH Receptor Chimera for Sensitive Direct Detection of TSH Receptor Antibodies Causing Graves' Disease: Analytical and Clinical Evaluation.

Graves' disease is caused by stimulating autoantibodies against the thyrotropin receptor inducing uncontrolled overproduction of thyroid hormones. A Bridge Assay is presented for direct detection of these thyroid-stimulating immunoglobulins using thyrotropin receptor chimeras. A capture receptor, formed by replacing aa residues 261-370 of the human thyrotropin receptor with residues 261-329 from rat lutropin/choriogonadotropin receptor and fixed to microtiter plates, binds one arm of the autoantibody. The second arm bridges to the signal receptor constructed from thyrotropin receptor (aa 21-261) and secretory alkaline phosphatase (aa 1-519) inducing chemiluminescence. The working range of the assay is from 0.3 IU/l to 50 IU/l with a cutoff of 0.54 IU/l and functional sensitivity of 0.3 IU/l. Sensitivity and specificity are 99.8 and 99.1%, respectively, with a diagnostic accuracy of 0.998. The low grey zone is from 0.3-0.54 IU/l. The stimulatory character of the assayed antibodies is shown through a good correlation (r=0.7079, p<10(-7)) to serum T4 levels of untreated patients. In Graves' disease, titers are increased in associated eye disease. In 3 hypothyroid patients with sera positive in the thyrotropin receptor competition assay and in the blocking bioassay, antibodies are not detected by the Bridge Assay, while the monoclonal blocking antibody K1-70 was detected. In Hashimoto disease thyrotropin receptor autoantibodies are detected in some patients, but not in goiter. This Bridge Assay delivers good diagnostic accuracy for identification of Graves' disease patients. Its high sensitivity may facilitate early detection of onset, remission, or recurrence of Graves' disease enabling timely adaption of the treatment.Human genes: TSHR, Homo sapiens, acc. no. M31774.1.

Integration of Peripheral and Glandular Regulation of Triiodothyronine Production by Thyrotropin in Untreated and Thyroxine-Treated Subjects.

The objective of the study was to evaluate the roles of central and peripheral T3 regulation. In a prospective study involving 1,796 patients, the equilibria between FT3 and TSH were compared in untreated and L-T4-treated patients with varying functional states, residual thyroid secretory capacities and magnitudes of TSH stimulation. T3 concentrations were stable over wide variations in TSH levels (from 0.2 to 7 mU/l) and endogenous T4 production in untreated patients, but unbalanced in L-T4-treated athyreotic patients where T3 correlated with exogenous T4 supply. T3 stability was related to TSH-stimulated deiodinase activity by clinical observation, as predicted by theoretical modelling. Deiodinase activity in treated patients was reduced due to both diminished responsiveness to TSH and lack of thyroidal capacity. Deiodinase activity was increased in high thyroid volume, compared to lower volumes in euthyroid patients (<5 ml, p<0.001). While deiodinase differed between euthyroid and subclinically hypothyroid patients in high volume, 26.7 nmol/s (23.6, 29.2), n=214 vs. 28.9 nmol/s (26.7, 31.5), n=20, p=0.02, it was equivalent between the 2 functional groups in low volume, 23.3 nmol/s (21.3, 26.1), n=117 vs. 24.6 nmol/s (22.2, 27.5), n=38, p=0.22. These findings suggest that the thyroid gland and peripheral tissues are integrated in the physiological process of T3 homeostasis in humans via a feed-forward TSH motif, which coordinates peripheral and central regulatory mechanisms. Regulatory and capacity deficiencies collectively impair T3 homeostasis in L-T4-treated patients.

[Refeeding syndrome: a review of the literature]. / Das Refeeding-Syndrom - Eine Literaturübersicht.

UNLABELLED: The refeeding syndrome is a dangerous condition, which may even lead to death. The syndrome occurs after re-establishment of adequate nutrition in malnourished and cachectic patients. More specifically its occurrence has been reported during oral, enteral and parenteral feeding. Early diagnosis is crucial for adequate and timely therapy. However, due to a lack of knowledge in the community this is not always achieved. The leading symptom is hypophosphatemia, often accompanied by electrolyte disturbances and vitamin and trace element deficiencies. Due to a concomitant administration of carbohydrates and intravenous fluid volume it may also lead to hypervolemia with cardiac failure. Compromise of other organ functions with a varying degree of severity, even leading to death, have been reported. The most efficient prevention of the refeeding syndrom is recommended by an early identification of patients at risk and the administration of an initially lower caloric nutrition accompanied by a tight and regularly scheduled observation of relevant laboratory parameters. METHODS: This literature research included the following terms: "refeeding syndrome" and "hypophosphataemia" including the 2006 guidelines from the National Institute for Health and Clinical Excellence (UK).

"Still crazy after all these years"--tuberculosis as an old disease with diverse facets in a thirty-five-year-old male patient.

We report about a thirty-five-year-old male patient with miliary TB as first manifestation of HIV-infection.

[Woman with type 1 diabetes mellitus and rapidly progressive edema]. / Patientin mit Diabetes mellitus Typ 1 und akut aufgetretenen Ödemen.

HISTORY AND CLINICAL FINDINGS: A 47-year-old woman with type 1 diabetes mellitus was presented for evaluation of progressive oedema, fatigue and weight gain. Her medical history was significant for arterial hypertension and autoimmune thyroiditis requiring substitution therapy with levothyroxine. Physical examination revealed bilateral malleolar and crural oedema, swelling of the eyelids and two-sided pleural effusions. DIAGNOSTIC, TREATMENT AND COURSE: The blood level of albumin was very low, urine analysis showed proteinuria of > 8 g/day. The kidney biopsy revealed only slight changes. This led in combination with the blood and urine results to the diagnosis of minimal change glomerulopathy. After initiation of high dose prednisolone the patient achieved near total remission within four weeks. Prednisolone therapy was tapered over several months. CONCLUSION: In patients with diabetes mellitus and suddenly occurring nephrotic syndrome other diseases than diabetic nephropathy have to be considered. In most cases a kidney biopsy is mandatory.

Correlation between total atrial conduction time estimated via tissue Doppler imaging (PA-TDI Interval), structural atrial remodeling and new-onset of atrial fibrillation after cardiac surgery.

BACKGROUND: Recent studies identified total atrial conduction time (TACT) as an independent and powerful predictor of new-onset atrial fibrillation (AF). The purpose of this study was to assess the association between the degree of atrial fibrosis, TACT, and frequency of postoperative atrial fibrillation (POAF) among patients undergoing cardiac surgery. METHODS AND RESULTS: Sixty patients in sinus rhythm (mean ± SD age 66 ± 10 years; 22% women) and without a history of AF undergoing cardiac surgery were prospectively enrolled. TACT was measured preoperatively in the left atrium by tissue-Doppler Imaging (PA-TDI interval). Holter-ECG/telemetry was used to screen for POAF throughout 10 days after cardiac surgery. Right atrial appendages (RAA) were obtained in 33 patients during surgery; atrial fibrosis was assessed by visual quantification (% area of positive van Gieson elastic staining). POAF occurred in 23 patients (38%). Fibrosis extent of RAA was higher in patients with POAF as compared to those without (27.5 ± 1.93 vs 15.8 ± 0.81% area; mean ± SEM; P < 0.001). PA-TDI interval was longer in patients with POAF versus patients who maintained in sinus rhythm (152.1 ± 3.0 vs 120.8 ± 1.8 milliseconds; P < 0.001) and correlated with the degree of atrial fibrosis (r = 0.73; P < 0.01). At the cut-off value of 133 milliseconds, TACT sensitivity and specificity related to POAF were 100% and 86%, respectively. CONCLUSION: PA-TDI interval is useful to identify patients at risk for POAF undergoing cardiac surgery and correlates with the degree of atrial fibrosis.

Syndrome of inadequate antidiuretic hormone secretion in pulmonary tuberculosis - a therapeutic challenge.

A forty-nine-year-old female patient with pulmonary tuberculosis developed syndrome of inadequate antidiuretic hormone secretion. Consequent restriction of fluid intake as a therapeutic measure was just as ineffective as a medication with tolvaptan which was performed later on. A probable explanation for the inefficacy of the aquaretic drug is an interaction of rifampicine and tolvaptan. This case report gives a short summary of SIADH in pulmonary TB and discusses possible reasons for the difficult antituberculotic treatment in this patient.

[Thyroid storm]. / Thyreotoxische Krise.

Thyroid storm is a complicated, life-threatening form of thyrotoxicosis. The causes are multifactorial and elevated iodothyronine levels are only one of many components. Usually, the transition from thyrotoxicosis to thyroid storm is ignited by non-thyroidal triggers. This is a rare condition observed with an incidence between 0.8 and 1.4 cases per 100,000 inhabitants. Diagnosis relies primarily on clinical criteria. Multimodal therapy aims at disrupting positive feedback loops between elevated levels of free T3 or T4 and their effects on target tissues and organs. Timely diagnosis and therapy help to reduce mortality to below 35%.

The proteomic signature of insulin-resistant human skeletal muscle reveals increased glycolytic and decreased mitochondrial enzymes.

AIMS/HYPOTHESIS: The molecular mechanisms underlying insulin resistance in skeletal muscle are incompletely understood. Here, we aimed to obtain a global picture of changes in protein abundance in skeletal muscle in obesity and type 2 diabetes, and those associated with whole-body measures of insulin action. METHODS: Skeletal muscle biopsies were obtained from ten healthy lean (LE), 11 obese non-diabetic (OB), and ten obese type 2 diabetic participants before and after hyperinsulinaemic-euglycaemic clamps. Quantitative proteome analysis was performed by two-dimensional differential-gel electrophoresis and tandem-mass-spectrometry-based protein identification. RESULTS: Forty-four protein spots displayed significant (p < 0.05) changes in abundance by at least a factor of 1.5 between groups. Several proteins were identified in multiple spots, suggesting post-translational modifications. Multiple spots containing glycolytic and fast-muscle proteins showed increased abundance, whereas spots with mitochondrial and slow-muscle proteins were downregulated in the OB and obese type 2 diabetic groups compared with the LE group. No differences in basal levels of myosin heavy chains were observed. The abundance of multiple spots representing glycolytic and fast-muscle proteins correlated negatively with insulin action on glucose disposal, glucose oxidation and lipid oxidation, while several spots with proteins involved in oxidative metabolism and mitochondrial function correlated positively with these whole-body measures of insulin action. CONCLUSIONS/INTERPRETATION: Our data suggest that increased glycolytic and decreased mitochondrial protein abundance together with a shift in muscle properties towards a fast-twitch pattern in the absence of marked changes in fibre-type distribution contribute to insulin resistance in obesity with and without type 2 diabetes. The roles of several differentially expressed or post-translationally modified proteins remain to be elucidated.

In vitro phage display in a rat beta cell line: a simple approach for the generation of a single-chain antibody targeting a novel beta cell-specific epitope.

AIMS/HYPOTHESIS: The aim of the present study was to evaluate in vitro phage display in a beta cell line as a novel strategy for the isolation of beta cell-specific agents/biomarkers. METHODS: A single-chain antibody (SCA) library was pre-incubated with AR42J cells in order to eliminate SCAs with exocrine binding properties. It was then panned against INS-1 cells to select beta cell-targeted antibodies. RESULTS: By these means, we isolated a novel antibody, SCA B5, that binds rapidly (6.0 min) and with a 450-fold higher specificity to beta cells relative to exocrine cells. We estimated for SCA B5 a binding affinity in the low micromol/l range and 858 binding sites per beta cell. Confocal microscopy showed binding to the beta cell surface and confirmed subsequent internalisation. Moreover, staining of rat and human pancreatic tissue sections with SCA B5 suggests that the target epitope is presented in pancreatic beta cells of different origins. Infrared imaging revealed that labelling of beta cells with tracer SCA B5 is strictly dependent on beta cell mass. With competition assays we excluded insulin, glutamate decarboxylase, C-peptide and islet amyloid polypeptide as SCA B5 targets. In accordance with these predictions, SCA B5 homed in vivo highly selectively to normal beta cells and dysfunctional beta cells of diabetic rats. Moreover, accumulation of radioactively labelled SCA B5 in the pancreas was reduced by 80% after pre-injection with unlabelled SCA B5, thereby confirming the specific uptake in the pancreas. CONCLUSIONS/INTERPRETATION: We report a simple strategy for the generation of an SCA targeting a novel beta cell-specific epitope.

[Absorption, transport and bio-availability of iodothyronines]. / Resorption, Transport und Bioverfügbarkeit von Schilddrüsenhormonen.

The frequently prescribed classical thyroid hormones (iodothyronines) are critical dose drugs with a narrow therapeutic index. Nowadays the mechanisms of their absorption, which takes place predominantly in the jejunum and ileum, have only partly been elucidated. Bioavailability of iodothyronines whose kinetics is subject to enterohepatic circulation, is about 70 %. Several factors influence their absorption including nutrients, drugs and concomitant diseases. After being absorbed only a small fraction of thyroid hormones circulates freely in plasma, whereas the greater portion is bound to plasma proteins. This binding, too, may be influenced by numerous factors; alterations by certain diseases and physiological conditions may lead to ambiguities in differential diagnosis. Intracellular accumulation of iodothyronines is accomplished by at least ten different active and energy-dependent transporters with variable tissue distribution. Particularly in critical illness (non-thyroidal illness syndrome) alterations of protein binding and membrane transport are common. In therapy of hypothyroid patients different brand-name products lack bioequivalence and thus requiring subsequent monitoring of thyroid status after treatment has been changed among different brand-name versions.

[Computer-assisted instruction in medicine: a multicenter evaluation study in 7 German language media resource centers]. / Rechnerunterstützte Instruktion in der Medizin: Eine multizentrische Evaluationsstudie in sieben deutschsprachigen Mediotheken.

EVA, a multicentre study of seven computer resource centres (CRCs) in three German-speaking nations, was carried out over a period of six months to gather structural and process data regarding the use of computer-based instruction (CBI) applications in medicine, and to identify the factors contributing to a more successful integration of CBI into the medical curriculum. 618 machine-readable questionnaires from CRC users and seven questionnaires on structural data of the participating CRCs covering 51 computer stations were evaluated. For Macintosh workstations (n = 34), an additional digital log-protocol was analysed. In conclusion, it seems that so far less than 10% of medical students use CBI programs in German-speaking countries. The data show the presently still poor integration of CBI into the medical curriculum.

Parathyroid hormone and related peptides for the treatment of postmenopausal osteoporosis.

Osteopenia, a skeletal condition characterised by bone loss, affects over 10% of the North American population, with a worldwide incidence of 200 m. In the absence of treatment, osteopenia usually progresses to osteoporosis, characterised by more severe bone loss and, ultimately, by fractures. In the US alone osteoporosis affects more than 25 m people, and causes more than 1.3 m fractures a year. This skeletal deterioration is accelerated subsequent to menopause and thus can affect women at a relatively young age. Treatment of postmenopausal osteoporosis primarily involves the use of hormones (calcitonin, oestrogen) or organic molecules (bisphosphonates) which are able to prevent skeletal loss through inhibition of osteoclastic bone resorption. While this may be adequate prior to significant skeletal deterioration and fractures, the patient who has already lost large amounts of bone, in the presence or absence of fractures, requires more aggressive therapy to rapidly rebuild the skeleton. There is now substantial evidence that parathyroid hormone (PTH) is an agent capable of reversing such skeletal loss characteristic of osteoporosis. Numerous animal studies, in conjunction with investigator-initiated clinical trials, have demonstrated the anabolic effects of PTH and related peptides in osteoporotic conditions associated with lack of oestrogen. Large, well-controlled clinical trials are underway to evaluate the safety and efficacy of PTH and PTH-like peptides in postmenopausal osteoporosis. The addition of these agents to the clinician's armamentarium should provide more effective treatment of this condition, thereby preventing the fractures and debilitation that frequently accompany osteoporosis.

Effect of antisperm antibodies in serum and cervical mucus on the capacity of human sperm to penetrate zona-free hamster ova.

Human sera with elevated titers of antisperm antibodies reduced the capacity of human sperm to penetrate zona-free hamster ova. Of 111 sera examined, 33 (30%) reduced the mean percentage of ova penetrated to less than 52%, which was significantly different from the overall control mean (75%). Three sera reduced the penetration of ova to 7% or less. The inhibitory effect of these three sera was still present in their respective Fab preparations. An analysis of antibody effects revealed that the presence of sperm-immobilizing antibodies had a significantly greater influence on sperm penetration capacity than agglutinating antibodies. Sperm motility per se appeared to be unaffected by the different sera. Sperm treated with cervical mucus (CM) samples generally exhibited a lesser degree of ova penetration than did sperm treated with serum or medium alone. Among CM groups, however, samples containing detectable sperm-immobilizing antibody activity or samples from women with circulating antisperm antibody caused significant reductions in sperm penetration capacity.

The incidence and influence of antisperm antibodies in infertile human couples on sperm-cervical mucus interactions and subsequent fertility.

Analysis of serum samples from 698 infertile couples revealed antisperm antibodies present in 16.5% of the men and 21.6% of the women. Overall, 31.1% of the couples possessed at least one individual with positive results. Sperm-immobilized activity was detected in 29.6% of the cervical mucus (CM) samples from 459 women. Reduced sperm penetration of CM was significantly associated with serum titers of antisperm antibodies in both sexes and also with immobilizing activity in CM of women. The incidence of subsequent pregnancy in 376 infertile couples was reduced significantly if one or both partners had antisperm antibodies in serum or in genital tract secretions. The latter was reflected by evaluation of the immobilization, penetration, and shaking phenomenon of sperm in CM.

PIP: Serum antisperm antibodies were analyzed for 698 human couples with primary or secondary infertility to evaluate the incidence of antisperm antibodies in the circulation of men and women and in the cervical mucus of women as well as to evaluate the association of these antibodies with sperm penetration of cervical mucus in vitro and the relationship of these factors with subsequent fertility. Questionnaires concerning fertility status were mailed to 520 couples that had been analyzed for sperm antibodies from 1-3 years earlier. Completed questionnaires were obtained from 402 couples, and 376 of these couples were suitable for inclusion in the study. The mean duration of infertility was 4.1 +or- 2.5 years, with a range of 1-15 years for all couples; for 31 couples with secondary infertility, the duration was 3.4 +or- 1.9 years, with a range of 1.5-5.5 years. 14.8% of the men 19.6% of the women had sperm-agglutinating antibodies. An examination of the type of agglutination indicated that 88% of the positive sera showed the tail-to-tail type and the remainder showed the head-to-head type. The overall incidences of immobilizing antibody were 5.6 for men and 6.4% for women. The incidence of immobilizing antibody increased significantly in both men and women with increasing agglutination titers, as reflected by the respective correlations of 0.50 and 0.34 between the 2 tests. The incidence of pregnancy was influenced significantly by the presence of circulating sperm-agglutinating and immobilizing antibodies in both sexes. Sperm-immobilizing activity was detected in 29.6% of the cervical mucus samples from 459 women. The frequency of immobilizing antibody activity was significantly greater in samples from women with positive serum samples by either the TAT or the SIT. Sperm penetration of cervical mucus was significantly affected by the presence of either type of serum antisperm antibody in men and by sperm agglutinins in women. The incidence of subsequent pregnancy among the couples was significantly associated with each of the techniques utilized to assess antisperm antibodies. The sperm shaking phenomenon showed a significant effect that was most dramatic in those couples with more than 75% of the motile sperm exhibiting shaking in which only 1 of 13 experienced a diagnosed pregnancy. Significant but low correlation coefficients were found for the occurrence of pregnancy with the results of the serum and cervical mucus techniques. Multiple partial correlation analyses of the variables with pregnancy occurrence revealed that of the serum tests, agglutinating titers had significantly greater coefficients for men and women.

Comparison of the phospholipid requirements and molecular form of CTP : phosphocholine cytidylyltransferase from rat lung, kidney, brain and liver.

The cytidylyltransferase activity in fresh cytosol from different tissues of the rat was measured in the absence and presence of phosphatidylglycerol. In all cases addition of this lipid produced large increases in enzyme activity. Agarose gel (A-5.0) filtration profiles of the enzyme activities indicated that the L-form of the enzyme (190 000 molecular weight) predominated in liver, brain, kidney, and fetal lung. However, adult lung cytosol contained 70--80% of the activity in the H-form (molecular weight greater than or equal to 5 x 10(6)). Removal of phospholipid material from the alveolar spaces by lavage produced a significant reduction of the H-form of the enzyme in the cytosol fraction. The L-form of the cytidylyltransferases from fetal lung and adult liver, kidney, and brain all possess the same specificities for activation by phospholipids in vitro. In all cases, phosphatidylglycerol was the most potent activator at 0.2 mM. Lysophosphatidylethanolamine stimulated enzyme activity, whereas lysophosphatidylglycerol was a potent inhibitor. These studies implicate the role of acidic phospholipids in the regulation of cytidylyltransferase activity in vivo and the existence of a common L-form of the enzyme in serveral tissues of the rat.