Resuscitation, stabilization and transport of the ill newborn infant. Part II: stabilization and transport.
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Female↗
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Results for “stability”
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[Dynamic stability and parametric stabilization of steady states of unbranched metabolic pathways].
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Chemical Phenomena↗
[Control of mRNA stability in plants--cis-acting elements which affect mRNA stability].
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Base Sequence↗
A meta-analysis of stability after anterior cruciate ligament reconstruction as a function of hamstring versus patellar tendon graft and fixation type.
PURPOSE: Four-strand hamstring graft (4HS) is stronger than 10-mm bone-patellar tendon-bone graft (BPTB) and has equal tunnel pullout strength, but is believed by some to produce lower rates of stability after anterior cruciate ligament reconstruction (ACLR). Our purpose was to test the hypothesis that 4HS ACLR with modern fixation would produce equal or greater stability than BPTB ACLR. TYPE OF STUDY: Meta-analysis. METHODS: A computer search was used to find all published reports of ACLR series using HS and/or BPTB. Inclusion criteria were minimum 24-month follow-up, stratified presentation of arthrometric stability data, and at least 30-lb arthrometric testing force. Twenty-four 4HS, 8 2-strand hamstring (2HS), and 32 BPTB series met these criteria and were subdivided into groups according to fixation type. We used the International Knee Documentation Committee classification of a side-to-side instrumented Lachman test difference of < or = 2 mm as normal stability, and > 5 mm difference as abnormal stability. Series with at least 80% normal and at most 3% abnormal stability were designated as high-stability. Meta-analytic methods were used to determine group level differences. RESULTS: Total 4HS had a higher normal stability rate than total BPTB: 77% versus 66%, P < .001; and lower abnormal stability: 4.4% versus 5.9%, P = .029. The 4HS ACLR using the EndoButton (Smith & Nephew Endoscopy, Andover, MA) and second-generation tibial fixation (EB2-4HS) had higher normal stability (80%) and lower abnormal stability (1.7%) than all other subgroups, including BPTB with 2 interference screws (70% normal, 5.0% abnormal) P < .001; 84% of the series in the EB2-4HS group were high-stability series. No more than 33% of the series from any other group were high-stability. CONCLUSIONS: The recent literature would suggest that 4HS ACLR produces higher stability rates than BPTB, that 4HS stability rates are fixation dependent, that aperture fixation offers no stability advantage, and that EndoButton with second-generation tibial fixation produces consistently high stability rates. LEVEL OF EVIDENCE: Level IV.
Anterior Cruciate Ligament↗
Stability of the i.v. and oral formulations of etoposide in solution.
Etoposide is a widely used cytotoxic drug that requires complex formulation for both the i.v. and oral preparation to ensure drug stability. Data on the stability of the i.v. formulation when diluted in infusion fluids are contradictory, and there is little information on the stability of the oral preparation in gastric or intestinal fluids. The stability of both i.v. and oral etoposide was therefore evaluated in the present investigation. The stability of the i.v. preparation was investigated across a range of concentrations in infusion fluids, being determined by regular sampling for high-performance liquid chromatography (HPLC) analysis and by visual inspection. The stability of the oral preparation was studied in both artificial gastric and intestinal fluids, again with regular sampling for HPLC analysis, and the influence of pH, concentration and the addition of ethanol and bile salts on oral stability was determined. The i.v. preparation showed a marked decrease in stability with increasing drug concentration, but stability was additionally reduced in i.v. bags regularly sampled with a syringe and needle as compared with bags that were inspected visually only (minimal stability in sampled bags, 24 h at 0.5 mg/ml and 5 h at 1.0 mg/ml, as compared with 10 days and 18 h at the respective concentrations in unsampled bags). Stability was also greater at room temperature, 20-23 degrees C, as compared with 8-12 degrees C. Loss of stability was indicated by a decrease in etoposide concentration (measured by HPLC) and the appearance of a fine white precipitate, shown to be pure etoposide. Importantly, the appearance of precipitate was as sensitive as a specific HPLC assay in detecting loss of stability and was in many cases apparent when the etoposide concentration was within 5% of the starting concentration. The oral formulation also showed a marked concentration-dependent decrease in stability in artificial intestinal fluid at pH 7.5 (percentage of etoposide in solution after 2 h at 0.5, 1.0, 1.5 and 2.0 mg/ml, 94 +/- 2%, 80 +/- 5%, 68 +/- 13% and 41 +/- 9%, respectively). There was no concentration effect on stability in gastric fluid at pH 3.0, although stability was much greater at pH 3 and pH 5 as compared with pH 1 or in intestinal fluid at pH 7.5.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Coalescence stability of emulsions containing globular milk proteins.
This review summarizes a large set of related experimental results about protein adsorption and drop coalescence in emulsions, stabilized by globular milk proteins, beta-lactoglobulin (BLG) or whey protein concentrate (WPC). First, we consider the effect of drop coalescence on the mean drop size, d32, during emulsification. Two regimes of emulsification, surfactant-rich (negligible drop coalescence) and surfactant-poor (significant drop coalescence) are observed in all systems studied. In the surfactant-rich regime, d32 does not depend on emulsifier concentration and is determined mainly by the interfacial tension and the power dissipation density in the emulsification chamber, epsilon. In the surfactant-poor regime and suppressed electrostatic repulsion, d32 is a linear function of the inverse initial emulsifier concentration, 1/C(INI), which allows one to determine the threshold emulsifier adsorption needed to stabilize the oil drops during emulsification, Gamma* (the latter depends neither on oil volume fraction nor on epsilon). Second, we study how the BLG adsorption on drop surface changes while varying the protein and electrolyte concentrations, and pH of the aqueous phase. At low electrolyte concentrations, the protein adsorbs in a monolayer. If the pH is away from the isoelectric point (IEP), the electrostatic repulsion keeps the adsorbed BLG molecules separated from each other, which precludes the formation of strong intermolecular bonds during shelf-storage as well as after heating of the emulsion. At higher electrolyte concentration, the adsorption Gamma increases, as a result of suppressed electrostatic repulsion between the protein molecules; monolayer or multilayer is formed, depending on protein concentration and pH. The adsorption passes through a maximum (around the protein IEP) as a function of pH. Third, the effect of various factors on the coalescence stability of "fresh" emulsions (up to several hours after preparation) was studied. Important conclusion from this part of the study is the establishment of three different cases of emulsion stabilization: (1) electrostatically-stabilized emulsions with monolayer adsorption, whose stability is described by the DLVO theory; (2) emulsions stabilized by steric repulsion, created by protein adsorption multilayers - a simple model was adapted to describe the stability of these emulsions; and (3) emulsions stabilized by steric repulsion, created by adsorption monolayers. Fourth, we studied how the emulsion stability changes with storage time and after heating. At high electrolyte concentrations, we find a significant decrease of the coalescence stability of BLG-emulsions after one day of shelf-storage (aging effect). The results suggest that aging is related to conformational changes in the protein adsorption layer, which lead to formation of extensive lateral non-covalent bonds (H-bonds and hydrophobic interactions) between the adsorbed molecules. The heating of BLG emulsions at high electrolyte concentration leads to strong increase of emulsion stability and to disappearance of the aging effect, which is explained by the formation of disulfide bonds between the adsorbed molecules. The emulsion heating at low electrolyte concentration does not affect emulsion stability - this result is explained with the electrostatic repulsion between the adsorbed molecules, which keeps them separated so that no intermolecular disulfide bonds are formed. Parallel experiments with WPC-stabilized emulsions show that these emulsions are less sensitive to variations of pH and thermal treatment; no aging effect is detected up to 30 days of storage. The observed differences between BLG and WPC are explained with the different procedures of preparation of these protein samples (freeze-drying and thermally enhanced spray-drying, respectively). Our data for emulsion coalescence stability are compared with literature results about the flocculation stability of BLG emulsions, and the observed similarities/differences are explained by considering the structure of the protein adsorption layers.
Computer Simulation↗
Optimizing the glenoid contribution to the stability of a humeral hemiarthroplasty without a prosthetic glenoid.
BACKGROUND: In a shoulder requiring arthroplasty, if the glenoid is flat or biconcave, the surgeon can restore the desired glenoid stability by using a glenoid prosthesis with a known surface geometry or by modifying the surface of the glenoid to a geometry that provides the desired glenoid stability. This study tested the hypotheses that (1) the stability provided by the glenoid is reduced by the removal of the articular cartilage; (2) the stability contributed by the glenoid is compromised by loss of its articular cartilage, and this lost stability can be restored by spherical reaming along the glenoid centerline; and (3) the stability of a reamed glenoid is comparable with that of a native glenoid and with that of a polyethylene glenoid with similar surface geometry; and (4) the glenoid stability can be predicted from the glenoid surface geometry. METHODS: The stability provided by the glenoid in a given direction can be characterized by the maximal angle that the humeral joint reaction force can make with the glenoid centerline before the humeral head dislocates; this quantity is defined as the balance stability angle in the specified direction. The balance stability angles were both calculated and measured in eight different directions for an unused polyethylene glenoid component and eleven cadaveric glenoids in four different states: (1) native without the capsule or the rotator cuff, (2) denuded of cartilage and labrum, (3) after reaming the glenoid surface around the glenoid centerline with use of a spherical reamer with a radius of 25 mm, and (4) after reaming around the glenoid centerline with use of a spherical reamer with a radius of 22.5 mm. RESULTS: The calculated and measured balance stability angles for each direction in each glenoid were strongly correlated. Denuding the glenoids of the articular cartilage reduced the glenoid contribution to stability, especially in the posterior direction. Reaming the glenoid restored the stability to values comparable with those of the normal glenoid. For example, the average calculated balance stability angle (and standard deviation) in the posterior direction for all eleven glenoids was 24 degrees for the native glenoids, 14 degrees for the denuded glenoids, 25 degrees for the glenoids reamed to a radius of 25 mm, and 33 degrees for the glenoids reamed to a radius of 22.5 mm. The values for the glenoids reamed to 25 mm (25 degrees ) were similar to those of a polyethylene glenoid of the same radius of curvature. For glenoids reamed to 22.5 mm, the average difference between the actual balance stability angle and that predicted from the glenoid geometry was 3.4 degrees +/- 2.4 degrees. CONCLUSIONS: The glenoid contribution to shoulder stability was decreased by the removal of cartilage and labrum and was restored by spherical reaming to a level similar to resurfacing the glenoid with a polyethylene component.
Arthroplasty, Replacement↗
Structure and function relationship of phosphatidylglycerol in the stabilization of the phosphatidylethanolamine bilayer.
Differential scanning calorimetry was used to examine the structure-function relationship of the phospholipids on the L alpha-phase stabilization of phosphatidylethanolamine (PE). Phosphatidylglycerol (PG) was chosen as a model stabilizer. Dielaidoylphosphatidylethanolamine (DEPE) was mixed with various PGs to study the effects of (i) chain length, (ii) chain unsaturation, and (iii) chain number of the stabilizer on the L alpha-phase stabilization. At low concentrations of stabilizer, both bilayer stabilization and destabilization were observed. Phase separations also were seen, as revealed by split peaks of the L beta----L alpha transition; these were particularly prone to occur in the destabilization cases. When saturated PGs were compared, shorter chains (C12:0 and C14:0) promoted bilayer stabilization whereas longer chains (C16:0 and C18:0) promoted bilayer destabilization. Unsaturated PG with larger hydrophobic volumes (C18:2) favored bilayer destabilization, relative to unsaturated PG with smaller hydrophobic volumes (C18:1). Lyso-PG (C14:0) showed higher bilayer stabilization activity than their double-chain counterparts. Thus, at low concentrations of stabilizer, the acyl chain composition plays a vital role in bilayer-phase stabilization. However, at higher concentrations (greater than or equal to 8 mol %), all PGs become active bilayer stabilizers. This is probably because the increased head-group hydration becomes the dominant factor in the stabilization. The effect of acyl chain composition of the stabilizer was also studied by using small unilamellar vesicles composed of dioleoylphosphatidylethanolamine (DOPE). Fluorescence quenching of calcein entrapped in liposomes was used to monitor the stability of the liposomes. Similar acyl chain effects on liposomal stabilization were obtained.(ABSTRACT TRUNCATED AT 250 WORDS)
Calorimetry, Differential Scanning↗
[What is the meaning of "stabilization" in schizophrenic patients?].
UNLABELLED: The notion of stabilization in schizophrenia has been investigated, in France, through a survey of 875 psychiatrists. This survey, which has been conducted on the 9th, 10th and 11th of December 1997, looked into the clinical, therapeutic and socio-demographic variables, and the means of patient management, which are used by psychiatrists to ascertain that their patients are stabilized. The data was collected by each psychiatrist by way of a questionnaire administered to his or her next three patients, either at the hospital or in private practice (2,464 questionnaires were completed). RESULTS: 65% of the patients seen during this survey were considered stabilized by their psychiatrist (n = 1,597). The most common clinical presentation was of the paranoïd type. An insiduous onset of disease seems to be correlated with an absence of stabilization. Stabilization appears to be estimated at a given time rather than over a time period, since over half the patients who were considered stabilized had suffered at least one relapse over the last 2 years, and had been rehospitalized an average of 2.4 times over that period. In terms of drug therapy, they received 1.4 neuroleptic drugs, which does not differ markedly from the 1.5 neuroleptics administered to patients who were considered non stabilized. Co-prescriptions of anticholinergic medications, benzodiazepines and antidepressants were very common in these patients considered stabilized (49.9%, 39.8% and 24.8% respectively), which is similar to that observed in their non-stabilized counterparts (47.6%, 45%, 8% and 26.4%, respectively). Patient follow-up remained above an average of 1 patient visit per month (an average of 8.9 visit over the last 6 months), despite the fact that patients were considered stabilized. Two primary criteria were used by psychiatrists to determine that a patient was stabilized: treatment compliance and the absence of positive symptoms. However, 43% of the patients which were considered stabilized still presented with positive symptoms. Negative symptoms were also very prevalent in these patients (65%), as well as concomitant depressive signs (36%) and anxiety (64%). CONCLUSION: Even though the concept of stabilization remains difficult to define, it appears that schizophrenic patients are considered by their psychiatrist as stabilized on the grounds of good treatment compliance and decreased positive symptoms. Therefore, even in these so-called stabilized patients, enhancements are still possible, as symptoms remain present.
Adult↗
Stability of yellow fever vaccine.
Yellow fever, an acute mosquito-borne viral haemorrhagic fever, is preventable by use of the live, attenuated 17D vaccine. The vaccine is used principally in tropical climates and is subject to potentially adverse conditions. Lyophilized vaccine without stabilizers deteriorates rapidly when exposed to temperatures above -20 degrees C. In 1987, the WHO recommended that each lot of vaccine meet the following stability test: maintenance of potency (> 1,000 mouse i.c.LD50/human dose) with mean loss of titre < 1.0 log10 after being held at 37 degrees C for 14 days. In 1987, only 5 out of 12 yellow fever vaccines produced worldwide met the stability standards. To improve stability of the vaccine, a number of additives have been systematically investigated. A successful formulation, now used by a number of manufacturers, employs sugars, amino acids, and divalent cations [lactose (4%), sorbitol (2%), histidine (0.01 M), alanine (0.01 M), in phosphate buffered saline with Ca2+ and Mg2+]. As opposed to vaccine produced without stabilizers, which loses 1.5-2.5 log10/dose, stabilized vaccines lose only 0.3-0.5 log10 after being held at 37 degrees C for 14 days. The vaccine is stable after storage for > or = two years at 4 degrees C and 22 degrees C, and has a stability profile as good or better than many other live and inactivated vaccines currently used in the EPI, including measles, pertussis, oral and inactivated poliomyelitis vaccines. WHO is taking steps to enssure that all 11 current YF vaccine manufacturers produce vaccines that meet accepted stability standards. The principal rationale for increasing 17D vaccine stability beyond that achieved with the present stabilizers would be the improvement in stability of other EPI vaccines, to the point where yellow fever vaccine was the most sensitive vaccine among those deployed. The acceptable characteristics of current stabilized 17D vaccines and the high cost of changing and validating new vaccine formulations precludes a major investment at this time. Despite its stability when freeze dried, yellow fever 17D vaccine is quite unstable after reconstitution and must be discarded after one hour. Improvement in vaccine stability after reconstitution would thus reduce cost, stretch supplies of vaccine, and ensure against vaccine failures due to use of degraded vaccine. This is an area for future research.
Animals↗
Animal flight dynamics II. Longitudinal stability in flapping flight.
Stability is essential to flying and is usually assumed to be especially problematic in flapping flight. If so, problems of stability may have presented a particular hurdle to the evolution of flapping flight. In spite of this, the stability of flapping flight has never been properly analysed. Here we use quasi-static and blade element approaches to analyse the stability provided by a flapping wing. By using reduced order approximations to the natural modes of motion, we show that wing beat frequencies are generally high enough compared to the natural frequencies of motion for a quasi-static approach to be valid as a first approximation. Contrary to expectations, we find that there is noting inherently destabilizing about flapping: beating the wings faster simply amplifies any existing stability or instability, and flapping can even enhance stability compared to gliding at the same air speed. This suggests that aerodynamic stability may not have been a particular hurdle in the evolution of flapping flight. Hovering animals, like hovering helicopters, are predicted to possess neutral static stability. Flapping animals, like fixed wing aircraft, are predicted to be stable in forward flight if the mean flight force acts above and/or behind the centre of gravity. In this case, the downstroke will always be stabilizing. The stabilizing contribution may be diminished by an active upstroke with a low advance ratio and more horizontal stroke plane; other forms of the upstroke may make a small positive contribution to stability. An active upstroke could, therefore, be used to lower stability and enhance manoeuvrability. Translatory mechanisms of unsteady lift production are predicted to amplify the stability predicted by a quasi-static analysis. Non-translatory mechanisms will make little or no contribution to stability. This may be one reason why flies, and other animals which rely upon non-translatory aerodynamic mechanisms, often appear inherently unstable.
Animals↗
Melting of cross-linked DNA v. cross-linking effect caused by local stabilization of the double helix.
DNA interstrand cross-links are usually formed due to bidentate covalent or coordination binding of a cross-linking agent to nucleotides of different strands. However interstrand linkages can be also caused by any type of chemical modification that gives rise to a strong local stabilization of the double helix. These stabilized sites conserve their helical structure and prevent local and total strand separation at temperatures above the melting of ordinary AT and GC base pairs. This local stabilization makes DNA melting fully reversible and independent of strand concentration like ordinary covalent interstrand cross-links. The stabilization can be caused by all the types of chemical modifications (interstrand cross-links, intrastrand cross-links or monofunctional adducts) if they give rise to a strong enough local stabilization of the double helix. Our calculation demonstrates that an increase in stability by 25 to 30 kcal in the free energy of a single base pair of the double helix is sufficient for this "cross-linking effect" (i.e. conserving the helicity of this base pair and preventing strand separation after melting of ordinary base pairs). For the situation where there is more then one stabilized site in a DNA duplex (e.g., 1 stabilized site per 1000 bp), a lower stabilization per site is sufficient for the "cross-linking effect" (18 - 20 kcal). A substantial increase in DNA stability was found in various experimental studies for some metal-based anti-tumor compounds. These compounds may give rise to the effect described above. If ligand induced stabilization is distributed among several neighboring base pairs, a much lower minimum increase per stabilized base pair is sufficient to produce the cross-linking effect (1 bp- 24.4 kcal; 5 bp- 5.3 kcal; 10 bp- 2.9 kcal, 25 bp- 1.4 kcal; 50 bp- 1.0 kcal). The relatively weak non-covalent binding of histones or protamines that cover long regions of DNA (20- 40 bp) can also cause this effect if the salt concentration of the solution is sufficiently low to cause strong local stabilization of the double helix. Stretches of GC pairs more than 25 bp in length inserted into poly(AT) DNA also exhibit properties of stabilizing interstrand cross-links.
Algorithms↗
Stability of dynamic trunk movement.
STUDY DESIGN: Nonlinear systems analyses of trunk kinematics were performed to estimate control of dynamic stability during repetitive flexion and extension movements. OBJECTIVE: Determine whether movement pace and movement direction of dynamic trunk flexion and extension influence control of local dynamic stability. SUMMARY OF BACKGROUND DATA: Spinal stability has been previously characterized in static, but not in dynamic movements. Biomechanical models make inferences about static spinal stability, but existing analyses provide limited insight into stability of dynamic movement. Stability during dynamic movements can be estimated from Lyapunov analyses of empirical data. METHODS: There were 20 healthy subjects who performed repetitive trunk flexion and extension movements at 20 and 40 cycles per minute. Maximum Lyapunov exponents describing the expansion of the kinematic state-space were calculated from the measured trunk kinematics to estimate stability of the dynamic system. RESULTS: The complexity of torso movement dynamics required at least 5 embedded dimensions, which suggests that stability components of lumbar lordosis may be empirically measurable in addition to global stability of trunk dynamics. Repeated trajectories from fast paced movements diverged more quickly than slower movement, indicating that local dynamic stability is limited in fast movements. Movements in the midsagittal plane showed higher multidimensional kinematic divergence than asymmetric movements. CONCLUSION: Nonlinear dynamic systems analyses were successfully applied to empirically measured data, which were used to characterize the neuromuscular control of stability during repetitive dynamic trunk movements. Movement pace and movement direction influenced the control of spinal stability. These stability assessment techniques are recommended for improved workplace design and the clinical assessment of spinal stability in patients with low back pain.
Adult↗
A comparative analysis of the evolutionary patterning and mechanistic bases of lactate dehydrogenase thermal stability in porcelain crabs, genus Petrolisthes.
The kinetic properties of orthologous homologs (orthologs) of enzymes are typically correlated with environmental temperatures in species adapted to different thermal regimes, but correlations between adaptation temperature and enzyme thermal stability are less clear. Although the thermal stability of a protein is related chiefly to its primary structure (including post-translational modification), thermal stability can also be altered by extrinsic factors present in the intracellular milieu. Here, we present a comparative analysis of the thermal stability of lactate dehydrogenase (LDH) orthologs from 22 congeneric species of porcelain crab (genera Petrolisthes and Allopetrolisthes) from a broad range of thermal habitats. Interspecific diversity of LDH stability is high: temperatures required for a 50 % loss of activity in 10 min ranged from 65 to 75.5 degrees C, corresponding to half-lives of less than 1 min to more than 3 h at 70 degrees C. Although stability is positively correlated with maximal habitat temperature in some sister taxa, phylogenetic comparative analysis incorporating all 22 species does not indicate that the interspecific diversity of LDH stability represents an adaptive response to current thermal habitats. Examination of the mechanistic bases of LDH stabilization indicates that differences in stability are related both to properties of the LDH molecule itself (intrinsic stability) and to the effects of extrinsic protein(s). Intrinsic differences were shown by the unfolding of structure during heating, as measured by circular dichroism spectroscopy. Stabilizing effects of extrinsic proteins are implied by the results of cellular fractionation experiments that removed low-molecular-mass solutes and proteins from the muscle homogenates. We conclude that the overall structural stability and functional properties of proteins can evolve independently and that in vivo protein-protein interactions can provide another means to regulate protein stability selectively.
Animals↗
Transition to turbulence in pulsatile flow through heart valves--a modified stability approach.
The presence of turbulence in the cardiovascular system is generally an indication of some type of abnormality. Most cardiologists agree that turbulence near a valve indicates either valvular stenosis or regurgitation, depending on the phase of its occurrence during the cardiac cycle. As no satisfying analytical solutions of the stability of turbulent pulsatile flow exist, accurate, unbiased flow stability criteria are needed for the identification of turbulence initiation. The traditional approach uses a stability diagram based upon the stability of a plane Stokes layer where alpha (the Womersley parameter) is defined by the fundamental heart rate. We suggest a modified approach that involves the decomposition of alpha into its frequency components, where alpha is derived from the preferred modes induced on the flow by interaction between flow pulsation and the valve. Transition to turbulence in pulsatile flow through heart values was investigated in a pulse duplicator system using three polymer aortic valve models representing a normal aortic valve, a 65 percent stenosed valve and a 90 percent severely stenosed valve, and two mitral valve models representing a normal mitral valve and a 65 percent stenosed valve. Valve characteristics were closely simulated as to mimic the conditions that alter flow stability and initiate turbulent flow conditions. Valvular velocity waveforms were measured by laser Doppler anemometry (LDA). Spectral analysis was performed on velocity signals at selected spatial and temporal points to produce the power density spectra, in which the preferred frequency modes were identified. The spectra obtained during the rapid closure stage of the valves were found to be governed by the stenosis geometry. A shift toward higher dominant frequencies was correlated with the severity of the stenosis. According to the modified approach, stability of the flow is represented by a cluster of points, each corresponding to a specific dominant mode apparent in the flow. In order to compare our results with those obtained by the traditional approach, the cluster of points was averaged to collapse into a single point that represents the flow stability. The comparison demonstrates the bias of the traditional stability diagram that leads to unreliable stability criteria. Our approach derives the stability information from measured flow phenomena known to initiate flow instabilities. It differentiates between stabilizing and destabilizing modes and depicts an unbiased and explicit stability diagram of the flow, thus offering a more reliable stability criteria.
Aortic Valve↗
Tumor suppressor von Hippel-Lindau (VHL) stabilization of Jade-1 protein occurs through plant homeodomains and is VHL mutation dependent.
The von Hippel-Lindau (VHL) gene is the major renal cancer gene in adults. The mechanism of renal tumor suppression by VHL protein is only partly elucidated. VHL loss increases expression of the hypoxia-inducible factor alpha transcription factors. However, clinical and biochemical data indicate that the hypoxia-inducible factors are necessary but not sufficient for renal tumorigenesis, which suggests other VHL effector pathways are involved. Jade-1 protein interacts strongly with VHL and is most highly expressed in renal proximal tubules, precursor cells of renal cancer. Short-lived Jade-1 protein contains plant homeodomain (PHD) and candidate PEST degradation motifs and is substantially stabilized by VHL. The effect of VHL on Jade-1 protein abundance and relative protein stability was further examined in immunoblots and metabolic labeling experiments using two time points. VHL-Jade-1 binding was tested in coimmunoprecipitations. In cotransfection studies with wild-type VHL, the Jade-1 PHD-extended PHD module, not the candidate PEST domain, was required for full VHL-mediated stabilization. This module is also found in leukemia transcription factors AF10 and AF17, as well as closely related Jade-like proteins, which suggests all might be VHL regulated. Intriguingly, naturally occurring truncations and mutations of VHL affected wild-type Jade-1 binding and stabilization. Although the VHL beta domain was sufficient for Jade-1 binding, both the alpha and beta domains were required for Jade-1 stabilization. Thus, truncating VHL mutations, which are severe and associated with renal cancer development, prevented Jade-1 stabilization. Moreover, well-controlled cotransfection and metabolic labeling experiments revealed that VHL missense mutations that cause VHL disease without renal cancer, such as Tyr98His and Tyr112His, stabilized Jade-1 fully. In contrast, like the VHL truncations, VHL missense mutations commonly associated with renal cancer, such as Leu118Pro or Arg167Trp, did not stabilize Jade-1 fully. Therefore, loss of Jade-1 stability may correlate with renal cancer risk. Endogenous Jade-1 in stable renal cancer lines also exhibited VHL mutation-dependent regulation. As in the cotransfections, VHL truncations did not increase endogenous Jade-1 abundance, whereas the VHL missense mutations tested partially increased Jade-1 expression. Additional studies with non-PHD proteins indicated that Jade-1 stabilization by VHL is highly specific. Fibronectin was not stabilized like Jade-1 by VHL, nor were candidate VHL interactors from a yeast screen. Thus, protein stabilization likely reflects the biological activity of largely intact VHL protein on the PHD-extended PHD module of Jade-1. Dysregulation of the VHL protein stabilization pathway or of Jade-1 itself may therefore contribute to VHL renal disease and renal cancer pathogenesis.
Amino Acid Sequence↗
The effect of solvent environment on the conformation and stability of human polyclonal IgG in solution.
Stability of therapeutic IgG preparations is an important issue as adequate efficacy and safety has to be ensured throughout a long shelf life. To this end, denaturation and aggregation have to be avoided. In many cases sugars are applied for stabilizing IgG in relatively high concentration (5-10%). However, certain sugars (sucrose, maltose) are responsible for adverse effects including renal failure. In this work we reassessed the effect of pH and stabilizers to optimize the solvent environment and minimize the amount of additives without endangering quality and stability. Since both biological function and aggregation depend on the conformational properties of individual IgG molecules, two sensitive and rapid physical methods were introduced to assess conformational changes and structural stability as a function of pH and addition of standard stabilizers. It was observed that the conformational stability decreases with decreasing pH, while the resistance against aggregation improves. The optimum pH range for storage is 5.0-6.0, as a compromise between conformational stability and the tendency for oligomerization. Intriguingly, additives in physiologically acceptable concentration have no effect on the thermal stability of IgG. On the other hand, glucose or sorbitol, even at a concentration as low as 1%, have significant effect on the tertiary structure as revealed by near-UV-CD spectroscopy, reflecting changes in the environment of aromatic side-chains. Although, 0.3% leucine does not increase conformational stability, it decreases the aggregation tendency even more efficiently than 1% glucose or sorbitol. Both pH and storage temperature are decisive factors for the long-term stability of IgG solutions. An increase in the dimer content was observed upon storage at 5 degrees C which was partly reverted upon incubation at 37 degrees C. Storage at temperatures higher than 5 degrees C may help to maintain an optimal proportion of dimers. Regarding the known side effects, and their limited stabilizing capacity at low concentration, it is advisable to omit sugars at intravenous immunoglobulin (IVIG) formulation. Hydrophobic amino acids give promising alternatives.
Circular Dichroism↗
Influence of protein emulsifier interfacial properties on oil-in-water emulsion stability.
The purpose of this study was to determine whether the interfacial properties of emulsifier films could be related to emulsion stability and therefore be used as stability predictors using Bovine serum albumin (BSA) as a model oil-in water (o/w) emulsifier. Soybean o/w emulsions were prepared by ultrasonication, emulsion droplet interfacial charge was determined by microelectrophoresis, droplet size distribution was measured using an Accusizer, and centrifugal stress was studied using an ultracentrifuge. Real time, thermal kinetic, and centrifugal stress accelerated stability tests were performed. Stability data obtained from centrifugal stress tests followed the same trends as real time stability data and these data were in general agreement with stability predictions made based on interfacial properties. The thermal kinetic accelerated tests were not predictive of stability, because emulsion breakdown was rapid and did not allow differentiation between the emulsions. Emulsion stability increased with an increase in emulsifier concentration (emulsions prepared at 2% w/v BSA had not cracked at 60 days, whereas those prepared at 0.1% w/v had cracked-by 30 days), increase in ionic strength (emulsions prepared at an ionic strength of 1 mM had cracked by 60 days, whereas those prepared at an ionic strength of 10 mM had cracked by 90 days), and decrease in temperature (emulsions prepared at 37 and 60 degrees C had cracked by 5 days, whereas those prepared at 5 and 25 degrees C had not cracked at 60 days). There was no significant change in stability for emulsions prepared at pH 5.3 and pH 7.4. The addition of dextran sulfate improved emulsion stability, whereas the addition of acacia decreased stability. Emulsions prepared with BSA alone cracked by 90 days, those prepared with BSA and acacia cracked by 30 days, and those prepared with BSA and dextran sulfate had not cracked at 90 days. Interfacial properties were useful in predicting emulsion stability.
Drug Stability↗