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At least 217 records · Page 12Linked to original sources
PubMed2006

Intrinsic stability and functional properties of disulfide bond-stabilized coagulation factor VIIIa variants.

BACKGROUND: The utility of purified coagulation factor (F)VIII for treatment of hemophilia A is limited in part by its instability following activation by thrombin, which is caused by spontaneous dissociation of the A2 domain from the activated FVIII (FVIIIa) heterotrimer. To prevent this A2 domain dissociation in FVIIIa, we previously engineered a cysteine pair (C664-C1826) in recombinant FVIII that formed a disulfide bond cross-linking the A2 domain in the heavy chain to the A3 domain in the light chain. This engineered disulfide bond resulted in a more stable FVIIIa. AIMS: Here, we characterize the functional parameters of C664-C1828 FVIII and of a new disulfide bond-stabilized FVIII (C662-C1828 FVIII). METHODS: In order to assess whether these FVIII variants might be good candidates for a new therapeutic agent to treat hemophilia A, we investigated a variety of functional parameters that might affect the in vivo properties of the variants, including half-life of disulfide bond-stabilized FVIII and FVIIIa and the potency of these FVIIIa molecules in the FXase complex. RESULTS: Both disulfide bond-stabilized variants had improved affinity for von Willebrand factor (VWF). In studies of FX activation by purified FIXa and FVIIIa, C662-C1828 FVIIIa had normal activity while C664-C1826 FVIIIa had reduced activity. Both C664-C1826 FVIIIa and C662-C1828 FVIIIa were inactivated by activated protein C (APC) but the rates of inactivation were different. CONCLUSION: Overall, the specific location of the disulfide bridge between the A2 and A3 domains appears to affect functional properties of FVIIIa. In summary, introduction of engineered interdomain disulfides results in FVIIIa variants that resist spontaneous loss of activity while retaining susceptibility to APC proteolytic inactivation and maintaining VWF binding.

Factor IXa↗
PubMed2003

Endoscopic exposure and stabilization of posterior and inferior branches using the endo-starfish cardiac positioner and the endo-octopus stabilizer for closed-chest beating heart multivessel CABG: hemodynamic changes in the pig.

BACKGROUND: Closed-chest, off-pump, multivessel CABG requires modified instruments to expose and stabilize posterior and inferior coronary branches. Using three new prototype devices, we explored the feasibility of endoscopic bypass grafting on these branches and assessed cardiac function during cardiac displacement. METHODS: Eight pigs (75 to 85 kg) were instrumented for hemodynamics and paced at 80 to 100 bpm. After closure of the sternotomy wound, the Da Vinci endoscope was inserted subxiphoidally. A sternal hook was used to hoist the sternum ventrally by 5 cm. The articulating EndoStarfish cardiac positioner was placed through a trocar (Ø12 mm). The positioner was fixed to the apex using -400 mm Hg suction and the heart was displaced anteriorly to 90 degrees. In 12 other pigs (75 to 85 kg), both internal mammary arteries (IMA) were harvested and the sternal wound was closed. Five trocar ports were placed for instrumentation (Ø12 mm, two in left chest, two in right chest, and one subxiphoidally). For coronary stabilization, a novel deployable EndoOctopus cardiac stabilizer was employed (suction -400 mm Hg). The Da Vinci robot-telemanipulator system was used for endoscopic grafting of the left and right IMA on posterior and inferior branches (16 anastomoses). RESULTS: When circumflex arteries were fully exposed and accessible for coronary surgery, stroke volume decreased by 18%+/-3 versus baseline (P=0.02) and mean arterial pressure decreased by 27%+/-6 (P=0.001). Additional 10 degrees Trendelenburg head-down positioning normalized stroke volume and arterial pressure. In the displaced heart, obtuse marginal branches (OM) and the ramus descending posterior (RDP) of the right coronary artery became fully exposed with a mean arterial pressure >70 mm Hg during grafting. No accidental detachment occurred. Coronary target motion was restrained to approximately 1x1 mm. In two test cases, five sham distal anastomoses were created (grafts sewn to epicardium, left IMA to OM2 jump to OM3, right IMA to RDP, and composite graft from left IMA jump to diagonal branch). In 10 animals, 16 successfully completed anastomoses to RPD and OM branches of Ø1.75 to 2.5 mm required 25 to 60 minutes each to construct. At sacrifice, all anastomoses were patent. CONCLUSIONS: In the closed-chest pig in Trendelenburg position and during lifting of the sternum, the EndoStarfish and EndoOctopus enabled IMA grafting of posterior and inferior branches on the beating heart without mean arterial pressure dropping below 70 mm Hg.

Animals↗
PubMed2006

A simple method of stabilizing a coronary graft onto a suction stabilizer in coronary surgery.

Because a suction-type stabilizer does not move once it is attached to the heart in either on-pump or off-pump coronary surgery, we have been using a simple method of stabilizing mammary radial, or epigastric artery grafts with a suction stabilizer in anastomosis of coronary artery grafts. This method excludes the need for assistants to hold the graft, which can bel cumbersome, thereby reducing graft movement. This experience prompted us to report this method.

Anastomosis, Surgical↗
PubMed2005

Evaluation of aneurysm stability after endovascular embolization with Guglielmi detachable coils: correlation between long-term stability and volume embolization ratio.

The correlation between volume embolization ratio (VER), the percentage of aneurysm volume occupied by coils, and aneurysm stability after endovascular treatment with platinum coils was studied in 86 patients who underwent embolization of 88 cerebral saccular aneurysms with standard platinum coils between March 1997 and January 2003. Radiographic follow up was possible of 62 aneurysms with greater than 70% obliteration on immediate post-procedure angiograms for more than 6 months. Immediate post-procedure evaluation found that 12 of 14 small (<4 mm), 12 of 38 medium (4-<10 mm), and two of 10 large (> or =10 mm) aneurysms had high (> or =25%) VER. In addition, the VER was high in 22 of 40 aneurysms with small (<4 mm) and four of 22 with wide necks (> or =4 mm). Evaluation of 57 aneurysms at 6 months after coil embolization found recanalization in two of 25 aneurysms with high VER and 21 of 32 with low (<25%) VER, indicating that aneurysms with high VER are significantly more stable than those with low VER (p < 0.01). VER strongly affects aneurysm stability, so high VER is desirable and a useful predictor of aneurysm stability.

Adult↗
PubMed1998

Platelet-released ADP stabilizes PAF-induced rabbit platelet aggregation by stabilizing intracellular calcium.

AIM: To examine whether platelet-released adenosine diphosphate (ADP) would contribute to the stabilization of rabbit platelet aggregation induced by platelet activating factor (PAF). METHODS: Rabbit platelet aggregation induced by PAF was measured turbimetrically. ADP release from rabbit platelets stimulated by PAF was determined by HPLC. Intracellular Ca2+ was measured using Ca(2+)-sensitive fluorescent indicator Fura 2-AM. RESULTS: PAF > or = 1 nmol.L-1 induced full platelet aggregation, which did not deaggregate over 5 min after aggregation reached peak. Platelet aggregation was deaggregated in a concentration-dependent manner by subsequent addition of ADP scavenger ATP-diphosphohydrolase (apyrase) at 5-100 mg.L-1. PAF 3 nmol.L-1 stimulated release of ADP (29% vs 6% of control), and elicited a rapid rise in intracellular calcium ([Ca2+]i) which peaked at approximately 15 s. Then the [Ca2+]i gradually decayed from 585 +/- 80 nmol.L-1 within 100 s to a low level (364 +/- 82 nmol.L-1). Apyrase 100 mg.L-1, added 2 min after PAF, reduced [Ca2+]i to a lower level (171 +/- 29 nmol.L-1). CONCLUSION: Platelet-released ADP stabilizes PAF-induced rabbit platelet aggregation by stabilizing [Ca2+]i at elevated level.

Adenosine Diphosphate↗
PubMed2002

On the temporal stability of personality: evidence for differential stability and the role of life experiences.

The authors investigated the stability of personality and trait affect in young adults. In Studies 1 and 2, young adults were retested on a Big Five personality measure and a trait affect inventory over a 2.5-year and a 2-month period, respectively. Results from Study 1 point to positive mean-level changes; participants scored higher on Extraversion, Openness, Agreeableness, and Conscientiousness at Time 2. Affectively, participants experienced less negative affect and more positive affect at Time 2. Results from both retests provide clear evidence of differential stability. Affective traits were consistently less stable than the Big Five. Other analyses suggest that life events influence the stability of affective traits more than the Big Five.

Adult↗
PubMedDate not supplied

[Calculations of stability of A and B forms of dA6.dT6 and dG6.dC6 duplexes by molecular mechanics method in an aqueous solution and approximation of the statistical model. Analysis of unusual stability of the dA6.dT6 B form].

The statistical model of the environment for estimating the influence of the aqueous electrolyte solution on the macromolecule has been developed. The energy of the water-fasteners between macromolecule atoms has been calculated. The calculations of A and B form dA6.dT6 and dG6.dC6 duplexes have been made. The unusual stability of B form in dA6.dT6 and their unstability in dG6.dC6 have been analysed. B form duplexes have optimal energy of Van-der-Waals interactions, but a more strained ribose-phosphate backbone, the latter being the reason of its high conformational lability. The aqueous solution stabilizes B form duplexes. The main types of sequence-dependent B form stabilizing interactions are: electrostatic interactions between phosphate groups and bases, the effect of the solvent molecular structure and energy of water fasteners between nucleic bases and ribose-phosphate backbone.

DNA↗
PubMed1989

[Supination stability of the Adimed-Stabil-II shoe in capsule-ligament instability of the upper ankle joint].

A prerequisite for functional treatment of an unstable capsular ligament of the ankle joint is sufficient protection against supination through exterior stabilization. Examination of 20 such patients provided with a Adimed-Stabil II shoe proved that the new, improved Adimed-Stabil II shoe is reliable and sufficient protection against supination. All 20 patients had an unstable capsular ligament of the ankle joint, which was later proved by operation. In suitable cases, treatment with this shoe can be recommended to reduce the duration of disablement.

Adolescent↗
PubMed1985

Stability, heat stability and heat sensitivity of proteins: thermodynamic considerations.

The heat sensitivity and stability of a protein should be characterized by the Arrhenius parameters of the irreversible denaturation. The terms "thermostability" or "activation enthalpy" and "activation entropy" of denaturation as "thermodynamic parameters of protein stability" are misleading. The terms "measure of heat sensitivity" and "measure of stability" should be used as comparative data for protein structure.

Hot Temperature↗
PubMed1997

Screw omission and the stability of posterior pedicle screw constructs for short-segment stabilization.

To determine the net contribution of a spinal construct to stability, and whether extending the construct to another level in situations in which a defective pedicle cannot have a screw inserted, we performed biomechanical tests in which we evaluated three-, four-, and five-level synthetic spinal constructs in which the location and number of pedicle screws were varied above and below a vertebrectomy defect. We subjected all constructs to axial, compression, lateral bending, flexion, extension, and torsional forces with the use of an Instron biaxial machine. Left-right symmetrical constructs were more stable than asymmetrical ones. Three-level constructs were statistically stiffer than the longer ones in compression, left bending, and flexion. Torsional stability, however, was greater in the longer constructs. Five-level constructs with both end screws in place had greater torsional stiffness than when they were missing a screw. In vertebrectomy defects, if four screws cannot be placed across it, then the engagement of two screws is indicated. The stability provided by a single screw at a spinal level is minimal. Additional screws augment the purchase of the construct in the bone; however, they do not afford further protection to the defect.

Bone Screws↗
PubMed1981

Prediction of stability in pharmaceutical preparations XVIII: application of high-pressure liquid chromatographic assays to study of nafronyl stability and bioanalysis.

Specific, sensitive, reversed-phase high-pressure liquid chromatographic assays of nafronyl (I) and its acidic metabolite and hydrolysis product (II) were developed in aqueous solutions and in biological fluids with sensitivities of 100 ng/ml using butacaine as the internal standard and spectrophotometric detection of 224 nm. Heparinized plasma can be analyzed easily in the organic phase immediately after acetonitrile denaturation. Both I and II can be extracted with haloalkane solvents, and the extracts are evaporated, reconstituted, and assayed in a minimal amount of acetonitrile. Conditions are presented that minimize the interference of II and extracted plasma components. The assay was used to determine the stability of nafronyl in aqueous solutions, to establish its log k-pH profiles at various temperatures, and to evaluate the Arrhenius parameters. Nafronyl is hydrolyzed by specific hydrogen-ion (15.2 kcal/mole) and hydroxide-ion (7.72 kcal/mole) catalysis of the neutral species and specific hydroxide-ion catalysis (5.91 kcal/mole) of the protonated species. The pH of maximum stability is 3.0, and pH 5.4 is the maximum that can be tolerated at 30 degrees, with a 10% solvolysis in 3 years. The half-life of nafronyl at 30 degrees was 7 days at pH 7, 12 hr at pH 10, and 21 min in 0.5 N NaOH. Since nafronyl has a half-life of 3.2 hr in heparinized dog plasma at 25 degrees, blood samples for pharmacokinetic studies of nafronyl must be assayed immediately after sampling. The partition coefficients of I and II determined as functions of pH permit the extraction of both compounds at pH 4.5, but only I can be extracted at pH values above 9.5.

Animals↗
PubMed1982

Predictions of stability in pharmaceutical preparations XIX: Stability evaluation and bioanalysis of clofibric acid esters by high-pressure liquid chromatography.

Specific, sensitive, reversed-phase high-pressure liquid chromatographic assays of clofibric acid esters, clofibrate and etofibrate, and their hydrolysis products, clofibric acid and its monoglycolate and nicotinic acid and its monoglycolate, have been developed in aqueous solution and in biological fluids. Sensitivities of 100 ng/ml of injected mobile phase, a 10-fold increase over existing methods, are reported. Plasma concentrations as low as 200 ng/ml can be analyzed easily in the miscible phase after acetonitrile denaturation. The compounds and their products can be extracted with haloalkane solvents. The extracts were evaporated, reconstituted, and assayed in minimal amounts of mobile phase, resulting in sensitivities of 10 ng/ml of plasma. Conditions are presented that minimize interferences with plasma components. The assay was used to determine the stability of the clofibric acid esters in aqueous solutions, to establish log k-pH profiles at various temperatures, and to evaluate Arrhenius parameters. Hydrolysis was by specific acid-base catalysis. The initial product of etofibrate solvolysis at pH greater than 6 is the monoglycol ester of clofibric acid; at pH less than 3, it is the monoglycol ester of nicotinic acid. Clofibric acid esters are highly unstable to mild alkali (1-3 hr at pH 10 and 30 degrees); even in the estimated pH range of maximum stability, they have half-lives of 100-200 days at 30 degrees. They have half-lives of 4-7 min at 37.5 degrees in fresh dog plasma, and data presented indicate that clofibric acid monoglycolate is an initial product of etofibrate solvolysis.

Animals↗
PubMed1984

Intravaginal controlled administration of flurogestone acetate I: Development of a stability-indicating liquid chromatographic method and stability kinetics of flurogestone acetate.

Flurogestone acetate is a synthetic progestin useful for estrus synchronization in sheep. The estrus synchronization is achieved by inserting the drug-impregnated vaginal sponge in the sheep for up to 15 d, during which time flurogestone acetate is administered continuously by intravaginal absorption to suppress estrus and ovulation. The sponge is then withdrawn to regain estrus within 2-4 d. A review of the literature suggests that the analytical methods currently available are not specific, sensitive, and rapid enough. A stability-indicating high-performance liquid chromatographic method was developed, which is capable of characterizing the stability kinetics of flurogestone acetate under various environmental conditions and quantifying the release and absorption profiles of the drug from the vaginal sponges.

Animals↗
PubMed1992

Stability and reconstitution of pyruvate oxidase from Lactobacillus plantarum: dissection of the stabilizing effects of coenzyme binding and subunit interaction.

Pyruvate oxidase from Lactobacillus plantarum is a homotetrameric flavoprotein with strong binding sites for FAD, TPP, and a divalent cation. Treatment with acid ammonium sulfate in the presence of 1.5 M KBr leads to the release of the cofactors, yielding the stable apoenzyme. In the present study, the effects of FAD, TPP, and Mn2+ on the structural properties of the apoenzyme and the reconstitution of the active holoenzyme from its constituents have been investigated. As shown by circular dichroism and fluorescence emission, as well as by Nile red binding, the secondary and tertiary structures of the apoenzyme and the holoenzyme do not exhibit marked differences. The quaternary structure is stabilized significantly in the presence of the cofactors. Size-exclusion high-performance liquid chromatography and analytical ultracentrifugation demonstrate that the holoenzyme retains its tetrameric state down to 20 micrograms/mL, whereas the apoenzyme shows stepwise tetramer-dimer-monomer dissociation, with the monomer as the major component, at a protein concentration of < 20 micrograms/mL. In the presence of divalent cations, the coenzymes FAD and TPP bind to the apoenzyme, forming the inactive binary FAD or TPP complexes. Both FAD and TPP affect the quaternary structure by shifting the equilibrium of association toward the dimer or tetramer. High FAD concentrations exert significant stabilization against urea and heat denaturation, whereas excess TPP has no effect. Reconstitution of the holoenzyme from its components yields full reactivation. The kinetic analysis reveals a compulsory sequential mechanism of cofactor binding and quaternary structure formation, with TPP binding as the first step. The binary TPP complex (in the presence of 1 mM Mn2+/TPP) is characterized by a dimer-tetramer equilibrium transition with an association constant of Ka = 2 x 10(7) M-1. The apoenzyme TPP complex dimer associates with the tetrameric holoenzyme in the presence of 10 microM FAD. This association step obeys second-order kinetics with an association rate constant k = 7.4 x 10(3) M-1 s-1 at 20 degrees C. FAD binding to the tetrameric binary TPP complex is too fast to be resolved by manual mixing.

Apoenzymes↗
PubMed2006

The determinants of stability in the human prion protein: insights into folding and misfolding from the analysis of the change in the stabilization energy distribution in different conditions.

The dynamic evolution of the PrP(C) from its NMR-derived conformation to a beta-sheet-rich, aggregation-prone conformation is studied through all-atom, explicit solvent molecular dynamics in different temperature and pH conditions. The trajectories are analyzed by means of a recently introduced energy decomposition approach aimed at identifying the key residues for the stabilization and folding of the protein. It is shown that under native conditions the stabilization energy is concentrated in regions of the helices H1 and H3, whereas under misfolding conditions (low pH, high temperature, or mutations in selected sites) it is spread out over helix H2. Misfolding appears to be a rearrangement of the chain that disrupts most of the native secondary structure of the protein, producing some beta-rich conformations with an energy distribution similar to that of the native state.

Computer Simulation↗
PubMed1989

Phospholipid bilayers enhance the stability of leukotriene A4 and epoxytetraenes: stabilization of eicosanoids by liposomes.

The hydrolysis of leukotriene A4 and two epoxytetraenes was examined in the presence and absence of liposomes. When added to liposomes in suspension, the stability of LTA4 was increased in a time- and dose-dependent fashion. At 10 min, the half-life of LTA4 was increased 67.1 +/- 6.8% in the presence of liposomes which was comparable to that observed with albumin (10 mg/ml): 68.3 +/- 6.9%. Phosphatidylcholine, in a non-bilayer configuration, was also effective in enhancing the half-life of LTA4, albeit to a lesser extent than liposomes. At equal molar concentrations, the enhanced stability of eicosanoid epoxides with liposomes gave a rank order with leukotriene A4 greater than 5(6)epoxytetraene greater than 14(15)epoxytetraene. Results indicate that phospholipid bilayers can protect leukotriene A4 and 5(6)epoxytetraene from non-enzymatic hydrolysis. Moreover, they suggest that the biological half-life of intermediates involved in the formation of both leukotrienes and lipoxins can be increased by their association with membranes.

Albumins↗
PubMed2002

Failure of stability prediction for minodronic acid injectable by accelerated stability testing.

A liquid formulation containing 0.5 mg/ml minodronic acid, 40 mM, pH 4.5, citrate, and sodium chloride added to adjust the osmolarity of the final formulation was stored in flint glass ampoules at 25, 40, 50, and 60 degrees C. At specified times, the drug potency and pH, and the tendency to generate particulate matter, were measured. Test samples stored at 40 degrees C for 6 months or at 50 and 60 degrees C for 3 months were stable with no potency loss and no particulate increase. However, despite the satisfactory stability at high temperatures, the amount of particulate matter increased when the formulation was stored at 25 degrees C. Scanning electron microscopy-energy dispersive X-ray analysis of the particulate matter revealed that it contains aluminum and phosphorus, the latter thought to be derived from minodronic acid. In contrast, the number of the particulate matter did not increase, when the formulation was stored in either plastic containers or in SiO(2)-treated glass ampoules(.) The spike of minodronic acid solution with aluminum ions led to the particulate generation. These results demonstrate that the particulate matter is a complex of minodronic acid molecules and aluminum ions, which apparently leached from the glass of regular ampoules. Since the particulate generation could not be observed at higher temperatures, it was suggested that the complex formation was exothermic and accelerated testing did not predict the stability in terms of particulate generation.

Absorptiometry, Photon↗
PubMed2002

Enhancement of operational stability of an enzyme biosensor for glucose and sucrose using protein based stabilizing agents.

With the incorporation of lysozyme during the immobilization step, considerable enhancement of the operational stability of a biosensor has been demonstrated in the case of an immobilized single enzyme (glucose oxidase) system for glucose and multienzyme (invertase, mutarotase and glucose oxidase) system for sucrose. Thus an increased number of repeated analyses of 750 samples during 230 days for glucose and 400 samples during 40 days of operation for sucrose have been achieved. The increased operational stability of immobilized single and multienzyme system, will improve the operating cost effectiveness of the biosensor.

Animals↗