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Synaptic activation of efferent neuromodulatory neurones in the locust Schistocerca gregaria.

The segmental ganglia of the locust contain efferent neuromodulatory neurones with cell bodies at the dorsal midline and axons that supply muscles and other tissue on both sides of the body. These are the dorsal unpaired median (DUM) neurones. Intracellular recordings were made from pairs of known metathoracic efferent DUM neurones in locusts in which all nerves were intact and in isolated metathoracic ganglia. The 19 metathoracic, efferent DUM neurones were identified according to the nerve roots through which their axons emerge from the ganglion. The synaptic potentials in these DUM neurones have been analysed to investigate how these neurones are activated and how their spikes are controlled. The degree of correlation between the synaptic potentials in particular pairs of neurones was quantified using a correlation analysis. This allowed the population of DUM neurones to be divided into three subsets that also map onto an anatomical grouping based on the distribution of their axons in the lateral nerves: (i) DUM1 neurones (DUMDL and DUM1b); (ii) DUM3 and DUM3,4 neurones; and (iii) DUM3,4,5, DUM5b neurones and DUMETi. Individual neurones within each subset showed strong correlations between their synaptic potentials, in both intact locusts and isolated ganglia, and tended to spike at the same time. Neurones in different subsets had few synaptic potentials in common and tended to spike independently. The persistence of common synaptic potentials in neurones of the three subsets in isolated ganglia indicates that they are derived from neurones within the metathoracic ganglion. The DUM neurones that had many common synaptic potentials in a quiescent locust responded in similar ways to mechanosensory stimulation of different parts of the body. DUM3,4, 5 and DUM5 neurones gave the clearest and most consistent responses to stimulation of mechanoreceptors on either hind leg. DUM3 and DUM3, 4 neurones responded variably, but usually with a hyperpolarisation. DUM1 neurones were rarely excited by mechanosensory stimuli but, like the preceding group, their responses were dependent upon whether the locust was moving its legs. These results lend further support to the idea that there is a subdivision of action amongst this population of DUM neurones, with those supplying the same targets being driven by the same presynaptic local neurones.

Animals↗

Disseminated spinal and cerebral ependymoma with unusual histological pattern: clinicopathological study of a case with retrograde tumor spread.

The subject of this study is a case of anaplastic ependymoma originally arising from the central canal of the lower spinal cord followed by the 13 years history of events of upper spinal dissemination and retrograde intracranial spread. The specimens from four subsequent surgeries generally displayed the same microscopic features of neoplastic tissue and were consistent with the diagnosis of anaplastic ependymoma. The histological diagnosis was based upon the high cellularity, considerable nuclear atypia and pleomorphism, brisk mitotic activity, focally exhibited vascular endothelial proliferation and extensive necrosis. Apart from the typical pattern of ependymoma, the tumors contained areas composed almost entirely of large, uniform clear cells or pseudogemistocytes indicating the morphological heterogeneity of neoplastic cells population. The surgical specimens from four surgical resections shared light microscopic similarities suggesting spinal and intracranial dissemination from the primary spinal tumor. Since the retrograde spread via the cerebrospinal fluid (CSF) pathway is extremely rare, the authors of this study discuss the mechanism of such way of tumor metastases.

Adult↗

[The pyramidal tract: new pathways].

OBJECTIVE: To review some anatomofunctional aspects of the pyramidal tract which are relevant in clinical practice, especially the newer concepts. DEVELOPMENT: a) Although the motor function is best known, the pyramidal tract also has sensory functions, modulating the transmission of impulses in the spinal cord. In fact, motor function is a recent acquisition on the evolutionary scale. b) Other descending pathways, such as the cortico reticulospinal path, participate in voluntary movements. However, the pyramidal pathway is necessary for fine movements of the hand. c) Most of the pyramidal fibres control movements of the contralateral side of the body, but there are a few fibres which do not cross to the other side and play a part in ipsilateral body movements. These fibres seem to contribute to motor recovery following a brain lesion. d) Classically it is recognized that the motor cortex and pyramidal fibres follow a somatotopical distribution. Nevertheless territories corresponding to different parts of the body are superimposed to a considerable extent and may be modified on very diverse occasions. e) Experimentally it has been proved that a circumscribed lesion of the pyramidal pathway does not cause hyper reflexia or spasticity. The hyper reflexia and spasticity habitually seen in patients with pyramidal syndrome is due to lesions of other descending pathways. CONCLUSION: The pyramidal tract is anatomically and functionally related to other nerve structures and its activity is therefore integrated within the nervous system.

Animals↗

The effects of dynamic visual stimulation on perception and motor control.

A set of research findings is described that deals with three principal laboratory measures of visual orientation (vection and postural and manual control). Two studies are highlighted, one of which compared the latencies of vection and visually induced postural change and the other of which investigated manual tracking under visually disorienting conditions. The first study showed that although vection and postural change are somewhat related to each other (for example, both were greater in response to roll and pitch as opposed to linear visual motion), the onset of vection is delayed by several seconds relative to the initiation of visually induced postural shifts. The second study showed that manual biases induced by visual roll motion are not overcome using a thumb-and-forefinger (pyramidal) motor strategy, and may not be equivalent to the "giant hand" illusion that is believed to reflect the predominance of the vestibulospinal (extrapyramidal) motor pathways during extreme spatial disorientation. These and other findings indicate that various visual orientation effects may involve at least partially independent mechanisms.

Humans↗

[Functional significance of 2 pathways of energy transport in cardiomyocytes].

To study the relative roles of creatine kinase (CK) and adenylate systems in cardiac energy turnover, the effect of CK inhibitor, iodoacetamide- (IAA, 0.5 mM), and 2-deoxyglucose-(DOG, 2 mM) induced) 65% depletion of adenine nucleotides at slightly decreased CK flux was determined in isolated rat heart. Both substances did not substantially affect contractile parameters of the isovolumic heart. However, an augmentation of cardiac work induced by isoproterenol addition was feeble and transient in IAA-treated hearts while the response of DOG-treated hearts was well preserved. The cardiac failure after IAA treatment was associated with irreversible fall in myocardial ATP content as evidenced by 31P-NMR technique. Furthermore, these hearts were unable to perform cardiac pump function due to insufficient cardiac filling and distensibility. The DOG-treated hearts exhibited 50% reduction in the pump function and were able to increase their work in elevated resistance. The results suggest that CK pathway is extremely important for both full cardiac relaxation and maximal contractile function.

Adenosine Triphosphate↗

[Role of the p53 gene in apoptosis].

Cell numbers are controlled by a homeostatic mechanism between cell growth, arrest and programmed cell death (apoptosis) in normal and cancerous tissues. One of the tumor suppressor genes, p53, functions as a transcription factor or transcriptional regulator through DNA and protein binding properties, and plays an important role in regulating cell cycle and induction of apoptosis. Although there are two apoptotic pathways, p53-independent and p53-dependent, the latter will be emphasized and discussed in this section. Since p53 is often inactivated due to mutation in human cancers, understanding the p53-dependent apoptotic pathway is extremely important. Analysis of p53-dependent apoptosis as well as apoptosis caused by other p53-related genes should provide a clue to a new strategy for cancer therapy.

Apoptosis↗

Glycolytic pathway and hydrogen yield studies of the extreme thermophile Caldicellulosiruptor saccharolyticus.

NMR analysis of (13)C-labelling patterns showed that the Embden-Meyerhof (EM) pathway is the main route for glycolysis in the extreme thermophile Caldicellulosiruptor saccharolyticus. Glucose fermentation via the EM pathway to acetate results in a theoretical yield of 4 mol of hydrogen and 2 mol of acetate per mole of glucose. Previously, approximately 70% of the theoretical maximum hydrogen yield has been reached in batch fermentations. In this study, hydrogen and acetate yields have been determined at different dilution rates during continuous cultivation. The yields were dependent on the growth rate. The highest hydrogen yields of 82 to 90% of theoretical maximum (3.3 to 3.6 mol H(2) per mol glucose) were obtained at low growth rates when a relatively larger part of the consumed glucose is used for maintenance. The hydrogen productivity showed the opposite effect. Both the specific and the volumetric hydrogen production rates were highest at the higher growth rates, reaching values of respectively 30 mmol g(-1) h(-1) and 20 mmol l(-1) h(-1). An industrial process for biohydrogen production will require a bioreactor design, which enables an optimal mix of high productivity and high yield.

Acetates↗

A critical pathway to treat proximal lower-extremity deep vein thrombosis.

To address variation in treatment of deep vein thrombosis (DVT) while maximizing the efficiency and quality of care, our institution developed a critical pathway guideline. This paper presents this critical pathway and the clinical rationale underlying its recommendations. The DVT pathway synthesizes recommendations for all aspects of patient care, including laboratory evaluation at admission, dosing and management of heparin therapy, timing of warfarin initiation, elements of patient education, discharge planning, and anticipated duration of heparinization and hospitalization. Differences among interpretations of the medical literature, patient populations, physician skills, test availability, and other variables make it unlikely that all elements of this pathway would best meet the needs of another institution. Nevertheless, the critical pathway format and the specific contents of this pathway may serve as a useful benchmark for others involved in creating clinical guidelines for this patient population.

Activities of Daily Living↗

Screening of stable proteins in an extreme thermophile, Thermus thermophilus.

The leuB gene codes for 3-isopropylmalate dehydrogenase of the leucine biosynthetic pathway in an extreme thermophile, Thermus thermophilus. The leuB gene of the thermophile was replaced with a temperature-sensitive chimeric leuB gene. The resultant transformant was adapted to high temperature, a thermostable mutant strain being obtained. A single base substitution that replaces isoleucine at 93 with leucine was found in the chimeric leuB gene of the thermostable mutant. The resultant amino acid residue coincided with the corresponding residue of the T. thermophilus enzyme. It was confirmed that the mutant enzyme is more stable than the original chimeric enzyme. This system can be used to produce stabilized mutants of other enzymes without structural knowledge of them.

3-Isopropylmalate Dehydrogenase↗

Structure and mechanism of bacterial periplasmic transport systems.

Bacterial periplasmic transport systems are complex, multicomponent permeases, present in Gram-negative bacteria. Many such permeases have been analyzed to various levels of detail. A generalized picture has emerged indicating that their overall structure consists of four proteins, one of which is a soluble periplasmic protein that binds the substrate and the other three are membrane bound. The liganded periplasmic protein interacts with the membrane components, which presumably form a complex, and which by a series of conformational changes allow the formation of an entry pathway for the substrate. The two extreme alternatives for such pathway involve either the formation of a nonspecific hydrophilic pore or the development of a ligand-binding site(s) on the membrane-bound complex. One of the membrane-bound components from each system constitutes a family of highly homologous proteins containing sequence domains characteristic of nucleotide-binding sites. Indeed, in several cases, they have been shown to bind ATP, which is thus postulated to be involved in the energy-coupling mechanism. Interestingly, eukaryotic proteins homologous to this family of proteins have been identified (mammalian mdr genes and Drosophila white locus), thus indicating that they perform a universal function, presumably related to energy coupling in membrane-related processes. The mechanism of energy coupling in periplasmic permeases is discussed.

Cell Membrane↗

Extremely low doses of tissue factor pathway inhibitor decrease mortality in a rabbit model of septic shock.

OBJECTIVE: We sought to determine the lowest dose of recombinant human tissue factor pathway inhibitor (TFPI) that can provide protection from lethality in a rabbit model of septic shock. METHODS: Sepsis was induced in New Zealand white rabbits by intraperitoneal implantation of 7.0 ml of a solution containing hemoglobin (4.8 g/dl), porcine mucin (6 g/dl), and 0.8-1.4 x 10(4) viable Escherichia coli (strain O:18 K+). Gentamicin (5 mg/kg) was administered 4 h following surgery, and this dose was repeated every 12 h for 3 days. Beginning 4 h following the induction of sepsis, animals were treated with a bolus (1 ml) plus a continuous infusion (100 ml over 24) of either TFPI (various doses) or its vehicle. Four different doses of TFPI were studied, and each experiment included a contemporaneous control group. The primary outcome parameter was survival time. Results were analyzed using the Wilcoxen log rank test. RESULTS: The average survival time for rabbits treated with the highest dose of TFPI tested (50 microg/kg bolus and 0.5 microg/kg per minute infusion) was 118 h, as compared to 81 h in vehicle-treated controls). The average survival time for septic rabbits treated with a much lower dose of TFPI (100 ng/kg bolus and 1.0 ng/kg per minute infusion) was 119 h as compared to 57 h in surviving vehicle-treated controls. Treatment with an even lower dose of TFPI (10 ng/kg bolus and 0.1 ng/kg per minute infusion) still produced a marginally significant prolongation of average survival time (80 h) relative to contemporaneously studied controls (47 h). When the dose of TFPI was decreased still further (1.0 ng/kg bolus and 0.01 ng/kg per minute infusion), average survival times were not significantly different between TFPI-treated and vehicle-treated rabbits (77 and 51 h, respectively). CONCLUSIONS: Delayed infusion with remarkably low doses of recombinant human TFPI prolongs survival in a rabbit model of antibiotic-treated Gram-negative bacterial sepsis. In planning human trials of TFPI as an adjuvant treatment for sepsis it may be reasonable to use much lower doses of the agent than were heretofore contemplated.

Animals↗

A systematically generated, pressure-dependent mechanism for high-conversion ethane pyrolysis. 1. Pathways to the minor products.

The deposition of carbon during hydrocarbon pyrolysis is part of many industrial processes. The rate and nature of deposition depend, in part, on the gas-phase chemistry of the minor pyrolysis products, which serve as deposition precursors. But the specific reaction pathways governing the formation and destruction of these minor gas-phase products are only partially known. We apply an updated version of our automated mechanism generation tool XMG-PDep to the high-conversion, pyrocarbon-depositing ethane pyrolysis system of Glasier and Pacey, to systematically uncover the likely reaction pathways governing the observed minor products acetylene, propylene, 1,3-butadiene, and benzene. Thorough examination by means of sensitivity, equilibrium, and reaction-pathway analyses reveals an extremely complex, intertwined set of reaction pathways controlling these deposition precursors, some of which are not often considered in the wider pyrolysis literature. Large, aggregated sets of disproportionation reactions, for example, appear to play an important role in the formation of benzene. The analyses motivate a companion paper (following paper in this issue) which explores in greater depth the effects of large groups of radical disproportionation reactions, omitted reaction families, and the possibility that pressure changes in the reactor could alter the distribution of the deposition precursors.

Journal Article↗

Pathway information for systems biology.

Pathway information is vital for successful quantitative modeling of biological systems. The almost 170 online pathway databases vary widely in coverage and representation of biological processes, making their use extremely difficult. Future pathway information systems for querying, visualization and analysis must support standard exchange formats to successfully integrate data on a large scale. Such integrated systems will greatly facilitate the constructive cycle of computational model building and experimental verification that lies at the heart of systems biology.

Animals↗

Reactions of the alkoxy radicals formed following OH-addition to alpha-pinene and beta-pinene. C-C bond scission reactions.

The atmospheric degradation pathways of the atmospherically important terpenes alpha-pinene and beta-pinene are studied using density functional theory. We employ the correlation functional of Lee, Yang, and Parr and the three-parameter HF exchange functional of Becke (B3LYP) together with the 6-31G(d) basis set. The C-C bond scission reactions of the beta-hydroxyalkoxy radicals that are formed after OH addition to alpha-pinene and beta-pinene are investigated. Both of the alkoxy radicals formed from the alpha-pinene-OH adduct possess a single favored C-C scission pathway with an extremely low barrier (approximately 3 kcal/mol) leading to the formation of pinonaldehyde. Neither of these pathways produces formaldehyde, and preliminary computational results offer some support for suggestions that 1,5 or 1,6 H-shift (isomerization) reactions of alkoxy radicals contribute to formaldehyde production. In the case of the alkoxy radical formed following OH addition to the methylene group of beta-pinene, there exists two C-C scission reactions with nearly identical barrier heights (approximately 7.5 kcal/mol); one leads to known products (nopinone and formaldehyde) but the ultimate products of the competing reaction are unknown. The single C-C scission pathway of the other alkoxy radical from beta-pinene possesses a very low (approximately 4 kcal/mol) barrier. The kinetically favored C-C scission reactions of all four alkoxy radicals appear to be far faster than expected rates of reaction with O2. The rearrangement of the alpha-pinene-OH adduct, a key step in the proposed mechanism of formation of acetone from alpha-pinene, is determined to possess a barrier of 11.6 kcal/mol. This value is consistent with another computational result and is broadly consistent with the modest acetone yields observed in product yield studies.

Acetone↗

Isolevuglandin-protein adducts in humans: products of free radical-induced lipid oxidation through the isoprostane pathway.

A family of extremely reactive electrophiles, isolevuglandins (isoLGs), is generated in vivo by free radical-induced lipid oxidation and rearrangement of endoperoxide intermediates of the isoprostane pathway. Protein adducts of two different oxidized lipids, isoLGE(2) and iso[4]LGE(2), and the corresponding autoantibodies are present in human blood. Western blot analysis of a polyacrylamide gel electrophoresis gel detects several immunoreactive plasma proteins. Only a minor fraction of the isoLG-protein modifications is associated with low density lipoprotein since mean levels were decreased only 20-22% by immunoprecipitation of apolipoprotein B (apoB). Mean levels of both isoLGE(2) and iso[4]LGE(2)-protein adducts in plasma from patients with atherosclerosis (AS) (n=16) or end-stage renal disease (RD) (n=8) are about twice those in healthy individuals (n=25). These elevated levels are not related to variations in age, total cholesterol or apoB. A linear correlation (r=0.79) between plasma isoLGE(2) and iso[4]LGE(2)-protein adduct levels in all 49 individuals is consistent with a common free radical-induced mechanism for the production of both oxidized lipids in vivo. The correlation is even stronger (r=0.86) for patients with AS or RD. That isoLG-protein adduct levels are more strongly correlated with disease than are total cholesterol or apoB suggests an independent defect that results in an abnormally high level of oxidative injury associated with AS and RD.

Adult↗

Extremely indirect dermal lymphatic channels: value of areolar-cutaneous junction injection technique for breast lymphoscintigraphy.

This case describes a patient who initially had peri-excisional injections of radiocolloid around a lumpectomy site that failed to visualize sentinel nodes during lymphoscintigraphy. After additional areolar-cutaneous junction injections, extremely indirect dermal lymphatic pathways were evident with resultant drainage to two sentinel nodes, both of which contained disease. Hybrid combination injections of radiotracer during sentinel lymph node biopsy is gaining in popularity. This case illustrates the validity of the hybrid injection techniques and the demonstrated accuracy despite seemingly disconnected and extremely tortuous pathways as demonstrated in the figure.

Aged↗

Factors associated with ulceration and amputation in the neuropathic foot.

The purpose of this paper is to review selected literature on the relationship of neuropathy and other related factors in foot ulceration and lower extremity amputation. There is strong evidence that sensory loss and mechanical stress are the primary cause of foot ulceration and common factors in the pathway to lower extremity amputation. Foot stress results from extrinsic factors such as footwear and intrinsic factors such as deformity and limited joint mobility. Understanding the interplay of these factors is valuable in identifying persons whose feet are at risk, effectively preventing and treating foot ulcerations and ultimately preventing lower extremity amputation.

Amputation, Surgical↗