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PubMed1986

Effects of tolbutamide pretreatment on the rate of conversion of newly synthesized proinsulin to insulin and the compartmental characteristics of insulin storage in isolated rat islets.

Tolbutamide (1 g/kg body wt) was administered to male rats for 3 days to determine the effects of this pretreatment on subsequent insulin biosynthesis and compartmental storage characteristics of freshly isolated islets. Islets were isolated 16 h after the last tolbutamide administration, at a time when fed plasma glucose concentrations were normal. Islet glucagon was unchanged but insulin content was significantly reduced (38 +/- 1.2 ng IRI/islet from seven untreated rats versus 7.9 +/- 1.2 ng IRI/islet from eight treated rats). After tolbutamide pretreatment, the rate of incorporation of 3H-leucine into islet proinsulin was unchanged, but the t1/2 of labeled proinsulin-to-insulin conversion was significantly (P less than 0.001) decreased from 36 to 20 min. After treatment, actual rates of glucose-stimulated insulin secretion were 50% lower, however, because due to the proportionately greater depletion of islet insulin content, the fractional rate of secretion was increased two-fold. After treatment, there was evidence of compartmental, heterogeneous insulin storage, and glucose still marked newly synthesized insulin for preferential release; however, the differential release of new and old insulin converged rapidly with time. Mathematical integration of the data suggested dilution of the newly synthesized insulin compartment with unlabeled insulin during the chase period, but additionally indicated more rapid mixing of newly synthesized with previously stored, unlabeled insulin. Thus, tolbutamide-treated rats partially compensated for acute insulin depletion by increasing the rate of proinsulin-to-insulin conversion, but not increasing the rate of proinsulin biosynthesis; doubling the glucose-stimulated fractional secretory rate of the depleted cellular insulin storage compartment; and retaining compartmental storage characteristics but mixing newly synthesized insulin more rapidly with the compartment of previously stored, unlabeled insulin.

Animals↗
PubMed2005

Dual role of phosphofructokinase-2/fructose bisphosphatase-2 in regulating the compartmentation and expression of glucokinase in hepatocytes.

Hepatic glucokinase is regulated by a 68-kDa regulatory protein (GKRP) that is both an inhibitor and nuclear receptor for glucokinase. We tested the role of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK2) in regulating glucokinase compartmentation in hepatocytes. PFK2 catalyzes formation or degradation of the regulator of glycolysis fructose 2,6-bisphosphate (fructose 2,6-P2), depending on its phosphorylation state (ser-32), and is also a glucokinase-binding protein. Incubation of hepatocytes at 25 mmol/l glucose causes translocation of glucokinase from the nucleus to the cytoplasm and an increase in fructose 2,6-P2. Glucagon caused phosphorylation of PFK2-ser-32, lowered the fructose 2,6-P2 concentration, and inhibited glucose-induced translocation of glucokinase. These effects of glucagon were reversed by expression of a kinase-active PFK2 mutant (S32A/H258A) that overrides the suppression of fructose 2,6-P2 but not by overexpression of wild-type PFK2. Overexpression of PFK2 potentiated glucokinase expression in hepatocytes transduced with an adenoviral vector-encoding glucokinase by a mechanism that does not involve stabilization of glucokinase protein from degradation. It is concluded that PFK2 has a dual role in regulating glucokinase in hepatocytes: it potentiates glucokinase protein expression by posttranscriptional mechanisms and favors its cytoplasmic compartmentation. Thus, it acts in a complementary mechanism to GKRP, which also regulates glucokinase protein expression and compartmentation.

Adenoviridae↗
PubMed1982

Compartmental syndrome following subclavian vein hemodialysis.

Compartmental syndrome occurred in a patient when the subclavian vein was used for hemodialysis. This complication has not yet been reported in subclavian vein hemodialysis. Compartmental syndrome has been more commonly reported as affecting the lower extremities. Increased edema formation due to venous congestion in a tight compartment is the cause for this syndrome. Prompt recognition and treatment can prevent serious complications. The incidence of compartmental syndrome will increase, as both the subclavian vein and internal jugular vein area used more frequently for hemodialysis.

Arm↗
PubMed2001

Compartmentalization of vascular endothelial growth factor to the epithelial surface of the human lung.

BACKGROUND: Based on assessment of mRNA expression, the lung is a major site of expression of the vascular endothelial growth factor (VEGF) gene, largely from type II alveolar epithelial cells. With the knowledge that VEGF can function to induce vascular leak, we hypothesized that to protect the lung from pulmonary edema, the VEGF produced in the lung must be compartmentalized from the pulmonary endothelium, and thus must be compartmentalized to the surface of the respiratory epithelium. MATERIAL AND METHODS: To assess this hypothesis, we quantified the levels of VEGF in human respiratory epithelial lining fluid recovered by bronchoalveolar lavage from normal individuals. RESULTS: Strikingly, human respiratory epithelial lining fluid contains 11 +/- 5 ng/mL as quantified by ELISA, a 500-fold greater concentration than plasma (22 +/- 10 pg/mL, p < 0.0005). Western analysis of BAL fluid proteins showed the major VEGF isoform in respiratory epithelial lining fluid is VEGF165. CONCLUSIONS: With the knowledge that proteins of molecular mass like VEGF (34 to 46 kDa) slowly diffuse across the alveolar epithelium, it is likely that this high level "reservoir" of VEGF protein on the respiratory epithelial surface plays a role in normal lung endothelial biology. However, this compartmentalized VEGF reservoir may also be a "Damocles sword" poised to induce lung endothelial permeability in conditions of acute lung injury when the integrity of the alveolar epithelial barrier is breached.

Blotting, Western↗
PubMed1991

IFN-gamma- and IL-5-producing cells compartmentalize to different lymphoid organs in Trichinella spiralis-infected mice.

The differential induction of cytokines associated with Th1 and Th2 subsets has recently been described during Trichinella spiralis infection. Increased levels of resistance appear to correlate with elevated levels of the Th1-associated cytokines, IFN-gamma and IL-2. In the present report, a filter immunoplaque assay is used to quantify the actual numbers of cells that secrete IFN-gamma and IL-5. It is demonstrated that, in T. spiralis-infected B10.Q mice, Th1- and Th2-associated responses are compartmentalized to different lymphoid organs. Thus, Ag-induced IFN-gamma-producing cells predominate in the spleen, whereas IL-5-producing cells prevail in the mesenteric lymph nodes (MLN). A corresponding compartmentalization of Ag-specific IgA and IgG1 antibody-secreting cells to the MLN is also noted. The virtual absence of Th1-associated responses in the MLN appears to be an Ag-associated phenomenon. MLN from either naive or T. spiralis-infected mice do have the capacity to secrete IFN-gamma if stimulated with Con A. The striking compartmentalization of Ag-driven cytokine responses seen in this parasite system may facilitate study of the mechanisms that regulate the induction of Th1 and Th2 subsets.

Animals↗
PubMed1989

Selective elimination of cross-compartmental innervation in rat lateral gastrocnemius muscle.

The calf muscles of the rat hindlimb are composed of smaller entities, called neuromuscular compartments, which are the territories of muscle innervated by a single, naturally occurring primary (first-order) muscle nerve branch. While it is quite clear that a precise connectivity exists very early in development between motoneuron pools and individual muscles, the mechanisms responsible for producing the adult pattern of compartmental innervation are unknown. This study uses intracellular recording techniques to demonstrate that neuromuscular compartments are essentially established at birth and that postnatal synapse elimination has little role in establishing neuromuscular compartments. Our results demonstrate the existence of a small number of cross-compartmental connections in neonates which are not present in adults. Examining the removal of these cross-compartmental connections in both normal muscles and in muscles that have had synapse elimination delayed by tenotomy reveals that the synapses responsible for this innervation are eliminated in a selective manner.

Animals↗
PubMed1988

Use of compartmental analysis to describe effects of dietary fat saturation and load on plasma triglyceride dynamics in the rat.

Model-based compartmental analysis was used to interpret data on temporal changes in plasma triglyceride (TG) response to a chronic infusion of chylomicrons (CM) in the rat. Male rats were fed purified diets which varied in fat load [L = 10% (w/w), H = 30%] and P/S ratio (P = 4.6, S = 0.2). Lymph CM isolated from donor rats which were absorbing the P or S fat were infused into recipients for 8 h on 3 consecutive days: on d 1 and 3, CM infusion rate reflected the fat content of the previous diet and on d 2, the other load; the infusion replaced dietary fat. Serial plasma samples from each period were analyzed for TG concentration; TG distribution in plasma lipoproteins and liver lipids was measured after d 3. To describe observed group average data, a compartmental model was developed using the Simulation, Analysis and Modeling computer program. Two compartments were needed in plasma (CM vs nonCM TG); each had 2 outputs: removal of TG-fatty acids by lipoprotein lipase (LPL) and uptake of remnant lipoproteins by the liver. After a delay in the liver, there were 3 fates for TG-derived fatty acids: oxidation, retention, or secretion in very low density lipoproteins. Simulation of changes in the rate constant for total CM TG turnover indicated that the basal level of LPL rose rapidly and dramatically in response to TG infusion; the rise was higher for H vs L. After 3-5 h, apparent LPL activity decreased. Simulation of the rate of CM TG turnover indicated that the turnover rate rose immediately after infusion began to levels higher than the infusion rate, and then came into a slight negative balance. Although the observed data could be qualitatively described based on current understanding of TG metabolism, application of model-based compartmental analysis generated testable hypotheses about quantitative aspects of the system dynamics.

Animals↗
PubMed1988

Compartmental syndrome complicating Salter-Harris type II distal radius fracture.

Distal radius fractures are common in children, yet complications are rare. A rarely described complication, acute volar compartmental syndrome, occurred in a 15-year-old boy. An accurate physical examination and awareness of the syndrome are essential for diagnosis. Compartmental pressures can be obtained easily and afford a rapid means of corroboration. Once the diagnosis is established, adequate decompression of all involved compartments, including carpal tunnel release, is essential. The literature is unclear regarding the etiology of this complication. There is nothing structurally intrinsic to the distal radius that should lead to a compartmental syndrome. Both the amount of soft tissue damage at the time of fracture and the mode of immobilization (excessive elevation, constricting splint, etc.) are the ultimate determinants of a successful (or unsuccessful) outcome.

Adolescent↗
PubMed1979

Further evidence for the superiority of a 3-compartmental model for distribution analyses of i.v. injected bile acids in men: studies in patients with liver diseases.

In 15 patients (n = 6 without and n = 9 with liver diseases) we measured the plasma disappearance curves after single injections of C 14-glycocholate, calculated the distribution and excretion kinetics on the basis of a 2- and 3-compartmental model and compared the calculated values for the maximal C 14-accumulation within compartment 2 that should correspond to the liver in both compartmental models. The results demonstrate that only the 3-compartmental model reproduces the pathophysiological situation in the patients with liver injuries, namely a decrease of the maximal C 14-accumulation within the liver and an increased C 14-accumulation within the extrahepatoplasmatic compartment. The results therefore confirm our previous studies in healthy patients even for the patient with liver diseases.

Carbon Radioisotopes↗
PubMedDate not supplied

Further investigations on the pathophysiology of the compartmental syndrome.

A model compartmental syndrome is described in rabbits in which the intracompartmental pressure may be accurately controlled to investigate the pathophysiologic changes resulting from increased intracompartmental pressure. Oxygenation in the tibialis anterior muscle was measured using a medical mass spectrometer. The Po2 declined with increasing intracompartmental pressure from a control value of 10.8 mmHg to a minumum of 2.8 mmHg at a pressure of 90 mmHg. The functional integrity of the peroneal nerve and compartmental muscle was tested by direct electrical stimulation. Functional deficits were first noted when an intracompartmental pressure of 40 mmHg was exerted for 6 hours. The incidence of functional losses increased with increasing pressures and durations of pressure application. All animals subjected to 100 mmHg for eight or more hours lost both nerve and muscle function. These investigations demonstrate that increased intracompartmental pressure alone, without other associated vascular injury, may produce muscle hypoxia and loss of neuromuscular function. The continuous monitoring of intracompartmental pressures may, therefore, be a useful clinical adjunct in the management of patients at risk for a compartmental syndrome.

Animals↗
PubMed1983

The role of protein glycosylation in the compartmentalization and processing of mouse mammary tumor virus glycoproteins in mouse mammary tumor virus-infected rat hepatoma cells.

The relationship of protein glycosylation to compartmentalization and processing of mouse mammary tumor virus (MTV) glycoproteins has been examined in M1.54, a cloned line of MTV-infected rat hepatoma tissue culture cells. Previous work established that full maturation of MTV glycoproteins in this cell line requires dexamethasone, a synthetic glucocorticoid (Firestone, G. L., Payvar, F., and Yamamoto, K. R. (1982) Nature (Lond.) 300, 221-225). The ability to regulate production of the full complement of five mature membrane-associated and secreted viral glycoproteins from one initially synthesized precursor has been used to advantage in the present work. At concentrations of tunicamycin that specifically inhibit N-linked protein glycosylation, incorporation of [35S]methionine into total cellular and secreted protein is not detectably affected, MTV-specific mRNAs are produced normally, and the nonglycosylated form of the glycosylated viral precursor polyprotein accumulates within the cells. However, tunicamycin inhibits the site-specific cleavage of the glycosylated polyprotein and distribution of MTV polypeptides to the cell surface and extracellular fractions. Thus, when tunicamycin-treated cultures of M1.54 are exposed to dexamethasone and [35S]methionine, no labeled viral antigens are detected in the culture medium. Similarly, tunicamycin prevents the appearance of membrane-associated viral antigens that can be labeled externally by lactoperoxidase-mediated iodination and it protects the cells against the cytolytic effects of MTV-specific antiserum and complement. Taken together, these results are consistent with the view that while glycosylation of some proteins may be unessential for their compartmentalization and processing, it does appear to be correlated with proper maturation of others. The hormone-dependent maturation of MTV glycoproteins in M1.54 may be particularly useful for study of this latter class since glycosylation is stringently associated with their compartmentalization and cleavage.

Animals↗
PubMed1983

Compartmental relationships between anuran primary spinal motoneurons and somitic muscle fibers that they first innervate.

The compartmental and clonal relationships between primary motoneurons and the myotubes they innervate have been studied in Xenopus laevis embryos by initiating clones at blastula stages (32 to 512 cells) with intracellular injections of horseradish peroxidase (HRP). Primary motoneurons and ventral myotome belong to the posterior-ventral compartment, whereas sensory neurons and dorsal myotome belong to the posterior-dorsal compartment (Jacobson, M. (1983) J. Neurosci. 3: 1019-1038). The pathways of HRP-labeled primary motor axons, which pioneer the peripheral pathway to the adjacent myotome beginning at stage 21/22, were traced. Within the spinal cord, the axons remained in the posterior-ventral compartment. Upon leaving the cord they were confronted with both dorsal and ventral myotome; they remained almost exclusively in the ventral myotome. At late embryonic stages (40/42) primary motoneurons could be retrogradely labeled by applying HRP to the dorsal myotome, indicating that their axons or a branch had crossed the compartmental boundary. The primary motor axon also displayed a highly significant preferred association with clonally related myotubes within the ventral myotome. Axon growth only in the compartmentally related myotome and preferred association with clonally related myotubes suggest that the guidance of pioneer axons in the periphery may be based upon factors derived from common ancestry and lineage.

Animals↗
PubMed1980

Diagnosis and management of compartmental syndromes.

Patients at risk for compartmental syndromes challenge both the diagnostic and the therapeutic abilities of the physician. Suboptimum results may be due to delays in diagnosis and treatment, to incomplete surgical decompression, and to difficulties in the management of the limb after decompression. Although careful clinical assessment permits the diagnosis of a compartmental syndrome in most patients, we have found measurement of tissue pressure and direct nerve stimulation to be helpful for resolving ambiguous or equivocal cases. In our experience, the four-compartment parafibular approach to the leg and the ulnar approach to the volar compartments of the forearm provide efficient and complete decompression of potentially involved compartments. The skeletal stabilization of fractures associated with compartmental syndromes may facilitate management of the limb after surgical decompression.

Adult↗
PubMed1996

A compartmental brain model for chemical transport and CO2 controlled blood flow.

A compartmental transport model is developed, capable of predicting the evolution of CO2, HCO-3 and H+ in the cerebrovascular system. In the model, the transport of these components is simulated at a subset of three compartments: cerebrospinal fluid (CSF), capillary-choroid plexus and brain tissue, belonging to a seven compartmental assembly representing the entire brain. The remaining ones are; artery, vein, venous sinus and jugular bulb. The model accounts for advection associated with non-steady perfusion fluxes across semi-previous boundaries. Pressures, associated with perfusion, are solved in the seven-compartment model. The three-compartment transport model also takes into account changes in compartmental volume due to displacement of its boundaries, diffusion through boundaries and rate of generation of substances by chemical reactions. A first-order reaction rate is assumed in the CSF compartment. A parameter estimation method is then developed to assess boundary diffusivities from time-averaged observed values of perfusion pressure, tension of carbon dioxide, pH values, and concentration of free hydrogen and bicarbonate ions. An equation of state describing the regulation of flow from arteries to capillaries, as a function of CO2 tension in the CSF, is then suggested. Upon solving all coupled mass balance equations, and for a pre-evaluated perfusion pressure in the artery and capillary compartments, one can estimate the change in arteries to capillaries conductance at every time step. Boundary diffusivities between the capillary, cerebrospinal fluid and brain tissue compartments, were estimated. A sensitivity analysis proves the consistency between model predictions and available clinical observations, this, in terms of the influence of the parameter associated with CO2 metabolic rate on CO2 tension. It was shown that decrease of this tension caused an abrupt pressure fall at the first instant which later increased to an asymptotic value. This, however, was not evident in the capillaries at which pressure slightly falls and then remains constant.

Bicarbonates↗
PubMed1996

A compartmental model for alveolar clearance of pertechnegas.

UNLABELLED: The washout of an inhaled water soluble radiotracer from the lungs is a measure of alveolar integrity. Data evaluation of 99mTc-DTPA studies were previously performed mainly with monoexponential fitting with or without background subtraction. The introduction of 99mTc-pertechnegas for the assessment of alveolar permeability necessitates the investigation of adequate data evaluation schemes for this radiotracer. METHODS: We developed a three-compartmental model to describe 99mTc-pertechnegas kinetics after inhalation. Monoexponential fitting of the first 5 min was investigated as simplification for clinical use. Different background corrections based on blood samples or representative regions of interest were compared. RESULTS: Correction of intra- and extravascular background by subtraction of calibrated curves, which are derived from blood or background areas, resulted in monoexponential washout curves. Clearance rates based on the three-compartmental model were nearly the same as those derived from a monoexponential fit after blood-activity subtraction (r = 0.96). A monoexponential analysis of the first 5 min without any background correction correlates well with the first component of the biexponential analysis (r = 0.97). CONCLUSION: A dynamic study of more than 45 min allows quantitative determination of the transfer rate of 99mTc-pertechnegas from the alveoli into the blood using compartmental analysis. A simplified monoexponential analysis of the first 5 min allows assessment of lung clearance without any background correction.

Administration, Inhalation↗
PubMed1998

Quantitative studies of enzyme-substrate compartmentation, functional coupling and metabolic channelling in muscle cells.

Some historical aspects of development of the concepts of functional coupling, metabolic channelling, compartmentation and energy transfer networks are reviewed. Different quantitative approaches, including kinetic and mathematical modeling of energy metabolism, intracellular energy transfer and metabolic regulation of energy production and fluxes in the cells in vivo are analyzed. As an example of the system with metabolic channelling, thermodynamic aspects of the functioning the mitochondrial creatine kinase functionally coupled to the oxidative phosphorylation are considered. The internal thermodynamics of the mitochondrial creatine kinase reaction is similar to that for other isoenzymes of creatine kinase, and the oxidative phosphorylation process specifically influences steps of association and dissociation of MgATP with the enzyme due to channelling of ATP from adenine nucleotide translocase. A new paradigm of muscle bioenergetics-the paradigm of energy transfer and feedback signaling networks based on analysis of compartmentation phenomena and structural and functional interactions in the cell is described. Analysis of the results of mathematical modeling of the compartmentalized energy transfer leads to conclusion that both calcium and ADP, which concentration changes synchronously in contraction cycle, may simultaneously activate oxidative phosphorylation in the muscle cells in vivo. The importance of the phosphocreatine circuit among other pathways of intracellular energy transfer network is discussed on the basis of the recent data published in the literature, with some experimental demonstration. The results of studies of perfused rat hearts with completely inhibited creatine kinase show significantly decreased work capacity and respectively, energy fluxes, in these hearts in spite of significant activation of adenylate kinase system (Dzeja et al. this volume). These results, combined with those of mathematical analysis of the energy metabolism of hearts of transgenic mice with switched off creatine kinase isoenzymes confirm the importance of phosphocreatine pathway for energy transfer for cell function and energetics in mature heart and many other types of cells, as one of major parts of intracellular energy transfer network and metabolic regulation.

Adenine Nucleotides↗
PubMed1996

Mitochondrial- and nuclear-encoded subunits of cytochrome oxidase in neurons: differences in compartmental distribution, correlation with enzyme activity, and regulation by neuronal activity.

Cytochrome oxidase (CO), a mitochondrial energy-generating enzyme, contains both mitochondrial- and nuclear-encoded subunits. In neurons, local levels of CO activity vary among different neuronal compartments, reflecting local demands for energy. The goals of the present study were to determine if compartmental distribution of CO subunit proteins from the two genomes was correlated with local CO activity, and if their expression was regulated proportionately in neurons. The subcellular distributions of mitochondrial-encoded CO III and nuclear-encoded CO Vb proteins were quantitatively analyzed in mouse cerebellar sections subjected to postembedding immunocytochemistry. Local levels of subunit proteins were also compared to local CO activity, as revealed by CO cytochemistry. In order to study the regulation of subunit protein expression, we assessed changes in immunoreactivity of the two CO subunits as well as changes in CO activity in mouse superior colliculus after 1 to 7 days of monocular enucleation. We found that immunoreaction product for both CO III and CO Vb existed almost exclusively in mitochondria, but their compartmental distributions were different. CO III was nonhomogeneously distributed among different neuronal compartments, where its local level was positively correlated with that of CO activity. In contrast, the subcellular distribution of CO Vb was relatively uniform and did not bear a direct relationship with that of CO activity. Moreover, the two subunit proteins were disproportionately regulated by neuronal activity. CO III and CO activity exhibited parallel decreases after the deprivation of afferent input, and their changes were earlier and to a greater degree than that of CO Vb proteins. Thus, the present findings indicate that the local expression and/or distribution of CO subunit proteins from the two genomes may involve different regulatory mechanisms in neurons. Our data also suggest that the activity-dependent regulation of mitochondrial-encoded CO subunits is likely to play a major role in controlling the local levels of CO content and its activity.

Amino Acid Sequence↗
PubMed1998

Cytological compartmentalization in the staggerer cerebellum, as revealed by calbindin immunohistochemistry for Purkinje cells.

The staggerer mouse carries a deletion in a gene encoding the nuclear hormone receptor RORalpha, which leads to severe impairments in phenotypic differentiation of cerebellar Purkinje cells. We previously found parasagittal compartments in the mature staggerer cerebellum, as defined by different transcription levels of Purkinje cell-specific molecules including calbindin. In the present study, we developed a hightiter anti-calbindin antibody to examine morphological features of the staggerer Purkinje cells. Immunohistochemistry for calbindin revealed compartmentalized Purkinje cell populations with different cell sizes, alignments, cell densities, and dendritic arborization, as well as different immunoreactivities, corresponding to the "transcriptional" compartments. Based on these immunohistochemical and cytological characteristics, the rostral cerebellum was clearly subdivided into three to seven parasagittal zones (Zones I-VII). Purkinje cells in Zones I and III were associated with the strongest calbindin immunoreactivities and exhibited morphological features reminiscent of the wild-type cells, i.e., large flask-shaped cell bodies, monolayer alignment, and arborized dendrites. Purkinje cells in Zone V were also labeled strongly, but they were small in cell size, ectopic and possessed long unbranched dendrites. On the other hand, Purkinje cells in Zones II, IV, and VI were very low in calbindin immunoreactivity and marked by small cell size, ectopia, poorly-developed dendrites and low cell density. Considering that this unique cytological compartmentalization emerges as the result of RORalpha gene mutation, it is suggested that normal cytodifferentiation of Purkinje cells is governed by both RORalpha-dependent and -independent mechanisms, and further that the latter mechanism might exert unevenly along the mediolateral cerebellar axis.

Animals↗