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PubMedDate not supplied

Patent ductus arteriousus in the premature neonate: current concepts in pharmacological management.

In utero, the ductus arteriosus shunts deoxygenated blood away from the pulmonary artery and towards the placental circulation where foetal gas exchange occurs. As a result of an intricately intertwined network of both physiological and biochemical changes, this vessel constricts rapidly after birth. Deoxygenated blood is diverted away from the placenta and through the lungs now vital for gas exchange. Premature closure of the ductus in utero can cause pulmonary hypertension and even death. Conversely, failure to close after birth can exacerbate respiratory distress, precipitate congestive heart failure and increase the risk of subsequent intestinal ischaemia leading to necrotising enterocolitis, bronchopulmonary dysplasia, renal hypoperfusion and/or cerebral ischaemia. In this review we summarise current knowledge of the delicately orchestrated control of the ductus arteriosus, focusing on the role of cyclo-oxygenase isoforms on prostaglandin production, on the interaction between prostaglandins and oxygen, and on the effects of these on ductal patency. We also seek to describe some of the standard and nonstandard therapeutic approaches available to the clinician when natural closure fails, reviewing alternative protocols for indomethacin administration and comparing indomethacin treatment with newer approaches such as ibuprofen. In summary, we will follow the course of this unique blood vessel as it is transformed over several hours from an organ absolutely vital to survival into programmed obsolescence.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2006

Microarray tools for deciphering complex diseases.

Individual genetic findings associated with complex diseases are unlikely to fully explain their substantial impact or provide new comprehensive insights into disease pathogenesis. These also lack the comprehensive data much needed for development of new effective drugs in majority of the disease cases in a population. In fact multilevel etiologic factors underlie almost all human diseases, including: environmental causes, epigenetic factors, DNA mutations, amplifications, and deletions, RNA expression levels, protein (translation, post translation modification, localization) and combinations thereof. Each individual might consist of different combinations of these multiple etiologic factors. Integrative evaluation of all these modifications will shed light on the whole identity of the disease and the underlying molecular mechanisms. Until now it was inconceivable to have a full grasp of such a complex etiology. Microarrays enable us to interrogate the individualized various factors (DNA, RNA and protein content) involved in disease state on genome-wide scale simultaneously and expeditiously in single cell or the tissue of interest (Figure 1). The new disciplines of microarray studies in combination hold the promise of effective, current, and comprehensive understanding of complex diseases and may be a good approach for reducing the costs and time lines associated with discovery and efficacy improvement of therapeutic drugs. In the future, through utilizing the colossal amount of microarray data findings, defining the structure, function, and dynamics of entire biological pathways and cellular networks under various physiological states, and the development of robust and efficient methods for analyzing and interpreting high dimensional data, it will be possible to connect combination of experimental results with individualized disease state. This will facilitate precise diagnosis prognosis and therapy.

Alternative Splicing↗
PubMed1999

Epileptogenic action of caffeine during anoxia in the neonatal rat hippocampus.

Excessive maternal caffeine consumption can lead to fetal and neonatal pathology, but the underlying mechanisms have not been determined. Here, we report that low doses of caffeine generate seizures when applied in conjunction with brief anoxic episodes in the hippocampus of neonatal rats in vitro. In control conditions, brief (4-6 minutes) anoxic episodes reversibly depressed evoked synaptic responses and blocked the physiological pattern of network activity. In the presence of caffeine (50 microM), similar anoxic episodes generated ictal (29%) or interictal (33%) epileptiform activities often followed during reoxygenation by recurrent spontaneous seizure activity that persisted for several hours. These effects are likely mediated by a blockade of adenosine receptors by caffeine because (1) in control conditions, caffeine antagonized the inhibitory effect of selective A1 receptor agonist N6-cyclopentyladenosine on excitatory synaptic responses, and (2) epileptogenic effects of caffeine were reproduced by selective A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine and theophylline. Our findings suggest that endogenous adenosine released during anoxia acting via A1 receptors prevents seizures in the neonatal hippocampus and that the antagonism of these receptors by caffeine leads to epileptogenesis. This study suggests concerns about the safety of caffeine in the fetus and newborn.

Action Potentials↗
PubMed2000

[Neuronal and synaptic properties: fundamentals of network plasticity].

Neurons, within the nervous system, are organized in different neural networks through synaptic connections. Two fundamental components are dynamically interacting in these functional units. The first one are the neurons themselves, and far from being simple action potential generators, they are capable of complex electrical integrative properties due to various types, number, distribution and modulation of voltage-gated ionic channels. The second elements are the synapses where a similar complexity and plasticity is found. Identifying both cellular and synaptic intrinsic properties is necessary to understand the links between neural networks behavior and physiological function, and is a useful step towards a better control of neurological diseases.

Animals↗
PubMed1982

Anti-idiotypes to monoclonal anti-H-2 antibodies. III. Syngeneic anti-idiotypes on antibodies induced by in vivo administration of xenogeneic anti-idiotypes.

Idiotype-positive molecules induced by xenogeneic anti-idiotypes (anti-Id) to monoclonal anti-H-2 antibodies were studied using syngeneic anti-Id reagents. Syngeneic reagents detected idiotypes on both H-2 antigen-binding and nonbinding Id' induced by xenogeneic anti-Id. In addition, idiotopes were readily detected by alloimmunization after xenogeneic anti-Id reagents interact with some of the same antibodies as syngeneic anti-Id and support the hypothesis that treatment with xenogeneic anti-Id may affect a physiologically important idiotypic network.

Animals↗
PubMed1993

Galloway Memorial Lecture. Protein engineering of tumor necrosis factor-beta and its applications in cancer, septicaemia and cachexia.

The tumour necrosis factors (TNFs) are cytokines, small proteins produced by cells as part of the intercellular signalling network. The exact physiological role of TNFs is unknown, but interest in them focused on three of their capabilities: as potential anti-tumour agents, as humoral mediators of an organism's response to injury and as effector molecules in cachexia. The first TNF to be described, now known as TNF-alpha, has been relatively well studied because the recombinant protein was easily produced since it was cloned in 1984. Studies on TNF-beta or lymphotoxin were hampered by the inability of most groups to express the recombinant protein. This paper describes the expression and purification of recombinant TNF-beta in Escherichia coli, followed by studies to localise the receptor binding site of the molecule through site-directed mutagenesis. Mutants with single amino acid changes at either of two distinct loop regions, at positions aspartic acid-50 or tyrosine-108, were found to have greatly reduced receptor binding and cytotoxic activity. These two regions in TNF-beta correspond to known loop regions where mutations also result in loss of biological activity of TNF-alpha, a related cytokine which shares the same cellular receptors with TNF-beta. This provides evidence for a new hypothesis that both the TNFs bind to their receptors as trimers, each of which is capable of binding simultaneously to three receptors. This leads further to the intriguing possibility of a new mechanism of receptor clustering through simultaneous binding to a single ligand.

Cachexia↗
PubMed1998

[Our challenge in Kagoshima University Hospital--development of more useful clinical laboratory].

In 1995, we newly developed a clinical laboratory system equipped with an expert system, which was named HIPOCLATES (Hospital Intelligent POwers of Clinical Laboratory Automation Technology with Expert System). Since this system includes an expert system, we have been able to support diagnostic and therapeutic procedure in clinics and begin developing a "zonal verification method" and "early-stage DIC diagnosis support system". The former is one of the individual quality control methods and we have attempted to develop a test assurance system in HIPOCLATES using this method. The latter system is to diagnosis DIC in the early phase. Here, we introduce the detail of our project using HIPOCLATES. Following the introduction HIPOCLATES, we attempted to develop a highly integrated system in physiological examinations, and succeeded in establishment PLATON (Physiological LAboratory TOtal Network system) in 1997. Thereafter, we planned a graphic reporting system named GALIREO (Graphic Assistant Laboratory Informational REport Operating system). In GALIREO, we attempted to connect the Department of Clinical Laboratory, Ultrasonic waves test room, Fiberscope test room, Department of Pathology and Surgical center by computer network. Developing these computer network system in our clinical laboratory we want to create electronic medical record linking with THINK (HIS in our hospital). We plan to make these expert system and electronic medical record available to clinical staff via a network to realize evidence-based medicine (EBM) and utilize these to support treatment and education.

Clinical Laboratory Information Systems↗
PubMed2000

Finite element modeling of human skin using an isotropic, nonlinear elastic constitutive model.

The collagen network in skin is largely responsible for the nonlinear mechanical stress-strain response of skin. We hypothesize that the force-stretch response of collagen is governed by the entropics of long-chain molecules. We show that a constitutive model derived from the statistical mechanics of long-chain molecules, corresponding to the fibrous collagen network in skin, captures the mechanical response of skin. A connection between the physiologically meaningful parameters of network molecular chain density and free length of collagen fibers and the constitutively significant parameters of initial modulus and limiting stretch is thus established. The relevant constitutive law is shown to have predictive capabilities related to skin histology by replicating in vivo and in vitro experimental results. From finite element simulations, this modeling approach predicts that the collagen network in hypertrophic scars is more dense and the constituent collagen fibers have shorter free lengths than in healthy skin. Additionally, the model is shown to predict that as rat skin ages, collagen network density increases and fiber free length decreases. The importance of knowledge of the in situ stress state for analyzing skin response and validating constitutive laws is also demonstrated.

Aging↗
PubMed2003

Application of filter technology in photomorphogenesis gene network.

Light regulates almost all physiological and biochemical processes in plants. Plants react to quantitative and qualitative light characteristics owing to the system of photoreceptors and a branched network for light signal transduction. Comprehensible visual representations of gene networks using of filter technology in the GeneNet system assist understanding the types of the relationships between the components inside the networks and to define their hierarchical structure.

Computational Biology↗
PubMed2002

Integration of concepts: cardiac extracellular matrix remodeling after myocardial infarction.

The cardiac extracellular matrix consists of a three-dimensional structural network of interstitial collagens to which other matrix components are attached. The main physiological functions of this network are to retain tissue integrity and cardiac pump function. Collagen deposition is controlled and can be modulated by hormonal factors, growth factors, cytokines, regulatory proteins and/or hemodynamic factors. Increased collagen deposition is a prerequisite to prevent dilatation of the infarcted area. Excessive accumulation of collagen leads to ventricular diastolic and systolic dysfunction and ultimately contributes to heart failure. An appropriate balance of extracellular matrix synthesis and degradation is required for normal morphogenesis and maintenance of tissue architecture. A disbalance in the extracellular matrix turnover either by decreased matrix synthesis and/or increased degradation leads to less than normal extracellular matrix in the myocardium which in its turn may lead to cardiac dilatation or even rupture. Extracellular matrix degrading enzymes expressed after myocardial infarction belong to the families of serine and matrix metalloproteinases (MMPs) and are secreted as latent proenzymes that have to be activated. It is crucial to keep the activity of these enzymes under tight control by either influencing the synthesis, activation or inhibition by tissue inhibitors of MMPs (TIMPs) or alpha2-macroglobulin. First studies using MMP inhibitors in experimental models of myocardial infarction seem to give attenuation of ventricular geometry but not always improvement of cardiac function. A central role in the activation of MMPs plays the plasminogen-plasmin system. Invasion of inflammatory cells and hitherto the rest of the wound healing cascade is inhibited in plasminogen or uPA deficient mice, most likely by the inhibition of MMP activity. Regulating the balance of extracellular matrix remodeling either by extracellular matrix synthesis or degradation might be one of the possible prevention mechanisms for heart failure. But also regeneration of the vascular and cardiomyocyte network might be potential new treatments for people with heart failure.

Animals↗
PubMed2006

Role of nuclear lamina-cytoskeleton interactions in the maintenance of cellular strength.

The response of individual cells to cellular stress is vital for cellular functioning. A large network of physically interconnected cellular components, starting from the structural components of the cells' nucleus, via cytoskeleton filaments to adhesion molecules and the extracellular matrix, constitutes an integrated matrix that functions as a scaffold allowing the cell to cope with mechanical stress. Next to a role in mechanical properties, this network also has a mechanotransductional function in the response to mechanical stress. This signaling route does not only regulate a rapid reorganization of structural components such as actin filaments, but also stimulates for example gene activation via NFkappaB and other transcription factors. The importance of an intact mechano-signaling network is illustrated by the physiological consequences of several genetic defects of cellular network components e.g. actin, dystrophin, desmin and lamins. These give rise to an impaired response of the affected cells to mechanical stress and often result in dystrophy of the affected tissue. Recently, the importance of the cell nucleus in cellular strength has been established. Several new interconnecting proteins, such as the nesprins that link the nuclear lamina to the cytoskeleton, have been identified. Furthermore, the function of nuclear lamins in determining cellular strength and nuclear stability was illustrated in lamin-knock-out cells. Absence of the A-type lamins or mutations in these structural components of the nuclear lamina lead to an impaired cellular response to mechanical stress and disturbances in cytoskeletal organization. In addition, laminopathies show clinical phenotypes comparable to those seen for diseases resulting from genetic defects in cytoskeletal components, further indicating that lamins play a central role in maintaining the mechanical properties of the cell.

Animals↗
PubMed2003

Gene expression in chondrocytes assessed with use of microarrays.

BACKGROUND: Despite considerable limitations such as low sensitivity and insensitivity to alternative splicing, posttranscriptional regulation, and posttranslational modification, cDNA array technology provides a powerful tool with which to obtain an overview of gene expression patterns, hardly achievable with other techniques. This has been shown to be true for the analysis of known genes as well as the discovery of new genes of interest. METHODS: Samples of normal and late-stage osteoarthritic cartilage of human knee joints were analyzed with use of the Human Cancer 1.2 cDNA-array and TaqMan analysis. RESULTS: In spite of a large variability of expression levels among different patients, significant expression patterns for many known genes of interest such as cartilage matrix proteins (e.g., collagen types II, VI, and XI; aggrecan; decorin; biglycan) and matrix-degrading proteases were detected. Of the latter, MMP-3 appeared to be strongly expressed in normal and early degenerative cartilage and downregulated in the late disease stages. This indicates that, in the late stages of cartilage degeneration, other degradation pathways might be more important, for example, those involving enzymes such as MMP-2 and MMP-13, both of which were upregulated in late-stage disease. CONCLUSION: Most results have to be considered to be preliminary to a certain degree, as technical tools and interpretation approaches are still emerging and need more validation. Clearly, there is a major challenge to distill information and knowledge out of the obtained mass of data. However, these data will be one basis of a new world of biological understanding. These new insights will be network-based and no longer molecule-centered. Today, molecules have a biochemical and physiological context; tomorrow, biological networks will have molecules as constituents.

Adult↗
PubMed1994

Trends in physiological role of opioids in psychoneuroendocrine-immune network.

Extensive evidence suggests that opioid influences on the immune response are mediated through opioid receptors on the surface of immune cells. In addition, the binding of opioid agonists to centrally located opioid receptors appears also to alter immune activity through interactions with the neuroendocrine and the nervous systems. Finally, other findings summarized in this review provide evidence consistent with the hypothesis that under stressful stimuli, the immune system is altered through the interrelations among the neuroendocrine system, the sympathetic nervous system and central opioidergic pathways.

Animals↗
PubMed2004

Essentiality and damage in metabolic networks.

Understanding the architecture of physiological functions from annotated genome sequences is a major task for postgenomic biology. From the annotated genome sequence of the microbe Escherichia coli, we propose a general quantitative definition of enzyme importance in a metabolic network. Using a graph analysis of its metabolism, we relate the extent of the topological damage generated in the metabolic network by the deletion of an enzyme to the experimentally determined viability of the organism in the absence of that enzyme. We show that the network is robust and that the extent of the damage relates to enzyme importance. We predict that a large fraction (91%) of enzymes causes little damage when removed, while a small group (9%) can cause serious damage. Experimental results confirm that this group contains the majority of essential enzymes. The results may reveal a universal property of metabolic networks.

Computer Simulation↗
PubMed1991

Network antibodies identify nuclear lamin B as a physiological attachment site for peripherin intermediate filaments.

We studied the molecular associations between peripherin (a neuronal, type III intermediate filament subunit) and nuclear lamins. We show here that isolated peripherin binds selectively to mammalian lamin B under in vitro conditions. We further demonstrate that a synthetic peptide, representing the proximal part of peripherin's tail domain (P1), also associates with mammalian lamin B in a saturable, cooperative, and specific fashion. Laboratory animals immunized with P1 spontaneously develop idiotypic and anti-idiotypic antibodies recognizing peripherin and lamin B, respectively. These data provide essentially in vivo evidence that lamin B represents a constitutive nuclear "receptor" site for the tail domains of peripherin intermediate filaments.

Amino Acid Sequence↗
PubMed2004

Distinct roles for the kainate receptor subunits GluR5 and GluR6 in kainate-induced hippocampal gamma oscillations.

Kainate receptors (KARs) play an important role in synaptic physiology, plasticity, and pathological phenomena such as epilepsy. However, the physiological implications for neuronal networks of the distinct expression patterns of KAR subunits are unknown. Using KAR knock-out mice, we show that subunits glutamate receptor (GluR) 5 and GluR6 play distinct roles in kainate-induced gamma oscillations and epileptiform burst activity. Ablation of GluR5 leads to a higher susceptibility of the network to the oscillogenic and epileptogenic effects of kainate, whereas lack of GluR6 prevents kainate-induced gamma oscillations or epileptiform bursts. Based on experimental and simulated neuronal network data as well as the consequences of GluR5 and GluR6 expression for cellular and synaptic physiology, we propose that the functional interplay of GluR5-containing KARs on axons of interneurons and GluR6-containing KARs in the somatodendritic region of both interneurons and pyramidal cells underlie the oscillogenic and epileptogenic effects of kainate.

Animals↗
PubMed1995

Modulation of neural network activity in vitro by cyclothiazide, a drug that blocks desensitization of AMPA receptors.

To determine whether AMPA receptor channel desensitization has a physiological role in shaping network activity by modulating signal transmission through excitatory circuits, we examined the effects of cyclothiazide (CYT), the most potent known blocker of AMPA receptor desensitization, on the behavior of an endogenously active neural system in vitro, the brainstem network generating rhythmic respiratory oscillations in neonatal rat medullary slices. Bath application of 100 microM CYT significantly increased the frequency of endogenously generated rhythm and increased the amplitude of the circuit output [i.e., discharge of hypoglossal (XII) respiratory motoneurons]. Local application of CYT within the XII motor nucleus produced a concentration-dependent increase (up to 35%) in amplitude of the motoneuron population discharge as well as an increase in the peak current (23%) and total charge transfer of the rhythmic inspiratory synaptic drive (33%) to individual XII motoneurons. CYT also acted postsynaptically to increase the amplitude of spontaneous EPSCs in motoneurons. In addition, CYT produced a profound, long-term augmentation of network frequency and motor output that may be secondary to block of desensitization. These results suggest that AMPA receptor desensitization has functionally significant effects on the temporal behavior and output of the rhythmic, respiratory neural network, and, by extrapolation, on other integrative actions of the mammalian CNS.

Animals↗
PubMed2001

Activity of cardiorespiratory networks revealed by transsynaptic virus expressing GFP.

A fluorescent transneuronal marker capable of labeling individual neurons in a central network while maintaining their normal physiology would permit functional studies of neurons within entire networks responsible for complex behaviors such as cardiorespiratory reflexes. The Bartha strain of pseudorabies virus (PRV), an attenuated swine alpha herpesvirus, can be used as a transsynaptic marker of neural circuits. Bartha PRV invades neuronal networks in the CNS through peripherally projecting axons, replicates in these parent neurons, and then travels transsynaptically to continue labeling the second- and higher-order neurons in a time-dependent manner. A Bartha PRV mutant that expresses green fluorescent protein (GFP) was used to visualize and record from neurons that determine the vagal motor outflow to the heart. Here we show that Bartha PRV-GFP-labeled neurons retain their normal electrophysiological properties and that the labeled baroreflex pathways that control heart rate are unaltered by the virus. This novel transynaptic virus permits in vitro studies of identified neurons within functionally defined neuronal systems including networks that mediate cardiovascular and respiratory function and interactions. We also demonstrate superior laryngeal motorneurons fire spontaneously and synapse on cardiac vagal neurons in the nucleus ambiguus. This cardiorespiratory pathway provides a neural basis of respiratory sinus arrhythmias.

Animals↗