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PubMed1989

Correlated functional and structural analysis of enteric neural circuits.

Views about the roles and nature of the enteric nervous system have changed dramatically in the last ten years. This system of neurons is recognized to control, through reflex pathways intrinsic to the gut wall, motility, transport of water and electrolytes, and blood flow in the small and large intestines. There are thus a range of neuron types in the enteric nervous system, including sensory neurons, motor neurons, and interneurons, involved in the control of each of these functions. The present paper deals with the recent efforts to provide an integrated functional and structural description of the nerve circuits. One of the challenges in this quest has been to identify primary sensory neurons and final motor neurons involved in motility control. Evidence is presented that in the guinea-pig small intestine the primary sensory neurons have Dogiel type II morphology and are, electrophysiologically, AH neurons. They send circumferential processes to adjacent myenteric ganglia and some of them, at least, have processes leading from the mucosa. Motor neurons are S neurons, with cell bodies in the myenteric plexus. Those that supply the circular muscle are Dogiel type I neurons and provide processes that run circumferentially for about one third of the circumference of the intestine. The circuits for secretomotor reflexes have been partly worked out. The secretomotor neurons have cell bodies in the submucous ganglia and are activated to return water and electrolytes to the lumen during digestion. The secretomotor reflexes are regulated, in accord with whole body water and electrolyte homeostasis, via sympathetic neurons which lower the excitability of secretomotor neurons.

Animals↗

PubMed2005

Enhancing dynamic graphical analysis with the Lisp-Stat language and the ViSta statistical program.

Presented is a sample of computerized methods aimed at multidimensional scaling and psychometric item analysis that offer a dynamic graphical interface to execute analyses and help visualize the results. These methods show how the Lisp-Stat programming language and the ViSta statistical program can be jointly applied to develop powerful computer applications that enhance dynamic graphical analysis methods. The feasibility of this combined strategy relies on two main features: (1) The programming architecture of ViSta enables users to add new statistical methods as plug-ins, which are integrated into the program environment and can make use of all the functions already available in ViSta (e.g., data manipulation, editing, printing); and (2) the set of powerful statistical and graphical functions integrated into the Lisp-Stat programming language provides the means for developing statistical methods with dynamic graphical visualizations, which can be implemented as ViSta plug-ins.

Computer Graphics↗

PubMed2003

Functional blocks in caspase activation pathways are common in leukemia and predict patient response to induction chemotherapy.

Defects in apoptosis mechanisms contribute to chemoresistance in malignancy. However, correlations of apoptosis-regulating proteins with clinical outcome in cancer patients are variable, presumably reflecting the difficulty of using static tests of gene expression in a scenario influenced by a dynamic interplay of multiple pro- and antiapoptotic molecules. Therefore, we assessed the functional integrity of apoptosis pathways in intact primary leukemia cells and correlated the functional status of these pathways with clinical outcome. Active apoptogenic proteins were introduced into primary leukemia cells by electroporation followed by measurement of active caspases by flow cytometric techniques. Cytochrome c was introduced to activate the intrinsic (mitochondrial) pathway, whereas caspase-8 was introduced to activate the extrinsic (death receptor) pathway. In a series of 24 patients with acute myeloid leukemia, 79% had a block in at least one pathway, indicating that defects in caspase activation mechanisms are common in patients with leukemia. Simultaneous blocks in both pathways correlated with chemoresistant disease (92% of patients with chemoresistant disease versus 33% of patients with chemosensitive disease; P = 0.005) and decreased overall patient survival (35% versus 89% 1-year survival; P = 0.02). Simultaneous blockage of the intrinsic and extrinsic pathways could be explained by a defect located at a point of convergence of the two pathways, probably related to overexpression of endogenous inhibitors of the effector-caspases, rather than decreased levels of these proteases. This study supports the importance of apoptosis pathways in determining response to chemotherapy and suggests that functional defects in caspase activation are prognostic in patients with leukemia.

Adult↗

PubMed2005

Hyperplasia of the colonic neuroendocrine cells after pinealectomy in rats. The new evidence for the existence of connections between the distant parts of the diffuse neuroendocrine system.

OBJECTIVES: The diffuse neuroendocrine system (DNES) participates in the systemic homeostasis and may work as a unified system with integrated functions but anatomically disperse. However, the mechanisms that are involved in the integration of the distant parts of the DNES are poorly known. This study is aimed on the effects of a pinealectomy on the population of the neuroendocrine cells (NECs) in the colon of rats. METHODS: A group of seven newborn rats and one of adult rats were submitted to a pinealectomy. The animals were sacrificed after 15 days and 90 days, respectively. The control groups of adult and newborn rats were subjected to a 'sham surgery' and then sacrificed after similar periods of time. Paraffin-included sections of the colon samples were stained by the Churukian-Schenk method in order to selectively stain the NECs. The NEC index was estimated by the expression: iNEC = NECs population per crypt/Total cell population of the crypt. The results were expressed as median and absolute range, and the statistical significance was demonstrated by the Mann-Whitney (U) test. RESULTS: The morphometric analysis showed a significant increase in the number of colonic NECs of the adult rats subjected to a pinealectomy when compared to the controls. No statistical difference was observed between the iNECs of the newborn groups of rats. CONCLUSION: This finding suggests the existence of regulatory mechanisms that integrate distant parts of the DNES, by adapting the population of the endocrine cells after the ablation of an important component of the system. Further studies on the mechanisms involved in the integration of the DNES may be facilitated by the simple experimental model that we propose.

Aging↗

PubMed1995

Increased production of inositol phosphates and diacylglycerol in aged cognitively impaired rats after stimulation of muscarinic, metabotropic-glutamate and endothelin receptors.

Investigations of the functional integrity of receptor-mediated signal transduction are crucial to the understanding of the biochemical cascade underlying memory deficits and neurodegenerative processes of normal and pathological aging. In order to evaluate possible alterations in intracellular transduction components in aging, we studied two groups of 24- to 25-month-old Long-Evans rats selected on the basis of their cognitive performance in the Morris maze task, the aged, cognitively impaired (AI) and cognitively unimpaired (AU) animals. Production of diacylglycerol and inositol phosphates (IPs), two intracellular metabolites generated by the hydrolysis of phosphatidylinositol, were measured in selected brain areas after stimulation by various receptor agonists (1 mM carbachol, muscarinic receptors; 100 microM trans-1-aminocyclopentane-1, 3-dicarboxylate, metabotropic-glutamatergic receptors and 100 nM endothelin-1). Diacylglycerol and IPs were measured following the respective incorporation of [3H]cytidine and [3H]inositol. Data suggest that the stimulation of the inositide cascade via these receptors is at least preserved, or potentiated in the hippocampus and cortex of AI animals. Significant increases in [3H]cytidine and [3H]inositol incorporations were seen in these regions in AI vs. AU and young animals. It remains to be established if these modifications are related directly to the cognitive abilities of the aged rat as AU rats were often comparable to young animals in regard to inositide production. However, higher levels of incorporation in the AI group could reflect modifications in membrane fluidity and possibly increases in IP turnover. Because the IP cascade regulates intracellular Ca++ homeostasis, alterations of this pathway could have complex effects on normal cellular integrity as Ca++ equilibrium must be maintained for adequate neuronal viability and functions.

Aging↗

PubMed1994

Ca2+ homeostasis and mitochondrial bioenergetics in Trypanosoma cruzi.

Digitonin can be used to selectively permeabilize the plasma membrane of Trypanosoma cruzi without significantly affecting the functional integrity of mitochondria or the endoplasmic reticulum. This permits the study of functional properties of these subcellular organelles in situ, such as respiration, oxidative phosphorylation and Ca2+ transport. The ability of these cells to take up and hydrolyze Fura-2/AM, followed by the retention of the fluorescent Ca2+ indicator Fura-2, permits the determination of cytosolyc free Ca2+ concentrations in different T. cruzi stages.

Animals↗

PubMed1997

Organ preservation. An effective and safe form of cancer treatment.

In this article we review the current strategies for organ preservation in the treatment of cancer. Organ preservation with functional integrity is particularly beneficial for older patients because the need for complex functional rehabilitation and for the care of permanent stomas may be avoided.

Aged↗

PubMedDate not supplied

Altered basement membrane synthesis in the testis after tissue injury.

The basement membrane plays an important role in maintaining the structural and functional integrity of tissues. Altered basement membrane structure has been associated with severe functional impairment of the testis in several conditions, including vasectomy, autoimmune orchitis, cryptorchidism, and following x-irradiation. We have used efferent duct ligation as a model to examine seminiferous tubular basement membrane morphology, synthesis, and gene expression to determine whether altered basement membrane synthesis is responsible for the aberrant structures noted after tissue injury. On days 2 and 3 after ligation, both the seminiferous epithelium and the basement membrane appeared normal, but 7 days after ligation, the seminiferous epithelium began to degenerate. The basement membrane appeared detached from the epithelium, and redundant patches of basement membrane were observed adjacent to the Sertoli cells at 14 and 21 days postligation. Immunoprecipitation indicated an increase in laminin protein synthesis in the ligated tubules at the same time. Northern blot analysis showed increases in transcript levels for laminin as well as collagen IV and heparan sulfate proteoglycan. These data show that new protein synthesis is responsible, at least in part, for the duplication of the basement membrane coincident with the tissue damage caused by efferent duct ligation.

Animals↗

PubMed2006

[Dissociative disorders: clinical, neurobiological and therapeutical approaches].

Dissociation is a dysfunction of normally integrated functions like memory, consciousness and perception of environment. This review discusses the clinical and etiological issues of dissociative disorder and highlights the importance of differential diagnosis and psychiatric comorbidities, with special attention for the development of reliable evaluation instruments and treatment guidelines. New approaches of dissociative disorder focus on the importance of the integration of anatomical and functional neuroimaging data, combined with endocrinological and biological studies (lipids), in order to develop some specific neurobiological models. Beyond the inherent singularity of psychotherapeutic intervention, the therapeutic approach varies according to frequently associated comorbidities.

Diagnosis, Differential↗

PubMed2004

A microassay for measurement of Fc function of human immunoglobulin preparations by using tetanus toxoid as antigen.

In order to minimize possible adverse reactions, the functional integrity of proteins in products derived from human plasma has to be unaffected by methods of preparation and storage conditions. Numerous biologically relevant functions of IgG, a major component of immunoglobulin for intravenous use preparations (IVIG), rely on the integrity of Fc fragments. Manufacturers are obliged to prove that Fc-mediated functions are maintained in IVIG preparations. The European Pharmacopoeia's monograph proposes a Rubella antigen-based test for Fc function of immunoglobulins. We present a modification of the proposed method achieved by using more convenient and readily available tetanus toxoid as an alternative antigen target and by adapting the procedure for the use on microtitre plates, thus greatly enhancing its feasibility and sample throughput. The test conditions were optimized so that batch-to-batch variability in tetanus antibody content did not influence the result. The precision of the test was within +/- 5%. By using this test, we compared Fc functionality of 9 commercial IVIG-7S preparations, which were prepared by using different virus inactivation/removal approaches. No significant differences between them have been found.

Antibody Formation↗

PubMed1995

Membrane topology of P-glycoprotein as determined by epitope insertion: transmembrane organization of the N-terminal domain of mdr3.

P-Glycoproteins (P-gps) are membrane glycoproteins encoded by the mdr gene family, and their overexpression is associated with multidrug resistance (MDR). Sequence analyses of mdr cDNAs predict a protein formed by two symmetrical halves, each composed of six transmembrane (TM) segments and one ATP-binding domain. To determine the topology of the N-terminal half of P-gp, a small antigenic peptide epitope (YPYDVPDYAIEGR) containing part of the hemagglutinin (HA) of influenza virus was inserted at six different positions of the Mdr3 protein (101, 161, 206, 244, 320, and 376). Functional integrity of the modified proteins was tested by measuring their capacity to confer MDR in Chinese hamster ovary cells. Intracellular and extracellular localization of the tag in the full-length protein was determined in intact or permeabilized cells by immunofluorescence using a mouse monoclonal antibody (12CA5) specific for the HA epitope. While insertions at positions 101, 161, 320, and 376 did not alter P-gp function, insertions at positions 206 and 244 abrogated the capacity of P-gp to confer drug resistance. The epitope tags inserted at positions 161 and 376 were found to be located intracellularly, whereas the tags at positions 101 and 320 were located on the extracellular side of the membrane. These results indicate that the intervening segments separating predicted TM1-TM2 and TM5-TM6 correspond to extracellular regions, while the segments linking TM2-TM3 and the one located downstream of TM6 correspond to intracellular regions. These results are consistent with a six TM domain model for the N-terminal half of P-gp with an extracellular glycosylated region (TM1-TM2) and an intracellular ATP-binding site (downstream TM6). Epitope insertion in segments linking TM3-TM4 and TM4-TM5 caused a loss of P-gp function, suggesting that the integrity of these sequences is essential either for drug transport or for proper maturation and accurate targeting of P-gp to the plasma membrane.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1989

Effects of amphotericin B on the excretory function and the colloid clearance capacity of the perfused rat liver.

The effects of amphotericin B (AmB) on the hepatic excretory function and the colloid clearance capacity were investigated in the perfused rat liver. AmB at 5 or 10 microM caused dose-dependent reductions in bile and perfusate flow rates and in biliary bile acid (BA) excretion. BA concentration in bile tended to increase, due to a prominent reduction in bile water induced by the drug. At 5 microM, AmB also caused an increase in [14C]sucrose clearance by the liver and a release of hepatocytic enzymes into the perfusate. These alterations were not related to the decrease in the perfusate flow induced by AmB. In addition, the drug, at 5 microM, caused a significant decrease in the colloidal carbon clearance by the liver. In this case also, the effect was independent of the reduction in the perfusate flow induced by the drug. The toxic effects of AmB on the rat liver could be interpreted as a derangement of the cell membrane functional integrity, which causes cholestasis, enzyme leakage and an impairment of the reticuloendothelial system function. This latter effect deserves careful evaluation of its clinical implications.

Amphotericin B↗

PubMed2006

Heavy neurofilament accumulation and alpha-spectrin degradation accompany cerebellar white matter functional deficits following forebrain fluid percussion injury.

Evidence for diffuse traumatic axonal injury (TAI) in clinical cases and animal models of traumatic brain injury (TBI) indicate that pathophysiological mechanisms extend to regions remote from the injury epicenter. The potential for indirect cerebellar trauma contributing to TBI pathophysiology is of significance since impairment of motor function and coordination is a common consequence of TBI but is also a domain associated with cerebellar function. The relationship between cerebellar white matter structure and function following traumatic head injury has not been examined. Using the fluid percussion injury (FPI) device applied unilaterally in the forebrain, evoked compound action potential (CAP) recordings from cerebellar white matter of Sprague-Dawley rats indicated a spatial and temporal pattern of electrophysiological deficits throughout the cerebellar vermis. The posterior and middle lobules of the cerebellum exhibited significant declines in evoked CAP amplitude compared to sham controls (p=0.004, p=0.005, respectively). Duration of the CAP decay also increased, suggesting that functional white matter deficits were a combination of axonal loss and compromised axonal integrity. Functional white matter deficits persisted at 14 days post-injury in the posterior and middle regions of the cerebellum. Evidence of heavy chain neurofilament (NF200) degradation was observed at 1 day post-injury by Western blot. Immunohistochemistry labeling for NF200 indicated the presence of highly immunoreactive NF200 axonal swellings consistent with morphological features of TAI. alpha-Spectrin degradation was also observed between 1 and 14 days post-injury. This study demonstrates the electrophysiological consequences of cerebellar white matter injury and a temporal profile of NF200 and spectrin degradation following forebrain FPI.

Action Potentials↗

PubMed2000

Toward a quantitative description of large-scale neocortical dynamic function and EEG.

A general conceptual framework for large-scale neocortical dynamics based on data from many laboratories is applied to a variety of experimental designs, spatial scales, and brain states. Partly distinct, but interacting local processes (e.g., neural networks) arise from functional segregation. Global processes arise from functional integration and can facilitate (top down) synchronous activity in remote cell groups that function simultaneously at several different spatial scales. Simultaneous local processes may help drive (bottom up) macroscopic global dynamics observed with electroencephalography (EEG) or magnetoencephalography (MEG). A local/global dynamic theory that is consistent with EEG data and the proposed conceptual framework is outlined. This theory is neutral about properties of neural networks embedded in macroscopic fields, but its global component makes several qualitative and semiquantitative predictions about EEG measures of traveling and standing wave phenomena. A more general "metatheory" suggests what large-scale quantitative theories of neocortical dynamics may be like when more accurate treatment of local and nonlinear effects is achieved. The theory describes the dynamics of excitatory and inhibitory synaptic action fields. EEG and MEG provide large-scale estimates of modulation of these synaptic fields around background levels. Brain states are determined by neuromodulatory control parameters. Purely local states are dominated by local feedback gains and rise and decay times of postsynaptic potentials. Dominant local frequencies vary with brain region. Other states are purely global, with moderate to high coherence over large distances. Multiple global mode frequencies arise from a combination of delays in corticocortical axons and neocortical boundary conditions. Global frequencies are identical in all cortical regions, but most states involve dynamic interactions between local networks and the global system. EEG frequencies may involve a "matching" of local resonant frequencies with one or more of the many, closely spaced global frequencies.

Cerebral Cortex↗

PubMed2000

Is there an evolutionary mismatch between the normal physiology of the human dopaminergic system and current environmental conditions in industrialized countries?

A large body of evidence has recently defined a field theory known as 'evolutionary mismatch', which derives its attributes largely from the fact that current environmental conditions are completely different from those in which the human central nervous system evolved. Current views on the evolutionary mismatch theory lack, however, any attempts to define which brain areas or neuronal circuits should be mostly involved in coding such misevolved traits and to what extent our neurobiological knowledge can be applied to the topographical localization of a specific psychopathology. In this respect the mesocorticolimbic dopaminergic circuits have long been misconceptualized as simple reward or reinforcement systems. Instead, they motivate and coordinate the functions of the higher brain areas that mediate planning and foresight and direct finalized movement in both animals and humans. These systems make animals intensely interested in exploring the world around them, but by the same means they also make them susceptible to the environmental stimuli that have been sought and consumed. It is has been speculated that the cortical dopamine targets that developed most recently in phylogeny are of particular functional value, and that the mesocorticolimbic dopaminergic system is involved in more complex integrative functions than previously assumed. In the present paper I will argue that some mental disorders may have their deep roots in the evolutionary mismatch between the normal physiology of the mesocorticolimbic dopaminergic system and the current environmental conditions in affluent societies.

Animals↗

PubMed1996

Disruption of muscle architecture and myocardial degeneration in mice lacking desmin.

Desmin, the muscle specific intermediate filament (IF) protein encoded by a single gene, is expressed in all muscle tissues. In mature striated muscle, desmin IFs surround the Z-discs, interlink them together and integrate the contractile apparatus with the sarcolemma and the nucleus. To investigate the function of desmin in all three muscle types in vivo, we generated desmin null mice through homologous recombination. Surprisingly, desmin null mice are viable and fertile. However, these mice demonstrated a multisystem disorder involving cardiac, skeletal, and smooth muscle. Histological and electron microscopic analysis in both heart and skeletal muscle tissues revealed severe disruption of muscle architecture and degeneration. Structural abnormalities included loss of lateral alignment of myofibrils and abnormal mitochondrial organization. The consequences of these abnormalities were most severe in the heart, which exhibited progressive degeneration and necrosis of the myocardium accompanied by extensive calcification. Abnormalities of smooth muscle included hypoplasia and degeneration. The present data demonstrate the essential role of desmin in the maintenance of myofibril, myofiber, and whole muscle tissue structural and functional integrity, and show that the absence of desmin leads to muscle degeneration.

Animals↗

PubMed2001

DNA-bound transcription factor complexes analysed by mass-spectrometry: binding of novel proteins to the human c-fos SRE and related sequences.

Transcription factors control eukaryotic polymerase II function by influencing the recruitment of multiprotein complexes to promoters and their subsequent integrated function. The complexity of the functional 'transcriptosome' has necessitated biochemical fractionation and subsequent protein sequencing on a grand scale to identify individual components. As a consequence, much is now known of the basal transcription complex. In contrast, less is known about the complexes formed at distal promoter elements. The c-fos SRE, for example, is known to bind Serum Response Factor (SRF) and ternary complex factors such as Elk-1. Their interaction with other factors at the SRE is implied but, to date, none have been identified. Here we describe the use of mass-spectrometric sequencing to identify six proteins, SRF, Elk-1 and four novel proteins, captured on SRE duplexes linked to magnetic beads. This approach is generally applicable to the characterisation of nucleic acid-bound protein complexes and the post-translational modification of their components.

Amino Acid Sequence↗

PubMed1988

Densely calcified adrenals with preserved cortical function.

A patient with preserved adrenocortical function despite densely calcified adrenals is described. Similar cases have demonstrated a discrepancy between the apparent destruction of the glands, as judged by the extent of calcification radiographically, and their functional integrity. This case provided a unique opportunity to compare the results of adrenal function testing, adrenal appearance by computed tomograms, and adrenal histology with an actual clinical response to a variety of stresses capable of precipitating acute adrenal insufficiency.

Adrenal Cortex Function Tests↗