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Normal Function (normal + function)
Selected AbstractsThe future: genes, physical activity and healthACTA PHYSIOLOGICA, Issue 4 2010F. W. Booth Abstract The assigned title for the Lindhard presentation was to examine the future of genes, physical activity and health. The current review is a summary of this presentation. Caution is expressed that technology is improving so rapidly that a future view is limited to a few years as opposed to the 100 years passing since Lindhard's achievements. The near futuristic opportunities and challenges for four major topic topics are reviewed here. Concerns are expressed over current usage of the terms ,control' group and ,non-responders' in exercise research. Our view is that ,control' needs to be differentiated between its usage for treatments of exercise to restore natural functions in individuals with less than healthy levels of physical activity and the inherited genome's expectation for physical activity levels to maintain normal function. For the second discussed topic, it is proposed that the term ,non-responders' should be replaced by the term ,low sensitivity' as there may be no such human who is a non-responder to every exercise adaptation. The third futuristic topic is exercise prescription as envisioned for individualized medicine. However, numerous limitations and challenges exist to truly optimal exercise medicine at the level of one individual. Finally, preventative physical activity medicine is discussed. Physical activity as a therapy now exists to prevent most of the chronic diseases. The future needs to understand the molecular basis for how the body becomes dysfunctional when its level of physical activity does not match the norm of physical activity that selected our inherited genome. [source] Mechanisms of metabotropic glutamate receptor-mediated synaptic signalling in cerebellar Purkinje cellsACTA PHYSIOLOGICA, Issue 1 2009J. Hartmann Abstract The metabotropic glutamate receptors type 1 (mGluR1s) are required for a normal function of the mammalian cerebellum. These G-protein-coupled receptors are abundantly expressed in the principle cerebellar cells, namely the Purkinje neurones. Under physiological conditions, mGluR1s are activated during repetitive activity of both afferent glutamatergic synaptic inputs provided by the climbing and parallel fibres respectively. Unlike the common ionotropic glutamate receptors that underlie rapid synaptic excitation, mGluR1s produce a complex post-synaptic response consisting of a Ca2+ -release signal from intracellular stores and a slow excitatory post-synaptic potential. While it is well established that the mGluR1-dependent Ca2+ -release signal from intracellular stores involves the activation of inositol-trisphosphate receptors, the mechanisms underlying the slow synaptic excitation remained unclear. Here we will review recent evidence indicating an essential role of C-type transient receptor potential (TRPC) cation channels, especially that of the subunit TRPC3, for the generation of the mGluR1-dependent synaptic current. For the signalling pathways underlying both, Ca2+ -release from intracellular stores and the slow synaptic potential, we present current knowledge about the activators, downstream effectors and possible roles for mGluR1-dependent signalling in Purkinje neurones. [source] Reattachment of subgingivally fractured central incisor with an open apexDENTAL TRAUMATOLOGY, Issue 3 2007Ece Eden Abstract,,, A case report of a 6-year-old girl with a fractured maxillary left central incisor with an open apex is presented. The procedure used to repair the fracture included flap surgery with an intrasulcular incision and endodontic treatment. The patient was called for 3 months regular follow-up to check the root formation. At the end of 32 months just before the root was obturated by guttaperka, she fractured the same tooth. Flap surgery was repeated and the tooth was restored. The root canal was obturated with a root filling paste and guttaperka as the apex was closed. Examination 10 months after treatment revealed good periodontal health, aesthetics and normal function. [source] Mutation in the abcb7 gene causes abnormal iron and fatty acid metabolism in developing medaka fishDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 9 2008Akimitsu Miyake The medaka fish (Oryzias latipes) is an emerging model organism for which a variety of unique developmental mutants have now been generated. Our recent mutagenesis screening of the medaka isolated a unique mutant that develops a fatty liver at larval stages. Positional cloning identified the responsible gene as medaka abcb7. Abcb7, a mitochondrial ABC (ATP binding cassette) half-transporter, has been implicated in iron metabolism. Recently, human Abcb7 was found to be mutated in X-linked sideroblastic anemia with cerebellar ataxia (XLSA/A). The homozygous medaka mutant exhibits abnormal iron metabolism in erythrocytes and accumulation of lipid in the liver. Microarray and in situ hybridization analyses demonstrated that the expression of genes involved in iron and lipid metabolisms are both affected in the mutant liver, suggesting novel roles of Abcb7 in the development of physiologically functional liver. The medaka abcb7 mutant thus could provide insights into the pathogenesis of XLSA/A as well as the normal function of the gene. [source] Developmental delay and unstable state of the testes in the rdw rat with congenital hypothyroidismDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 4 2004Yasuhiro Sakai From the present study of the rdw rat, it is clear that the thyroid hormone is essential for the development and maintenance of the testes. In previous studies, the thyroid hormone has few serious effects on the testes except during the neonatal stage when the thyroid hormone receptor is mainly present. However, there is little knowledge concerning the prolonged effect of thyroid hormone deficiency throughout the rat's life span. In the present study, a morphological analysis was performed on the testes of rdw rats with congenital hypothyroidism. The rdw testes required a longer time to develop into the normal adult structure. Moreover, the developed, normal structure began to degenerate after full maturation. Specific characteristics of the rdw testes include: (i) a prolonged proliferation of Sertoli cells during postnatal development; (ii) a developmental delay in the appearance of spermatocytes and spermatid; (iii) direct contact with each other for both spermatocytes and spermatids, without Sertoli cell cytoplasm completely intervening between adjacent germ cells; (iv) subsequent apoptosis of germ cells after maturation; (v) reduction in the height of the seminiferous epithelium; and (vi) lower testosterone levels in the rdw rats, especially during old age. Thus, we conclude that the thyroid hormone plays an important role in developing and maintaining normal function of testes. [source] Drosophila neuromuscular synapse assembly and function require the TGF-, type I receptor saxophone and the transcription factor MadDEVELOPMENTAL NEUROBIOLOGY, Issue 2 2003Joel M. Rawson Abstract Transforming growth factor-,s (TGF-,) comprise a superfamily of secreted proteins with diverse functions in patterning and cell division control. TGF-, signaling has been implicated in synapse assembly and plasticity in both vertebrate and invertebrate systems. Recently, wishful thinking, a Drosophila gene that encodes a protein related to BMP type II receptors, has been shown to be required for the normal function and development of the neuromuscular junction (NMJ). These findings suggest that a TGF-,-related ligand activates a signaling cascade involving type I and II receptors and the Smad family of transcription factors to orchestrate the assembly of the NMJ. Here we demonstrate that the TGF-, type I receptor Saxophone and the downstream transcription factor Mothers against dpp (Mad) are essential for the normal structural and functional development of the Drosophila NMJ, a synapse that displays activity-dependent plasticity. © 2003 Wiley Periodicals, Inc. J Neurobiol 55: 134,150, 2003 [source] Visual Quantitative Estimation: Semiquantitative Wall Motion Scoring and Determination of Ejection FractionECHOCARDIOGRAPHY, Issue 5 2003M.D., Steven J. Lavine Ejection fraction (EF) is the most commonly used parameter of left ventricular (LV) systolic function and can be assessed by echocardiography. Quantitative echocardiography is time consuming and is as accurate as visual estimation, which has significant variability. We hypothesized that each echocardiographer has developed a mental set of guidelines that relate to how much individual segment shortening constitutes normal function or hypokinesis of varying extents. We determined the accuracy of applying these guidelines to an accepted technique of EF determination using a retrospective analysis of consecutive two-dimensional echocardiographic studies performed on patients who had radioventriculography (RVG) within 48 hours. Using a 12 segment model, we scored each segment at the base and mid-ventricular level based on segmental excursion and thickening. The apex was scored similarly but with 1/3 of the value based on a cylinder-cone model. EF was determined from the sum of segment scores and was estimated visually. We termed this approach visual quantitative estimation (VQE). We correlated the EF derived from VQE and visual estimation with RVG EF. In the training set, VQE demonstrated a strong correlation with RVG(r = 0.969), which was significantly greater than visual estimation(r = 0.896, P < 0.01). The limits of agreement for VQE (+12% to ,7%) were similar to the limits of RVG agreement with contrast ventriculography (+10% to ,11%) with similar intraobserver and interobserver variabilities. Similar correlation was noted in the prediction set between VQE and RVG EF(r = 0.967, P < 0.001). We conclude that VQE provides highly correlated estimates of EF with RVG. (ECHOCARDIOGRAPHY, Volume 20, July 2003) [source] Translating nociceptor sensitivity: the role of axonal protein synthesis in nociceptor physiologyEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2009Theodore J. Price Abstract The increased sensitivity of peripheral pain-sensing neurons, or nociceptors, is a major cause of the sensation of pain that follows injury. This plasticity is thought to contribute to the maintenance of chronic pain states. Although we have a broad knowledge of the factors that stimulate changes in nociceptor sensitivity, the cellular mechanisms that underlie this plasticity are still poorly understood; however, they are likely to involve changes in gene expression required for the phenotypic and functional changes seen in nociceptive neurons after injury. While the regulation of gene expression at the transcriptional level has been studied extensively, the regulation of protein synthesis, which is also a tightly controlled process, has only recently received more attention. Despite the established role of protein synthesis in the plasticity of neuronal cell bodies and dendrites, little attention has been paid to the role of translation control in mature undamaged axons. In this regard, several recent studies have demonstrated that the control of protein synthesis within the axonal compartment is crucial for the normal function and regulation of sensitivity of nociceptors. Pathways and proteins regulating this process, such as the mammalian target of rapamycin signaling cascade and the fragile X mental retardation protein, have recently been identified. We review here recent evidence for the regulation of protein synthesis within a nociceptor's axonal compartment and its contribution to this neuron's plasticity. We believe that an increased understanding of this process will lead to the identification of novel targets for the treatment of chronic pain. [source] Hypothalamic,endocrine aspects in Huntington's diseaseEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2006Åsa Petersén Abstract Huntington's disease (HD) is a hereditary and fatal disorder caused by an expanded CAG triplet repeat in the HD gene, resulting in a mutant form of the protein huntingtin. Wild-type and mutant huntingtin are expressed in most tissues of the body but the normal function of huntingtin is not fully known. In HD, the neuropathology is characterized by intranuclear and cytoplasmic inclusions of huntingtin aggregates, and cell death primarily in striatum and cerebral cortex. However, hypothalamic atrophy occurs at early stages of HD with loss of orexin- and somatostatin-containing cell populations. Several symptoms of HD such as sleep disturbances, alterations in circadian rhythm, and weight loss may be due to hypothalamic dysfunction. Endocrine changes including increased cortisol levels, reduced testosterone levels and increased prevalence of diabetes are found in HD patients. In HD mice, alterations in the hypothalamic,pituitary,adrenal axis occurs as well as pancreatic ,-cell and adipocyte dysfunction. Increasing evidence points towards important pathology of the hypothalamus and the endocrine system in HD. As many neuroendocrine factors are secreted into the cerebrospinal fluid, blood and urine, it is possible that their levels may reflect the disease state in the central nervous system. Investigating neuroendocrine changes in HD opens up the possibility of finding biomarkers to evaluate future therapies for HD, as well as of identifying novel targets for therapeutic interventions. [source] Mapping the functional domain of the prion proteinFEBS JOURNAL, Issue 16 2003Taian Cui Prion diseases such as Creutzfeldt,Jakob disease are possibly caused by the conversion of a normal cellular glycoprotein, the prion protein (PrPc) into an abnormal isoform (PrPSc). The process that causes this conversion is unknown, but to understand it requires a detailed insight into the normal activity of PrPc. It has become accepted from results of numerous studies that PrPc is a Cu-binding protein and that its normal function requires Cu. Further work has suggested that PrPc is an antioxidant with an activity like that of a superoxide dismutase. We have shown in this investigation that this activity is optimal for the whole protein and that deletion of parts of the protein reduce or abolish this activity. The protein therefore contains an active domain requiring certain regions such as the Cu-binding octameric repeat region and the hydrophobic core. These regions show high evolutionary conservation fitting with the idea that they are important to the active domain of the protein. [source] The N-terminal cysteine pair of yeast sulfhydryl oxidase Erv1p is essential for in vivo activity and interacts with the primary redox centreFEBS JOURNAL, Issue 7 2003Götz Hofhaus Yeast Erv1p is a ubiquitous FAD-dependent sulfhydryl oxidase, located in the intermembrane space of mitochondria. The dimeric enzyme is essential for survival of the cell. Besides the redox-active CXXC motif close to the FAD, Erv1p harbours two additional cysteine pairs. Site-directed mutagenesis has identified all three cysteine pairs as essential for normal function. The C-terminal cysteine pair is of structural importance as it contributes to the correct arrangement of the FAD-binding fold. Variations in dimer formation and unique colour changes of mutant proteins argue in favour of an interaction between the N-terminal cysteine pair with the redox centre of the partner monomer. [source] Clinical Benefits of Early Triptan Therapy for MigraineHEADACHE, Issue 2002Julio Pascual MD Although triptans have been proven effective for acute treatment of migraine, reserving them for moderate or severe pain may produce suboptimal pain relief and higher rates of recurrence. Recent evidence indicates that early intervention at the onset of pain improves outcomes. Post hoc analysis of a long-term, open-label European study of almotriptan 12.5 mg found that the percentage of attacks rendered pain-free at 2 hours was significantly greater when patients treated mild pain (84%) than when the intervention occurred during moderate or severe pain (53%). A similar pattern emerged with respect to the consistency of pain relief, with a significant advantage for early intervention (88% versus 56%, respectively). A difference in favor of early intervention was also seen with respect to recurrence, need for rescue medication, and adverse events. The recurrence rate was significantly lower in patients treating mild pain (28%) than in those delaying treatment until the pain became moderate or severe (33%), which suggests that achieving pain freedom results in less recurrence. These results were generally replicated in post hoc analysis of a subgroup of patients from a randomized, placebo-controlled trial (the Spectrum Study) of oral sumatriptan 50 mg in migraineurs. This analysis demonstrated that with early intervention, pain was less likely to intensify, fewer attacks required redosing, more attacks remained pain-free 24 hours postdose, and normal function returned more quickly. In sum, early intervention with triptans can improve outcomes, avoiding much of the pain and disability associated with treating moderate or severe attacks. [source] Mutation spectrum of MYO7A and evaluation of a novel nonsyndromic deafness DFNB2 allele with residual function,,HUMAN MUTATION, Issue 4 2008Saima Riazuddin Abstract Recessive mutations of MYO7A, encoding unconventional myosin VIIA, can cause either a deaf-blindness syndrome (type 1 Usher syndrome; USH1B) or nonsyndromic deafness (DFNB2). In our study, deafness segregating as a recessive trait in 24 consanguineous families showed linkage to markers for the DFNB2/USH1B locus on chromosome 11q13.5. A total of 23 of these families segregate USH1 due to 17 homozygous mutant MYO7A alleles, of which 14 are novel. One family segregated nonsyndromic hearing loss DFNB2 due to a novel three-nucleotide deletion in an exon of MYO7A (p.E1716del) encoding a region of the tail domain. We hypothesized that DFNB2 alleles of MYO7A have residual myosin VIIA. To address this question we investigated the effects of several mutant alleles by making green fluorescent protein (GFP) tagged cDNA expression constructs containing engineered mutations of mouse Myo7a at codons equivalent to pathogenic USH1B and DFNB2 alleles of human MYO7A. We show that in transfected mouse hair cells an USH1B mutant GFP-myosin VIIa does not localize properly to inner ear hair cell stereocilia. However, a GFP-myosin VIIa protein engineered to have an equivalent DFNB2 mutation to p.E1716del localizes correctly in transfected mouse hair cells. This finding is consistent with the hypothesis that p.E1716del causes a less severe phenotype (DFNB2) than the USH1B -associated alleles because the resulting protein retains some degree of normal function. Hum Mutat 29(4), 502,511, 2008. Published 2008 Wiley-Liss, Inc. [source] True corrected seminal fructose level: a better marker of the function of seminal vesicles in infertile menINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 5 2001Gustavo F. Gonzales This study was designed to determine if the value obtained after multiplying motile sperm concentration by seminal fructose concentration, named ,true corrected fructose', correlates with sperm motility in asthenozoospermic men. Forty-two male partners in infertile couples were studied. Men were treated with 100 mg daily of clomiphene citrate for 5 days. Blood and semen samples were collected before treatment and 24 h after the end of treatment. Serum testosterone, seminal fructose and sperm motility were measured in each subject. Corrected fructose (log. sperm concentration multiplied by seminal fructose), and true corrected fructose (log. motile sperm concentration multiplied by seminal fructose) values were calculated. Prevalence of asthenozoospermia was 42.85% (18 of 42). Prevalence of hypofunction of the seminal vesicles was 9.5% using seminal fructose as a marker; 40.5% using seminal corrected fructose as a marker and 47.6% using true corrected fructose as a marker of seminal vesicle function. Regression analysis showed a better coefficient of determination between true corrected fructose and motile sperm concentration (R2=0.20, p < 0.001) than with corrected fructose (R2=0.05, p < 0.1) or fructose concentration (R2=0.006, p < 0.5). Asthenozoospermia was observed in 22.7% of subjects with normal function of the seminal vesicles, and in 65% of men with low values of true corrected fructose (z=6.02, p < 0.0001). Multivariate analysis showed that sperm motility grade 3 improved after treatment with clomiphene if true corrected fructose increased (p < 0.002). In those men whose seminal vesicle function improved after clomiphene treatment, a reduction in the prevalence of asthenozoospermia from 50 to 28.6% (z=3.10, p < 0.002) was observed whereas in those whose seminal vesicles did not respond to clomiphene the prevalence of asthenozoospermia was not reduced (z=1.05; p: NS). In conclusion, true corrected fructose measurement relates with sperm motility in cases of asthenozoospermia. Asthenozoospermia improves with clomiphene treatment if seminal vesicle function improves after treatment. [source] Scanning electron micrograph analysis of hypomineralized enamel in permanent first molarsINTERNATIONAL JOURNAL OF PAEDIATRIC DENTISTRY, Issue 4 2005B. JÄLEVIK Summary. First molars with cream- to yellow-coloured demarcated opacities of the enamel, often in combination with severe loss of substance, are common in many child populations. The aetiology is obscure. Aim and Method., The aim of this study was to study the ultrastructure of the enamel of 10 affected teeth by means of scanning electron microscopy (SEM) in order to gain a better understanding of the clinical appearance and treatment problems of this condition, and to find some clues to its aetiology. Results., The basic enamel structure with enamel rods and interrod zones was found in porous parts of the enamel, as well as in normal parts, but the packing of the hydroxylapatite crystals seemed to be looser and less well organized in the porous parts. The border between normal and hypomineralized enamel was usually distinct, and followed the direction of the rods. The preserved basic structure indicates normal function of the ameloblasts during their secretion phase, but impaired function during their maturation stage. Conclusion., Considering the poor etch profile, it seems reasonable to recommend removal of all affected enamel surrounding the cavity, if possible, and to use a glass ionomer filling with its chemical bonding to tooth substrate, when restoring first molars with remaining affected enamel. [source] Genetic mapping of dominant white (W), a homozygous lethal condition in the horse (Equus caballus)JOURNAL OF ANIMAL BREEDING AND GENETICS, Issue 6 2004C. Mau Summary Dominant white coat colour (W) is a depigmentation syndrome, known in miscellaneous species. When homozygous in the horse (similar in mice), the mutation responsible for the white phenotype is lethal in a very early stage of gestation. It seems, that the action of the dominant white allele is not always fully penetrant, resulting occasionally in spotted look alike offspring. These horses resemble a coat colour pattern known as sabino spotting. So far, it is not known whether dominant white (W) and sabino spotting (S) share a common genetic background. In this study, a pedigree consisting of 87 horses segregating for dominant white (W) was used to genetically localize the horse (W)-locus. Microsatellite ASB23 was found linked to (W), which allowed us to map dominant white to a region on horse chromosome 3q22. Tyrosine kinase receptor (KIT) was previously mapped to this same chromosome region (3q21,22). KIT and its ligand (KITLG) are responsible for the normal function of melanogenesis, haematopoiesis and gametogenesis. So far, sequence analysis of different KIT gene fragments did not lead to new polymorphisms, except for a SNP detected in KIT intron 3 (KITSNPIn3). Additional microsatellites from ECA3q (TKY353 and LEX7), together with KITSNPIn3 allowed us to state more precisely the (W)-mutation. The positional results and comparative functional data strongly suggest that KIT encodes for the horse (W)-locus. Zusammenfassung Die dominant weisse Fellfarbe (W) ist eine Form der Depigmentierung, die bei vielen Spezies auftritt. Beim Pferd wirkt die Mutation für Dominant Weiss (W) in homozygoter Form (analog zur Maus), bereits in einem sehr frühen Stadium der Trächtigkeit letal. Es scheint, dass die Wirkung des dominant weissen Allels nicht immer mit vollständiger Penetranz erfolgt. Dies führt gelegentlich zu Nachkommen mit einer Art Schecken-Fellzeichnung. Solche Pferde sind phänotypisch mit den sogenannten ,,Sabino-Schecken,, vergleichbar. Es ist bis jetzt nicht bekannt ob Dominant Weiss (W) und Sabino-Scheckung (S) einen gemeinsamen genetischen Hintergrund besitzen. Mittels eines Pedigrees aus 87 Pferden, in dem Dominant Weiss (W) segregiert, konnte in der vorliegenden Studie der equine (W)-Locus genetisch lokalisiert werden. Der Mikrosatellit ASB23 erwies sich als gekoppelt mit (W) und ermöglichte die Zuweisung des (W)-Locus auf eine Region von Chromosom ECA 3q22. Das Gen für den Tyrosinkinaserezeptor (KIT) liegt ebenfalls in dieser Chromosomenregion (3q21,22). Das KIT -Gen ist zusammen mit dem KIT -Liganden (KITLG) verantwortlich für einen normal funktionierenden Ablauf der Melanogenese, Hämatopoese und Gametogenese. Die direkte Sequenzierung von KIT -Genfragmenten führte bis jetzt zu keinen neuen Polymorphismen, ausser einem SNP in KIT Intron 3 (KITSNPIn3). Mittels weiterer Mikrosatelliten von ECA3q (TKY353 and LEX7) sowie KITSNPIn3 gelang es, die (W)-Mutation genauer zu positionieren. Die vorliegenden Lokalisierungsresultate und vergleichende funktionelle Erkenntnisse deuten stark darauf hin, dass KIT für den Pferde (W)-Locus kodiert. [source] Sinus Pacemaker Function after Cardioversion of Chronic Atrial Fibrillation: Is Sinus Node Remodeling Related with Recurrence?JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 7 2001EMMANUEL G. MANIOS M.D. Sinus Node Remodeling and Atrial Fibrillation. Introduction: The objective of this study was to investigate the temporal changes in sinus node function in postcardioversion chronic atrial fibrillation (AF) patients and their possible relation with the recurrence rates of AF. Methods and Results: In 37 chronic AF patients, internally cardioverted to sinus rhythm, corrected sinus node recovery time (CSNRT), and the pattern of corrected return cycle lengths were assessed 5 to 20 minutes and 24 hours after conversion. The last 20 consecutive patients also were evaluated after autonomic blockade. Twenty subjects with normal atrial structure and no history of AF served as the control group. Patients were followed-up for 1 month for recurrence, and the density of supraventricular ectopic beats per hour was obtained during the first 24 hours after conversion. Fifteen patients (40.5%) relapsed during follow-up. CSNRT values at 600 msec (371 ± 182 msec) and 500 ms (445 ± 338 msec) were significantly higher than those of control subjects (278 ± 157 msec, P = 0.050, and 279 ± 130 msec, P = 0.037, respectively). Significant temporal changes in CSNRT also were observed during the first 24 hours after conversion (600 msec: 308 ± 120 msec, P = 0.034; 500 msec: 340 ± 208 msec, P = 0.017). No significant interaction and temporal effects were observed with regard to corrected return cycle length pattern. Similar data regarding CSNRT and corrected return cycle length pattern were obtained after autonomic blockade. Patients with abnormal CSNRT after cardioversion had higher recurrence rates (50%) than those with normal function (37%; P = NS). Patients who relapsed had a higher density of supraventricular ectopic beats per hour (159 ± 120) compared with those who did not (35 ± 37; P = 0.001). Conclusion: Depressed sinus node function is observed after conversion of chronic AF. Recovery from this abnormality and its independence from autonomic function suggest that AF remodels the sinus node. Our data do not support a causative role of sinus node function in AF recurrence, but they do indicate such a role for the density of atrial ectopic beats. [source] The effects of osmotic stress on the structure and function of the cell nucleusJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2010John D. Finan Abstract Osmotic stress is a potent regulator of the normal function of cells that are exposed to osmotically active environments under physiologic or pathologic conditions. The ability of cells to alter gene expression and metabolic activity in response to changes in the osmotic environment provides an additional regulatory mechanism for a diverse array of tissues and organs in the human body. In addition to the activation of various osmotically- or volume-activated ion channels, osmotic stress may also act on the genome via a direct biophysical pathway. Changes in extracellular osmolality alter cell volume, and therefore, the concentration of intracellular macromolecules. In turn, intracellular macromolecule concentration is a key physical parameter affecting the spatial organization and pressurization of the nucleus. Hyper-osmotic stress shrinks the nucleus and causes it to assume a convoluted shape, whereas hypo-osmotic stress swells the nucleus to a size that is limited by stretch of the nuclear lamina and induces a smooth, round shape of the nucleus. These behaviors are consistent with a model of the nucleus as a charged core/shell structure pressurized by uneven partition of macromolecules between the nucleoplasm and the cytoplasm. These osmotically-induced alterations in the internal structure and arrangement of chromatin, as well as potential changes in the nuclear membrane and pores are hypothesized to influence gene transcription and/or nucleocytoplasmic transport. A further understanding of the biophysical and biochemical mechanisms involved in these processes would have important ramifications for a range of fields including differentiation, migration, mechanotransduction, DNA repair, and tumorigenesis. J. Cell. Biochem. 109: 460,467, 2010. © 2009 Wiley-Liss, Inc. [source] Mechanical loading stimulates ecto-ATPase activity in human tendon cellsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2005M. Tsuzaki Abstract Response to external stimuli such as mechanical signals is critical for normal function of cells, especially when subjected to repetitive motion. Tenocytes receive mechanical stimuli from the load-bearing matrix as tension, compression, and shear stress during tendon gliding. Overloading a tendon by high strain, shear, or repetitive motion can cause matrix damage. Injury may induce cytokine expression, matrix metalloproteinase (MMP) expression and activation resulting in loss of biomechanical properties. These changes may result in tendinosis or tendinopathy. Alternatively, an immediate effector molecule may exist that acts in a signal-dampening pathway. Adenosine 5,-triphosphate (ATP) is a candidate signal blocker of mechanical stimuli. ATP suppresses load-inducible inflammatory genes in human tendon cells in vitro. ATP and other extracellular nucleotide signaling are regulated efficiently by two distinct mechanisms: purinoceptors via specific receptor,ligand binding and ecto-nucleotidases via the hydrolysis of specific nucleotide substrates. ATP is released from tendon cells by mechanical loading or by uridine 5,-triphosphate (UTP) stimulation. We hypothesized that mechanical loading might stimulate ecto-ATPase activity. Human tendon cells of surface epitenon (TSC) and internal compartment (TIF) were cyclically stretched (1 Hz, 0.035 strain, 2 h) with or without ATP. Aliquots of the supernatant fluids were collected at various time points, and ATP concentration (ATP) was determined by a luciferin-luciferase bioluminescence assay. Total RNA was isolated from TSC and TIF (three patients) and mRNA expression for ecto-nucleotidase was analyzed by RT-PCR. Human tendon cells secreted ATP in vitro (0.5,1 nM). Exogenous ATP was hydrolyzed within minutes. Mechanical load stimulated ATPase activity. ATP was hydrolyzed in mechanically loaded cultures at a significantly greater rate compared to no load controls. Tenocytes (TSC and TIF) expressed ecto-nucleotidase mRNA (ENTPD3 and ENPP1, ENPP2). These data suggest that motion may release ATP from tendon cells in vivo, where ecto-ATPase may also be activated to hydrolyze ATP quickly. Ecto-ATPase may act as a co-modulator in ATP load-signal modulation by regulating the half-life of extracellular purine nucleotides. The extracellular ATP/ATPase system may be important for tendon homeostasis by protecting tendon cells from responding to excessive load signals and activating injurious pathways. © 2005 Wiley-Liss, Inc. [source] A rapid onset, post-capture muscle necrosis in the Norway lobster, Nephrops norvegicus (L.) from the West coast of ScotlandJOURNAL OF FISH DISEASES, Issue 4 2000G D Stentiford A post-capture, abdominal muscle necrosis of rapid onset has been identified in Norway lobsters, Nephrops norvegicus (L.), captured off the West coast of Scotland. Economic losses, as a result of the mortality of these animals in transport, were encountered by Scottish wholesalers during the summer and autumn of 1999. Affected animals show a characteristic whitening of individual muscle fibres and fibre bundles of the abdomen within hours of capture, with a progression towards complete opacity of the abdominal musculature within a number of days. The pathology causes a loss of the normal function of the abdomen; thus, preventing the normal ,tail flip' swimming. Electron microscopy failed to reveal any obvious causative agent but showed that affected tissue displayed a progressive disruption of sarcomere organization, loss of Z-line material, condensation of myofibrils and infiltration of necrotic regions by granulocytes. SDS,PAGE of affected muscle tissue showed that there was a great reduction of most of the major contractile proteins. The condition most closely resembles idiopathic or spontaneous muscle necrosis, a pathology previously reported from both wild and cultured crustaceans. Damage to the integument in conjunction with exposure to various stressors during and immediately after capture is the most likely cause of the pathology. The rapid onset of the pathology has implications for the post-capture handling procedure for N. norvegicus and their subsequent vivier transport to market. It may also be partially responsible for the high mortality rate of undersized N. norvegicus returned to the sea after capture and aerial emersion. [source] Progranulin: normal function and role in neurodegenerationJOURNAL OF NEUROCHEMISTRY, Issue 2 2008Jason L. Eriksen Abstract Progranulin (PGRN) is a multifunctional protein that has attracted significant attention in the neuroscience community following the recent discovery of PGRN mutations in some cases of frontotemporal dementia. Most of the pathogenic mutations result in null alleles, and it is thought that frontotemporal dementia in these families results from PGRN haploinsufficiency. The neuropathology associated with PGRN mutations is characterized by the presence of tau-negative, ubiquitin-immunoreactive neuronal inclusions (frontotemporal lobar degeneration with ubiquitinated inclusions) that are also positive for the transactivation response DNA binding protein with Mr 43 kD. The clinical phenotype includes behavioral abnormalities, language disorders and parkinsonism but not motor neuron disease. There is significant clinical variation between families with different PGRN mutations and among members of individual families. The normal function of PGRN is complex, with the full-length form of the protein having trophic and anti-inflammatory activity, whereas proteolytic cleavage generates granulin peptides that promote inflammatory activity. In the periphery, PGRN functions in wound healing responses and modulates inflammatory events. In the CNS, PGRN is expressed by neurons and microglia; consequently, reduced levels of PGRN could affect both neuronal survival and CNS inflammatory processes. In this review, we discuss current knowledge of the molecular genetics, neuropathology, clinical phenotype and functional aspects of PGRN in the context of neurodegenerative disease. [source] Glutamine synthetase enhances the clearance of extracellular glutamate by the neural retinaJOURNAL OF NEUROCHEMISTRY, Issue 3 2002Iftach Shaked Abstract Clearance of synaptic glutamate by glial cells is required for the normal function of excitatory synapses and for prevention of neurotoxicity. Although the regulatory role of glial glutamate transporters in glutamate clearance is well established, little is known about the influence of glial glutamate metabolism on this process. This study examines whether glutamine synthetase (GS), a glial-specific enzyme that amidates glutamate to glutamine, affects the uptake of glutamate. Retinal explants were incubated in the presence of [14C]glutamate and glutamate uptake was assessed by measurement of the amount of radioactively labeled molecules within the cells and the amount of [14C]glutamine released to the medium. An increase in GS expression in Müller glial cells, caused by induction of the endogenous gene, did not affect the amount of glutamate accumulated within the cells, but led to a dramatic increase in the amount of glutamine released. This increase, which was directly correlated with the level of GS expression, was dependent on the presence of external sodium ions, and could be completely abolished by methionine sulfoximine, a specific inhibitor of GS activity. Our results demonstrate that GS activity significantly influences the uptake of glutamate by the neural retina and suggest that this enzyme may represent an important target for neuroprotective strategies. [source] Mitochondrial dysfunction in a neural cell model of spinal muscular atrophyJOURNAL OF NEUROSCIENCE RESEARCH, Issue 12 2009Gyula Acsadi Abstract Mutations of the survival motor neuron (SMN) gene in spinal muscular atrophy (SMA) lead to anterior horn cell death. The cause is unknown, but motor neurons depend substantially on mitochondrial oxidative phosphorylation (OxPhos) for normal function. Therefore, mitochondrial parameters were analyzed in an SMA cell culture model using small interfering RNA (siRNA) transfection that decreased Smn expression in NSC-34 cells to disease levels. Smn siRNA knock-down resulted in 35% and 66% reduced Smn protein levels 48 and 72 hr posttransfection, respectively. ATP levels were reduced by 14% and 26% at 48 and 72 hr posttransfection, respectively, suggesting decreased ATP production or increased energy demand in neural cells. Smn knock-down resulted in increased mitochondrial membrane potential and increased free radical production. Changes in activity of cytochrome c oxidase (CcO), a key OxPhos component, were observed at 72 hr with a 26% increase in oxygen consumption. This suggests a compensatory activation of the aerobic pathway, resulting in increased mitochondrial membrane potentials, a condition known to lead to the observed increase in free radical production. Further testing suggested that changes in ATP at 24 hr precede observable indices of cell injury at 48 hr. We propose that energy paucity and increased mitochondrial free radical production lead to accumulated cell damage and eventual cell death in Smn-depleted neural cells. Mitochondrial dysfunction may therefore be important in SMA pathology and may represent a new therapeutic target. © 2009 Wiley-Liss, Inc. [source] Topology and patch-clamp analysis of the sodium channel in relationship to the anti-lipid a antibody in campylobacteriosisJOURNAL OF NEUROSCIENCE RESEARCH, Issue 15 2008Seigo Usuki Abstract An infecting strain VLA2/18 of Campylobacter jejuni was obtained from an individual with campylobacteriosis and used to prepare chicken sera by experimental infection to investigate the role of serum anti-ganglioside antibodies in Guillain-Barré syndrome. Both sera of the patient and chicken contained anti-ganglioside antibodies and anti-Lipid A (anti-Kdo2-Lipid A) antibodies directed against the lipid A portion of the bacterial lipooligosaccharide. The anti-Kdo2-Lipid A activities inhibited voltage-gated Na (Nav) channel of NSC-34 cells in culture. We hypothesized that anti-Kdo2-Lipid A antibody acts on the functional inhibition of Nav1.4. To test this possibility, a rabbit peptide antibody (anti-Nav1.4 pAb) against a 19-mer peptide (KELKDNHILNHVGLTDGPR) on the , subunit of Nav1.4 was produced. Anti-Nav1.4 pAb was cross-reactive to Kdo2-Lipid A. Anti-Kdo2-lipid A antibody activity in the chicken serum was tested for the Na+ current inhibition in NSC-34 cells in combination with ,-Conotoxin and tetrodotoxin. Contrary to our expectations, the anti-Kdo2-Lipid A antibody activity was extended to Nav channels other than Nav1.4. By overlapping structural analysis, it was found that there might be multiple peptide epitopes containing certain dipeptides showing a structural similarity with v-Lipid A. Thus, our study suggests the possibility that there are multiple epitopic peptides on the extracellular domains of Nav1.1 to 1.9, and some of them may represent target sites for anti-Kdo2-Lipid A antibody, to induce neurophysiological changes in GBS by disrupting the normal function of the Nav channels. © 2008 Wiley-Liss, Inc. [source] Bone morphogenetic proteins 4, 6, and 7 are up-regulated in mouse spinal cord during experimental autoimmune encephalomyelitisJOURNAL OF NEUROSCIENCE RESEARCH, Issue 1 2008Jahan Ara Abstract Although spontaneous remyelination occurs in multiple sclerosis (MS), the extent of myelin repair is often inadequate to restore normal function. Oligodendrocyte precursors remaining in nonremyelinating MS plaques may be restricted by an inhibitory signal. Bone morphogenetic proteins (BMPs) have been implicated as repressors of oligodendrocyte development and inducers of astrogliogenesis. We hypothesized that BMPs are up-regulated in MS lesions and play a role in demyelination and astrogliosis. We examined expression of BMPs in an animal model of MS, chronic experimental autoimmune encephalomyelitis (EAE) induced by the myelin oligodendrocyte glycoprotein (MOG) peptide in C57BL/6 mice. By 14 days postimmunization, compared to those of control mice, the lumbar spinal cords of MOG-peptide EAE mice demonstrated prominent astrogliosis, infiltration of inflammatory cells, and disrupted expression of myelin proteins. Quantitative RT-PCR showed that expression of BMP4, BMP6, and BMP7 mRNA increased 2- to 4-fold in the lumbar spinal cords of animals with symptomatic EAE versus in vehicle-treated and untreated controls on days 14, 21, and 42 postimmunization. BMP2 mRNA expression was not altered. BMP4 mRNA was much more abundant in the spinal cords of all animals than was mRNA encoding BMP2, BMP6, and BMP7. Immunoblot analysis confirmed the increased expression of BMP4 in the EAE animals. Immunohistochemistry revealed increased BMP4 immunoreactivity in areas of inflammation in MOG-peptide EAE animals. BMP4 labeling was mostly limited to macrophages but was sometimes associated with astrocytes and oligodendrocytes. These results indicate that members of the BMP family are differentially expressed in adult spinal cord and are up-regulated during EAE. © 2007 Wiley-Liss, Inc. [source] Effects of Ethanol on Persistent Activity and Up-States in Excitatory and Inhibitory Neurons in Prefrontal CortexALCOHOLISM, Issue 12 2009John J. Woodward Background:, Elucidating mechanisms that underlie the neural actions of ethanol is critical for understanding how this drug affects behavior. Increasing evidence suggests that, in addition to mid-brain dopaminergic regions, higher cortical structures play an important role in the pathophysiology associated with alcohol abuse. Previous studies from this laboratory used a novel slice co-culture system to demonstrate that ethanol reduces network-dependent patterns of activity in excitatory pyramidal neurons of the prefrontal cortex (PFC). In the present study, we examine the effect of ethanol on the activity of fast-spiking (FS) interneurons, a sub-population of neurons critically involved in shaping cortical activity. Methods:, Slices containing the dorsolateral PFC were prepared from neonatal C57 mice and maintained in culture. After 2 to 3 weeks in vitro, whole-cell patch-clamp electrophysiology was used to monitor spontaneous episodes of persistent activity in prelimbic PFC neurons. In some experiments, the use-dependent NMDA receptor blocker, MK801, was included in the pipette recording solution to assess the contribution of NMDA receptors to up-states. Results:, MK801 reduced up-state amplitude and revealed underlying fast EPSPs in excitatory pyramidal neurons while having little effect on these parameters in FS interneurons. Despite this difference, ethanol (44 mM), significantly reduced up-state duration and up-state area in both pyramidal and FS interneurons. Conclusions:, These results suggest that ethanol reduces the activity of FS interneurons due to disruption of network-dependent activity. This would be expected to further impair the ability of PFC networks to carry out their normal function and may contribute to the adverse effects of ethanol on PFC-dependent behaviors. [source] Proximal interphalangeal joint instability in the dogJOURNAL OF SMALL ANIMAL PRACTICE, Issue 9 2003M. J. Guilliard A prospective study into the use of transarticular external skeletal fixation in the treatment of proximal interphalangeal instability was undertaken. Only dogs with soft tissue injuries were included. All the dogs except one were greyhounds or related breeds. A hypothesis was proposed that if the articular surfaces were held in normal congruency for a period of time then the development of periarticular fibrosis would alone give sufficient joint support. Joint congruency was maintained by the application of a unilateral external skeletal fixator for approximately three weeks. Complications were common and were due to frame impingement on the neighbouring digit, pin tract infection and pin loosening, and all resolved following frame removal and antibiotic therapy. Careful pinplacement and prophylactic antibiotic treatment prevented complications in subsequent cases. All dogs returned to normal function with no lameness, with the exception of one racing greyhound which had a recurrence of the instability. [source] Expression and Cytoskeletal Association of Integrin Subunits Is Selectively Increased in Rat Perivenous Hepatocytes After Chronic Ethanol AdministrationALCOHOLISM, Issue 12 2001Courtney S. Schaffert Background: For normal function and survival, hepatocytes require proper cell,extracellular matrix (ECM) contacts mediated by integrin receptors and focal adhesions. Previous studies have shown that chronic ethanol consumption selectively impairs perivenous (PV) hepatocyte attachment and spreading on various ECM substrates but increases expression of the ,1 integrin subunit, the common , subunit for two major hepatocyte-ECM receptors, ,1,1 and ,5,1 integrins. This study examined the effects of ethanol treatment on the expression and cytoskeletal distribution of ,1, ,5, and ,1 integrin subunits, the epidermal growth factor receptor (EGF-R), and the cytoskeletal proteins focal adhesion kinase, paxillin, vinculin, and actin in periportal and PV hepatocytes. Methods: Periportal and PV hepatocytes were isolated from control and ethanol-fed rats. For expression analysis, lysates were examined by SDS-PAGE and immunoblotting procedures. For cytoskeletal distribution studies, Triton-soluble and -insoluble (cytoskeletal) fractions from hepatocytes cultured on collagen IV were analyzed by SDS-PAGE and immunoblotting. Results: Chronic ethanol administration caused PV-specific increases in expression and cytoskeletal association of the integrin subunits. Although ethanol treatment did not affect expression of the EGF-R in either cell type, it did increase the association of the EGF-R with the cytoskeleton selectively in PV hepatocytes. Ethanol treatment had no significant effect on either the expression or the cytoskeletal distribution of focal adhesion kinase, paxillin, vinculin, or actin in either cell type. Conclusions: The increases in integrin expression and cytoskeletal association observed after chronic ethanol administration suggest that a process downstream of integrin-ECM interactions is impaired selectively in PV hepatocytes, possibly involving altered focal adhesion assembly or turnover, processes essential for efficient cell-ECM adhesion. Alterations in these processes could contribute to the impaired hepatocyte function and structure observed after chronic ethanol administration. [source] Diabetic neuropathies: components of etiologyJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 2 2008David R. Tomlinson Abstract This review examines the putative role of glucose in the etiology of diabetic neuropathies. Excessive glucose generates several secondary metabolic anomalies , principally oxidative stress (via both the polyol pathway and glucoxidation) and non-enzymic glycation of macromolecules. The latter is also facilitated by glucoxidation. These metabolic deviations trigger cellular responses that are inappropriate to normal function. Principal among these are neurotrophic deficits and phosphorylation of mitogen-activated protein kinases (MAPK). Downstream of these events are aberrant ion channel function and disordered gene expression, leading to changes in cellular phenotype. This leads directly to disordered nerve conduction, a recognised early clinical sign, and indirectly, via as yet undisclosed links, to sensory loss and axonopathy. Recent work also links MAPK activation to the development of neuropathic pain. [source] Engineering tissues, organs and cellsJOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, Issue 2 2007Anthony Atala Abstract Patients suffering from diseased and injured organs may be treated with transplanted organs; however, there is a severe shortage of donor organs that is worsening yearly, given the ageing population. In the field of regenerative medicine and tissue engineering, scientists apply the principles of cell transplantation, materials science and bioengineering to construct biological substitutes that will restore and maintain normal function in diseased and injured tissues. Therapeutic cloning, where the nucleus from a donor cell is transferred into an enucleated oocyte in order to extract pluripotent embryonic stem cells, offers a potentially limitless source of cells for tissue engineering applications. The stem cell field is also advancing rapidly, opening new options for therapy, including the use of amniotic and placental fetal stem cells. This review covers recent advances that have occurred in regenerative medicine and describes applications of these technologies using chemical compounds that may offer novel therapies for patients with end-stage organ failure. Copyright © 2007 John Wiley & Sons, Ltd. [source] | ||||||||||||||||||||||||||||