Gq-activated fibroblasts induce cardiomyocyte action potential prolongation and automaticity in a three-dimensional microtissue environment.

Cardiac fibroblasts (CFs) are known to regulate cardiomyocyte (CM) function in vivo and in two-dimensional in vitro cultures. This study examined the effect of CF activation on the regulation of CM electrical activity in a three-dimensional (3-D) microtissue environment. Using a scaffold-free 3-D platform with interspersed neonatal rat ventricular CMs and CFs, Gq-mediated signaling was selectively enhanced in CFs by Gαq adenoviral infection before coseeding with CMs in nonadhesive hydrogels. After 3 days, the microtissues were analyzed by signaling assay, histological staining, quantitative PCR, Western blots, optical mapping with voltage- or Ca2+-sensitive dyes, and microelectrode recordings of CF resting membrane potential (RMPCF). Enhanced Gq signaling in CFs increased microtissue size and profibrotic and prohypertrophic markers. Expression of constitutively active Gαq in CFs prolonged CM action potential duration (by 33%) and rise time (by 31%), prolonged Ca2+ transient duration (by 98%) and rise time (by 65%), and caused abnormal electrical activity based on depolarization-induced automaticity. Constitutive Gq activation in CFs also depolarized RMPCF from -33 to -20 mV and increased connexin 43 and connexin 45 expression. Computational modeling confers that elevated RMPCF and increased cell-cell coupling between CMs and CFs in a 3-D environment could lead to automaticity. In conclusion, our data demonstrate that CF activation alone is capable of altering action potential and Ca2+ transient characteristics of CMs, leading to proarrhythmic electrical activity. Our results also emphasize the importance of a 3-D environment where cell-cell interactions are prevalent, underscoring that CF activation in 3-D tissue plays a significant role in modulating CM electrophysiology and arrhythmias.NEW & NOTEWORTHY In a three-dimensional microtissue model, which lowers baseline activation of cardiac fibroblasts but enables cell-cell, paracrine, and cell-extracellular matrix interactions, we demonstrate that selective cardiac fibroblast activation by enhanced Gq signaling, a pathophysiological trigger in the diseased heart, modulates cardiomyocyte electrical activity, leading to proarrhythmogenic automaticity.

In vitro to in vivo extrapolation from three-dimensional hiPSC-derived cardiac microtissues and physiologically based pharmacokinetic modeling to inform next-generation arrhythmia risk assessment.

Proarrhythmic cardiotoxicity remains a substantial barrier to drug development as well as a major global health challenge. In vitro human pluripotent stem cell-based new approach methodologies have been increasingly proposed and employed as alternatives to existing in vitro and in vivo models that do not accurately recapitulate human cardiac electrophysiology or cardiotoxicity risk. In this study, we expanded the capacity of our previously established three-dimensional human cardiac microtissue model to perform quantitative risk assessment by combining it with a physiologically based pharmacokinetic model, allowing a direct comparison of potentially harmful concentrations predicted in vitro to in vivo therapeutic levels. This approach enabled the measurement of concentration responses and margins of exposure for two physiologically relevant metrics of proarrhythmic risk (ie, action potential duration and triangulation assessed by optical mapping) across concentrations spanning three orders of magnitude. The combination of both metrics enabled accurate proarrhythmic risk assessment of four compounds with a range of known proarrhythmic risk profiles (ie, quinidine, cisapride, ranolazine, and verapamil) and demonstrated close agreement with their known clinical effects. Action potential triangulation was found to be a more sensitive metric for predicting proarrhythmic risk associated with the primary mechanism of concern for pharmaceutical-induced fatal ventricular arrhythmias, delayed cardiac repolarization due to inhibition of the rapid delayed rectifier potassium channel, or hERG channel. This study advances human induced pluripotent stem cell-based three-dimensional cardiac tissue models as new approach methodologies that enable in vitro proarrhythmic risk assessment with high precision of quantitative metrics for understanding clinically relevant cardiotoxicity.

Cross talk between cardiac myocytes and fibroblasts: from multiscale investigative approaches to mechanisms and functional consequences.

The heart is comprised of a syncytium of cardiac myocytes (CM) and surrounding nonmyocytes, the majority of which are cardiac fibroblasts (CF). CM and CF are highly interspersed in the myocardium with one CM being surrounded by one or more CF. Bidirectional cross talk between CM and CF plays important roles in determining cardiac mechanical and electrical function in both normal and diseased hearts. Genetically engineered animal models and in vitro studies have provided evidence that CM and CF can regulate each other's function. Their cross talk contributes to structural and electrical remodeling in both atria and ventricles and appears to be involved in the pathogenesis of various heart diseases that lead to heart failure and arrhythmia disorders. Mechanisms of CM-CF cross talk, which are not yet fully understood, include release of paracrine factors, direct cell-cell interactions via gap junctions and potentially adherens junctions and nanotubes, and cell interactions with the extracellular matrix. In this article, we provide an overview of the existing multiscale experimental and computational approaches for the investigation of cross talk between CM and CF and review recent progress in our understanding of the functional consequences and underlying mechanisms. Targeting cross talk between CM and CF could potentially be used therapeutically for the modulation of the cardiac remodeling response in the diseased heart and may lead to new strategies for the treatment of heart failure or rhythm disturbances.

Functional scaffold-free 3-D cardiac microtissues: a novel model for the investigation of heart cells.

To bridge the gap between two-dimensional cell culture and tissue, various three-dimensional (3-D) cell culture approaches have been developed for the investigation of cardiac myocytes (CMs) and cardiac fibroblasts (CFs). However, several limitations still exist. This study was designed to develop a cardiac 3-D culture model with a scaffold-free technology that can easily and inexpensively generate large numbers of microtissues with cellular distribution and functional behavior similar to cardiac tissue. Using micromolded nonadhesive agarose hydrogels containing 822 concave recesses (800 µm deep × 400 µm wide), we demonstrated that neonatal rat ventricular CMs and CFs alone or in combination self-assembled into viable (Live/Dead stain) spherical-shaped microtissues. Importantly, when seeded simultaneously or sequentially, CMs and CFs self-sorted to be interspersed, reminiscent of their myocardial distribution, as shown by cell type-specific CellTracker or antibody labeling. Microelectrode recordings and optical mapping revealed characteristic triangular action potentials (APs) with a resting membrane potential of -66 ± 7 mV (n = 4) in spontaneously contracting CM microtissues. Under pacing, optically mapped AP duration at 90% repolarization and conduction velocity were 100 ± 30 ms and 18.0 ± 1.9 cm/s, respectively (n = 5 each). The presence of CFs led to a twofold AP prolongation in heterogenous microtissues (CM-to-CF ratio of 1:1). Importantly, Ba(2+)-sensitive inward rectifier K(+) currents and Ca(2+)-handling proteins, including sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a, were detected in CM-containing microtissues. Furthermore, cell type-specific adenoviral gene transfer was achieved, with no impact on microtissue formation or cell viability. In conclusion, we developed a novel scaffold-free cardiac 3-D culture model with several advancements for the investigation of CM and CF function and cross-regulation.

Does an impaired adenosine mediated feedback control play a role in the development of hereditary dystrophic cardiomyopathy?

A study was carried out to investigate whether or not an impairment of the adenosine mediated negative inotropic effect in the presence of beta adrenoceptor stimulation plays a role in the pathogenesis of the hereditary cardiomyopathy of the Syrian hamster. In electrically driven papillary muscles isolated from the hearts of cardiomyopathic (strain BIO 8262) and age matched healthy control Syrian hamsters the effects of isoprenaline, adenosine, and adenosine in the presence of isoprenaline were studied within the first 30 days of life (the prenecrotic stage of the disorder). In both cardiomyopathic and control hamsters adenosine antagonised the positive inotropic effect of isoprenaline, whereas adenosine alone had no or, only a weak, inhibitory effect on the force of contraction. The effects in both groups were similar. The effect of isoprenaline on the force of contraction also did not differ in the two groups. The data show that in both cardiomyopathic and control hamsters adenosine reduces the force of contraction during beta adrenergic stimulation. The potency or efficacy of adenosine did not differ in the two groups. An impaired adenosine mediated feedback control of the heart does not therefore seem to play a role in the pathogenesis of the hereditary dystrophic cardiomyopathy of the Syrian hamster.

Reduced alpha 1- and beta 2-adrenoceptor-mediated positive inotropic effects in human end-stage heart failure.

1. alpha 1-Adrenoceptor (phenylephrine in the presence of propranolol) and beta 2-adrenoceptor (fenoterol)-mediated positive inotropic effects were investigated in human ventricular preparations isolated from five non-failing (prospective organ donors) and from eight explanted failing hearts with end-stage idiopathic dilative cardiomyopathy (NYHA IV). 2. For comparison, the nonselective beta-adrenoceptor agonist isoprenaline, the phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (IBMX), the cardiac glycoside dihydroouabain, and calcium were studied. 3. Furthermore, the influence of IBMX on adenosine 3':5'-cyclic monophosphate (cyclic AMP) PDE activity as well as total beta-adrenoceptor density, beta 1- and beta 2-adrenoceptor subtype distribution, and alpha 1-adrenoceptor density were compared in nonfailing and failing human heart preparations. The radioligands (-)-[125I]-iodocyanopindolol for beta-adrenoceptor binding and [3H]-prazosin for alpha 1-adrenoceptor binding were used. 4. The inotropic responses to calcium and dihydroouabain in failing human hearts were unchanged, whereas the maximal alpha 1- and beta 2-adrenoceptor-mediated positive inotropic effects were greatly reduced. The inotropic effects of the other cyclic AMP increasing compounds, i.e. isoprenaline and IBMX, were also reduced to about 60% of the effects observed in nonfailing controls. The potency of these compounds was decreased by factors 4-10. 5. The basal PDE activity and the PDE inhibition by IBMX were similar in nonfailing and failing preparations. 6. The total beta-adrenoceptor density in nonfailing hearts was about 70 fmol mg-1 protein. In failing hearts the total number of beta-adrenoceptors was markedly reduced by about 60%. The betal/beta2-adrenoceptor ratio was shifted from about 80/20% in nonfailing to approximately 60/40% in failing hearts which was due to a selective reduction of beta1-adrenoceptors. The beta2-adrenoceptor population remaining unchanged. alpha-Adrenoceptor density was increased from about 4 fmol mg-' protein in nonfailing to 10 fmol mgprotein in failing hearts.7. Changes in PDE activity and adrenoceptor downregulation cannot completely explain the reduced positive inotropic effects of alpha 1- and beta 2-adrenoceptor agonists in failing human hearts. This supports the hypothesis that impairment of other processes such as the coupling between receptor and effector system, i.e. the respective G-proteins, are equally important in end-stage heart failure.

Increased responsiveness to stimulation of alpha- but not beta-adrenoceptors in the hereditary cardiomyopathy of the Syrian hamster. Intact adenosine- and cholinoceptor-mediated isoprenaline antagonistic effect.

The effects of phenylephrine (in the presence of propranolol) or isoprenaline and of adenosine or carbachol (alone and in the presence of isoprenaline) were studied on the force of contraction in electrically driven papillary muscles isolated from the hearts of cardiomyopathic (strain BIO 8262) and age-matched, healthy Syrian hamsters. All experiments were performed in the so-called prenecrotic stage of the disorder within the first 30 days of life. Phenylephrine exerted a positive inotropic effect in all preparations from the cardiomyopathic hamsters. In contrast, in thirteen preparations from healthy Syrian hamsters, phenylephrine increased force of contraction in only four preparations. The positive inotropic effect of isoprenaline was similar in both cardiomyopathic and healthy Syrian hamsters. Adenosine and carbachol apparently reduced the isoprenaline-induced increase in force of contraction in both cardiomyopathic and healthy Syrian hamsters. We conclude that an increased responsiveness to alpha-adrenergic stimulation occurs in the hearts of cardiomyopathic Syrian hamsters and may be related to the myocardial injury occurring in this syndrome. An increased responsiveness to beta-adrenoceptor stimulation or an impaired adenosine-mediated or cholinoceptor-mediated feedback inhibition is unlikely to play a role in the aetiology of this syndrome.

Increased sensitivity to alpha-adrenoceptor stimulation but intact purinergic and muscarinergic effects in prehypertensive cardiac hypertrophy of spontaneously hypertensive rats.

The effects of phenylephrine, isoprenaline and adenosine, (-)-N6-phenylisopropyladenosine (PIA) or carbachol alone and in the presence of isoprenaline on force of contraction were studied in isolated electrically driven papillary muscles of spontaneously hypertensive rats (SHR) and age-matched Wistar control rats. In SHR an increased heart to body weight ratio was observed when blood pressure was not yet elevated. During this stage of the syndrome (i.e. between the 27th and 35th day of life) phenylephrine was about 3.4 times more potent to increase force of contraction in SHR (mean EC50: 2.8 mumol l-1) than in control rats (mean EC50: 9.4 mumol l-1). The positive inotropic effect of isoprenaline was similar in SHR and control rats. Also no difference could be detected in the isoprenaline-antagonistic effect of adenosine, the adenosine receptor agonist PIA or carbachol. We conclude that an increased sensitivity to cardiac alpha-adrenoceptor stimulation might be related to prehypertensive cardiac hypertrophy in SHR.

Isoprenaline-induced increase in mRNA levels of inhibitory G-protein alpha-subunits in rat heart.

Long-term beta-adrenergic stimulation has been shown to desensitize the beta-adrenoceptor/adenylyl cyclase signalling pathway at both the receptor and the G-protein level. To further elucidate the cellular mechanism of G-protein regulation we investigated the influence of prolonged infusion of isoprenaline (2.4 mg/kg.d) on myocardial mRNA levels of different G-protein alpha-subunits in rats. For comparison rats were treated with triiodothyronine (T3; 0.5 mg/kg.d) which induces cardiac hypertrophy like isoprenaline but has different effects on the adenylyl cyclase system. Isoprenaline- and T3-treated animals developed an increase in heart/body weight ratio of 41 +/- 3% and 27 +/- 4%, respectively (P less than 0.05). Isoprenaline increased myocardial total RNA concentration by 39 +/- 6% (P less than 0.05). Hybridization with 32P-labeled rat cDNAs demonstrated an expression rank order of Gs alpha-mRNA greater than Gi alpha-2-mRNA greater than Gi alpha-3-mRNA and no detectable expression of Gi alpha-1-mRNA in rat myocardium. mRNA levels of Gs alpha, Gi alpha-2 and Gi alpha-3 were 36.9 +/- 1.28, 10.7 +/- 1.07 and 3.7 +/- 0.19 pg/micrograms total RNA, respectively. Isoprenaline increased Gi alpha-2- and Gi alpha-3-mRNA concentrations per microgram total RNA by 49 +/- 18% and 27 +/- 7%, respectively (P less than 0.05). This effect was abolished by simultaneously administered propranolol (9.9 mg/kg.d), indicating a beta-adrenoceptor-mediated mechanism. In contrast, T3-induced cardiac hypertrophy was not accompanied by changes in Gi alpha-mRNA expression. Gs alpha-mRNA levels were unaffected by either treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism underlying the reduced positive inotropic effects of the phosphodiesterase III inhibitors pimobendan, adibendan and saterinone in failing as compared to nonfailing human cardiac muscle preparations.

The present study was performed to compare the effects of the new positive inotropic phosphodiesterase III inhibitors pimobendan, adibendan, and saterinone on the isometric force of contraction in electrically driven ventricular trabeculae carneae isolated from explanted failing (end-stage myocardial failure) with those from nonfailing (prospective organ donors) human hearts. In preparations from nonfailing hearts the phosphodiesterase inhibitors, as well as the beta-adrenoceptor agonist isoprenaline, the cardiac glycoside dihydro-ouabain, and calcium, which were studied for comparison, revealed pronounced positive inotropic effects. The maximal effects of pimobendan, adibendan, and saterinone amounted to 56%, 36% and 45%, respectively, of the maximal effect of calcium. In contrast, in preparations from failing hearts the phosphodiesterase III inhibitors failed to significantly increase the force of contraction and the effect of isoprenaline was markedly reduced. The effects of dihydroouabain and calcium were almost unaltered. The diminished effects of isoprenaline were restored by the concomitant application of phosphodiesterase inhibitors. To elucidate the underlying mechanism of the lack of effect of the phosphodiesterase III inhibitors in the failing heart we also investigated the inhibitory effects of these compounds on the activities of the phosphodiesterase isoenzymes I-III separated by DEAE-cellulose chromatography from both kinds of myocardial tissue. Furthermore, the effects of pimobendan and isoprenaline on the content of cyclic adenosine monophosphate (determined by radioimmunoassays) of intact contracting trabeculae were studied. The lack of effect of the phosphodiesterase inhibitors in failing human hearts could not be explained by an altered phosphodiesterase inhibition, since the properties of the phosphodiesterase isoenzymes I-III and also the inhibitory effects of the phosphodiesterase inhibitors on these isoenzymes did not differ between failing and nonfailing human myocardial tissue. Instead, it may be due to a diminished formation of cyclic adenosine monophosphate in failing hearts, presumably caused mainly by a defect in receptor-adenylate cyclase coupling at least in idiopathic dilated cardiomyopathy. Both the basal and the pimobendan-stimulated or isoprenaline-stimulated contents of cyclic adenosine monophosphate of intact contracting trabeculae from failing hearts were decreased compared with the levels in nonfailing hearts. However, under the combined action of isoprenaline and pimobendan the cyclic adenosine monophosphate level reached values as high as with each compound alone in nonfailing preparations, and in addition the positive inotropic effect of isoprenaline was restored. These findings may have important clinical implications. Along with the elevated levels of circulating catecholamines the positive inotropic effects of the phosphodiesterase inhibitors may be maintained in patients with heart failure.(ABSTRACT TRUNCATED AT 400 WORDS)

Signal transduction pathway of the muscarinic receptors mediating gallbladder contraction.

In gallbladder smooth muscle, carbachol interacts with M3 receptors to mediate contraction. To examine components of the intracellular second messenger system that is coupled to these receptors we have tested whether carbachol stimulates the formation of inositol phosphates (IP) to cause contraction. Guinea pig gallbladder muscle strips were prelabeled with [3H]inositol and were incubated with 0.1 mmol/l carbachol, a concentration causing maximal contraction. [3H]inositol monophosphates, [3H]inositol bisphosphates and [3H]inositol trisphosphates and contraction were measured at various times (0-90 s). To examine whether a pertussis toxin-sensitive guanine nucleotide binding protein is coupled to the muscarinic receptors, guinea pigs were pretreated with pertussis toxin (180 micrograms/kg i.v./24 h). The effectiveness of pertussis toxin treatment was determined by measuring [32P]ADP-ribosylation of a approximately 40/41 kDa protein from gallbladder homogenates. Carbachol caused a significant time-dependent increase in the formation of [3H]inositol monophosphates, [3H]inositol bisphosphates and [3H]inositol trisphosphates. The time course of [3H]inositol trisphosphate turnover caused by carbachol was biphasic, and was detectable at 15 s and maximal at 60 s; at 75 s and 90 s formation of [3H]inositol trisphosphates decreased, whereas the time course of carbachol-induced contraction of the gallbladder smooth muscle strips reached a plateau after 90 s. The effects of carbachol on [3H]inositol trisphosphates and on contraction were abolished by atropine.(ABSTRACT TRUNCATED AT 250 WORDS)

Isoprenaline-induced increase in the 40/41 kDa pertussis toxin substrates and functional consequences on contractile response in rat heart.

Chronic beta-adrenoceptor stimulation leads to desensitization of the myocardial adenylyl cyclase signalling pathway which includes beta-adrenoceptor downregulation and upregulation of Gi-protein alpha-subunits. However, these investigations have mainly been done in cellular preparations. In this study we report that isoprenaline infusion in vivo leads to an increase in myocardial Gi alpha and present evidence for functional consequences of this increase. Rats were treated by a 4-day subcutaneous infusion with isoprenaline (2.4 mg/kg.d), propranolol (9.9 mg/kg.d) and triiodothyronine (T3, 0.5 mg/kg.d) for comparison. Isoprenaline treatment increased the pertussis toxin-sensitive amount of Gi alpha by 22 +/- 6% and decreased beta 1- and beta 2-adrenoceptor density from 35 +/- 4 to 23 +/- 6 fmol/mg protein and 24 +/- 4 to 8 +/- 6 fmol/mg protein, respectively. Contraction experiments on electrically driven papillary muscles revealed that the negative inotropic potency of the M-cholinoceptor agonist carbachol in the presence of isoprenaline was increased as compared to control (mean EC50-values: 0.04 mumol/l vs. 0.28 mumol/l). All isoprenaline-induced effects were antagonized by simultaneously administered propranolol. T3 treatment had no influence on the parameters investigated. The results suggest that chronic beta-adrenoceptor stimulation desensitizes myocardial adenylyl cyclase by at least two mechanisms: beta-adrenoceptor downregulation leading to diminished signal transduction in the stimulatory pathway and Gi alpha upregulation leading to sensitization of the inhibitory pathway. Such adaptation might protect the heart from chronic exposure to catecholamines in heart diseases with elevated plasma catecholamine levels.

[Real-time sonography. An important imaging procedure in the diagnosis and treatment planning of bone metastases]. / Die real-time-Sonographie. Ein wichtiges bildgebendes Verfahren bei Diagnostik und Therapieplanung von Skelettmetastasen.

The value of sonography for diagnosis and therapy planning of bone metastases is shown in 110 affected skeletal regions (60 patients with malignant diseases). Whereas sonography is inferior to conventional x-ray in respect of defects of the spongiosa, it is equal with regard to defects of the cortical layer but superior in respect of changes of the periosteum and the surrounding soft tissue. Moreover, there is an excellent correlation (97%) between pain and the reaction of periosteum and soft-tissue layer. Because of the three dimensional representation of the tumourous processes sonography has proved valuable in radiotherapy planning (field size, radiation method, risk organs etc.).

[Indications for and value of computed tomography and conventional skeletal diagnosis in suspected bone metastases]. / Indikation und Wertigkeit von Computertomographie und konventioneller Skelettdiagnostik bei Verdacht auf Knochenmetastasen.

In 1003 patients with a total of 2467 clinically or scintigraphically suspect skeletal parts, conventional x-ray examination at the time of first study resulted in 95% of cases (2331 skeletal parts) in a correct diagnosis. Computed tomography permitted an exact diagnosis in 52% of roentgenologically equivocal findings (136 skeletal parts). In 40% of these patients even by computed tomography metastasis was only suspected, in 8% there were unspecific findings, while by follow-up bone metastasis was proven. In 64.8% of the whole patient collective there were metastatic destructions and in 32.6% of patients benign lesions were found. Superiority of CT compared to conventional x-ray diagnosis resulted from exact demonstration of the intra- and extraosseous extent of lesions and the possibility of density measurements. It depended mainly upon the localisation of the pathologic process.

[Nuclear magnetic resonance tomographic staging of tumors of the oral cavity, oro- and hypopharynx and the larynx. A comparison with computed tomography and sonography]. / Kernspintomographisches Staging von Tumoren der Mundhöhle, des Oro- und Hypopharynx sowie des Larynx. Vergleich mit Computertomographie und Somographie.

Thirty-six patients with tumours of the mouth, the oropharynx and hypopharynx and the larynx were examined by nuclear resonance tomography. The results were compared with the clinical findings of inspection and palpation and with CT and sonography, with respect to T and N classification. In seven patients the classification could be confirmed at operation. NMR provides very good anatomical detail and marked contrast between tumour and the surrounding tissues, particularly on T2 weighted images. NMR showed the best correlation with the clinical findings as regards the T classification and was the most accurate method, as confirmed by surgery. It is superior to CT and sonography for diseases in the oropharynx and hypopharynx. For the examination of the cervical lymphatics, sonography remains the recommended method.

[Angio-CT: an improvement in the diagnosis of malignant liver diseases]. / Angio-CT: Eine Erweiterung der Diagnostik maligner Leberprozesse.

Dynamic contrast studies of the liver make it possible to evaluate the vascularity of liver metastases. Up to the present, the examination has only been carried out in single planes, whereas studies of the whole of the liver during one examination have not yet been published. This can be obtained by performing sequential CT (angio-CT), using special software. A clinical study of the value of the procedure has been undertaken on 64 patients with suspected liver metastases. In addition to the plain scans, the examination was repeated during the early phase of a bolus injection and subsequently ten minutes after injection (enhancement). The various structures which can be seen are described and the changes in density patterns have been interpreted according to contrast kinetics derived from nephrographic examinations. The advantages of angio-CT as compared with plain films and with scans after normal contrast infusions are described. The improved sensitivity and specificity obtained by using the three modes of examination, as compared with a single examination, is stressed.

[99m-Tc-MIBI for recurrent and metastatic differentiated thyroid carcinoma]. / 99mTc-MIBI zur Rezidiv- und Metastasensuche bei differenzierten Schilddrüsenkarzinomen.

AIM: The aim of the study has been the examination of the diagnostic value of 99mTc-MIBI scintigraphy for the detection of local tumor or metastases following total thyroidectomy and 131I ablation therapy in differentiated thyroid carcinoma. METHODS: MIBI-scintigraphy has been indicated in 85 patients because of ascending thyroglobulin values or suspected local recurrencies by ultrasonography. The results have been compared to cytology or histology or ultrasonography, computed tomography, X-ray and radioiodine scanning. RESULTS: MIBI scintigraphy was found positive in 32 of 40 metastases. Only 18 metastases have been seen by radioiodine. MIBI scintigraphy was most effective in detecting local tumor recurrencies and lymph node metastases (94%). The specificity of MIBI and radioiodine was similar (100%). In inflammatory enlarged lymph nodes no MIBI uptake was found, so it is possible to differentiate reactive lymph node enlargement from metastatic disease. CONCLUSION: In conclusion scintigraphy with 99mTc-MIBI is advisable in suspected local recurrencies and negative radioiodine scan. It is favourable that withdrawing TSH-suppressive hormone medication is not necessary.

Free fat transplantation in the face.

Several operative procedures have been described for correction of soft tissue defects in the face. Free fat transplantation has been criticised many times. In a twelve-year period, we have carried out 19 free fat transfers from the gluteal fold, of a size ranging from the palm of a child's hand to the size of an adult hand. Follow-up has been possible in 12 patients with 14 such transfers. Initially, grafts tended to be too large and subsequent fat reduction was required. It is apparent that the tendency to resorption of non-vascularised fat can only be estimated to a limited extent. Ultrasound examination in the course of long-term follow-up showed structural changes within the grafts but none was particularly striking. The fat has a good consistency on palpation particularly for the cheeks and remains in situ after healing. This technique still has a role in suitable cases.

Osteoradionecrosis of the jaws as a side effect of radiotherapy of head and neck tumour patients--a report of a thirty year retrospective review.

This retrospective study aimed to demonstrate the incidence and the aetiological factors involved in osteoradionecrosis (ORN) in a group of 830 head and neck tumour patients who received radiotherapy between 1969 and 1999. The data showed an over all incidence of 8.2% and a 3-fold higher incidence for men than for women. Osteoradionecrosis was most commonly located in the body of the mandible. Concerning the risk factors, a negative influence was shown for advanced tumours, segmental resections of the mandible and pre-/post-radiation tooth extractions. Tooth extractions were found to be responsible for 50% of all cases. The osteoradionecroses were observed significantly earlier in patients who received pre-surgical radiotherapy than those who received post-surgical radiotherapy. Combined pre-surgical radio- and chemotherapy significantly hastened the appearance of osteoradionecrosis compared to pre-surgical radiotherapy alone. Only 40% of patients with osteoradionecrosis could be healed completely by means of surgery and antibiotic medication. Hyperbaric oxygenation (HBO) therapy was performed only in individual cases. The data suggest that osteoradionecrosis has a multifactorial aetiology. Therefore, a very close follow-up of tumour patients and a strict prophylactic management are required.

Optimization of preoperative chemotherapy by ultrasound. Follow-up in tumours of the oral cavity and oropharyngeal region.

The results in 53 patients with tumours of the oral cavity and oropharyngeal region who received Cisplatinum/5-FU indicate that ultrasound monitoring of preoperative antineoplastic chemotherapy is a valuable, effective, and economical/imaging method which improves the early adjustment of the therapy concept to response rates at the C2-level.