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PubMed1998

Interactions between scatter factors and their receptors: hints for therapeutic applications.

The scatter factors, which include hepatocyte growth factor and macrophage stimulating protein, stand out from other cytokines because of their uncommon biological properties. In addition to promoting cell growth and protection from apoptosis, they are involved in the control of cell dissociation, migration into extracellular matrices, and a unique process of differentiation called 'branching morphogenesis'. Through the concerted regulation of these complex phenomena, scatter factors promote development, regeneration, and reconstruction of normal organ architecture. In transformed epithelia, scatter factors can mediate tumor invasive growth, a harmful feature of neoplastic progression in which cancer cells invade surrounding tissues, penetrate across the vascular walls, and eventually disseminate throughout the body, giving rise to systemic metastases. A much-debated issue in basic biology, which has strong implications for experimental medicine, is how to dissociate the favorable effects of growth factors from their adverse ones. Accordingly, to find agonists or antagonists with potential therapeutic applications is a crucial undertaking for current research. Domain-mapping analyses of growth factor molecules can help to isolate specific structural requirements for the induction of selective biological effects. Based on the observation that certain growth factors must undergo posttranslational modifications to exert a full response, it is possible to interfere with their activation mechanisms to modulate their functions. Finally, the identification of cell type-specific coreceptors able to potentiate their activity allows drawing of a functional body map, where some organs or tissues may be more responsive than others to growth factors. This review is focused on how, and to what extent, scatter factors can behave 'well' or 'badly' according to their molecular structure, the way they are activated, and the way they interact with cell surface receptors and coreceptors.

Amino Acid Sequence↗
PubMed2004

A neural model of quantity discrimination.

A neural network model is proposed with the ability to extract abstract numerical representation from visual input. It simulates properties of a number detection system which is hypothesized to underlie simple language-independent numerical abilities. The network has three layers where the first layer computes the sum of the nearest neighbour inputs. The first layer is also augmented with multiplicative gating and gradient tonic activation which prevents interference. The second layer implements local lateral inhibition which enables a single node to represent a single object. The third layer exhibits number-tuning similar to recently described responses of neurons in the prefrontal cortex. Computer simulations showed that network response does not depend on visual attributes like the object's size, position or shape. The model is based on several biophysical mechanisms such as multiplicative interaction on dendrites, independent processing on different dendritic branches and disinhibition by glutamate spill-over on kainate receptors on inhibitory axons.

Animals↗
PubMed2000

Observation of B --> K(+/-) pi(0) and B --> (K)0 pi(0), and evidence for B --> pi(+)pi(-).

We have studied charmless hadronic decays of B mesons into two-body final states with kaons and pions and observe three new processes with the following branching fractions: beta(B-->pi(+)pi(-)) = (4.3(+1. 6)(-1.4)+/-0.5)x10(-6), beta(B-->K(0)pi(0)) = (14.6(+5.9+2.4)(-5.1-3. 3))x10(-6), and beta(B-->K(+)/-pi(0)) = (11.6(+3.0+1.4)(-2.7-1.3))x10(-6). We also update our previous measurements for the decays B-->K(+)/-pi(-/+) and B+/--->K(0)pi(+/-).

Journal Article↗
PubMed2004

First observation of four-body breakup in electron recombination: C2D+5.

We report the first observation of four-body breakup in electron dissociative recombination of a molecular ion: C2D+5. In an ion storage ring experiment, the branching ratio for the process C2D+5 + e(-)-->C2D2 + D + D + D was determined to be 13%. This means that three covalent chemical bonds are broken as a result of the action of a single electron. This is the first time a four-body breakup of chemical bonds has been observed in a low-energy binary reaction.

Journal Article↗
PubMed1997

Alcohol-induced bone disease: impact of ethanol on osteoblast proliferation.

The habitual consumption of even moderate quantities of alcohol (1 to 2 drinks/day) is clearly linked with reduced bone mass (osteopenia). Biochemical and histological evaluation of patients with alcoholic bone disease reveal a marked impairment in bone formation in the face of relatively normal bone resorption. Experiments using well-defined osteoblastic model systems indicate that the observed reductions in bone formation result from a direct, antiproliferative effect of ethanol on the osteoblast itself. As bone remodeling and mineralization are dependent on osteoblasts, it follows that the deleterious effect of alcohol on these cells would result in slowed bone formation, aberrant remodeling of skeletal tissue and, ultimately, osteopenia and fractures. The skeletal consequences of alcohol intake during adolescence, when the rapid skeletal growth ultimately responsible for achieving peak bone mass is occurring, may be especially harmful. The specific subcellular mechanisms whereby ethanol inhibits cell proliferation are, as yet, unknown. During the last few years, attention has shifted from nonspecific membrane perturbation effects to actions on certain signaling proteins. Specifically, there is increasing evidence that ethanol may exert significant effects on transmembrane signal transduction processes that constitute major branches of cellular control mechanisms. At present, abstinence is the only effective therapy for alcohol-induced bone disease. An improved understanding of the pathogenesis of alcohol-induced bone disease may eventually result in alternative therapeutic avenues for those who are unable to abstain.

Alcohol Drinking↗
PubMedDate not supplied

A new dissection technique for approach to right-sided intrahepatic portosystemic shunts: anatomic study and use in three dogs.

OBJECTIVE: To determine the feasibility of indirect suture passage around the right portal vein for attenuation of right-sided intrahepatic portosystemic shunts (IHPSS). STUDY DESIGN: Anatomic study of cadavers and prospective evaluation of clinical cases. ANIMALS: Nine canine cadavers (median weight, 20.5 kg) and 6 client-owned dogs suspected of having right-sided IHPSS. METHODS: Silicone casts of the caudal vena cava and pre- and intrahepatic portal veins were made in fresh canine cadavers. A suture was passed dorsal to the portal vein above and below its bifurcation and pulled laterally so that it surrounded the right portal vein. The number and size of portal and caudal vena cava branches that interfered with the suture passage were recorded. Intra- and postoperative complications were evaluated in 3 dogs with right-sided IHPSS and 3 dogs suspected of having right-sided IHPSS that had right portal vein dissection and occlusion using this technique. RESULTS: Suture passage and placement around the right portal vein were easily accomplished in all 9 specimens. A 1 mm branch from the dorsal surface of the right portal vein was included in the encircling ligature in 4 specimens. The dissection technique was used successfully in 3 dogs with right-sided IHPSS and 2 other clinical cases. The portal branch to the papillary process of the caudate lobe interfered with suture placement in 1 dog with a central IHPSS. CONCLUSIONS: Indirect suture passage for ligation of the right portal vein can be successfully performed in normal dogs and dogs with congenital portosystemic shunts. CLINICAL RELEVANCE: Hemorrhage, vascular trauma, and surgery time may be reduced using this technique for attenuation of right-sided IHPSS.

Animals↗
PubMed2005

Proteases and glioma angiogenesis.

Angiogenesis, the process by which new branches sprout from existing vessels, requires the degradation of the vascular basement membrane and remodeling of the ECM in order to allow endothelial cells to migrate and invade into the surrounding tissues. Serine, metallo, and cysteine proteinases are 3 types of a family of enzymes that proteolytically degrade various components of extracellular matrix. These proteases release various growth factors and also increase adhesive molecules and signaling pathway molecules upon their activation, which plays a significant role in angiogenesis. Downregulation of these molecules by antisense/siRNA or synthetic inhibitors decreases the levels of these molecules, inhibits the release of growth factors, and decreases the levels of various signaling pathway molecules, thereby leading to the inhibition of angiogenesis. Furthermore, MMPs degrade specific substrates and release angiogenic inhibitors which inhibit angiogenesis. Downregulation of 2 molecules, such as uPA and uPAR, uPAR and MMP-9, or Cathepsin B and MMP-9, are more effective to inhibit angiogenesis rather than downregulation of single molecules. However, careful testing of these combinations are most important because multiple effects of these combinations play a significant role in angiogenesis.

Animals↗
PubMed1996

Detection and modulation of acetylcholine release from neurites of rat basal forebrain cells in culture.

1. Nicotinic acetylcholine (ACh) receptor-rich patches prepared from rat myotubes were used as focal ACh detectors to record the release of ACh from magnocellular basal forebrain (MBF) neurones from 11- to 14-day-old postnatal rats maintained in dissociated cell culture. 2. An action potential generated by intracellularly stimulating the MBF cell soma through a patch electrode induced a brief (mean tau(decay), 6.3 ms) short latency (1.35-5.1 ms; median 3.1 ms) burst of nicotinic channel openings in the detector patch when the latter was positioned at discrete loci along the MBF neurites. Detected ACh concentrations ranged from approximately 480 nM to > 50 microM. Concentrations increased markedly during the first 14 days in vitro and were inversely related to response latency. 3. Sites of release were generally confined to the more proximal neurites within 100 microm of the cell body and were invariably associated with the presence of small (2-3 microm diameter) phase-dark puncta located at discrete intervals along the length of the neurites or at points where short collaterals branched from the main process. Release was never detected from the cell soma except under extreme non-physiological conditions but could occasionally be elicited from growth cones at the ends of the shorter thicker neurites in the absence of a target cell. 4. Evoked release was abolished by tetrodotoxin (0.5 microM) and by superfusing with low Ca(2+)-high Mg(2+)-containing solutions (0.25 mM Ca(2+), 5 mM Mg(2+)). Myotube patch responses were antagonized by d-tubocurarine (3 microM). 5. Muscarine (10 microM) inhibited release by 70 +/- 3% (n = 12 cells). This effect was antagonized by 100 nM methoctramine but not by 100 nM pirenzepine, indicating that it was mediated by M(2) muscarinic ACh receptors. 6. These results indicate that ACh release from the processes of magnocellular cholinergic basal forebrain neurones arises from highly specialized and discrete sites, and that it can be inhibited through activation of muscarinic receptors. It is suggested that the latter results from inhibition of presynaptic Ca(2+) channels and that it might be responsible for feedback autoinhibition of ACh release from cortical afferents of nucleus basalis neurones in vivo.

Acetylcholine↗
PubMed2000

Perisphincteric injection of botulinum toxin type A. A treatment option for patients with chronic prostatic pain?

BACKGROUND: Chronic prostatic pain is still a diagnostic and therapeutic problem. The clinical observation that prostatic and pelvic pain is accompanied by motoric and sensoric disorders of the pelvic floor muscles led to the hypothesis that prostatic pain roots in a changed processing of afferent and efferent information with the central nervous system (CNS). METHODS: Neuro-urological work-up of 11 male patients with chronic prostatic pain was completed. This included a clinical evaluation of pelvic floor function, urodynamic investigation of bladder and urethra function and a cystoscopy to exclude morphological aberrations. A transurethral perisphincteric injection of 200 units botulinum toxin type A (BTX) was followed by a 2- to 4-week visit to evaluate their influence on the neuro-urological symptomatology. RESULTS: All chronic prostatic pain patients suffered from a pathological pelvic floor tenderness, an inability of sufficient conscious pelvic floor control, a urethral hypersensitivity/hyperalgesia and a urethral muscle hyperactivity. Basic parameters of bladder function (capacity, sensitivity, compliance) were normal. The BTX injection was followed by a pelvic floor muscle weakening and a relief of prostatic pain and urethral hypersensitivity/hyperalgesia. A botulinum-related decrease of the functional urethral length, the urethral sphincter closure pressure, the postvoid residual volume and an increase of the peak and average uroflow were objectivated. CONCLUSION: A weakening of the urethral sphincter muscle via blocking acetylcholine release by BTX injection is followed by pain relief and symptom improvement. It can therefore be concluded that a barrage of nociceptive information from the dysfunctional pelvic floor overflood the CNS and induce a changed CNS processing. Interrupting the efferent branch of the disturbed central circle is one opportunity to treat chronic prostatic pain.

Adult↗
PubMed2005

Key bacterial multi-centered metal enzymes involved in nitrate and sulfate respiration.

Many essential life processes, such as photosynthesis, respiration, nitrogen fixation, depend on transition metal ions and their ability to catalyze multi-electron redox and hydrolytic transformations. Here we review some recent structural studies on three multi-site metal enzymes involved in respiratory processes which represent important branches within the global cycles of nitrogen and sulfur: (i) the multi-heme enzyme cytochrome c nitrite reductase, (ii) the FAD, FeS-enzyme adenosine-5'-phosphosulfate reductase, and (iii) the siroheme, FeS-enzyme sulfite reductase. Structural information comes from X-ray crystallography and spectroscopical techniques, in special cases catalytically competent intermediates could be trapped and characterized by X-ray crystallography.

Bacteria↗
PubMed1990

Expert systems as a diagnostic aid in otoneurology.

Expert systems (ES) are a new tool for information processing developed by the branch of computer science known as artificial intelligence. ES are capable of solving problems in a given domain by using the knowledge and emulating the behaviour of specialists in that field. ES can be used as powerful tools for education since they are able to justify their own conclusions and to make the underlying reasoning explicit. This paper presents 'Vertigo', an ES aimed at the classification and diagnosis of different forms of dizziness. It has been conceived mainly as a teaching tool in otoneurological departments. The rationale of this project, its development, the structure and the use of the system are described. So far, 'Vertigo' has been tested on more than 200 cases of dizziness and is presently being used by ENT residents during their otoneurology stage.

Diagnosis, Computer-Assisted↗
PubMed2005

Segmentation and quantitative analysis of intrathoracic airway trees from computed tomography images.

The segmentation of the human airway tree from volumetric multidetector-row computed tomography images is an important prerequisite for many clinical applications and physiologic studies. We present a new airway segmentation method based on fuzzy connectivity. Small adaptive regions of interest are used that follow the airway branches as they are segmented. This method works on various types of scans (low dose and regular dose, normal subjects and diseased subjects) without the need for the user to manually adjust any parameters. Comparison with a commonly used region-growing segmentation algorithm shows that this method retrieves a significantly higher count of airway branches. In an additional processing step, this method provides accurate cross-sectional airway measurements that are conducted in the original gray-level volume. Validation on a phantom shows that subvoxel accuracy is achieved for all airway sizes and airway orientations. The utility of the reported method is demonstrated in a comparative analysis of normal and cystic fibrosis airway trees.

Algorithms↗
PubMed2004

Activation of cAMP signaling facilitates the morphological maturation of newborn neurons in adult hippocampus.

Previous studies have demonstrated that activation of the cAMP cascade, including the cAMP response element-binding protein (CREB), increases the proliferation and survival of newborn neurons in adult mouse hippocampus. In the present study, we determined whether the cAMP-CREB cascade also influences the morphological maturation of newborn neurons in the subgranular zone of the hippocampus. Rolipram, a selective inhibitor of the cAMP-specific phosphodiesterase type 4, was administered to activate the cAMP cascade, and neuronal morphology was determined by analysis of Golgi-impregnated neurons in the subgranular zone of hippocampus. Rolipram administration significantly increased the number of branch points and length of dendrites relative to vehicle treatment. Increased branch number and length were accompanied by increased levels of phosphorylated CREB, the active form of this transcription factor, in immature neurons. In contrast, the morphology of Golgi-impregnated neurons was not significantly influenced by rolipram treatment in inducible transgenic mice expressing a dominant-negative mutant of CREB in hippocampus. We also tested the influence of cAMP analogs in primary hippocampal cultures and found that activation of the cAMP pathway increased and inhibition of the cAMP cascade decreased the number of branches and length of processes as observed in vivo. These findings indicate that the cAMP-CREB cascade plays an important role in the differentiation and maturation of newborn neurons in hippocampus.

Animals↗
PubMed2004

Astrocyte-associated fibronectin is critical for axonal regeneration in adult white matter.

Although it has been suggested that astroglia guide pioneering axons during development, the cellular and molecular substrates that direct axon regeneration in adult white matter have not been elucidated. We show that although adult cortical neurons were only able to elaborate very short, highly branched, dendritic-like processes when seeded onto organotypic slice cultures of postnatal day 35 (P35) rat brain containing the corpus callosum, adult dorsal root ganglion (DRG) neurons were able to regenerate lengthy axons within the reactive glial environment of this degenerating white matter tract. The callosum in both P35 slices and adult rat brain was rich in fibronectin, but not laminin. Furthermore, the fibronectin was intimately associated with the intratract astrocytes. Blockade of fibronectin function in situ with an anti-fibronectin antibody dramatically decreased outgrowth of DRG neurites, suggesting that fibronectin plays an important role in axon regeneration in mature white matter. The critical interaction between regrowing axons and astroglial-associated fibronectin in white matter may be an additional factor to consider when trying to understand regeneration failure and devising strategies to promote regeneration.

Aging↗
PubMed1998

Co-expression of cytokeratins and vimentin by highly invasive trophoblast in the white-winged vampire bat, Diaemus youngi, and the black mastiff bat, Molossus ater, with observations on intermediate filament proteins in the decidua and intraplacental trophoblast.

Histological and immunocytochemical studies of gravid reproductive tracts obtained from the white-winged vampire bat (Diaemus youngi) and the black mastiff bat (Molossus ater) have established that both species develop unusually invasive trophoblast. This is released by the developing discoidal haemochorial placenta, expresses both cytokeratins and vimentin, and invades the myometrium and adjacent tissues (including the ovaries) via interstitial migration within the walls of maternal blood vessels. Hence, this trophoblast is noteworthy for the extent to which it undergoes an epithelial-mesenchymal transformation. In Molossus, it originates from the cytotrophoblastic shell running along the base of the placenta, is mononuclear, and preferentially invades maternal arterial vessels serving the discoidal placenta. This trophoblast may have a role in dilatation of these vessels when the discoidal placenta becomes functional. In Diaemus, the highly invasive trophoblast appears to originate instead from a layer of syncytiotrophoblast on the periphery of the placenta is multinucleated, and vigorously invades both arterial and venous vessels. During late pregnancy, it becomes extensively branched and sends attenuated processes around many of the myometrial smooth muscle fibres. In view of its distribution, this trophoblast could have important influences upon myometrial contractility and the function of blood vessels serving the gravid tract. Other aspects of intermediate filament expression in the uteri and placentae of these bats are also noteworthy. Many of the decidual giant cells in Molossus co-express cytokeratins and vimentin, while the syncytiotrophoblast lining the placental labyrinth in Diaemus late in pregnancy expresses little cytokeratin.

Animals↗
PubMedDate not supplied

[Triatoma bassolsae sp. n. from Mexico, with a key to species of phyllosoma complex (Hemiptera, Reduviidae)].

According to the descriptions of five closely related species of the genus Triatoma Laporte, 1832: T. phyllosoma (Burmeister, 1835), T. pallidipennis (Stal, 1872), T. picturata Usinger, 1939, T. longipennis Usinger, 1939 and T. mazzottii Usinger, 1941 and further published studies, these species could be included in a "specific complex" named as the species formerly described. All these species are typical from Mexico and another species was found in the same country, in the State of Puebla: Triatoma bassolsae sp. n. This species was morphologically compared with the other five of the "phyllosoma" complex, including the external male genitalia. The most important characters used to separate T. bassolsae from T. phyllosoma (which is the most similar to the other species) are the morphometric relationships on the head, with a longer anteocular region and a significant longer second rostral segment, a long and conspicuous pilosity in different areas of the body and specially on the head, and the characters of the anterolateral, lateral and discal tubercles of the pronotum, very long and sharp in the new species. The male genitalia has several differences between T. bassolsae and T. phyllosoma specially significant on the surface of the endosome process and on the branches of the phallosome support, separated at the apex in the new species. Types and paratypes are incorporated in the respective institutions in Mexico DF and Rio de Janeiro.

Animals↗
PubMed2002

Ischaemic preconditioning reduces spinal cord injury in transient ischaemia.

OBJECTIVE: Paraplegia remains a devastating complication after thoracic and thoracoabdominal aortic surgery for coarctations, dissections or aneurysms. Since the advent of ischaemic preconditioning of the myocardium, attention has been directed to the nervous system. This study was designed to evaluate the acute protective effect of ischaemic preconditioning on the spinal cord. MEDHODS AND RESULTS: Thirty-six New Zealand white rabbits were randomly assigned to one of three groups. The preconditioning group had 5 minutes of aortic occlusion, 25 minutes reperfusion and 20 minutes of ischaemia, whereas the controls had only 20 minutes of ischaemia. The sham group was anaesthetized and subjected to laparotomy without aortic occlusion. Physiological parameters and somatosensory evoked potentials were monitored during the experiment. Neurological outcome was clinically evaluated up to 48 hour after ischaemia and motor function was scored. Then the animals were sacrificed. Their spinal cord, abdominal aorta and its branches were removed and processed for histopathological examination. Histhopathological changes of the gray matter in the lumbosacral segments were scored from 0 to 6 according to a semi-quantitative scala. The changes in amplitudes of evoked potentials during ischaemia and recovery periods were similar in preconditioning and control groups. The average motor function score was significantly higher in the preconditioning group than the control group at 24 and 48 hours after the ischaemic event (p < 0.05). Histological observations were consistent with the neurological findings. The histopathological scores in the control group and the preconditioning group were 3.2 (1.4-5.2) and 2.4 (0.8-4.4), respectively (p < 0.05). CONCLUSIONS: The results suggest that ischaemic preconditioning reduces the spinal cord injury and improves neurological outcome in transient ischaemia in rabbits. This protective mechanism is rapidly invoked within only 25 minutes interval between the preconditioning stimulus and the ischaemic insult.

Animals↗