Treatment of progressive supranuclear palsy with amitriptyline: therapeutic and toxic effects.

Background: Progressive supranuclear palsy (PSP) is a parkinsonian-like disorder characterized by postural instability, rigidity, bradykinesia, supranuclear ocular palsy, dysarthria, dysphagia, and dementia. There is no satisfactory treatment. Two patients with advanced (PSP) reported here had clinically meaningful improvement in motor function on low dose amitriptyline (AMI) but developed cognitive and behavioral disturbances at higher doses.

Theory of wear as related to the Björk-Shiley Delrin disc heart valve.

Background And Aims Of The Study: Mechanical wear is an important consideration for the Björk-Shiley Delrin (BSD) heart valve, the disc of which is periodically impacted against the inlet strut by the momentum of the blood flow during closure. Impact wear theory was used in designing experiments as well as establishing theoretical evaluation and projections of wear life.

Materials And Methods: The experimental apparatus involved a pivotal hammer device where the striking face could be varied by the inclusion of distinct spherical shapes; the sharper the radius, the higher the contact stress induced.

Surface and edge wear of Björk-Shiley Delrin heart valve discs.

Background And Aims Of The Study: Wear of Björk-Shiley Delrin (BSD) heart valve discs is known to have occurred in some patients, possibly contributing to increased regurgitation. This paper specifically addresses surface and edge wear that have been observed on some discs of explanted BSD valves after implant durations up to 22.4 years.

Involvement of p72syk kinase, p53/56lyn kinase and phosphatidyl inositol-3 kinase in signal transduction via the human B lymphocyte antigen CD22.

CD22 is a B lymphocyte-specific membrane protein that functions as an adhesion molecule via its interactions with a subset of alpha 2-6-linked sialic acid-containing glycoproteins. Engagement of CD22 with a monoclonal antibody (HB22.23) that blocks the binding of CD22 to its ligands results in rapid CD22 tyrosine phosphorylation and in increased association of CD22 with p53/56lyn kinase, p85 phosphatidyl inositol-3 kinase, and p72syk kinase.

Engagement of the adhesion receptor CD22 triggers a potent stimulatory signal for B cells and blocking CD22/CD22L interactions impairs T-cell proliferation.

The B-lymphocyte-restricted adhesion protein CD22 mediates sialic acid-dependent cell-cell interactions. Engagement of CD22 on B lymphocytes with a CD22 monoclonal antibody (MoAb) HB22.7 that blocks the binding of CD22 to its ligand(s) directly stimulated B-cell proliferation.

Insights into the molecular basis of thermal stability from the structure determination of Pyrococcus furiosus glutamate dehydrogenase.

The structure determination of the glutamate dehydrogenase from the hyperthermophile Pyrococcus furiosus has been completed at 2.2 A resolution. The structure has been compared with the glutamate dehydrogenases from the mesophiles Clostridium symbiosum, Escherichia coli and Neurospora crassa.

Growth of vestibular schwannomas: in situ model employing the monoclonal antibody Ki-67 and DNA flow cytometry.

Vestibular schwannoma (VS) growth potentials were studied in an in situ model, in which the cycling cellular fraction was determined immunohistochemically by applying the mouse monoclonal Ki-67 antibody, and the tumor ploidy was estimated by DNA flow cytometry in a consecutive series of 124 VSs. The tumors were classified according to the average number of positively stained nuclei in 10 high-power fields into three groups: 28 highly (> 10), 33 moderately (> 5-10) and 63 low proliferating (< or = 5). The intratumoral proliferative variation was studied in 10 tumors.

The mechanism of substrate and coenzyme binding to clostridial glutamate dehydrogenase during reductive amination.

The binding of NADH and 2-oxoglutarate to glutamate dehydrogenase (GDH) from Clostridium symbiosum has been studied by fluorescence spectroscopy. The Kd values for the binding of these ligands have been measured by titration of either the nucleotide or protein fluorescence. During ternary complex formation, the substrate and coenzyme binding sites interact in a positive cooperative manner, but steady-state studies reveal a decrease in affinity of the catalytic complex indicative of negative cooperativity.

The structure of Pyrococcus furiosus glutamate dehydrogenase reveals a key role for ion-pair networks in maintaining enzyme stability at extreme temperatures.

Background: The hyperthermophile Pyrococcus furiosus is one of the most thermostable organisms known, with an optimum growth temperature of 100 degrees C. The proteins from this organism display extreme thermostability. We have undertaken the structure determination of glutamate dehydrogenase from P.

Urea-induced inactivation and denaturation of clostridial glutamate dehydrogenase: the absence of stable dimeric or trimeric intermediates.

Urea-induced effects in clostridial glutamate dehydrogenase (GDH, EC 1.4.1.

Positive cooperativity with Hill coefficients of up to 6 in the glutamate concentration dependence of steady-state reaction rates measured with clostridial glutamate dehydrogenase and the mutant A163G at high pH.

Glutamate dehydrogenases from many sources display nonclassical kinetic behavior suggestive of allosteric interaction among the six subunits of the hexamer. A three-dimensional structure now potentially offers a framework for explaining the basis of such behavior in clostridial glutamate dehydrogenase, and this paper offers evidence of extreme, all-or-none cooperativity in the binding of glutamate by this enzyme. A site-directed mutant of clostridial glutamate dehydrogenase in which Ala163 in the glutamate binding site is replaced by glycine displays a markedly sigmoid dependence of reaction rate on glutamate concentration (S0.

Thymomas and thymic carcinomas. A retrospective investigation with histological reclassification.

The morphological heterogeneity of thymomas has caused much confusion respecting their classification. Recently Kirchner & Müller-Hermelink (4) proposed a histological subclassification which has been claimed to represent an independent prognostic factor: medullary and mixed thymomas are benign; organoid and cortical type as well as well-differentiated thymic carcinomas are low-grade malignant tumors, which have the capacity to recur and spread, even if they are clinically benign. High-grade malignant thymomas are always malignant.

Alteration in relative activities of phenylalanine dehydrogenase towards different substrates by site-directed mutagenesis.

Glycine-124 and leucine-307 of phenylalanine dehydrogenase from Bacillus sphaericus were altered by site-specific mutagenesis to the corresponding residues in leucine dehydrogenase: alanine and valine, respectively. These two residues have previously been implicated from molecular modelling as important in determining the substrate discrimination of the two enzymes. Single and double mutants displayed lower activities towards L-phenylalanine and enhanced activity towards almost all aliphatic amino acid substrates tested compared to the wild-type, thus confirming the predictions made from molecular modelling.

Structural requirements regulate endoproteolytic release of the L-selectin (CD62L) adhesion receptor from the cell surface of leukocytes.

L-selectin mediates leukocyte rolling on vascular endothelium at sites of inflammation and lymphocyte migration to peripheral lymph nodes. L-selectin is rapidly shed from the cell surface after leukocyte activation by a proteolytic mechanism that cleaves the receptor in a membrane proximal extracellular region. This process may allow rapid leukocyte detachment from the endothelial surface before entry into tissues.

Abnormal B lymphocyte development, activation, and differentiation in mice that lack or overexpress the CD19 signal transduction molecule.

CD19-deficient mice were generated to examine the role of CD19 in B cell growth regulation in vivo. Deletion of CD19 had no deleterious effects on the generation of B cells in the bone marrow, but there was a significant reduction in the number of B cells in peripheral lymphoid tissues. B cells from CD19-deficient mice exhibited markedly decreased proliferative responses to mitogens, and serum immunoglobulin levels were also significantly decreased.

The selectins: vascular adhesion molecules.

The selectin family of adhesion molecules mediates the initial attachment of leukocytes to venular endothelial cells before their firm adhesion and diapedesis at sites of tissue injury and inflammation. The selectin family consists of three closely related cell-surface molecules with differential expression by leukocytes (L-selectin), platelets (P-selectin), and vascular endothelium (E- and P-selectin). The selectins have characteristic extracellular regions composed of an amino-terminal lectin domain that binds a carbohydrate ligand, an epidermal growth factor-like domain, and two to nine short repeat units homologous to domains found in complement binding proteins.

Insights into thermal stability from a comparison of the glutamate dehydrogenases from Pyrococcus furiosus and Thermococcus litoralis.

In the light of the solution of the three-dimensional structure of the NAD(+)-linked glutamate dehydrogenase from the mesophile Clostridium symbiosum, we have undertaken a detailed examination of the alignment of the sequences for the thermophilic glutamate dehydrogenases from Thermococcus litoralis and Pyrococcus furiosus against the sequence and the molecular structure of the glutamate dehydrogenase from C. symbiosum, to provide insights into the molecular basis of their thermostability. This homology-based modelling is simplified by the relatively small number of amino acid substitutions between the two thermophilic glutamate dehydrogenase sequences.

Heart disease and pregnancy.

Pregnancy is associated with major hemodynamic changes in the cardiovascular system that can contribute to greater morbidity and mortality in women with underlying heart disease. Therefore, the diagnosis and management of these disorders in the pregnant patient require understanding of cardiovascular physiology during pregnancy, labor, delivery, and the puerperium. It is also essential to have knowledge about safety and utility of various diagnostic modalities and drugs during pregnancy to treat maternal heart disease without compromising fetal well-being.

Identification of the ligand-binding domains of CD22, a member of the immunoglobulin superfamily that uniquely binds a sialic acid-dependent ligand.

CD22 is a B cell-restricted member of the immunoglobulin (Ig) superfamily that functions as an adhesion receptor for leukocytes and erythrocytes. CD22 is unique among members of the Ig superfamily in that it has been suggested to bind a series of sialic acid-dependent ligands, potentially through different functional domains expressed by different splice variants of CD22. In this study, the epitopes identified by a large panel of function-blocking and non-function-blocking CD22 monoclonal antibodies were localized to specific Ig-like domains, revealing that all function-blocking monoclonal antibodies bound to the first and/or second Ig-like domains.