Late-onset palsy of the recurrent laryngeal nerve after thyroid surgery.

BACKGROUND: A small subset of patients may develop late-onset palsy of the recurrent laryngeal nerve (RLN) after thyroid surgery. However, no conclusive data have been published regarding the incidence of, and possible risk factors for, this complication. METHODS: Preoperative, intraoperative and postoperative data from consecutive patients who underwent thyroid surgery at a single centre between 1999 and 2012 were analysed. Late-onset palsy of the RLN was defined as deterioration of RLN function after normal vocal cord function as investigated by routine preoperative and postoperative laryngoscopy. RESULTS: The cohort included 16 692 patients with 28 757 nerves at risk. Early postoperative palsy of the RLN was diagnosed in 1183 nerves at risk (4·1 per cent), whereas late-onset RLN palsy was found in 41 (0·1 per cent). Late-onset palsy of the RLN was diagnosed after a median interval of 2·5 (range 0·5-12) weeks and nerve function recovered completely in 28 patients after a median interval of 3 months. This recovery rate was significantly lower than that for early-onset RLN palsy: 1068 (90·3 per cent) of 1183 nerves (P < 0·001). No particular risk factor for late-onset RLN palsy was identified. CONCLUSION: Late-onset palsy of the RLN was diagnosed in a small subset of patients after thyroid surgery, and recovery of nerve function occurred less frequently than in patients with early-onset RLN palsy.

Allosteric modulators of solute carrier function: a theoretical framework.

Large-scale drug screening is currently the basis for the identification of new chemical entities. This is a rather laborious approach, because a large number of compounds must be tested to cover the chemical space in an unbiased fashion. However, the structures of targetable proteins have become increasingly available. Thus, a new era has arguably been ushered in with the advent of methods, which allow for structure-based docking campaigns (i.e., virtual screens). Solute carriers (SLCs) are among the most promising drug targets. This claim is substantiated by the fact that a large fraction of the 400 solute carrier genes is associated with human diseases. The ability to dock large ligand libraries into selected structures of solute carriers has set the stage for rational drug design. In the present study, we show that these structure-based approaches can be refined by taking into account how solute carriers operate. We specifically address the feasibility of targeting solute carriers with allosteric modulators, because their actions differ fundamentally from those of ligands, which bind to the substrate binding site. For the pertinent analysis we used transition state theory in conjunction with the linear free energy relationship (LFER). These provide the theoretical framework to understand how allosteric modulators affect solute carrier function.

Risk factors for postoperative bleeding after thyroid surgery.

BACKGROUND: Postoperative bleeding after thyroid surgery is a feared and life-threatening complication. The aim of the study was to identify risk factors for postoperative bleeding, with special emphasis on the impact of the individual surgeon and the time to diagnosis of the complication. METHODS: Data on consecutive thyroid operations were collected prospectively in a database over 30 years and analysed retrospectively for potential risk factors for postoperative bleeding. RESULTS: There were 30,142 operations and postoperative bleeding occurred in 519 patients (1·7 per cent). Risk factors identified were older age (odds ratio (OR) 1·03 per year), male sex (OR 1·64), extent of resection (OR up to 1·41), bilateral procedure (OR 1·99) and operation for recurrent disease (OR 1·54). The risk of complications among individual surgeons differed by up to sevenfold. Postoperative bleeding occurred in 336 (80·6 per cent) of 417 patients within the first 6 h after surgery. Postoperative bleeding was diagnosed after 24 h in ten patients (2·4 per cent), all of whom had bilateral procedures. Nine patients required urgent tracheostomy. Three patients died, giving a mortality rate of 0·01 per cent overall and 0·6 per cent among patients who had surgery for postoperative bleeding. CONCLUSION: Observation for up to 24 h is recommended for the majority of patients undergoing bilateral thyroid surgery in an endemic goitre area. Same-day discharge is feasible in selected patients, especially after a unilateral procedure. Quality improvement by continuous outcome monitoring and retraining of individual surgeons is suggested.

Calmodulin dependence of presynaptic metabotropic glutamate receptor signaling.

Glutamatergic neurotransmission is controlled by presynaptic metabotropic glutamate receptors (mGluRs). A subdomain in the intracellular carboxyl-terminal tail of group III mGluRs binds calmodulin and heterotrimeric guanosine triphosphate-binding protein (G protein) betagamma subunits in a mutually exclusive manner. Mutations interfering with calmodulin binding and calmodulin antagonists inhibit G protein-mediated modulation of ionic currents by mGluR 7. Calmodulin antagonists also prevent inhibition of excitatory neurotransmission via presynaptic mGluRs. These results reveal a novel mechanism of presynaptic modulation in which Ca(2+)-calmodulin is required to release G protein betagamma subunits from the C-tail of group III mGluRs in order to mediate glutamatergic autoinhibition.

JunB is a gatekeeper for B-lymphoid leukemia.

Loss of JunB has been observed in human leukemia and lymphoma, but it remains unknown, whether this loss is relevant to disease progression. Here, we investigated the consequences of JunB deficiency using Abelson-induced B-lymphoid leukemia as a model system. Mice deficient in JunB expression succumbed to Abelson-induced leukemia with increased incidence and significantly reduced latency. Similarly, bcr/abl p185-transformed JunB-deficient (junB(Delta/Delta)) cells induced leukemia in RAG2(-/-) mice displaying a more malignant phenotype. These observations indicated that cell intrinsic effects within the junB(Delta/Delta) tumor cells accounted for the accelerated leukemia development. Indeed, explantated bcr/abl p185 transformed junB(Delta/Delta) cells proliferated faster than the control cells. The proliferative advantage emerged slowly after the initial transformation process and was associated with increased expression levels of the cell cycle kinase cdk6 and with decreased levels of the cell cycle inhibitor p16(INK4a). These alterations were due to irreversible reprogramming of the cell, because - once established - accelerated disease induced by junB(Delta/Delta) cells was not reverted by re-introducing JunB. Consistent with this observation, we found that the p16 promoter was methylated. Thus, JunB functions as a gatekeeper during tumor evolution. In its absence, transformed leukemic cells acquire an enhanced proliferative capacity, which presages a more malignant disease.

The A(2A)-adenosine receptor: a GPCR with unique features?

The A(2A)-adenosine receptor is a prototypical G(s)-coupled receptor. However, the A(2A)-receptor has several structural and functional characteristics that make it unique. In contrast to the classical model of collision coupling described for the beta-adrenergic receptors, the A(2A)-receptor couples to adenylyl cyclase by restricted collision coupling and forms a tight complex with G(s). The mechanistic basis for this is not clear; restricted collision coupling may arise from the interaction of the receptor with additional proteins or due to the fact that G protein-coupling is confined to specialized membrane microdomains. The A(2A)-receptor has a long C-terminus (of >120 residues), which is for the most part dispensable for coupling to G(s). It was originally viewed as the docking site for kinases and the beta-arrestin family to initiate receptor desensitization and endocytosis. The A(2A)-receptor is, however, fairly resistant to agonist-induced internalization. Recently, the C-terminus has also been appreciated as a binding site for several additional 'accessory' proteins. Established interaction partners include alpha-actinin, ARNO, USP4 and translin-associated protein-X. In addition, the A(2A)-receptor has also been reported to form a heteromeric complex with the D(2)-dopamine receptor and the metabotropic glutamate receptor-5. It is clear that (i) this list cannot be exhaustive and (ii) that all these proteins cannot bind simultaneously to the receptor. There must be rules of engagement, which allow the receptor to elicit different biological responses, which depend on the cellular context and the nature of the concomitant signal(s). Thus, the receptor may function as a coincidence detector and a signal integrator.

Kinetics of serum parathyroid hormone during and after thyroid surgery.

BACKGROUND: Hypocalcaemia after thyroidectomy is thought to result from surgical damage to the parathyroid glands. This study analysed postoperative outcomes related to perioperative parathyroid hormone (PTH) levels. METHODS: Some 402 consecutive patients undergoing thyroid surgery were studied prospectively to monitor perioperative changes in serum PTH and Ca2+ levels, and clinical symptoms of hypocalcaemia. RESULTS: Transient symptomatic hypocalcaemia and persistent hypoparathyroidism occurred in 61 (15 per cent) and six (1.5 per cent) of 402 patients respectively. The intraoperative decline in PTH was 20.2 per cent; the trough (63.8 per cent of preoperative value) was reached 3 h after surgery. Before surgery, PTH levels were correlated inversely with serum Ca2+ concentration. The correlation remained positive from 3 h after surgery until postoperative day 14. Thus, PTH secretion was reduced, but remained sufficient to prevent symptomatic hypocalcaemia in most patients. A low serum PTH level was predictive of persistent hypoparathyroidism (sensitivity and negative predictive value 100 per cent, but poor specificity of 54.1 per cent). CONCLUSION: Thyroid surgery impairs hormone secretion by the parathyroid glands resulting in postoperative latent parathyroid insufficiency. Normal PTH levels 3 h after surgery and a normal serum calcium level on the first postoperative day rule out persistent hypoparathyroidism.

Interactions between ephrin-B and metabotropic glutamate 1 receptors in brain tissue and cultured neurons.

We examined the interaction between ephrins and metabotropic glutamate (mGlu) receptors in the developing brain and cultured neurons. EphrinB2 coimmunoprecipitated with mGlu1a receptors, in all of the brain regions examined, and with mGlu5 receptors in the corpus striatum. In striatal slices, activation of ephrinB2 by a clustered form of its target receptor, EphB1, amplified the mGlu receptor-mediated stimulation of polyphosphoinositide (PI) hydrolysis. This effect was abolished in slices treated with mGlu1 or NMDA receptor antagonists but was not affected by pharmacological blockade of mGlu5 receptors. An interaction among ephrinB2, mGlu1 receptor, and NMDA was supported by the following observations: (1) the NR1 subunit of NMDA receptors coimmunoprecipitated with mGlu1a receptors and ephrinB2 in striatal lysates; (2) clustered EphB1 amplified excitatory amino acid-stimulated PI hydrolysis in cultured granule cells grown under conditions that favored the expression of mGlu1a receptors; and (3) clustered EphB1 amplified the enhancing effect of mGlu receptor agonists on NMDA toxicity in cortical cultures, and its action was sensitive to mGlu1 receptor antagonists. Finally, fluorescence resonance energy transfer and coclustering analysis in human embryonic kidney 293 cells excluded a physical interaction between ephrinB2 and mGlu1a (or mGlu5 receptors). A functional interaction between ephrinB and mGlu1 receptors, which likely involves adaptor or scaffolding proteins, might have an important role in the regulation of developmental plasticity.

Oligomerization of neurotransmitter transporters: a ticket from the endoplasmic reticulum to the plasma membrane.

Cellular localization of neurotransmitter transporters is important for the precise control of synaptic transmission. By removing the neurotransmitters from the synaptic cleft, these transporters terminate signalling and affect duration and intensity of neurotransmission. Thus, a lot of work has been invested in the determination of the cellular compartment to which neurotransmitter transporters localize. In particular, the polarized distribution has received substantial attention. However, trafficking of transporters in the early secretory pathway has been largely ignored. Oligomer formation is a prerequisite for newly formed transporters to pass the stringent quality control mechanisms of the endoplasmic reticulum (ER), and this quaternary structure is also the preferred state which transporters reside in at the plasma membrane. Only properly assembled transporters are able to recruit the coatomer coat proteins that are needed for ER-to-Golgi trafficking. In this review, we will start with a brief description on transporter oligomerization that underlies ER-to-Golgi trafficking, followed by an introduction to ER-to-Golgi trafficking of neurotransmitter transporters. Finally, we will discuss the importance of oligomer formation for the pharmacological action of the illicitly used amphetamines and its derivatives.

Reverse intrinsic activity of antagonists on G protein-coupled receptors.

Biological effects observed with an antagonist are usually interpreted as the result of its ability to block receptor activation produced by an endogenous agonist. In this Principles article, Wolfgang Schütz and Michael Freissmuth show how considerable evidence has now been accumulated for G protein-coupled receptors that antagonists not only bind to the receptor, but also induce a conformational change that favours uncoupling of the receptor from its G protein. The spontaneous activity of the unliganded receptor (i.e. the receptor not occupied by any ligand) is a well-established phenomenon in reconstituted systems with purified components. However, its physiological relevance needs to be verified in a more physiological environment before biological effect of antagonists can be primarily ascribed to negative intrinsic activity.

G protein antagonists.

Heterotrimeric G proteins couple membrane-bound heptahelical receptors to their cellular effector systems (ion channels or enzymes generating a second messenger). In current pharmacotherapy, the input to G protein-regulated signalling is typically manipulated by targeting the receptor with appropriate agonists or antagonists and, to a lesser extent, by altering second messenger levels, most notably by inhibiting phosphodiesterases that hydrolyse cyclic nucleotides. When stimulated, G proteins undergo a cycle of activation and deactivation in which the alpha-subunits and the betagamma-dimers sequentially expose binding sites for their reaction partners (receptors, guanine nucleotides and effectors, as well as regulatory proteins). These domains can be blocked by inhibitors and this produces effects that cannot be achieved by receptor antagonists. Here, the structural and mechanistic information on G protein antagonists is summarized and an outline of the arguments supporting the hypothesis that G proteins per se are also potential drug targets is provided.

Growth hormone-prolactin-thyrotropin-secreting pituitary adenoma in atypical McCune-Albright syndrome with functionally normal Gs alpha protein.

The McCune-Albright syndrome (MAS) comprises a triad of physical signs: localized bone lesions termed polyostotic fibrous dysplasia, café-au-lait pigmentation of the skin, and autonomous hyperfunction of multiple endocrine systems, including overproduction of GH and T4. A somatic activating point mutation in the gene for the alpha-subunit of the G-protein (Gs alpha) in the affected tissue has been claimed to be the underlying defect. A 29-yr-old patient with MAS, showing polyostotic fibrous dysplasia associated with acromegalic features, underwent endocrinological studies, including oral glucose tolerance test and pituitary stimulation test, and magnetic resonance imaging, revealing elevated plasma concentrations of GH, PRL, and secondary hyperthyroidism due to pituitary macroadenoma infiltrating the sphenoid cavity and extending to the suprasellar space. Subsequently, reduction of tumor mass by a transsphenoidal and a subsequent subfrontal operation led to only marginal amelioration of the excessive hormone production. Postsurgery octreotide and bromocriptine therapy induced near-normalization of hormone concentrations. Immunohistochemistry of tumor tissue confirmed the plurihormonal character, but DNA sequence analysis did not detect any of the two known activating mutations in the Gs alpha gene. Furthermore, biochemical tests revealed normal Gs alpha function, ruling out other mutations that lead to constitutive Gs alpha activation. Our study documents that MAS is a heterogeneous disease. Some, but clearly not all, patients have oncogenic mutations of the gene coding for Gs alpha. Any gene acting down-stream of Gs can theoretically be predicted to result in the same phenotype. In addition, hyperthyroidism of MAS may be secondary to a TSH-producing pituitary macroadenoma.

G protein coupling of the rat A1-adenosine receptor--partial purification of a protein which stabilizes the receptor-G protein association.

A membrane protein identified in cortical brain membranes and termed 'coupling cofactor', modulates G protein-coupling of the A1-adenosine receptor by reducing the catalytic efficiency of the receptor. Coupling cofactor traps the A1-adenosine receptor in the high affinity complex and, thus, is responsible for the resistance of high affinity A1-agonist binding to modulation by guanine nucleotides. In the present work, this effect was used for assaying the activity of coupling cofactor by reconstituting guanine-nucleotide resistant agonist binding to rat A1-adenosine receptors in detergent extracted brain membranes or in membranes from 293 cells after stable transfection with receptor cDNA. Coupling cofactor was partially purified from porcine brain membranes. The specific activity was modestly enriched (approximately 5-fold) after three chromatographic steps (DEAE-Sephacel, AcA34, MonoQ pH 8). Rechromatography of coupling cofactor over MonoQ at pH 7 resulted in a loss in specific activity if membranes of 293 cells but not if brain membranes were used as acceptor membranes. In addition, the molecular mass estimated by gel filtration decreased from > 150 kDa in the initial stage of purification to 40-30 kDa after this fourth chromatographic step. These two observations suggest that coupling cofactor requires an additional component that is present in brain membranes and is lost in later stages of purification. The activity of partially purified preparations of coupling cofactor activity relied also on the abundance of G protein alpha-subunits in the membrane. The activity on reconstitution with brain membranes or pertussis toxin pretreated 293 membranes was supported by addition of Gi alpha (rank order of protency: alpha i1 > alpha i3 > alpha i2) but not of G(o alpha). The selectivity for G protein alpha-subunits suggests that coupling cofactor may provide for an additional level of specificity in organizing receptor-G protein coupling.

Binding and structure-activity-relation of benzo[f]isoquinoline- and norcodeinone-derivatives at mu-opioid receptors in the rat cerebral cortex.

1. We have probed the ligand binding site of the mu-opioid receptor using a series of isoquinoline- and norcodeinone-derivatives; in these morphine- and codeine-analogues, the position of the piperidine-nitrogen as well as its mobility is altered relative to that found in morphine. 2. The mu-receptor in rat cortical membranes was labelled with [3H]-naloxone and competition experiments were carried out in the absence and presence of Gpp(NH)p and NaCl: conditions, which are associated with affinity shifts for agonists whilst antagonist affinity remains unaffected. Moving the piperidine-nitrogen closer to the phenolic ring or reducing its mobility by incorporation into an additional ring drastically decreases the affinity. 3. In contrast, we find that the piperidine-nitrogen in a distal position is well tolerated provided that additional structural criteria, in particular a phenolic hydroxyl-group and a 6 carbon ring corresponding to ring C in morphine, are met. This assumption was verified by the synthesis of WB4/PH (4aR, 10bS, 11R)-10, 11-epoxy-1, 2, 3, 4, 5, 6-hexahydro-9-hydroxy-3-methyl-4a,10b-butano- benzo[f]isochinolin-12-on(10). This compound is an agonist with an affinity comparable to that of morphine. 4. We therefore conclude that both the mobility of the piperidine nitrogen of the ligand and of its counterpart anionic site in the ligand binding pocket of the mu-opioid receptor (presumably aspartic acid) are important determinants for fruitful interaction. The mobility of the anionic site is restricted in one direction but is sufficient to bridge the 2A distance that exists between the position of the nitrogen in morphine and WB4/PH.

P2-, but not P1-purinoceptors mediate formation of 1, 4, 5-inositol trisphosphate and its metabolites via a pertussis toxin-insensitive pathway in the rat renal cortex.

1. The adenosine receptor (P1-purinoceptor) agonists N6-cyclopentyladenosine and N-5'-ethyl-carboxamidoadenosine at concentrations up to 10 mumols 1(-1) affected neither basal, nor noradrenaline- and angiotensin II-stimulated formation of inositol-1-phosphate, inositol-1,4-bisphosphate, and inositol-1,4,5-trisphosphate in slices of rat renal cortex. 2. In contrast, adenine nucleotides (P2-purinoceptor agonists) markedly stimulated inositol phosphate formation. The observed rank order of potency adenosine-5'-O-(2-thiodiphosphate) (EC50 39 mumols 1(-1] greater than adenosine-5'-O-(3-thiotriphosphate) (587) greater than or equal to 5'-adenylylimidodiphosphate (App(NH)p, 899) greater than adenylyl-(beta, gamma-methylene)-diphosphate (4,181) was consistent with the interaction of the compounds with the P2Y-subtype of P2-purinoceptors. AMP and the ADP analogue (alpha, beta-methylene)-adenosine-5'-diphosphate were ineffective. ATP and ADP (less than or equal to 10 mmol 1(-1] did not produce a consistent increase, owing to their hydrolytic degradation in the incubation medium. 3. Whereas the inositol phosphate response to App(NH)p was linear only up to 5 min incubation, the time-dependent stimulation of noradrenaline declined at a slower rate. Following pre-exposure of the renal cortical slices to App(NH)p, renewed addition of App(NH)p caused no further enhancement in the accumulation of inositol phosphates, whilst noradrenaline was still capable of eliciting a response. This suggests that the apparent loss of responsiveness to App(NH)p is not due to substrate depletion or enzymatic inactivation, but most likely attributable to homologous desensitization of the purinoceptor. 4. Pretreatment of the animals with pertussis toxin caused a substantial reduction of functional Gi-protein, as indicated by the lack of [32P]-NAD incorporation in a membrane preparation of the renal cortex. Nevertheless, the increase in inositol phosphate formation induced by noradrenaline, angiotensin II, and App(NH)p was not significantly impaired. 5. We conclude that P2 gamma-purinoceptors are present in the renal cortex; these receptors stimulate formation of inositol phosphates via a pertussis toxin-insensitive pathway and undergo homologous desensitization. On the other hand, our results suggest that renal A,-adenosine receptors do not use stimulation of phosphoinositide breakdown as a transmembrane signalling system.

Stimulation of human umbilical vein endothelial cell proliferation by A2-adenosine and beta 2-adrenoceptors.

1. Adenosine is known to stimulate capillary outgrowth and endothelial cell proliferation, but the underlying mechanism has not been identified. In order to identify the receptor subtype involved, the effects of adenosine receptor agonists and antagonists on human umbilical vein endothelial cell (HUVEC) proliferation were investigated. 2. Raising intracellular adenosine levels by use of the adenosine transport inhibitor, 4-nitrobenzylthioinosine (NBMPR) did not affect cell growth. This observation suggests that stimulation of an extracellular adenosine receptor generates the mitogenic signal. 3. In the presence of adenosine deaminase (ADA), which was used to remove adenosine present in the culture medium, the adenosine receptor agonists N-ethylcarboxamidoadenosine (NECA, non-selective) and CGS21680 (A2A-receptor-selective) stimulated [3H]-thymidine incorporation with a half-maximum effect at about 10 nM, while N6-cyclopentyladenosine (CPA, A1-selective) was about 100 fold less potent. The adenosine receptor antagonist, xanthine amine congener (XAC) produced a concentration-dependent decrease in endothelial cell proliferation with a half-maximum effect at about 10 nM. Hence, stimulation of an endothelial A2A-adenosine receptor seems responsible for the mitogenic signal. 4. In the presence of ADA, isoprenaline is also able to stimulate [3H]-thymidine incorporation with a half maximal effect of about 3 nM, an effect, which is reversed by the highly beta 2-selective antagonist, ICI 118,551. In the absence of ADA, isoprenaline exerts only a minor stimulatory effect. Combination of A2A adenosine and beta 2-adrenoceptor agonists did not further enhance [3H]-thymidine incorporation when compared to the sole addition of each agonist. We therefore conclude that both receptors stimulate endothelial cell proliferation via a common signal transduction pathway. 5. Both receptors are coupled to stimulation of adenylyl cyclase via the stimulatory G protein G8.However, direct activation of downstream effectors in the cyclic AMP-signalling cascade (G8 with cholera toxin, adenylyl cyclase with forskolin, protein kinase A with 8Br-cyclic AMP) not only failed to mimic the action of receptor-activation, but even reduced cell proliferation.6. Similarly, pertussis toxin-treatment which inactivated the Gi 2 protein present in HUVEC and thus inhibited cell proliferation per se, did not impair the ability of A2A-receptor agonists to stimulate cell proliferation. This suggests that the A2A-adenosine and beta2-adrenoceptor-mediated stimulation of endothelial cell proliferation occurs via a mechanism that is independent of G8 and Gi.

Thyroid surgery in untreated severe hyperthyroidism: perioperative kinetics of free thyroid hormones in the glandular venous effluent and peripheral blood.

BACKGROUND AND METHODS: It is generally believed that thyroid surgery in Graves' disease requires a euthyroid state to avoid thyrotoxic reactions. We carried out a prospective study on 23 patients who had severe hyperthyroidism with free thyroid hormone concentrations (fT3 or fT4) exceeding the upper normal boundary by 300% or more and who were not pretreated with thyrostatic agents. We determined hormone levels during operation in the thyroid venous effluent before and after surgical trauma and monitored their postoperative elimination kinetics. RESULTS: The concentration of fT3 and fT4 in the venous effluent of the hyperactive gland did not exceed the peripheral levels. Surgery did not induce any intraoperative or postoperative increase in fT4 or fT3, whereas thyroglobulin concentrations rose sharply. Both fT4 and fT3 followed biphasic elimination kinetics, and a significant decline of circulating free hormone concentrations was measurable within the first postoperative hour. CONCLUSIONS: Contrary to widely held assumptions, the surgical trauma does not stimulate the release of thyroid hormones. Hence this mechanism cannot account for the postoperative development of thyroid storm. Our observations imply that immediate operation should generally be considered for the emergency treatment of an imminent thyroid storm.

Early relapse after operation for Graves' disease: postoperative hormone kinetics and outcome after subtotal, near-total, and total thyroidectomy.

BACKGROUND: The relative merit of operation in the treatment of Graves' disease has been questioned, and the extent of surgical resection is still a matter of debate. METHODS: We have analyzed retrospectively the incidence of recurrent hyperthyroidism (frequency and time point) in 215 consecutive patients subjected sequentially to subtotal thyroidectomy (n = 63; remnant mass 6 to 8 g, based on surgeons' estimates and dimensions measured during operation), extensive subtotal thyroidectomy (n = 106; remnant mass approximately 4 g), and near-total (n = 27; unilateral capsular remnant of < 2 g) or total thyroidectomy (n = 19). In addition, we have evaluated the postoperative kinetics of thyroid hormone elimination (free triiodothyronine and free thyroxine) in 14 selected patients with hyperthyroidism who underwent operation under beta-adrenergic blockade but without any thyrostatic pretreatment. RESULTS: The size of the remnant significantly (P < .05) affected the relapse rate (23.8%, 9.4%, and 0% in subtotal, extensive subtotal, and near-total/total thyroidectomy, respectively). However, the time point at which the relapse occurred did not differ in subtotal and extensive subtotal thyroidectomy. All relapses occurred within the first 70 weeks. The incidence of complications (permanent recurrent nerve paresis and persistent hypocalcemia) was comparable in all groups. The elimination of fT3 was biphasic and rapid such that the levels were within the normal range on the second day. In contrast, 15 days were required until the fT4 level had declined below the upper limit in all patients. CONCLUSIONS: We propose that the therapeutic goal in thyroid operations is to avoid recurrent hyperthyroidism. This is not reliably achieved by subtotal thyroidectomy; in contrast, near-total and total thyroidectomy are effective and safe. On the basis of the postoperative elimination kinetics, hormone replacement is to be instituted within 2 weeks after operation.

Reoperation as treatment of relapse after subtotal thyroidectomy in Graves' disease.

BACKGROUND AND METHODS: In Graves' disease radioiodine is the recommended treatment for relapses after subtotal thyroidectomy. If patients reject radioiodine, hyperthyroidism is managed with antithyroid drugs; surgery is generally not considered as an alternative. Here we retrospectively analyzed 30 consecutive patients with Graves' disease who had recurrent hyperthyroidism after subtotal thyroidectomy. RESULTS: On relapse after the first operation, the patients were initially treated by medication; 25 opted for definitive treatment (19 for reoperation and 6 for radioiodine). Operations consisted of 10 unilateral and 8 bilateral resections (total or near-total with capsular remnants of < 1 g) and 1 transsternal approach (because of dystopic intrathoracic thyroid tissue). The decision between a unilateral and a bilateral reintervention was based on the ultrasonographic determination of remnant volumes. These size estimates were valid because they were significantly correlated to the weight of the resected remnants (r = 0.92, slope = 0.95). Eighteen of the 19 patients were adequately treated by this approach. Unilateral resection was performed in 1 patient with a remaining contralateral remnant of 5.4 mL; this patient had a second relapse. The complication rate was low (2 cases of transient recurrent nerve injury and 1 of transient hypocalcemia). CONCLUSION: Provided that no contraindication is present, reoperation is safe, effective, and expeditious in recurrent hyperthyroidism. Because the likelihood of a recurrence depends on the total remnant size, the goal is to keep it below 2 g. Preoperative ultrasonography can effectively guide the decision between a unilateral and a bilateral resection.

Stimulation of adenylate cyclase activity via A2-adenosine receptors in isolated tubules of the rabbit renal cortex.

Adenylate cyclase activity in a tubular fraction obtained from rabbit renal cortex was stimulated by typical adenosine receptor agonists with a rank order of potency NECA (5'-(N-ethyl-carboxamido)-adenosine) (EC50 = 0.48 mumol/l) greater than R-PIA [(-)N6 (R-phenylisopropyl)-adenosine] (3.22 mumol/l). The stimulatory effect of NECA was competitively antagonized by 8-phenyltheophylline. Contamination of the tubular fraction with glomeruli and microvessels was less than 2%, as verified by tissue renin determination and could, therefore, be ruled out as being responsible for the observed effect. Tubular A2-adenosine receptors are probably involved in the control of renal electrolyte secretion and may represent the site of action of methylxanthines.