Heart failure and first dose hypotension after angiotensin converting enzyme inhibitors

The first-dose induced decrease in blood pressure in some patients following the administration of ACE inhibitors is a fact causing some concern among clinicians prescribing these drugs. However, an overview of clinical trials and the authors' own experience clearly point to the possibility of reducing the incidence and/or severity of first-dose hypotension. Apart from appropriate clinical measures to be taken, the choice of the ACE inhibitor seems to be of crucial importance as some (fosinopril, perindopril) produce less hypotension than others. Thus, with due circumspection, ACE inhibitors can safely retain their position as the cornerstone of the treatment of chronic heart failure.     

Inhibition of apoptosis prevents West Nile virus induced cell death

Background  

West Nile virus (WNV) infection can cause severe meningitis and encephalitis in humans. Apoptosis was recently shown to contribute to the pathogenesis of WNV encephalitis. Here, we used WNV-infected glioma cells to study WNV-replication and WNV-induced apoptosis in human brain-derived cells.     

A hypothesis for the function of braking forces during running turns

We examined the functional role of braking forces observed when humans execute turning maneuvers. Deceleration caused by braking forces contributes to changing the movement direction of the center of mass (COM) and maintaining constant velocity. We argue that braking forces also prevent over-rotation of the body about the vertical axis during maneuvers. We analyzed data from sidestep and crossover cuts at average initial running velocities of 3 m s(-1). Absent braking, lateral forces would result in body rotations 1.4-3 times the change in COM movement direction, causing the orientation of the body to be substantially mis-aligned with the direction of movement at the end of the step. A simple model based on the hypothesis that body rotation should match COM deflection can explain 70% of the variance in braking forces employed during running turns.     

Identification of CD21-binding peptides with phage display and investigation of binding properties of HPMA copolymer-peptide conjugates

Cancer targeting with peptides has become promising with the emergence of combinatorial peptide techniques such as phage display. Using phage display under stringent screening conditions, we selected five distinct peptides that specifically recognized the CD21 receptor, a cell surface marker of malignant B cell lymphoma. Two highly hydrophobic sequences were excluded (RLAYWCFSGLFLLVC and PVAAVSFVPYLVKTY). The binding affinity toward CD21 of the other three selected peptides (RMWPSSTVNLSAGRR, PNLDFSPTCSFRFGC, and GRVPSMFGGHFFFSR) was analyzed with fluorescence quenching. Their dissociation constants were determined to be within the micromolar range. On the basis of the results of phage ELISA, competitive phage ELISA, and fluorescence quenching, the binding sites of the three selected peptides were found to reside within the first four short consensus repeats of CD21 (SCR1-4). The peptide RMWPSSTVNLSAGRR (P1) was bound to the N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer, a potential drug carrier for chemotherapeutic agents, and the surface binding properties of HPMA copolymer-P1 conjugates were investigated. Specific interactions were observed between HPMA copolymer-P1 conjugates and surface-bound receptor. Binding of HPMA copolymer-P1 conjugates was directly related to the amount of surface (MaxiSorp plate) bound receptor, and the binding of the conjugates could be inhibited by the application of a 3-4 orders-of-magnitude excess of free peptide over the peptide concentration in conjugates. The enhanced binding of polymer-bound peptide was ascribed to multivalent interactions between the HPMA copolymer-P1 conjugate and the surface-bound CD21 receptor.     

Glucose-2-oxidase activity and accumulation of D-arabino-2-hexosulose in cultures of the basidiomyceteOudemansiella mucida

Submerged cultures of the basidiomyceteOudemansiella mucidd, strain III, accumulate D-arabino-2-hexosulose. The maximum yields during cultivations in shaker flasks or in a laboratory fermentor are 6–12 and 15 mg/ml, respectively (20–50 % conversion of substrate glucose). The accumulation is transient, the aldoketose being again utilized after glucose exhaustion. Its production is stimulated by fluoride ions. The enzyme responsible for the C₍₂₎-specific oxidation ofd-glucose acts as an intracellular oxidase with a maximum activity in the exponential phase of growth.d-arabino-2-Hexosulose was also detected in the cultivation medium of the wood-rotting fungiPleurotus ostreatus, Laetiporus sulphureus, andPhellinus abietis. Part III of the series Enzymatic activity of Basidiomycetes; part II:Folia Microbiol. 13, 334 (1968).     

Tablet Keyboard Configuration Affects Performance,Discomfort and Task Difficulty for Thumb Typing in a Two-Handed Grip

When holding a tablet computer with two hands, the touch keyboard configuration imposes postural constraints on the user because of the need to simultaneously hold the device and type with the thumbs. Designers have provided users with several possible keyboard configurations (device orientation, keyboard layout and location). However, potential differences in performance, usability and postures among these configurations have not been explored. We hypothesize that (1) the narrower standard keyboard layout in the portrait orientation leads to lower self-reported discomfort and less reach than the landscape orientation; (2) a split keyboard layout results in better overall outcomes compared to the standard layout; and (3) the conventional bottom keyboard location leads to the best outcomes overall compared to other locations. A repeated measures laboratory experiment of 12 tablet owners measured typing speed, discomfort, task difficulty, and thumb/wrist joint postures using an active marker system during typing tasks for different combinations of device orientation (portrait and landscape), keyboard layout (standard and split), and keyboard location (bottom, middle, top). The narrower standard keyboard with the device in the portrait orientation was associated with less discomfort (least squares mean (and S.E.) 2.9±0.6) than the landscape orientation (4.5±0.7). Additionally, the split keyboard decreased the amount of reaching required by the thumb in the landscape orientation as defined by a reduced range of motion and less MCP extension, which may have led to reduced discomfort (2.7±0.6) compared to the standard layout (4.5±0.7). However, typing speed was greater for the standard layout (127±5 char./min.) compared to the split layout (113±4 char./min.) regardless of device orientation and keyboard location. Usage guidelines and designers can incorporate these findings to optimize keyboard design parameters and form factors that promote user performance and usability for thumb interaction.     

Pharmacological activity of DTPA linked to protein-based drug carrier systems

The chelating agent diethylenetriaminepentaacetic acid (DTPA) inhibits human cytomegalovirus replication. Since chelating agents are known to exhibit anti-cancer effects, DTPA-induced cytotoxicity was evaluated in breast cancer cells (MCF-7) and neuroblastoma cells (UKF-NB-3). DTPA inhibited cancer cell growth in threefold lower concentrations compared to human foreskin fibroblasts (HFF). Antiviral and anti-cancer activity of chelating agents is caused by intracellular complexation of metal ions. DTPA, an extracellular chelator, was covalently coupled to human serum albumin (HSA) molecules, HSA nanoparticles (HSA-NP), gelatin type B (GelB) molecules, and GelB nanoparticles (GelB-NP) to increase cellular uptake. Coupling of DTPA to drug carrier systems increased its cytotoxic and antiviral activity by 5- to 8-fold. Confocal laser scanning microscope examination revealed uptake of DTPA-HSA-NP in UKF-NB-3 cells and HFF. Therefore, coupling of DTPA to protein-based drug carrier systems increases its antiviral and anti-cancer activity probably by mediating cellular uptake.     

Swelling pressure induced phase-volume transition in hybrid biopolymer gels caused by unfolding of folded crosslinks: a model

A thermodynamic model is proposed describing swelling changes and swelling transitions of hybrid gels in which domains of folded chains are chemically built in as cross-links. These folded domains can be unfolded to random coils by osmotic forces produced by the synthetic gel matrix. Uncoiling takes place if the osmotic force acting on the cross-links exceeds the critical value. By unfolding, a new interacting surface is exposed to interactions and affects the swelling pressure. The chains of the folded domains may have ionized groups. The model is based on mean-field statistical-thermodynamic treatment of swelling of polyelectrolyte gels with finite extensibility of network chains. This study is related to hybrid hydrogels with built in protein motifs. A continuous change in external variables increasing the degree of swelling of the hydrogel brings about an abrupt increase in volume (transition) of the gel. The position and magnitude of the transition depend on structural parameters of the hybrid gel, such as fraction of the folded domains in the gel, degree of ionization of chains in the domain, presence of additional chemical cross-links, or degree of dilution at gel formation. Two options for reversibility of the changes are considered: (a) unfolding is irreversible and deswelling proceeds along other curve than swelling and (b) swelling is reversible when the osmotic force decrease below the critical value. In the latter case, swelling changes are described by a closed loop with two transitions. Under certain conditions (high dilution at network formation and sufficiently high degree of ionization of chains of the folded domains), a transition appears known as the collapse transition induced by balance of hydrophobic and hydrophillic interactions. This collapse transition induces the folding transition by which the folded domains are reformed.     

Plant gamma-tubulin interacts with alphabeta-tubulin dimers and forms membrane-associated complexes

gamma-Tubulin is assumed to participate in microtubule nucleation in acentrosomal plant cells, but the underlying molecular mechanisms are still unknown. Here, we show that gamma-tubulin is present in protein complexes of various sizes and different subcellular locations in Arabidopsis and fava bean. Immunoprecipitation experiments revealed an association of gamma-tubulin with alphabeta-tubulin dimers. gamma-Tubulin cosedimented with microtubules polymerized in vitro and localized along their whole length. Large gamma-tubulin complexes resistant to salt treatment were found to be associated with a high-speed microsomal fraction. Blue native electrophoresis of detergent-solubilized microsomes showed that the molecular mass of the complexes was >1 MD. Large gamma-tubulin complexes were active in microtubule nucleation, but nucleation activity was not observed for the smaller complexes. Punctate gamma-tubulin staining was associated with microtubule arrays, accumulated with short kinetochore microtubules interacting in polar regions with membranes, and localized in the vicinity of nuclei and in the area of cell plate formation. Our results indicate that the association of gamma-tubulin complexes with dynamic membranes might ensure the flexibility of noncentrosomal microtubule nucleation. Moreover, the presence of other molecular forms of gamma-tubulin suggests additional roles for this protein species in microtubule organization.