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At least 343 records · Page 19Linked to original sources
PubMed2006

Fabry's disease cardiomyopathy: echocardiographic detection of endomyocardial glycosphingolipid compartmentalization.

OBJECTIVES: We sought to identify echocardiographic hallmarks of Fabry's disease cardiomyopathy (FC). BACKGROUND: The recognition of FC from other forms of left ventricular hypertrophy (LVH) by noninvasive imaging techniques is not yet available, and diagnosis, mostly in the absence of systemic manifestations, still relies on genetic and invasive studies. METHODS: Forty consecutive patients (mean age 39 +/- 15 years, 22 men and 18 women) with an established diagnosis of Fabry's disease were submitted to echocardiographic evaluation. Control population consisted of 40 consecutive patients with hypertrophic cardiomyopathy (HCM), 40 hypertensive patients with echocardiographic evidence of LVH, and 40 age- and gender-matched healthy subjects with no LVH. All HCM patients and FC with LVH and/or cardiac symptoms underwent cardiac catheterization with left ventricular endomyocardial biopsy. RESULTS: Echocardiography showed in 83% of FC patients (95% of FC patients with LVH) a binary appearance of endocardial border absent in all HCM, hypertensive, and healthy subjects. The sensitivity and specificity of this echocardiographic feature in detecting Fabry patients in study population were 94% and 100%, respectively. Comparison of echocardiographic with histologic and ultrastructural findings showed the binary appearance to reflect an endomyocardial glycosphingolipids compartmentalization, consisting of thickened glycolipid-rich endocardium, free glycosphingolipid subendocardial storage, and an inner severely affected myocardial layer with a clear subendocardial-midwall layer gradient of disease severity. CONCLUSIONS: Echocardiographic binary appearance of left ventricular endocardial border, reflecting endomyocardial glycosphingolipids compartmentalization, represents a sensitive and specific diagnostic hallmark of Fabry's disease cardiomyopathy.

Adolescent↗
PubMed2004

Directed evolution of protein inhibitors of DNA-nucleases by in vitro compartmentalization (IVC) and nano-droplet delivery.

In vitro compartmentalization (IVC) uses water-in-oil emulsions to create artificial cell-like compartments in which genes can be individually transcribed and translated. Here, we present a new application of IVC for the selection of DNA-nuclease inhibitors. We developed a nano-droplets delivery system that allows the transport of various solutes, including metal ions, into the emulsion droplets. This transport mechanism was used to regulate the activity of colicin nucleases that were co-compartmentalized with the genes, so that the nucleases were activated by nickel or cobalt ions only after the potential inhibitor genes have been translated. Thus, genes encoding nuclease inhibitors survived the digestion and were subsequently amplified and isolated. Selection is therefore directly for inhibition, and not for binding of the nuclease. The stringency of selection can be easily modulated to give high enrichments (100-500-fold) and recoveries. We demonstrated its utility by selecting libraries of the gene encoding the cognate inhibitor of colicin E9 (immunity protein 9, or Im9) for inhibition of another colicin (ColE7). The in vitro evolved inhibitors show significant inhibition of ColE7 both in vitro and in vivo. These Im9 variants carry mutations into residues that determine the selectivity of the natural counterpart (Im7) while completely retaining the residues that are conserved throughout the family of immunity protein inhibitors. The in vitro evolution process confirms earlier hypotheses regarding the "dual recognition" binding mechanism and the way in which new colicin-immunity pairs diverged from existing ones.

Colicins↗
PubMed2006

Disrupted compartmental organization of axons and dendrites within olfactory glomeruli of mice deficient in the olfactory cell adhesion molecule, OCAM.

There is an overall topographic connectivity in the axonal projections of olfactory sensory neurons from the olfactory epithelium (OE) to the olfactory bulb (OB). The molecular determinants of this overall topographic OE-OB connectivity are not known. For 20 years, the intriguing expression pattern of the olfactory cell adhesion molecule (OCAM) has made it the leading candidate as determinant of overall topographic OE-OB connectivity. Here, we have generated a strain of OCAM knockout mice by gene targeting. There were no obvious alterations in the distribution of olfactory sensory neurons within the OE or in the coalescence of axons into specific glomeruli. However, the compartmental organization of dendrites and axons within the glomeruli was disrupted. Surprisingly, the mutant mice exhibited an increase in olfactory acuity; they appeared to have a better sense of smell. Thus, despite its striking expression pattern, OCAM is not essential for overall topographic OE-OB connectivity. Instead, OCAM is required for establishing or maintaining the compartmental organization and the segregation of axodendritic and dendrodendritic synapses within glomeruli.

Animals↗
PubMed2005

Compartmentalization of human natural killer cells.

Human natural killer (NK) cells are bone marrow-derived cells that are found in the bloodstream, but can extravasate into various tissue sites upon inflammation. NK cells that migrate toward inflamed sites must be activated prior to their extravasation. However, the factors responsible for NK cell compartmentalization are not clearly defined. Resting human NK cells (CD16(-) and CD16(+)) express constitutive chemokine receptors, as well as receptors that have both constitutive and inflammatory functions. Upon activation, NK cells up-regulate the expression of the inflammatory chemokine receptors which facilitate their distribution into inflammatory sites. However, chemokines are not expected to play any role in maintaining resting NK cells in the blood circulation. In contrast, members of the lysolipids which are abundant in the bloodstream may be the major factors responsible for maintaining resting NK cells in the bloodstream, and also for facilitating their extravasation into inflamed tissues. Both resting and activated NK cells express receptors for various lysolipids. Hence, chemoattractants which include chemokines and lysolipids have important roles in determining the compartmentalization of NK cells where resting NK cells are found in the blood circulation, and activated NK cells extravasate into inflamed sites.

Chemokines↗
PubMed1990

Intracellular diffusion, binding, and compartmentalization of the fluorescent calcium indicators indo-1 and fura-2.

We studied intracellular binding and possible compartmentalization of the fluorescent Ca2+ indicators, indo-1 and fura-2, in single mammalian cardiac ventricular cells that had been loaded with indo-1 and fura-2 by exposure to the acetoxymethylester form of the indicators (indo-1/AM and fura-2/AM). Techniques similar to those used in experiments on fluorescence recovery after photobleaching (FRAP) were used. It was assumed that reversible binding in myoplasm would be evident as slowed recovery of fluorescence after photobleaching, and that irreversible binding of the indicators to immobile myoplasmic sites (or "compartmentalization" in organelles) would be evident as incomplete recovery. Through the use of a mask, one half of a cell was exposed to high-intensity ultraviolet (UV) light to bleach the indo-1 or fura-2 in only that part of the cell. Upon removal of the mask and termination of the high-intensity UV illumination, fluorescence recovered in the bleached half of the cell, indicating diffusion of indo-1 and fura-2. Mathematical modeling of the diffusional redistribution of the indicators indicated that in these cells the apparent diffusion coefficient for indo-1 is 1.57 x 10(-7) cm2 s-1 (SD 0.48 x 10(-7) cm2 s-1; n = 5 cells, 21 degrees C), and for fura-2 is 3.19 x 10(-7) cm2 s-1 (SD 1.85 x 10(-7) cm2 s-1; n = 6 cells, 21 degrees C). These values are approximately 6 and 3, respectively, times smaller than those expected for free diffusion in the myoplasm. In the bleached half of the cell the recovered level of fluorescence never reached the final level in the half not exposed to UV light. The extent of incomplete recovery was variable amongst the cells. Our analysis indicated that, under the conditions we used, approximately one-third of the intracellular dye is not diffusible in the myoplasm.

Animals↗
PubMedDate not supplied

Detecting autocatalytic dynamics in data modeled by a compartmental model.

Modeling growth or reaction dynamics within a compartment in a compartmental model is often based on theoretical or first principle considerations. This approach is frequently applied due to the inability to observe or collect data directly from the compartment. When the internal dynamics are difficult to surmise, it is often the case that several competing models are constructed and compared in some way. In this paper, the dynamics which characterize the data of an autocatalytic process are used to describe a quantitative data analysis strategy to both recognize the presence of the autocatalytic process and to obtain some estimates of important parameters in the process. The compartmental model structure serves to communicate this dynamical information to the downstream compartments. This method has been applied to examine the dynamics of the engraftment of blood cells following hematopoietic stem cell transplantation in a clinical setting [Modeling the time to engraftment of white blood cells and platelets following autologous peripheral blood stem cell transplantation (2001)].

Catalysis↗
PubMed2003

WinSAAM: a windows-based compartmental modeling system.

Over the last 50 years, complex, dynamic, compartmental models have been used to describe and to make predictions on a host of pharmacokinetic, metabolic, and biological systems. Sophisticated modeling software is required to fit data to such models and to make predictions using these compartmental models. WinSAAM is one such modeling program. The purpose the current report is to describe the features of WinSAAM that make this program suited for modeling all manner of biological systems. We highlight new features, especially those that are unique to WinSAAM, and illustrate with examples how WinSAAM is used to construct models of metabolic systems, to simulate the effects of experiments on systems, and to fit models to data.

Blood Glucose↗
PubMed2000

Compartmentalization of enzymes and distribution of products in aqueous two-phase systems.

Phase separation is a common phenomenon in water solutions of polymers due to "polymer incompatibility." Polymeric aqueous two-phase systems are much used for separations in biochemistry and cell biology. When macromolecules are included in a phase system, it is often possible to obtain a one-sided distribution to one of the phases, i.e., the macromolecule is compartmentalized within one aqueous phase. This chapter describes the thermodynamic forces which govern the partitioning of molecules in aqueous two-phase systems. For a high molecular weight macromolecule, e.g., an enzyme, both enthalpic and entropic effects contribute to a one-sided partitioning. Molecules of low molecular weight will be more evenly distributed between the phases. These mechanisms are significant in biological systems and can be used for enzyme reactors in bioconversions. Enzymatic reactions can take place with enzyme and substrate compartmentalized in one of the phases. A low-molecular weight product which is evenly partitioned between the phases can be continuously removed from the enzyme-substrate compartment. These principles are described in the enzymatic conversion of cellulose in an aqueous two-phase system.

Animals↗
PubMed2003

Mean residence times in linear compartmental systems. Symbolic formulae for their direct evaluation.

A complete analysis has been performed of the mean residence times in linear compartmental systems, closed or open, with or without traps and with zero input. This analysis allows the derivation of explicit and simple general symbolic formulae to obtain the mean residence time in any compartment of any linear compartmental system, closed or open, with or without traps, as well as formulae to evaluate the mean residence time in the entire system like the above situations. The formulae are given as functions of the fractional transfer coefficients between the compartments and, in the case of open systems, they also include the excretion coefficients to the environment from the different compartments. The relationship between the formulae derived and the particular connection properties of the compartments is discussed. Finally, some examples have been solved.

Algorithms↗
PubMed1997

On the accuracy of an [18F]FDOPA compartmental model: evidence for vesicular storage of [18F]fluorodopamine in vivo.

The biological accuracy of a nonlinear compartmental model describing the in vivo kinetics of L-3,4-dihydroxy-6-[18F]fluorophenylalanine ([18F]FDOPA) metabolism was investigated. Tissue activities for [18F]FDOPA and its labeled metabolites 3-O-methyl-[18F]FDOPA ([18F]OMFD), 6-[18F]fluorodopamine ([18F]FDA), L-3,4-dihydroxy-6-[18F]fluorophenylacetic acid ([18F]FDOPAC), and 6-[18F]fluorohomovanillic acid ([18F]FHVA) were calculated using a plasma [18F]FDOPA input function, and kinetic constants estimated previously by chromatographic fractionation of 18F-labeled compounds in plasma and brain extracts from rat. Present data accurately reflected the measured radiochemical composition in rat brain for tracer circulation times past 10 min. We formulated the hypothesis that the discrepancy between calculated and measured fractions of [18F]FDOPA and the deaminated metabolite [18F]FDOPAC at times earlier than 10 min reflected storage of [18F]FDA in vesicles without monoamine oxidase. This hypothesis explained the initially rapid appearance of [18F]FDOPAC in striatum by delayed transfer of [18F]FDA from cytosol into vesicles. We conclude that the simpler model of [18F]FDOPA compartmentation is accurate when the cytosolic and vesicular fractions of [18F]FDA are at steady-state; the approach to equilibrium has a time constant of 15-30 min. The present model is valid for positron emission tomography studies of [18F]FDOPA metabolism in living brain.

Animals↗
PubMed1997

The kinetic behaviour of [3H]DOPA in living rat brain investigated by compartmental modelling of static autoradiograms.

The kinetic behaviour of [3H]DOPA in living rat brain was investigated by compartmental modelling of measured activities from combined metabolite pools in a time-series (180 min) of static autoradiograms from right cerebral hemispheres. Two models of [3H]DOPA uptake and metabolism that incorporated the removal of the decarboxylation product, [3H]dopamine, from brain were significantly more accurate than a model in which [3H]dopamine accumulated irreversibly in situ. Present estimates of [3H]DOPA kinetic constants were compared to previously published results based on the analysis of measured activities from individual metabolite pools separated by chromatographic fractionation of [3H]DOPA metabolites in the left cerebral hemispheres of the same rats. Autoradiographic estimates of DOPA decarboxylase activity with respect to [3H]DOPA in brain (k3DOPA) were under-estimated several-fold relative to chromatographic estimates; this discrepancy is explained by post-mortem enzyme activity and omission of biological compartments from the models. However, autoradiographic estimates of the unidirectional blood-brain clearance of [3H]DOPA (K1DOPA) and monoamine oxidase activity with respect to [3H]dopamine in brain (k7DA') agreed with chromatographic estimates. This concordance represents the first empirical validation of compartmental modelling of autoradiographic data as a method for quantitatively investigating the kinetic behaviour of radiolabelled L-DOPA in living mammalian brain.

Animals↗
PubMed1998

Striatal cholinergic interneurons: birthdates predict compartmental localization.

The striatal patch and matrix compartment neurons are born at different times during rat development. The majority of the early born neurons preferentially end up in the patch compartment, while the majority of the later born neurons end up in the matrix compartment. Although the cholinergic interneurons are all born early in neurogenesis (between embryonic day E12 and E17), and we would therefore expect them to be located mainly in the patches, they are relatively homogeneously distributed in the adult, with a preference for the matrix area just outside the patches (the intermediate zone). To ask if birthdate can predict the compartmental localization of cholinergic neurons in the striatum, we marked new postmitotic neurons in the embryo with a maternal injection of bromodeoxyuridine (BrdU) on E13, E15 or E17 and labeled the patch compartment with an injection of the retrograde tracer True Blue into the substantia nigra on postnatal day (P) 1. The pups were sacrificed at P40 and the tissue was processed for BrdU, choline acetyltransferase, and True Blue triple labeling. Cholinergic neurons that became postmitotic at E13, had a higher chance of ending up in the patch compartment compared to either the intermediate zone or the rest of the matrix compartment. On the other hand cholinergic neurons that became postmitotic at E17 had a higher chance of ending up in the matrix compartment (including the intermediate zone). We conclude that birthdate can predict compartmental localization, with the cholinergic neurons in the intermediate zone following the same pattern as the cholinergic neurons in the rest of the matrix compartment. Cholinergic neurons show the same relative birthdate/compartment relationship as do other striatal neurons, although the absolute birthdates of cholinergic neurons are shifted earlier in neurogenesis.

Acetylcholine↗
PubMed1998

Compartmental models for glycaemic prediction and decision-support in clinical diabetes care: promise and reality.

This paper reviews and critically appraises the application of compartmental models for generating glycaemic predictions and offering clinical decision support in diabetes care. Comparisons are made with alternative algorithmic-based approaches. Unresolved issues raised for model-based techniques include the relative lack of input data necessary for generating reasonable blood glucose predictions, and the high level of uncertainty associated with such predictions which limits their use as guides for therapeutic insulin-dosage adjustments. It is concluded that compartmental model-based approaches, while not offering much benefit for clinical/therapeutic application, will have a role to play as research tools and for educational use. By contrast it is proposed that algorithmic-based approaches, especially in conjunction with telemedicine and Internet applications, are likely to see growing use for day-to-day therapeutic decision support. Randomised controlled clinical trials however will be required, together with other evaluation efforts, before algorithmic-based approaches-like any other clinical technique-can be widely adopted into routine medical practice.

Algorithms↗
PubMedDate not supplied

In vivo 13C NMR studies of compartmentalized cerebral carbohydrate metabolism.

Localized 13C nuclear magnetic resonance (NMR) spectroscopy provides a unique window for studying cerebral carbohydrate metabolism through, e.g. the completely non-invasive measurement of cerebral glucose and glycogen metabolism. In addition, label incorporation into amino acid neurotransmitters such as glutamate (Glu), GABA and aspartate can be measured providing information on Krebs cycle flux and oxidative metabolism. Given the compartmentation of key enzymes such as pyruvate carboxylase and glutamine synthetase, the detection of label incorporation into glutamine indicated that neuronal and glial metabolism can be measured in vivo. The purpose of this paper is to provide a critical overview of these recent advances into measuring compartmentation of brain energy metabolism using localized in vivo 13C NMR spectroscopy. The studies reviewed herein showed that anaplerosis is significant in brain, as is oxidative ATP generation in glia and the rate of glial glutamine synthesis attributed to the replenishment of the neuronal Glu pool and that brain glycogen metabolism is slow under resting conditions. This new modality promises to provide a new investigative tool to study aspects of normal and diseased brain hitherto unaccessible, such as the interplay between glutamatergic action, glucose and glycogen metabolism during brain activation, and the derangements thereof in patients with hepatic encephalopathy, neurodegenerative diseases and diabetes.

Animals↗
PubMed2000

Compartmentation of TCA cycle metabolism in cultured neocortical neurons revealed by 13C MR spectroscopy.

Cultured neocortical neurons were incubated in medium containing [U-13C]glucose (0.5 mM) and in some cases unlabeled glutamine (0.5 mM). Subsequently the cells were "superfused" for investigation of the effect of depolarization by 55 mM K+. Cell extracts were analyzed by 13C magnetic resonance spectroscopy and gas chromatography/mass spectrometry to determine incorporation of 13C in glutamate, GABA, aspartate and fumarate. The importance of the tricarboxylic acid (TCA) cycle for conversion of the carbon skeleton of glutamine to GABA was evident from the effect of glutamine on the labeling pattern of GABA and glutamate. Moreover, analysis of the labeling patterns of glutamate in particular indicated a depolarization induced increased oxidative metabolism. This effect was only observed in glutamate and not in neurotransmitter GABA. Based on this a hypothesis of mitochondrial compartmentation may be proposed in which mitochondria associated with neurotransmitter synthesis are distinct from those aimed at energy production and influenced by depolarization. The hypothesis of mitochondrial compartmentation was further supported by the finding that the total percent labeling of fumarate and aspartate differed significantly from each other. This can only be explained by the existence of multiple TCA cycles with different turnover rates.

Amino Acids↗
PubMed1998

Compartmentation and kinetics of urea cycle enzymes in porcine enterocytes.

We have recently reported the synthesis of urea from ammonia, glutamine and arginine in enterocytes of postweaning pigs. The present study was conducted to determine the compartmentation and kinetics of urea cycle enzymes in these cells. Carbamoyl phosphate synthase I (CPS I) and ornithine carbamoyltransferase (OCT) were located exclusively in mitochondria, whereas argininosuccinate synthase (ASS) and argininosuccinate lyase (ASL) were found in the cytosol. Arginase isozymes were present in both the cytosol and mitochondria of enterocytes, and differed in their sensitivity to heat inactivation. Except for OCT, Vmax values of urea cycle enzymes were much lower in enterocytes than in the liver of pigs, and vice versa for their Km values. Because of a low rate of ureagenesis in enterocytes compared with the liver, intestinal urea cycle enzymes may function primarily to synthesize citrulline. The co-localization of CPS I and OCT and a high activity of OCT in enterocyte mitochondria favors the intestinal synthesis of citrulline from ammonia, HCO3- and ornithine. Low activities of cytosolic ASS and ASL minimize the conversion of citrulline into arginine and therefore, the recycling of citrulline into ornithine via arginase in postweaning-pig enterocytes. These kinetic properties of intestinal urea cycle enzymes maximize the net synthesis of citrulline from glutamine and explain the release of large amounts of citrulline by the pig small intestine. The two compartmentally separated arginase isozymes in enterocytes may play an important role in regulating the intestinal metabolism of proline, nitric oxide and polyamines.

Animals↗
PubMed2002

Impact of human variability on the biological monitoring of exposure to toluene, phenol, lead, and mercury: II. Compartmental based toxicokinetic modelling.

In order to quantify the effect of human variability on a wide range of biological exposure indicators (EIs), a general compartmental model was developed and tested on several chemicals. The model consists of four compartments. In a first step, it was applied to four chemicals: toluene (TOL), phenol (Ph), lead (Pb), and mercury (Hg). Individuals were to be exposed 8 h a day, 5 days a week. Physiological parameter values were set to consider a physical workload of 50 W 12 h/day and at rest for the remaining 12 h. Monte Carlo simulations were carried out using realistic distributions of physiological and metabolic parameters. The variability extent index (VEI) and the main parameters of influence were determined for each of the EIs. The results were in agreement with literature data. The present compartmental model provides a fair description of the toxicokinetic (TK) variability of very different chemicals. It will, therefore, further be applied to investigate the variability of a wide range of biological indicators.

Environmental Monitoring↗
PubMed2000

Modeling brain compartmental lactate response to metabolic challenge: a feasibility study.

Magnetic resonance spectroscopy has been used to characterize abnormal brain lactate response in panic disorder (PD) subjects following lactate infusion. The present study integrated water quantification and tissue segmentation to evaluate compartmental lactate response within brain and cerebrospinal fluid (CSF). As there is evidence of brain parenchymal pH changes during lactate infusion, water scans were collected at baseline and post-infusion to address brain water stability. Water levels remained essentially stable across the protocol suggesting internal water provides an improved reference signal for measuring dynamic changes in response to metabolic challenge paradigms such as lactate infusion. To model brain lactate changes by compartments, we took the null hypothesis that lactate rises occur only in tissue. The approach referenced lactate amplitude (potentially from both compartments) to 'voxel' water (water scan corrected for differential T(2) between CSF brain at long-echo times - synonymous to a short-echo water scan). If the magnitude of lactate rise in CSF was equal to or greater than brain, voxels with substantial CSF fractions should demonstrate an equivalent or elevated response to voxels comprised only of tissue. The magnitude of lactate increases paralleled voxel tissue fraction suggesting the abnormal lactate rise observed in PD is tissue-based. The feasibility of lactate quantification and compartmental modeling are discussed.

Adult↗