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PubMed2004

[The Stewart model. "Modern" approach to the interpretation of the acid-base metabolism].

About twenty years ago, Peter Stewart had already published his modern quantitative approach to acid-base chemistry. According to his interpretations, the traditional concepts of the mechanisms behind the changes in acid-base balance are considerably questionable. The main physicochemical principle which must be accomplished in body fluids, is the rule of electroneutrality. There are 3 components in biological fluids which are subject to this principle: a)Water, which is only in minor parts dissociated into H+ and OH-, b)"strong", i.e. completely dissociated, electrolytes, which thus do not interact with other substances, and body substances, such as lactate, and c)"weak", i.e. incompletely dissociated, substances. Peter Stewart strictly distinguished between dependent and independent variables and thus indeed described a new order of acid-base chemistry. The 3 dependent variables (bicarbonate concentration [Bic(-)], pH, and with this also hydrogen ion concentration [H(+)]) can only change if the 3 independent variables allow this change. These 3 independent variables are: 1. Carbon dioxide partial pressure, 2.the total amount of all weak acids ([A-] (Stewart called these ATOT), and 3.strong ion difference (SID). [A(-)] can be calculated from the albumin (Alb) and the phosphate concentration (Pi): [A(-)]=[Alb x (0.123 x pH - 0.631)] + [Pi x (0.309 x pH - 0.469)]. An apparent SID (or "bedside" SID) can be calculated using measurable ion concentrations: SID=[Na(+)] + [K(+)] - [Cl(-)]-lactate. Regarding the metabolic disturbances of acid-base chemistry, according to Stewart's terminology, changes in pH, [H(+)], and [Bic(-)] are only possible if either SID or [A(-)] itself changes. If, for example, SID decreases (e.g. in case of hyperchloremia), this increase in independent negative charges leads to a decrease in dependent negative charges in terms of [Bic(-)] resulting in acidosis (and vice versa). Therefore, according to Stewart, the decrease in SID during hyperchloremic acidosis results from the increase in serum chloride concentration and is the causal mechanism behind this acidosis. Contrary for example, a decrease in [A(-)] (e. g. during hypoalbuminemia) leads to an increase in [Bic(-)] and therefore to an alcalosis (and vice versa). Thus, by Stewart's approach, completely new acid-base disturbances, like "hyperchloremic acidosis" or "hypoalbuminemic alcalosis" (which, of course, can also exist in combination) can be detected, which had been unrecognised by the classic acid-base concepts. Consequently, Stewart's analysis can lead to a better understanding of the mechanisms behind the changes in acid-base balance.

Acid-Base Equilibrium↗
PubMed2000

Effect of maturation on nerve excitability in an experimental model of threshold electrotonus.

Threshold electrotonus (TE) is a new tool for investigating axonal function noninvasively in vivo. To increase its potential clinical value, we developed a rat model of TE, and examined the effects of maturation and pharmacological intervention. We recorded TE in 92 male rats (body weight 90-650 g) by stimulating the motor nerve in the tail, and applying 100-ms conditioning currents. Motor conduction velocities increased up to a body weight of 330 g, and remained constant thereafter. TE in mature rats was similar to that in humans, and two parameters were analyzed: TEd(10-20) or the mean threshold reduction 10-20 ms after the onset of the depolarizing conditioning current at 40% of threshold intensity; and TEh(10-20) or the corresponding threshold decrease on hyperpolarization. Like latency, the absolute value of TEh(10-20) decreased up to 330 g, and then stabilized thereafter, probably reflecting the progressive increase in the axonal diameter and relative reduction in internodal impedance. In contrast, TEd(10-20) gradually decreased up to 330 g, and then jumped to a higher level, which was maintained for animals of >400 g. 4-Aminopyridine, a blocker of fast potassium channels, selectively increased TEd(10-20) only in the immature or young (<330 g) rats. This suggests that, in the mature animals, fast potassium channels become sequestrated from the nodal membrane and not activated in response to nodal depolarization. These findings indicate that mature rats (>400 g) may provide a useful experimental model for interpreting abnormal TE responses in humans, and provide evidence for nonlinear maturation of potassium channel function in myelinated axons.

4-Aminopyridine↗
PubMed2000

Mechanisms of heparin transport through expanded poly(tetrafluoroethylene) vascular grafts.

Thrombosis and neointimal hyperplasia limit the utility of small-caliber artificial vascular grafts. Surface modifications and adjunctive pharmacological therapy might mediate these complications. We examined the mechanisms by which a model vasoactive compound, heparin, transverses porous graft materials and how material modifications alters this drug's transport. The effective permeance of [(3)H]heparin was measured after application of a uniform concentration of drug to either the internal or external surface of the graft and in the presence or absence of pressure-driven physiologic hydraulic flows. Transgraft permeance was equivalent to those observed in normal arteries and, while enhanced by convection, was mediated in major part by diffusion. Peclet numbers under the various conditions examined ranged from 0.05 to 1.2, indicating that diffusive forces were equal to or exceeded convective forces in governing transmural heparin motion. Heparin traversed the graft even when applied from the outer perivascular surface, against adverse hydraulic flows. Modifications of the grafts that included a yarn barrier of spun poly(tetrafluoroethylene) or chemical modification of surface tension energy altered permeances as well. A unifying model for interpretation of these data incorporates the concept of entrapped air and surface tension energy in the graft. These characterizations allow for the design of vascular grafts that are optimized for pharmacotherapy to help prolong graft patency, especially in small-caliber vascular beds.

Air↗
PubMed1996

Young infants' long-term auditory memory: evidence for changes in preference as a function of delay.

Infants' preferences for a novel or familiar nursery rhyme were examined as an index of long-term memory. One-to 2-month-old infants' preference were tested, using a nonnutritive sucking, discrimination-learning procedure, at 1, 2, or 3 days after the last of multiple familiarization sessions. A consistent novelty preference was observed at the 1-day retention interval, no consistent preference occurred at the 2-day interval, and familiarity preference was found following the 3-day interval. This pattern of results is consistent with attentional preference models which interpret novelty and familiarity preferences as reflecting the discrepancy between an external stimulus and the infants' representation of the stimulus. The findings also reveal that infants as young as 1 month of age encoded and subsequently recognized a repeatedly experienced nursery rhyme after a 3-day retention interval.

Female↗
PubMed1988

WISC-R factor structure in a referred pediatric population.

The factor structure of the WISC-R was examined with a large metropolitan pediatric clinic population of referred children. The robustness of the two-factor solution, which parallels the verbal-performance dichotomy, was supported for a group of non-LD children (n = 272) and, with the exception of the Coding subtest, for a cohort of LD children (n = 155), as well as with the entire pediatric population (n = 427). Kaufman's (1975) three-factor solution was applicable only for the LD cohort. The validity and utility of the factor analytic model for interpreting the WISC-R were supported and extended to include a pediatric referred population. Cautious interpretation of the third factor, however, is recommended on the basis of the present results, as well as those of other investigations.

Adolescent↗
PubMed2000

Longitudinal assessment of hormonal and physical alterations during normal puberty in boys. VI. Modeling of growth velocity, mean growth hormone (GH mean), and serum testosterone (T) concentrations.

The growth and hormonal status of 23 prepubertal and early pubertal normally growing boys were evaluated for at least 6 years as they entered and progressed through puberty. Each subject was observed during a 24-hr hospital admission approximately every 4 months. Standing height was measured upon arising. At the same time an early morning (0600hr) serum level of testosterone was obtained. A mean growth hormone level was determined from a pool of equal quantities of serum from 72 samples obtained every 20 min for 24 hr. The early morning testosterone level was used as an index of pubertal status. The effect of the chronological age, mean growth hormone, and testosterone levels on the growth velocity was investigated. In addition to age, the interaction between the mean growth hormone level and testosterone concentration has a significant effect on the velocity of growth. Several nonlinear models were explored to describe growth velocity, mean growth hormone level, and testosterone concentration in terms of chronological age of each subject. Models used were chosen for simplicity, interpretability of the model itself and its parameters, and the ability to estimate (and then test) the parameters. Unknown parameters of the model were estimated using ordinary least squares (OLS), which minimizes the L(2) norm of the observed and the predicted values. The L(2) norm may be unduly influenced by outlying observations which commonly occur in many biological data sets. Hence, in addition to the OLS estimators, the least absolute deviation (LAD) estimator which minimizes the L(1) norm of the observed and the predicted values was also considered. Typically, the LAD estimators are more robust than OLS estimators. From a clinical point of view it may be important to know the "normal" values of growth velocity, mean growth hormone level, and testosterone at a given age during puberty. For this reason population models for each of these variables along with their 90% confidence regions were developed. These will permit identification of those children who are outside the boundaries of normal growth for the purpose of evaluation for the etiology of the deviation. Am. J. Hum. Biol. 12:814-824, 2000. Copyright 2000 Wiley-Liss, Inc.

Journal Article↗
PubMed2000

DNA polymerases and SOS mutagenesis: can one reconcile the biochemical and genetic data?

Until recently, it had been concluded from genetic evidence that DNA polymerase III (Pol III, the main replicative polymerase in E. coli) was also responsible for mutagenic translesion synthesis on damaged templates, albeit under the influence of inducible proteins UmuD' and UmuC. Now it appears that these proteins themselves have polymerase activity (and are now known as Pol V) and can carry out translesion synthesis in vitro in the absence of Pol III. Here I discuss the apparent contradictions between genetics and biochemistry with regard to the role of Pol III in translesion synthesis. Does Pol V interact with Pol III and constitute an alternative component of the replication factory (replisome)? Where do the other three known polymerases fit in? What devices does the cell have to ensure that the "right" polymerase is used in a given situation? The debate about the role of Pol III in translesion synthesis reveals a deeper divide between models that interpret everything in terms of mass action effects and those that embrace a replisome held together by protein-protein interactions and located as a structural entity within the cell.

Animals↗
PubMed1992

End-stabilized microtubules observed in vitro: stability, subunit, interchange, and breakage.

We report a reliable method to prepare, in vitro, microtubules that are stabilized at both ends by axonemal structures, and report studies of their properties. Such "end-stabilized" microtubules neither grow nor shorten over times of several hours when tubulin subunits are present in the surrounding solution. When subunits are removed, the microtubules eventually break. Breakage occurs within a sinuous and flexible region, a few microns in length, that begins at a single point on the microtubule and grows. When breakage does occur, the resulting two free ends shorten very rapidly until the flexible part has depolymerized and the region of straight microtubule is reached. The remainder of the microtubule then shortens at rates comparable to those ordinarily observed in dynamic instability. Formation of the flexible region can be reversed if subunits are added to the buffer prior to breakage. End-stabilized microtubules are a useful tool for studying interactions of molecules with the microtubular wall. They may be a good model for interpreting stabilizing events that happen in the cell. A preliminary study of the effects of microtubule poisons on the wall is presented.

Alkaloids↗
PubMedDate not supplied

Nerve collagens from diabetic and nondiabetic Sprague-Dawley and biobreeding rats: an atomic force microscopy study.

BACKGROUND: Alterations in rat's nerve collagens due to diabetes may be related to the permanence of damage due to diabetic neuropathy. We (1) provide a methodology for determining the diameters of collagen fibers accounting for atomic force microscope (AFM) imaging artifacts, (2) present data on structural differences in sciatic nerve endoneurial, epineurial and tail tendon collagens of control and diabetic Sprague-Dawley and BioBreeding rats, and (3) compare results with literature values. METHODS: We measured collagen diameters and band spacing on endoneurial and epineurial sciatic nerve tissue, and tail tendon, in control and diabetic rats (STZ-induced 12-week diabetic SD and 16-week spontaneously diabetic BB rats). We also developed a model to interpret the raw AFM data. RESULTS: All types of fibrillar collagen diameters studied became larger for diabetic versus control animals. Values for diabetic and control collagen fiber diameters in SD rats were 78 nm and 72 nm for SN epineurium, and 49 nm and 43 nm for SN endoneurium. For diabetic and control BB rats, these values were 83 nm and 77 nm (SN epineurium) and 49 nm and 43 nm (SN endoneurium). Values of 161 nm and 125 nm were found for diabetic and control tail tendon of BB rats. No significant changes were observed in any of the five comparisons made in D-band spacings that ranged from 63 to 69 nm. CONCLUSIONS: The best means we have found to reduce raw AFM data is to measure several diameters with a single scan, using valley-to-valley measurements. Structural, fibrillar collagens of the nerve and tendon become larger in rats exposed to prolonged diabetes.

Animals↗
PubMed2006

DNA microelectrophoresis using double focus fluorescence correlation spectroscopy.

Double focus fluorescence correlation spectroscopy (dfFCS) was used to determine electrophoretic mobilities of short double-stranded DNA (dsDNA)-fragments (75 base pairs (bp) -1019 bp) in microfluidic channels. The electrokinetic flow profile across a microchannel was measured with 1 microm spatial resolution and separated in electroosmotic and electrophoretic contributions. Experiments show that the free solution mobility is independent of DNA length. The diffusion constant is additionally determined by FCS and follows a length dependent rod-diffusion model. We interpret the electrophoretic mobilities using a modified Nernst Einstein relation, which additionally takes Manning condensation and counterion induced hydrodynamic retardation forces into account. In 3% w/v polyethylene oxide (PEO)-network (M(r) 3 .10(5) Dalton) the electrophoretic velocities become size-dependent with a power-law exponent be-tween 0.28 and 0.31. Mixtures of dsDNA-fragments exhibit distinguishable peaks in the dfFCS cross-correlation function. The potential of dfFCS for realtime micro-analysis in terms of speed and spatial resolution is discussed.

DNA↗
PubMedDate not supplied

Origin and fate of autophagosomes in Leydig cells of normal adult rats.

Autophagosomes were observed frequently in electron microscope photographs of Leydig cells from normal adult rat testis. Their formation, evolution and fate were analyzed morphologically in preparations treated to show cytidine monophosphatase (CMPase) and glucose-6-phosphatase (G-6-Pase) activities and in animals sacrificed at various time intervals ranging from 5 min to 6 hrs after a single intratesticular injection of cationic ferritin. Analysis of the morphologic data led to the following interpretation and model. Preautophagosomal structures appeared as flattened, elongated membranous profiles. These expanded, took on a C-shape and fused at their edges to demarcate a small cytoplasmic territory containing normal-looking smooth endoplasmic reticulum (ER) and mitochondria. Such early autophagosomes were thus delimited by two membranes separated by a narrow lumen. Following fusion of these elements with secondary lysosomes, the space between the two membranes increased in size, the inner membrane disintegrated and the enclosed organelles no longer could be identified. The late autophagosomes then reached the cell surface and appeared to exocytose their residual content. In contrast to secondary lysosomes and trans-Golgi elements, which were CMPase-positive, the preautophagosomal flattened membranous elements and early autophagosomes were CMPase-negative. The late autophagosomes on the contrary were CMPase-positive. While ER cisternae were G-6-Pase-positive, the pre-, early and late autophagosomal structures were unreactive for this enzyme. Cationic ferritin tracer experiments showed that only late autophagosomes became labeled with cationic ferritin following their fusion with secondary lysosomes into which the tracer had accumulated following its endocytosis from the cell surface.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Experimental studies of transient mass transfer and reaction in the liver: interpretation with a heterogeneous compartment model.

The uptake and metabolism of lipophilic compounds by the liver were studied by administering a model compound, lidocaine, to the isolated rat liver. Lidocaine was continuously infused into the liver until steady state was reached. Subsequent step changes in the inlet concentration were used to obtain information on rates of cellular uptake and release and to assess the extent of mixing within the organ. A simple heterogeneous model combining mass transfer and enzyme reactions was required to simulate the effluent levels of lidocaine and two primary metabolites, monoethylglycinexylidide and 3-hydroxylidocaine. The rate constants for uptake and release of lidocaine were 1200 and 46 min-1, respectively. The rate-limiting step was intracellular reaction, with a rate constant of 0.49 min-1. Although the rate of lidocaine uptake was fast, it was 50 times slower than the rate of facilitated uptake of galactose, a fact suggesting passive transport of lidocaine between the tissue and the vasculature. The rates of mass transfer of lidocaine and its metabolites differed, but the ratios of the rate of uptake to the rate of release were the same. The results suggested that all three species had an affinity for the cellular region of the liver; concentrations in tissue were approximately five times greater than concentrations in effluent. Because of the large capacity of the organ for uptake of lidocaine and its metabolites, concentrations from washout experiments were controlled by linear mass transfer from the tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Assessment of glutamate and glutamine contribution to in vivo N-acetylaspartate quantification in human brain by (1)H-magnetic resonance spectroscopy.

N-Acetylaspartate (NAA) is one of the most important metabolites detectable by brain (1)H-MRS being considered an index of neuronal integrity. At the low magnetic field used in most clinical settings beta,gamma-glutamate/glutamine (Glx) resonances are very close and partially overlap the methyl-NAA resonance interfering with NAA quantification especially at low TE and in the presence of increased Glx signals. NAA overestimation due to Glx on a set of model solutions containing NAA, glutamate, and glutamine in variable amounts was evaluated and the result tested in vivo in six healthy controls and five age- and sex-matched patients with hepatic encephalopathy (HE), the latter having an increased Glx content. A method to assess in vivo the NAA overestimation caused by Glx is proposed. A perfect match was obtained between the assessment of Glx contamination on the NAA of healthy controls and that obtained on the model solutions. However, a substantial difference in NAA overestimation was found between controls and HE patients that cannot be explained by our model. An interpretative hypothesis is provided.

Algorithms↗
PubMed2001

Marginal and dynamic regression models for longitudinal data.

Regression models for longitudinal data often employ random effects and serial correlation to account for residual variation between and within subjects. Most of these models are marginal models, separating the mean and covariance parameters. This paper discusses the use of dynamic models in which a lagged response serves as a predictor and compares these to marginal models. Regression parameters have a different interpretation in dynamic models as they describe changes in response levels, rather than the levels themselves. Lagged predictors are also useful with longitudinal data, explicitly quantifying the effect of previous levels of risk factors. These models are explored through analysis of data from the Childhood Respiratory Study, modelling lung function (FEV(1)) levels as a function of age, height, sex and smoking status in children measured over a five-year period.

Adolescent↗
PubMed1996

Tip-of-the-tongue states and lexical access in dementia.

We induced tip-of-the-tongue (TOT) states in elderly participants with probable Alzheimer's disease (AD). We found that they experienced TOTs but, unlike control subjects, were unable to provide any information about the target word for which they were searching. The related words produced by the AD participants were almost all semantically related to the target, with very few phonological relatives. (Adults normally produce more phonological relatives than semantic.) We examine the relationship between the target and non-target words produced in terms of their syntactic category, frequency, and imageability. The results are discussed with regard to their implications for speech production models. We interpret the results in terms of a two-stage interactive account where the retrieval deficit in dementia lies between the semantic and lexical levels.

Aged↗
PubMed1993

Cyclosporine, tolerance, and autoimmunity.

A large number of studies have documented the effects of CsA on immunologic tolerance. Initially, these studies concentrated on the ability of CsA to induce tolerance to allografts, particularly in rats. However, it has become apparent that CsA can sometimes block the induction of tolerance, and provoke or aggravate specific autoimmune diseases in several species (Table 1). CsA can inhibit at least three processes thought to contribute to tolerance (Table 2). In the thymus, CsA has been reported by some investigators to block negative selection, but surprisingly, large numbers of undeleted or "forbidden" T-cells are rarely observed in the periphery. In mature T-cells (extrathymic), CsA can block the induction of anergy which occurs after immunization with superantigens, and in vitro this drug can block anergy induction in Th1 clones which occurs when antigenic peptides are presented by metabolically inactive (treated with a fixative) antigen-presenting cells. However, CsA can also enhance the deletion of peripheral superantigen-reactive T-cells, when the drug is administered at high doses. Thus, responses to superantigens can be either enhanced or inhibited depending on the protocol of CsA administration. Whether or not these phenomena apply to conventional antigens has not been determined. Numerous studies demonstrate that CsA treatment can either enhance or depress suppressor T-cell function in various experimental models. The interpretation of data on suppressor cells is complicated by the current poor understanding of the function of the cells. In CsA-induced syngeneic (or autologous) GVHD, CsA may inhibit both T-cell anergy induction and the generation and/or function of suppressor cells. CsA can alter Th1/Th2 antagonism, such that DTH responses are enhanced. Enhanced Th1 activity could explain the deterioration that CsA sometimes provokes in autoimmune diseases where DTH is important, e.g., collagen-induced arthritis and EAE. CsA can prevent the development of neonatal tolerance. The latter effect may account, at least in part, for the induction of organ-specific autoimmunity observed after treating mice with CsA during the neonatal period. However, in all the situations mentioned the effects of CsA on tolerance cannot be easily explained by a single mechanism. There is redundancy in the immune tolerance mechanism, such that clonal deletion, clonal anergy, and suppressor cells may all be capable of maintaining tolerance to similar antigens. Thus, it is likely that CsA must inhibit more than one of these mechanisms for autoimmunity to occur.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1997

Adsorption of Copper at Aqueous Illite Surfaces

In this paper, we conducted potentiometric titrations, batch adsorption experiments and FT-IR analysis to study the uptake of copper in illite/water suspensions and then applied the constant capacitance surface complexation model to interpret the reaction mechanism at the aqueous illite surfaces. Our research shows that the copper adsorption at these surfaces is strongly dependent on pH and that the adsorption causes a deprotonation of surface groups. We propose that the uptake of copper in the carbonate-free illite suspensions can be explained by the formation of mononuclear surface complexes, identical withSOCu+ and identical withSOCuOH, and a multinuclear surface complex, identical withSOCu2(OH)2+, followed by the formation of a bulk precipitate, Cu(OH)2(s), or a surface precipitate, identical withSOCu2(OH)3(sp). For the illite suspensions containing carbonates, we propose that the copper-illite interaction can be depicted by the formation of mononuclear surface complexes, identical withSOCu+ and identical withSOCuOH, followed by the formation of a copper hydroxylcarbonate precipitate, Cu2(OH)2CO3(s), rather than a copper hydroxide precipitate. The existence of Cu2(OH)2CO3(s) in the carbonate-containing illite suspensions was identified by FT-IR analysis.

Journal Article↗