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.

Comparison of quantum and classical relaxation in spin dynamics.

The classical Landau-Lifshitz equation with a damping term has been derived from the time evolution of a quantum mechanical wave function under the assumption of a non-Hermitian Hamilton operator. Further, the trajectory of a classical spin (S) has been compared with the expectation value of the spin operator (S). A good agreement between classical and quantum mechanical trajectories can be found for Hamiltonians linear in S or S, respectively. Quadratic or higher order terms in the Hamiltonian result in a disagreement.

Investigation of the temperature phase diagram of the 2D semi-classical ferrimagneticJ1-J2model.

The temperature phase diagram (ToverJ2) of the 2D semiclassicalJ1-J2Heisenberg model is discussed. The investigation was carried out using the self-consistent Bloch equation and a quantum statistical description of the magnetization. In addition to the three states of the zero-temperature phase diagram, theJ2-Tphase diagram shows two new phases, the paramagnetic phase and the semi-paramagneticS1-Néel state. The five occurring ground states, as well as the transitions between these states, are discussed. In particular, attention is paid to the interplay between temperature and frustration.

Indirect control of antiferromagnetic domain walls with spin current.

The indirect controlled displacement of an antiferromagnetic domain wall by a spin current is studied by Landau-Lifshitz-Gilbert spin dynamics. The antiferromagnetic domain wall can be shifted both by a spin-polarized tunnel current of a scanning tunneling microscope or by a current driven ferromagnetic domain wall in an exchange coupled antiferromagnetic-ferromagnetic layer system. The indirect control of antiferromagnetic domain walls opens up a new and promising direction for future spin device applications based on antiferromagnetic materials.

Domain wall manipulation with a magnetic tip.

A theoretical concept of local manipulation of magnetic domain walls is introduced. In the proposed procedure, a domain wall is driven by a spin-polarized current induced by a magnetic tip, as used in a scanning tunneling microscope, placed above a magnetic nanostripe and then moved along its long axis with a current flowing through the vacuum barrier. The angular momentum from the spin-polarized current exerts a torque on the magnetic moments underneath the tip and leads to a displacement of the domain wall. Particularly, the manipulation of a ferromagnetic 180° transverse domain wall has been studied by means of Landau-Lifshitz-Gilbert dynamics and Monte Carlo simulations. Different relative orientations of the tip and the sample magnetization have been considered.

Investigation of the magnetic phase diagram of the 2D ferrimagnetic J 1-J 2 model.

The zero-temperature phase diagram and spin dynamics of the 2D ferrimagnetic J 1-J 2 model with (S 1, S 2) = (1/2, 1) are investigated using the time-dependent cluster mean-field theory (t-CMFT). The t-CMFT enables the investigation of the quantum-mechanical as well as semi-classical phase diagram and spin dynamics by control of the entanglement. For the characterization of the ferrimagnetic system, the magnetization, the energy per atom, the cluster quantum states and the von Neumann entropy have been determined.

Contact inhibition of growth of human diploid fibroblasts by immobilized plasma membrane glycoproteins.

The human embryonic fibroblasts used in this study show pronounced inhibition of growth when reaching a critical cell density. High cell density and growth inhibition has previously been mimicked by the addition of glutaraldehyde-fixed cells or of isolated plasma membranes to sparsely seeded proliferating fibroblasts (Wieser, R. J., R. Heck, and F. Oesch, 1985, Exp. Cell Res., 158:493-499). In this report, we describe the successful solubilization of the growth-inhibiting glycoproteins and their covalent coupling to silicabeads (10 microns), which had been derivatized with 3-isothiocyanatopropyltriethoxysilane. The beads, bearing the plasma membrane proteins, were added to sparsely seeded, actively proliferating fibroblasts, and growth was measured by the determination of cell number or of incorporation of [3H]thymidine into DNA. The growth was inhibited in a concentration-dependent manner, whereby 50% inhibition was achieved with 0.3 micrograms of immobilized protein added to 5 X 10(3) cells. Terminal galactose residues of plasma membrane glycoproteins with N-glycosydically bound carbohydrates were responsible for the inhibition of growth. Dense cultures of human fibroblasts are characterized by an accelerated synthesis of procollagen type III. We have found that this cellular response can also be induced by the addition of immobilized plasma membrane glycoproteins to sparsely seeded cells. These observations support the conclusion that the addition of immobilized plasma membrane glycoproteins to sparsely seeded fibroblasts mimics the situation occurring at high cell density. These results show that cell-cell contacts via plasma membrane glycoproteins carrying terminal galactose residues are important for the regulation of the proliferation of cultured human fibroblasts and presumably of the accelerated synthesis of collagen type III.

Isolation and characterization of a 60-70-kD plasma membrane glycoprotein involved in the contact-dependent inhibition of growth.

Previous studies have shown that plasma membrane compounds are involved in the contact-dependent inhibition of growth of human diploid fibroblasts. The purification of the active plasma membrane glycoprotein is described in this report. The glycoprotein has an apparent molecular mass of 60-70 kD and, due to differential sialylation, isoelectric points between pH 5.5. and 6.2. Treatment with sialidase yielded one spot in two-dimensional gel electrophoresis with an isoelectric point of 6.3. After removal of the N-glycosidically linked oligosaccharide chains, the apparent molecular mass is reduced by approximately 22 kD. Treatment was diluted NaOH, which removes the O-glycosidically linked portion of oligosaccharides, resulted in a reduction of the apparent molecular mass by approximately 5 kD. The addition of 50 ng/ml of this glycoprotein-for which the term "contactinhibin" is proposed-in immobilized form to sparsely seeded human fibroblasts resulted in a reversible 70-80% inhibition of growth. The inhibition was not confined to human fibroblasts as other cells were also inhibited, with the exclusion of transformed cells, which are refractory to contactinhibin. The inhibitory activity was abolished by treatment with beta-galactosidase or glycopeptidase F, indicating that the glycan moiety is the biologically active part of the molecule. Confluent cultures treated with antibodies raised against contactinhibin were released from the contact-dependent inhibition of growth. In addition to enhanced saturation density, these cultures exhibited a crisscross growth pattern and the formation of foci. Immunocytochemical studies showed that contactinhibin was associated with vimentin. Furthermore, contactinhibin was found to be not expressed in a species- or organ-specific manner.

Investigation of quantum and thermal fluctuations ferromagnetic spin chains with easy-plane anisotropy.

One-dimensional ferromagnetic S = 1/2 and S = 1 spin chains with easy-plane and easy-axis exchange anisotropy are studied by the double-time Green's function method. The XYZ model can be used to describe several chain systems as the ferromagnetic spin chain of [Formula: see text] (CHAB). Alternatively, ferromagnetic spin-spirals with Dzyaloshinsky-Moriya interaction. To study quantum and thermal fluctuations the magnetization and susceptibility are calculated and analyzed as a function of the external field, the strength of the anisotropy and the chain length.

Integrated QCM-Microtribometry: Friction of Single-Crystal MoS2 and Gold from µm/s to m/s.

Two opposing microtribometry approaches have been developed over the past decade to help connect the dots between fundamental and practical tribology measurements: spring-based (e.g., AFM) approaches use low speed, low stiffness, and long relative slip length to quantify friction, while quartz crystal microbalance (QCM)-based approaches use high speed, high stiffness, and short relative slip length. Because the friction forces generated in these experiments are attributed to entirely different phenomena, it is unclear if or how the resulting friction forces are related. This study aims to resolve this uncertainty by integrating these distinct techniques into a single apparatus that allows two independent measurements of friction at a single interface. Alumina microspheres were tested against single-crystal MoS2, a model nominally wear-free solid lubricant, and gold, a model metal control, at loads between 0.01 and 1 mN. The combined results from both measurement approaches gave friction coefficients (mean ± standard error) of 0.087 ± 0.007 and 0.27 ± 0.02 for alumina-MoS2 and alumina-gold, respectively. The observed agreement between these methods for two different material systems suggests that friction in microscale contacts can be far less sensitive to external effects from compliance and slip speed than currently thought. Perhaps more importantly, this Article describes and validates a novel approach to closing the "tribology gap" while demonstrating how integration creates new opportunities for fundamental studies of practical friction.

Bortezomib in relapsed multiple myeloma: response rates and duration of response are independent of a chromosome 13q-deletion.

Studies of bortezomib in patients with relapsed multiple myeloma (MM) suggested that bortezomib may be active even in the presence of adverse prognostic factors. We therefore evaluated 62 patients with relapsed/refractory MM who were treated with single-agent bortezomib, and addressed the question whether or not the negative prognostic impact of unfavorable cytogenetic abnormalities may be overcome by bortezomib. By interphase fluorescence in situ hybridization (FISH), a deletion of chromosome 13q14 [del(13q14)] was present in 33 patients (53%). Overall response rates to bortezomib were similar in patients with and without del(13q14) (45 versus 55%; P=0.66), and rates of complete remission (CR) near CR were also not different between the two patient populations (18 versus 14%). Three patients had a t(4;14)(p16;q32) in addition to del(13q14), and all of them had a >50% paraprotein reduction. Median duration of response was 12.3 months in patients with del(13q14) compared with 9.3 months in patients with normal 13q-status (P=0.25), and survival was also not different between the two patient populations. Patients not benefiting from single-agent bortezomib were characterized by the combined presence of a del(13q14) and low serum albumin (median survival 4.6 months). Our results provide evidence for remarkable activity of bortezomib in MM with del(13q14). Patients who do not respond to bortezomib and consecutively have short time to treatment failure and overall survival can be identified by low serum albumin in addition to del(13q14) and should be considered for bortezomib combinations.

Density-dependent regulation of cell growth by contactinhibin and the contactinhibin receptor.

BACKGROUND: The number of cells within mammalian tissues is maintained by growth-stimulating and growth-inhibiting mechanisms, with inhibitory signals being superimposed over growth stimuli. This is reflected, in the culture of normal adherent cells, by the phenomenon of density-dependent inhibition of growth: cells cease proliferation after becoming a confluent monolayer. We have shown previously that a plasma membrane glycoprotein, contactinhibin, is a major effector of negative growth regulation. Although transformed cells express contactinhibin in a functionally active form, they are not growth-inhibited, suggesting that the defects that lead to their aberrant growth are located 'downstream' of contactinhibin. RESULTS: Here, we provide evidence that a 92 kD plasma membrane protein, which we call CiR, binds specifically to contactinhibin and acts as a receptor mediating the contact-dependent inhibition of growth of cultured human fibroblasts. When polyclonal antibodies against CiR were introduced into cells using liposomes, confluent cells were released from density-dependent growth control. By contrast, cross-linking CiR that is localized to the plasma membrane, using anti-CiR antibodies, led to growth inhibition, suggesting that CiR is a signalling molecule and implicating CiR oligomerization in signal generation. This conclusion is supported by the finding that binding of contactinhibin by CiR is strongly dependent on the local concentration of both molecules and has a sharp threshold. When CiR was isolated by immuno-precipitation under conditions favouring phosphorylation, it was hyperphosphorylated on serine and threonine residues and had reduced contactinhibin-binding capacity; the binding capacity of CiR was restored after treatment with potato acid phosphatase. Fibroblasts transformed with simian virus 40 had reduced CiR expression, higher CiR phosphorylation levels, and a strongly reduced capacity of CiR to bind to contactinhibin. Phosphatase treatment of the CiR isolated from transformed cells only partially restored its contactinhibin-binding capacity. CONCLUSIONS: Homeostasis is the net result of a highly balanced network of growth-stimulating and growth-inhibitory signals. We have shown that density-dependent inhibition of growth in vitro is mediated by the interaction of contactinhibin with a 92 kD plasma membrane glycoprotein, CiR, the contactinhibin-binding capacity of which is regulated by phosphorylation.

TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development.

Breast cancer frequently metastasizes to the skeleton, and the associated bone destruction is mediated by the osteoclast. Growth factors, including transforming growth factor-beta (TGF-beta), released from bone matrix by the action of osteoclasts, may foster metastatic growth. Because TGF-beta inhibits growth of epithelial cells, and carcinoma cells are often defective in TGF-beta responses, any role of TGF-beta in metastasis is likely to be mediated by effects on the surrounding normal tissue. However, we present evidence that TGF-beta promotes breast cancer metastasis by acting directly on the tumor cells. Expression of a dominant-negative mutant (TbetaRIIDeltacyt) of the TGF-beta type II receptor rendered the human breast cancer cell line MDA-MB-231 unresponsive to TGF-beta. In a murine model of bone metastases, expression of TbetaRIIDeltacyt by MDA-MB-231 resulted in less bone destruction, less tumor with fewer associated osteoclasts, and prolonged survival compared with controls. Reversal of the dominant-negative signaling blockade by expression of a constitutively active TGF-beta type I receptor in the breast cancer cells increased tumor production of parathyroid hormone-related protein (PTHrP), enhanced osteolytic bone metastasis, and decreased survival. Transfection of MDA-MB-231 cells that expressed the dominant-negative TbetaRIIDeltacyt with the cDNA for PTHrP resulted in constitutive tumor PTHrP production and accelerated bone metastases. These data demonstrate an important role for TGF-beta in the development of breast cancer metastasis to bone, via the TGF-beta receptor-mediated signaling pathway in tumor cells, and suggest that the bone destruction is mediated by PTHrP.

Control of Saccharomyces cerevisiae catalase T gene (CTT1) expression by nutrient supply via the RAS-cyclic AMP pathway.

In Saccharomyces cerevisiae, lack of nutrients triggers a pleiotropic response characterized by accumulation of storage carbohydrates, early G1 arrest, and sporulation of a/alpha diploids. This response is thought to be mediated by RAS proteins, adenylate cyclase, and cyclic AMP (cAMP)-dependent protein kinases. This study shows that expression of the S. cerevisiae gene coding for a cytoplasmic catalase T (CTT1) is controlled by this pathway: it is regulated by the availability of nutrients. Lack of a nitrogen, sulfur, or phosphorus source causes a high-level expression of the gene. Studies with strains with mutations in the RAS-cAMP pathway and supplementation of a rca1 mutant with cAMP show that CTT1 expression is under negative control by a cAMP-dependent protein kinase and that nutrient control of CTT1 gene expression is mediated by this pathway. Strains containing a CTT1-Escherichia coli lacZ fusion gene have been used to isolate mutants with mutations in the pathway. Mutants characterized in this investigation fall into five complementation groups. Both cdc25 and ras2 alleles were identified among these mutants.

Signaling activity of transforming growth factor beta type II receptors lacking specific domains in the cytoplasmic region.

The transforming growth factor beta (TGF-beta) type II receptor (T beta R-II) is a transmembrane serine/threonine kinase that contains two inserts in the kinase region and a serine/threonine-rich C-terminal extension. T beta R-II is required for TGF-beta binding to the type I receptor, with which it forms a heteromeric receptor complex, and its kinase activity is required for signaling by this complex. We investigated the role of various cytoplasmic regions in T beta R-II by altering or deleting these regions and determining the signaling activity of the resulting products in cell lines made resistant to TGF-beta by inactivation of the endogenous T beta R-II. TGF-beta binding to receptor I and responsiveness to TGF-beta in these cells can be restored by transfection of wild-type T beta R-II. Using this system, we show that the kinase insert 1 and the C-terminal tail of T beta R-II, in contrast to the corresponding regions in most tyrosine kinase receptors, are not essential to specify ligand-induced responses. Insert 2 is necessary to support the catalytic activity of the receptor kinase, and its deletion yields a receptor that is unable to mediate any of the responses tested. However, substitution of this insert with insert 2 from the activin receptor, ActR-IIB, does not diminish the ability of T beta R-II to elicit these responses. A truncated T beta R-II lacking the cytoplasmic domain still binds TGF-beta, supports ligand binding to receptor I, and forms a complex with this receptor. However, TGF-beta binding to receptor I facilitated by this truncated T beta R-II fails to inhibit cell proliferation, activate extracellular matrix protein production, or activate transcription from a promoter containing TGF-beta-responsive elements. We conclude that the transcriptional and antiproliferative responses to TGF-beta require both components of a heteromeric receptor complex that differs from tyrosine kinase receptors in its mode of signaling.

Type I receptors specify growth-inhibitory and transcriptional responses to transforming growth factor beta and activin.

Transforming growth factor beta (TGF-beta) and activin bind to receptor complexes that contain two distantly related transmembrane serine/threonine kinases known as receptor types I and II. The type II receptors determine ligand binding specificity, and each interacts with a distinct repertoire of type I receptors. Here we identify a new type I receptor for activin, ActR-IB, whose kinase domain is nearly identical to that of the recently cloned TGF-beta type I receptor, T beta R-I. ActR-IB has the structural and binding properties of a type I receptor: it binds activin only in the presence of an activin type II receptor and forms a heteromeric noncovalent complex with activin type II receptors. In Mv1Lu lung epithelial cells, ActR-IB and T beta R-I signal a common set of growth-inhibitory and transcriptional responses in association with their corresponding ligands and type II receptors. The transcriptional responses include elevated expression of fibronectin and plasminogen activator inhibitor 1. Although T beta R-I and ActR-IB are nearly identical in their kinase domains (90% amino acid sequence identity), their corresponding type II receptor kinase domains are very different from each other (42% amino acid sequence identity). Therefore, signaling of a specific set of responses by TGF-beta and activin correlates with the presence of similar type I kinases in their complex. Indeed, other TGF-beta and activin type I receptors (TSR-I and ActR-I) whose kinase domains significantly diverge from those of T beta R-I and ActR-IB do not substitute as mediators of these growth-inhibitory and extracellular matrix transcriptional responses. Hence, we conclude that the type I receptor subunits are primary specifiers of signals sent by TGF-beta and activin receptor complexes.

Self-consistent mean field theory studies of the thermodynamics and quantum spin dynamics of magnetic Skyrmions.

A self-consistent mean field theory is introduced and used to investigate the thermodynamics and spin dynamics of an S = 1 quantum spin system with a magnetic Skyrmion. The temperature dependence of the Skyrmion profile as well as the phase diagram are calculated. In addition, the spin dynamics of a magnetic Skyrmion is described by solving the time dependent Schrödinger equation with additional damping term. The Skyrmion annihilation process driven by an electric field is used to compare the trajectories of the quantum mechanical simulation with a semi-classical description for the spin expectation values using a differential equation similar to the classical Landau-Lifshitz-Gilbert equation.

Activation of a novel gene in 3q21 and identification of intergenic fusion transcripts with ecotropic viral insertion site I in leukemia.

We have identified a novel gene, GR6, located within the leukemia breakpoint region of 3q21, that is normally expressed in early fetal development but not in adult peripheral blood. GR6 is activated in the UCSD-AML1 cell line and in a leukemic sample, both of which carry a t(3;3)(q21;q26). In UCSD-AML1, we have also identified fusion transcripts between the ecotropic viral insertion site I (EVI1) gene in 3q26 and GR6 and between EVI1 and Ribophorin I that maps 30 kb telomeric to GR6 in 3q21. All fusions splice the 5' ends of the 3q21 genes into exon 2 of the EVI1 gene, an event that is similar to the normal intergenic splicing of MDS1-EVI1 and to those previously documented in leukemias with t(3;21) and t(3;12), in which acute myelogenous leukemia 1-EVI1 fusions and ETV6-EVI1 fusions, respectively, occur. The Ribophorin I-EVI1 fusion in particular may be a common occurrence in t(3;3).

Derivation of a time dependent Schrödinger equation as the quantum mechanical Landau-Lifshitz-Bloch equation.

The derivation of the time dependent Schrödinger equation with transversal and longitudinal relaxation, as the quantum mechanical analog of the classical Landau-Lifshitz-Bloch equation, has been described. Starting from the classical Landau-Lifshitz-Bloch equation the transition to quantum mechanics has been performed and the corresponding von-Neumann equation deduced. In a second step the time Schrödinger equation has been derived. Analytical proofs and computer simulations show the correctness and applicability of the derived Schrödinger equation.

Differences in the mechanisms of growth control in contact-inhibited and serum-deprived human fibroblasts.

In the present work we studied mechanisms of growth control in contact-inhibited and serum-deprived human diploid fibroblasts. The observation that the effects on [3H]thymidine incorporation and reduction of retinoblastoma gene product-phosphorylation were additive when contact-inhibition and serum-deprivation were combined led us to the conclusion that the underlying mechanisms might be different. Both contact-inhibition and serum-deprivation led to a strong decrease of cdk4-kinase-activity and cdk2-phosphorylation at Thr 160, while the total amounts of cdk4 and cdk2 remained constant. In contact-inhibited cells, we revealed a strong protein accumulation of the cdk2-inhibitor p27 and a slight, but significant increase of the cdk4-inhibitor p16. In serum-deprived cells, the protein levels in p27 and p16 remained low. In contrast, we detected a rapid decrease of cyclin D1 and cyclin D3 which did not occur in contact-inhibited cells. These results indicate that serum-deprivation and contact-inhibition have different mechanisms although they affect the same pathway cyclin D-cdk4, pRB, cyclin E-cdk2.