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Similar Mechanisms (similar + mechanism)
Selected AbstractsInteractions between microvascular and macrovascular disease in diabetes: pathophysiology and therapeutic implicationsDIABETES OBESITY & METABOLISM, Issue 6 2007Andrew J. Krentz Convention partitions the complications of diabetes into two main subtypes. First are the diabetes-specific microvascular complications of retinopathy, nephropathy and neuropathy; second are the atherothrombotic macrovascular complications that account for the majority of premature deaths. Pathological interactions between microvascular and macrovascular complications, for example, nephropathy and macrovascular disease, are common. Similar mechanisms and shared risk factors drive the development and progression of both small and large vessel disease. This concept has therapeutic implications. Mounting evidence points to the need for multifactorial strategies to prevent vascular complications in subjects with diabetes and/or the metabolic syndrome. We advocate a combined therapeutic approach that addresses small and large vessel disease. Preferential use should be made of drug regimens that (i) maximize vascular protection, (ii) reduce the risk of iatrogenic vascular damage and (iii) minimize the increasing problem of polypharmacy. [source] Molecular determinants of the face map development in the trigeminal brainstemTHE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 2 2006Reha S. Erzurumlu Abstract The perception of external sensory information by the brain requires highly ordered synaptic connectivity between peripheral sensory neurons and their targets in the central nervous system. Since the discovery of the whisker-related barrel patterns in the mouse cortex, the trigeminal system has become a favorite model for study of how its connectivity and somatotopic maps are established during development. The trigeminal brainstem nuclei are the first CNS regions where whisker-specific neural patterns are set up by the trigeminal afferents that innervate the whiskers. In particular, barrelette patterns in the principal sensory nucleus of the trigeminal nerve provide the template for similar patterns in the face representation areas of the thalamus and subsequently in the primary somatosensory cortex. Here, we describe and review studies of neurotrophins, multiple axon guidance molecules, transcription factors, and glutamate receptors during early development of trigeminal connections between the whiskers and the brainstem that lead to emergence of patterned face maps. Studies from our laboratories and others' showed that developing trigeminal ganglion cells and their axons depend on a variety of molecular signals that cooperatively direct them to proper peripheral and central targets and sculpt their synaptic terminal fields into patterns that replicate the organization of the whiskers on the muzzle. Similar mechanisms may also be used by trigeminothalamic and thalamocortical projections in establishing patterned neural modules upstream from the trigeminal brainstem. © 2006 Wiley-Liss, Inc. [source] Functional neural correlates of mindfulness meditations in comparison with psychotherapy, pharmacotherapy and placebo effect.ACTA NEUROPSYCHIATRICA, Issue 3 2010Is there a link? Chiesa A, Brambilla P, Serretti A. Functional neural correlates of mindfulness meditations in comparison with psychotherapy, pharmacotherapy and placebo effect. Is there a link? Objective: Mindfulness meditations (MM) are a group of meditation practices which are increasingly receiving attention. The aim of the present work is to review current findings about the neural correlates of MM and compare such findings with other specific and non-specific treatments. Methods: A literature search was undertaken using MEDLINE, ISI web of knowledge, the Cochrane database and references of retrieved articles. Studies which focused on the functional neural correlates of MM, psychotherapy, pharmacotherapy and placebo published up to August 2009 were screened in order to be considered for the inclusion. Results: Main findings suggest that long-term MM practice allows a more flexible emotional regulation by engaging frontal cortical structures to dampen automatic amygdala activation. A large overlap exists between cerebral areas activated during MM, psychotherapy, pharmacotherapy and those activated by placebo. However, while MM, psychotherapy and placebo seem to act through a top-down regulation, antidepressants seem to act through a bottom-up process. Conclusion: MM seem to target specific brain areas related to emotions and emotional regulation. Similar mechanisms have been observed also in other interventions, particularly psychotherapy. [source] Animal Foraging and the Evolution of Goal-Directed CognitionCOGNITIVE SCIENCE - A MULTIDISCIPLINARY JOURNAL, Issue 1 2006Thomas T. Hills Abstract Foraging- and feeding-related behaviors across eumetazoans share similar molecular mechanisms, suggesting the early evolution of an optimal foraging behavior called area-restricted search (ARS), involving mechanisms of dopamine and glutamate in the modulation of behavioral focus. Similar mechanisms in the vertebrate basal ganglia control motor behavior and cognition and reveal an evolutionary progression toward increasing internal connections between prefrontal cortex and striatum in moving from amphibian to primate. The basal ganglia in higher vertebrates show the ability to transfer dopaminergic activity from unconditioned stimuli to conditioned stimuli. The evolutionary role of dopamine in the modulation of goal-directed behavior and cognition is further supported by pathologies of human goal-directed cognition, which have motor and cognitive dysfunction and organize themselves, with respect to dopaminergic activity, along the gradient described by ARS, from perseverative to unfocused. The evidence strongly supports the evolution of goal-directed cognition out of mechanisms initially in control of spatial foraging but, through increasing cortical connections, eventually used to forage for information. [source] Plasticity of the visual system after early brain damageDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 10 2010ANDREA GUZZETTA The aim of this review is to discuss the existing evidence supporting different processes of visual brain plasticity after early damage, as opposed to damage that occurs during adulthood. There is initial evidence that some of the neuroplastic mechanisms adopted by the brain after early damage to the visual system are unavailable at a later stage. These are, for example, the ability to differentiate functional tissue within a larger dysplastic cortex during its formation, or to develop new thalamo-cortical connections able to bypass the lesion and reach their cortical destination in the occipital cortex. The young brain also uses the same mechanisms available at later stages of development but in a more efficient way. For example, in people with visual field defects of central origin, the anatomical expansion of the extrastriatal visual network is greater after an early lesion than after a later one, which results in more efficient mechanisms of visual exploration of the blind field. A similar mechanism is likely to support some of the differences found in people with blindsight, the phenomenon of unconscious visual perception in the blind field. In particular, compared with people with late lesions, those with early brain damage appear to have stronger subjective awareness of stimuli hitting the blind visual field, reported as a conscious feeling that something is present in the visual field. Expanding our knowledge of these mechanisms could help the development of early therapeutic interventions aimed at supporting and enhancing visual reorganization at a time of greatest potential brain plasticity. [source] Modeling of tRNA-assisted mechanism of Arg activation based on a structure of Arg-tRNA synthetase, tRNA, and an ATP analog (ANP)FEBS JOURNAL, Issue 17 2009Michiko Konno The ATP,pyrophosphate exchange reaction catalyzed by Arg-tRNA, Gln-tRNA and Glu-tRNA synthetases requires the assistance of the cognate tRNA. tRNA also assists Arg-tRNA synthetase in catalyzing the pyrophosphorolysis of synthetic Arg-AMP at low pH. The mechanism by which the 3,-end A76, and in particular its hydroxyl group, of the cognate tRNA is involved with the exchange reaction catalyzed by those enzymes has yet to be established. We determined a crystal structure of a complex of Arg-tRNA synthetase from Pyrococcus horikoshii, tRNAArgCCU and an ATP analog with Rfactor = 0.213 (Rfree = 0.253) at 2.0 Ĺ resolution. On the basis of newly obtained structural information about the position of ATP bound on the enzyme, we constructed a structural model for a mechanism in which the formation of a hydrogen bond between the 2,-OH group of A76 of tRNA and the carboxyl group of Arg induces both formation of Arg-AMP (Arg + ATP , Arg-AMP + pyrophosphate) and pyrophosphorolysis of Arg-AMP (Arg-AMP + pyrophosphate , Arg + ATP) at low pH. Furthermore, we obtained a structural model of the molecular mechanism for the Arg-tRNA synthetase-catalyzed deacylation of Arg-tRNA (Arg-tRNA + AMP , Arg-AMP + tRNA at high pH), in which the deacylation of aminoacyl-tRNA bound on Arg-tRNA synthetase and Glu-tRNA synthetase is catalyzed by a quite similar mechanism, whereby the proton-donating group (,NH,C+(NH2)2 or ,COOH) of Arg and Glu assists the aminoacyl transfer from the 2,-OH group of tRNA to the phosphate group of AMP at high pH. [source] Identification of alternative promoter usage for the matrix Gla protein geneFEBS JOURNAL, Issue 6 2005Evidence for differential expression during early development in Xenopus laevis Recent cloning of the Xenopus laevis (Xl) matrix Gla protein (MGP) gene indicated the presence of a conserved overall structure for this gene between mammals and amphibians but identified an additional 5,-exon, not detected in mammals, flanked by a functional, calcium-sensitive promoter, 3042 bp distant from the ATG initiation codon. DNA sequence analysis identified a second TATA-like DNA motif located at the 3, end of intron 1 and adjacent to the ATG-containing second exon. This putative proximal promoter was found to direct transcription of the luciferase reporter gene in the X. laevis A6 cell line, a result confirmed by subsequent deletion mutant analysis. RT-PCR analysis of XlMGP gene expression during early development identified a different temporal expression of the two transcripts, strongly suggesting differential promoter activation under the control of either maternally inherited or developmentally induced regulatory factors. Our results provide further evidence of the usefulness of nonmammalian model systems to elucidate the complex regulation of MGP gene transcription and raise the possibility that a similar mechanism of regulation may also exist in mammals. [source] A spectroscopic study of the reaction of NAMI, a novel ruthenium(III)anti-neoplastic complex, with bovine serum albuminFEBS JOURNAL, Issue 4 2000Luigi Messori The reaction of Na[transRuCl4Me2SO(Im)] (NAMI; where Im is imidazole), a novel anti-neoplastic ruthenium(III) complex, with BSA, was studied in detail by various physico-chemical techniques. It is shown that NAMI, following chloride hydrolysis, binds bovine serum albumin tightly; spectrophotometric and atomic absorption data point out that up to five ruthenium ions are bound per albumin molecule when BSA is incubated for 24 h with an eightfold excess of NAMI. CD and electronic absorption results show that the various ruthenium centers bound to albumin exhibit well distinct spectroscopic features. The first ruthenium equivalent produces a characteristic positive CD band at 415 nm whereas the following NAMI equivalents produce less specific and less marked spectral effects. At high NAMI/BSA molar ratios a broad negative CD band develops at 590 nm. Evidence is provided that the bound ruthenium centers remain in the oxidation state +3. By analogy with the case of transferrins it is proposed that the BSA-bound ruthenium ions are ligated to surface histidines of the protein; results from chemical modification experiments with diethylpyrocarbonate seem to favor this view. Spectral patterns similar to those shown by NAMI are observed when BSA is reacted with two strictly related ruthenium(III) complexes Na[transRuCl4(Me2SO)2] and H(Im)[transRuCl4(Im)2] (ICR), implying a similar mechanism of interaction in all cases. It is suggested that the described NAMI-BSA adducts may form in vivo and may be relevant for the biological properties of this complex; alternatively NAMI/BSA adducts may be tested as specific carriers of the ruthenium complex to cancer cells. Implications of these findings for the mechanism of action of NAMI and of related ruthenium(III) complexes are discussed. [source] Rearrangement of the MOZ gene in pediatric therapy-related myelodysplastic syndrome with a novel chromosomal translocation t(2;8)(p23;p11)GENES, CHROMOSOMES AND CANCER, Issue 4 2003Toshihiko Imamura In this study, we examined a pediatric case of therapy-related myelodysplastic syndrome (tMDS). The symptoms developed 17 months after treatment for acute myeloblastic leukemia (AML, M2 subtype according to the French,American,British [FAB] classification) involving a chromosome abnormality at t(8;21)(q22;q22). Upon diagnosis of tMDS, spectral karyotyping analysis detected a new chromosomal translocation at t(2;8)(p23;p11.2). In addition, fluorescence in situ hybridization analysis suggested a rearrangement in the monocytic leukemia zinc finger (MOZ) gene, located in the 8p11 region of chromosome 8. However, no partner gene on 2p23 could be identified. To our knowledge, this is the first report of tMDS associated with a rearrangement of the MOZ gene. MOZ-linked fusion proteins such as MOZ-CBP (CREB binding protein), MOZ-TIF2 (transcriptional intermediary factor 2), and MOZ-p300 (adenoviral E1A-associated protein) are associated with AML chromosomal abnormalities at t(8;16)(p11;p13), inv(8)(p11q13), and t(8;22)(p11;q13), respectively, and are thought to account for leukemogenesis occurring through the aberrant regulation of histone acetylation. Through a similar mechanism, we believe that MOZ, fused to an unidentified partner gene at 2p23, may have caused an alteration in histone acetylation, resulting in the development of tMDS in this patient. © 2003 Wiley-Liss, Inc. [source] G-protein coupled receptors: SAR analyses of neurotransmitters and antagonistsJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2004C. L. Kuo MS Summary Background:, From the deductive point of view, neurotransmitter receptors can be divided into categories such as cholinergic (muscarinic, nicotinic), adrenergic (, - and , -), dopaminergic, serotoninergic (5-HT1,5-HT5), and histaminergic (H1 and H2). Selective agonists and antagonists of each receptor subtype can have specific useful therapeutic applications. For understanding the molecular mechanisms of action, an inductive method of analysis is useful. Objective:, The aim of the present study is to examine the structure,activity relationships of agents acting on G-protein coupled receptors. Method:, Representative sets of G-PCR agonists and antagonists were identified from the literature and Medline [P.M. Walsh (2003) Physicians' desk reference; M.J. O'Neil (2001) The Merck index]. The molecular weight (MW), calculated logarithm of octanol/water partition coefficient (C log P) and molar refraction (CMR), dipole moment (DM), Elumo (the energy of the lowest unoccupied molecular orbital, a measure of the electron affinity of a molecule and its reactivity as an electrophile), Ehomo (the energy of the highest occupied molecular orbital, related to the ionization potential of a molecule, and its reactivity as a nucleophile), and the total number of hydrogen bonds (Hb) (donors and receptors), were chosen as molecular descriptors for SAR analyses. Results:, The data suggest that not only do neurotransmitters share common structural features but their receptors belong to the same ensemble of G-protein coupled receptor with seven to eight transmembrane domains with their resultant dipoles in an antiparallel configuration. Moreover, the analysis indicates that the receptor exists in a dynamic equilibrium between the closed state and the open state. The energy needed to open the closed state is provided by the hydrolysis of GTP. A composite 3-D parameter frame setting of all the neurotransmitter agonists and antagonists are presented using MW, Hb and , as independent variables. Conclusion:, It appears that all neurotransmitters examined in this study operate by a similar mechanism with the G-protein coupled receptors. [source] Insights into the mechanisms of flavoprotein oxidases from kinetic isotope effects,JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 11-12 2007Paul F. Fitzpatrick Abstract Deuterium, solvent, and 15N kinetic isotope effects have been used to probe the mechanisms by which flavoproteins oxidize carbon,oxygen and carbon,nitrogen bonds in amines, hydroxy acids, and alcohols. For the amine oxidases D -amino acid oxidase, N -methyltryptophan oxidase, and tryptophan monooxygenase, D -serine, sarcosine, and alanine are slow substrates for which CH bond cleavage is fully rate limiting. Inverse isotope effects for each of 0.992,0.996 are consistent with a common mechanism involving hydride transfer from the uncharged amine. Computational analyses of possible mechanisms support this conclusion. Deuterium and solvent isotope effects with wild-type and mutant variants of the lactate dehydrogenase flavocytochrome b2 show that OH and CH bond cleavage are not concerted, but become so in the Y254F enzyme. This is consistent with a highly asynchronous reaction in which OH bond cleavage precedes hydride transfer. The results of Hammett analyses and solvent and deuterium isotope effects support a similar mechanism for alcohol oxidase. Copyright © 2007 John Wiley & Sons, Ltd. [source] Ethanol inhibits cold-menthol receptor TRPM8 by modulating its interaction with membrane phosphatidylinositol 4,5-bisphosphateJOURNAL OF NEUROCHEMISTRY, Issue 1 2007Jan Benedikt Abstract Ethanol has opposite effects on two members of the transient receptor potential (TRP) family of ion channels: it inhibits the cold-menthol receptor TRPM8, whereas it potentiates the activity of the heat- and capsaicin-gated vanilloid receptor TRPV1. Both thermosensitive cation channels are critically regulated by the membrane lipid, phosphatidylinositol 4,5-bisphosphate (PIP2). The effects of this phospholipid on TRPM8 and TRPV1 are also functionally opposite: PIP2 is necessary for the activation of TRPM8 but it constitutively inhibits TRPV1. This parallel led us to investigate the possible role of PIP2 in the ethanol-induced modulation of rat TRPM8, heterologously expressed in HEK293T cells. In this study, we characterize the effects of ethanol (0.1,10%) on whole-cell currents produced by menthol and by low temperature (< 17°C). We show that the inclusion of PIP2 in the intracellular solution results in a strong reduction in the ethanol-induced inhibition of menthol-evoked responses. Conversely, intracellular dialysis with anti-PIP2 antibody or with the PIP2 scavenger, poly l -lysine, enhanced the ethanol-induced inhibition of TRPM8. A 20 min pre-incubation with wortmannin caused a modest decrease in inhibition produced by 1% ethanol, indicating that the ethanol-induced inhibition is not mediated by lipid kinases. These findings suggest that ethanol inhibits TRPM8 by weakening the PIP2,TRPM8 channel interaction; a similar mechanism may contribute to the ethanol-mediated modulation of some other PIP2 -sensitive TRP channels. [source] Characterization of heat shock protein 90 in the shrimp Metapenaeus ensis: Evidence for its role in the regulation of vitellogenin synthesisMOLECULAR REPRODUCTION & DEVELOPMENT, Issue 5 2008Long Tao Wu Abstract Estrogen hormones play a vital role in the regulation of female reproductive maturation. In oviparous vertebrates, the synthesis of vitellogenin (VTG) is tightly controlled by estrogen hormone signal transduction pathway, which is mediated by estrogen receptor and heat shock protein 90 (Hsp90). In order to investigate whether a similar mechanism exists in crustaceans, the Hsp90 gene was cloned and isolated from the shrimp Metapenaeus ensis by homology cloning strategy. The Hsp90 is 2,524 bp in length, containing an open reading frame of 2,163 bp that encodes a 720 amino acid polypeptide (83 kD). The Hsp90 -coding region is interrupted by four introns. MeHsp90 is differentially expressed in eyestalk, ovary, and hepatopancreas at different ovarian maturation stages, and consistently expressed in other tissues including heart, gill, gut, muscle, and central nervous system. In vitro ovary explant assay reveals that MeHsp90 expression in immature ovary can be induced by the addition of exogenous estradiol-17,, but expression in fully mature ovary exhibits no response to estradiol-17, treatment. In situ hybridization shows that MeHsp90 is highly expressed in previtellogenic oocytes and its expression decreases with the progress of maturation, and finally stops in late-vitellogenic oocytes. Our results indicate a strong correlation between estrogen hormones and Hsp90 expression in shrimp, suggesting that the expression of VTG may be under the regulation of estrogen hormones through a mechanism similar to that in vertebrates. The result provides insights on the control of vitellogenesis in invertebrates. Mol. Reprod. Dev. 75: 952,959, 2008. © 2008 Wiley-Liss, Inc. [source] Immobilized HIV-1 Tat protein promotes gene transfer via a transactivation-independent mechanism which requires binding of Tat to viral particlesTHE JOURNAL OF GENE MEDICINE, Issue 11 2009Filomena Nappi Abstract Background Retroviral transduction of cells is improved upon virus adsorption onto immobilized fibronectin (FN) fragments. Because HIV-1 Tat possesses the same functional domains that lead to increased transduction efficiency in FN by colocalization of bound virus and cells, we hypothesized that Tat could enhance gene transfer by a similar mechanism. Methods Single-cycle replication retro- or lentivirus carrying green fluorescent protein or cloramphenicol acetyltransferase as reporter genes were added to wells coated with Tat or Tat peptides. Wells were extensively washed to remove unbound virus and levels of transduction were detected by measuring reporter gene expression. Virus adsorption to immobilized Tat was measured using a p24 antigen capture assay. Results Immobilized Tat efficiently binds retro- and lentiviral particles and mediates virus transmission at virus input doses that were otherwise unable to transduce susceptible cells. Virus adsorption to Tat is not mediated by envelope glycoprotein (Env) because immobilized Tat binds and retains vesicular stomatitis virus G (VSV-G) pseudotypes as well as envelope-free particles. HIV-1 Env or VSV-G are required for Tat-assisted transduction, which is abrogated by an antibody blocking the HIV-1 Env,CD4 interaction. Tat-assisted transduction is mediated by the cysteine-rich region of Tat, which is known to be essential for Tat transactivation activity. However, Tat transactivation is not required for Tat-assisted transduction, as indicated by the enhancement of transduction by transactivation-silent Tat mutants. Conclusions Immobilized Tat promotes virus transduction by a transactiva- tion-independent mechanism, which requires binding of virus to Tat. Recombinant Tat or Tat fragments provide a new method to increase efficiency of retro- and lentiviral based gene transfer and gene therapy. Copyright © 2009 John Wiley & Sons, Ltd. [source] Primary motor cortical metaplasticity induced by priming over the supplementary motor areaTHE JOURNAL OF PHYSIOLOGY, Issue 20 2009Masashi Hamada Motor cortical plasticity induced by repetitive transcranial magnetic stimulation (rTMS) sometimes depends on the prior history of neuronal activity. These effects of preceding stimulation on subsequent rTMS-induced plasticity have been suggested to share a similar mechanism to that of metaplasticity, a homeostatic regulation of synaptic plasticity. To explore metaplasticity in humans, many investigations have used designs in which both priming and conditioning are applied over the primary motor cortex (M1), but the effects of priming stimulation over other motor-related cortical areas have not been well documented. Since the supplementary motor area (SMA) has anatomical and functional cortico-cortical connections with M1, here we studied the homeostatic effects of priming stimulation over the SMA on subsequent rTMS-induced plasticity of M1. For priming and subsequent conditioning, we employed a new rTMS protocol, quadripulse stimulation (QPS), which produces a broad range of motor cortical plasticity depending on the interval of the pulses within a burst. The plastic changes induced by QPS at various intervals were altered by priming stimulation over the SMA, which did not change motor-evoked potential sizes on its own but specifically modulated the excitatory I-wave circuits. The data support the view that the homeostatic changes are mediated via mechanisms of metaplasticity and highlight an important interplay between M1 and SMA regarding homeostatic plasticity in humans. [source] Oxidation of alkanes and alcohols with hydrogen peroxide catalyzed by complex Os3(CO)10(µ-H)2,APPLIED ORGANOMETALLIC CHEMISTRY, Issue 6 2010Georgiy B. Shul'pin Abstract Trinuclear carbonyl hydride cluster, Os3(CO)10(µ-H)2, catalyzes oxidation of cyclooctane to cyclooctyl hydroperoxide by hydrogen peroxide in acetonitrile solution. The hydroperoxide partly decomposes in the course of the reaction to afford cyclooctanone and cyclooctanol. Selectivity parameters obtained in oxidations of various linear and branched alkanes as well as kinetic features of the reaction indicated that the alkane oxidation occurs with the participation of hydroxyl radicals. A similar mechanism operates in transformation of benzene into phenol and styrene into benzaldehyde. The system also oxidizes 1-phenylethanol to acetophenone. The kinetic study led to a conclusion that oxidation of alcohols does not involve hydroxyl radicals as main oxidizing species and apparently proceeds with the participation of osmyl species, ,OsO'. Copyright © 2010 John Wiley & Sons, Ltd. [source] Gabapentin withdrawal syndrome in the presence of a taperBIPOLAR DISORDERS, Issue 3 2005Kien T Tran Objective:, To report a case report of a geriatric patient with a 5-year history of gabapentin use for enhanced bipolar control, who was tapered off of gabapentin over 1 week. The patient displayed unique withdrawal symptoms after the taper of gabapentin. Methods:, The patient is an 81-year-old white female with a life-long history of schizoaffective disorder with bipolar type I tendencies who had been prescribed gabapentin for 5 years. Results:, The patient displayed moderate upper respiratory tract infection symptoms and somatic complaints 1 day after termination of gabapentin. These symptoms gradually worsened until 10 days after, at which time she acutely developed severe mental status changes, severe somatic chest pain, and hypertension. Physical examination, electrolytes, electrocardiogram, computerized tomography, magnetic resonance imaging, and magnetic resonance angiography were all normal. Upon reintroduction of gabapentin, the patient returned to baseline within 1,2 days. Conclusions:, Gabapentin is widely utilized currently for the chronic treatment of recalcitrant migraines, bipolar illness, pain, and epilepsy. It has a wide therapeutic index with few side effects and drug interactions, is not hepatically metabolized, and is excreted by the kidneys. Past reports have suggested that some withdrawal symptoms can present after 1,2 days upon abrupt discontinuation of gabapentin after chronic use within young to middle-aged patients. These symptoms mimic that of alcohol and benzodiazepine withdrawal purportedly due to a similar mechanism of action. Unique to this case is that this geriatric patient developed debilitating withdrawal symptoms after a gradual, week-long taper of gabapentin along with flu-like symptoms. It is proposed herein that a gabapentin taper should follow a course similar to that of a benzodiazepine taper , slowly and over a period of weeks to months. [source] Subaqueous artesian springs and associated spring pits in a Himalayan pondBOREAS, Issue 2 2003ERICH DRAGANITS Subaqueous, bowl-shaped depressions found in a Himalayan pond formed in an abandoned river channel in the Lingti Valley (Spiti, NW India) are spring pits (Quirke 1930). The occurrence of the spring pits is restricted to the western end of the pond, where coarse-grained, highly permeable alluvial fan material continues below lacustrine mud deposits. The spring pits formed by active vertical discharge of ground water from an underlying artesian alluvial fan aquifer, confined by the overlying fine-grained lacustrine sediments. The aquifer is continuously recharged by down-slope ground-water flow in the alluvial fan. These small artesian springs are comparable with much larger artesian springs described in the literature and a similar mechanism of formation is proposed. Some similarities in their shapes and mechanisms of formation may indicate that spring pits represent small, nearshore examples of pockmarks. The differences of these features, formed by persistent fluidization from short-lived seismic liquefaction processes, are discussed and the utility of the structures for palaeo-environmental and palaeo-ground-water interpretation is evaluated. [source] A Proposed Mechanism for the Reductive Ring Opening of the Cyclodiphosphate MEcPP, a Crucial Transformation in the New DXP/MEP Pathway to Isoprenoids Based on Modeling Studies and Feeding ExperimentsCHEMBIOCHEM, Issue 3 2004Wolfgang Brandt Dr. Abstract Experimental and theoretical investigations concerning the second-to-last step of the DXP/MEP pathway in isoprenoid biosynthesis in plants are reported. The proposed intrinsic or late intermediates 4-oxo-DMAPP (12) and 4-hydroxy-DMAPP (11) were synthesized in deuterium- or tritium-labeled form according to new protocols especially adapted to work without protection of the diphosphate moiety. When the labeled compounds MEcPP (7), 11, and 12 were applied to chromoplast cultures, aldehyde 12 was not incorporated. This finding is in agreement with a mechanistic and structural model of the responsible enzyme family: a three-dimensional model of the fragment L271,A375 of the enzyme GcpE of Streptomyces coelicolor including NADPH, the Fe4S4cluster, and MEcPP (7) as ligand has been developed based on homology modeling techniques. The model has been accepted by the Protein Data Bank (entry code 1OX2). Supported by this model, semiempirical PM3 calculations were performed to analyze the likely catalysis mechanism of the reductive ring opening of MEcPP (7), hydroxyl abstraction, and formation of HMBPP (8). The mechanism is characterized by a proton transfer (presumably from a conserved arginine 286) to the substrate, accompanied by a ring opening without high energy barriers, followed by the transfer of two electrons delivered from the Fe4S4cluster, and finally proton transfer from a carboxylic acid side chain to the hydroxyl group to be removed from the ligand as water. The proposed mechanism is in agreement with all known experimental findings and the arrangement of the ligand within the enzyme. Thus, a very likely mechanism for the second to last step of the DXP/MEP pathway in isoprenoid biosynthesis in plants is presented. A principally similar mechanism is also expected for the reductive dehydroxylation of HMBPP (8) to IPP (9) and DMAPP (10) in the last step. [source] Anisotropic contraction in forisomes: Simple models won't fitCYTOSKELETON, Issue 5 2008Winfried S. Peters Abstract Forisomes are ATP-independent, Ca2+ -driven contractile protein bodies acting as reversible valves in the phloem of plants of the legume family. Forisome contraction is anisotropic, as shrinkage in length is associated with radial expansion and vice versa. To test the hypothesis that changes in length and width are causally related, we monitored Ca2+ - and pH-dependent deformations in the exceptionally large forisomes of Canavalia gladiata by high-speed photography, and computed time-courses of derived geometric parameters (including volume and surface area). Soybean forisomes, which in the resting state resemble those of Canavalia geometrically but have less than 2% of the volume, were also studied to identify size effects. Calcium induced sixfold volume increases in forisomes of both species; in soybean, responses were completed in 0.15 s, compared to about 0.5 s required for a rapid response in Canavalia followed by slow swelling for several minutes. This size-dependent behavior supports the idea that forisome contractility might rest on similar mechanisms as those of polyelectrolyte gels, a class of artificial "smart" materials. In both species, time-courses of forisome length and diameter were variable and lacked correlation, arguing against a simple causal relationship between changes in length and width. Moreover, changes in the geometry of soybean forisomes differed qualitatively between Ca2+ - and pH-responses, suggesting that divalent cations and protons target different sites on the forisome proteins. Cell Motil. Cytoskeleton 2008. © 2008 Wiley-Liss, Inc. [source] Short-term nocturnal hypoglycaemia increases morning food intake in healthy humansDIABETIC MEDICINE, Issue 2 2008S. M. Schmid Abstract Aims Hypoglycaemia during wakefulness increases hunger and food intake. Patients with Type 1 diabetes mellitus are at high risk of recurrent hypoglycaemia and weight gain. Given the background of frequent hypoglycaemic episodes during night-time sleep in diabetic patients, we investigated morning food intake after nocturnal hypoglycaemia. Methods We tested 16 healthy normal-weight subjects (eight women) on three nights. A linear fall in plasma glucose to a nadir of 2.2 mmol/l within 60 min was induced by insulin infusion immediately after sleep onset (,early hypo') or after about 3.5 h of sleep (,late hypo'). On a control night, no hypoglycaemia was induced. Spontaneous food intake at a breakfast buffet was registered on the subsequent morning. Results Compared with the control condition (700 ± 93 kcal), subjects ate more after ,late hypo' (867 ± 108 kcal; P = 0.041), but not after ,early hypo' (852 ± 111 kcal; P = 0.130). Analyses of macronutrient fractions revealed that in comparison with the control condition, subjects ate significantly more carbohydrates after both ,late hypo' (277 ± 25 kcal vs. 206 ± 23 kcal, P < 0.001) and ,early hypo' (245 ± 23 kcal, P = 0.048), with this effect being more pronounced after late than early nocturnal hypoglycaemia (P = 0.026). Conclusions In healthy subjects, nocturnal hypoglycaemia during sleep stimulates spontaneous food intake the following morning, with carbohydrate intake being especially affected. Effects were more pronounced after ,late hypo', suggesting the influence of temporal dynamics. Although healthy non-diabetic subjects were studied, similar mechanisms may contribute to the frequently observed body weight gain in insulin-treated diabetic patients. [source] Antimutagenicity of green tea polyphenols in the liver of transgenic medakaENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 2 2005Richard N. Winn Abstract We examined the ability of a mixture of the predominant green tea polyphenolic compounds (GTP) to reduce benzo[a]pyrene (B[a]P)-induced mutations in the cII gene of the , transgenic medaka. Fish were treated with 50 ppb B[a]P for 24 hr, followed by exposure to 2 ppm or 10 ppm GTP for 28 days. cII mutations in livers of fish exposed to B[a]P were increased significantly, 2.6-fold above controls. In contrast, the addition of GTP significantly reduced the frequency of cII mutants by 84%, comparable to that of controls. The frequencies of mutations at G:C basepairs, mutations that are highly characteristic of B[a]P exposure, were elevated significantly in treated fish. By comparison, B[a]P-exposed fish also treated with GTP showed reductions in these mutations, demonstrating a protective effect of GTP against B[a]P-induced mutagenesis. The antioxidant mechanism of GTP possibly played an important role in the reduction of B[a]P mutagenicity. These results corroborate findings from rodent models, showing that the protective effects of green tea extend to different species, and suggesting that similar mechanisms of B[a]P mutagenesis and GTP antimutagenesis are shared among the models. These studies illustrate the utility of , transgenic medaka for in vivo mutation analyses and suggest that this fish may be a valuable model in chemoprevention studies. Environ. Mol. Mutagen., 2005. © 2005 Wiley-Liss, Inc. [source] Antiepileptic Drugs: How They Work in HeadacheHEADACHE, Issue 2001F. Michael Cutrer MD Antiepileptic drugs (AEDs) are promising agents for the prevention of migraine and other head pain. Migraine and epilepsy share several clinical features and respond to many of the same pharmacologic agents, suggesting that similar mechanisms may be involved in their pathophysiology. The mechanisms of action of AEDs are not fully understood, and a single drug may have more than one mechanism, both in epilepsy and in migraine. Valproate, topiramate, and gabapentin are likely to affect nociception by modulating gamma-aminobutyric acid- (GABA-) and/or glutamate-mediated neurotransmission. All three AEDs enhance GABA-mediated inhibition. Valproate and gabapentin interfere with GABA metabolism to prevent its ultimate conversion to succinate, and topiramate potentiates GABA-mediated inhibition by facilitating the action of GABA receptors. In addition, topiramate acts directly on non- N -methyl-D-aspartate, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate glutamate receptors. Valproate, topiramate, and possibly gabapentin inhibit sodium ion channels. All three drugs modulate calcium ion channel activity. Valproate blocks T-type calcium ion channels; topiramate inhibits high-voltage-activated L-type calcium ion channels; and gabapentin binds to the ,2, subunit of L-type calcium ion channels. AEDs may be useful in migraine prevention through such mechanisms as modulating the biochemical phenomena of aura or acting directly on the nociceptive system. Further evaluations of AEDs in migraine models will provide a better understanding of the pathophysiology and prevention of migraine. [source] The effect of single oral low-dose losartan on posture-related sodium handling in post-TIPS ascites-free cirrhosis,HEPATOLOGY, Issue 3 2006George Therapondos Post-TIPS ascites-free patients with cirrhosis and previous refractory ascites demonstrate subtle sodium retention when challenged with a high sodium load. This is also observed in pre-ascitic patients with cirrhosis. This phenomenon is dependent on an intrarenal angiotensin II (ANG II) mechanism related to the assumption of erect posture. We investigated whether similar mechanisms were involved in post-TIPS ascites-free patients, by studying 10 patients with functioning TIPS and no ascites. We measured the effect of changing from supine to erect posture on sodium excretion at baseline and after single oral low dose losartan (7.5 mg) which has been shown to blunt proximal and distal tubular sodium reabsorption in pre-ascites. At baseline, the assumption of erect posture produced a reduction in sodium excretion (from 0.30 ± 0.06 to 0.13 ± 0.02 mmol/min, P = .05), which was mainly due to an increase in proximal tubular reabsorption of sodium (PTRNa) (69.7 ± 3.1% to 81.1 ± 1.8%, P = .003). The administration of losartan resulted in a blunting of PTRNa (supine 69.7 ± 3.1% to 63.9 ± 3.9%, P = .01 and erect 81.1 ± 1.8% to 73.8 ± 2.4%, P = .01), accompanied by an increased distal tubular reabsorption of sodium in both postures, with no overall improvement in sodium excretion on standing. In conclusion, post-TIPS ascites-free patients with cirrhosis exhibit erect posture-induced sodium retention. We speculate that (1) this effect is partly mediated by the effect of ANG II on PTRNa and (2) that the inability of low dose losartan to block the erect posture-induced sodium retention may be related to the erect posture-induced rise in aldosterone which is unmodified by losartan. (HEPATOLOGY 2006;44:640,649.) [source] Tyrosine phosphorylation of the GluR2 subunit is required for long-term depression of synaptic efficacy in young animals in vivoHIPPOCAMPUS, Issue 8 2007Christopher J. Fox Abstract The study of the intracellular mechanics that underlay changes in synaptic efficacy is a rapidly evolving field of research. It is currently believed that NMDA receptors play a significant role in the induction of synaptic plasticity, whereas AMPA receptors play a significant role in its expression. For AMPA receptors, it has been shown that tyrosine phosphorylation of the GluR2 carboxyl termini is required for the expression of long-term depression of synaptic efficacy (LTD) in vitro (Ahmadian et al. (2004) EMBO J 23:1040,1050). In the present study, we sought to determine whether similar mechanisms are involved in vivo, where different stimulation parameters are required for the induction of LTD. We initially used a paired-burst (PB) paradigm that reliably induces LTD in vivo. In these animals we were able to prevent the induction and expression of PB-LTD by administering a peptide (GluR-3Y) that acted as a competitive inhibitor of tyrosine phosphorylation. In a separate set of animals, we exposed animals to brief periods of stress (S) before using low-frequency stimuli to induce LTD (S-LTD). Again, GluR2,3Y blocked both the induction and expression of S-LTD. In contrast, an inert version of the peptide, with alanine replacing the three tyrosine residues, did not inhibit LTD induction. In addition, we demonstrated that GluR2,3Y did not affect the induction of long-term potentiation in vivo. These findings support the hypothesis that tyrosine phosphorylation and AMPA receptor endocytosis are necessary steps for the induction and maintenance of two forms of LTD in the CA1 region. © 2007 Wiley-Liss, Inc. [source] Sarcopenia is prevalent in patients with Crohn's disease in clinical remissionINFLAMMATORY BOWEL DISEASES, Issue 11 2008Stéphane M. Schneider MD Abstract Background: Patients with Crohn's disease (CD) are prone to osteoporosis. A loss of muscle mass, called sarcopenia, is responsible for an increased risk of disability. Many factors associated with osteopenia also decrease muscle mass. The aim of the present study was to measure the prevalence of sarcopenia in CD patients in remission and uncover its relationship with osteopenia. Methods: In all, 82 CD patients (43 female / 39 male; 36 ± 14 years; body mass index [BMI] 21.1 ± 3.4) and 50 healthy volunteers (30F/20M; 39 ± 13 years; BMI 22.2 ± 2.5) were studied. Body composition was assessed using dual-energy x-ray absorptiometry. Sarcopenia was defined as an appendicular skeletal muscle index (ASMI) below 5.45 kg/m2 for women and 7.26 for men. Osteopenia was defined as a T-score for bone mineral density (BMD) (g/cm2) below ,1.0. Results: In all, 60% of CD patients were found to be sarcopenic and 30% osteopenic, compared to 16% and 4% of controls, respectively (P < 0.01). ASMI was significantly lower in patients than in controls (6.0 ± 1.1 versus 6.5 ± 1.2; P < 0.05). Sarcopenic patients had significantly (P < 0.01) lower BMI (20.0 ± 3.5 versus 22.7 ± 2.8 kg/m2), lean mass (41.5 ± 9.1 versus 48.1 ± 9.1 kg), and BMD (1.09 ± 0.12 versus 1.15 ± 0.08 g/cm2) than nonsarcopenic patients; 91% of sarcopenic patients were also osteopenic. ASMI correlated with BMD (r = 0.46; P < 0.01) and BMI (r = 0.38; P < 0.01). Conclusions: The prevalence of sarcopenia is high in young CD patients and strongly related to osteopenia. These 2 phenomena may share similar mechanisms. Simultaneous screening for sarcopenia and osteopenia may be useful in CD patients. (Inflamm Bowel Dis 2008) [source] Mechanical implications of estrogen supplementation in early postmenopausal womenJOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2010Felix W Wehrli Abstract Whereas the structural implications of drug intervention are well established, there are few data on the possible mechanical consequences of treatment. In this work we examined the changes in elastic and shear moduli (EM and SM) in a region of trabecular bone in the distal radius and distal tibia of early postmenopausal women on the basis of MRI-based micro-finite-element (µFE) analysis. Whole-section axial stiffness (AS) encompassing both trabecular and cortical compartments was evaluated as well. The study was conducted on previously acquired high-resolution images at the two anatomic sites. Images were processed to yield a 3D voxel array of bone-volume fraction (BVF), which was converted to a µFE model of hexahedral elements in which tissue modulus was set proportional to voxel BVF. The study comprised 65 early postmenopausal women (age range 45 to 55 years), of whom 32 had chosen estrogen supplementation (estradiol group); the remainder had not (control group). Subjects had been scanned at baseline and 12 and 24 months thereafter. At the distal tibia, EM and SM were reduced by 2.9% to 5.5% in the control group (p,<,.05 to <.005), but there was no change in the estradiol subjects. AS decreased 3.9% (4.0%) in controls (p,<,.005) and increased by 5.8% (6.2%) in estradiol group subjects (p,<,.05) at 12 (24) months. At the distal radius, EM and SM changes from baseline were not significant, but at both time points AS was increased in estradiol group subjects and decreased in controls (p,<,.005 to <.05), albeit by a smaller margin than at the tibia. EM and SM were strongly correlated with BV/TV (r2,=,0.44 to 0.92) as well as with topologic parameters expressing the ratio of plates to rods (r2,=,0.45 to 0.82), jointly explaining up to 96% of the variation in the mechanical parameters. Finally, baseline AS was strongly correlated between the two anatomic sites (r2,=,0.58), suggesting that intersubject variations in the bone's mechanical competence follows similar mechanisms. In conclusion, the results demonstrate that micro-MRI-based µFE models are suited for the study of the mechanical implications of antiresorptive treatment. The data further highlight the anabolic effect of short-term estrogen supplementation. © 2010 American Society for Bone and Mineral Research [source] The efficiency of mitochondrial electron transport chain is increased in the long-lived mrg19 Saccharomyces cerevisiaeAGING CELL, Issue 6 2009Nitish Mittal Summary Integrity of mitochondrial functionality is a key determinant of longevity in several organisms. In particular, reduced mitochondrial ROS (mtROS) production leading to decreased mtDNA damage is believed to be a crucial aspect of longevity. The generation of low mtROS was thought to be due to low mitochondrial oxygen consumption. However, recent studies have shown that higher mitochondrial oxygen consumption could still result in low mtROS and contribute to longevity. This increased mitochondrial efficiency (i.e. low mtROS generated despite high oxygen consumption) was explained as a result of mitochondrial biogenesis, which provides more entry points for the electrons to the electron transport chain (ETC), thereby resulting in low mtROS production. In this study, we provide evidence for the existence of an alternative pathway to explain the observed higher mitochondrial efficiency in the long-lived mrg19 mutant of Saccharomyces cerevisiae. Although we observe similar amounts of mitochondria in mrg19 and wild-type (wt) yeast, we find that mrg19 mitochondria have higher expression of ETC components per mitochondria in comparison with the wt. These findings demonstrate that more efficient mitochondria because of increased ETC per mitochondria can also produce less mtROS. Taken together, our findings provide evidence for an alternative explanation for the involvement of higher mitochondrial activity in prolonging lifespan. We anticipate that similar mechanisms might also exist in eukaryotes including human. [source] Non-homologous DNA end joining in the mature rat brainJOURNAL OF NEUROCHEMISTRY, Issue 6 2002Keqin Ren Abstract Recent evidence suggests that DNA double strand breaks (DSBs) are introduced in neurons during the course of normal development, and that repair of such DSBs is essential for neuronal survival. Here we describe a non-homologous DNA end joining (NHEJ) system in the adult rat brain that may be used to repair DNA DSBs. In the brain NHEJ system, blunt DNA ends are joined with lower efficiency than cohesive or non-matching protruding ends. Moreover, brain NHEJ is blocked by DNA ligase inhibitors or by dATP and can occur in the presence or absence of exogenously added ATP. Comparison of NHEJ activities in several tissues showed that brain and testis share similar mechanisms for DNA end joining, whereas the activity in thymus seems to utilize different mechanisms than in the nervous system. The developmental profile of brain NHEJ showed increasing levels of activity after birth, peaking at postnatal day 12 and then gradually decreasing along with age. Brain distribution analysis in adult animals showed that NHEJ activity is differentially distributed among different regions. We suggest that the DNA NHEJ system may be utilized in the postnatal brain for the repair of DNA double strand breaks introduced within the genome in the postnatal brain. [source] Drug-induced apoptosis in osteosarcoma cell lines is mediated by caspase activation independent of CD95-receptor/ligand interactionJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 1 2000J. Fellenberg Osteosarcoma is one of the most common primary malignant tumors of bone. Treatment of this tumor with systemic chemotherapy dramatically improves the prognosis, although the molecular mechanisms involved in the drug action are poorly understood. In chemosensitive leukaemic T cells and certain solid tumors. cytotoxic drugs mediate the induction of apoptosis by activation of the CD95/APO-1/Fas system. Triggering of the corresponding signaling pathway may involve CD95-receptor/ligand interaction, activation of caspases, or alterations in mitochondrial function. The purpose of our study was to determine if similar mechanisms are involved in the chemosensitivity of osteosarcomas. We found that cytotoxic drugs induce characteristic biochemical and morphological alterations related to apoptosis in osteosarcoma cell lines, including activation of caspases and disturbance of mitochondrial function. However, drug treatment did not result in activation of CD95-receptor or CD95-ligand mRNA. In addition, drug-induced apoptosis was blocked by caspase inhibitors but not by inhibition of CD95-ligand action, indicating a CD95-receptor/ligand-independent mechanism in osteosarcoma cell lines. [source] | |||||||||||||||||||||||||||||||