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Sample records for antagonistic muscular actions

  1. Calcium antagonists and their mode of action

    PubMed Central

    Nayler, Winifred G.; Dillon, J. S.

    1986-01-01

    1 The Ca2+ antagonists are a novel group of drugs useful in management of a variety of cardiac disorders. They differ from one another in terms of their chemistry, tissue specificity and selectivity. As a group, however, they share the common property of slowing Ca2+ entry through voltage-activated, ion-selective channels. Some of them exhibit other properties, including that of interfering with Na+ transport. At least one of them, diltiazem, has an intracellular action. 2 Specific high and low affinity binding sites have been identified for two of the major groups of Ca2+-antagonists, with the binding sites for verapamil and its derivatives being distinct from those which can be occupied by the dihydropyridines. The number (Bmax) and affinity (KD) of these binding sites changes under certain pathological conditions—including a reduction in ischaemia and in spontaneous hypertension, an increase in the latter, at present, only demonstrated for the dihydropyridine binding sites. 3 The sensitivity of a particular tissue to these drugs will depend upon a number of factors including the number of binding sites that are present, the contribution made by the Ca2+ entering through the voltage-activated channels to the functioning of the tissue, and properties which are peculiar to a particular type of Ca2+ antagonist, for example, whether, as in the case of verapamil, they exhibit use-dependence. PMID:3019374

  2. A new approach to assess the spasticity in hamstrings muscles using mechanomyography antagonist muscular group.

    PubMed

    Krueger, Eddy; Scheeren, Eduardo M; Nogueira-Neto, Guilherme N; Button, Vera Lúcia da S N; Nohama, Percy

    2012-01-01

    Several pathologies can cause muscle spasticity. Modified Ashworth scale (MAS) can rank spasticity, however its results depend on the physician subjective evaluation. This study aims to show a new approach to spasticity assessment by means of MMG analysis of hamstrings antagonist muscle group (quadriceps muscle). Four subjects participated in the study, divided into two groups regarding MAS (MAS0 and MAS1). MMG sensors were positioned over the muscle belly of rectus femoris (RF), vastus lateralis (VL) and vastus medialis (VM) muscles. The range of movement was acquired with an electrogoniometer placed laterally to the knee. The system was based on a LabVIEW acquisition program and the MMG sensors were built with triaxial accelerometers. The subjects were submitted to stretching reflexes and the integral of the MMG (MMG(INT)) signal was calculated to analysis. The results showed that the MMG(INT) was greater to MAS1 than to MAS0 [muscle RF (p = 0.004), VL (p = 0.001) and VM (p = 0.007)]. The results showed that MMG was viable to detect a muscular tonus increase in antagonist muscular group (quadriceps femoris) of spinal cord injured volunteers. PMID:23366325

  3. Central actions of a novel and selective dopamine antagonist

    SciTech Connect

    Schulz, D.W.

    1985-01-01

    Receptors for the neurotransmitter dopamine traditionally have been divided into two subgroups: the D/sub 1/ class, which is linked to the stimulation of adenylate cyclase-activity, and the D/sub 2/ class which is not. There is much evidence suggesting that it is the D/sub 2/ class which is not. There is much evidence suggesting that it is the D/sub 2/ dopamine receptor that mediates the physiological and behavioral actions of dopamine in the intact animal. However, the benzazepine SCH23390 is a dopamine antagonist which has potent behavioral actions while displaying apparent neurochemical selectivity for the D/sub 1/ class of dopamine receptors. The purpose of this dissertation was to (1) confirm and characterize this selectivity, and (2) test certain hypothesis related to possible modes of action of SCH233390. The inhibition of adenylate cyclase by SCH23390 occurred via an action at the dopamine receptor only. A radiolabeled analog of SCH23390 displayed the receptor binding properties of a specific high-affinity ligand, and regional receptor densities were highly correlated with dopamine levels. The subcellular distribution of (/sup 3/H)-SCH23390 binding did not correspond completely with that of dopamine-stimulated adenylate cyclase. The neurochemical potency of SCH23390 as a D/sub 1/ receptor antagonist was preserved following parental administration. A variety of dopamine agonists and antagonists displayed a high correlation between their abilities to compete for (/sup 3/H)-SCH23390 binding in vitro and to act at an adenylate cyclase-linked receptor. Finally, the relative affinities of dopamine and SCH23390 for both D/sub 1/ receptors and (/sup 3/H)-SCH23390 binding sites were comparable. It is concluded that the behavioral effects of SCH23390 are mediated by actions at D/sub 1/ dopamine receptors only, and that the physiological importance of this class of receptors should be reevaluated.

  4. Integrative role for serotonergic and glutamatergic receptor mechanisms in the action of NMDA antagonists: potential relationships to antipsychotic drug actions on NMDA antagonist responsiveness.

    PubMed

    Breese, George R; Knapp, Darin J; Moy, Sheryl S

    2002-06-01

    NMDA receptor antagonists worsen symptoms in schizophrenia and induce schizophrenic-like symptoms in normal individuals. In animals, NMDA antagonist-induced behavioral responses include increased activity, head weaving, deficits in paired pulse inhibition and social interaction, and increased forced swim immobility. Repeated exposure to NMDA antagonists in animals results in behavioral sensitization-a phenomenon accentuated in rats with dopaminergic neurons lesioned during development. In keeping with an involvement of serotonin and glutamate release in NMDA antagonist action, selected behaviors induced by NMDA antagonists are minimized by 5-HT(2A) receptor antagonists and mGLU2 receptor agonists. These observations provide promising new approaches for treating acute NMDA antagonist-induced psychosis. Further, acute atypical antipsychotic drugs also minimize NMDA antagonist actions to a greater degree than typical antipsychotics. However, because knowledge concerning acute versus chronic effectiveness of various antipsychotic drugs against NMDA antagonist neuropathology is limited, future studies to define more fully the basis of their differences in efficacy after chronic treatment could provide an understanding of their actions on neural mechanisms responsible for the core pathogenesis of schizophrenia. PMID:12204191

  5. Muscular Proprioception Contributes to the Control of Interceptive Actions

    ERIC Educational Resources Information Center

    Bastin, Julien; Calvin, Sarah; Montagne, Gilles

    2006-01-01

    The authors proposed a model of the control of interceptive action over a ground plane (Chardenon, Montagne, Laurent, & Bootsma, 2004). This model is based on the cancellation of the rate of change of the angle between the current position of the target and the direction of displacement (i.e., the bearing angle). While several sources of visual…

  6. Effects of certain muscarinic antagonists on the actions of anticholinesterases on cat skeletal muscle.

    PubMed

    Brimblecombe, R W; French, M C; Webb, S N

    1979-04-01

    1. The effects of some muscarinic antagonists, namely, N-ethyl-2-pyrrolidylmethyl-cyclopentylphenyl glycollate (PMCG), N-methyl-4-piperidyl-phenylcyclohexyl glycollate (PPCG, racemate and R and S enantiomers) and 4'-N-methyl-piperidyl-1-phenyl-cyclopentane carboxylate (G3063) on organophosphate (sarin, soman)- and carbamate (neostigmine)-induced twitch augmentation have been studied in cat soleus muscle. 2. The results of a preliminary study comparing the potency of sarin and soman in inhibiting the acetylcholinesterase activity of muscle in relation to the effect on the maximal twitch response indicated that there is not a simple relationship between degree of enzyme inhibition by these drugs and alteration of muscle function. 3. The muscarinic antagonists studied were capable of preventing or reversing sarin-, soman- or neostigmine-induced twitch augmentation. Doses sufficient to give complete protection from the effects of the anticholinesterase agents had little or no effect on the twitch response of normal muscle. 4. The protective action of these muscarinic antagonists is dose-dependent but independent of known antagonist actions at muscarinic receptors. 5. The effects of some local anaesthetics (lignocaine, prilocaine, cinchocaine, procaine) and other membrane stabilizers (quinine, ketamine, chlorpromazine, triflupromazine) were compared with those of the muscarinic antagonists in an attempt to elucidate the mode of action of these acetylcholine antagonists. The evidence is insufficient to exclude the involvement of a membrane stabilizing action. PMID:435681

  7. Physico-chemical pathways in radioprotective action of calmodulin antagonists

    NASA Astrophysics Data System (ADS)

    Varshney, Rajeev; Kale, R. K.

    1996-04-01

    Ghost membranes prepared from erythrocytes of Swiss albino mice were irradiated with gamma rays at a dose rate of 0.9 Gy/s. The fluidity of membrane decreased with radiation dose and in the presence of calmodulin antagonists (CA) like chlorpromazine (CPZ), promethazine (PMZ) and trimeprazine (TMZ) it increased. Radiation induced release of Ca 2+ from membranes. This release was inhibited by CA mainly by CPZ and PMZ. Being Ca 2+ dependent, the changes in the activity of acetylcholine estrase (AchE) following irradiation was also studied. Radiation decreased the activity of AchE in dose dependent manner. Presence of CPZ and PMZ diminished the radiation induced inhibition of AchE but not in the presence of TMZ at the lower concentration tested. It is suggested that apart from scavenging of free radicals, CA perhaps exert their euxoic radioprotective effect through Ca 2+ dependent processes.

  8. Dihydromorphine-peptide hybrids with delta receptor agonistic and mu receptor antagonistic actions

    SciTech Connect

    Smith, C.B.; Medzihradsky, F.; Woods, J.H.

    1986-03-05

    The actions of two morphine derivatives with short peptide side chains were evaluated upon the contraction of the isolated mouse vas deferens and upon displacement of /sup 3/H-etorphine from rat brain membranes. NIH-9833 (N-(6,14-endoetheno-7,8-dihydromorphine-7-alpha-carbonyl)-L-phenylalanyl-L-leucine ethyl ester HCl) was a potent agonist upon the vas deferens. Its EC50 for inhibition of the twitch was 1.2 +/- 0.1 nM. Both naltrexone (10/sup -7/ M) a relatively nonselective opioid antagonist, and ICI-174864 (10/sup -/' M) a highly selective delta receptor antagonist, blocked the actions of NIH-9833 which indicates that this drug is a delta receptor agonist. In contrast, NIH-9835 (N-(6,14-endoetheno-7,8-dihydromorphine-7-alpha-carbonyl)-L-glycyl-L-phenylalanyl-L-leucine ethyl ester HCl), which differs from NIH-9835 by the presence of a single amino acid residue, was devoid of opioid agonistic activity but was a potent antagonist of the inhibitory actions on the vas deferens of morphine and sufentanil. NIH-9833 and NIH-9835 were potent displacers of /sup 3/H-etorphine from rat cerebral membranes with EC50's of 0.58 nM and 1.7 nM, respectively. The observation that addition of a single glycyl group changes a dihydromorphine-peptide analog from a potent delta receptor agonist to an equally potent mu receptor antagonist suggests that the two receptor sites might be structurally quite similar.

  9. The mechanism of action of calcium antagonists relative to their clinical applications.

    PubMed

    Singh, B N

    1986-01-01

    As a class of therapeutic agents calcium antagonists have attracted increasing attention in recent years. Their major indications have been in the treatment of ischaemic myocardial syndromes, certain cardiac arrhythmias, hypertension, obstructive cardiomyopathies, and a number of lesser clinical disorders in which their role is less clearly defined. With the widening spectrum of therapeutic utility and an increasing plethora of newer agents under development, it is of importance to relate the overall pharmacodynamics of individual agents to their clinical effects. Calcium antagonists have a variable specificity for cardiac and peripheral activity. Based on such activity, it is useful to construct a classification of these compounds, new and old, into four categories. Type I agents, typified by verapamil and its congeners (tiapamil and gallopamil) and diltiazem, prolong AV nodal conduction and refractoriness with little effect on ventricular or atrial refractory period. These actions account for their direct antiarrhythmic properties. Type II agents include nifedipine and other dihydropyridines. In vivo, these agents are devoid of electrophysiologic effects in usual doses. They are potent peripheral vasodilators with some selectivity of action for different vascular beds; their overall haemodynamic effects are dominated by this peripheral vasodilatation and reflex augmentation of sympathetic reflexes. Type III agents include flunarizine and cinnarizine (piperazine derivatives), which, in vitro and in vivo, are potent dilators of peripheral vessels, with no corresponding calcium-blocking actions in the heart. Type IV agents are agents with a broader pharmacologic profile (perhexiline, lidoflazine and bepridil); they block calcium fluxes in the heart, in the peripheral vessels, or both. They may inhibit the fast channel in the heart and have other electrophysiologic actions. A clear understanding of the varied pharmacologic properties of the different classes of

  10. Structural insights into Resveratrol’s antagonist and partial agonist actions on estrogen receptor alpha

    PubMed Central

    2013-01-01

    Background Resveratrol, a naturally occurring stilbene, has been categorized as a phytoestrogen due to its ability to compete with natural estrogens for binding to estrogen receptor alpha (ERα) and modulate the biological responses exerted by the receptor. Biological effects of resveratrol (RES) on estrogen receptor alpha (ERα) remain highly controversial, since both estrogenic and anti-estrogenic properties were observed. Results Here, we provide insight into the structural basis of the agonist/antagonist effects of RES on ERα ligand binding domain (LBD). Using atomistic simulation, we found that RES bound ERα monomer in antagonist conformation, where Helix 12 moves away from the ligand pocket and orients into the co-activator binding groove of LBD, is more stable than RES bound ERα in agonist conformation, where Helix 12 lays over the ligand binding pocket. Upon dimerization, the agonistic conformation of RES-ERα dimer becomes more stable compared to the corresponding monomer but still remains less stable compared to the corresponding dimer in antagonist conformation. Interestingly, while the binding pocket and the binding contacts of RES to ERα are similar to those of pure agonist diethylstilbestrol (DES), the binding energy is much less and the hydrogen bonding contacts also differ providing clues for the partial agonistic character of RES on ERα. Conclusions Our Molecular Dynamics simulation of RES-ERα structures with agonist and antagonist orientations of Helix 12 suggests RES action is more similar to Selective Estrogen Receptor Modulator (SERM) opening up the importance of cellular environment and active roles of co-regulator proteins in a given system. Our study reveals that potential co-activators must compete with the Helix 12 and displace it away from the activator binding groove to enhance the agonistic activity. PMID:24160181

  11. Evaluation of growth hormone (GH) action in mice: discovery of GH receptor antagonists and clinical indications.

    PubMed

    Kopchick, John J; List, Edward O; Kelder, Bruce; Gosney, Elahu S; Berryman, Darlene E

    2014-04-01

    The discovery of a growth hormone receptor antagonist (GHA) was initially established via expression of mutated GH genes in transgenic mice. Following this discovery, development of the compound resulted in a drug termed pegvisomant, which has been approved for use in patients with acromegaly. Pegvisomant treatment in a dose dependent manner results in normalization of IGF-1 levels in most patients. Thus, it is a very efficacious and safe drug. Since the GH/IGF-1 axis has been implicated in the progression of several types of cancers, many have suggested the use of pegvisomant as an anti-cancer therapeutic. In this manuscript, we will review the use of mouse strains that possess elevated or depressed levels of GH action for unraveling many of GH actions. Additionally, we will describe experiments in which the GHA was discovered, review results of pegvisomant's preclinical and clinical trials, and provide data suggesting pegvisomant's therapeutic value in selected types of cancer. PMID:24035867

  12. Action of adenosine receptor antagonists on the cardiovascular response to defence area stimulation in the rat.

    PubMed Central

    St Lambert, J H; Dawid-Milner, M S; Silva-Carvalho, L; Spyer, K M

    1994-01-01

    1. The action of adenosine in the mediation of the cardiovascular changes associated with the defence reaction has been investigated in the rat using two A1 receptor antagonists. 2. Cumulative doses of 1,3 dipropyl-cyclopentylxanthine (DPCPX) (0.3-3 mg kg-1) and ethanol (0.03-0.25 ml) and bolus doses of DPCPX (3 mg kg-1) and 8-sulphophenyltheophylline (8-SPT) (20 mg kg-1) were given into alpha-chloralose, paralysed and artificially ventilated rats. Recordings were made of arterial blood pressure and heart rate. 3. Ethanol, the vehicle for DPCPX, failed to modify the magnitude of the defence response; however, cumulative doses of DPCPX produced a dose-dependent decrease in the HDA (hypothalamic defence area)-evoked increase in arterial blood pressure, accompanied by a similar fall in the magnitude of the evoked heart rate response. 4. The evoked rise in arterial blood pressure was reduced significantly by intravenous injection of DPCPX (3 mg kg-1) but not 8-SPT (20 mg kg-1), a purely peripherally acting adenosine antagonist. 5. These results suggest that adenosine acting at A1 receptors located in the central nervous system, is involved in the HDA-evoked pressor response. Whilst the site of action of the A1 receptors is not known, possible locations are discussed. PMID:7812606

  13. Actions of picrodendrin antagonists on dieldrin-sensitive and -resistant Drosophila GABA receptors.

    PubMed Central

    Hosie, A. M.; Ozoe, Y.; Koike, K.; Ohmoto, T.; Nikaido, T.; Sattelle, D. B.

    1996-01-01

    1. A series of terpenoid compounds, recently isolated from Picrodendron baccatum, share a picrotoxane skeleton with picrotoxinin, an antagonist of ionotropic GABA receptors. Referred to as picrodendrins, they inhibit the binding of [35S]-tert-butylbicyclophosphorothionate (TBPS) to rat GABAA receptors. Hitherto, their effects on GABA receptors have not been investigated electrophysiologically. Under two-electrode voltage-clamp, the actions of picrodendrins and related terpenoids have been assayed on homooligomeric GABA receptors formed by the expression of a Drosophila GABA receptor subunit (RDLac) in Xenopus oocytes. 2. All the terpenoids tested, dose-dependently antagonized currents induced by 30 microM (EC50) GABA. 3. Tutin and its analogues (dihydrotutin and isohyenanchin) differ in the structure of their axial C4 substituents. Of these compounds, tutin, which bears an isopropenyl group at this carbon atom, was the most potent antagonist of RDLac homo-oligomers, whereas isohyenanchin, which bears a hydroxyisopropyl group, was the least potent antagonist tested. 4. Picrodendrins differ mainly in the structure of their C9 substituents. The IC50s of picrodendrins ranged from 17 +/- 1.3 nM (picrodendrin-Q) to 1006 +/- 1.3 nM (picrodendrin-O). As such, the most potent picrodendrins (Q, A and B) were approximately equipotent with picrotoxinin as antagonists of RDLac homo-oligomers. 5. Certain picrodendrin compounds effected a use-dependent blockade of RDLac homo-oligomers. Such a biphasic block was not observed with tutin analogues. 6. Picrotoxin-resistant RDLacA3025 homo-oligomers, which have a single amino acid substitution (A302S) in the 2nd transmembrane region, were markedly less sensitive to picrodendrin-O than the wild-type, dieldrin-sensitive, homo-oligomers. 7. The relative potency of tutin analogues demonstrates that the structure-activity relationship of the C4 substituent of picrotoxane-based compounds is conserved in vertebrates and insects. However, the

  14. Neuroprotective and memory-related actions of novel alpha-7 nicotinic agents with different mixed agonist/antagonist properties.

    PubMed

    Meyer, E M; Tay, E T; Zoltewicz, J A; Meyers, C; King, M A; Papke, R L; De Fiebre, C M

    1998-03-01

    The goals of this study were to develop compounds that were selective and highly efficacious agonists at alpha-7 receptors, while varying in antagonist activity; and to test the hypothesis that these compounds had memory-related and neuroprotective actions associated with both agonist and antagonist alpha-7 receptor activities. Three compounds were identified; E,E-3-(cinnamylidene)anabaseine (3-CA), E,E-3-(2-methoxycinnamylidene) anabaseine (2-MeOCA) and E,E-3-(4-methoxycinnamylidene) anabaseine (4-MeOCA) each displaced [125I]alpha-bungarotoxin binding from rat brain membranes and activated rat alpha-7 receptors in a Xenopus oocyte expression system fully efficaciously. The potency series for binding and receptor activation was 2-MeOCA > 4-MeOCA = 3-CA and 2-MeOCA = 3-CA > 4-MeOCA, respectively. No compound significantly activated oocyte-expressed alpha-4beta-2 receptors. Although each cinnamylidene-anabaseine caused a long-term inhibition of alpha-7 receptors, as measured by ACh-application 5 min later, this inhibition ranged considerably, from less than 20% (3-CA) to 90% (2-MeOCA) at an identical concentration (10 microM). These compounds improved passive avoidance behavior in nucleus basalis lesioned rats, with 2-MeOCA most potent in this respect. In contrast, only 3-CA was neuroprotective against neurite loss during nerve growth factor deprivation in differentiated rat pheochromocytoma (PC12) cells. Choline, an efficacious alpha-7 agonist without antagonist activity, was also protective in this model. These results suggest that the neurite-protective action of alpha-7 receptor agonists may be more sensitive to potential long-term antagonist properties than acute behavioral actions are. PMID:9495863

  15. Bradykinin as a pain mediator: receptors are localized to sensory neurons, and antagonists have analgesic actions

    SciTech Connect

    Steranka, L.R.; Manning, D.C.; DeHaas, C.J.; Ferkany, J.W.; Borosky, S.A.; Connor, J.R.; Vavrek, R.J.; Stewart, J.M.; Snyder, S.H.

    1988-05-01

    Autoradiographic studies localize (/sup 3/H)bradykinin receptor binding sites to the substantia gelatinosa, dorsal root, and a subset of small cells in both the dorsal root and trigeminal ganglia of the guinea pig. (/sup 3/H)Bradykinin labeling is also observed over myocardinal/coronary visceral afferent fibers. The localization of (/sup 3/H)bradykinin receptors to nociceptive pathways supports a role for bradykinin in pain mediation. Several bradkykinin antagonists block bradykinin-induced acute vascular pain in the rat. The bradykinin antagonists also relieve bradykinin- and urate-induced hyperalgesia in the rat paw. These results indicate that bradykinin is a physiologic mediator of pain and that bradykinin antagonists have analgesic activity in both acute and chronic pain models.

  16. Sepsis Strengthens Antagonistic Actions of Neostigmine on Rocuronium in a Rat Model of Cecal Ligation and Puncture

    PubMed Central

    Wu, Jin; Jin, Tian; Wang, Hong; Li, Shi-Tong

    2016-01-01

    Background: The antagonistic actions of anticholinesterase drugs on non-depolarizing muscle relaxants are theoretically related to the activity of acetylcholinesterase (AChE) in the neuromuscular junction (NMJ). However, till date the changes of AChE activity in the NMJ during sepsis have not been directly investigated. We aimed to investigate the effects of sepsis on the antagonistic actions of neostigmine on rocuronium (Roc) and the underlying changes of AChE activity in the NMJ in a rat model of cecal ligation and puncture (CLP). Methods: A total of 28 male adult Sprague-Dawley rats were randomized to undergo a sham surgery (the sham group, n = 12) or CLP (the septic group, n = 16). After 24 h, the time-response curves of the antagonistic actions of 0.1 or 0.5 μmol/L of neostigmine on Roc (10 μmol/L)-depressed diaphragm twitch tension were measured. Meanwhile, the activity of AChE in the NMJ was detected using a modified Karnovsky and Roots method. The mRNA levels of the primary transcript and the type T transcript of AChE (AChET) in the diaphragm were determined by real-time reverse transcription-polymerase chain reaction. Results: Four of 16 rats in the septic group died within 24 h. The time-response curves of both two concentrations of neostigmine in the septic group showed significant upward shifts from those in the sham group (P < 0.001 for 0.1 μmol/L; P = 0.009 for 0.5 μmol/L). Meanwhile, the average optical density of AChE in the NMJ in the septic group was significantly lower than that in the sham group (0.517 ± 0.045 vs. 1.047 ± 0.087, P < 0.001). The AChE and AChET mRNA expression levels in the septic group were significantly lower than those in the sham group (P = 0.002 for AChE; P = 0.001 for AChET). Conclusions: Sepsis strengthened the antagonistic actions of neostigmine on Roc-depressed twitch tension of the diaphragm by inhibiting the activity of AChE in the NMJ. The reduced content of AChE might be one of the possible causes of the

  17. Quinazoline-derived alpha1-adrenoceptor antagonists induce prostate cancer cell apoptosis via an alpha1-adrenoceptor-independent action.

    PubMed

    Benning, Cynthia M; Kyprianou, Natasha

    2002-01-15

    Recent evidence suggests that the quinazoline-based alpha1-adrenoceptor antagonists, doxazosin and terazosin, exhibit a potent apoptotic effect against prostate tumor epithelial cells, whereas tamsulosin, a sulfonamide-based alpha1-adrenoceptor antagonist, was ineffective in inducing a similar apoptotic effect against prostate cells (Cancer Res., 60: 4550-4555, 2000). In this study, to identify the precise molecular mechanism underlying this apoptosis induction, we examined whether doxazosin and terazosin (both piperazinyl quinazolines) affect prostate growth via an alpha1-adrenoceptor-independent action. Transfection-mediated overexpression of alpha1-adrenoceptor in human prostate cancer cells, DU-145 (that lack alpha1-adrenoceptor), did not alter the ability of prostate cancer cells to undergo apoptosis in response to quinazolines. Significantly enough, there was no modification of the apoptotic threshold of the androgen-sensitive prostate cancer cells, LNCaP, to either quinazoline-based alpha1-agonist by androgens. Furthermore, human normal prostate epithelial cells exhibited a very low sensitivity to the apoptotic effects of doxazosin compared with that observed for the malignant prostate cells. These findings provide the first evidence that the apoptotic activity of the quinazoline-based alpha1-adrenoceptor antagonists (doxazosin and terazosin) against prostate cancer cells is independent of: (a) their capacity to antagonize alpha1-adrenoceptors; and (b) the hormone sensitivity status of the cells. This may have potential therapeutic significance in the use of quinazoline-based alpha1-adrenoceptor antagonists (already in clinical use for the treatment of hypertension and benign prostate hyperplasia) for the treatment of androgen-independent human prostate cancer. PMID:11809715

  18. Antagonistic action of Streptococcus salivarius and Streptococcus faecalis to Mycobacterium tuberculosis.

    PubMed Central

    Darling, C L; Hart, G D

    1976-01-01

    Streptococcus salivarius and Streptococcus faecalis were found to inhibit the growth of Mycobacterium tuberculosis on Löwenstein-Jensen and Middlebrook 7H11 agars, but not on the latter medium when antibacterial drugs were added. S. faecalis was found to be more inhibitory than S. salivarius to 15 strains of M. tuberculosis. S. salivarius produced little or no inhibition of growth of Runyon group III organisms but was very antagonistic to Runyon group I mycobacteria. Images PMID:824304

  19. Convulsant and anticonvulsant actions of agonists and antagonists of group III mGluRs.

    PubMed

    Ghauri, M; Chapman, A G; Meldrum, B S

    1996-06-17

    Group III metabotropic glutamate receptors (mGluR4, 6, 7, 8) are negatively coupled to adenylate cyclase and, when activated presynaptically, decrease the release of glutamate and GABA. We have used intracerebroventricular injections of agonists and antagonists believed to act selectively on these receptors to study the pro- or anti-convulsant effects of mGluR III activation in nonepileptic (Swiss-Webster) and epileptic (DBA/2) mice. In both mouse strains the prototypic agonists L-2-amino-4-phosphonobutanoate (LAP4) and L-serine-O-phosphate are proconvulsant. The supposed antagonists (S)-2-methyl-2-amino-4-phosphonobutanoate (MAP4) and (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG), have a predominantly proconvulsant effect. (S)-alpha-methyl-3-carboxyphenylalanine, which is a potent and selective antagonist for LAP4 in the cortex, is anticonvulsant in DBA/2 mice and decreases the convulsant effect of N-methyl-D-aspartate, 3,5-dihydroxyphenylglycine, LAP4 and MPPG in Swiss-Webster mice. These data suggest that reduced inhibitory transmission may be more significant than reduced synaptic release of glutamate following group III mGluR activation. PMID:8856700

  20. Enhanced attention and impulsive action following NMDA receptor GluN2B-selective antagonist pretreatment.

    PubMed

    Higgins, Guy A; Silenieks, Leo B; MacMillan, Cam; Sevo, Julia; Zeeb, Fiona D; Thevarkunnel, Sandy

    2016-09-15

    NMDA GluN2B (NR2B) subtype selective antagonists are currently in clinical development for a variety of indications, including major depression. We previously reported the selective NMDA GluN2B antagonists Ro 63-1908 and traxoprodil, increase premature responding in a 5-choice serial reaction time task (5-CSRTT) suggesting an effect on impulsive action. The present studies extend these investigations to a Go-NoGo and delay discounting task, and the 5-CSRTT under test conditions of both regular (5s) and short (2-5s) multiple ITI (Intertrial interval). Dizocilpine was included for comparison. Both Ro 63-1908 (0.1-1mg/kg SC) and traxoprodil (0.3-3mg/kg SC) increased premature and perseverative responses in both 5-CSRT tasks and improved attention when tested under a short ITI test condition. Ro 63-1908 but not traxoprodil increased motor impulsivity (false alarms) in a Go-NoGo task. Dizocilpine (0.01-0.06mg/kg SC) affected both measures of motor impulsivity and marginally improved attention. In a delay discounting test of impulsive choice, both dizocilpine and Ro 63-1908 decreased impulsive choice (increased choice for the larger, delayed reward), while traxoprodil showed a similar trend. Motor stimulant effects were evident following Ro 63-1908, but not traxoprodil treatment - although no signs of motor stereotypy characteristic of dizocilpine (>0.1mg/kg) were noted. The findings of both NMDA GluN2B antagonists affecting measures of impulsive action and compulsive behavior may underpin emerging evidence to suggest glutamate signaling through the NMDA GluN2B receptor plays an important role in behavioural flexibility. The profiles between Ro 63-1908 and traxoprodil were not identical, perhaps suggesting differences between members of this drug class. PMID:27180168

  1. Efficacy and putative mode of action of native and commercial antagonistic yeasts against postharvest pathogens of pear.

    PubMed

    Lutz, M Cecilia; Lopes, Christian A; Rodriguez, M Eugenia; Sosa, M Cristina; Sangorrín, Marcela P

    2013-06-17

    Putative mechanisms of action associated with the biocontrol capacity of four yeast strains (Cryptoccocus albidus NPCC 1248, Pichia membranifaciens NPCC 1250, Cryptoccocus victoriae NPCC 1263 and NPCC 1259) against Penicillium expansum and Botrytis cinerea were studied by means of in vitro and in situ assays. C. albidus(YP), a commercial yeast was also evaluated for comparative purposes. The yeast strains exhibited a variety of different mechanisms including: wound colonization, germination inhibition, biofilm formation, secretion of killer toxins, competition for nutrient and secretion of hydrolytic enzymes (protease, chitinase and glucanase). The relationship between strains (and their associated antagonist mechanisms) and in situ antagonist activity was also evaluated. Results indicate that mechanisms such as production of hydrolytic enzymes, the ability for colonization of wounds, production of killer toxin and inhibition of germination are the most important for biocontrol activity. Our study indicate that multiple modes of action may explain why P. membranifaciens NPCC 1250 and C. victoriae NPCC 1263 provided excellent control of postharvest pears disease. PMID:23680800

  2. Calcium antagonists.

    PubMed

    Grossman, Ehud; Messerli, Franz H

    2004-01-01

    Calcium antagonists were introduced for the treatment of hypertension in the 1980s. Their use was subsequently expanded to additional disorders, such as angina pectoris, paroxysmal supraventricular tachycardias, hypertrophic cardiomyopathy, Raynaud phenomenon, pulmonary hypertension, diffuse esophageal spasms, and migraine. Calcium antagonists as a group are heterogeneous and include 3 main classes--phenylalkylamines, benzothiazepines, and dihydropyridines--that differ in their molecular structure, sites and modes of action, and effects on various other cardiovascular functions. Calcium antagonists lower blood pressure mainly through vasodilation and reduction of peripheral resistance. They maintain blood flow to vital organs, and are safe in patients with renal impairment. Unlike diuretics and beta-blockers, calcium antagonists do not impair glucose metabolism or lipid profile and may even attenuate the development of arteriosclerotic lesions. In long-term follow-up, patients treated with calcium antagonists had development of less overt diabetes mellitus than those who were treated with diuretics and beta-blockers. Moreover, calcium antagonists are able to reduce left ventricular mass and are effective in improving anginal pain. Recent prospective randomized studies attested to the beneficial effects of calcium antagonists in hypertensive patients. In comparison with placebo, calcium antagonist-based therapy reduced major cardiovascular events and cardiovascular death significantly in elderly hypertensive patients and in diabetic patients. In several comparative studies in hypertensive patients, treatment with calcium antagonists was equally effective as treatment with diuretics, beta-blockers, or angiotensin-converting enzyme inhibitors. From these studies, it seems that a calcium antagonist-based regimen is superior to other regimens in preventing stroke, equivalent in preventing ischemic heart disease, and inferior in preventing congestive heart failure

  3. Muscular dystrophy

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/001190.htm Muscular dystrophy To use the sharing features on this page, please enable JavaScript. Muscular dystrophy is a group of inherited disorders that cause ...

  4. Muscular Dystrophy

    MedlinePlus

    Muscular dystrophy (MD) is a group of more than 30 inherited diseases. They all cause muscle weakness and ... ability to walk. There is no cure for muscular dystrophy. Treatments can help with the symptoms and prevent ...

  5. LY303870, a centrally active neurokinin-1 antagonist with a long duration of action.

    PubMed

    Iyengar, S; Hipskind, P A; Gehlert, D R; Schober, D; Lobb, K L; Nixon, J A; Helton, D R; Kallman, M J; Boucher, S; Couture, R; Li, D L; Simmons, R M

    1997-02-01

    The selective neurokinin (NK)-1 antagonist LY303870 has high affinity and specificity for human and guinea pig brain NK-1 receptors labeled with 125I-substance P. It has approximately 15- to 30-fold lower affinity for rat and mouse brain NK-1 receptors, consistent with previously reported species differences in the affinities of nonpeptide antagonists for NK-1 receptors. In vivo, LY303870 blocked the characteristic, caudally directed, biting and scratching response elicited by intrathecal administration of the selective NK-1 agonist Ac-[Arg6,Sar9,Met(O2)11]substance P6-11 in conscious mice. The potentiation of the tail-flick response elicited by intrathecal administration of the NK-1 agonist [Sar9,Met(O2)11]substance P in rats was also selectively blocked by LY303870. When tested in a model of persistent nociceptive activation induced by tissue injury (the formalin test), LY303870 blocked licking behavior in the late phase of the formalin test, in a dose-dependent manner. After oral administration of 10 mg/kg, the blockade of the late-phase licking behavior was evident for at least 24 hr. Ex vivo binding studies in guinea pigs showed that orally administered LY303870 potently inhibited binding to central and peripheral NK-1 receptors labeled with 125I-substance P. This inhibition was long-lasting, consistent with other in vivo activities. LY306155, the opposite enantiomer of LY303870, was less active in all of the functional assays. In rodents, LY303870 did not exhibit any neurological, motor, cardiovascular, gastrointestinal or autonomic side effects at doses of < or = 50 mg/kg p.o. Thus, LY303870 is a potent, centrally active, NK-1 antagonist in vivo, with long-lasting oral activity. PMID:9023291

  6. Action of pinaverium bromide, a calcium-antagonist, on gastrointestinal motility disorders.

    PubMed

    Christen, M O

    1990-01-01

    1. The evidence reviewed here indicates that pinaverium bromide (Dicetel) relaxes gastrointestinal (GI) structures primarily by inhibiting Ca2+ influx through potential-dependent channels of surface membranes of smooth muscle cells. 2. The in vivo selectivity of pinaverium bromide for the GI tract appears to be due mainly to its pharmacokinetic properties. Because of its low absorption (typical for quaternary ammonium compounds) and marked hepatobiliary excretion, most of the orally-administered dose of pinaverium bromide remains in the GI tract. 3. Orally-administered pinaverium bromide does not elicit adverse cardiovascular side-effects at doses that effectively relieve GI spasm, pain, transit disturbances and other symptoms related to motility disorders. 4. Pinaverium bromide is the only Ca2(+)-antagonist with known therapeutic efficacy in the treatment of irritable bowel syndrome and certain other functional intestinal disorders. PMID:2177709

  7. Synergistic and Antagonistic Action of Phytochrome (Phy) A and PhyB during Seedling De-Etiolation in Arabidopsis thaliana.

    PubMed

    Su, Liang; Hou, Pei; Song, Meifang; Zheng, Xu; Guo, Lin; Xiao, Yang; Yan, Lei; Li, Wanchen; Yang, Jianping

    2015-01-01

    It has been reported that Arabidopsis phytochrome (phy) A and phyB are crucial photoreceptors that display synergistic and antagonistic action during seedling de-etiolation in multiple light signaling pathways. However, the functional relationship between phyA and phyB is not fully understood under different kinds of light and in response to different intensities of such light. In this work, we compared hypocotyl elongation of the phyA-211 phyB-9 double mutant with the wild type, the phyA-211 and phyB-9 single mutants under different intensities of far-red (FR), red (R), blue (B) and white (W) light. We confirmed that phyA and phyB synergistically promote seedling de-etiolation in B-, B plus R-, W- and high R-light conditions. The correlation of endogenous ELONGATED HYPOCOTYL 5 (HY5) protein levels with the trend of hypocotyl elongation of all lines indicate that both phyA and phyB promote seedling photomorphogenesis in a synergistic manner in high-irradiance white light. Gene expression analyses of RBCS members and HY5 suggest that phyB and phyA act antagonistically on seedling development under FR light. PMID:26030677

  8. Antagonistic Action of Bacillus subtilis Strain SG6 on Fusarium graminearum

    PubMed Central

    Zhao, Yueju; Selvaraj, Jonathan Nimal; Xing, Fuguo; Zhou, Lu; Wang, Yan; Song, Huimin; Tan, Xinxin; Sun, Lichao; Sangare, Lancine; Folly, Yawa Minnie Elodie; Liu, Yang

    2014-01-01

    Fusarium graminearum causes Fusarium head blight (FHB), a devastating disease that leads to extensive yield and quality loss of wheat and barley. Bacteria isolated from wheat kernels and plant anthers were screened for antagonistic activity against F. graminearum. Based on its in vitro effectiveness, strain SG6 was selected for characterization and identified as Bacillus subtilis. B. subtilis SG6 exhibited a high antifungal effect on the mycelium growth, sporulation and DON production of F. graminearum with the inhibition rate of 87.9%, 95.6% and 100%, respectively. In order to gain insight into biological control effect in situ, we applied B. subtilis SG6 at anthesis through the soft dough stage of kernel development in field test. It was revealed that B. subtilis SG6 significantly reduced disease incidence (DI), FHB index and DON (P≤0.05). Further, ultrastructural examination shows that B. subtilis SG6 strain induced stripping of F. graminearum hyphal surface by destroying the cellular structure. When hypha cell wall was damaged, the organelles and cytoplasm inside cell would exude, leading to cell death. The antifungal activity of SG6 could be associated with the coproduction of chitinase, fengycins and surfactins. PMID:24651513

  9. Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice

    PubMed Central

    Vezzani, A.; Moneta, D.; Conti, M.; Richichi, C.; Ravizza, T.; De Luigi, A.; De Simoni, M. G.; Sperk, G.; Andell-Jonsson, S.; Lundkvist, J.; Iverfeldt, K.; Bartfai, T.

    2000-01-01

    IL-1β and its endogenous receptor antagonist (IL-1Ra) are rapidly induced by seizures in the rodent hippocampus. Exogenously applied IL-1β prolongs seizures in an IL-1R type I-mediated manner. This effect depends on N-methyl-d-aspartate receptor activation. We report here that intrahippocampal application of recombinant IL-1Ra or its selective endogenous overexpression in astrocytes under the control of glial acidic fibrillary protein promoter potently inhibits motor and electroencephalographic seizures induced by bicuculline methiodide in mice. Accordingly, transgenic mice show a reduced seizure-related c-fos mRNA expression in various forebrain areas compared with their wild-type littermates. Recombinant IL-1Ra was ineffective in mice deficient in IL-1R type I, having per se a delayed onset to generalized convulsions. These results demonstrate that IL-1Ra mediates potent anticonvulsant effects acting on IL-1R type I and suggest that the balance between brain IL-1β and IL-1Ra represents a crucial mechanism to control seizure generalization. PMID:11016948

  10. A model for antagonistic pleiotropic gene action for mortality and advanced age.

    PubMed

    Toupance, B; Godelle, B; Gouyon, P H; Schächter, F

    1998-06-01

    Association or linkage studies involving control and long-lived populations provide information on genes that influence longevity. However, the relationship between allele-specific differences in survival and the genetic structure of aging cohorts remains unclear. We model a heterogeneous cohort comprising several genotypes differing in age-specific mortality. In its most general form, without any specific assumption regarding the shape of mortality curves, the model permits derivation of a fundamental property underlying abrupt age-related changes in the composition of a cohort. The model is applied to sex-specific survival curves taken from period life tables, and Gompertz-Makeham mortality coefficients are calculated for the French population. Then, adjustments are performed under Gompertz-Makeham mortality functions for three genotypes composing a heterogeneous cohort, under the constraint of fitting the resultant mortality to the real French population mortality obtained from life tables. Multimodal curves and divergence after the 8th decade appear as recurrent features of the frequency trajectories. Finally, a fit to data previously obtained at the angiotensin-converting-enzyme locus is realized, explaining what had seemed to be paradoxical results-namely, that the frequency of a genotype known as a cardiovascular risk factor was increased in centenarians. Our results help explain the well-documented departure from Gompertz-Makeham mortality kinetics at older ages. The implications of our model are discussed in the context of known genetic effects on human longevity and age-related pathologies. Since antagonistic pleiotropy between early and late survival emerges as a general rule, extrapolating the effects measured for a gene in a particular age class to other ages could be misleading. PMID:9585593

  11. Mechanism of action of calcium antagonists on myocardial and smooth muscle membranes.

    PubMed

    Zakhari, S

    1986-01-01

    Although calcium channel blockers vary considerably in their chemical structure and pharmacologic profile, the widely accepted mechanism of their action is an inhibition of Ca2+ influx - via voltage-activated slow channels - into smooth and cardiac muscle. Other ways of Ca2+ entry, such as passive diffusion and Na+/Ca2+ and K+/Ca2+ exchange, are not affected by these compounds. However, various blockers exert a slightly different inhibitory action on the slow channels, which indicates that various binding sites in the cell membranes, or even in intracellular sites, may be involved. Potential sites of action of calcium channel blockers in the myocardium include: the slow calcium channels; Na+/Ca2+ channels; mitochondria; sarcoplasmic reticulum; myofilaments; and calcium efflux. However, experimental evidence has been given for only the first site, and the third and fourth sites are still controversial. In the vascular smooth muscles, calcium channel blockers could possibly block the potential-dependent or receptor-operated channels, or bind to calmodulin. Again, only the first site of action has been experimentally proven. An important feature of calcium channel blockers is their different affinities for various tissues. For instance, cinnarizine and its difluorinated derivative flunarizine are 1000 times more effective in blocking slow channels in vascular smooth muscles than those in the myocardium. Even within the same system, such as the cardiovascular system, differences in tissue specificity are encountered. Thus, while nimodipine acts preferentially on cerebral vessels, diltiazem has more affinity for the coronary vasculature. Tissue specificity is exhibited even for different myocardial structures; thus, while verapamil affects the nodal and conductive tissues in the myocardium (hence its use as an antiarrhythmic agent), nifedipine is almost devoid of such activity. Organ selectivity of calcium channel blockers is one of the attractive features of this group

  12. Selective antagonistic effects of exposure to bright light on the hypothermic action of ethanol.

    PubMed

    Overstreet, D H; Dilsaver, S C; Rezvani, A H; Janowsky, D S

    1990-01-01

    Flinders Sensitive and Resistant Lines of rats, which are differentially sensitive to the hypothermic effects of both muscarinic agonists and ethanol, were exposed to full spectrum artificial bright light for eight days, because exposure to bright light has been shown to blunt hypothermic responses to muscarinic agonists. There was a selective blunting of the hypothermic effects of ethanol, but no significant change in the intoxicating effects of ethanol, as measured by evaluation of the righting reflex. The selective effect of exposure to bright light on the hypothermic actions of ethanol suggests that bright light may be modifying the function of only a limited number of brain regions, including the hypothalamus. PMID:2085349

  13. Selective actions of calcium antagonistic drugs on the haemodynamics and regional organ blood flow in rats.

    PubMed

    McCann, E; Lundberg, C; Gerdin, B; Arfors, K E

    1986-01-01

    Six substances, all of which influence calcium utilization by smooth muscle, namely nimodipine (50 micrograms/kg), flunarizine (1 mg/kg), verapamil (0.2 mg/kg), lidoflazine (1 mg/kg), magnesium (600 mumol Mg++/kg), and manganese (180 mumol Mn++/kg), were given intravenously to rats and their effects on regional blood flows and on cardiac output were determined by the radioactive microsphere technique. All compounds caused a temporary fall in mean arterial blood pressure. Cardiac output was decreased by manganese, and minute work by nimodipine, manganese and lidoflazine. Nimodipine increased blood flow in the liver, skeletal muscle and heart and decreased that in the stomach, ileum, colon, kidney, spleen and skin; manganese increased flow in the duodenum, jejunum, liver and myocardium and decreased that in the stomach, ileum, colon, spleen and skin; flunarizine increased flow in the liver, heart and brain; and magnesium increased flow in the liver, spleen and brain. Lidoflazine and verapamil, although leading to haemodynamic alterations, had no selective effect on organ blood flow. Selective actions by calcium effector drugs can provide information on mechanisms of calcium flux in various types of vascular smooth muscle, and show that it is possible to tailor combinations of anti-calcium agents with optimal effects on a given organ. PMID:3781760

  14. Non-specific actions of the non-peptide tachykinin receptor antagonists, CP-96,345, RP 67580 and SR 48968, on neurotransmission.

    PubMed

    Wang, Z Y; Tung, S R; Strichartz, G R; Håkanson, R

    1994-01-01

    1. Three non-peptide tachykinin receptor antagonists, CP-96,345, RP 67580 and SR 48968, were found to inhibit the electrically-evoked, tachykinin-mediated contractile responses of the rabbit iris sphincter in a concentration-dependent fashion; the pIC50 values were 5.6 +/- 0.01, 5.4 +/- 0.07 and 4.8 +/- 0.03, respectively. 2. These antagonists also inhibited the electrically-evoked, parasympathetic response of the rabbit iris sphincter and the sympathetic response of the guinea-pig vas deferens in a concentration-dependent manner; the pIC50 values were 0.3-1.2 log units lower than those recorded for the tachykinin-mediated responses. 3. Two local anaesthetics, bupivacaine and oxybuprocaine, were also found to inhibit the tachykinin-mediated, cholinergic and sympathetic contractile responses in these tissues in a concentration-dependent manner; the concentration ranges for producing the inhibition were similar to those of the non-peptide tachykinin receptor antagonists. 4. On the sciatic nerves of frogs, the tachykinin receptor antagonists inhibited action potentials in a concentration-dependent manner; the potency of the three drugs was similar to that of bupivacaine. 5. Our results suggest that, in addition to blocking tachykinin receptors, the non-peptide tachykinin receptor antagonists, CP-96,345, RP 67580 and SR 48968, may exert non-specific inhibitory effects on neurotransmission. PMID:8012694

  15. Muscular Dystrophy

    MedlinePlus

    ... in Duchenne muscular dystrophy. Dev. Med. Child Neurol. Mar 1995;37(3):260-269. 4. Centers for ... DM1) . The International Myotonic Dystrophy Consortium (IDMC). Neurology. Mar 28 2000;54(6):1218-1221. 5. Harper ...

  16. Muscular Dystrophy

    MedlinePlus

    ... be affected. Limb-girdle muscular dystrophy (LGMD) affects boys and girls equally, weakening muscles in the shoulders and upper ... weakness and poor muscle tone. Occurring in both girls and boys, it can have different symptoms. It varies in ...

  17. [Muscular mechanisms of lowering of physical working capacity in chronic heart failure and action of beta-adrenoblockers].

    PubMed

    Syrkin, A L; Poltavskaia, M G; Molchanova, I V; Churganova, L Iu; Chaplygin, A V

    2005-01-01

    Parameters of physical working capacity (symptom limited treadmill test with gas analysis, 6 min walk test and usual everyday activity), activity of muscular metaboreflex, efficacy of pulmonary ventilation, and heart rate variability were studied in 50 patients with postinfarction cardiosclerosis with chronic class I-III heart failure and 30 patients without heart failure. Patients with heart failure of all functional classes had lowered parameters of working capacity while metaboloreflex hyperactivation and diminished effectiveness of ventilation were found only in patients with clinical signs of chronic heart failure but not in those with symptomless left ventricular dysfunction. Therapy with metoprolol was associated with lowering of activity of metaboloreflex, augmented effectiveness of ventilation and heart rate variability, improvement of results of 6 min test and everyday activity without considerable changes of peak oxygen consumption. PMID:16234766

  18. Comparison of the β-Adrenergic Receptor Antagonists Landiolol and Esmolol: Receptor Selectivity, Partial Agonism, and Pharmacochaperoning Actions.

    PubMed

    Nasrollahi-Shirazi, Shahrooz; Sucic, Sonja; Yang, Qiong; Freissmuth, Michael; Nanoff, Christian

    2016-10-01

    Blockage of β1-adrenergic receptors is one of the most effective treatments in cardiovascular medicine. Esmolol was introduced some three decades ago as a short-acting β1-selective antagonist. Landiolol is a more recent addition. Here we compared the two compounds for their selectivity for β1-adrenergic receptors over β2-adrenergic receptors, partial agonistic activity, signaling bias, and pharmacochaperoning action by using human embryonic kidney (HEK)293 cell lines, which heterologously express each human receptor subtype. The affinity of landiolol for β1-adrenergic receptors and β2-adrenergic receptors was higher and lower than that of esmolol, respectively, resulting in an improved selectivity (216-fold versus 30-fold). The principal metabolite of landiolol (M1) was also β1-selective, but its affinity was very low. Both landiolol and esmolol caused a very modest rise in cAMP levels but a robust increase in the phosphorylation of extracellular signal regulated kinases 1 and 2, indicating that the two drugs exerted partial agonist activity with a signaling bias. If cells were incubated for ≥24 hours in the presence of ≥1 μM esmolol, the levels of β1-adrenergic-but not of β2-adrenergic-receptors increased. This effect was contingent on export of the β1-receptor from endoplasmic reticulum and was not seen in the presence of landiolol. On the basis of these observations, we conclude that landiolol offers the advantage of: 1) improved selectivity and 2) the absence of pharmacochaperoning activity, which sensitizes cells to rebound effects upon drug discontinuation. PMID:27451411

  19. The mechanism of action of calcium antagonists on arrhythmias in early myocardial ischaemia: studies with nifedipine and DHM9.

    PubMed Central

    Curtis, M. J.; Walker, M. J.

    1988-01-01

    1. Nifedipine and DHM9 (carboxymethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate) were studied for their effects on arrhythmias resulting from regional myocardial ischaemia in conscious rats, and for their effects on left ventricular developed pressure in vitro. 2. Nifedipine possessed antiarrhythmic activity at a high dose of 10 mg kg-1 i.v., but not at 0.5 or 2 mg kg-1. Ventricular fibrillation (VF), tachycardia (VT), and ventricular premature beats (VPB) were all attenuated to a similar degree; nifedipine did not have a selectivity of action for high frequency arrhythmias. 3. Before coronary occlusion, the three doses of nifedipine reduced arterial blood pressure by a similar magnitude, indicating a similar (maximal) degree of systemic vasodilatation. The reductions in blood pressure were accompanied by reflex tachycardia. Heart rate and blood pressure did not correlate with the incidence or severity of arrhythmias. 4. DHM9 had no influence on arrhythmias, haemodynamic variables or the ECG, even at 20 mg kg-1 i.v. 5. Nifedipine concentration-dependently reduced contractility in perfused paced (5 Hz) rat ventricles in vitro. Raising the concentration of K+ in the perfusion fluid from 3 to 10 mequiv.l-1 increased the potency (-log10 EC50) of nifedipine up to four fold, and caused a significant depression in excitability. 6. DHM9 at up to 3 x 10(-5) M had no significant influence on ventricular contractility in vitro. 7. The results provided indirect evidence in support of the hypothesis that calcium antagonists inhibit ischaemia-induced arrhythmias by virtue of inhibition of the slow inward current (Isi) in the ischaemic ventricular myocardium. PMID:3207985

  20. Meaning of Muscular Dystrophy

    MedlinePlus

    ... Help White House Lunch Recipes The Meaning of Muscular Dystrophy KidsHealth > For Kids > The Meaning of Muscular Dystrophy ... you know someone who has MD. What Is Muscular Dystrophy? Muscular dystrophy (say: MUS-kyoo-lur DIS-troh- ...

  1. Effects of calcium channel antagonists on action potential conduction and transmitter release in the guinea-pig vas deferens.

    PubMed Central

    Beattie, D. T.; Cunnane, T. C.; Muir, T. C.

    1986-01-01

    The effects of the Ca2+ channel antagonists amlodipine, cobalt, diltiazem, nifedipine and verapamil and the local anaesthetic lignocaine were investigated on action potential conduction in and on evoked transmitter release from sympathetic nerves in the guinea-pig isolated vas deferens. Transmitter release was investigated by measurement of evoked (trains of pulses at 1 and 2 Hz, 0.1-0.5 ms supramaximal voltage) excitatory junction potentials (e.j.ps) using microelectrodes; tension was recorded simultaneously; tritium [3H] overflow from vasa preincubated (37 degrees C, 30 min) in Krebs solution containing either [3H]-noradrenaline (NA, 25 microCi ml-1, 2 X 10(-6) M NA) or [3H]-adenosine (50 microCi ml-1, 1 X 10(-6) M adenosine). Amlodipine (0.5-2 X 10(-4) M), verapamil (0.5-2 X 10(-4) M), diltiazem (1-8 X 10(-4) M), lignocaine (0.1-2 X 10(-3) M) and cobalt (2-6 X 10(-2) M) in descending order of potency, but not nifedipine (1-5 X 10(-3) M), increased the latency and inhibited, then abolished, the amplitude and number of action potentials in a concentration-dependent manner. Amlodipine (0.5-1 X 10(-4) M), verapamil (1-2 X 10(-4) M), diltiazem (1-5 X 10(-4) M) and cobalt (1 X 10(-3) M), in descending order of potency, but not nifedipine (5 X 10(-4) M), inhibited then abolished evoked e.j.ps in a concentration-dependent manner. Cobalt inhibited e.j.ps at a lower concentration than that (2-6 X 10(-2) M) required to block action potential conduction. In unstimulated tissues, the resting [3H] overflow following preincubation with [3H]-NA consisted largely of 4-hydroxy 3-methoxymandelic acid (VMA), 4-hydroxy 3-methoxy phenylglycol (MOPEG), 3,4 dihydroxyphenylglycol (DOPEG) and NA; stimulated tissues (300 pulses at 20 Hz, 0.5 ms supramaximal voltage) released mainly NA. Verapamil (0.1-1 X 10(-4) M), amlodipine (0.05-1 X 10(-4) M) and nifedipine (1-5 X 10(-4) M), but not cobalt (2 X 10(-3) M), increased, significantly, the resting overflow of 3H comprising mainly DOPEG

  2. Novel, isoform-selective, cholecystokinin A receptor antagonist inhibits colon and pancreatic cancers in preclinical models through novel mechanism of action.

    PubMed

    Ponnusamy, Suriyan; Lattmann, Eric; Lattmann, Pornthip; Thiyagarajan, Thirumagal; Padinjarethalakal, Balaram N; Narayanan, Ramesh

    2016-04-01

    Colon and pancreatic cancers contribute to 90,000 deaths each year in the USA. These cancers lack targeted therapeutics due to heterogeneity of the disease and multiple causative factors. One important factor that contributes to increased colon and pancreatic cancer risk is gastrin. Gastrin mediates its actions through two G-protein coupled receptors (GPCRs): cholecystokinin receptor A (CCK-A) and CCK-B/gastrin receptor. Previous studies have indicated that colon cancer predominantly expresses CCK-A and responds to CCK-A isoform antagonists. However, many CCK-A antagonists have failed in the clinic due to poor pharmacokinetic properties or lack of efficacy. In the present study, we synthesized a library of CCK-A isoform-selective antagonists and tested them in various colon and pancreatic cancer preclinical models. The lead CCK-A isoform, selective antagonist PNB-028, bound to CCK-A at 12 nM with a 60-fold selectivity towards CCK-A over CCK-B. Furthermore, it inhibited the proliferation of CCK-A-expressing colon and pancreatic cancer cells without affecting the proliferation of non-cancerous cells. PNB-028 was also extremely effective in inhibiting the growth of MAC-16 and LoVo colon cancer and MIA PaCa pancreatic cancer xenografts in immune-compromised mice. Genome‑wide microarray and kinase-array studies indicate that PNB-028 inhibited oncogenic kinases and angiogenic factors to inhibit the growth of colon cancer xenografts. Safety pharmacology and toxicology studies have indicated that PNB-028 is extremely safe and has a wide safety margin. These studies suggest that targeting CCK-A selectively renders promise to treat colon and pancreatic cancers and that PNB-028 could become the next-generation treatment option. PMID:26820391

  3. [Isolation of endophytic bacteria in potato and test of antagonistic action to bacterial ring rot of potato].

    PubMed

    Cui, Lin; Sun, Zhen; Tian, Hong Xian; Wang, Li Qin; Xu, Huei Yuen; Sun, Fu Zai; Yuan, Jun

    2002-12-01

    In this study, two hundred and forty bacterial strains were isolated from inner tissue of potato tubers collected from DaTong, TaiYuan and Inner Mongolia Autonomous regions. On the basis of antagonistic examination in vitro, fifty and five bacteria strains were characterized for antagonistic bacteria to ring rot of potato. It was 22.9 percentage of all bacteria strains. The biggest radius of suppression circle was 13 mm. Nine strains were chosen for their suppression of bacterial ring rot, blackleg and dry rot of potato. These strains were bacteriologically ideatified. Strain 118 was Pseudomonas fluorescens biovar V. Strain 110 was Bacillus pumilus. Strain 085 was Bacillus stearothermophilus. Strain 069 was Erwinia herbicola. Strain 043 was Xanthomomas fragariae. Strain 116 was Curtobacterium. Strains A-10' and T3 were Bacillus. Strain H1-6 was Pseudomonas fluorescens. PMID:15346992

  4. Effects of oxytocin-related peptides on acute morphine tolerance: opposite actions by oxytocin and its receptor antagonists.

    PubMed

    Kovács, G L; Sarnyai, Z; Izbéki, F; Szabó, G; Telegdy, G; Barth, T; Jost, K; Brtnik, F

    1987-05-01

    The hormonally and behaviorally active nonapeptide oxytocin (OXT), its behaviorally active N-terminal octapeptide desglycinamide9-OXT and Z-prolyl-D-leucine, a synthetic analog of the C-terminal prolyl7-leucine8 sequence, inhibited the development both of a moderate and of a strong tolerance to morphine. N-alpha-Acetyl-(2-0-methyltyrosine)-OXT and (penicillamine1-2-0-methyltyrosine)- lysine8-vasopressin, both OXT receptor antagonists, facilitated the development of a moderate morphine tolerance. The i.c.v. injection of either antagonist prevented the effects of i.c.v. and s.c. OXT treatment on the development of tolerance. The effect of desglycinamide9-OXT, but not that of Z-prolyl-D-leucine was also prevented by N-alpha-acetyl-(2-0-methyltyrosine)-OXT. It is concluded that OXT and desglycinamide9-OXT, but not Z-prolyl-D-leucine, attenuate morphine tolerance by affecting putative oxytocinergic binding sites in the mouse brain. The fact that i.c.v. injection of the receptor antagonist also blocked the effect of s.c. OXT treatment argues in favor of the possibility that a minor proportion of s.c. OXT (or behaviorally active fragments thereof) may reach central nervous system target sites. PMID:3033220

  5. Muscular dystrophy - resources

    MedlinePlus

    Resources - muscular dystrophy ... The following organizations are good resources for information on muscular dystrophy : Muscular Dystrophy Association -- www.mdausa.org National Institute of Neurological Disorders and Stroke -- www.ninds.nih. ...

  6. Myotonic Muscular Dystrophy

    MedlinePlus

    ... a Difference How to Get Involved Donate Myotonic Muscular Dystrophy (MMD) Share print email share facebook twitter google plus linkedin Myotonic Muscular Dystrophy (MMD) What is myotonic muscular dystrophy (MMD)? Myotonic ...

  7. Early Illustrations of Geste Antagoniste in Cervical and Generalized Dystonia

    PubMed Central

    Broussolle, Emmanuel; Laurencin, Chloé; Bernard, Emilien; Thobois, Stéphane; Danaila, Teodor; Krack, Paul

    2015-01-01

    Background Geste antagoniste, or sensory trick, is a voluntary maneuver that temporarily reduces the severity of dystonic postures or movements. We present a historical review of early reports and illustrations of geste antagoniste. Results In 1894, Brissaud described this phenomenon in Paris in patients with torticollis. He noted that a violent muscular contraction could be reversed by a minor voluntary action. He considered the improvement obtained by what he called “simple mannerisms, childish behaviour or fake pathological movements” was proof of the psychogenic origin of what he named mental torticollis. This concept was supported by photographical illustrations of the patients. The term geste antagoniste was used by Brissaud’s pupils, Meige and Feindel, in their 1902 monograph on movement disorders. Other reports and illustrations of this sign were published in Europe between 1894 and 1906. Although not mentioned explicitly, geste antagoniste was also illustrated in a case report of generalized dystonia in Oppenheim’s 1911 seminal description of dystonia musculorum deformans in Berlin. Discussion Brissaud-Meige’s misinterpretation of the geste antagoniste unfortunately anchored the psychogenic origin of dystonia for decades. In New York, Herz brought dystonia back into the realm of organic neurology in 1944. Thereafter, it was given prominence by other authors, notably Fahn and Marsden in the 1970–1980s. Nowadays, neurologists routinely investigate for geste antagoniste when a dystonic syndrome is suspected, because it provides a further argument in favor of dystonia. The term alleviating maneuver was proposed in 2014 to replace sensory trick or geste antagoniste. This major sign is now part of the motor phenomenology of the 2013 Movement Disorder Society’s classification of dystonia. PMID:26417535

  8. Actions of adenosine A1 and A2 receptor antagonists on CFTR antibody-inhibited β-adrenergic mucin secretion response

    PubMed Central

    Pereira, M M C; Lloyd Mills, C; Dormer, R L; McPherson, M A

    1998-01-01

    The cystic fibrosis gene protein, the cystic fibrosis transmembrane conductance regulator (CFTR) acts as a chloride channel and is a key regulator of mucin secretion. The mechanism by which 3-isobutyl-1-methylxanthine (IBMX) corrects the defect in CFTR mediated β-adrenergic stimulation of mucin secretion has not been determined. The present study has investigated the actions of adenosine A1 and A2 receptor antagonists to determine whether ability to stimulate mucin secretion correlates with correction of CFTR antibody inhibited β-adrenergic response and whether excessive cyclic AMP rise is required.CFTR antibodies were introduced into living rat submandibular acini by hypotonic swelling. Following recovery, mucin secretion in response to isoproterenol was measured.The adenosine A1 receptor antagonist, 8 cyclopentyltheophylline (CPT) was a less potent stimulator of mucin secretion than was the A2 receptor antagonist dimethylpropargylxanthine (DMPX). A concentration of CPT close to the Ki for A1 receptor antagonism (10 nM) did not stimulate mucin secretion.DMPX, although a potent stimulator of mucin secretion, did not correct CFTR antibody inhibited mucin secretion.CPT corrected defective CFTR antibody inhibited mucin secretion at a high (1 mM) concentration, suggesting a mechanism other than adenosine receptor antagonism.DMPX potentiated the isoproterenol induced cyclic AMP rise, whereas CPT did not.Correction of the defective CFTR mucin secretion response did not correlate with ability to stimulate mucin secretion and did not require potentiation of β-adrenergic induced increases in cyclic AMP. This affords real promise for the development of a selective drug treatment for cystic fibrosis. PMID:9831904

  9. Combined cardioprotectant and antithrombotic actions of platelet P2Y12 receptor antagonists in acute coronary syndrome: just what the doctor ordered.

    PubMed

    Cohen, Michael V; Downey, James M

    2014-03-01

    Since the P2Y12 receptor antagonists were first introduced, they have been extensively tested in patients with acute coronary syndrome and are now standard of care. These antiplatelet drugs are very effective in reducing subsequent cardiovascular events, stent thromboses, and mortality in patients with acute myocardial infarction undergoing reperfusion therapy. Although the prevailing view is that their benefit derives from their antithrombotic properties, other unrelated pleiotropic effects appear to be equally beneficial. Accumulating clinical and animal evidence indicates that, if present at the time of reperfusion, these drugs have a direct anti-infarct effect similar to that of ischemic postconditioning. Four oral antagonists have been developed in rapid succession: ticlopidine, clopidogrel, prasugrel, and ticagrelor. Each agent had a more consistent and rapid onset of action than the previous one, and this has correlated with improved clinical outcomes when given early in treatment. Unfortunately, gut absorption causes an appreciable delay in the onset of effect, especially when morphine is used, and the constant push to minimize the door-to-balloon time has made it difficult to achieve adequate platelet inhibition at the time of percutaneous coronary intervention with an oral agent. An intravenous P2Y12 antagonist such as cangrelor may optimize treatment because it produces nearly maximal inhibition of platelet aggregation within minutes. If antiplatelet agents do protect through postconditioning's mechanism, then they would render any other intervention that protects through that mechanism redundant. Indeed, animals treated with cangrelor cannot be further protected by pre- or postconditioning. However, interventions that use a different mechanism such as mild hypothermia or cariporide, a Na(+)-H(+) exchange blocker, do add to cangrelor's protection. Future research should be directed toward identifying interventions that can augment the protection from

  10. The SnRK2-APC/CTE regulatory module mediates the antagonistic action of gibberellic acid and abscisic acid pathways

    PubMed Central

    Lin, Qibing; Wu, Fuqing; Sheng, Peike; Zhang, Zhe; Zhang, Xin; Guo, Xiuping; Wang, Jiulin; Cheng, Zhijun; Wang, Jie; Wang, Haiyang; Wan, Jianmin

    2015-01-01

    Abscisic acid (ABA) and gibberellic acid (GA) antagonistically regulate many developmental processes and responses to biotic or abiotic stresses in higher plants. However, the molecular mechanism underlying this antagonism is still poorly understood. Here, we show that loss-of-function mutation in rice Tiller Enhancer (TE), an activator of the APC/CTE complex, causes hypersensitivity and hyposensitivity to ABA and GA, respectively. We find that TE physically interacts with ABA receptor OsPYL/RCARs and promotes their degradation by the proteasome. Genetic analysis also shows OsPYL/RCARs act downstream of TE in mediating ABA responses. Conversely, ABA inhibits APC/CTE activity by phosphorylating TE through activating the SNF1-related protein kinases (SnRK2s), which may interrupt the interaction between TE and OsPYL/RCARs and subsequently stabilize OsPYL/RCARs. In contrast, GA can reduce the level of SnRK2s and may promote APC/CTE-mediated degradation of OsPYL/RCARs. Thus, we propose that the SnRK2-APC/CTE regulatory module represents a regulatory hub underlying the antagonistic action of GA and ABA in plants. PMID:26272249

  11. Pharmacological characterization of LY233053: A structurally novel tetrazole-substituted competitive N-methyl-D-aspartic acid antagonist with a short duration of action

    SciTech Connect

    Schoepp, D.D.; Ornstein, P.L.; Leander, J.D.; Lodge, D.; Salhoff, C.R.; Zeman, S.; Zimmerman, D.M. )

    1990-12-01

    This study reports the activity of a structurally novel excitatory amino acid receptor antagonist, LY233053 (cis-(+-)-4-((2H-tetrazol-5-yl)methyl)piperidine-2-carboxylic acid), the first tetrazole-containing competitive N-methyl-D-aspartic acid (NMDA) antagonist. LY233053 potently inhibited NMDA receptor binding to rat brain membranes as shown by the in vitro displacement of (3H) CGS19755 (IC50 = 107 +/- 7 nM). No appreciable affinity in (3H)alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or (3H)kainate binding assays was observed (IC50 values greater than 10,000 nM). In vitro NMDA receptor antagonist activity was further demonstrated by selective inhibition of NMDA-induced depolarization in cortical wedges (IC50 = 4.2 +/- 0.4 microM vs. 40 microM NMDA). LY233053 was effective after in vivo systemic administration in a number of animal models. In neonatal rats, LY233053 selectively blocked NMDA-induced convulsions (ED50 = 14.5 mg/kg i.p.) with a relatively short duration of action (2-4 hr). In pigeons, LY233053 potently antagonized (ED50 = 1.3 mg/kg i.m.) the behavioral suppressant effects of 10 mg/kg of NMDA. However, a dose of 160 mg/kg, i.m., was required to produce phencyclidine-like catalepsy in pigeons. In mice, LY233053 protected against maximal electroshock-induced seizures at lower doses (ED50 = 19.9 mg/kg i.p.) than those that impaired horizontal screen performance (ED50 = 40.9 mg/kg i.p.). Cholinergic and GABAergic neuronal degenerations after striatal infusion of NMDA were prevented by single or multiple i.p. doses of LY233053. In summary, the antagonist activity of LY233053 after systemic administration demonstrates potential therapeutic value in conditions of neuronal cell loss due to NMDA receptor excitotoxicity.

  12. Carbamazepine and oxcarbazepine, but not eslicarbazepine, enhance excitatory synaptic transmission onto hippocampal CA1 pyramidal cells through an antagonist action at adenosine A1 receptors.

    PubMed

    Booker, Sam A; Pires, Nuno; Cobb, Stuart; Soares-da-Silva, Patrício; Vida, Imre

    2015-06-01

    This study assessed the anticonvulsant and seizure generation effects of carbamazepine (CBZ), oxcarbazepine (OXC) and eslicarbazepine (S-Lic) in wild-type mice. Electrophysiological recordings were made to discriminate potential cellular and synaptic mechanisms underlying anti- and pro-epileptic actions. The anticonvulsant and pro-convulsant effects were evaluated in the MES, the 6-Hz and the Irwin tests. Whole-cell patch-clamp recordings were used to investigate the effects on fast excitatory and inhibitory synaptic transmission in hippocampal area CA1. The safety window for CBZ, OXC and eslicarbazepine (ED50 value against the MES test and the dose that produces grade 5 convulsions in all mice), was 6.3, 6.0 and 12.5, respectively. At high concentrations the three drugs reduced synaptic transmission. CBZ and OXC enhanced excitatory postsynaptic currents (EPSCs) at low, therapeutically-relevant concentrations. These effects were associated with no change in inhibitory postsynaptic currents (IPSCs) resulting in altered balance between excitation and inhibition. S-Lic had no effect on EPSC or IPSC amplitudes over the same concentration range. The CBZ mediated enhancement of EPSCs was blocked by DPCPX, a selective antagonist, and occluded by CCPA, a selective agonist of the adenosine A1 receptor. Furthermore, reduction of endogenous adenosine by application of the enzyme adenosine deaminase also abolished the CBZ- and OXC-induced increase of EPSCs, indicating that the two drugs act as antagonists at native adenosine receptors. In conclusion, CBZ and OXC possess pro-epileptic actions at clinically-relevant concentrations through the enhancement of excitatory synaptic transmission. S-Lic by comparison has no such effect on synaptic transmission, explaining its lack of seizure exacerbation. PMID:25656478

  13. The diuretic action of 8-cyclopentyl-1,3-dipropylxanthine, a selective A1 adenosine receptor antagonist.

    PubMed Central

    Knight, R. J.; Bowmer, C. J.; Yates, M. S.

    1993-01-01

    1. The diuretic effect of the selective A1 adenosine receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPX), was investigated in anaesthetized rats. 2. CPX (0.1 mg kg-1, i.v.) produced significant increases in urine flow, and the excretion rate and fractional excretion of both sodium and chloride. By contrast, CPX administration did not result in any significant change in the excretion of potassium. 3. The diuretic effect of CPX was accompanied by a transient increase in inulin clearance although p-amino-hippurate clearance was unaffected, indicating the CPX induced a temporary elevation of glomerular filtration rate but no change in renal blood flow. 4. The fractional excretion of lithium (a marker of delivery of fluid out of the proximal tubule) was also significantly increased by CPX. However, other measures of tubular function derived from lithium clearance indicated that there were no changes in the handling of sodium or water in the distal regions of the nephron. 5. CPX did not significantly alter the relationship between either free water reabsorption or free water clearance and the distal delivery of sodium, which suggests that CPX does not affect the renal concentration/dilution mechanism. 6. The results of this study show that the diuresis and increased excretion of sodium and chloride induced by CPX (0.1 mg kg-1) in the rat, occurs with only transient elevation in glomerular filtration rate and no change in renal blood flow. The primary reason for the diuresis appears to be inhibition of sodium reabsorption in the proximal tubule.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8495243

  14. Biphenylacetic acid enhances the antagonistic action of fluoroquinolones on the GABA(A)-mediated responses of the isolated guinea-pig ileum.

    PubMed

    Koutsoviti-Papadopoulou, M; Nikolaidis, E; Kounenis, G

    2001-09-01

    This paper examines the effect of biphenylacetic acid on the antagonistic action of norfloxacin and enoxacin on the GABA(A)-mediated responses of the isolated guinea-pig ileum. GABA produced transient contractions followed by relaxation. The contractile effect of exogenously applied GABA was concentration-dependent with EC(50)= 9.8 x 10(-6) M. This contractile effect was not significantly modified by biphenylacetic acid, and the EC(50) value for GABA in the presence of 10(-5) M biphenylacetic acid was 1.15 x 10(-5) M. The GABA contractile effect was inhibited, dose-dependently, by either norfloxacin or enoxacin, but only at concentrations higher than 10(-5) M. The response of the ileum to GABA (at EC(50)) was reduced to 35 and 36% by pretreatment with 10(-5) M norfloxacin or enoxacin, respectively. However, in the presence of 10(-5) M biphenylacetic acid, the response of the ileum to GABA was reduced to 2.2% by pretreatment with 10(-5) M enoxacin, while it was completely abolished by pretreatment with 10(-5) M norfloxacin and the IC(50) values were 5.5 x 10(-7) and 1.5 x 10(-6) M for norfloxacin and enoxacin, respectively. These data show that biphenylacetic acid whilst having no effect at the GABA(A)-mediated contractile response of the guinea-pig ileum, enhances the antagonistic effect of both enoxacin and norfloxacin. This suggests that combined administration of fluoroquinolones and biphenylacetic acid synergistically inhibits GABA(A)-receptors at the intestinal level. PMID:11529690

  15. Anxiolytic-like actions of the selective 5-HT4 receptor antagonists SB 204070A and SB 207266A in rats.

    PubMed

    Kennett, G A; Bright, F; Trail, B; Blackburn, T P; Sanger, G J

    1997-01-01

    The highly selective 5-HT4 receptor antagonists, SB 204070A (0.001-0.1 mg/kg s.c., 30 min pretest) and SB 207266A (0.01, 1 and 10 mg/kg p.o., 1 hr pre-test), increased time spent in social interaction without affecting locomotor activity, in a rat 15 min social interaction test under high light, unfamiliar conditions. At 1 and 10 mg/kg s.c., SB 204070A was no longer active. These results are consistent with the profile expected of anxiolytic treatments in this procedure. In a rat 5 min elevated x-maze test, SB 204070A (0.01 and 1 mg/kg s.c., 30 min pre-test) significantly increased the percentage of time spent on the open arms. SB 204070A (0.01 mg/kg s.c.) and SB 207266A (1 mg/kg p.o., 1 hr pre-test) also increased percentage entries to the open arms. Neither compound affected locomotion at any dose tested in the procedure. The effects of both compounds in this procedure are also consistent with anxiolysis. Neither SB 204070A (0.1 or 1 mg/kg s.c., 30 min pre-test) nor SB 207266A (0.1 or 1 mg/kg p.o., 1 hr pre-test) affected either unpunished or punished responding, in a rat Geller-Seifter conflict model of anxiety. The maximal efficacy of both SB 204070A and SB 207266A in the rat social interaction test was similar to that of the benzodiazepine anxiolytic chlordiazepoxide (5 mg/kg s.c. or p.o.) used as a positive control, but was considerably less in the elevated x-maze procedure. The results suggest that 5-HT4 receptor antagonists may have modest anxiolytic-like actions in rats. PMID:9225297

  16. Flexibility and Muscular Strength.

    ERIC Educational Resources Information Center

    Liemohn, Wendell

    1988-01-01

    This definition of flexibility and muscular strength also explores their roles in overall physical fitness and focuses on how increased flexibility and muscular strength can help decrease or eliminate lower back pain. (CB)

  17. Mechanistic insights into mode of action of potent natural antagonists of BACE-1 for checking Alzheimer’s plaque pathology

    SciTech Connect

    Dhanjal, Jaspreet Kaur; Goyal, Sukriti; Sharma, Sudhanshu; Hamid, Rabia; Grover, Abhinav

    2014-01-17

    Highlights: •Accumulation of Aβ plaques is one of the major pathology associated with Alzheimer’s disease. •Inhibition of β-Secretase or BACE-1 offers a viable prospect to check the growth of these plaques. •A large virtual dataset of natural compounds was screened against BACE-1. •Top two hits were analyzed for thermodynamic and structural stability using MD simulations. •Their detailed binding mode of actions were elucidated. -- Abstract: Alzheimer’s is a neurodegenerative disorder resulting in memory loss and decline in cognitive abilities. Accumulation of extracellular beta amyloidal plaques is one of the major pathology associated with this disease. β-Secretase or BACE-1 performs the initial and rate limiting step of amyloidic pathway in which 37–43 amino acid long peptides are generated which aggregate to form plaques. Inhibition of this enzyme offers a viable prospect to check the growth of these plaques. Numerous efforts have been made in recent years for the generation of BACE-1 inhibitors but many of them failed during the preclinical or clinical trials due to drug related or drug induced toxicity. In the present work, we have used computational methods to screen a large dataset of natural compounds to search for small molecules having BACE-1 inhibitory activity with low toxicity to normal cells. Molecular dynamics simulations were performed to analyze molecular interactions between the screened compounds and the active residues of the enzyme. Herein, we report two natural compounds of inhibitory nature active against β-secretase enzyme of amyloidic pathway and are potent lead molecules against Alzheimer’s disease.

  18. Antagonistic actions of analogs related to growth hormone-releasing hormone (GHRH) on receptors for GHRH and vasoactive intestinal peptide on rat pituitary and pineal cells in vitro

    PubMed Central

    Rekasi, Zoltan; Varga, Jozsef L.; Schally, Andrew V.; Halmos, Gabor; Groot, Kate; Czompoly, Tamas

    2000-01-01

    Peptide analogs of growth hormone-releasing hormone (GHRH) can potentially interact with vasoactive intestinal peptide (VIP) receptors (VPAC1-R and VPAC2-R) because of the structural similarities of these two hormones and their receptors. We synthesized four new analogs related to GHRH (JV-1–50, JV-1–51, JV-1–52, and JV-1–53) with decreased GHRH antagonistic activity and increased VIP antagonistic potency. To characterize various peptide analogs for their antagonistic activity on receptors for GHRH and VIP, we developed assay systems based on superfusion of rat pituitary and pineal cells. Receptor-binding affinities of peptides to the membranes of these cells were also evaluated by radioligand competition assays. Previously reported GHRH antagonists JV-1–36, JV-1–38, and JV-1–42 proved to be selective for GHRH receptors, because they did not influence VIP-stimulated VPAC2 receptor-dependent prolactin release from pituitary cells or VPAC1 receptor-dependent cAMP efflux from pinealocytes but strongly inhibited GHRH-stimulated growth hormone (GH) release. Analogs JV-1–50, JV-1–51, and JV-1–52 showed various degrees of VPAC1-R and VPAC2-R antagonistic potency, although also preserving a substantial GHRH antagonistic effect. Analog JV-1–53 proved to be a highly potent VPAC1 and VPAC2 receptor antagonist, devoid of inhibitory effects on GHRH-evoked GH release. The antagonistic activity of these peptide analogs on processes mediated by receptors for GHRH and VIP was consistent with the binding affinity. The analogs with antagonistic effects on different types of receptors expressed on tumor cells could be utilized for the development of new approaches to treatment of various human cancers. PMID:10655511

  19. Identification of Glycyrrhiza as the rikkunshito constituent with the highest antagonistic potential on heterologously expressed 5-HT3A receptors due to the action of flavonoids

    PubMed Central

    Herbrechter, Robin; Ziemba, Paul M.; Hoffmann, Katrin M.; Hatt, Hanns; Werner, Markus; Gisselmann, Günter

    2015-01-01

    The traditional Japanese phytomedicine rikkunshito is traditionally used for the treatment of gastrointestinal motility disorders, cachexia and nausea. These effects indicate 5-HT3 receptor antagonism, due to the involvement of these receptors in such pathophysiological processes. E.g., setrons, specific 5-HT3 receptor antagonists are the strongest antiemetics, developed so far. Therefore, the antagonistic effects of the eight rikkunshito constituents at heterologously expressed 5-HT3Areceptors were analyzed using the two-electrode voltage-clamp technique. The results indicate that tinctures from Aurantii, Ginseng, Zingiberis, Atractylodis and Glycyrrhiza inhibited the 5-HT3A receptor response, whereas the tinctures of Poria cocos, Jujubae and Pinellia exhibited no effect. Surprisingly, the strongest antagonism was found for Glycyrrhiza, whereas the Zingiberis tincture, which is considered to be primarily responsible for the effect of rikkunshito, exhibited the weakest antagonism of 5-HT3A receptors. Rikkunshito contains various vanilloids, ginsenosides and flavonoids, a portion of which show an antagonistic effect on 5-HT3 receptors. A screening of the established ingredients of the active rikkunshito constituents and related substances lead to the identification of new antagonists within the class of flavonoids. The flavonoids (-)-liquiritigenin, glabridin and licochalcone A from Glycyrrhiza species were found to be the most effective inhibitors of the 5-HT-induced currents in the screening. The flavonoids (-)-liquiritigenin and hesperetin from Aurantii inhibited the receptor response in a non-competitive manner, whereas glabridin and licochalcone A exhibited a potential competitive antagonism. Furthermore, licochalcone A acts as a partial antagonist of 5-HT3A receptors. Thus, this study reveals new 5-HT3A receptor antagonists with the aid of increasing the comprehension of the complex effects of rikkunshito. PMID:26191003

  20. Facioscapulohumeral muscular dystrophy

    MedlinePlus

    ... of cases, the parents do not carry the gene. Facioscapulohumeral muscular dystrophy affects about 5 out of 100,000 people. ... Treatment There is no ... worse. Physical therapy may help maintain muscle strength. Other possible treatments ...

  1. Becker muscular dystrophy

    MedlinePlus

    ... and wheelchairs may improve movement and self-care. Genetic counseling may be recommended. Daughters of a man with ... Genetic counseling may be advised if there is a family history of Becker muscular dystrophy.

  2. Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Registry

    ClinicalTrials.gov

    2016-08-26

    Myotonic Dystrophy; Facioscapulohumeral Muscular Dystrophy; Muscular Dystrophy; Myotonic Dystrophy Type 1; Myotonic Dystrophy Type 2; Congenital Myotonic Dystrophy; PROMM (Proximal Myotonic Myopathy); Steinert's Disease; Myotonic Muscular Dystrophy

  3. The renal action of spirorenone and other 6 beta,7 beta; 15 beta,16 beta-dimethylene-17-spirolactones, a new type of steroidal aldosterone antagonists.

    PubMed

    Casals-Stenzel, J; Buse, M; Wambach, G; Losert, W

    1984-01-01

    The aldosterone antagonistic activity in vivo and the affinity for mineralocorticoid receptors (MCR) in vitro of 3-(17 beta-hydroxy-6 beta,7 beta; 15 beta,16 beta-dimethylene-3-oxo-1, 4-androstadiene-17 alpha-yl) propionic acid gamma-lactone (spirorenone), a new aldosterone antagonist, and four of its derivatives were studied in comparison with spironolactone in rats. Spirorenone was 8.6 times as potent as spironolactone, but showed a lower affinity for the MCR than the standard. The C1/C2 saturated derivative (compound I) had 7.6 times the antialdosterone potency and 2 times the binding activity of spironolactone. The 17-spiroether derivative of spirorenone (compound II) showed a lower aldosterone antagonistic activity (1.7 the potency of spironolactone) as well as a lower affinity for the MCR (0.5 the affinity of spironolactone). The analogue with a 17 beta-hydroxyl group and a 17 alpha-hydroxypropyl side chain (compound III) possessed a very low binding capacity for MCR (1/10 of that of spironolactone) but still a 1.3 times higher antialdosterone activity than spironolactone. This result is probably due to a transformation of compound III to an active metabolite in vivo. Finally, the derivative with a reversed configuration of the 17-spirolactone ring (compound IV) had no biological activity in vivo and no affinity for the MCR. These results show that spirorenone or one of its active derivatives might lead to a new series of potent aldosterone antagonists. PMID:6329237

  4. ACTH Antagonists.

    PubMed

    Clark, Adrian John; Forfar, Rachel; Hussain, Mashal; Jerman, Jeff; McIver, Ed; Taylor, Debra; Chan, Li

    2016-01-01

    Adrenocorticotropin (ACTH) acts via a highly selective receptor that is a member of the melanocortin receptor subfamily of type 1 G protein-coupled receptors. The ACTH receptor, also known as the melanocortin 2 receptor (MC2R), is unusual in that it is absolutely dependent on a small accessory protein, melanocortin receptor accessory protein (MRAP) for cell surface expression and function. ACTH is the only known naturally occurring agonist for this receptor. This lack of redundancy and high degree of ligand specificity suggests that antagonism of this receptor could provide a useful therapeutic aid and a potential investigational tool. Clinical situations in which this could be useful include (1) Cushing's disease and ectopic ACTH syndrome - especially while preparing for definitive treatment of a causative tumor, or in refractory cases, or (2) congenital adrenal hyperplasia - as an adjunct to glucocorticoid replacement. A case for antagonism in other clinical situations in which there is ACTH excess can also be made. In this article, we will explore the scientific and clinical case for an ACTH antagonist, and will review the evidence for existing and recently described peptides and modified peptides in this role. PMID:27547198

  5. ACTH Antagonists

    PubMed Central

    Clark, Adrian John; Forfar, Rachel; Hussain, Mashal; Jerman, Jeff; McIver, Ed; Taylor, Debra; Chan, Li

    2016-01-01

    Adrenocorticotropin (ACTH) acts via a highly selective receptor that is a member of the melanocortin receptor subfamily of type 1 G protein-coupled receptors. The ACTH receptor, also known as the melanocortin 2 receptor (MC2R), is unusual in that it is absolutely dependent on a small accessory protein, melanocortin receptor accessory protein (MRAP) for cell surface expression and function. ACTH is the only known naturally occurring agonist for this receptor. This lack of redundancy and high degree of ligand specificity suggests that antagonism of this receptor could provide a useful therapeutic aid and a potential investigational tool. Clinical situations in which this could be useful include (1) Cushing’s disease and ectopic ACTH syndrome – especially while preparing for definitive treatment of a causative tumor, or in refractory cases, or (2) congenital adrenal hyperplasia – as an adjunct to glucocorticoid replacement. A case for antagonism in other clinical situations in which there is ACTH excess can also be made. In this article, we will explore the scientific and clinical case for an ACTH antagonist, and will review the evidence for existing and recently described peptides and modified peptides in this role. PMID:27547198

  6. Evaluation of Limb-Girdle Muscular Dystrophy

    ClinicalTrials.gov

    2014-03-06

    Becker Muscular Dystrophy; Limb-Girdle Muscular Dystrophy, Type 2A (Calpain-3 Deficiency); Limb-Girdle Muscular Dystrophy, Type 2B (Miyoshi Myopathy, Dysferlin Deficiency); Limb-Girdle Muscular Dystrophy, Type 2I (FKRP-deficiency)

  7. Quantitative analysis of the agonist and antagonist actions of some ATP analogues at P2X-purinoceptors in the rabbit ear artery.

    PubMed

    Leff, P; Wood, B E; O'Connor, S E; McKechnie, K

    1993-02-01

    1. The agonist and antagonist effects of a series of beta, gamma-methylene dihalo- and 2-methylthio-substituted analogues of ATP at P2x-purinoceptors have been analysed on the rabbit isolated ear artery preparation. Cumulative and sequential dosing experimental protocols were employed in the construction of agonist concentration-effect curves in order to address the possible influence of acute receptor desensitization on subsequent analyses. 2. Using the cumulative curve design the following results were obtained: D-AMP-PCBr2P, 2-methylthio-D-AMP-PCCl2P, L-AMP-PCF2P, L-AMP-PCCl2P and LAMP-PCBr2P each behaved as partial agonists. D-AMP-CPP was used as a reference full agonist and these analogues were analysed by the comparative method of Barlow et al. (1967), to provide estimates of affinity and efficacy. 2-Methylthio-L-AMP-PCBr2P was virtually silent as an agonist and was analysed as a competitive antagonist by Schild analysis. 3. Two agonists, L-AMP-PCCl2P and L-AMP-PCBr2P, were analysed by the sequential curve design, and the antagonist effects of one of the agonists, L-AMP-PCBr2P were also analysed using this protocol. The resulting estimates of affinity and efficacy, while similar to those obtained with the cumulative design, indicated that acute desensitization may affect curve definition and estimation of these quantities. 4. The following structure-activity trends emerged: D-analogues tended to have higher efficacy but lower affinity than L-analogues; efficacy varied markedly and inversely with the atomic weight of the halogen while affinity was only minimally affected; 2-methylthio- substitution also reduced efficacy with minimal effect on affinity. 5. The results of this analysis are discussed in terms of the utility of affinity and efficacy information in the classification of purinoceptors and the design of chemical probes for them. PMID:8448598

  8. Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. II. Agonist and antagonist properties at subtypes of dopamine D(2)-like receptor and alpha(1)/alpha(2)-adrenoceptor.

    PubMed

    Newman-Tancredi, Adrian; Cussac, Didier; Audinot, Valérie; Nicolas, Jean-Paul; De Ceuninck, Frédéric; Boutin, Jean-A; Millan, Mark J

    2002-11-01

    The accompanying multivariate analysis of the binding profiles of antiparkinson agents revealed contrasting patterns of affinities at diverse classes of monoaminergic receptor. Herein, we characterized efficacies at human (h)D(2SHORT(S)), hD(2LONG(L)), hD(3), and hD(4.4) receptors and at halpha(2A)-, halpha(2B)-, halpha(2C)-, and halpha(1A)-adrenoceptors (ARs). As determined by guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding, no ligand displayed "full" efficacy relative to dopamine (100%) at all "D(2)-like" sites. However, at hD(2S) receptors quinpirole, pramipexole, ropinirole, quinerolane, pergolide, and cabergoline were as efficacious as dopamine (E(max)100%); TL99, talipexole, and apomorphine were highly efficacious (79-92%); piribedil, lisuride, bromocriptine, and terguride showed intermediate efficacy (40-55%); and roxindole displayed low efficacy (11%). For all drugs, efficacies were lower at hD(2L) receptors, with terguride and roxindole acting as antagonists. At hD(3) receptors, efficacies ranged from 33% (roxindole) to 94% (TL99), whereas, for hD(4) receptors, highest efficacies (approximately 70%) were seen for quinerolane, quinpirole, and TL99, whereas piribedil and terguride behaved as antagonists and bromocriptine was inactive. Although efficacies at hD(2S) versus hD(2L) sites were highly correlated (r = 0.79), they correlated only modestly to hD(3)/hD(4) sites (r = 0.44-0.59). In [(35)S]GTPgammaS studies of halpha(2A)-ARs, TL99 (108%), pramipexole (52%), talipexole (51%), pergolide (31%), apomorphine (16%), and quinerolane (11%) were agonists and ropinirole and roxindole were inactive, whereas piribedil and other agents were antagonists. Similar findings were obtained at halpha(2B)- and halpha(2C)-ARs. Using [(3)H]phosphatidylinositol depletion, roxindole, bromocriptine, lisuride, and terguride displayed potent antagonist properties at halpha(1A)-ARs. In conclusion, antiparkinson agents display diverse agonist and antagonist

  9. Locomotor adaptation to a soleus EMG-controlled antagonistic exoskeleton.

    PubMed

    Gordon, Keith E; Kinnaird, Catherine R; Ferris, Daniel P

    2013-04-01

    Locomotor adaptation in humans is not well understood. To provide insight into the neural reorganization that occurs following a significant disruption to one's learned neuromuscular map relating a given motor command to its resulting muscular action, we tied the mechanical action of a robotic exoskeleton to the electromyography (EMG) profile of the soleus muscle during walking. The powered exoskeleton produced an ankle dorsiflexion torque proportional to soleus muscle recruitment thus limiting the soleus' plantar flexion torque capability. We hypothesized that neurologically intact subjects would alter muscle activation patterns in response to the antagonistic exoskeleton by decreasing soleus recruitment. Subjects practiced walking with the exoskeleton for two 30-min sessions. The initial response to the perturbation was to "fight" the resistive exoskeleton by increasing soleus activation. By the end of training, subjects had significantly reduced soleus recruitment resulting in a gait pattern with almost no ankle push-off. In addition, there was a trend for subjects to reduce gastrocnemius recruitment in proportion to the soleus even though only the soleus EMG was used to control the exoskeleton. The results from this study demonstrate the ability of the nervous system to recalibrate locomotor output in response to substantial changes in the mechanical output of the soleus muscle and associated sensory feedback. This study provides further evidence that the human locomotor system of intact individuals is highly flexible and able to adapt to achieve effective locomotion in response to a broad range of neuromuscular perturbations. PMID:23307949

  10. Effects of opioid antagonists naloxone and naltrexone on neuropeptide Y-induced feeding and brown fat thermogenesis in the rat. Neural site of action.

    PubMed Central

    Kotz, C M; Grace, M K; Briggs, J; Levine, A S; Billington, C J

    1995-01-01

    Neuropeptide Y administered intracerebroventricularly and into the paraventricular nucleus of the hypothalamus stimulates feeding and decreases brown adipose tissue thermogenesis. Although specific neuropeptide Y antagonists are not yet available, previous studies had shown that the opioid antagonist naloxone blocked neuropeptide Y-induced feeding when both drugs were injected intracerebroventricularly. We wanted to find out if naloxone injected into specific brain sites would block neuropeptide Y effects on feeding and brown fat thermogenesis. Rats were double injected in specific brain sites with neuropeptide Y and either naloxone or naltrexone (a congener of naloxone). Food intake and brown fat measures were assessed. Naloxone or naltrexone in the paraventricular nucleus weakly decreased paraventricular nucleus neuropeptide Y-induced feeding and did not affect neuropeptide Y-induced reductions in brown fat activity. Peripheral naloxone blocked intracerebroventricular neuropeptide Y-induced feeding and brown fat alterations. Fourth ventricular naloxone decreased paraventricular nucleus neuropeptide Y-induced feeding, and naltrexone given into the nucleus of the solitary tract blocked paraventricular nucleus neuropeptide Y-induced alterations in feeding and brown fat. These data indicate that neuropeptide Y in the paraventricular nucleus may act on feeding and brown fat thermogenesis through opioidergic pathways in the nucleus of the solitary tract. PMID:7615787

  11. How Is Muscular Dystrophy Diagnosed?

    MedlinePlus

    ... Information Clinical Trials Resources and Publications How is muscular dystrophy diagnosed? Skip sharing on social media links Share this: Page Content The first step in diagnosing muscular dystrophy (MD) is a visit with a health care ...

  12. Duchenne muscular dystrophy.

    PubMed

    Yiu, Eppie M; Kornberg, Andrew J

    2015-08-01

    Duchenne muscular dystrophy, an X-linked disorder, has an incidence of one in 5000 boys and presents in early childhood with proximal muscle weakness. Untreated boys become wheelchair bound by the age of 12 years and die of cardiorespiratory complications in their late teens to early 20s. The use of corticosteroids, non-invasive respiratory support, and active surveillance and management of associated complications have improved ambulation, function, quality of life and life expectancy. The clinical features, investigations and management of Duchenne muscular dystrophy are reviewed, as well as the latest in some of the novel therapies. PMID:25752877

  13. Structure-activity relationships and mechanism of action of Eph-ephrin antagonists: interaction of cholanic acid with the EphA2 receptor

    PubMed Central

    Tognolini, Massimiliano; Incerti, Matteo; Mohamed, Iftiin Hassan; Giorgio, Carmine; Russo, Simonetta; Bruni, Renato; Lelli, Barbara; Bracci, Luisa; Noberini, Roberta; Pasquale, Elena B.; Barocelli, Elisabetta; Vicini, Paola; Mor, Marco

    2012-01-01

    The Eph–ephrin system, including the EphA2 receptor and the ephrin-A1 ligand, plays a critical role in tumor and vascular functions during carcinogenesis. We previously identified (3α,5β)-3-hydroxycholan-24-oic acid (lithocholic acid) as an Eph-ephrin antagonist able to inhibit EphA2 receptor activation and therefore potentially useful as a novel EphA2 receptor targeting agent. Here, we explore the structure-activity relationships of a focused set of lithocholic acid derivatives, based on molecular modelling investigation and displacement binding assays. Our exploration shows that while the 3-α-hydroxyl group of lithocholic acid has a negligible role in the recognition of the EphA2 receptor, its carboxylate group is critical for disrupting the binding of ephrin-A1 to the EphA2. As a result of our investigation, we identified (5β)-cholan-24-oic acid (cholanic acid) as a novel compound that competitively inhibits EphA2-ephrin-A1 interaction with higher potency than lithocholic acid. Surface plasmon resonance analysis indicates that cholanic acid binds specifically and reversibly to the ligand-binding domain of EphA2, with a steady-state dissociation constant (KD) in the low micromolar range. Furthermore, cholanic acid blocks the phosphorylation of EphA2 and cell retraction and rounding in PC3 prostate cancer cells, two effects that depend on EphA2 activation by the ephrin-A1 ligand. These findings suggest that cholanic acid can be used as a template structure to design effective EphA2 antagonists, with potential impact in the elucidation of the role played by this receptor in pathological conditions. PMID:22529030

  14. Insights into the molecular basis of action of the AT1 antagonist losartan using a combined NMR spectroscopy and computational approach.

    PubMed

    Zervou, Maria; Cournia, Zoe; Potamitis, Constantinos; Patargias, George; Durdagi, Serdar; Grdadolnik, Simona Golic; Mavromoustakos, Thomas

    2014-03-01

    The drug:membrane interactions for the antihypertensive AT1 antagonist losartan, the prototype of the sartans class, are studied herein using an integrated approach. The pharmacophore arrangement of the drug was revealed by rotating frame nuclear Overhauser effect spectroscopy (2D ROESY) NMR spectroscopy in three different environments, namely water, dimethyl sulfoxide (DMSO), and sodium dodecyl sulfate (SDS) micellar solutions mimicking conditions of biological transport fluids and membrane lipid bilayers. Drug association with micelles was monitored by diffusion ordered spectroscopy (2D DOSY) and drug:micelle intermolecular interactions were characterized by ROESY spectroscopy. The localisation of the drug in the micellar environment was investigated by introducing 5-doxyl and 16-doxyl stearic acids. The use of spin labels confirmed that losartan resides close to the micelle:water interface with the hydroxymethyl group and the tetrazole heterocyclic aromatic ring facing the polar surface with the potential to interact with SDS charged polar head groups in order to increase amphiphilic interactions. The spontaneous insertion, the diffusion pathway and the conformational features of losartan were monitored by Molecular Dynamics (MD) simulations in a modeled SDS micellar aggregate environment and a long exploratory MD run (580ns) in a phospholipid dipalmitoylphosphatidylcholine (DPPC) bilayer with the AT1 receptor embedded. MD simulations were in excellent agreement with experimental results and further revealed the molecular basis of losartan:membrane interactions in atomic-level detail. This applied integrated approach aims to explore the role of membranes in losartan's pathway towards the AT1 receptor. PMID:24374319

  15. Preadolescent male perceptions of action figure physiques.

    PubMed

    Baghurst, Timothy; Carlston, David; Wood, Julie; Wyatt, Frank B

    2007-12-01

    This study investigated the preference and reasoning of 176 preadolescent and adolescent males when presented with original and current action figures that had statistically different physiques. Current action figures were perceived as significantly more muscular and healthier. Participants also preferred to resemble current action figures citing muscularity and size for their preference. PMID:18023792

  16. Novel mode of action of the calcium antagonist mibefradil (Ro 40-5967): potent immunosuppression by inhibition of T-cell infiltration through allogeneic endothelium.

    PubMed Central

    Blaheta, R A; Hailer, N P; Brude, N; Wittig, B; Oppermann, E; Leckel, K; Harder, S; Scholz, M; Weber, S; Encke, A; Markus, B H

    1998-01-01

    Cyclosporin A reduces the mitotic activity of allosensitized lymphocytes, but fails to limit emigration of these cells into the donor organ. However, the modulation of both lymphocyte proliferation and infiltration are desirable characteristics of immunosuppressive therapy. The calcium-channel blocker, verapamil, has recently been shown to effectively prevent the transmigration of CD4+ and CD8+ T cells through allogeneic endothelium. Mibefradil (Ro 40-5967) represents a new generation of calcium antagonists with high potency and long-term activity. To evaluate the immunosuppressive potential of this drug, the influence of mibefradil on lymphocyte adhesion to, horizontal locomotion along, and penetration through allogeneic endothelium (HUVEC) was performed. When lymphocytes were prestimulated for 24 hr with mibefradil, adhesion and penetration were dose-dependently reduced. The adhesion ID50 values were 3.4 microM (CD4+ T cells) versus 9.2 microM (CD8+ T cells) and 2.1 microM (CD4+ T cells) versus 3.9 microM (CD8+ T cells) with regard to penetration. Mibefradil also effectively blocked horizontal locomotion. Specific down-regulation of T-cell binding to the P-selection receptor (ID50: CD4+ T cells, 0.8 microM: CD8+ T cells, 1.2 microM) and to the intracellular adhesion molecule-1 (ICAM-1) receptor (ID50: CD4+ T cells, 1.9 microM; CD8+ T cells, 1.5 microM) by mibefradil seems to be responsible for the decreased adhesion and penetration rates. Reduction of intracellular F-actin in T lymphocytes could diminish cell locomotion. In conclusion, the potent suppressive properties of mibefradil support its use as a co-medication in cyclosporin A-based immunosuppressive therapy. PMID:9741343

  17. Protein Kinase A and Mitogen-Activated Protein Kinase Pathways Antagonistically Regulate Fission Yeast fbp1 Transcription by Employing Different Modes of Action at Two Upstream Activation Sites

    PubMed Central

    Neely, Lori A.; Hoffman, Charles S.

    2000-01-01

    A significant challenge to our understanding of eukaryotic transcriptional regulation is to determine how multiple signal transduction pathways converge on a single promoter to regulate transcription in divergent fashions. To study this, we have investigated the transcriptional regulation of the Schizosaccharomyces pombe fbp1 gene that is repressed by a cyclic AMP (cAMP)-dependent protein kinase A (PKA) pathway and is activated by a stress-activated mitogen-activated protein kinase (MAPK) pathway. In this study, we identified and characterized two cis-acting elements in the fbp1 promoter required for activation of fbp1 transcription. Upstream activation site 1 (UAS1), located approximately 900 bp from the transcriptional start site, resembles a cAMP response element (CRE) that is the binding site for the atf1-pcr1 heterodimeric transcriptional activator. Binding of this activator to UAS1 is positively regulated by the MAPK pathway and negatively regulated by PKA. UAS2, located approximately 250 bp from the transcriptional start site, resembles a Saccharomyces cerevisiae stress response element. UAS2 is bound by transcriptional activators and repressors regulated by both the PKA and MAPK pathways, although atf1 itself is not present in these complexes. Transcriptional regulation of fbp1 promoter constructs containing only UAS1 or UAS2 confirms that the PKA and MAPK regulation is targeted to both sites. We conclude that the PKA and MAPK signal transduction pathways regulate fbp1 transcription at UAS1 and UAS2, but that the antagonistic interactions between these pathways involve different mechanisms at each site. PMID:10938120

  18. Antagonism of the presumed presynaptic action of L-AP4 on GABAergic transmission in the ventrobasal thalamus by the novel mGluR antagonist MPPG.

    PubMed

    Salt, T E; Turner, J P

    1996-02-01

    The metabotropic glutamate receptor (mGluR) agonists CCG-I and L-AP4, acting at Group II and Group III mGluRs respectively, can reduce GABAergic synaptic inhibition on single neurones in the rat thalamus in vivo via a presumed presynaptic mechanism. The actions of L-AP4 were antagonized by (+/-)-alpha-methyl-4-phosphonophenylglycine (MPPG), whereas CCG-I was significantly less affected. Thus MPPG may be a useful tool for detecting physiological roles for Group III mGluRs. PMID:8734494

  19. Genetics Home Reference: tibial muscular dystrophy

    MedlinePlus

    ... Names for This Condition tardive tibial muscular dystrophy TMD Udd distal myopathy Udd-Markesbery muscular dystrophy Udd ... titin may cause more severe tibial muscular dystrophy (TMD). Neuromuscul Disord. 2008 Dec;18(12):922-8. ...

  20. Cardio-Muscular Conditioner

    NASA Technical Reports Server (NTRS)

    1993-01-01

    In the mid-sixties, Gary Graham, a Boeing designer, developed a cardiovascular conditioner for a planned Air Force orbiting laboratory. After the project was cancelled, Graham participated in space station conditioning studies for the Skylab program. Twenty years later, he used this expertise to develop the Shuttle 2000-1, a physical therapy and athletic development conditioner, available through Contemporary Designs. The machine is used by football teams, sports clinics and medical rehabilitation centers. Cardiovascular fitness and muscular strength development are promoted through both kinetic and plyometric exercises.

  1. Congenital muscular torticollis.

    PubMed

    Nilesh, Kumar; Mukherji, Srijon

    2013-07-01

    Congenital muscular torticollis (CMT) is a rare congenital musculoskeletal disorder characterized by unilateral shortening of the sternocleidomastoid muscle (SCM). It presents in newborn infants or young children with reported incidence ranging from 0.3% to 2%. Owing to effective shortening of SCM on the involved side there is ipsilateral head tilt and contralateral rotation of the face and chin. This article reports a case of CMT in a 3½-year-old male child successfully managed by surgical release of the involved SCM followed by physiotherapy. PMID:24205484

  2. Congenital muscular torticollis

    PubMed Central

    Nilesh, Kumar; Mukherji, Srijon

    2013-01-01

    Congenital muscular torticollis (CMT) is a rare congenital musculoskeletal disorder characterized by unilateral shortening of the sternocleidomastoid muscle (SCM). It presents in newborn infants or young children with reported incidence ranging from 0.3% to 2%. Owing to effective shortening of SCM on the involved side there is ipsilateral head tilt and contralateral rotation of the face and chin. This article reports a case of CMT in a 3½-year-old male child successfully managed by surgical release of the involved SCM followed by physiotherapy. PMID:24205484

  3. ADN-1184, a monoaminergic ligand with 5-HT6/7 receptor antagonist action, exhibits activity in animal models of anxiety.

    PubMed

    Partyka, Anna; Wasik, Anna; Jastrzębska-Więsek, Magdalena; Mierzejewski, Paweł; Bieńkowski, Przemysław; Kołaczkowski, Marcin; Wesołowska, Anna

    2016-06-01

    Behavioral and psychological symptoms of dementia (BPSD) include apathy, sleep problems, irritability, wandering, elation, agitation/aggression, and mood disorders such as depression and/or anxiety. Elderly patients are usually treated with second-generation antipsychotics; however, they present not enough efficacy against all symptoms observed. Hence, there still is an unmet need for novel pharmacotherapeutic agents targeted BPSD. A novel arylsulfonamide derivative ADN-1184 has been developed that possesses a preclinical profile of activity corresponding to criteria required for treatment of both psychosis and depressive symptoms of BPSD without exacerbating cognitive impairment or inducing motor disturbances. To broaden its pharmacological efficacy toward anxiety symptoms, its anxiolytic properties have been examined in common animal preclinical models in rats and mice. ADN-1184 significantly increased the number of entries into open arms measured in the elevated plus-maze test; however, it simultaneously increased parameters of exploratory activity. In the Vogel conflict drinking test, ADN-1184 dose-dependently and significantly increased the number of shocks accepted and the number of licks. Moreover, in mice, it also had specific anxiolytic-like activity in the four-plate test, and only negligible one at a specific mid-range dose measured in the spontaneous marble burying test. The obtained findings reveal that ADN-1184 displays anxiolytic-like activity in animal models of anxiety which employed punished stimuli. In its unusual combination of some anxiolytic action with already proven antipsychotic and antidepressant properties, and lack of any disruptive impact on learning and memory processes and motor coordination, ADN-1184 displays a profile that would be desired for a novel therapeutic for BPSD. PMID:26979176

  4. Wasting Mechanisms in Muscular Dystrophy

    PubMed Central

    Shin, Jonghyun; Tajrishi, Marjan M.; Ogura, Yuji; Kumar, Ashok

    2013-01-01

    Muscular dystrophy is a group of more than 30 different clinical genetic disorders that are characterized by progressive skeletal muscle wasting and degeneration. Primary deficiency of specific extracellular matrix, sarcoplasmic, cytoskeletal, or nuclear membrane protein results in several secondary changes such as sarcolemmal instability, calcium influx, fiber necrosis, oxidative stress, inflammatory response, breakdown of extracellular matrix, and eventually fibrosis which leads to loss of ambulance and cardiac and respiratory failure. A number of molecular processes have now been identified which hasten disease progression in human patients and animal models of muscular dystrophy. Accumulating evidence further suggests that aberrant activation of several signaling pathways aggravate pathological cascades in dystrophic muscle. Although replacement of defective gene with wild-type is paramount to cure, management of secondary pathological changes has enormous potential to improving the quality of life and extending lifespan of muscular dystrophy patients. In this article, we have reviewed major cellular and molecular mechanisms leading to muscle wasting in muscular dystrophy. PMID:23669245

  5. Alternative splicing and muscular dystrophy

    PubMed Central

    Pistoni, Mariaelena; Ghigna, Claudia; Gabellini, Davide

    2013-01-01

    Alternative splicing of pre-mRNAs is a major contributor to proteomic diversity and to the control of gene expression in higher eukaryotic cells. For this reasons, alternative splicing is tightly regulated in different tissues and developmental stages and its disruption can lead to a wide range of human disorders. The aim of this review is to focus on the relevance of alternative splicing for muscle function and muscle disease. We begin by giving a brief overview of alternative splicing, muscle-specific gene expression and muscular dystrophy. Next, to illustrate these concepts we focus on two muscular dystrophy, myotonic muscular dystrophy and facioscapulohumeral muscular dystrophy, both associated to disruption of splicing regulation in muscle. PMID:20603608

  6. Myoglobin in Primary Muscular Disease: I. Duchenne Muscular Dystrophy: and: II. Muscular Dystrophy of Distal Type

    PubMed Central

    Romero-Herrera, A. E.; Lehmann, H.; Tomlinson, B. E.; Walton, J. N.

    1973-01-01

    Skeletal myoglobin from two cases of muscular dystrophy, one of Duchenne muscular dystrophy, and one of muscular dystrophy of distal type, have been examined and no differences from normal human myoglobin were found. The opportunity has been taken to discuss the nature of minor fractions of myoglobin-like material which are found when human skeletal myoglobin is isolated. Those which have been observed in the present study have been artefacts and it was possible to demonstrate that they were due to deamidation of certain glutamine and asparagine residues. Images PMID:4590363

  7. Muscular activity and its relationship to biomechanics and human performance

    NASA Technical Reports Server (NTRS)

    Ariel, Gideon

    1994-01-01

    The purpose of this manuscript is to address the issue of muscular activity, human motion, fitness, and exercise. Human activity is reviewed from the historical perspective as well as from the basics of muscular contraction, nervous system controls, mechanics, and biomechanical considerations. In addition, attention has been given to some of the principles involved in developing muscular adaptations through strength development. Brief descriptions and findings from a few studies are included. These experiments were conducted in order to investigate muscular adaptation to various exercise regimens. Different theories of strength development were studied and correlated to daily human movements. All measurement tools used represent state of the art exercise equipment and movement analysis. The information presented here is only a small attempt to understand the effects of exercise and conditioning on Earth with the objective of leading to greater knowledge concerning human responses during spaceflight. What makes life from nonliving objects is movement which is generated and controlled by biochemical substances. In mammals. the controlled activators are skeletal muscles and this muscular action is an integral process composed of mechanical, chemical, and neurological processes resulting in voluntary and involuntary motions. The scope of this discussion is limited to voluntary motion.

  8. Bed Rest Muscular Atrophy

    NASA Technical Reports Server (NTRS)

    Greenleaf, John E.

    2000-01-01

    A major debilitating response from prolonged bed rest (BR) is muscle atrophy, defined as a "decrease in size of a part of tissue after full development has been attained: a wasting away of tissue as from disuse, old age, injury or disease". Part of the complicated mechanism for the dizziness, increased body instability, and exaggerated gait in patients who arise immediately after BR may be a result of not only foot pain, but also of muscular atrophy and associated reduction in lower limb strength. Also, there seems to be a close association between muscle atrophy and bone atrophy. A discussion of many facets of the total BR homeostatic syndrome has been published. The old adage that use determines form which promotes function of bone (Wolff's law) also applies to those people exposed to prolonged BR (without exercise training) in whom muscle atrophy is a consistent finding. An extreme case involved a 16-year-old boy who was ordered to bed by his mother in 1932: after 50 years in bed he had "a lily-white frame with limbs as thin as the legs of a ladder-back chair". These findings emphasize the close relationship between muscle atrophy and bone atrophy. In addition to loss of muscle mass during deconditioning, there is a significant loss of muscle strength and a decrease in protein synthesis. Because the decreases in force (strength) are proportionately greater than those in fiber size or muscle cross-sectional area, other contributory factors must be involved; muscle fiber dehydration may be important.

  9. [Muscular isokinetic dynamometry].

    PubMed

    Svetlize, H D

    1991-01-01

    In the past, muscular strength has primarily been measured using isometric, isotonic or tensiometric techniques. The advent of isokinetic dynamometers has supplied an objective method of measuring peak torque throughout a full range of motion at a predetermined speed of contraction. An isokinetic contraction is a refinement of the controlled motion concept. The isokinetic contraction is dynamic, but the speed of the motion is held constant by a special device. In this way, resistance is in direct ratio to the varying force applied through the full course of a natural movement. The purpose of this study was to determine the peak torque of quadriceps (Q), and hamstrings (H), and their biomechanical angle of production, H to Q ratio and bilateral comparisons of these variables for the first time in a Southamerican population. Twenty healthy and voluntary males (age: 21.9 +/- 3.1 years, height 193.2 +/- 6.5 cm, weight: 84.2 +/- 5.2 kgs.), were tested on the Cybex II Dynamometer and Cybex Data Reduction Computer (CDRC). Quadriceps and hamstrings peak torque (pkTQ), in Newton-meters, were obtained at angular velocities of 60, 180 and 240 degrees. sec-1. Also, the angle of the range of motion at which peak torque occurred in both directions, H and Q peak torque to body weight ratios, H to Q ratio were measured. Finally, CDRC provided the bilateral comparison of the different variables expressed in percentages. All measurements were automatically corrected for the effect of gravity. The absolute maximal pkTQ of dominant (D), and non-dominant (ND), quadriceps at 60 degrees/sec was DQ 297 +/- 25 Nwm and nDQ 303 +/- 13 Nwm.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1921692

  10. Facioscapulohumeral muscular dystrophy.

    PubMed

    Sacconi, Sabrina; Salviati, Leonardo; Desnuelle, Claude

    2015-04-01

    Facioscapulohumeral muscular dystrophy (FSHD) is characterized by a typical and asymmetric pattern of muscle involvement and disease progression. Two forms of FSHD, FSHD1 and FSHD2, have been identified displaying identical clinical phenotype but different genetic and epigenetic basis. Autosomal dominant FSHD1 (95% of patients) is characterized by chromatin relaxation induced by pathogenic contraction of a macrosatellite repeat called D4Z4 located on the 4q subtelomere (FSHD1 patients harbor 1 to 10 D4Z4 repeated units). Chromatin relaxation is associated with inappropriate expression of DUX4, a retrogene, which in muscles induces apoptosis and inflammation. Consistent with this hypothesis, individuals carrying zero repeat on chromosome 4 do not develop FSHD1. Not all D4Z4 contracted alleles cause FSHD. Distal to the last D4Z4 unit, a polymorphic site with two allelic variants has been identified: 4qA and 4qB. 4qA is in cis with a functional polyadenylation consensus site. Only contractions on 4qA alleles are pathogenic because the DUX4 transcript is polyadenylated and translated into stable protein. FSHD2 is instead a digenic disease. Chromatin relaxation of the D4Z4 locus is caused by heterozygous mutations in the SMCHD1 gene encoding a protein essential for chromatin condensation. These patients also harbor at least one 4qA allele in order to express stable DUX4 transcripts. FSHD1 and FSHD2 may have an additive effect: patients harboring D4Z4 contraction and SMCHD1 mutations display a more severe clinical phenotype than with either defect alone. Knowledge of the complex genetic and epigenetic defects causing these diseases is essential in view of designing novel therapeutic strategies. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis. PMID:24882751

  11. Endothelin receptors and their antagonists.

    PubMed

    Maguire, Janet J; Davenport, Anthony P

    2015-03-01

    All three members of the endothelin (ET) family of peptides, ET-1, ET-2, and ET-3, are expressed in the human kidney, with ET-1 being the predominant isoform. ET-1 and ET-2 bind to two G-protein-coupled receptors, ETA and ETB, whereas at physiological concentrations ET-3 has little affinity for the ET(A) receptor. The human kidney is unusual among the peripheral organs in expressing a high density of ET(B). The renal vascular endothelium only expresses the ET(B) subtype and ET-1 acts in an autocrine or paracrine manner to release vasodilators. Endothelial ETB in kidney, as well as liver and lungs, also has a critical role in scavenging ET-1 from the plasma. The third major function is ET-1 activation of ET(B) in in the nephron to reduce salt and water re-absorption. In contrast, ET(A) predominate on smooth muscle, causing vasoconstriction and mediating many of the pathophysiological actions of ET-1. The role of the two receptors has been delineated using highly selective ET(A) (BQ123, TAK-044) and ET(B) (BQ788) peptide antagonists. Nonpeptide antagonists, bosentan, macitentan, and ambrisentan, that are either mixed ET(A)/ET(B) antagonists or display ET(A) selectivity, have been approved for clinical use but to date are limited to pulmonary hypertension. Ambrisentan is in clinical trials in patients with type 2 diabetic nephropathy. This review summarizes ET-receptor antagonism in the human kidney, and considers the relative merits of selective versus nonselective antagonism in renal disease. PMID:25966344

  12. Blockade by ifenprodil of high voltage-activated Ca2+ channels in rat and mouse cultured hippocampal pyramidal neurones: comparison with N-methyl-D-aspartate receptor antagonist actions.

    PubMed Central

    Church, J; Fletcher, E J; Baxter, K; MacDonald, J F

    1994-01-01

    1. The block by ifenprodil of voltage-activated Ca2+ channels was investigated in intracellular free calcium concentration ([Ca2+]i) evoked by 50 mM K+ (high-[K+]o) in Fura-2-loaded rat hippocampal pyramidal neurones in culture and on currents carried by Ba2+ ions (IBa) through Ca2+ channels in mouse cultured hippocampal neurones under whole-cell voltage-clamp. The effects of ifenprodil on voltage-activated Ca2+ channels were compared with its antagonist actions on N-methyl-D-aspartate- (NMDA) evoked responses in the same neuronal preparations. 2. Rises in [Ca2+]i evoked by transient exposure to high-[K+]o in our preparation of rat cultured hippocampal pyramidal neurones are mediated predominantly by Ca2+ flux through nifedipine-sensitive Ca2+ channels, with smaller contributions from nifedipine-resistant, omega-conotoxin GVIA-sensitive Ca2+ channels and Ca2+ channels sensitive to crude funnel-web spider venom (Church et al., 1994). Ifenprodil (0.1-200 microM) reversibly attenuated high-[K+]o-evoked rises in [Ca2+]i with an IC50 value of 17 +/- 3 microM, compared with an IC50 value of 0.7 +/- 0.1 microM for the reduction of rises in [Ca2+]i evoked by 20 microM NMDA. Tested in the presence of nifedipine 10 microM, ifenprodil (1-50 microM) produced a concentration-dependent reduction of the dihydropyridine-resistant high-[K+]o-evoked rise in [Ca2+]i with an IC50 value of 13 +/- 4 microM. The results suggest that ifenprodil blocks Ca2+ flux through multiple subtypes of high voltage-activated Ca2+ channels. 3. Application of the polyamine, spermine (0.25-5 mM), produced a concentration-dependent reduction of rises in [Ca2+]i evoked by high-[K+]o.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7834201

  13. What Are the Treatments for Muscular Dystrophy?

    MedlinePlus

    ... Resources and Publications What are the treatments for muscular dystrophy? Skip sharing on social media links Share this: ... available to stop or reverse any form of muscular dystrophy (MD). Instead, certain therapies and medications aim to ...

  14. Trainability of muscular activity level during maximal voluntary co-contraction: comparison between bodybuilders and nonathletes.

    PubMed

    Maeo, Sumiaki; Takahashi, Takumi; Takai, Yohei; Kanehisa, Hiroaki

    2013-01-01

    Antagonistic muscle pairs cannot be fully activated simultaneously, even with maximal effort, under conditions of voluntary co-contraction, and their muscular activity levels are always below those during agonist contraction with maximal voluntary effort (MVE). Whether the muscular activity level during the task has trainability remains unclear. The present study examined this issue by comparing the muscular activity level during maximal voluntary co-contraction for highly experienced bodybuilders, who frequently perform voluntary co-contraction in their training programs, with that for untrained individuals (nonathletes). The electromyograms (EMGs) of biceps brachii and triceps brachii muscles during maximal voluntary co-contraction of elbow flexors and extensors were recorded in 11 male bodybuilders and 10 nonathletes, and normalized to the values obtained during the MVE of agonist contraction for each of the corresponding muscles (% EMGMVE). The involuntary coactivation level in antagonist muscle during the MVE of agonist contraction was also calculated. In both muscles, % EMGMVE values during the co-contraction task for bodybuilders were significantly higher (P<0.01) than those for nonathletes (biceps brachii: 66±14% in bodybuilders vs. 46±13% in nonathletes, triceps brachii: 74±16% vs. 57±9%). There was a significant positive correlation between a length of bodybuilding experience and muscular activity level during the co-contraction task (r = 0.653, P = 0.03). Involuntary antagonist coactivation level during MVE of agonist contraction was not different between the two groups. The current result indicates that long-term participation in voluntary co-contraction training progressively enhances muscular activity during maximal voluntary co-contraction. PMID:24260233

  15. Spinal muscular atrophy

    PubMed Central

    2011-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis. Estimated incidence is 1 in 6,000 to 1 in 10,000 live births and carrier frequency of 1/40-1/60. This disease is characterized by generalized muscle weakness and atrophy predominating in proximal limb muscles, and phenotype is classified into four grades of severity (SMA I, SMAII, SMAIII, SMA IV) based on age of onset and motor function achieved. This disease is caused by homozygous mutations of the survival motor neuron 1 (SMN1) gene, and the diagnostic test demonstrates in most patients the homozygous deletion of the SMN1 gene, generally showing the absence of SMN1 exon 7. The test achieves up to 95% sensitivity and nearly 100% specificity. Differential diagnosis should be considered with other neuromuscular disorders which are not associated with increased CK manifesting as infantile hypotonia or as limb girdle weakness starting later in life. Considering the high carrier frequency, carrier testing is requested by siblings of patients or of parents of SMA children and are aimed at gaining information that may help with reproductive planning. Individuals at risk should be tested first and, in case of testing positive, the partner should be then analyzed. It is recommended that in case of a request on carrier testing on siblings of an affected SMA infant, a detailed neurological examination should be done and consideration given doing the direct test to exclude SMA. Prenatal diagnosis should be offered to couples who have previously had a child affected with SMA (recurrence risk 25%). The role of follow-up coordination has to be managed by an expert in neuromuscular disorders and in SMA who is able to plan a multidisciplinary intervention that includes pulmonary, gastroenterology/nutrition, and orthopedic care. Prognosis depends on the phenotypic

  16. Eyeball pseudo-muscular actuators for an android face

    NASA Astrophysics Data System (ADS)

    Carpi, Federico; De Rossi, Danilo

    2005-05-01

    The human attention system is based on the capability of the eye of focusing and tracking. These actions are performed by the eyeball muscle system, as a consequence of visual stimuli. The F.A.C.E. (Facial Automaton for Conveying Emotions) project at our lab concerns the development of an android face endowed with dynamic expressiveness and artificial vision. Aimed at realising an artificial attention system for such an automaton, we present here a study for the development of pseudo-muscular polymer actuators for its eyeballs. The system is based on the mimicry of the muscular architecture of the human eye. In particular, linear actuators made of dielectric elastomers have been designed to replicate actions exerted by the main ocular muscles.

  17. Vasopressin receptor antagonists.

    PubMed

    Palmer, Biff F

    2015-01-01

    Arginine vasopressin (AVP) is the principal hormone involved in regulating the tonicity of body fluids. Less appreciated is the role that AVP plays in a variety of other physiologic functions including glucose metabolism, cardiovascular homeostasis, bone metabolism, and cognitive behavior. AVP receptor antagonists are now available and currently approved to treat hyponatremia. There is a great deal of interest in exploring the potential benefits that these drugs may play in blocking AVP-mediated effects in other organ systems. The purpose of this report is to provide an update on the expanding role of AVP receptor antagonists and what disease states these drugs may eventually be used for. PMID:25604388

  18. A new alcohol antagonist: Phaclofen

    SciTech Connect

    Allan, A.M. ); Harris, R.A. )

    1989-01-01

    The ability of the GABA{sub B} receptor antagonist, phaclofen to alter behavioral effects of ethanol was evaluated by loss of righting reflex (sleep time), motor incoordination (bar holding), spontaneous locomotion (open field activity) and hypothermia. Pretreatment with phaclofen significantly decreased the effects of ethanol on motor incoordination, locomotor activity and hypothermia. However, phaclofen had no effect on either pentobarbital- or diazepam-induced motor incoordination. Phaclofen slightly increased the ED{sub 50} for loss of the righting reflex but did not alter either the duration of reflex loss produced by ethanol or blood ethanol levels at awakening. Our results suggest phaclofen is rapidly inactivated resulting in difficulty in observing antagonism of long duration ethanol effects. These findings suggest that the GABA{sub B} system may play a role in mediating several important actions of ethanol.

  19. Porcine models of muscular dystrophy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Duchenne muscular dystrophy is a progressive, fatal, X-linked disease caused by a failure to accumulate the cytoskeletal protein, dystrophin. This disease is modeled by a variety of animal models including several fish models, mice, rats, and dogs. While these models have contributed substantially t...

  20. Modifying muscular dystrophy through TGFβ

    PubMed Central

    Ceco, Ermelinda; McNally, Elizabeth M.

    2013-01-01

    Muscular dystrophy arises from ongoing muscle degeneration and insufficient regeneration. This imbalance leads to loss of muscle with replacement by scar or fibrosis resulting in muscle weakness and, eventually, loss of muscle function. Human muscular dystrophy is characterized by a wide range of disease severity, even when the same genetic mutation is present. This variability implies that other factors, both genetic and environmental, modify the disease outcome. There has been an ongoing effort to define the genetic and molecular bases that influence muscular dystrophy onset and progression. Modifier genes for muscle disease have been identified through candidate gene approaches as well as genomewide surveys. Multiple lines of experimental evidence have now converged on the TGFβ pathway as a modifier for muscular dystrophy. TGFβ signaling is upregulated in dystrophic muscle as a result of a destabilized plasma membrane and/or altered extracellular matrix. Given the important biological role of the TGFβ pathway, and its role beyond muscle homeostasis, we review modifier genes that alter the TGFβ pathway and approaches to modulate TGFβ activity to ameliorate muscle disease. PMID:23551962

  1. Wasting mechanisms in muscular dystrophy.

    PubMed

    Shin, Jonghyun; Tajrishi, Marjan M; Ogura, Yuji; Kumar, Ashok

    2013-10-01

    Muscular dystrophy is a group of more than 30 different clinical genetic disorders that are characterized by progressive skeletal muscle wasting and degeneration. Primary deficiency of specific extracellular matrix, sarcoplasmic, cytoskeletal, or nuclear membrane protein results in several secondary changes such as sarcolemmal instability, calcium influx, fiber necrosis, oxidative stress, inflammatory response, breakdown of extracellular matrix, and eventually fibrosis which leads to loss of ambulance and cardiac and respiratory failure. A number of molecular processes have now been identified which hasten disease progression in human patients and animal models of muscular dystrophy. Accumulating evidence further suggests that aberrant activation of several signaling pathways aggravate pathological cascades in dystrophic muscle. Although replacement of defective gene with wild-type is paramount to cure, management of secondary pathological changes has enormous potential to improving the quality of life and extending lifespan of muscular dystrophy patients. In this article, we have reviewed major cellular and molecular mechanisms leading to muscle wasting in muscular dystrophy. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. PMID:23669245

  2. Chronic spinal muscular atrophy of facioscapulohumeral type.

    PubMed Central

    Furukawa, T; Toyokura, Y

    1976-01-01

    Chronic spinal muscular atrophy of FSH type affecting a mother and her son and daughter is reported. The relevant literature is reviewed and the relation between this conditon and Kugelberg-Welander (K-W) disease is discussed. Chronic spinal muscular atrophy of FSH type is considered to be a different entity from the eponymous K-W disease. Each type of muscular dystrophy, e.g. limb-girdle, FSH, distal, ocular, or oculopharyngeal type, has its counterpart of nuclear origin. A classification of the chronic spinal muscular atrophies is suggested following the classification of muscular dystrophy. Images PMID:957378

  3. Opioid Antagonist Impedes Exposure.

    ERIC Educational Resources Information Center

    Merluzzi, Thomas V.; And Others

    1991-01-01

    Thirty spider-phobic adults underwent exposure to 17 phobic-related, graded performance tests. Fifteen subjects were assigned to naltrexone, an opioid antagonist, and 15 were assigned to placebo. Naltrexone had a significant effect on exposure, with naltrexone subjects taking significantly longer to complete first 10 steps of exposure and with…

  4. Spiropiperidine CCR5 antagonists.

    PubMed

    Rotstein, David M; Gabriel, Stephen D; Makra, Ferenc; Filonova, Lubov; Gleason, Shelley; Brotherton-Pleiss, Christine; Setti, Lina Q; Trejo-Martin, Alejandra; Lee, Eun Kyung; Sankuratri, Surya; Ji, Changhua; Derosier, Andre; Dioszegi, Marianna; Heilek, Gabrielle; Jekle, Andreas; Berry, Pamela; Weller, Paul; Mau, Cheng-I

    2009-09-15

    A novel series of CCR5 antagonists has been identified, utilizing leads from high-throughput screening which were further modified based on insights from competitor molecules. Lead optimization was pursued by balancing opposing trends of metabolic stability and potency. Selective and potent analogs with good pharmacokinetic properties were successfully developed. PMID:19674898

  5. Intramuscular pressure and torque during isometric, concentric and eccentric muscular activity

    NASA Technical Reports Server (NTRS)

    Styf, J.; Ballard, R.; Aratow, M.; Crenshaw, A.; Watenpaugh, D.; Hargens, A. R.

    1995-01-01

    Intramuscular pressures, electromyography (EMG) and torque generation during isometric, concentric and eccentric maximal isokinetic muscle activity were recorded in 10 healthy volunteers. Pressure and EMG activity were continuously and simultaneously measured side by side in the tibialis anterior and soleus muscles. Ankle joint torque and position were monitored continuously by an isokinetic dynamometer during plantar flexion and dorsiflexion of the foot. The increased force generation during eccentric muscular activity, compared with other muscular activity, was not accompanied by higher intramuscular pressure. Thus, this study demonstrated that eccentric muscular activity generated higher torque values for each increment of intramuscular pressure. Intramuscular pressures during antagonistic co-activation were significantly higher in the tibilis anterior muscle (42-46% of maximal agonistic activity) compared with the soleus muscle (12-29% of maximal agonistic activity) and was largely due to active recruitment of muscle fibers. In summary, eccentric muscular activity creates higher torque values with no additional increase of the intramuscular pressure compared with concentric and isometric muscular activity.

  6. Phase 3 Study of Ataluren in Patients With Nonsense Mutation Duchenne Muscular Dystrophy

    ClinicalTrials.gov

    2016-08-02

    Muscular Dystrophy, Duchenne; Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn

  7. Xanthines as Adenosine Receptor Antagonists

    PubMed Central

    Jacobson, Kenneth A.

    2013-01-01

    The natural plant alkaloids caffeine and theophylline were the first adenosine receptor (AR) antagonists described in the literature. They exhibit micromolar affinities and are non-selective. A large number of derivatives and analogs have subsequently been synthesized and evaluated as AR antagonists. Very potent antagonists have thus been developed with selectivity for each of the four AR subtypes. PMID:20859796

  8. Species‐specific action of (Pro3)GIP – a full agonist at human GIP receptors, but a partial agonist and competitive antagonist at rat and mouse GIP receptors

    PubMed Central

    Sparre‐Ulrich, A H; Hansen, L S; Svendsen, B; Christensen, M; Knop, F K; Hartmann, B; Holst, J J

    2015-01-01

    Background and Purpose Specific, high potency receptor antagonists are valuable tools when evaluating animal and human physiology. Within the glucose‐dependent, insulinotropic polypeptide (GIP) system, considerable attention has been given to the presumed GIP receptor antagonist, (Pro3)GIP, and its effect in murine studies. We conducted a pharmacological analysis of this ligand including interspecies differences between the rodent and human GIP system. Experimental Approach Transiently transfected COS‐7 cells were assessed for cAMP accumulation upon ligand stimulation and assayed in competition binding using 125I‐human GIP. Using isolated perfused pancreata both from wild type and GIP receptor‐deficient rodents, insulin‐releasing, glucagon‐releasing and somatostatin‐releasing properties in response to species‐specific GIP and (Pro3)GIP analogues were evaluated. Key Results Human (Pro3)GIP is a full agonist at human GIP receptors with similar efficacy (E max) for cAMP production as human GIP, while both rat and mouse(Pro3)GIP were partial agonists on their corresponding receptors. Rodent GIPs are more potent and efficacious at their receptors than human GIP. In perfused pancreata in the presence of 7 mM glucose, both rodent (Pro3)GIP analogues induced modest insulin, glucagon and somatostatin secretion, corresponding to the partial agonist activities observed in cAMP production. Conclusions and Implications When evaluating new compounds, it is important to consider interspecies differences both at the receptor and ligand level. Thus, in rodent models, human GIP is a comparatively weak partial agonist. Human (Pro3)GIP was not an antagonist at human GIP receptors, so there is still a need for a potent antagonist in order to elucidate the physiology of human GIP. PMID:26359804

  9. Prostanoid receptor antagonists: development strategies and therapeutic applications

    PubMed Central

    Jones, RL; Giembycz, MA; Woodward, DF

    2009-01-01

    Identification of the primary products of cyclo-oxygenase (COX)/prostaglandin synthase(s), which occurred between 1958 and 1976, was followed by a classification system for prostanoid receptors (DP, EP1, EP2 …) based mainly on the pharmacological actions of natural and synthetic agonists and a few antagonists. The design of potent selective antagonists was rapid for certain prostanoid receptors (EP1, TP), slow for others (FP, IP) and has yet to be achieved in certain cases (EP2). While some antagonists are structurally related to the natural agonist, most recent compounds are ‘non-prostanoid’ (often acyl-sulphonamides) and have emerged from high-throughput screening of compound libraries, made possible by the development of (functional) assays involving single recombinant prostanoid receptors. Selective antagonists have been crucial to defining the roles of PGD2 (acting on DP1 and DP2 receptors) and PGE2 (on EP1 and EP4 receptors) in various inflammatory conditions; there are clear opportunities for therapeutic intervention. The vast endeavour on TP (thromboxane) antagonists is considered in relation to their limited pharmaceutical success in the cardiovascular area. Correspondingly, the clinical utility of IP (prostacyclin) antagonists is assessed in relation to the cloud hanging over the long-term safety of selective COX-2 inhibitors. Aspirin apart, COX inhibitors broadly suppress all prostanoid pathways, while high selectivity has been a major goal in receptor antagonist development; more targeted therapy may require an intermediate position with defined antagonist selectivity profiles. This review is intended to provide overviews of each antagonist class (including prostamide antagonists), covering major development strategies and current and potential clinical usage. PMID:19624532

  10. Age-Related Differences in Muscular Strength and Muscular Endurance among Female Masters Swimmers.

    ERIC Educational Resources Information Center

    Dummer, Gail M.; And Others

    1985-01-01

    This study investigated age-related differences in muscular strength and muscular endurance among 73 female masters swimmers aged 24 to 71 years. While an age-related decline in muscular strength was apparent, the results failed to reveal a similar trend for endurance, suggesting that swimming influences endurance more than strength among women.…

  11. Validity of Field Tests of Upper Body Muscular Strength.

    ERIC Educational Resources Information Center

    Pate, Russell, R; And Others

    1993-01-01

    Examined the validity of field tests of elementary students' upper body muscular strength and endurance. Field tests were found to be moderately valid measures of weight-relative muscular strength but not of absolute strength and muscular endurance. (SM)

  12. Genetics Home Reference: Emery-Dreifuss muscular dystrophy

    MedlinePlus

    ... Health Conditions Emery-Dreifuss muscular dystrophy Emery-Dreifuss muscular dystrophy Enable Javascript to view the expand/collapse boxes. ... PDF Open All Close All Description Emery-Dreifuss muscular dystrophy is a condition that chiefly affects muscles used ...

  13. Genetics Home Reference: Duchenne and Becker muscular dystrophy

    MedlinePlus

    ... Duchenne and Becker muscular dystrophy Duchenne and Becker muscular dystrophy Enable Javascript to view the expand/collapse boxes. Download PDF Open All Close All Description Muscular dystrophies are a group of genetic conditions characterized by ...

  14. Muscular Calf Injuries in Runners.

    PubMed

    Fields, Karl B; Rigby, Michael D

    2016-01-01

    Calf pain is a common complaint among runners of all ages but is most frequent in masters athletes. This article focuses on injuries to the triceps surae or true 'calf muscles.' The most common calf injury is a tear of the medial gastrocnemius muscle (Tennis Leg) but other structures including the lateral gastrocnemius, plantaris and soleus also may be the cause of muscular pain. This article looks at the presentation, evaluation, and treatment of these injuries. We also highlight some examples of musculoskeletal ultrasound which is a valuable tool for rapid diagnosis of the cause and extent of injury. PMID:27618240

  15. Arrhythmias in the muscular dystrophies.

    PubMed

    Rajdev, Archana; Groh, William J

    2015-06-01

    In patients with muscular dystrophies, cardiac involvement leading to cardiomyopathy and arrhythmias occurs with variable prevalence, mirroring the phenotypic variability seen among and within the various hereditary myopathies. Knowledge of the incidence of arrhythmias and predictors of sudden death in the various hereditary myopathies can help guide screening and appropriate management of these patients, thereby improving survival. The noncardiac manifestations can lead to delayed recognition of symptoms, affect the decision to implant a prophylactic device, and once a decision is made to proceed with device implant, increase peri-procedural respiratory and anesthesia-related complications. PMID:26002394

  16. Nutrition Considerations in Duchenne Muscular Dystrophy.

    PubMed

    Davis, Jillian; Samuels, Emily; Mullins, Lucille

    2015-08-01

    Duchenne muscular dystrophy (DMD) is a serious degenerative muscular disease affecting males. Diagnosis usually occurs in childhood and is confirmed through genetic testing and/or muscle biopsy. Accompanying the disease are several nutrition-related concerns: growth, body composition, energy and protein requirements, constipation, swallowing difficulties, bone health, and complementary medicine. This review article addresses the nutrition aspects of DMD. PMID:25977513

  17. The Muscular Dystrophies: From Genes to Therapies

    PubMed Central

    Porter, Neil C; Bloch, Robert J

    2015-01-01

    The genetic basis of many muscular disorders, including many of the more common muscular dystrophies, is now known. Clinically, the recent genetic advances have improved diagnostic capabilities, but they have not yet provided clues about treatment or management. Thanks to better management strategies and therapeutic interventions, however, many patients with a muscular dystrophy are more active and are living longer. Physical therapists, therefore, are more likely to see a patient with a muscular dystrophy, so understanding these muscle disorders and their management is essential. Physical therapy offers the most promise in caring for the majority of patients with these conditions, because it is unlikely that advances in gene therapy will significantly alter their clinical treatment in the near future. This perspective covers some of the basic molecular biological advances together with the clinical manifestations of the muscular dystrophies and the latest approaches to their management. PMID:16305275

  18. Cannabinoid withdrawal in mice: inverse agonist vs neutral antagonist

    PubMed Central

    Tai, Sherrica; Nikas, Spyros P.; Shukla, Vidyanand G.; Vemuri, Kiran; Makriyannis, Alexandros; Järbe, Torbjörn U.C.

    2015-01-01

    Rationale Previous reports shows rimonabant's inverse properties may be a limiting factor for treating cannabinoid dependence. To overcome this limitation neutral antagonists were developed, to address mechanisms by which an inverse agonist and neutral antagonist elicit withdrawal. Objective Introduces an animal model to study cannabinoid dependence by incorporating traditional methodologies and profiling novel cannabinoid ligands with distinct pharmacological properties/modes of action by evaluating their pharmacological effects on CB1-receptor (CB1R) related physiological/behavioral endpoints. Methods The cannabinergic AM2389 was acutely characterized in the tetrad (locomotor activity, analgesia, inverted screen/catalepsy bar test and temperature); with some comparisons made to Δ9-tetrahydrocannabinol (THC). Tolerance was measured in mice repeatedly administered AM2389. Antagonist-precipitated withdrawal was characterized in cannabinoid-adapted mice induced by either centrally acting antagonists, rimonabant and AM4113, or an antagonist with limited brain penetration, AM6545. Results In the tetrad, AM2389 was more potent and longer acting than THC, suggesting a novel approach for inducing dependence. Repeated administration of AM2389 led to tolerance by attenuating hypothermia that was induced by acute AM2389 administration. Antagonist-precipitated withdrawal signs were induced by rimonabant or AM4113, but not by AM6545. Antagonist-precipitated withdrawal was reversed by reinstating AM2389 or THC. Conclusions These findings suggest cannabinoid-precipitated withdrawal may not be ascribed to the inverse properties of rimonabant, but rather to rapid competition with the agonist at the CB1R. This withdrawal syndrome is likely centrally-mediated, since only the centrally acting CB1R antagonists elicited withdrawal, i.e., such responses were absent after the purported peripherally selective CB1R antagonist AM6545. PMID:25772338

  19. Selective orexin receptor antagonists.

    PubMed

    Lebold, Terry P; Bonaventure, Pascal; Shireman, Brock T

    2013-09-01

    The orexin, or hypocretin, neuropeptides (orexin-A and orexin-B) are produced on neurons in the hypothalamus which project to key areas of the brain that control sleep-wake states, modulation of food intake, panic, anxiety, emotion, reward and addictive behaviors. These neuropeptides exert their effects on a pair of G-protein coupled receptors termed the orexin-1 (OX1) and orexin-2 (OX2) receptors. Emerging biology suggests the involvement of these receptors in psychiatric disorders as they are thought to play a key role in the regulation of multiple systems. This review is intended to highlight key selective OX1 or OX2 small-molecule antagonists. PMID:23891187

  20. Calmodulin antagonists induce platelet apoptosis.

    PubMed

    Wang, Zhicheng; Li, Suping; Shi, Quanwei; Yan, Rong; Liu, Guanglei; Dai, Kesheng

    2010-04-01

    Calmodulin (CaM) antagonists induce apoptosis in various tumor models and inhibit tumor cell invasion and metastasis, thus some of which have been extensively used as anti-cancer agents. In platelets, CaM has been found to bind directly to the cytoplasmic domains of several platelet receptors. Incubation of platelets with CaM antagonists impairs the receptors-related platelet functions. However, it is still unknown whether CaM antagonists induce platelet apoptosis. Here we show that CaM antagonists N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W7), tamoxifen (TMX), and trifluoperazine (TFP) induce apoptotic events in human platelets, including depolarization of mitochondrial inner transmembrane potential, caspase-3 activation, and phosphatidylserine exposure. CaM antagonists did not incur platelet activation as detected by P-selectin surface expression and PAC-1 binding. However, ADP-, botrocetin-, and alpha-thrombin-induced platelet aggregation, platelet adhesion and spreading on von Willebrand factor surface were significantly reduced in platelets pre-treated with CaM antagonists. Furthermore, cytosolic Ca(2+) levels were obviously elevated by both W7 and TMX, and membrane-permeable Ca(2+) chelator BAPTA-AM significantly reduced apoptotic events in platelets induced by W7. Therefore, these findings indicate that CaM antagonists induce platelet apoptosis. The elevation of the cytosolic Ca(2+) levels may be involved in the regulation of CaM antagonists-induced platelet apoptosis. PMID:20172594

  1. Animal Models of Muscular Dystrophy

    PubMed Central

    Ng, Rainer; Banks, Glen B.; Hall, John K.; Muir, Lindsey A.; Ramos, Julian N.; Wicki, Jacqueline; Odom, Guy L.; Konieczny, Patryk; Seto, Jane; Chamberlain, Joel R.; Chamberlain, Jeffrey S.

    2016-01-01

    The muscular dystrophies (MDs) represent a diverse collection of inherited human disorders, which affect to varying degrees skeletal, cardiac, and sometimes smooth muscle (Emery, 20021). To date, more than 50 different genes have been implicated as causing one or more types of MD (Bansal et al., 20032). In many cases, invaluable insights into disease mechanisms, structure and function of gene products, and approaches for therapeutic interventions have benefited from the study of animal models of the different MDs (Arnett et al., 20093). The large number of genes that are associated with MD and the tremendous number of animal models that have been developed preclude a complete discussion of each in the context of this review. However, we summarize here a number of the more commonly used models together with a mixture of different types of gene and MD, which serves to give a general overview of the value of animal models of MD for research and therapeutic development. PMID:22137430

  2. Arrhythmias in the Muscular Dystrophies

    PubMed Central

    Rajdev, Archana; Groh, William J.

    2015-01-01

    Synopsis In patients with muscular dystrophies, cardiac involvement leading to cardiomyopathy and arrhythmias occur with variable prevalence mirroring the phenotypic variability seen among and within the various hereditary myopathies. These patients are at risk for development for bradyarrhythmias and tachyarrhythmias including sudden cardiac death. Knowledge of the incidence of arrhythmias and predictors of sudden death in the various hereditary myopathies can help guide screening and appropriate management of these patients, thereby improving survival. The non-cardiac manifestations can lead to delayed recognition of symptoms (limited mobility and respiratory weakness masking cardiac manifestations), affect decision to implant prophylactic device (quantity vs. quality of life) and once a decision is made to proceed with device implant, increase peri-procedural respiratory and anesthesia-related complications. PMID:26002394

  3. Myofascial force transmission via extramuscular pathways occurs between antagonistic muscles.

    PubMed

    Huijing, Peter A; Baan, Guus C

    2008-01-01

    Most often muscles (as organs) are viewed as independent actuators. To test if this is true for antagonistic muscles, force was measured simultaneously at: (1) the proximal and distal tendons of the extensor digitorum muscle (EDL) to quantify any proximo-distal force differences, as an indicator of myofascial force transmission, (2) at the distal tendons of the whole antagonistic peroneal muscle group (PER) to test if effects of EDL length changes are present and (3) at the proximal end of the tibia to test if myofascially transmitted force is exerted there. EDL length was manipulated either at the proximal or distal tendons. This way equal EDL lengths are attained at two different positions of the muscle with respect to the tibia and antagonistic muscles. Despite its relatively small size, lengthening of the EDL changed forces exerted on the tibia and forces exerted by its antagonistic muscle group. Apart from its extramuscular myofascial connections, EDL has no connections to either the tibia or these antagonistic muscles. Proximal EDL lengthening increased distal muscular forces (active PER DeltaF approximately +1.7%), but decreased tibial forces (passive from 0.3 to 0 N; active DeltaF approximately -5%). Therefore, it is concluded that these antagonistic muscles do not act independently, because of myofascial force transmission between them. Such a decrease in tibial force indicates release of pre-strained connections. Distal EDL lengthening had opposite effects (tripling passive force exerted on tibia; active PER force DeltaF approximately -3.6%). It is concluded that the length and relative position of the EDL is a co-determinant of passive and active force exerted at tendons of nearby antagonistic muscle groups. These results necessitate a new view of the locomotor apparatus, which needs to take into account the high interdependence of muscles and muscle fibres as force generators, as well as proximo-distal force differences and serial and parallel

  4. Duchenne muscular dystrophy: current cell therapies

    PubMed Central

    Sienkiewicz, Dorota; Okurowska-Zawada, Bożena; Paszko-Patej, Grażyna; Kawnik, Katarzyna

    2015-01-01

    Duchenne muscular dystrophy is a genetically determined X-linked disease and the most common, progressive pediatric muscle disorder. For decades, research has been conducted to find an effective therapy. This review presents current therapeutic methods for Duchenne muscular dystrophy, based on scientific articles in English published mainly in the period 2000 to 2014. We used the PubMed database to identify and review the most important studies. An analysis of contemporary studies of stem cell therapy and the use of granulocyte colony-stimulating factor (G-CSF) in muscular dystrophy was performed. PMID:26136844

  5. A trial of flunarizine in the treatment of Duchenne muscular dystrophy.

    PubMed

    Dick, D J; Gardner-Medwin, D; Gates, P G; Gibson, M; Simpson, J M; Walls, T J

    1986-05-01

    Twenty-seven boys with Duchenne muscular dystrophy (DMD) entered a double-blind controlled trial of treatment with the calcium antagonist flunarizine. They were matched for age and disability. At monthly intervals, muscle power, functional ability, locomotor score, contractures, and forced vital capacity were measured by a team not involved in clinical care. Over a period of 1 year, flunarizine in a dose of up to 0.25 mg/kg/day had no effect on the clinical course of the disease. PMID:3520308

  6. Tannins as Gibberellin Antagonists 1

    PubMed Central

    Corcoran, Mary Ritzel; Geissman, T. A.; Phinney, Bernard O.

    1972-01-01

    Fourteen chemically defined hydrolyzable tannins and six impure mixtures of either condensed or hydrolyzable tannins were found to inhibit the gibberellin-induced growth of light-grown dwarf pea seedlings. The highest ratio of tannins to gibberellic acid tested (1000: 1 by weight) inhibited from 80 to 95% of the induced growth for all tannins tested except for two monogalloyl glucose tannins which inhibited only 50% of the induced growth. The lowest ratio tested (10: 1) inhibited the induced growth by less than 25% except for the case of terchebin where 50% inhibition was found. The inhibition of gibberellin-induced growth was found to be completely reversed by increasing the amount of gibberellin in three cases tested. Tannins alone did not inhibit endogenous growth of either dwarf or nondwarf pea seedlings. Eight compounds related to tannins, including coumarin, trans-cinnamic acid, and a number of phenolic compounds were also tested as gibberellin antagonists. Most of these compounds showed some inhibition of gibberellin-induced growth, but less than that of the tannins. At the highest ratio (1000: 1) the greatest inhibition was 55%; at the lowest ratio (10: 1) no more than 17% was observed. These compounds did not inhibit endogenous growth, and the inhibition of gibberellin-induced growth could be reversed by increasing the amount of gibberellin in two cases tested. Six chemically defined tannins were found to inhibit hypocotyl growth induced by gibberellic acid in cucumber seedlings. Growth induced by indoleacetic acid in the same test was not inhibited. The highest ratio of tannin to promotor tested gave strong inhibition of gibberellic acid-induced growth, but actually enhanced the growth induced by indoleacetic acid. This difference in action suggests a specificity between the tannins and gibberellic acid. PMID:16657953

  7. Pros and cons of vitamin K antagonists and non-vitamin K antagonist oral anticoagulants.

    PubMed

    Riva, Nicoletta; Ageno, Walter

    2015-03-01

    Anticoagulant treatment can be currently instituted with two different classes of drugs: the vitamin K antagonists (VKAs) and the newer, "novel" or non-vitamin K antagonist oral anticoagulant drugs (NOACs). The NOACs have several practical advantages over VKAs, such as the rapid onset/offset of action, the lower potential for food and drug interactions, and the predictable anticoagulant response. However, the VKAs currently have a broader spectrum of indications, a standardized monitoring test, and established reversal strategies. The NOACs emerged as alternative options for the prevention and treatment of venous thromboembolism and for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Nevertheless, there remain some populations for whom the VKAs remain the most appropriate anticoagulant drug. This article discusses the advantages and disadvantages of VKAs and NOACs. PMID:25703519

  8. Effects of Attentional Focusing Strategies on Muscular Power in Older Women.

    PubMed

    Makaruk, Hubert; Porter, Jared M; Dlugolecka, Barbara; Parnicka, Urszula; Makaruk, Beata

    2015-07-01

    The purpose of this study was to evaluate the effects of different foci of attention on parameters related to maximum muscular power in older women. Using a counterbalanced within-participant design, 23 physically active young-old women (age 59-69) completed a maximum effort cycle ergometer test following three types of verbal instructions. The external instruction (EXF) was designed to focus attention on moving the pedals as fast as possible, internal instruction (INF) directed attention toward moving the legs as fast as possible, and a control condition (CON) was created in which participants were instructed to perform the task to the best of their abilities. Results indicated that the EXF and CON conditions resulted in greater muscular power compared with the INF condition. Results also indicated that directing attention internally hindered muscular power performance in older women, which is consistent with the predictions of the constrained action hypothesis. PMID:24956607

  9. Reality television and the muscular male ideal.

    PubMed

    Dallesasse, Starla L; Kluck, Annette S

    2013-06-01

    Although researchers have examined the negative effects of viewing reality television (RTV) on women's body image, this research has not been extended to men. Exploring the extent to which RTV depicts men who embody the muscular ideal may enhance our understanding of the potential influence of this media genre. We explored the extent to which RTV depicted men who embodied the muscular ideal using a quantitative content analysis. Based on binomial tests, the primary male cast members of programs airing on networks popular among young adult men during the Fall 2009 broadcast season were more muscular, with lower levels of body fat, than average U.S. men. The chest-to-waist and shoulder-to-waist ratios of these cast members did not differ as a function of program type (i.e., reality drama, endurance, and romance). Young men who view RTV programs included in the present study would be exposed to an unrepresentative muscular ideal. PMID:23523084

  10. Physical Therapy and Facioscapulohumeral Muscular Dystrophy (FSHD)

    MedlinePlus

    Physical Therapy & FSHD Facioscapulohumeral Muscular Dystrophy A Guide for Patients & Physical Therapists Authors: Wendy M. King, P.T., ... expertise and patient preferences. The goals of any physical therapy plan of care are to assist patients to:  ...

  11. Genetics Home Reference: Fukuyama congenital muscular dystrophy

    MedlinePlus

    ... and walking. Fukuyama congenital muscular dystrophy also impairs brain development. People with this condition have a brain abnormality ... cobblestones). These changes in the structure of the brain lead to significantly delayed development of speech and motor skills and moderate to ...

  12. Hotspots of damage by antagonists shape the spatial structure of plant-pollinator interactions.

    PubMed

    Rodríguez-Rodríguez, María C; Jordano, Pedro; Valido, Alfredo

    2015-08-01

    The balance between mutualistic and antagonistic plant-animal interactions and their spatial variation results in a highly dynamic mosaic of reproductive success within plant populations. Yet, the ecological drivers of this small-scale heterogeneity of interaction patterns and their outcomes remain virtually unexplored. We analyzed spatial structure in the frequency and intensity of interactions that vertebrate pollinators (birds and lizards) and invertebrate antagonists (florivores, nectar larcenists, and seed predators) had when interacting with the insular plant Isoplexis canariensis, and their effect on plant fitness. Spatially autocorrelated variation in plant reproductive success (fruit and viable seed set) emerged from the combined action of mutualists and antagonists, rather than reflecting the spatial pattern of any specific animal group. However, the influence of antagonists on plant fitness was stronger primarily due to the florivores' action on earlier reproductive stages, consuming and damaging floral structures before the arrival of pollinators. Our results indicate that the early action of antagonists creates hotspots of increased plant damage, where the effects of later acting mutualists are not translated into increased reproductive benefits. We foresee the potential for antagonists to shape the intra-population mosaics of plant fitness in situations where antagonists outnumber mutualists, when their interactions occur before those of mutualists, and when mutualists can detect and avoid damaged plants while foraging. Severely damaged plants in antagonistic hotspots might be excluded from the mating network and render a limited production of viable seeds, reducing both the growth rate of the plant population and the effective population size. PMID:26405743

  13. Anti-inflammatory actions of Chemoattractant Receptor-homologous molecule expressed on Th2 by the antagonist MK-7246 in a novel rat model of Alternaria alternata elicited pulmonary inflammation.

    PubMed

    Gil, Malgorzata A; Caniga, Michael; Woodhouse, Janice D; Eckman, Joseph; Lee, Hyun-Hee; Salmon, Michael; Naber, John; Hamilton, Valerie T; Sevilla, Raquel S; Bettano, Kimberly; Klappenbach, Joel; Moy, Lily; Correll, Craig C; Gervais, Francois G; Siliphaivanh, Phieng; Zhang, Weisheng; Zhang-Hoover, Jie; McLeod, Robbie L; Cicmil, Milenko

    2014-11-15

    Alternaria alternata is a fungal allergen linked to the development of severe asthma in humans. In view of the clinical relationship between A. alternata and asthma, we sought to investigate the allergic activity of this antigen after direct application to the lungs of Brown Norway rats. Here we demonstrate that a single intratracheal instillation of A. alternata induces dose and time dependent eosinophil influx, edema and Type 2 helper cell cytokine production in the lungs of BN rats. We established the temporal profile of eosinophilic infiltration and cytokine production, such as Interleukin-5 and Interleukin-13, following A. alternata challenge. These responses were comparable to Ovalbumin induced models of asthma and resulted in peak inflammatory responses 48h following a single challenge, eliminating the need for multiple sensitizations and challenges. The initial perivascular and peribronchiolar inflammation preceded alveolar inflammation, progressing to a more sub-acute inflammatory response with notable epithelial cell hypertrophy. To limit the effects of an A. alternata inflammatory response, MK-7246 was utilized as it is an antagonist for Chemoattractant Receptor-homologous molecule expressed in Th2 cells. In a dose-dependent manner, MK-7246 decreased eosinophil influx and Th2 cytokine production following the A. alternata challenge. Furthermore, therapeutic administration of corticosteroids resulted in a dose-dependent decrease in eosinophil influx and Th2 cytokine production. Reproducible asthma-related outcomes and amenability to pharmacological intervention by mechanisms relevant to asthma demonstrate that an A. alternata induced pulmonary inflammation in BN rats is a valuable preclinical pharmacodynamic in vivo model for evaluating the pharmacological inhibitors of allergic pulmonary inflammation. PMID:25261040

  14. Muscular Oxygen Uptake Kinetics in Aged Adults.

    PubMed

    Koschate, J; Drescher, U; Baum, K; Eichberg, S; Schiffer, T; Latsch, J; Brixius, K; Hoffmann, U

    2016-06-01

    Pulmonary oxygen uptake (V˙O2) kinetics and heart rate kinetics are influenced by age and fitness. Muscular V˙O2 kinetics can be estimated from heart rate and pulmonary V˙O2. In this study the applicability of a test using pseudo-random binary sequences in combination with a model to estimate muscular V˙O2 kinetics was tested. Muscular V˙O2 kinetics were expected to be faster than pulmonary V˙O2 kinetics, slowed in aged subjects and correlated with maximum V˙O2 and heart rate kinetics. 27 elderly subjects (73±3 years; 81.1±8.2 kg; 175±4.7 cm) participated. Cardiorespiratory kinetics were assessed using the maximum of cross-correlation functions, higher maxima implying faster kinetics. Muscular V˙O2 kinetics were faster than pulmonary V˙O2 kinetics (0.31±0.1 vs. 0.29±0.1 s; p=0.004). Heart rate kinetics were not correlated with muscular or pulmonary V˙O2 kinetics or maximum V˙O2. Muscular V˙O2 kinetics correlated with maximum V˙O2 (r=0.35; p=0.033). This suggests, that muscular V˙O2 kinetics are faster than estimates from pulmonary V˙O2 and related to maximum V˙O2 in aged subjects. In the future this experimental approach may help to characterize alterations in muscular V˙O2 under various conditions independent of motivation and maximal effort. PMID:27116341

  15. Discovery of small molecule antagonists of TRPV1.

    PubMed

    Rami, Harshad K; Thompson, Mervyn; Wyman, Paul; Jerman, Jeffrey C; Egerton, Julie; Brough, Stephen; Stevens, Alexander J; Randall, Andrew D; Smart, Darren; Gunthorpe, Martin J; Davis, John B

    2004-07-16

    Small molecule antagonists of the vanilloid receptor 1 (TRPV1, also known as VR1) are disclosed. Ureas such as 5 (SB-452533) were used to explore the structure activity relationship with several potent analogues identified. Pharmacological studies using electrophysiological and FLIPR Ca(2+) based assays showed compound 5 was an antagonist versus capsaicin, noxious heat and acid mediated activation of TRPV1. Study of a quaternary salt of 5 supports a mode of action in which compounds from this series cause inhibition via an extracellularly accessible binding site on the TRPV1 receptor. PMID:15203132

  16. Muscular strength profile in Tunisian male national judo team

    PubMed Central

    Ghrairi, Mourad; Hammouda, Omar; Malliaropoulos, Nikos

    2014-01-01

    Summary Background: it is well established that muscle strength is a determinant factor in judo. However, little data are available for African athletes. Therefore, the aim of this study was to provide reference data of the muscular strength profile (MSP) for an African team, Tunisian judo team. Methods: the study was conducted among ten international judo athletes from Tunisia. To determine their MSP, we used an isokinetic dynamometer to assess Hamstrings, Quadriceps of both knees and external, internal rotators of both shoulders. The angular velocities of the assessments were; 90, 180, 240°/s for the knees and 60, 120°/s for the shoulders. Results: MSP was determined based on two parameters; the maximum peak torque (PT) of each muscle and the ratio agonistic/antagonistic muscles (R). The knee extensors and flexors in the “supporting leg” had higher PT than in the “attacking leg”; respectively, 245N.m versus 237 (p<0.05) and 147 N.m versus 145 (p>0.05). R was normal for both legs. Furthermore, both rotators of the dominant shoulder had higher PT; 84 N.m versus 71 for the internal rotators (p<0.05) and 34,7 N.m versus 29,0 for the lateral rotators (p<0.05). Inversely, R was higher in the non-dominant side; 45% versus 35, p<0.05). Conclusion: the MSP of the selected elites Tunisian judo athletes was characterized by 3 major features; a strength of the quadriceps in the standing leg significantly higher than in the attacking leg, a normal muscular balance Hamstrings/quadriceps in both legs and a strength of the shoulder’ rotators higher in the dominant side. PMID:25332926

  17. Treatment of facioscapulohumeral muscular dystrophy with Denosumab

    PubMed Central

    Lefkowitz, Stanley S.; Lefkowitz, Doris L.; Kethley, Jeremy

    2012-01-01

    Summary Background: Facioscapulohumeral muscular dystrophy (FSHD) is the 3rd most common form of muscular dystrophy. Effective treatments for any of the muscular dystrophies have yet to be realized. This report describes such a treatment. Case Report: A 66 year old female was diagnosed with osteoporosis. She had been diagnosed with FSHD muscular dystrophy a number of years previously by both genetic and clinical studies. Following a 2 year course with Forteo for osteoporosis, she was given an injection of Denosumab (Prolia) to maintain her bone density. By 24 hours, she exhibited increased strength and a dramatic reduction of her dystrophic symptoms e.g. she could walk unassisted in high heels. She was able to accomplish other things that had not been possible for a number of years. After approximately 5 weeks she gradually lost the newfound strength with a complete loss by about 6 weeks. A second injection of Denosumab resulted in the same effect, i.e. reversal of symptoms and increased functionality. A number of measurements and videos were taken to establish the beneficial effects of Prolia for future studies. This was repeated with a 3rd and 4th injection in order to establish the unequivocal beneficial effects on muscular dystrophy. Conclusions: Further studies will be required to establish Denosumab as a major “front line” treatment for this disease and possibly other muscular dystrophies. PMID:23569491

  18. [The heartache of muscular dystrophy].

    PubMed

    Hoogerwaard, E M; Ginjaar, H B; Wilde, A A; Leschot, N J; de Voogt, W G; de Visser, M

    2000-11-11

    Duchenne and Becker muscular dystrophy are caused by a mutation in the dystrophin gene, located on the short arm of the X chromosome. Three so called dystrophinopathy patients, a women aged 54 and two men aged 23 and 21 years, suffered from a severe dilated cardiomyopathy. Such a cardiomyopathy can develop in both carriers and patients. In addition, it is often more important for prognosis than muscle weakness. For these two reasons it is important to screen both groups for (early) cardiological abnormalities. If these are present, regular follow-up is necessary to start timely therapy. When cardiological investigations yield normal results, it is advised to screen carriers with a five-year interval. Dystrophinopathy patients should be checked every year, because the cardiomyopathy sometimes develops and deteriorates over a short period of time. Patients with dilated cardiomyopathy and with a positive family history for dilated cardiomyopathy, muscle weakness or high serum creatine kinase activity should be screened for a mutation in the dystrophin gene. PMID:11103252

  19. [Vitamin K antagonists overdose].

    PubMed

    Groszek, Barbara; Piszczek, Paweł

    2015-01-01

    Nowadays, anticoagulant therapy belongs to the most commonly used forms of pharmacotherapy in modern medicine. The most important representatives of anticoagulants are heparins (unfractionated heparin and low-molecular-weight heparin) and coumarin derivatives (vitamin K antagonists--VKA). Next to the many advantages of traditional oral anticoagulants may also have disadvantages. In Poland most often used two VKA: acenocoumarol and warfarin. The aim of the work is the analysis of the causes of the occurrence of bleeding disorders and symptoms of overdose VKA in patients to be hospitalized. In the years 2012 to 2014 were hospitalized 62 patients with overdose VKA (40 women and 22 men). The average age of patients was 75.3 years) and clotting disturbances and/or bleeding. At the time of the admission in all patients a significant increase in the value of the INR was stated, in 22 patients INR result was " no clot detected", on the remaining value of the INR were in the range of 7 to 13.1. On 51 patients observed different severe symptoms of bleeding (hematuria, bleeding from mucous membranes of the nose or gums ecchymoses on the extremities, bleeding from the gastrointestinal tract--as in 5 patients has led to significant anemia and transfusion of concentrated red blood cells. Up on 33 patients kidney function disorder were found--exacerbated chronic renal failure and urinary tract infection. 8 diagnosed inflammatory changes in the airways. On 13 patients, it was found a significant degree of neuropsychiatric disorders (dementia, cognitive impairment), which made impossible the understanding the sense of treatment and cooperation with the patient. In 6 patients the symptoms of overdose were probably dependent on the interaction with the congestants at the same time (change the preparation of anticoagulant, NSAIDs, antibiotics). In 2 cases, the overdose was a suicide attempt in nature. In addition to the above mentioned disorders, on two of those patients diagnosed

  20. Neurobiological actions of cysteamine

    SciTech Connect

    Brown, M.; Fisher, L.; Mason, R.T.; Rivier, J.; Vale, W.

    1985-06-01

    Somatostatin (SS)-related peptides act within discrete brain regions to inhibit adrenal epinephrine (E) secretion, to prevent hypothermia, and to produce hyperthermia. Depletion of brain concentrations of these SS-related peptides using cysteamine (CSH) or central administration of an SS receptor antagonist increases adrenal E secretion and impairs thermoregulation. These actions of CSH and the SS receptor antagonist are reversed by administration of SS into the central nervous system. These results support the hypothesis that endogenous brain SS-related peptides are involved in the regulation of adrenal E secretion and thermoregulation.

  1. Sexually antagonistic genes: experimental evidence.

    PubMed

    Rice, W R

    1992-06-01

    When selection differs between the sexes, a mutation beneficial to one sex may be harmful to the other (sexually antagonistic). Because the sexes share a common gene pool, selection in one sex can interfere with the other's adaptive evolution. Theory predicts that sexually antagonistic mutations should accumulate in tight linkage with a new sex-determining gene, even when the harm to benefit ratio is high. Genetic markers and artificial selection were used to make a pair of autosomal genes segregate like a new pair of sex-determining genes in a Drosophila melanogaster model system. A 29-generation study provides experimental evidence that sexually antagonistic genes may be common in nature and will accumulate in response to a new sex-determining gene. PMID:1604317

  2. Clinical features of spinal and bulbar muscular atrophy

    PubMed Central

    Rhodes, Lindsay E.; Freeman, Brandi K.; Auh, Sungyoung; Kokkinis, Angela D.; La Pean, Alison; Chen, Cheunju; Lehky, Tanya J.; Shrader, Joseph A.; Levy, Ellen W.; Harris-Love, Michael; Di Prospero, Nicholas A.

    2009-01-01

    Spinal and bulbar muscular atrophy is an X-linked motor neuron disease caused by a CAG repeat expansion in the androgen receptor gene. To characterize the natural history and define outcome measures for clinical trials, we assessed the clinical history, laboratory findings and muscle strength and function in 57 patients with genetically confirmed disease. We also administered self-assessment questionnaires for activities of daily living, quality of life and erectile function. We found an average delay of over 5 years from onset of weakness to diagnosis. Muscle strength and function correlated directly with serum testosterone levels and inversely with CAG repeat length, age and duration of weakness. Motor unit number estimation was decreased by about half compared to healthy controls. Sensory nerve action potentials were reduced in nearly all subjects. Quantitative muscle assessment and timed 2 min walk may be useful as meaningful indicators of disease status. The direct correlation of testosterone levels with muscle strength indicates that androgens may have a positive effect on muscle function in spinal and bulbar muscular atrophy patients, in addition to the toxic effects described in animal models. PMID:19846582

  3. Pharmacodynamic properties of leukotriene receptor antagonists.

    PubMed

    Nicosia, S

    1999-06-01

    Leukotrienes (LTs) are among the most important mediators of asthma; cysteine-containing LTs (cysteinyl-LTs, i.e. LTC4, LTD4 and LTE4) are very potent bronchoconstrictors and participate in the inflammatory component of asthma by inducing mucus hypersecretion, plasma extravasation, mucosal oedema and eosinophil recruitment. Therefore, compounds able to inhibit either the formation or the action of LTs are potential antiasthma drugs and, at present, the cysteinyl-LT receptor antagonists (LTRAs) appear to be the most promising. The receptors for cysteinyl-LTs, termed CysLT receptors, are heterogeneous; at least two different classes have so far been recognized, named CysLT1 (blocked by the so-called classical antagonists, such as FPL 55712, ICI 198,615, ICI 204,219, SK&F 104353, MK-476 and others) and CysLT2 (insensitive to the classical antagonists, but sensitive to BAY u9773). The authors' results indicate that even more receptor subclasses might exist in human airways, which discriminate between LTC4 and LTD4, both asthma mediators. Among the many LTRAs, zafirlukast (Accolate, ICI 204,219), montelukast (Singulair, MK-476) and pranlukast (Onon, ONO-1078) are available for clinical use. All the LTRAs are able to inhibit LTD4-induced bronchoconstriction in humans, albeit with different potencies. With respect to antigen challenge, all of them inhibit the early phase of response, whereas only the most recently developed and potent ones are effective in the late phase. LTRAs are effective in asthma triggered by exercise, cold or aspirin. Furthermore, although they are not bronchodilators per se, they increase basal forced expiratory volume in one second in patients with mild-to-moderate asthma, indicating that, in these individuals, constant cysteinyl-LT release contributes to maintaining increased bronchial tone. Finally, the effect of LTRAs is additive to that of beta-agonists and is potentiated by antihistamine compounds. In conclusion, the available results clearly

  4. [Muscular Dystrophies Involving the Retinal Function].

    PubMed

    Jägle, H

    2016-03-01

    Muscular dystrophies are rare disorders, with an incidence of approx. 20 in 100 000. Some dystrophies also affect retinal or optic nerve function. In such cases, the ophthalmological findings may be critical for differential diagnosis or patient counseling. For example in Duchenne muscular dystrophy, where the alteration in retinal function seems to reflect cerebral involvement. Other important forms are mitochondrial and metabolic disorders, such as the Kearns-Sayre syndrome and the Refsum syndrome. Molecular genetic analysis has become a major tool for differential diagnosis, but may be complex and demanding. This article gives an overview of major muscular dystrophies involving retinal function and their genetic origin, in order to guide differential diagnosis. PMID:27011029

  5. Genetics Home Reference: spinal muscular atrophy with progressive myoclonic epilepsy

    MedlinePlus

    ... myoclonic epilepsy spinal muscular atrophy with progressive myoclonic epilepsy Enable Javascript to view the expand/collapse boxes. ... All Description Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a neurological condition that causes ...

  6. Other limb-girdle muscular dystrophies.

    PubMed

    Amato, Anthony A

    2011-01-01

    The secondary α-dystroglycanopathies usually present in infancy as congenital muscular dystrophies but may manifest later in childhood or adult life (limb-girdle muscular dystrophy (LGMD) 2I, LGMD2K, LGMD2M, LGMD2N, and LGMD2O). Patients with telethoninopathy (LGMD2B) may present with mainly proximal or distal lower extremity weakness, and notably the muscle biopsies may demonstrate rimmed vacuoles. LGMD2L is caused by newly described mutations in ANO5 and can sometimes present with distal weakness resembling Miyoshi myopathy. PMID:21496628

  7. Advances in gene therapy for muscular dystrophies

    PubMed Central

    Abdul-Razak, Hayder; Malerba, Alberto; Dickson, George

    2016-01-01

    Duchenne muscular dystrophy (DMD) is a recessive lethal inherited muscular dystrophy caused by mutations in the gene encoding dystrophin, a protein required for muscle fibre integrity. So far, many approaches have been tested from the traditional gene addition to newer advanced approaches based on manipulation of the cellular machinery either at the gene transcription, mRNA processing or translation levels. Unfortunately, despite all these efforts, no efficient treatments for DMD are currently available. In this review, we highlight the most advanced therapeutic strategies under investigation as potential DMD treatments. PMID:27594988

  8. Advances in gene therapy for muscular dystrophies.

    PubMed

    Abdul-Razak, Hayder; Malerba, Alberto; Dickson, George

    2016-01-01

    Duchenne muscular dystrophy (DMD) is a recessive lethal inherited muscular dystrophy caused by mutations in the gene encoding dystrophin, a protein required for muscle fibre integrity. So far, many approaches have been tested from the traditional gene addition to newer advanced approaches based on manipulation of the cellular machinery either at the gene transcription, mRNA processing or translation levels. Unfortunately, despite all these efforts, no efficient treatments for DMD are currently available. In this review, we highlight the most advanced therapeutic strategies under investigation as potential DMD treatments. PMID:27594988

  9. Cellular and molecular mechanisms underlying muscular dystrophy

    PubMed Central

    2013-01-01

    The muscular dystrophies are a group of heterogeneous genetic diseases characterized by progressive degeneration and weakness of skeletal muscle. Since the discovery of the first muscular dystrophy gene encoding dystrophin, a large number of genes have been identified that are involved in various muscle-wasting and neuromuscular disorders. Human genetic studies complemented by animal model systems have substantially contributed to our understanding of the molecular pathomechanisms underlying muscle degeneration. Moreover, these studies have revealed distinct molecular and cellular mechanisms that link genetic mutations to diverse muscle wasting phenotypes. PMID:23671309

  10. 9 CFR 311.35 - Muscular inflammation, degeneration, or infiltration.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Muscular inflammation, degeneration, or infiltration. 311.35 Section 311.35 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE... PARTS § 311.35 Muscular inflammation, degeneration, or infiltration. (a) If muscular lesions are...

  11. 9 CFR 311.35 - Muscular inflammation, degeneration, or infiltration.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 2 2011-01-01 2011-01-01 false Muscular inflammation, degeneration, or infiltration. 311.35 Section 311.35 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE... PARTS § 311.35 Muscular inflammation, degeneration, or infiltration. (a) If muscular lesions are...

  12. 9 CFR 311.35 - Muscular inflammation, degeneration, or infiltration.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 2 2014-01-01 2014-01-01 false Muscular inflammation, degeneration, or infiltration. 311.35 Section 311.35 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE... PARTS § 311.35 Muscular inflammation, degeneration, or infiltration. (a) If muscular lesions are...

  13. 9 CFR 311.35 - Muscular inflammation, degeneration, or infiltration.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 2 2013-01-01 2013-01-01 false Muscular inflammation, degeneration, or infiltration. 311.35 Section 311.35 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE... PARTS § 311.35 Muscular inflammation, degeneration, or infiltration. (a) If muscular lesions are...

  14. 9 CFR 311.35 - Muscular inflammation, degeneration, or infiltration.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 2 2012-01-01 2012-01-01 false Muscular inflammation, degeneration, or infiltration. 311.35 Section 311.35 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE... PARTS § 311.35 Muscular inflammation, degeneration, or infiltration. (a) If muscular lesions are...

  15. Spinal muscular atrophy patient-derived motor neurons exhibit hyperexcitability

    PubMed Central

    Liu, Huisheng; Lu, Jianfeng; Chen, Hong; Du, Zhongwei; Li, Xue-Jun; Zhang, Su-Chun

    2015-01-01

    Spinal muscular atrophy (SMA) presents severe muscle weakness with limited motor neuron (MN) loss at an early stage, suggesting potential functional alterations in MNs that contribute to SMA symptom presentation. Using SMA induced pluripotent stem cells (iPSCs), we found that SMA MNs displayed hyperexcitability with increased membrane input resistance, hyperpolarized threshold, and larger action potential amplitude, which was mimicked by knocking down full length survival motor neuron (SMN) in non-SMA MNs. We further discovered that SMA MNs exhibit enhanced sodium channel activities with increased current amplitude and facilitated recovery, which was corrected by restoration of SMN1 in SMA MNs. Together we propose that SMN reduction results in MN hyperexcitability and impaired neurotransmission, the latter of which exacerbate each other via a feedback loop, thus contributing to severe symptoms at an early stage of SMA. PMID:26190808

  16. Genetics Home Reference: facioscapulohumeral muscular dystrophy

    MedlinePlus

    ... Padberg GW, Lunt PW, van der Maarel SM. Best practice guidelines on genetic diagnostics of Facioscapulohumeral muscular dystrophy: ... Reviewed : August 2014 Published : August 30, 2016 The resources on this site should not be used as a ... of Health & Human Services National Institutes of Health National Library of ...

  17. Cardiomyopathy in becker muscular dystrophy: Overview.

    PubMed

    Ho, Rady; Nguyen, My-Le; Mather, Paul

    2016-06-26

    Becker muscular dystrophy (BMD) is an X-linked recessive disorder involving mutations of the dystrophin gene. Cardiac involvement in BMD has been described and cardiomyopathy represents the number one cause of death in these patients. In this paper, the pathophysiology, clinical evaluations and management of cardiomyopathy in patients with BMD will be discussed. PMID:27354892

  18. Prevalence of congenital muscular dystrophy in Italy

    PubMed Central

    Graziano, Alessandra; Bianco, Flaviana; D'Amico, Adele; Moroni, Isabella; Messina, Sonia; Bruno, Claudio; Pegoraro, Elena; Mora, Marina; Astrea, Guja; Magri, Francesca; Comi, Giacomo P.; Berardinelli, Angela; Moggio, Maurizio; Morandi, Lucia; Pini, Antonella; Petillo, Roberta; Tasca, Giorgio; Monforte, Mauro; Minetti, Carlo; Mongini, Tiziana; Ricci, Enzo; Gorni, Ksenija; Battini, Roberta; Villanova, Marcello; Politano, Luisa; Gualandi, Francesca; Ferlini, Alessandra; Muntoni, Francesco; Santorelli, Filippo Maria; Bertini, Enrico; Pane, Marika

    2015-01-01

    Objective: We provide a nationwide population study of patients with congenital muscular dystrophy in Italy. Methods: Cases were ascertained from the databases in all the tertiary referral centers for pediatric neuromuscular disorders and from all the genetic diagnostic centers in which diagnostic tests for these forms are performed. Results: The study includes 336 patients with a point prevalence of 0.563 per 100,000. Mutations were identified in 220 of the 336 (65.5%). The cohort was subdivided into diagnostic categories based on the most recent classifications on congenital muscular dystrophies. The most common forms were those with α-dystroglycan glycosylation deficiency (40.18%) followed by those with laminin α2 deficiency (24.11%) and collagen VI deficiency (20.24%). The forms of congenital muscular dystrophy related to mutations in SEPN1 and LMNA were less frequent (6.25% and 5.95%, respectively). Conclusions: Our study provides for the first time comprehensive epidemiologic information and point prevalence figures for each of the major diagnostic categories on a large cohort of congenital muscular dystrophies. The study also reflects the diagnostic progress in this field with an accurate classification of the cases according to the most recent gene discoveries. PMID:25653289

  19. Exon Snipping in Duchenne Muscular Dystrophy.

    PubMed

    Kemaladewi, Dwi U; Cohn, Ronald D

    2016-03-01

    Duchenne muscular dystrophy (DMD) is a life-limiting neuromuscular disorder caused by mutations in the DMD gene encoding dystrophin. We discuss very recent studies that used CRISPR/Cas9 technology to 'snip out' mutated exons in DMD, restoring the reading frame of the gene. We also present cautionary aspects of translating this exciting technology into clinical practice. PMID:26856237

  20. Zebrafish orthologs of human muscular dystrophy genes

    PubMed Central

    Steffen, Leta S; Guyon, Jeffrey R; Vogel, Emily D; Beltre, Rosanna; Pusack, Timothy J; Zhou, Yi; Zon, Leonard I; Kunkel, Louis M

    2007-01-01

    Background Human muscular dystrophies are a heterogeneous group of genetic disorders which cause decreased muscle strength and often result in premature death. There is no known cure for muscular dystrophy, nor have all causative genes been identified. Recent work in the small vertebrate zebrafish Danio rerio suggests that mutation or misregulation of zebrafish dystrophy orthologs can also cause muscular degeneration phenotypes in fish. To aid in the identification of new causative genes, this study identifies and maps zebrafish orthologs for all known human muscular dystrophy genes. Results Zebrafish sequence databases were queried for transcripts orthologous to human dystrophy-causing genes, identifying transcripts for 28 out of 29 genes of interest. In addition, the genomic locations of all 29 genes have been found, allowing rapid candidate gene discovery during genetic mapping of zebrafish dystrophy mutants. 19 genes show conservation of syntenic relationships with humans and at least two genes appear to be duplicated in zebrafish. Significant sequence coverage on one or more BAC clone(s) was also identified for 24 of the genes to provide better local sequence information and easy updating of genomic locations as the zebrafish genome assembly continues to evolve. Conclusion This resource supports zebrafish as a dystrophy model, suggesting maintenance of all known dystrophy-associated genes in the zebrafish genome. Coupled with the ability to conduct genetic screens and small molecule screens, zebrafish are thus an attractive model organism for isolating new dystrophy-causing genes/pathways and for use in high-throughput therapeutic discovery. PMID:17374169

  1. Visuospatial Attention Disturbance in Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    De Moura, Maria Clara Drummond Soares; do Valle, Luiz Eduardo Ribeiro; Resende, Maria Bernadete Dutra; Pinto, Katia Osternack

    2010-01-01

    Aim: The cognitive deficits present in the Duchenne muscular dystrophy (DMD) are not yet well characterized. Attention, considered to be the brain mechanism responsible for the selection of sensory stimuli, could be disturbed in DMD, contributing, at least partially, to the observed global cognitive deficit. The aim of this study was to…

  2. Cardiomyopathy in becker muscular dystrophy: Overview

    PubMed Central

    Ho, Rady; Nguyen, My-Le; Mather, Paul

    2016-01-01

    Becker muscular dystrophy (BMD) is an X-linked recessive disorder involving mutations of the dystrophin gene. Cardiac involvement in BMD has been described and cardiomyopathy represents the number one cause of death in these patients. In this paper, the pathophysiology, clinical evaluations and management of cardiomyopathy in patients with BMD will be discussed. PMID:27354892

  3. Developing therapies for spinal muscular atrophy.

    PubMed

    Wertz, Mary H; Sahin, Mustafa

    2016-02-01

    Spinal muscular atrophy is an autosomal-recessive pediatric neurodegenerative disease characterized by loss of spinal motor neurons. It is caused by mutation in the gene survival of motor neuron 1 (SMN1), leading to loss of function of the full-length SMN protein. SMN has a number of functions in neurons, including RNA splicing and snRNP biogenesis in the nucleus, and RNA trafficking in neurites. The expression level of full-length SMN protein from the SMN2 locus modifies disease severity. Increasing full-length SMN protein by a small amount can lead to significant improvements in the neurological phenotype. Currently available interventions for spinal muscular atrophy patients are physical therapy and orthopedic, nutritional, and pulmonary interventions; these are palliative or supportive measures and do not address the etiology of the disease. In the past decade, there has been a push for developing therapeutics to improve motor phenotypes and increase life span of spinal muscular atrophy patients. These therapies are aimed primarily at restoration of full-length SMN protein levels, but other neuroprotective treatments have been investigated as well. Here, we discuss recent advances in basic and clinical studies toward finding safe and effective treatments of spinal muscular atrophy using gene therapy, antisense oligonucleotides, and other small molecule modulators of SMN expression. PMID:26173388

  4. [Muscular strength in patients with fibromyalgia. A literature review].

    PubMed

    Dombernowsky, Tilde; Dreyer, Lene; Bartels, Else Marie; Danneskiold-Samsøe, Bente

    2008-01-21

    Do patients with fibromyalgia (FM) have reduced muscular strength? We examined 22 articles and conclude from the results of these that FM patients have reduced muscular strength in their hands and quadriceps. The material also suggests generalised reduced muscular strength. However, the studies have several methodological shortcomings and future studies should be carefully designed with respect to patients as well as the control group and should be larger. To avoid CNS influence from e.g. fatigue and pain, muscular electro-stimulation may be used to ensure that the actual maximal muscular strength is also measured. PMID:18282450

  5. Muscular dystrophies due to glycosylation defects.

    PubMed

    Muntoni, Francesco; Torelli, Silvia; Brockington, Martin

    2008-10-01

    In the last few years, muscular dystrophies due to reduced glycosylation of alpha-dystroglycan (ADG) have emerged as a common group of conditions, now referred to as dystroglycanopathies. Mutations in six genes (POMT1, POMT2, POMGnT1, Fukutin, FKRP and LARGE) have so far been identified in patients with a dystroglycanopathy. Allelic mutations in each of these genes can result in a wide spectrum of clinical conditions, ranging from severe congenital onset with associated structural brain malformations (Walker Warburg syndrome; muscle-eye-brain disease; Fukuyama muscular dystrophy; congenital muscular dystrophy type 1D) to a relatively milder congenital variant with no brain involvement (congenital muscular dystrophy type 1C), and to limb-girdle muscular dystrophy (LGMD) type 2 variants with onset in childhood or adult life (LGMD2I, LGMD2L, and LGMD2N). ADG is a peripheral membrane protein that undergoes multiple and complex glycosylation steps to regulate its ability to effectively interact with extracellular matrix proteins, such as laminin, agrin, and perlecan. Although the precise composition of the glycans present on ADG are not known, it has been demonstrated that the forced overexpression of LARGE, or its paralog LARGE2, is capable of increasing the glycosylation of ADG in normal cells. In addition, its overexpression is capable of restoring dystroglycan glycosylation and laminin binding properties in primary cell cultures of patients affected by different genetically defined dystroglycanopathy variants. These observations suggest that there could be a role for therapeutic strategies to overcome the glycosylation defect in these conditions via the overexpression of LARGE. PMID:19019316

  6. Zebrafish models for human FKRP muscular dystrophies.

    PubMed

    Kawahara, Genri; Guyon, Jeffrey R; Nakamura, Yukio; Kunkel, Louis M

    2010-02-15

    Various muscular dystrophies are associated with the defective glycosylation of alpha-dystroglycan and are known to result from mutations in genes encoding glycosyltransferases. Fukutin-related protein (FKRP) was identified as a homolog of fukutin, the defective protein in Fukuyama-type congenital muscular dystrophy (FCMD), that is thought to function as a glycosyltransferase. Mutations in FKRP have been linked to a variety of phenotypes including Walker-Warburg syndrome (WWS), limb girdle muscular dystrophy (LGMD) 2I and congenital muscular dystrophy 1C (MDC1C). Zebrafish are a useful animal model to reveal the mechanism of these diseases caused by mutations in FKRP gene. Downregulating FKRP expression in zebrafish by two different morpholinos resulted in embryos which had developmental defects similar to those observed in human muscular dystrophies associated with mutations in FKRP. The FKRP morphants showed phenotypes involving alterations in somitic structure and muscle fiber organization, as well as defects in developing eye morphology. Additionally, they were found to have a reduction in alpha-dystroglycan glycosylation and a shortened myofiber length. Moreover, co-injection of fish or human FKRP mRNA along with the morpholino restored normal development, alpha-dystroglycan glycosylation and laminin binding activity of alpha-dystroglycan in the morphants. Co-injection of the human FKRP mRNA containing causative mutations found in human patients of WWS, MDC1C and LGMD2I could not restore their phenotypes significantly. Interestingly, these morphant fish having human FKRP mutations showed a wide phenotypic range similar to that seen in humans. PMID:19955119

  7. Zebrafish models for human FKRP muscular dystrophies

    PubMed Central

    Kawahara, Genri; Guyon, Jeffrey R.; Nakamura, Yukio; Kunkel, Louis M.

    2010-01-01

    Various muscular dystrophies are associated with the defective glycosylation of α-dystroglycan and are known to result from mutations in genes encoding glycosyltransferases. Fukutin-related protein (FKRP) was identified as a homolog of fukutin, the defective protein in Fukuyama-type congenital muscular dystrophy (FCMD), that is thought to function as a glycosyltransferase. Mutations in FKRP have been linked to a variety of phenotypes including Walker–Warburg syndrome (WWS), limb girdle muscular dystrophy (LGMD) 2I and congenital muscular dystrophy 1C (MDC1C). Zebrafish are a useful animal model to reveal the mechanism of these diseases caused by mutations in FKRP gene. Downregulating FKRP expression in zebrafish by two different morpholinos resulted in embryos which had developmental defects similar to those observed in human muscular dystrophies associated with mutations in FKRP. The FKRP morphants showed phenotypes involving alterations in somitic structure and muscle fiber organization, as well as defects in developing eye morphology. Additionally, they were found to have a reduction in α-dystroglycan glycosylation and a shortened myofiber length. Moreover, co-injection of fish or human FKRP mRNA along with the morpholino restored normal development, α-dystroglycan glycosylation and laminin binding activity of α-dystroglycan in the morphants. Co-injection of the human FKRP mRNA containing causative mutations found in human patients of WWS, MDC1C and LGMD2I could not restore their phenotypes significantly. Interestingly, these morphant fish having human FKRP mutations showed a wide phenotypic range similar to that seen in humans. PMID:19955119

  8. Serotonin 2C receptor antagonists induce fast-onset antidepressant effects.

    PubMed

    Opal, M D; Klenotich, S C; Morais, M; Bessa, J; Winkle, J; Doukas, D; Kay, L J; Sousa, N; Dulawa, S M

    2014-10-01

    Current antidepressants must be administered for several weeks to produce therapeutic effects. We show that selective serotonin 2C (5-HT2C) antagonists exert antidepressant actions with a faster-onset (5 days) than that of current antidepressants (14 days) in mice. Subchronic (5 days) treatment with 5-HT2C antagonists induced antidepressant behavioral effects in the chronic forced swim test (cFST), chronic mild stress (CMS) paradigm and olfactory bulbectomy paradigm. This treatment regimen also induced classical markers of antidepressant action: activation of cAMP response element-binding protein (CREB) and induction of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC). None of these effects were induced by subchronic treatment with citalopram, a prototypical selective serotonin reuptake inhibitor (SSRI). Local infusion of 5-HT2C antagonists into the ventral tegmental area was sufficient to induce BDNF in the mPFC, and dopamine D1 receptor antagonist treatment blocked the antidepressant behavioral effects of 5-HT2C antagonists. 5-HT2C antagonists also activated mammalian target of rapamycin (mTOR) and eukaryotic elongation factor 2 (eEF2) in the mPFC, effects recently linked to rapid antidepressant action. Furthermore, 5-HT2C antagonists reversed CMS-induced atrophy of mPFC pyramidal neurons. Subchronic SSRI treatment, which does not induce antidepressant behavioral effects, also activated mTOR and eEF2 and reversed CMS-induced neuronal atrophy, indicating that these effects are not sufficient for antidepressant onset. Our findings reveal that 5-HT2C antagonists are putative fast-onset antidepressants, which act through enhancement of mesocortical dopaminergic signaling. PMID:24166413

  9. Simultaneously cooperative, but serially antagonistic: a neuropsychological study of diagonistic dyspraxia in a case of Marchiafava-Bignami disease.

    PubMed

    Hirayama, Kazumi; Tachibana, Kaori; Abe, Nobuhito; Manabe, Hideaki; Fuse, Takahisa; Tsukamoto, Tetsuro

    2008-01-01

    We describe a patient with Marchiafava-Bignami disease who showed, in addition to signs of callosal interruption, a peculiar form of diagonistic dyspraxia. Unlike the typical diagonistic dyspraxia, both of the patient's hands could simultaneously cooperate in a sequence of bimanual actions. More specifically, his right hand could start a commanded action with the cooperation of his left hand. However, once the action was completed, his left hand started an antagonistic action, undoing the result, with the cooperation of his right hand. Once this countermanding action was completed, the original action started again. These antagonistic actions repeated themselves alternately unless he was restrained. The patient's diagonistic dyspraxia was apparent in only some bimanual actions, and he showed no diagonistic dyspraxia when performing voluntary actions; the antagonistic actions occurred in response to oral commands or by imitation. Magnetic resonance imaging showed symmetrical demyelination with partial necrosis in the genu, body, and anterior splenium of the corpus callosum. We speculate that the bimanual coordination is possible because part of the corpus callosum is intact, whereas the antagonistic actions may be caused by conflict between the two hemispheres due to interhemispheric disinhibition elicited by the demyelinated part of the corpus callosum. PMID:18641433

  10. Limb Girdle Muscular Dystrophy (LGMD): Case Report.

    PubMed

    Kanitkar, Shubhangi A; Kalyan, Meenakshi; Gaikwad, Anu N; Makadia, Ankit; Shah, Harshad

    2015-01-01

    We report a young male of autosomal recessive limb girdle muscular dystrophy (LGMD) with positive family history presented with gradual onset proximal muscle weakness in all four limbs since eight years and thinning of shoulders, arms and thighs. Neurological examination revealed atrophy of both shoulders with wasting of both deltoids thinning of thighs and pseudo hypertrophy of both calves, hypotonia in all four limbs. Gower's sign was positive. Winging of scapula was present. Power was 3/5 at both shoulders, 4/5 at both elbows, 5/5 at both wrists, 3/5 at both hip joints, 3/5 at both knees, 5/5 at both ankles. All deep tendon reflexes and superficial reflexes were present with plantars bilateral flexors. Electromyography (EMG) showed myopathic pattern. He had elevated creatinine phosphokinase levels and muscle biopsy findings consistent with muscular dystrophy. PMID:25738022

  11. Caveolae and caveolin-3 in muscular dystrophy.

    PubMed

    Galbiati, F; Razani, B; Lisanti, M P

    2001-10-01

    Caveolae are vesicular invaginations of the plasma membrane, and function as 'message centers' for regulating signal transduction events. Caveolin-3, a muscle-specific caveolin-related protein, is the principal structural protein of caveolar membrane domains in skeletal muscle and in the heart. Several mutations within the coding sequence of the human caveolin-3 gene (located at 3p25) have been identified. Mutations that lead to a loss of approximately 95% of caveolin-3 protein expression are responsible for a novel autosomal dominant form of limb-girdle muscular dystrophy (LGMD-1C) in humans. By contrast, upregulation of the caveolin-3 protein is associated with Duchenne muscular dystrophy (DMD). Thus, tight regulation of caveolin-3 appears essential for maintaining normal muscle health and homeostasis. PMID:11597517

  12. Limb Girdle Muscular Dystrophy (LGMD): Case Report

    PubMed Central

    Kalyan, Meenakshi; Gaikwad, Anu N.; Makadia, Ankit; Shah, Harshad

    2015-01-01

    We report a young male of autosomal recessive limb girdle muscular dystrophy (LGMD) with positive family history presented with gradual onset proximal muscle weakness in all four limbs since eight years and thinning of shoulders, arms and thighs. Neurological examination revealed atrophy of both shoulders with wasting of both deltoids thinning of thighs and pseudo hypertrophy of both calves, hypotonia in all four limbs. Gower’s sign was positive. Winging of scapula was present. Power was 3/5 at both shoulders, 4/5 at both elbows, 5/5 at both wrists, 3/5 at both hip joints, 3/5 at both knees, 5/5 at both ankles. All deep tendon reflexes and superficial reflexes were present with plantars bilateral flexors. Electromyography (EMG) showed myopathic pattern. He had elevated creatinine phosphokinase levels and muscle biopsy findings consistent with muscular dystrophy. PMID:25738022

  13. Neuronal involvement in muscular atrophy

    PubMed Central

    Cisterna, Bruno A.; Cardozo, Christopher; Sáez, Juan C.

    2014-01-01

    The innervation of skeletal myofibers exerts a crucial influence on the maintenance of muscle tone and normal operation. Consequently, denervated myofibers manifest atrophy, which is preceded by an increase in sarcolemma permeability. Recently, de novo expression of hemichannels (HCs) formed by connexins (Cxs) and other none selective channels, including P2X7 receptors (P2X7Rs), and transient receptor potential, sub-family V, member 2 (TRPV2) channels was demonstrated in denervated fast skeletal muscles. The denervation-induced atrophy was drastically reduced in denervated muscles deficient in Cxs 43 and 45. Nonetheless, the transduction mechanism by which the nerve represses the expression of the above mentioned non-selective channels remains unknown. The paracrine action of extracellular signaling molecules including ATP, neurotrophic factors (i.e., brain-derived neurotrophic factor (BDNF)), agrin/LDL receptor-related protein 4 (Lrp4)/muscle-specific receptor kinase (MuSK) and acetylcholine (Ach) are among the possible signals for repression for connexin expression. This review discusses the possible role of relevant factors in maintaining the normal functioning of fast skeletal muscles and suppression of connexin hemichannel expression. PMID:25540609

  14. Presumed primary muscular lymphoma in a dog.

    PubMed

    Thuilliez, Céline; Watrelot-Virieux, Dorothée; Chanut, Franck; Fournel-Fleury, Corinne; Ponce, Frédérique; Marchal, Thierry

    2008-11-01

    A case of presumed primary muscular lymphoma in an 8-year-old, intact, male Newfoundland dog is reported. The dog was presented for evaluation of an infiltrating ventral cervical mass, respiratory distress, and anorexia of 1-month duration. Fine-needle aspiration of the mass revealed anaplastic large cell lymphoma. Despite chemotherapy, health status declined and the animal was euthanized a few weeks later. At necropsy, the mass infiltrated the cervical muscles and extended ventrally to the left forelimb and cranially to the tongue and laryngeal musculature. Other muscles were infiltrated by the same neoplasm (diaphragm and intercostal, abdominal, and gluteal muscles) indicating a probable multicentric origin. Histological examination confirmed the diagnosis of anaplastic large cell lymphoma, which showed a strong muscular tropism. Immunohistochemical staining revealed neoplastic cell reactivity for cluster of differentiation 3 (CD3) and Ki-67 antigens (70% and 90%, respectively). The neoplastic cells were negative for CD79a. The presumed histological diagnosis in this dog was primary muscular anaplastic large T-cell lymphoma. PMID:18987239

  15. Congenital muscular dystrophy: from muscle to brain.

    PubMed

    Falsaperla, Raffaele; Praticò, Andrea D; Ruggieri, Martino; Parano, Enrico; Rizzo, Renata; Corsello, Giovanni; Vitaliti, Giovanna; Pavone, Piero

    2016-01-01

    Congenital muscular dystrophies (CMDs) are a wide group of muscular disorders that manifest with very early onset of muscular weakness, sometime associated to severe brain involvement.The histologic pattern of muscle anomalies is typical of dystrophic lesions but quite variable depending on the different stages and on the severity of the disorder.Recent classification of CMDs have been reported most of which based on the combination of clinical, biochemical, molecular and genetic findings, but genotype/phenotype correlation are in constant progression due to more diffuse utilization of the molecular analysis.In this article, the Authors report on CMDs belonging to the group of dystroglycanopathies and in particular on the most severe forms represented by the Fukuyama CMD, Muscle-Eye-Brain disease and Walker Walburg syndrome.Clinical diagnosis of infantile hypotonia is particularly difficult considering the different etiologic factors causing the lesions, the difficulty in localizing the involved CNS area (central vs. peripheral) and the limited role of the diagnostic procedures at this early age.The diagnostic evaluation is not easy mainly in differentiating the various types of CMDs, and represents a challenge for the neonatologists and pediatricians. Suggestions are reported on the way to reach a correct diagnosis with the appropriate use of the diagnostic means. PMID:27576556

  16. Lead Optimization Studies of Cinnamic Amide EP2 Antagonists

    PubMed Central

    2015-01-01

    Prostanoid receptor EP2 can play a proinflammatory role, exacerbating disease pathology in a variety of central nervous system and peripheral diseases. A highly selective EP2 antagonist could be useful as a drug to mitigate the inflammatory consequences of EP2 activation. We recently identified a cinnamic amide class of EP2 antagonists. The lead compound in this class (5d) displays anti-inflammatory and neuroprotective actions. However, this compound exhibited moderate selectivity to EP2 over the DP1 prostanoid receptor (∼10-fold) and low aqueous solubility. We now report compounds that display up to 180-fold selectivity against DP1 and up to 9-fold higher aqueous solubility than our previous lead. The newly developed compounds also display higher selectivity against EP4 and IP receptors and a comparable plasma pharmacokinetics. Thus, these compounds are useful for proof of concept studies in a variety of models where EP2 activation is playing a deleterious role. PMID:24773616

  17. Lead optimization studies of cinnamic amide EP2 antagonists.

    PubMed

    Ganesh, Thota; Jiang, Jianxiong; Yang, Myung-Soon; Dingledine, Ray

    2014-05-22

    Prostanoid receptor EP2 can play a proinflammatory role, exacerbating disease pathology in a variety of central nervous system and peripheral diseases. A highly selective EP2 antagonist could be useful as a drug to mitigate the inflammatory consequences of EP2 activation. We recently identified a cinnamic amide class of EP2 antagonists. The lead compound in this class (5d) displays anti-inflammatory and neuroprotective actions. However, this compound exhibited moderate selectivity to EP2 over the DP1 prostanoid receptor (∼10-fold) and low aqueous solubility. We now report compounds that display up to 180-fold selectivity against DP1 and up to 9-fold higher aqueous solubility than our previous lead. The newly developed compounds also display higher selectivity against EP4 and IP receptors and a comparable plasma pharmacokinetics. Thus, these compounds are useful for proof of concept studies in a variety of models where EP2 activation is playing a deleterious role. PMID:24773616

  18. A case of fascioscapulohumeral muscular dystrophy misdiagnosed as Becker's muscular dystrophy for 20 years.

    PubMed

    Ramos, Vesper Fe Marie Llaneza; Thaisetthawatkul, Pariwat

    2012-03-01

    A 60-year-old man diagnosed clinically with Becker's muscular dystrophy 20 years ago by another physician presented with gradually progressive proximal muscle weakness since teenage years. Family history revealed a strong paternal familial inheritance pattern of similar distribution of weakness-face, forearm flexion, knee extension and foot dorsiflexion. Work-ups revealed B12 deficiency and allele 1 deletion in fascioscapulohumeral muscular dystrophy (FSHD) DNA testing. FSHD is the third most common muscular dystrophy. Clinical diagnosis is made from the distinctive pattern of weakness, autosomal-dominant inheritance, and confirmed by genetic testing. This case strongly demonstrates the importance of a thorough and careful clinical evaluation even in a case with a long standing diagnosis. PMID:21795275

  19. Ways of increasing muscular activity by means of isometric muscular exertion

    NASA Technical Reports Server (NTRS)

    Kovalik, A. V.

    1980-01-01

    The effect of isometric muscular exertion on the human body was investigated by having subjects perform basic movements in a sitting position in the conventional manner with additional muscle tension at 50% maximum force and at maximum force. The pulse, arterial pressure, skin temperature, respiratory rate, minute respiratory volume and electrical activity of the muscles involved were all measured. Performance of the exercises with maximum muscular exertion for 20 sec and without movement resulted in the greatest shifts in these indices; in the conventional manner substantial changes did not occur; and with isometric muscular exertion with 50% maximum force with and without movement, optimal functional shifts resulted. The latter is recommended for use in industrial exercises for the prevention of hypodynamia. Ten exercises are suggested.

  20. Media's influence on the drive for muscularity in undergraduates.

    PubMed

    Cramblitt, Brooke; Pritchard, Mary

    2013-12-01

    Although research has found that body ideals presented by the media influence women's body dissatisfaction, less is known about media's influence on men's body satisfaction. An online survey examining media use, the drive for muscularity, and internalization of appearance and body shape ideals was given to a sample of 311 participants comprised of both men and women. Results indicated (a) the more time men and women reported watching television, the higher their reported drive for muscularity (b) total hours of viewing sports-related, image-focused, and entertainment television related to increased drive for muscularity in women (c) drive for muscularity in men related to watching image-focused television and reading men's health magazines, and (d) internalization of athletic attitudes towards appearance mediated the relationship between total television watched and drive for muscularity in both genders. Clinicians may wish to utilize these findings when treating men and women suffering from drive for muscularity and body dysmorphia. PMID:24183132

  1. Tachykinin antagonists and the airways.

    PubMed

    Joos, G F; Kips, J C; Peleman, R A; Pauwels, R A

    1995-01-01

    There is now convincing evidence for the presence of substance P (SP) and neurokinin A (NKA) in human airway nerves. Studies on autopsy tissue, on bronchoalveolar lavage fluid and on sputum suggest that SP may be present in increased amounts in the asthmatic airway. Substance P and NKA are potent bronchoconstrictors of human airways, asthmatics being more sensitive than normal persons. The major enzyme responsible for the degradation of the tachykinins, the neutral endopeptidase, is present in the airways and is involved in the breakdown of exogenously administered SP and NKA, both in normal and asthmatic persons. Other, less well documented airway effects of SP and NKA include mucus secretion, vasodilation and plasma extravasation, as well as the chemoattraction and stimulation of various cells presumed to be involved in asthmatic airway inflammation. NK2 receptors and, to a lesser extent, NK1 receptors have been shown to be involved in bronchoconstriction, whereas NK1 receptors were found to be involved in mucus secretion, microvascular leakage and vasodilatation, and in most of the effects on inflammatory cells. The first clinical trial with FK224, a peptide NK1 and NK2 receptor antagonist, and CP99994, a nonpeptide NK1 receptor antagonist, are negative. However, FK224 failed to block the bronchoconstrictor effect of NKA in asthmatics and the dose of CP99994, needed to antagonize tachykinin effects in man, remains to be determined. PMID:7543746

  2. Antagonistic neural networks underlying differentiated leadership roles

    PubMed Central

    Boyatzis, Richard E.; Rochford, Kylie; Jack, Anthony I.

    2014-01-01

    The emergence of two distinct leadership roles, the task leader and the socio-emotional leader, has been documented in the leadership literature since the 1950s. Recent research in neuroscience suggests that the division between task-oriented and socio-emotional-oriented roles derives from a fundamental feature of our neurobiology: an antagonistic relationship between two large-scale cortical networks – the task-positive network (TPN) and the default mode network (DMN). Neural activity in TPN tends to inhibit activity in the DMN, and vice versa. The TPN is important for problem solving, focusing of attention, making decisions, and control of action. The DMN plays a central role in emotional self-awareness, social cognition, and ethical decision making. It is also strongly linked to creativity and openness to new ideas. Because activation of the TPN tends to suppress activity in the DMN, an over-emphasis on task-oriented leadership may prove deleterious to social and emotional aspects of leadership. Similarly, an overemphasis on the DMN would result in difficulty focusing attention, making decisions, and solving known problems. In this paper, we will review major streams of theory and research on leadership roles in the context of recent findings from neuroscience and psychology. We conclude by suggesting that emerging research challenges the assumption that role differentiation is both natural and necessary, in particular when openness to new ideas, people, emotions, and ethical concerns are important to success. PMID:24624074

  3. Antagonistic neural networks underlying differentiated leadership roles.

    PubMed

    Boyatzis, Richard E; Rochford, Kylie; Jack, Anthony I

    2014-01-01

    The emergence of two distinct leadership roles, the task leader and the socio-emotional leader, has been documented in the leadership literature since the 1950s. Recent research in neuroscience suggests that the division between task-oriented and socio-emotional-oriented roles derives from a fundamental feature of our neurobiology: an antagonistic relationship between two large-scale cortical networks - the task-positive network (TPN) and the default mode network (DMN). Neural activity in TPN tends to inhibit activity in the DMN, and vice versa. The TPN is important for problem solving, focusing of attention, making decisions, and control of action. The DMN plays a central role in emotional self-awareness, social cognition, and ethical decision making. It is also strongly linked to creativity and openness to new ideas. Because activation of the TPN tends to suppress activity in the DMN, an over-emphasis on task-oriented leadership may prove deleterious to social and emotional aspects of leadership. Similarly, an overemphasis on the DMN would result in difficulty focusing attention, making decisions, and solving known problems. In this paper, we will review major streams of theory and research on leadership roles in the context of recent findings from neuroscience and psychology. We conclude by suggesting that emerging research challenges the assumption that role differentiation is both natural and necessary, in particular when openness to new ideas, people, emotions, and ethical concerns are important to success. PMID:24624074

  4. NF-kB overexpression and decreased immunoexpression of AR in the muscular layer is related to structural damages and apoptosis in cimetidine-treated rat vas deferens

    PubMed Central

    2013-01-01

    Background Cimetidine, histamine H2 receptors antagonist, has caused adverse effects on the male hormones and reproductive tract due to its antiandrogenic effect. In the testes, peritubular myoid cells and muscle vascular cells death has been associated to seminiferous tubules and testicular microvascularization damages, respectively. Either androgen or histamine H2 receptors have been detected in the mucosa and smooth muscular layer of vas deferens. Thus, the effect of cimetidine on this androgen and histamine-dependent muscular duct was morphologically evaluated. Methods The animals from cimetidine group (CMTG; n=5) received intraperitoneal injections of 100 mg/kg b.w. of cimetidine for 50 days; the control group (CG) received saline solution. The distal portions of vas deferens were fixed in formaldehyde and embedded in paraffin. Masson´s trichrome-stained sections were subjected to morphological and the following morphometrical analyzes: epithelial perimeter and area of the smooth muscular layer. TUNEL (Terminal deoxynucleotidyl-transferase mediated dUTP Nick End Labeling) method, NF-kB (nuclear factor kappa B) and AR (androgen receptors) immunohistochemical detection were also carried out. The birefringent collagen of the muscular layer was quantified in picrosirius red-stained sections under polarized light. The muscular layer was also evaluated under Transmission Electron Microscopy (TEM). Results In CMTG, the mucosa of vas deferens was intensely folded; the epithelial cells showed numerous pyknotic nuclei and the epithelial perimeter and the area of the muscular layer decreased significantly. Numerous TUNEL-labeled nuclei were found either in the epithelial cells, mainly basal cells, or in the smooth muscle cells which also showed typical features of apoptosis under TEM. While an enhanced NF-kB immunoexpression was found in the cytoplasm of muscle cells, a weak AR immunolabeling was detected in these cells. In CMTG, no significant difference was observed

  5. Nose muscular dynamics: the tip trigonum.

    PubMed

    Figallo, E E; Acosta, J A

    2001-10-01

    In 1995, the senior author (E.E.F.) published an article in which he described the musculus digastricus septi nasi labialis. In the article presented here, work carried out by anatomists and other researchers who, over the last two centuries, studied nose muscular dynamics is described. The present study is based on Gray's Anatomy, which, in 1858, first described the nasal tip muscles, along with the other nasal muscles. Later works not only used different terminology for these muscles but also ignored some, creating tremendous confusion. The study presented here provides an update of the exact terms, location, insertions, and muscle functions of the muscles of the nose. Each nose muscle is described with regard to the two portions able to produce separate contractions. In this study, the term "dual function" is used and characterizes the nasal mimetic muscles that do not have well-defined fascia. Therefore, there is doubt about the existence of a real nasal superficial muscle aponeurotic system. The musculus myrtiformis seems to have a dual function, inserting in the canine fosse and in the periosteum of the central incisors, forming two portions-one to the septum and the other to the nostril-each of which has specific functions. This study has been based on research in physiognomy, the science of expression. With regard to the basis for nose expressions, common anatomical research is excluded because it provides a different view of the dynamics studied to date. The term trigonum musculare apicis nasi defines the interaction of the musculi compressor narium minor and dilator naris anterior, connecting with the columellar bundle of the musculus digastricus and levering the nasal spine. This muscular trigone creates circular concentric and eccentric movements of the nasal tip. PMID:11604607

  6. [Treatment progress of Duchenne Muscular Dystrophy (DMD)].

    PubMed

    Smogorzewska, Elzbieta Monika; Weinberg, Kenneth I

    2004-01-01

    Duchenne muscular dystrophy (DMD) is a common lethal disease for which no effective treatment is currently available. There exists a mouse model of the disease in which the usefulness of gene therapy was established. However, no progress towards human application was made due to the lack of a proper method for gene delivery. During the past several years, researchers acquired data which led them to believe that bone marrow stem cells are capable of generating not only blood cells, but also liver, heart, skin, muscle, and other tissue. Although the term "stem cell plasticity" became very popular, other studies have suggested that bone marrow might contain different types of stem cells that can produce non-hematopoietic cells. For example, mesenchymal stem cell (MSC) in bone marrow give rise to osteocytes, chondrocytes, adipocytes, and skeletal muscle. Recently, researchers have been able to show that transplanted bone marrow cells can contribute to muscle cells in a human patient who was diagnosed with two genetic diseases: severe combined immunodeficiency (SCID) and Duchenne muscular dystrophy. The odds of this happening is estimated at one in seven million. The results of studying this patient's medical history were reported by collaborating researchers at Children's Hospital, Los Angeles and Children's Hospital, Boston in an article titled "Long-term persistence of donor nuclei in a Duchenne muscular dystrophy (DMD) patient receiving bone marrow transplantation" published in the September 2002 issue of the Journal of Clinical Investigation. This patient was transplanted 15 years ago at Children's Hospital Los Angeles with paternal HLA-haploidentical T cell-depleted bone marrow. He engrafted and became a hematopoietic chimera having T and NK lymphocytes of donor origin. Studies performed on the muscle biopsy from the patient 13 years after transplantation demonstrated that the muscle showed evidence of donor derived nuclei. In addition, analysis of his bone marrow

  7. Exon skipping therapy for Duchenne muscular dystrophy.

    PubMed

    Kole, Ryszard; Krieg, Arthur M

    2015-06-29

    Duchenne muscular dystrophy (DMD) is caused mostly by internal deletions in the gene for dystrophin, a protein essential for maintaining muscle cell membrane integrity. These deletions abrogate the reading frame and the lack of dystrophin results in progressive muscle deterioration. DMD patients experience progressive loss of ambulation, followed by a need for assisted ventilation, and eventual death in mid-twenties. By the method of exon skipping in dystrophin pre-mRNA the reading frame is restored and the internally deleted but functional dystrophin is produced. Two oligonucleotide drugs that induce desired exon skipping are currently in advanced clinical trials. PMID:25980936

  8. Long-acting muscarinic antagonists.

    PubMed

    Melani, Andrea S

    2015-01-01

    Chronic obstructive pulmonary disease (COPD) is a major cause of death and disability worldwide. Inhaled bronchodilators are the mainstay of COPD pharmacological treatment. Long-acting muscarinic antagonists (LAMAs) are a major class of inhaled bronchodilators. Some LAMA/device systems with different characteristics and dosing schedules are currently approved for maintenance therapy of COPD and a range of other products are being developed. They improve lung function and patient-reported outcomes and reduce acute bronchial exacerbations with good safety. LAMAs are used either alone or associated with long-acting β₂-agonists, eventually in fixed dose combinations. Long-acting β₂-agonist/LAMA combinations assure additional benefits over the individual components alone. The reader will obtain a view of the safety and efficacy of the different LAMA/device systems in COPD patients. PMID:26109098

  9. Induction of prostate apoptosis by alpha1-adrenoceptor antagonists: mechanistic significance of the quinazoline component.

    PubMed

    Anglin, I E; Glassman, D T; Kyprianou, N

    2002-01-01

    alpha(1)-Adrenoceptor antagonists, have been documented to induce apoptosis and reduce prostate tumor vascularity in benign and malignant prostate cells. The quinazoline based alpha(1)-antagonists, doxazosin and terazosin but not tamsulosin (a sulphonamide derivative) suppress prostate growth without affecting cell proliferation. These quinazoline-mediated apoptotic effects occur via an alpha(1)-adrenoceptor independent mechanism potentially involving activation of the TGF-beta signal transduction pathway. This review discusses the current knowledge of the action of quinazoline-derived alpha(1)-adrenoceptor antagonists in the benign and malignant prostate and their potential therapeutic use in the treatment of benign prostatic hyperplasia (BPH) and prostate cancer. Finally, a molecular pathway is proposed for their observed apoptotic function against prostate cells. Increased understanding of the action of these established and clinically accepted agents would provide a basis for the design of safe, effective therapeutic regimens in the treatment of prostatic diseases. PMID:12496995

  10. Toxicological Differences Between NMDA Receptor Antagonists and Cholinesterase Inhibitors.

    PubMed

    Shi, Xiaodong; Lin, Xiaotian; Hu, Rui; Sun, Nan; Hao, Jingru; Gao, Can

    2016-08-01

    Cholinesterase inhibitors (ChEIs), represented by donepezil, rivastigmine, and galantamine, used to be the only approved class of drugs for the treatment of Alzheimer's disease. After the approval of memantine by the Food and Drug Administration (FDA), N-methyl-d-aspartic acid (NMDA) receptor antagonists have been recognized by authorities and broadly used in the treatment of Alzheimer's disease. Along with complementary mechanisms of action, NMDA antagonists and ChEIs differ not only in therapeutic effects but also in adverse reactions, which is an important consideration in clinical drug use. And the number of patients using NMDA antagonists and ChEIs concomitantly has increased, making the matter more complicated. Here we used the FDA Adverse Event Reporting System for statistical analysis , in order to compare the adverse events of memantine and ChEIs. In general, the clinical evidence confirmed the safety advantages of memantine over ChEIs, reiterating the precautions of clinical drug use and the future direction of antidementia drug development. PMID:26769920

  11. Twisted Gastrulation, a BMP Antagonist, Exacerbates Podocyte Injury

    PubMed Central

    Yamada, Sachiko; Nakamura, Jin; Asada, Misako; Takase, Masayuki; Matsusaka, Taiji; Iguchi, Taku; Yamada, Ryo; Tanaka, Mari; Higashi, Atsuko Y.; Okuda, Tomohiko; Asada, Nariaki; Fukatsu, Atsushi; Kawachi, Hiroshi; Graf, Daniel; Muso, Eri; Kita, Toru; Kimura, Takeshi; Pastan, Ira; Economides, Aris N.; Yanagita, Motoko

    2014-01-01

    Podocyte injury is the first step in the progression of glomerulosclerosis. Previous studies have demonstrated the beneficial effect of bone morphogenetic protein 7 (Bmp7) in podocyte injury and the existence of native Bmp signaling in podocytes. Local activity of Bmp7 is controlled by cell-type specific Bmp antagonists, which inhibit the binding of Bmp7 to its receptors. Here we show that the product of Twisted gastrulation (Twsg1), a Bmp antagonist, is the central negative regulator of Bmp function in podocytes and that Twsg1 null mice are resistant to podocyte injury. Twsg1 was the most abundant Bmp antagonist in murine cultured podocytes. The administration of Bmp induced podocyte differentiation through Smad signaling, whereas the simultaneous administration of Twsg1 antagonized the effect. The administration of Bmp also inhibited podocyte proliferation, whereas simultaneous administration of Twsg1 antagonized the effect. Twsg1 was expressed in the glomerular parietal cells (PECs) and distal nephron of the healthy kidney, and additionally in damaged glomerular cells in a murine model of podocyte injury. Twsg1 null mice exhibited milder hypoalbuminemia and hyperlipidemia, and milder histological changes while maintaining the expression of podocyte markers during podocyte injury model. Taken together, our results show that Twsg1 plays a critical role in the modulation of protective action of Bmp7 on podocytes, and that inhibition of Twsg1 is a promising means of development of novel treatment for podocyte injury. PMID:24586548

  12. Client Perceptions of Two Antagonist Programs.

    ERIC Educational Resources Information Center

    Capone, Thomas A.; And Others

    1980-01-01

    Reports results of a questionnaire administered to participants in an antagonist drug outpatient clinic and an antagonist drug work-release program to obtain awareness of acceptance of the program participants. Naltrexone patients recommended an alternative method of administering the drug and changing the money system to award deserving inmates…

  13. Analysis of the characteristics of mouthguards that affect isokinetic muscular ability and anaerobic power

    PubMed Central

    Jung, Jae-Kwang; Chae, Woen-Sik

    2013-01-01

    PURPOSE The purpose of this study was to estimate the effects of occlusal stability to identify action mechanisms of mouthguards, known to have a modulatory effect on limb muscle function. MATERIALS AND METHODS This study included 20 male subjects to perform the isokinetic muscle tests and the Wingate anaerobic power test on both knee joints under five closed-mouth conditions: without or with 4 types of mouthguards with thickness of 2 mm based on premolar area: (1) full-coverage, (2) anterior partial-coverage, (3) right posterior partial-coverage, and (4) left posterior partial-coverage. The obtained results were subjected to One-way ANOVA with repeated measures, followed by post hoc test of the contrast method (α=.05). RESULTS There was no significant difference between the closed position with and without a full-coverage mouthguard in all variables. However, significant differences were observed between with and without a partial-coverage mouthguard in muscular endurance during extension of the left knee, muscular power and endurance during flexion of the right knee. Additionally, significant differences were found between occlusal states with full- and partial-coverage mouthguards in muscular power and endurance during extension of the left knee. CONCLUSION These findings indicate the elevation of vertical dimension by 2 mm or the inducement of occlusal stability had little effect on isokinetic muscle strength and anaerobic performance, while uneven distribution of occlusal force might have some positive effects. PMID:24353875

  14. Analgesic effectiveness of the narcotic agonist-antagonists

    PubMed Central

    Houde, Raymond W.

    1979-01-01

    1 Two fundamentally different types of narcotic-antogonists have been found to be very effective analgesics with relatively low dependence-producing potentials. 2 These two drug classes can be distinguished as being either morphine-like or nalorphine-like on the basis of their subjective and objective effects after single doses and on chronic administration, and by the character of their abstinence syndromes on abrupt withdrawal or on precipitation by other antagonists. 3 To explain differences in side effects associated with their analgesic actions, the existence of three types of receptors has been postulated: a μ receptor which is believed to be associated with euphoria and other typical morphine-like effects and a kappa (χ) and a sigma (σ) receptor which are believed to be associated with the sedative and psychotomimetic effects, respectively, of the nalorphine-like drugs. 4 The antagonist-analgesics of the morphine-type have the characteristics of being agonists of low intrinsic activity but with high affinity for the μ receptor. Representative analgesics of this type are profadol, propiram and buprenorphine. 5 The antagonist-analgesics of the nalorphine-type are drugs which are believed to have varying degrees of affinity and intrinsic activity at all three receptors, but characteristically seem to act merely as competitive antagonists with no intrinsic activity at the μ receptor. Representative analgesics of this type are pentazocine, nalbuphine and butorphanol. 6 There are considerable differences among the individual drugs of each type in terms of their analgesic and narcotic-antagonistic potencies. However, clear differences in analgesic efficacy among any of the antagonist-analgesics remain to be proved. All give evidence of being capable of relieving pain in nondependent patients in situations in which doses of morphine (or its surrogates) usually used would be effective. 7 The major advantages of the partial agonists of the morphine-type over the

  15. Dysphagia in Duchenne Muscular Dystrophy Assessed by Validated Questionnaire

    ERIC Educational Resources Information Center

    Archer, Sally K.; Garrod, Rachel; Hart, Nicholas; Miller, Simon

    2013-01-01

    Background: Duchenne muscular dystrophy (DMD) leads to progressive muscular weakness and death, most typically from respiratory complications. Dysphagia is common in DMD; however, the most appropriate swallowing assessments have not been universally agreed and the symptoms of dysphagia remain under-reported. Aims: To investigate symptoms of…

  16. Upper Body Muscular Endurance Among Children 2-5 Years.

    ERIC Educational Resources Information Center

    Gabbard, Carl P.; And Others

    The upper body muscular endurance of males and females 2-5 years of age was assessed, and relationships relative to sex, age, endurance and selected anthropometric measures were investigated. None of the relationships were found to be of practical predicative value; while upper body muscular strength increased with age, no significant differences…

  17. Systemic vascular function is associated with muscular power in adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Age-associated loss of muscular strength and muscular power are critical determinants of loss of physical function and progression to disability in older adults. In this study, we examined the association of systemic vascular function and measures of muscle strength and power in older adults. Measu...

  18. Emerging Drugs for Duchenne Muscular Dystrophy

    PubMed Central

    Malik, Vinod; Rodino-Klapac, Louise; Mendell, Jerry R.

    2012-01-01

    Introduction Duchenne muscular dystrophy (DMD) is the most common, severe childhood form of muscular dystrophy. Treatment is limited to glucocorticoids that have the benefit of prolonging ambulation by approximately 2 years and preventing scoliosis. Finding a more satisfactory treatment should focus on maintaining long-term efficacy with a minimal side effect profile. Areas covered Authors discuss different therapeutic strategies that have been used in pre-clinical and clinical settings. Expert opinion Multiple treatment approaches have emerged. Most attractive are molecular-based therapies that can express the missing dystrophin protein (exon skipping or mutation suppression) or a surrogate gene product (utrophin). Other approaches include increasing the strength of muscles (myostatin inhibitors), reducing muscle fibrosis, and decreasing oxidative stress. Additional targets include inhibiting NF-κB to reduce inflammation, or promoting skeletal muscle blood flow and muscle contractility using phosphodiesterase inhibitors or nitric oxide (NO) donors. The potential for each of these treatment strategies to enter clinical trials is a central theme of discussion. The review emphasizes that the goal of treatment should be to find a product at least as good as glucocorticoids with a lower side effect profile or with a significant glucocorticoid sparing effect. PMID:22632414

  19. Cardiac findings in congenital muscular dystrophies.

    PubMed

    Finsterer, Josef; Ramaciotti, Claudio; Wang, Ching H; Wahbi, Karim; Rosenthal, David; Duboc, Denis; Melacini, Paola

    2010-09-01

    Cardiac involvement (CI) in congenital muscular dystrophies (CMDs) has been only rarely investigated so far. By means of a systematic literature search we reviewed the literature about CI in CMD and found that CI is apparently absent in Ullrich CMD or CMD with integrin deficiency and only mild in Bethlem CMD. CI in merosin deficiency includes dilated cardiomyopathy and systolic dysfunction. CI in dystroglycanopathies seems most prevalent among all CMDs and includes dilated cardiomyopathy, systolic dysfunction, and myocardial fibrosis in Fukuyama CMD. Among the nonspecified dystroglycanopathies, CI manifests as dilated cardiomyopathy, hypertrophic cardiomyopathy (CMP) or systolic dysfunction. With CMD type 1C, as well as with limb-girdle muscular dystrophy 2I, up to half of the patients develop dilated cardiomyopathy. In rigid-spine syndrome, predominantly the right heart is affected secondary to thoracic deformity. In patients who carry LMNA mutations, CI may manifest as dilated cardiomyopathy, hypertrophic cardiomyopathy, or fatal ventricular arrhythmias. Overall, CI in patients with CMD varies considerably between the different CMD types from absent or mild CI to severe cardiac disease, particularly in merosin deficiency, dystroglycanopathies, and laminopathies. Patients with CMD with CI require regular cardiologic surveillance so that severe, treatable cardiac disease is not overlooked. PMID:20679303

  20. Upper Girdle Imaging in Facioscapulohumeral Muscular Dystrophy

    PubMed Central

    Tasca, Giorgio; Monforte, Mauro; Iannaccone, Elisabetta; Laschena, Francesco; Ottaviani, Pierfrancesco; Leoncini, Emanuele; Boccia, Stefania; Galluzzi, Giuliana; Pelliccioni, Marco; Masciullo, Marcella; Frusciante, Roberto; Mercuri, Eugenio; Ricci, Enzo

    2014-01-01

    Background In Facioscapulohumeral muscular dystrophy (FSHD), the upper girdle is early involved and often difficult to assess only relying on physical examination. Our aim was to evaluate the pattern and degree of involvement of upper girdle muscles in FSHD compared with other muscle diseases with scapular girdle impairment. Methods We propose an MRI protocol evaluating neck and upper girdle muscles. One hundred-eight consecutive symptomatic FSHD patients and 45 patients affected by muscular dystrophies and myopathies with prominent upper girdle involvement underwent this protocol. Acquired scans were retrospectively analyzed. Results The trapezius (100% of the patients) and serratus anterior (85% of the patients) were the most and earliest affected muscles in FSHD, followed by the latissimus dorsi and pectoralis major, whilst spinati and subscapularis (involved in less than 4% of the patients) were consistently spared even in late disease stages. Asymmetry and hyperintensities on short-tau inversion recovery (STIR) sequences were common features, and STIR hyperintensities could also be found in muscles not showing signs of fatty replacement. The overall involvement appears to be disease-specific in FSHD as it significantly differed from that encountered in the other myopathies. Conclusions The detailed knowledge of single muscle involvement provides useful information for correctly evaluating patients' motor function and to set a baseline for natural history studies. Upper girdle imaging can also be used as an additional tool helpful in supporting the diagnosis of FSHD in unclear situations, and may contribute with hints on the currently largely unknown molecular pathogenesis of this disease. PMID:24932477

  1. Proximal spinal muscular atrophy: current orthopedic perspective

    PubMed Central

    Haaker, Gerrit; Fujak, Albert

    2013-01-01

    Spinal muscular atrophy (SMA) is a hereditary neuromuscular disease of lower motor neurons that is caused by a defective “survival motor neuron” (SMN) protein that is mainly associated with proximal progressive muscle weakness and atrophy. Although SMA involves a wide range of disease severity and a high mortality and morbidity rate, recent advances in multidisciplinary supportive care have enhanced quality of life and life expectancy. Active research for possible treatment options has become possible since the disease-causing gene defect was identified in 1995. Nevertheless, a causal therapy is not available at present, and therapeutic management of SMA remains challenging; the prolonged survival is increasing, especially orthopedic, respiratory and nutritive problems. This review focuses on orthopedic management of the disease, with discussion of key aspects that include scoliosis, muscular contractures, hip joint disorders, fractures, technical devices, and a comparative approach of conservative and surgical treatment. Also emphasized are associated complications including respiratory involvement, perioperative care and anesthesia, nutrition problems, and rehabilitation. The SMA disease course can be greatly improved with adequate therapy with established orthopedic procedures in a multidisciplinary therapeutic approach. PMID:24399883

  2. Developments in gene therapy for muscular dystrophy.

    PubMed

    Hartigan-O'Connor, D; Chamberlain, J S

    Gene therapy for muscular dystrophy (MD) presents significant challenges, including the large amount of muscle tissue in the body, the large size of many genes defective in different muscular dystrophies, and the possibility of a host immune response against the therapeutic gene. Overcoming these challenges requires the development and delivery of suitable gene transfer vectors. Encouraging progress has been made in modifying adenovirus (Ad) vectors to reduce immune response and increase capacity. Recently developed gutted Ad vectors can deliver full-length dystrophin cDNA expression vectors to muscle tissue. Using muscle-specific promoters to drive dystrophin expression, a strong immune response has not been observed in mdx mice. Adeno-associated virus (AAV) vectors can deliver small genes to muscle without provocation of a significant immune response, which should allow long-term expression of several MD genes. AAV vectors have also been used to deliver sarcoglycan genes to entire muscle groups. These advances and others reviewed here suggest that barriers to gene therapy for MD are surmountable. PMID:10679969

  3. Congenital muscular dystrophy with inflammation: Diagnostic considerations

    PubMed Central

    Konkay, Kaumudi; Kannan, Meena Angamuthu; Lingappa, Lokesh; Uppin, Megha S.; Challa, Sundaram

    2016-01-01

    Background and Purpose: Muscle biopsy features of congenital muscular dystrophies (CMD) vary from usual dystrophic picture to normal or nonspecific myopathic picture or prominent fibrosis or striking inflammatory infiltrate, which may lead to diagnostic errors. A series of patients of CMD with significant inflammatory infiltrates on muscle biopsy were correlated with laminin α2 deficiency on immunohistochemistry (IHC). Material and Methods: Cryostat sections of muscle biopsies from the patients diagnosed as CMD on clinical and muscle biopsy features from 1996 to 2014 were reviewed with hematoxylin and eosin(H&E), enzyme and immunohistochemistry (IHC) with laminin α2. Muscle biopsies with inflammatory infiltrate were correlated with laminin α2 deficiency. Results: There were 65 patients of CMD, with inflammation on muscle biopsy in 16. IHC with laminin α2 was available in nine patients, of which six showed complete absence along sarcolemma (five presented with floppy infant syndrome and one with delayed motor milestones) and three showed discontinuous, and less intense staining. Conclusions: CMD show variable degrees of inflammation on muscle biopsy. A diagnosis of laminin α2 deficient CMD should be considered in patients of muscular dystrophy with inflammation, in children with hypotonia/delayed motor milestones. PMID:27570388

  4. Journey into muscular dystrophies caused by abnormal glycosylation.

    PubMed

    Muntoni, Francesco

    2004-09-01

    An increasing number of genes encoding for putative or demonstrated glycosyltransferases are being associated with muscular dystrophies of variable severity, ranging from severe congenital onset and associated structural eye and brain changes, to relatively mild forms with onset into adulthood. Five of these genes (POMT1; POMGnT1; FXRP; Fukutin; LARGE) encode for proteins involved in the glycosylation of alpha-dystroglycan and, indeed, abnormal glycosylation of this molecule is a common finding in all the respective conditions (Walker Warburg syndrome; Muscle-Eye-Brain disease; congenital muscular dystrophy type 1C and Limb girdle muscular dystrophy type 21; Fukuyama muscular dystrophy; congenital muscular dystrophy type 1D). A 6th gene, GNE, responsible for the hereditary form of inclusion body myositis, encodes for a glycosyltransferase the substrate(s) of which is, however, still unclear. This article provides an overview of the clinical, biochemical and genetic features of this group of disorders. PMID:15605948

  5. Social dominance orientation predicts drive for muscularity among British men.

    PubMed

    Swami, Viren; Neofytou, Rudolfos-Valentino; Jablonska, Joanna; Thirlwell, Holly; Taylor, Donna; McCreary, Donald R

    2013-09-01

    The present study tested the hypothesis that men's drive for muscularity would be associated with their valuation of domination, power, status, and aggression over others. A community sample of 359 men from London, UK, completed measures of drive for muscularity, social dominance orientation, right-wing authoritarianism, trait aggression, and need for power, as well as their demographic details. Bivariate correlations showed that greater drive for muscularity was significantly correlated with most of the measures and their subscales. However, in a multiple regression analysis, the only significant predictor of drive for muscularity was support for group-based dominance hierarchies (Adj. R(2)=.17). These results suggest that men's drive for muscularity is associated with a socio-political ideology that favours social dominance. PMID:23954197

  6. Consensus statement on standard of care for congenital muscular dystrophies.

    PubMed

    Wang, Ching H; Bonnemann, Carsten G; Rutkowski, Anne; Sejersen, Thomas; Bellini, Jonathan; Battista, Vanessa; Florence, Julaine M; Schara, Ulrike; Schuler, Pamela M; Wahbi, Karim; Aloysius, Annie; Bash, Robert O; Béroud, Christophe; Bertini, Enrico; Bushby, Kate; Cohn, Ronald D; Connolly, Anne M; Deconinck, Nicolas; Desguerre, Isabelle; Eagle, Michelle; Estournet-Mathiaud, Brigitte; Ferreiro, Ana; Fujak, Albert; Goemans, Nathalie; Iannaccone, Susan T; Jouinot, Patricia; Main, Marion; Melacini, Paola; Mueller-Felber, Wolfgang; Muntoni, Francesco; Nelson, Leslie L; Rahbek, Jes; Quijano-Roy, Susana; Sewry, Caroline; Storhaug, Kari; Simonds, Anita; Tseng, Brian; Vajsar, Jiri; Vianello, Andrea; Zeller, Reinhard

    2010-12-01

    Congenital muscular dystrophies are a group of rare neuromuscular disorders with a wide spectrum of clinical phenotypes. Recent advances in understanding the molecular pathogenesis of congenital muscular dystrophy have enabled better diagnosis. However, medical care for patients with congenital muscular dystrophy remains very diverse. Advances in many areas of medical technology have not been adopted in clinical practice. The International Standard of Care Committee for Congenital Muscular Dystrophy was established to identify current care issues, review literature for evidence-based practice, and achieve consensus on care recommendations in 7 areas: diagnosis, neurology, pulmonology, orthopedics/rehabilitation, gastroenterology/ nutrition/speech/oral care, cardiology, and palliative care. To achieve consensus on the care recommendations, 2 separate online surveys were conducted to poll opinions from experts in the field and from congenital muscular dystrophy families. The final consensus was achieved in a 3-day workshop conducted in Brussels, Belgium, in November 2009. This consensus statement describes the care recommendations from this committee. PMID:21078917

  7. Construction, purification, and characterization of a chimeric TH1 antagonist

    PubMed Central

    Bello-Rivero, Iraldo; Torrez-Ruiz, Yeny; Blanco-Garcés, Elizabeth; Pentón-Rol, Giselle; Fernández-Batista, Osmani; Javier-González, Luís; Gerónimo-Perez, Haydee; López-Saura, Pedro

    2006-01-01

    Background TH1 immune response antagonism is a desirable approach to mitigate some autoimmune and inflammatory reactions during the course of several diseases where IL-2 and IFN-γ are two central players. Therefore, the neutralization of both cytokines could provide beneficial effects in patients suffering from autoimmune or inflammatory illnesses. Results A chimeric antagonist that can antagonize the action of TH1 immunity mediators, IFN-γ and IL-2, was designed, engineered, expressed in E. coli, purified and evaluated for its in vitro biological activities. The TH1 antagonist molecule consists of the extracellular region for the human IFNγ receptor chain 1 fused by a four-aminoacid linker peptide to human 60 N-terminal aminoacid residues of IL-2. The corresponding gene fragments were isolated by RT-PCR and cloned in the pTPV-1 vector. E. coli (W3110 strain) was transformed with this vector. The chimeric protein was expressed at high level as inclusion bodies. The protein was partially purified by pelleting and washing. It was then solubilized with strong denaturant and finally refolded by gel filtration. In vitro biological activity of chimera was demonstrated by inhibition of IFN-γ-dependent HLA-DR expression in Colo 205 cells, inhibition of IFN-γ antiproliferative effect on HEp-2 cells, and by a bidirectional effect in assays for IL-2 T-cell dependent proliferation: agonism in the absence versus inhibition in the presence of IL-2. Conclusion TH1 antagonist is a chimeric protein that inhibits the in vitro biological activities of human IFN-γ, and is a partial agonist/antagonist of human IL-2. With these attributes, the chimera has the potential to offer a new opportunity for the treatment of autoimmune and inflammatory diseases. PMID:16716222

  8. NMDA antagonist properties of the putative antiaddictive drug, ibogaine.

    PubMed

    Popik, P; Layer, R T; Fossom, L H; Benveniste, M; Geter-Douglass, B; Witkin, J M; Skolnick, P

    1995-11-01

    Both anecdotal reports in humans and preclinical studies indicate that ibogaine interrupts addiction to a variety of abused substances including alcohol, opiates, nicotine and stimulants. Based on the similarity of these therapeutic claims to recent preclinical studies demonstrating that N-methyl-D-aspartate (NMDA) antagonists attenuate addiction-related phenomena, we examined the NMDA antagonist properties of ibogaine. Pharmacologically relevant concentrations of ibogaine produce a voltage-dependent block of NMDA receptors in hippocampal cultures (Ki, 2.3 microM at -60 mV). Consistent with this observation, ibogaine competitively inhibits [3H]1-[1-(2-thienyl)-cyclohexyl]piperidine binding to rat forebrain homogenates (Ki, 1.5 microM) and blocks glutamate-induced cell death in neuronal cultures (IC50, 4.5 microM). Moreover, at doses previously reported to interfere with drug-seeking behaviors, ibogaine substitutes as a discriminative stimulus (ED50, 64.9 mg/kg) in mice trained to discriminate the prototypic voltage-dependent NMDA antagonist, dizocilpine (0.17 mg/kg), from saline. Consistent with previous reports, ibogaine reduced naloxone-precipitated jumping in morphine-dependent mice (ED50, 72 mg/kg). Although pretreatment with glycine did not affect naloxone-precipitated jumping in morphine-dependent mice, it abolished the ability of ibogaine to block naloxone-precipitated jumping. Taken together, these findings link the NMDA antagonist actions of ibogaine to a putative "antiaddictive" property of this alkaloid, its ability to reduce the expression of morphine dependence. PMID:7473163

  9. Pulmonary vascular reactivity: effect of PAF and PAF antagonists.

    PubMed

    Chen, C R; Voelkel, N F; Chang, S W

    1992-11-01

    We investigated the effects of two different platelet-activating factor (PAF) antagonists, SRI 63-441 and WEB 2086, on PAF-, angiotensin II-, and hypoxia-induced vasoconstrictions in isolated rat lungs perfused with a physiological salt solution. Bolus injection of PAF (0.5 micrograms) increased pulmonary arterial and microvascular pressures and caused lung edema. Both SRI 63-441, a PAF-analogue antagonist, and WEB 2086, a thienotriazolodiazepine structurally unrelated to PAF, completely blocked PAF-induced vasoconstriction and lung edema at 10(-5) M. At a lower concentration (10(-6) M), WEB 2086 was more effective than SRI 63-441. WEB 2086 also blocked the pulmonary vasodilation induced by low-dose PAF (15 ng) in blood-perfused lungs preconstricted with hypoxia. SRI 63-441 and CV 3988 (another PAF analogue antagonist), but not WEB 2086, caused acute pulmonary vasoconstriction at 10(-5) M and severe lung edema at a higher concentration (10(-4) M). PAF-induced but not SRI- or CV-induced pulmonary vasoconstriction and edema were inhibited by WEB 2086. In addition, SRI 63-441 potentiated angiotensin II- and hypoxia-induced vasoconstrictions. This effect of SRI 63-441 is not due to PAF receptor blockade because 1) addition of PAF (1.6 nM) to the perfusate likewise potentiated angiotensin II-induced vasoconstriction and 2) WEB 2086 did not cause a similar response. We conclude that both SRI 63-441 and WEB 2086 are effective inhibitors of PAF actions in the rat pulmonary circulation. However, antagonists with structures analogous to PAF (SRI 63-441 and CV 3988) can have significant pulmonary vasoactive side effects. PMID:1474049

  10. New H1/H3 antagonists for treating allergic rhinitis: WO2010094643.

    PubMed

    Norman, Peter

    2011-03-01

    This application claims dual receptor specificity antihistamines, active as H(1) and H(3) antagonists, which additionally have a long duration of action that renders them suitable for once daily administration via inhalation for the treatment of allergic rhinitis. The compounds lack CNS penetration and have a high affinity for both histamine receptors. PMID:21342057

  11. Autonomic, locomotor and cardiac abnormalities in a mouse model of muscular dystrophy: targeting the renin-angiotensin system.

    PubMed

    Sabharwal, Rasna; Chapleau, Mark W

    2014-04-01

    New Findings What is the topic of this review? This symposium report summarizes autonomic, cardiac and skeletal muscle abnormalities in sarcoglycan-δ-deficient mice (Sgcd-/-), a mouse model of limb girdle muscular dystrophy, with emphasis on the roles of autonomic dysregulation and activation of the renin-angiotensin system at a young age. What advances does it highlight? The contributions of the autonomic nervous system and the renin-angiotensin system to the pathogenesis of muscular dystrophy are highlighted. Results demonstrate that autonomic dysregulation precedes and predicts later development of cardiac dysfunction in Sgcd-/- mice and that treatment of young Sgcd-/- mice with the angiotensin type 1 receptor antagonist losartan or with angiotensin-(1-7) abrogates the autonomic dysregulation, attenuates skeletal muscle pathology and increases spontaneous locomotor activity. Muscular dystrophies are a heterogeneous group of genetic muscle diseases characterized by muscle weakness and atrophy. Mutations in sarcoglycans and other subunits of the dystrophin-glycoprotein complex cause muscular dystrophy and dilated cardiomyopathy in animals and humans. Aberrant autonomic signalling is recognized in a variety of neuromuscular disorders. We hypothesized that activation of the renin-angiotensin system contributes to skeletal muscle and autonomic dysfunction in mice deficient in the sarcoglycan-δ (Sgcd) gene at a young age and that this early autonomic dysfunction contributes to the later development of left ventricular (LV) dysfunction and increased mortality. We demonstrated that young Sgcd-/- mice exhibit histopathological features of skeletal muscle dystrophy, decreased locomotor activity and severe autonomic dysregulation, but normal LV function. Autonomic regulation continued to deteriorate in Sgcd-/- mice with age and was accompanied by LV dysfunction and dilated cardiomyopathy at older ages. Autonomic dysregulation at a young age predicted later development of

  12. Shift of the Muscular Inhibition Latency during On-Line Acquisition of Anticipatory Postural Adjustments

    PubMed Central

    Barlaam, Fanny; Vaugoyeau, Marianne; Fortin, Carole; Assaiante, Christine; Schmitz, Christina

    2016-01-01

    During action, Anticipatory Postural Adjustments (APAs) cancel the consequences of a movement on postural stabilization. Their muscular expression is characterized by early changes in the activity of the postural muscles, before the movement begins. To explore the mechanisms enabling the acquisition of APAs, a learning paradigm was designed in which the voluntary lifting of a load with one hand triggered the unloading of another load suspended below the contralateral forearm. The aim of this study was to investigate changes in the muscular expression that uncovers the progressive learning of new APAs. A trial-by-trial analysis of kinematic and electromyographic signals recorded on the right arm was conducted in twelve adults through six sessions of learning. Kinematic results reported an enhancement of the postural stabilization across learning. The main EMG pattern found during learning consisted of a flexor inhibition, where latency was shifted towards an earlier occurrence in parallel with the improvement of the postural performance. A linear regression analysis conducted between the inhibition latency and the maximal amplitude of elbow rotation showed that the earlier the inhibition onset, the better the postural stabilization. This study revealed that the progressive shift of the postural flexor inhibition latency could be considered as a reliable neurophysiological marker of the progressive learning of new APAs. Importantly, this marker could be used to track motor learning abnormalities in pathology. We relate our findings to the update of a forward predictive model of action, defined as a system that predicts beforehand the consequences of the action on posture. PMID:27192604

  13. Optimization of Spinal Muscular Atrophy subject's muscle activity during gait

    NASA Astrophysics Data System (ADS)

    Umat, Gazlia; Rambely, Azmin Sham

    2014-06-01

    Spinal Muscular Atrophy (SMA) is a hereditary disease related muscle nerve disorder caused by degeneration of the anterior cells of the spinal cord. SMA is divided into four types according to the degree of seriousness. SMA patients show different gait with normal people. Therefore, this study focused on the effects of SMA patient muscle actions and the difference that exists between SMA subjects and normal subjects. Therefore, the electromyography (EMG) test will be used to track the behavior of muscle during walking and optimization methods are used to get the muscle stress that is capable of doing the work while walking. Involved objective function is non-linear function of the quadratic and cubic functions. The study concludes with a comparison of the objective function using the force that sought to use the moment of previous studies and the objective function using the data obtained from EMG. The results shows that the same muscles, peroneus longus and bisepsfemoris, were used during walking activity by SMA subjects and control subjects. Muscle stress force best solution achieved from part D in simulation carried out.

  14. Molecular Gymnastics: Mechanisms of HIV-1 Resistance to CCR5 Antagonists and Impact on Virus Phenotypes.

    PubMed

    Roche, Michael; Borm, Katharina; Flynn, Jacqueline K; Lewin, Sharon R; Churchill, Melissa J; Gorry, Paul R

    2016-01-01

    Human immunodeficiency virus type 1 (HIV-1) enters host cells through the binding of its envelope glycoproteins (Env) to the host cell receptor CD4 and then subsequent binding to a chemokine coreceptor, either CCR5 or CXCR4. CCR5 antagonists are a relatively recent class addition to the armamentarium of anti-HIV-1 drugs. These compounds act by binding to a hydrophobic pocket formed by the transmembrane helices of CCR5 and altering the conformation of the extracellular domains, such that they are no longer recognized by Env. Maraviroc is the first drug within this class to be licenced for use in HIV-1 therapy regimens. HIV resistance to CCR5 antagonists occurs either through outgrowth of pre-existing CXCR4-using viruses, or through acquisition of the ability of CCR5-using HIV-1 to use the antagonist bound form of CCR5. In the latter scenario, the mechanism underlying resistance is through complex alterations in the way that resistant Envs engage CCR5. These significant changes are unlikely to occur without consequence to the viral entry phenotype and may also open up new avenues to target CCR5 antagonist resistant viruses. This review discusses the mechanism of action of CCR5 antagonists, how HIV resistance to CCR5 antagonists occurs, and the subsequent effects on Env function. PMID:26324043

  15. Novel benzamide-based histamine h3 receptor antagonists: the identification of two candidates for clinical development.

    PubMed

    Letavic, Michael A; Aluisio, Leah; Apodaca, Richard; Bajpai, Manoj; Barbier, Ann J; Bonneville, Anne; Bonaventure, Pascal; Carruthers, Nicholas I; Dugovic, Christine; Fraser, Ian C; Kramer, Michelle L; Lord, Brian; Lovenberg, Timothy W; Li, Lilian Y; Ly, Kiev S; Mcallister, Heather; Mani, Neelakandha S; Morton, Kirsten L; Ndifor, Anthony; Nepomuceno, S Diane; Pandit, Chennagiri R; Sands, Steven B; Shah, Chandra R; Shelton, Jonathan E; Snook, Sandra S; Swanson, Devin M; Xiao, Wei

    2015-04-01

    The preclinical characterization of novel phenyl(piperazin-1-yl)methanones that are histamine H3 receptor antagonists is described. The compounds described are high affinity histamine H3 antagonists. Optimization of the physical properties of these histamine H3 antagonists led to the discovery of several promising lead compounds, and extensive preclinical profiling aided in the identification of compounds with optimal duration of action for wake promoting activity. This led to the discovery of two development candidates for Phase I and Phase II clinical trials. PMID:25893048

  16. Novel Benzamide-Based Histamine H3 Receptor Antagonists: The Identification of Two Candidates for Clinical Development

    PubMed Central

    2015-01-01

    The preclinical characterization of novel phenyl(piperazin-1-yl)methanones that are histamine H3 receptor antagonists is described. The compounds described are high affinity histamine H3 antagonists. Optimization of the physical properties of these histamine H3 antagonists led to the discovery of several promising lead compounds, and extensive preclinical profiling aided in the identification of compounds with optimal duration of action for wake promoting activity. This led to the discovery of two development candidates for Phase I and Phase II clinical trials. PMID:25893048

  17. [Statin intolerance and associated muscular dysfunctions].

    PubMed

    Boulanger-Piette, Antoine; Bergeron, Jean; Desgreniers, Joël; Côté-Levesque, Michèle; Brassard, Dominic; Joanisse, Denis R; Frenette, Jérôme

    2015-12-01

    Hypercholesterolemia is a major risk factor for cardiovascular diseases. The 2012-2013 survey of Canada's public health measures revealed that dyslipidemia was present in 38% of the respondents aged between 18 and 79 years. According to the American College of Cardiology, the American Heart Association, the Canadian Cardiovascular Society and the Canadian Working Group Consensus, statins remain the treatment of choice for dyslipidemia and the reduction of cardiovascular risk. However, concerns and questions persist regarding statins use and safety, potential and harmful muscular side-effects, interactions with exercise, and molecular mechanisms of myotoxicity. The goal of the present review is to provide a clear picture of the clinical situation and to investigate possible mechanisms of statin-induced myopathy. A better understanding of muscle pathology in statin users is absolutely essential to minimize their muscle symptoms and to provide a sound clinical basis for the management of cardiovascular risk. PMID:26672664

  18. [Vitamin D: skeletal and muscular effects].

    PubMed

    Thomas, Thierry; Briot, Karine

    2013-10-01

    Insufficient serum levels of 25-hydroxyvitamin D [25(OH)D] is a risk factor for osteoporosis. A new paradigm is emerging with the locally synthesized 1,25(OH)2D within osteoblasts and osteoclasts as the essential pathway for the effects of 25(OH)D in regulating bone remodeling via direct or indirect activation of the specific receptor VDR. Vitamin D has positive effects on fracture risk, muscular function and risk of falls; these effects are observed when serum levels of 25(OH)D are above 30 ng/ml (75 nmol/l). Vitamin D dosing interval may be relevant for reducing the risk of fracture, with evidence suggesting positive effects with short intervals of 3 months or less. It is recommended to maintain an optimal serum level of 25(OH)D when managing patients with osteoporosis or at risk of this bone disease. PMID:24054764

  19. Oculopharyngeal muscular dystrophy: a polyalanine myopathy.

    PubMed

    Brais, Bernard

    2009-01-01

    It has been 10 years since the identification of the first PABPN1 gene (GCN)(n)/polyalanine mutations responsible for oculopharyngeal muscular dystrophy (OPMD). These mutations have been found in most cases of OPMD diagnosed in more than 35 countries. Sequence analyses have shown that such mutations have occurred numerous times in human history. Although PABPN1 was found early on to be a component of the classic filamentous intranuclear inclusions (INIs), mRNA and other proteins also have been found to coaggregate in the INIs. It is still unclear if the INIs play a pathologic or a protective role. The generation of numerous cell and animal models of OPMD has led to greater insight into its complex molecular pathophysiology and identified the first candidate therapeutic molecules. This paper reviews basic and clinical research on OPMD, with special emphasis on recent developments in the understanding of its pathophysiology. PMID:19080757

  20. Congenital muscular torticollis and positional plagiocephaly.

    PubMed

    Kuo, Alice A; Tritasavit, Sophie; Graham, John M

    2014-02-01

    On the basis of observational studies, child health practitioners in primary care settings should consider the diagnosis of congenital muscular torticollis (CMT)in infants with risk factors from birth history for intrauterine malpositioning or constraint (C). On the basis of observational studies, CMT is often associated with other conditions, including positional plagiocephaly and gross motor delays from weakened truncal muscles and/or lack of head control in early infancy (C). On the basis of observational studies, child health practitioners should counsel parents that infants should be on their stomachs frequently whenever they are awake and under direct adult supervision to develop their prone motor skills (C). On the basis of consensus, early identification of CMT(with or without positional plagiocephaly) and prompt referral to a physical therapist experienced in the treatment of CMT should be considered to avoid more costly or invasive treatments, such as cranial orthoses or surgery (D). PMID:24488831

  1. Congenital Muscular Dystrophies: A Brief Review

    PubMed Central

    Bertini, Enrico; D'Amico, Adele; Gualandi, Francesca; Petrini, Stefania

    2011-01-01

    Congenital muscular dystrophies (CMDs) are clinically and genetically heterogeneous neuromuscular disorders with onset at birth or in infancy in which the muscle biopsy is compatible with a dystrophic myopathy. In the past 10 years, knowledge of neuromuscular disorders has dramatically increased, particularly with the exponential boost of disclosing the genetic background of CMDs. This review will highlight the clinical description of the most important forms of CMD, paying particular attention to the main keys for diagnostic approach. The diagnosis of CMDs requires the concurrence of expertise in multiple specialties (neurology, morphology, genetics, neuroradiology) available in a few centers worldwide that have achieved sufficient experience with the different CMD subtypes. Currently, molecular diagnosis is of paramount importance not only for phenotype-genotype correlations, genetic and prenatal counseling, and prognosis and aspects of management, but also concerning the imminent availability of clinical trials and treatments. PMID:22172424

  2. [Fukuyama congenital muscular dystrophy and related alpha-dystroglycanopathies].

    PubMed

    Murakami, Terumi; Nishino, Ichizo

    2008-10-01

    Alpha-dystroglycan (alpha-DG) is a glycoprotein that binds to laminin in the basal lamina and helps provide mechanical support. A group of muscular dystrophies are caused by glycosylation defects of alpha-DG and are hence collectively called alpha-dystroglycanopathy (alpha-DGP). Alpha-DGP is clinically characterized by a combination of muscular dystrophies, structural brain anomalies, and ocular involvement. So far, 6 causative genes have been identified: LARGE, POMGNT1, POMT1, POMT2, FKRP, and FKTN. Initially, alpha-DGP was classified under congenital muscular dystrophies; however, the clinical phenotype is now expanded to include a markedly wide spectrum ranging from the most severe, lethal congenital muscular dystrophy with severe brain deformity to the mildest limb girdle muscular dystrophy with minimal muscle weakness. This is exemplified by Fukuyama congenital muscular dystrophy (FCMD), which is the most prevalent alpha-DGP in Japan, and is caused by mutations in FKTN. FCMD is clinically characterized by a triad of mental retardation, brain deformities, and congenital muscular dystrophy, and a majority of FCMD patients have a homozygous 3-kb retrotransposal insertion in the 3'non-coding region. Typically, they are able to sit but never attain independent ambulation in their lives. Recently, a patient from Turkey harboring homozygous 1-bp insertion reportedly showed a severe brain deformity with hydrocephalus and died 10 days after birth. In contrast, the mildest FKTN phenotype, LGMD2L, was identified in 6 cases from 4 families in Japan. These patients harbored compound heterozygous mutation with 3-kb retrotransposal insertion in the 3'non-coding region and a novel missense mutation in the coding region. Clinically, these patients presented with minimal muscle weakness and dilated cardiomyopathy and had normal intelligence. These data clearly indicate that FKTN mutations can cause a broad spectrum of muscular dystrophies. Therefore, clinicians should always

  3. [MD-NET--muscular dystrophy network].

    PubMed

    Lochmüller, H; Straub, V

    2007-12-01

    Muscular dystrophies (MD) constitute a group of inherited disorders characterized by progressive weakness of skeletal and sometimes cardiac muscle. MD are rare disorders affecting approximately 26,000 to 40,000 people in Germany based on a pre valence of 1:2000 to 1:3000 (estimate of the Association Française contre les Myopathies, AFM) and a population of 80 million people residing in Germany. More than 30 forms of MD are recognized today caused by different genetic defects. Based on the symptoms of an individual patient the underlying genetic defect cannot be determined, since all MD have the following in common: Muscle fibers are destroyed and become replaced by fatty and fibrous tissue. Various forms of MD are caused by defects of proteins residing in the sarcolemma, the cell membrane of muscle fibers. Other forms are caused by defects of proteins that are associated to the nucleus, to the sarcomer or the cytoplasm. Moreover, there are numerous forms where the exact molecular defect is unknown to date. Even though the underlying defect is known for many MD, the pathogenic process that leads to the decay of musculature is poorly understood. At present, MD cannot be cured. MD are treated by physiotherapy, surgery and medication that may delay progression. Symptomatic therapy such as cardiac pace makers may be life-saving and improve quality of life in many patients. For optimizing research into the MD, a network, the muscular dystrophy network or MD-NET, was initiated and has been supported by the German ministry of education and research (BMBF) since 2003. PMID:18026885

  4. Porcine Models of Muscular Dystrophy1

    PubMed Central

    Selsby, Joshua T.; Ross, Jason W.; Nonneman, Dan; Hollinger, Katrin

    2015-01-01

    Duchenne muscular dystrophy is a progressive, fatal, X-linked disease caused by a failure to accumulate the cytoskeletal protein dystrophin. This disease has been studied using a variety of animal models including fish, mice, rats, and dogs. While these models have contributed substantially to our mechanistic understanding of the disease and disease progression, limitations inherent to each model have slowed the clinical advancement of therapies, which necessitates the development of novel large-animal models. Several porcine dystrophin-deficient models have been identified, although disease severity may be so severe as to limit their potential contributions to the field. We have recently identified and completed the initial characterization of a natural porcine model of dystrophin insufficiency. Muscles from these animals display characteristic focal necrosis concomitant with decreased abundance and localization of dystrophin-glycoprotein complex components. These pigs recapitulate many of the cardinal features of muscular dystrophy, have elevated serum creatine kinase activity, and preliminarily appear to display altered locomotion. They also suffer from sudden death preceded by EKG abnormalities. Pig dystrophinopathy models could allow refinement of dosing strategies in human-sized animals in preparation for clinical trials. From an animal handling perspective, these pigs can generally be treated normally, with the understanding that acute stress can lead to sudden death. In summary, the ability to create genetically modified pig models and the serendipitous discovery of genetic disease in the swine industry has resulted in the emergence of new animal tools to facilitate the critical objective of improving the quality and length of life for boys afflicted with such a devastating disease. PMID:25991703

  5. Left-Shifted Nav Channels in Injured Bilayer: Primary Targets for Neuroprotective Nav Antagonists?

    PubMed Central

    Morris, Catherine E.; Boucher, Pierre-Alexandre; Joós, Béla

    2012-01-01

    Mechanical, ischemic, and inflammatory injuries to voltage-gated sodium channel (Nav)-rich membranes of axon initial segments and nodes of Ranvier render Nav channels dangerously leaky. By what means? The behavior of recombinant Nav1.6 (Wang et al., 2009) leads us to postulate that, in neuropathologic conditions, structural degradation of axolemmal bilayer fosters chronically left-shifted Nav channel operation, resulting in ENa rundown. This “sick excitable cell Nav-leak” would encompass left-shifted fast- and slow-mode based persistent INa (i.e., Iwindow and slow-inactivating INa). Bilayer-damage-induced electrophysiological dysfunctions of native-Nav channels, and effects on inhibitors on those channels, should, we suggest, be studied in myelinated axons, exploiting INa(V,t) hysteresis data from sawtooth ramp clamp. We hypothesize that (like dihydropyridines for Ca channels), protective lipophilic Nav antagonists would partition more avidly into disorderly bilayers than into the well-packed bilayers characteristic of undamaged, healthy plasma membrane. Whereas inhibitors using aqueous routes would access all Navs equally, differential partitioning into “sick bilayer” would co-localize lipophilic antagonists with “sick-Nav channels,” allowing for more specific targeting of impaired cells. Molecular fine-tuning of Nav antagonists to favor more avid partitioning into damaged than into intact bilayers could reduce side effects. In potentially salvageable neurons of traumatic and/or ischemic penumbras, in inflammatory neuropathies, in muscular dystrophy, in myocytes of cardiac infarct borders, Nav-leak driven excitotoxicity overwhelms cellular repair mechanisms. Precision-tuning of a lipophilic Nav antagonist for greatest efficacy in mildly damaged membranes could render it suitable for the prolonged continuous administration needed to allow for the remodeling of the excitable membranes, and thus functional recovery. PMID:22375118

  6. Plant Evolution: Evolving Antagonistic Gene Regulatory Networks.

    PubMed

    Cooper, Endymion D

    2016-06-20

    Developing a structurally complex phenotype requires a complex regulatory network. A new study shows how gene duplication provides a potential source of antagonistic interactions, an important component of gene regulatory networks. PMID:27326708

  7. Benzodiazepinone Derivatives as CRTH2 Antagonists.

    PubMed

    Liu, Jiwen Jim; Cheng, Alan C; Tang, H Lucy; Medina, Julio C

    2011-07-14

    Multiple CRTH2 antagonists are currently evaluated in human clinical trials for asthma and chronic obstructive pulmonary disease (COPD). During our lead optimization for CRTH2 antagonists, an observation of an intramolecular hydrogen bond in ortho-phenylsulfonamido benzophenone derivatives led to the design and synthesis of conformationally constrained benzodiazepinones as potent CRTH2 antagonists. The benzodiazepinones are 2 orders of magnitude more potent than the original flexible bisaryl ethers in our binding assay. Selected benzodiazepinones, such as compound 6, were also potent in the human eosinophil shape change assay. Analysis of the rigid conformations of these benzodiazepinones and ortho-phenylsulfonamido benzophenones provided an explanation for the structure-activity relationship and revealed the possible bound conformations to CRTH2, which may be useful for building a pharmacophore model of CRTH2 antagonists. PMID:24900341

  8. Benign muscular dystrophy: risk calculation in families with consanguinity.

    PubMed Central

    Wolff, G; Müller, C R; Grimm, T

    1989-01-01

    This report concerns two families in which the index patients are sporadic cases of a benign form of muscular dystrophy. In both families the sisters of the patients have married a close relative. The respective risks for a child of these consanguineous marriages being affected with either X linked Becker muscular dystrophy or autosomal recessive limb girdle muscular dystrophy is calculated using pedigree information, results of serum creatine kinase determinations, and also, in one family, results of DNA typing using RFLPs from the short arm of the X chromosome. PMID:2732990

  9. Birdshot chorioretinopathy in a male patient with facioscapulohumeral muscular dystrophy.

    PubMed

    Papavasileiou, Evangelia; Lobo, Ann-Marie

    2015-01-01

    We report a case of birdshot chorioretinopathy (BSCR) in a patient with facioscapulohumeral muscular dystrophy (FSHD). A 40-year-old male with history of facioscapulohumeral muscular dystrophy with significant facial diplegia and lagophthalmos presents for an evaluation of bilateral choroiditis with vasculitis and optic disc edema. Clinical examination included fundus and autofluorescence photographs, fluorescein angiography, and optical coherence tomography. To our knowledge, this patient represents the first reported case of birdshot chorioretinopathy with facioscapulohumeral muscular dystrophy. Patients with FSHD can present with ocular findings and should be screened with dilated fundus examinations for retinal vascular changes and posterior uveitis. PMID:25861398

  10. Tetrahydroquinoline derivatives as opioid receptor antagonists.

    PubMed

    Zhang, Cunyu; Westaway, Susan M; Speake, Jason D; Bishop, Michael J; Goetz, Aaron S; Carballo, Luz Helena; Hu, Mike; Epperly, Andrea H

    2011-01-15

    Opioid receptors play an important role in both behavioral and homeostatic functions. We herein report tetrahydroquinoline derivatives as opioid receptor antagonists. SAR studies led to the identification of the potent antagonist 2v, endowed with 1.58nM (K(i)) functional activity against the μ opioid receptor. DMPK data suggest that novel tetrahydroquinoline analogs may be advantageous in peripheral applications. PMID:21193310

  11. Genetics Home Reference: limb-girdle muscular dystrophy

    MedlinePlus

    ... most common form of limb-girdle muscular dystrophy , accounting for about 30 percent of cases. Dysferlinopathy, also ... be inherited? More about Inheriting Genetic Conditions Diagnosis & Management These resources address the diagnosis or management of ...

  12. Efficacy of bipolar release in neglected congenital muscular torticollis patients.

    PubMed

    Seyhan, Nevra; Jasharllari, Lorenc; Keskin, Mustafa; Savacı, Nedim

    2012-06-01

    Surgical correction of the congenital muscular torticollis (CMT) is recommended for patients with unsuccessful conservative treatment. The aim of this study is to evaluate the efficacy of surgical release of congenital muscular torticollis in neglected cases. We retrospectively evaluated the data of our patients in terms of age, sex, clinical presentation, localization of the lesion, diagnostic tests, and additional abnormalities. The age at operation ranged from 6 to 23 years. Complete muscular release as determined by pre-operative and postoperative range of motion measurements was achieved in all of the patients by bipolar release. In this study, neck motion and head tilt showed marked improvement with surgical treatment in cases with CMT who were admitted to the hospital lately. Congenital muscular torticollis patients can benefit from surgical intervention above the age of 5. Bipolar release is an adequate and complication-free method. PMID:22045346

  13. Identification of spirooxindole and dibenzoxazepine motifs as potent mineralocorticoid receptor antagonists.

    PubMed

    Lotesta, Stephen D; Marcus, Andrew P; Zheng, Yajun; Leftheris, Katerina; Noto, Paul B; Meng, Shi; Kandpal, Geeta; Chen, Guozhou; Zhou, Jing; McKeever, Brian; Bukhtiyarov, Yuri; Zhao, Yi; Lala, Deepak S; Singh, Suresh B; McGeehan, Gerard M

    2016-03-15

    Mineralocorticoid receptor (MR) antagonists continue to be a prevalent area of research in the pharmaceutical industry. Herein we report the discovery of various spirooxindole and dibenzoxazepine constructs as potent MR antagonists. SAR analysis of our spirooxindole hit led to highly potent compounds containing polar solubilizing groups, which interact with the helix-11 region of the MR ligand binding domain (LBD). Various dibenzoxazepine moieties were also prepared in an effort to replace a known dibenzoxepane system which interacts with the hydrophobic region of the MR LBD. In addition, an X-ray crystal structure was obtained from a highly potent compound which was shown to exhibit both partial agonist and antagonist modes of action against MR. PMID:26897089

  14. Cardiac involvement in Duchenne and Becker muscular dystrophy

    PubMed Central

    Mavrogeni, Sophie; Markousis-Mavrogenis, George; Papavasiliou, Antigoni; Kolovou, Genovefa

    2015-01-01

    Duchenne and Becker muscular dystrophy (DMD/BMD) are X-linked muscular diseases responsible for over 80% of all muscular dystrophies. Cardiac disease is a common manifestation, not necessarily related to the degree of skeletal myopathy; it may be the predominant manifestation with or without any other evidence of muscular disease. Death is usually due to ventricular dysfunction, heart block or malignant arrhythmias. Not only DMD/BMD patients, but also female carriers may present cardiac involvement. Clinically overt heart failure in dystrophinopathies may be delayed or absent, due to relative physical inactivity. The commonest electrocardiographic findings include conduction defects, arrhythmias (supraventricular or ventricular), hypertrophy and evidence of myocardial necrosis. Echocardiography can assess a marked variability of left ventricular dysfunction, independently of age of onset or mutation groups. Cardiovascular magnetic resonance (CMR) has documented a pattern of epicardial fibrosis in both dystrophinopathies’ patients and carriers that can be observed even if overt muscular disease is absent. Recently, new CMR techniques, such as postcontrast myocardial T1 mapping, have been used in Duchenne muscular dystrophy to detect diffuse myocardial fibrosis. A combined approach using clinical assessment and CMR evaluation may motivate early cardioprotective treatment in both patients and asymptomatic carriers and delay the development of serious cardiac complications. PMID:26225202

  15. Cardiac function in muscular dystrophy associates with abdominal muscle pathology

    PubMed Central

    Gardner, Brandon B.; Swaggart, Kayleigh A.; Kim, Gene; Watson, Sydeaka; McNally, Elizabeth M.

    2015-01-01

    Background The muscular dystrophies target muscle groups differentially. In mouse models of muscular dystrophy, notably the mdx model of Duchenne Muscular Dystrophy, the diaphragm muscle shows marked fibrosis and at an earlier age than other muscle groups, more reflective of the histopathology seen in human muscular dystrophy. Methods Using a mouse model of limb girdle muscular dystrophy, the Sgcg mouse, we compared muscle pathology across different muscle groups and heart. A cohort of nearly 200 Sgcg mice were studied using multiple measures of pathology including echocardiography, Evans blue dye uptake and hydroxyproline content in multiple muscle groups. Spearman rank correlations were determined among echocardiographic and pathological parameters. Findings The abdominal muscles were found to have more fibrosis than other muscle groups, including the diaphragm muscle. The abdominal muscles also had more Evans blue dye uptake than other muscle groups. The amount of diaphragm fibrosis was found to correlate positively with fibrosis in the left ventricle, and abdominal muscle fibrosis correlated with impaired left ventricular function. Fibrosis in the abdominal muscles negatively correlated with fibrosis in the diaphragm and right ventricles. Together these data reflect the recruitment of abdominal muscles as respiratory muscles in muscular dystrophy, a finding consistent with data from human patients. PMID:26029630

  16. Extra-helical binding site of a glucagon receptor antagonist.

    PubMed

    Jazayeri, Ali; Doré, Andrew S; Lamb, Daniel; Krishnamurthy, Harini; Southall, Stacey M; Baig, Asma H; Bortolato, Andrea; Koglin, Markus; Robertson, Nathan J; Errey, James C; Andrews, Stephen P; Teobald, Iryna; Brown, Alastair J H; Cooke, Robert M; Weir, Malcolm; Marshall, Fiona H

    2016-05-12

    Glucagon is a 29-amino-acid peptide released from the α-cells of the islet of Langerhans, which has a key role in glucose homeostasis. Glucagon action is transduced by the class B G-protein-coupled glucagon receptor (GCGR), which is located on liver, kidney, intestinal smooth muscle, brain, adipose tissue, heart and pancreas cells, and this receptor has been considered an important drug target in the treatment of diabetes. Administration of recently identified small-molecule GCGR antagonists in patients with type 2 diabetes results in a substantial reduction of fasting and postprandial glucose concentrations. Although an X-ray structure of the transmembrane domain of the GCGR has previously been solved, the ligand (NNC0640) was not resolved. Here we report the 2.5 Å structure of human GCGR in complex with the antagonist MK-0893 (ref. 4), which is found to bind to an allosteric site outside the seven transmembrane (7TM) helical bundle in a position between TM6 and TM7 extending into the lipid bilayer. Mutagenesis of key residues identified in the X-ray structure confirms their role in the binding of MK-0893 to the receptor. The unexpected position of the binding site for MK-0893, which is structurally similar to other GCGR antagonists, suggests that glucagon activation of the receptor is prevented by restriction of the outward helical movement of TM6 required for G-protein coupling. Structural knowledge of class B receptors is limited, with only one other ligand-binding site defined--for the corticotropin-releasing hormone receptor 1 (CRF1R)--which was located deep within the 7TM bundle. We describe a completely novel allosteric binding site for class B receptors, providing an opportunity for structure-based drug design for this receptor class and furthering our understanding of the mechanisms of activation of these receptors. PMID:27111510

  17. The Peptide Oxytocin Antagonist F-792, When Given Systemically, Does Not Act Centrally in Lactating Rats.

    PubMed

    Leng, G; Russell, J A

    2016-04-01

    Oxytocin secreted by nerve terminals in the posterior pituitary has important actions for ensuring a successful outcome of pregnancy: it stimulates uterine contractions that lead to birth and it is essential in the milk-ejection reflex, enabling milk to be expelled from the mammary glands into the mouths of suckling young. Oxytocin also has important actions in the brain: released from dendrites of neurones that innervate the posterior pituitary, oxytocin auto-excites the neurones to fire action potentials in co-ordinated bursts, causing secretion of pulses of oxytocin. Central oxytocin actions are blocked by an oxytocin antagonist given into the brain and, consequently, milk transfer stops. Systemic peptide oxytocin antagonist (atosiban) treatment is used clinically in management of pre-term labour, a major obstetric problem. Hence, it is important to know whether an oxytocin antagonist given peripherally can enter the brain and interfere with central oxytocin actions. In the present study, we tested F792, a peptide oxytocin antagonist. In urethane-anaesthetised suckled rats, we show that the mammary gland responsiveness to oxytocin is blocked by i.v. injections of 7 μg/kg of F792, and the milk-ejection reflex is blocked when F792 is given directly into the brain at a dose of 0.2 μg. To critically test whether F792 given systemically can enter the brain, we recorded the suckling- and oxytocin-induced burst-firing of individual antidromically identified oxytocin neurones in the paraventricular nucleus. Given systemically at 100 μg/kg i.v., F792 acted only peripherally, blocking the milk-ejecting actions of oxytocin, but not the burst-firing of oxytocin neurones during suckling (n = 5 neurones in five rats). Hence, this peptide oxytocin antagonist does not enter the brain from the circulation to interfere with an essential oxytocin function in the brain. Furthermore, the functions of oxytocin in the brain evidently cannot be explored with a systemic peptide

  18. New insights into the stereochemical requirements of the bradykinin B1 receptor antagonists binding.

    PubMed

    Lupala, Cecylia S; Gomez-Gutierrez, Patricia; Perez, Juan J

    2016-07-01

    Bradykinin (BK) is a nonapeptide involved in several pathophysiological conditions including among others, septic and haemorrhagic shock, anaphylaxis, arthritis, rhinitis, asthma, inflammatory bowel disease. Accordingly, BK antagonists have long been sought after for therapeutic intervention. Action of BK is mediated through two different G-protein coupled receptors known as B1 and B2. Although there are several B1 antagonists reported in literature, their pharmacological profile is not yet optimal so that new molecules need to be discovered. In the present work we have constructed an atomistic model of the B1 receptor and docked diverse available non-peptide antagonists in order to get a deeper insight into the structure-activity relationships involving binding to this receptor. The model was constructed by homology modeling using the chemokine CXC4 and bovine rhodopsin receptors as template. The model was further refined using molecular dynamics for 600ns with the protein embedded in a POPC bilayer. From the refinement process we obtained an average structure that was used for docking studies using the Glide software. Antagonists selected for the docking studies include Compound 11, Compound 12, Chroman28, SSR240612, NPV-SAA164 and PS020990. The results of the docking study underline the role of specific receptor residues in ligand binding. The results of this study permitted to define a pharmacophore that describes the stereochemical requirements of antagonist binding, and can be used for the discovery of new compounds. PMID:27469392

  19. Characterization of a new CCK antagonist, L364,718: In vitro and in vivo studies

    SciTech Connect

    Louie, D.S.; Liang, Jiang Ping; Owyang, Chung )

    1988-09-01

    In this study the authors examined a novel, orally effective, nonpeptidal cholecystokinin (CCK) antagonist, 3S(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-1H-indole-2-carboxamide (L364,718) on CCK-induced amylase release. They used isolated rat pancreatic acini and incubated them with CCK-8 with or without various CCK receptor antagonists. L364,718, proglumide, and the proglumide derivative CR1409 each caused a progressive rightward shift in the CCK-8-dose-response curve without a change in maximal amylase secretion. L364,718 was 600-fold more potent than CR1409 and 2,000,000-fold more potent than proglumide in inhibiting CCK-8-induced amylase release. Inhibition of {sup 125}I-Bolton-Hunter-CCK-8 binding to acini by these receptor antagonists had a similar rank potency. L364,718 was tested against other pancreatic exocrine secretagogues and was effective against agonists that only act through the CCK receptor. To verify that L364,718 is an effective receptor antagonists against the various molecular forms of CCK released endogenously in humans, postprandial plasma CCK was extracted and bioassayed using amylase release from isolated pancreatic acini. Thus L364,718 is the most potent, selective peripheral CCK receptor antagonist reported to data, and it is capable of antagonizing the stimulatory action of exogenously as well as endogenously released CCK to evoke amylase release from pancreatic acini.

  20. Modeling the interactions between alpha(1)-adrenergic receptors and their antagonists.

    PubMed

    Du, Lupei; Li, Minyong

    2010-09-01

    As crucial members of the G-protein coupled receptor (GPCR) superfamily, alpha (1)-adrenergic receptors (alpha(1)-ARs) are recognized to intervene the actions of endogenous catecholamines such as norepinephrine and epinephrine. So far three distinct alpha(1)-AR subtypes, alpha(1A), alpha(1B) and alpha(1D), have been characterized by functional analysis, radio-ligand binding and molecular biology studies. The alpha(1)-ARs are of therapeutic interest because of their distinct and critical roles in many physiological processes, containing hypertension, benign prostatic hyperplasia, smooth muscle contraction, myocardial inotropy and chronotropy, and hepatic glucose metabolism. Accordingly, designing subtype-selective antagonists for each of the three alpha(1)-AR subtypes has been an enthusiastic region of medicinal research. Even though a large number of studies on GPCRs have been conducted, understanding of how known antagonists bind to alpha(1)-ARs still remains sketchy and has been a serious impediment to search for potent and subtype-selective alpha(1)-AR antagonists because of the lack of detailed experimental structural knowledge. This review deliberates the simulation of alpha(1)-ARs and their interactions with antagonists by using ligand-based (pharmacophore identification and QSAR modeling) and structure-based (comparative modeling and molecular docking) approaches. Combined with experimental data, these computational attempts could improve our understanding of the structural basis of antagonist binding and the molecular basis of receptor activation, thus offering a more reasonable approach in the design of drugs targeting alpha(1)-ARs. PMID:20412040

  1. Spinal Muscular Atrophy: Current Therapeutic Strategies

    NASA Astrophysics Data System (ADS)

    Kiselyov, Alex S.; Gurney, Mark E.

    Proximal spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by death of motor neurons in the spinal cord. SMA is caused by deletion and/or mutation of the survival motor neuron gene (SMN1) on chromosome 5q13. There are variable numbers of copies of a second, related gene named SMN2 located in the proximity to SMN1. Both genes encode the same protein (Smn). Loss of SMN1 and incorrect splicing of SMN2 affect cellular levels of Smn triggering death of motor neurons. The severity of SMA is directly related to the normal number of copies of SMN2 carried by the patient. A considerable effort has been dedicated to identifying modalities including both biological and small molecule agents that increase SMN2 promoter activity to upregulate gene transcription and produce increased quantities of full-length Smn protein. This review summarizes recent progress in the area and suggests potential target product profile for an SMA therapeutic.

  2. Prenatal prediction of spinal muscular atrophy.

    PubMed Central

    Daniels, R J; Suthers, G K; Morrison, K E; Thomas, N H; Francis, M J; Mathew, C G; Loughlin, S; Heiberg, A; Wood, D; Dubowitz, V

    1992-01-01

    Spinal muscular atrophy (SMA) is a common cause of inherited morbidity and mortality in childhood. The wide range of phenotypes in SMA, uncertainty regarding its mode of inheritance, and the suggestion of linkage heterogeneity have complicated the genetic counselling of parents of affected children. The locus responsible for autosomal recessive SMA has been mapped to 5q11.2-q13.3. The most likely order of loci is cen-D5S6-(SMA,D5S125)-(JK53CA1/2,D5S112)-D5S3 9-qter, with highly polymorphic loci being identified at JK53CA1/2 and D5S39. We describe linkage studies with another highly polymorphic locus, D5S127, that is closely linked to D5S39. This genetic map can be used as the basis for genetic counselling in families with autosomal recessive SMA. Appropriate allowance can be made for sporadic cases owing to non-inherited causes and for linkage heterogeneity or misdiagnoses. Images PMID:1348091

  3. Optimizing Bone Health in Duchenne Muscular Dystrophy

    PubMed Central

    Buckner, Jason L.; Bowden, Sasigarn A.; Mahan, John D.

    2015-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive muscle weakness, with eventual loss of ambulation and premature death. The approved therapy with corticosteroids improves muscle strength, prolongs ambulation, and maintains pulmonary function. However, the osteoporotic impact of chronic corticosteroid use further impairs the underlying reduced bone mass seen in DMD, leading to increased fragility fractures of long bones and vertebrae. These serious sequelae adversely affect quality of life and can impact survival. The current clinical issues relating to bone health and bone health screening methods in DMD are presented in this review. Diagnostic studies, including biochemical markers of bone turnover and bone mineral density by dual energy X-ray absorptiometry (DXA), as well as spinal imaging using densitometric lateral spinal imaging, and treatment to optimize bone health in patients with DMD are discussed. Treatment with bisphosphonates offers a method to increase bone mass in these children; oral and intravenous bisphosphonates have been used successfully although treatment is typically reserved for children with fractures and/or bone pain with low bone mass by DXA. PMID:26124831

  4. Measuring quality of life in muscular dystrophy

    PubMed Central

    Abresch, Richard T.; Biesecker, Barbara; Conway, Kristin Caspers; Heatwole, Chad; Peay, Holly; Scal, Peter; Strober, Jonathan; Uzark, Karen; Wolff, Jodi; Margolis, Marjorie; Blackwell, Angela; Street, Natalie; Montesanti, Angela; Bolen, Julie

    2015-01-01

    Objectives: The objectives of this study were to develop a conceptual model of quality of life (QOL) in muscular dystrophies (MDs) and review existing QOL measures for use in the MD population. Methods: Our model for QOL among individuals with MD was developed based on a modified Delphi process, literature review, and input from patients and patient advocacy organizations. Scales that have been used to measure QOL among patients with MD were identified through a literature review and evaluated using the COSMIN (Consensus-Based Standards for the Selection of Health Measurement Instruments) checklist. Results: The Comprehensive Model of QOL in MD (CMQM) captures 3 broad domains of QOL (physical, psychological, and social), includes factors influencing self-reported QOL (disease-related factors, support/resources, and expectations/aspirations), and places these concepts within the context of the life course. The literature review identified 15 QOL scales (9 adult and 6 pediatric) that have been applied to patients with MD. Very few studies reported reliability data, and none included data on responsiveness of the measures to change in disease progression, a necessary psychometric property for measures included in treatment and intervention studies. No scales captured all QOL domains identified in the CMQM model. Conclusions: Additional scale development research is needed to enhance assessment of QOL for individuals with MD. Item banking and computerized adaptive assessment would be particularly beneficial by allowing the scale to be tailored to each individual, thereby minimizing respondent burden. PMID:25663223

  5. Molecular analysis of facioscapulohumeral muscular dystrophy (FSHD)

    SciTech Connect

    Upadhyaya, M.; Maynard, J.; Osborn, M.

    1994-09-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder characterized by progressive muscle weakness. The disease locus maps to 4q35 and is associated with a de novo DNA rearrangement, detected by a probe p13E-11 (D4F104S1) which maps proximal to the disease locus. An informative distal flanking marker for this condition is still required. Using p13E-11, we have analyzed 35 FSHD families in which the disease is apparently associated with a new mutation. Twenty three of these cases were found to have a smaller rearranged DNA fragment which was not present in either of the parents. Pulsed-field gel analysis of 5 of these families also revealed evidence of DNA deletion. During the course of this study, we identified one case with a DNA rearrangement which was also present in the unaffected mother, but at very low intensity. This finding has been confirmed by pulsed-field gel analysis, and indicates that the mother is probably a gonosomal mosaic. In order to saturate the FSHD region with new DNA markers, a laser microdissection and microcloning technique was used to construct a genomic library from the distal end of chromosome 4. Of the 72 microclones analyzed, 42 mapped into the relevant 4q35 region. 4 sequences were conserved and may be considered potential candidate genes for FSHD. The microclones mapping to 4q35 are under study to identify additional polymorphic markers for the FSHD region.

  6. Gene Therapy for Duchenne muscular dystrophy

    PubMed Central

    Ramos, Julian; Chamberlain, Jeffrey S

    2015-01-01

    Introduction Duchenne muscular dystrophy (DMD) is a relatively common inherited disorder caused by defective expression of the protein dystrophin. The most direct approach to treating this disease would be to restore dystrophin production in muscle. Recent progress has greatly increased the prospects for successful gene therapy of DMD, and here we summarize the most promising developments. Areas Covered Gene transfer using vectors derived from adeno-associated virus (AAV) has emerged as a promising method to restore dystrophin production in muscles bodywide, and represents a treatment option applicable to all DMD patients. Using information gleaned from PubMed searches of the literature, attendance at scientific conferences and results from our own lab, we provide an overview of the potential for gene therapy of DMD using AAV vectors including a summary of promising developments and issues that need to be resolved prior to large-scale therapeutic implementation. Expert Opinion Of the many approaches being pursued to treat DMD and BMD, gene therapy based on AAV-mediated delivery of microdystrophin is the most direct and promising method to treat the cause of the disorder. The major challenges to this approach are ensuring that microdystrophin can be delivered safely and efficiently without eliciting an immune response. PMID:26594599

  7. Facioscapulohumeral muscular dystrophy: consequences of chromatin relaxation

    PubMed Central

    van der Maarel, Silvère M.; Miller, Daniel G.; Tawil, Rabi; Filippova, Galina N.; Tapscott, Stephen J.

    2013-01-01

    Purpose of review In recent years we have seen remarkable progress in our understanding of the disease mechanism underlying facioscapulohumeral muscular dystrophy (FSHD). The purpose of this review is to provide a comprehensive overview of our current understanding of the disease mechanism and to discuss the observations supporting the possibility of a developmental defect in this disorder. Recent findings In the majority of cases FSHD is caused by contraction of the D4Z4 repeat array (FSHD1). This results in local chromatin relaxation and stable expression of the DUX4 retrogene in skeletal muscle, but only when a polymorphic DUX4 polyadenylation signal is present. In some cases (FSHD2), D4Z4 chromatin relaxation and stable DUX4 expression occurs in the absence of D4Z4 array contraction. DUX4 is a germline transcription factor and its expression in skeletal muscle leads to activation of early stem cell and germline programs and transcriptional activation of retroelements. Summary Recent studies have provided a plausible disease mechanism for FSHD where FSHD results from inappropriate expression of the germline transcription factor DUX4. The genes regulated by DUX4 suggest several mechanisms of muscle damage, and provide potential biomarkers and therapeutic targets that should be investigated in future studies. PMID:22892954

  8. Chronic oral administration of Ang-(1-7) improves skeletal muscle, autonomic and locomotor phenotypes in muscular dystrophy.

    PubMed

    Sabharwal, Rasna; Cicha, Michael Z; Sinisterra, Ruben D M; De Sousa, Frederico B; Santos, Robson A; Chapleau, Mark W

    2014-07-01

    Muscular dystrophies are a group of heterogeneous genetic disorders that cause progressive muscle weakness and wasting, dilated cardiomyopathy and early mortality. There are different types of muscular dystrophies with varying aetiologies but they all have a common hallmark of myofibre degeneration, atrophy and decreased mobility. Mutation in Sgcd (sarcoglycan-δ), a subunit of dystrophin glycoprotein complex, causes LGMD2F (limb girdle muscular dystrophy 2F). Previously, we have reported that Sgcd-deficient (Sgcd-/-) mice exhibit AngII (angiotensin II)-induced autonomic and skeletal muscle dysfunction at a young age, which contributes to onset of dilated cardiomyopathy and mortality at older ages. Two counter-regulatory RAS (renin-angiotensin system) pathways have been identified: deleterious actions of AngII acting on the AT1R (AngII type 1 receptor) compared with the protective actions of Ang-(1-7) [angiotensin-(1-7)] acting on the receptor Mas. We propose that the balance between the AngII/AT1R and Ang-(1-7)/Mas axes is disturbed in Sgcd-/- mice. Control C57BL/6J and Sgcd-/- mice were treated with Ang-(1-7) included in hydroxypropyl β-cyclodextrin (in drinking water) for 8-9 weeks beginning at 3 weeks of age. Ang-(1-7) treatment restored the AngII/AT1R compared with Ang-(1-7)/Mas balance, decreased oxidative stress and fibrosis in skeletal muscle, increased locomotor activity, and prevented autonomic dysfunction without lowering blood pressure in Sgcd-/- mice. Our results suggest that correcting the early autonomic dysregulation by administering Ang-(1-7) or enhancing its endogenous production may provide a novel therapeutic approach in muscular dystrophy. PMID:24502705

  9. A Platform Stratifying a Sequestering Agent and a Pharmacological Antagonist as a Means to Negate Botulinum Neurotoxicity

    PubMed Central

    2014-01-01

    Botulinum neurotoxicity is characterized by peripheral neuromuscular blockade/flaccid paralysis that can lead to respiratory failure and ultimately death. Current therapeutic options provide relief in a pre-exposure scenario, but there are no clinically approved postexposure medical countermeasures. Here, we introduce a platform that utilizes a combination of a toxin sequestering agent and a pharmacological antagonist to ablate botulinum neurotoxicity in a well-defined mouse lethality assay. The platform was constructed to allow for ready exchange of sequestering agent and/or pharmacological antagonist for therapeutic optimization. As such, we attempted to improve upon the pharmacological antagonist, a potassium channel blocker, 3,4-diaminopyridine, through a prodrug approach; thus, a complete kinetic decomposition pathway is described. These experiments provide the first proof-of-principle that a synergistic combination strategy can be used to reduce toxin burden in the peripheral using a sequestering antibody, while restoring muscle action via a pharmacological small molecule antagonist. PMID:25000171

  10. 3D pharmacophore models for thromboxane A(2) receptor antagonists.

    PubMed

    Wei, Jing; Liu, Yixi; Wang, Songqing

    2009-10-01

    Thromboxane A(2) (TXA(2)) is an endogenous arachidonic acid derivative closely correlated to thrombosis and other cardiovascular diseases. The action of TXA(2) can be effectively inhibited with TXA(2) receptor antagonists (TXRAs). Previous studies have attempted to describe the interactions between the TXA(2) receptor and its ligands, but their conclusions are still controversial. In this study, ligand-based computational drug design is used as a new and effective way to investigate the structure-activity relationship of TXRAs. Three-dimensional pharmacophore models of TXRAs were built with HypoGenRefine and HipHop modules in CATALYST software. The optimal HypoGenRefine model was developed on the basis of 25 TXRAs. It consists of two hydrophobic groups, one aromatic ring, one hydrogen-bond acceptor and four excluded volumes. The optimal HipHop model contains two hydrophobic groups and two hydrogen-bond acceptors. These models describe the key structure-activity relationship of TXRAs, can predict their activities, and can thus be used to design novel antagonists. PMID:19263096

  11. Antagonistic formation motion of cooperative agents

    NASA Astrophysics Data System (ADS)

    Lu, Wan-Ting; Dai, Ming-Xiang; Xue, Fang-Zheng

    2015-02-01

    This paper investigates a new formation motion problem of a class of first-order multi-agent systems with antagonistic interactions. A distributed formation control algorithm is proposed for each agent to realize the antagonistic formation motion. A sufficient condition is derived to ensure that all of the agents make an antagonistic formation motion in a distributed manner. It is shown that all of the agents can be spontaneously divided into several groups and that agents in the same group collaborate while agents in different groups compete. Finally, a numerical simulation is included to demonstrate our theoretical results. Project supported by the National Natural Science Foundation of China (Grant Nos. 61203080 and 61473051) and the Natural Science Foundation of Chongqing City (Grant No. CSTC 2011BB0081).

  12. Endothelin receptor antagonists in pulmonary arterial hypertension.

    PubMed

    Channick, Richard N; Sitbon, Olivier; Barst, Robyn J; Manes, Alessandra; Rubin, Lewis J

    2004-06-16

    Endothelin receptor antagonism has emerged as an important therapeutic strategy in pulmonary arterial hypertension (PAH). Laboratory and clinical investigations have clearly shown that endothelin (ET)-1 is overexpressed in several forms of pulmonary vascular disease and likely plays a significant pathogenetic role in the development and progression of pulmonary vasculopathy. Oral endothelin receptor antagonists (ERAs) have been shown to improve pulmonary hemodynamics, exercise capacity, functional status, and clinical outcome in several randomized placebo-controlled trials. Bosentan, a dual-receptor antagonist, is approved by the U.S. Food and Drug Administration for class III and IV patients with PAH, based on two phase III trials. In addition to its efficacy as sole therapy, bosentan may have a role as part of a combination of drugs such as a prostanoid or sildenafil. The selective endothelin receptor-A antagonists sitaxsentan and ambrisentan are currently undergoing investigation. PMID:15194180

  13. Histamine-2 Receptor Antagonists and Semen Quality.

    PubMed

    Banihani, Saleem A

    2016-01-01

    Histamine-2 receptor antagonists are a class of drugs used to treat the acid-related gastrointestinal diseases such as ulcer and gastro-oesophageal reflux disease. Although such drugs, especially ranitidine and famotidine, are still widely used, their effects on semen quality, and hence on male infertility, is still unclear. This MiniReview systematically addresses and summarizes the effect of histamine-2 receptor antagonists (cimetidine, ranitidine, nizatidine and famotidine) on semen quality, particularly, on sperm function. Cimetidine appears to have adverse effects on semen quality. While the effects of ranitidine and nizatidine on semen quality are still controversial, famotidine does not appear to change semen quality. Therefore, additional studies will be required to clarify whether histamine-2 receptor-independent effects of these drugs play a role in semen quality as well as further clinical studies including direct comparison of the histamine-2 receptor antagonists. PMID:26176290

  14. Enjoying vs. smiling: Facial muscular activation in response to emotional language.

    PubMed

    Fino, Edita; Menegatti, Michela; Avenanti, Alessio; Rubini, Monica

    2016-07-01

    The present study examined whether emotionally congruent facial muscular activation - a somatic index of emotional language embodiment can be elicited by reading subject-verb sentences composed of action verbs, that refer directly to facial expressions (e.g., Mario smiles), but also by reading more abstract state verbs, which provide more direct access to the emotions felt by the agent (e.g., Mario enjoys). To address this issue, we measured facial electromyography (EMG) while participants evaluated state and action verb sentences. We found emotional sentences including both verb categories to have valence-congruent effects on emotional ratings and corresponding facial muscle activations. As expected, state verb-sentences were judged with higher valence ratings than action verb-sentences. Moreover, despite emotional congruent facial activations were similar for the two linguistic categories, in a late temporal window we found a tendency for greater EMG modulation when reading action relative to state verb sentences. These results support embodied theories of language comprehension and suggest that understanding emotional action and state verb sentences relies on partially dissociable motor and emotional processes. PMID:27164178

  15. Molecular etiopathogenesis of limb girdle muscular and congenital muscular dystrophies: boundaries and contiguities.

    PubMed

    Guglieri, Michela; Magri, Francesca; Comi, Giacomo P

    2005-11-01

    The muscular dystrophies are a heterogeneous group of inherited disorders characterized by progressive muscle wasting and weakness. These disorders present a large clinical variability regarding age of onset, patterns of skeletal muscle involvement, heart damage, rate of progression and mode of inheritance. Difficulties in classification are often caused by the relatively common sporadic occurrence of autosomal recessive forms as well as by intrafamilial clinical variability. Furthermore recent discoveries, particularly regarding the proteins linking the sarcolemma to components of the extracellular matrix, have restricted the gap existing between limb girdle (LGMD) and congenital muscular dystrophies (CMD). Therefore a renewed definition of boundaries between these two groups is required. Molecular genetic studies have demonstrated different causative mutations in the genes encoding a disparate collection of proteins involved in all aspects of muscle cell biology. These novel skeletal muscle genes encode highly diverse proteins with different localization within or at the surface of the skeletal muscle fibre, such as the sarcolemmal muscle membrane (dystrophin, sarcoglycans, dysferlin, caveolin-3), the extracellular matrix (alpha2 laminin, collagen VI), the sarcomere (telethonin, myotilin, titin, nebulin and ZASP), the muscle cytosol (calpain-3, TRIM32), the nucleus (emerin, lamin A/C) and the glycosilation pathway enzymes (fukutin and fukutin related proteins). The accumulating knowledge about the role of these different proteins in muscle pathology has led to a profound change in the original phenotype-based classification and shed new light on the molecular pathogenesis of these disorders. PMID:16002060

  16. [Specific features of Becker Muscular Dystrophy patients and female carriers of Duchenne Muscular Dystrophy].

    PubMed

    Magot, A; Mercier, S; Péréon, Y

    2015-12-01

    Becker muscular dystrophy (BMD) was first described in 1955 and linked to the DMD gene in 1987. Compared to Duchenne muscular dystrophy (DMD), clinical onset of BMD usually occurs after the age of 12 and wheelchair is required after the age of 16. BMD is characterized by generalized weakness first affecting limb girdle muscles, hypertrophy of the calves and cardiomyopathy in males. Some patients have only mild symptoms such as cramps or elevated serum creatine kinases (SCK) throughout all their lives. SCK levels are usually elevated. Muscle biopsy (immunohistochemistry or immunoblotting) shows a dystrophic pattern with abnormal dystrophin staining. Diagnosis is confirmed by DMD gene sequencing. Deletions or duplications of one or several exons are identified in the majority of cases. A multidisciplinary approach is recommended for the care management of these patients with a particular attention to the cardiomyopathy, which is typically responsible for death but can be prevented by specific treatment. X-linked dilated cardiomyopathies linked to DMD gene are a phenotypic continuum of BMD. Some female carriers of DMD mutations exhibit clinical symptoms of variable severity, often milder and beginning later than in males. The cardiomyopathy is the most frequent feature that should be especially monitored in these patients. Genetic counselling should be systematically proposed. PMID:26773584

  17. Iontophoretic studies on rat hippocampus with some novel GABA antagonists.

    PubMed

    Dalkara, T; Saederup, E; Squires, R F; Krnjevic, K

    1986-08-01

    Twelve substances which appear to be GABA antagonists, judging by their ability to reverse the inhibitory effect of GABA on 35S-TBPS binding to rat brain membranes, were tested iontophoretically on population spikes in the rat hippocampus. Eight of them, including seven which completely reversed the inhibitory action of GABA on 35S-TBPS binding, caused a marked enhancement of population spikes, with slow onset and long duration and they antagonized the inhibition of population spikes by GABA. These effects were similar to those produced by bicuculline. Electrophysiologically, the most potent of the "complete reversers" were bathophenanthroline disulfonate and brucine. In vitro, amoxapine and brucine most effectively reversed the inhibitory action of GABA on 35S-TBPS binding. Of the five substances which only partly reversed the inhibitory effect of GABA on 35S-TBPS binding, four depressed the population spikes and potentiated the inhibitory action of GABA. The fifth "partial reverser", pipazethate, potently increased the population spikes, like the "complete reversers". Although other interpretations are possible the results are consistent with the existence of several GABA-A receptor types in brain, only some of which are blocked by certain partial reversers. PMID:2874465

  18. Prostaglandins, H2-receptor antagonists and peptic ulcer disease.

    PubMed

    Bright-Asare, P; Habte, T; Yirgou, B; Benjamin, J

    1988-01-01

    Peptic ulcer develops when offensive factors overwhelm defensive processes in the gastroduodenal mucosa. Offensive factors include NSAIDs, hydrochloric acid-peptic activity, bile reflux, and some products of the lipoxygenase pathway such as leukotriene B4; whereas defensive processes are largely mediated by prostaglandins through poorly understood mechanisms uniformly termed cytoprotection. Cytoprotection, a physiological process working through the products of arachidonic acid metabolism, may result from the net effect of the protective actions of prostaglandins versus the damaging actions of leukotrienes. Some prostaglandins also have antisecretory effects. Therefore the peptic ulcer healing effects of prostaglandin analogues, all of which have significant antisecretory activity, may be more due to their antisecretory effects than primarily to their effects on mucosal defences. Certain drug-induced gastroduodenal lesions, e.g. NSAID-induced ulcers, which are often unresponsive to H2-receptor antagonists, have been healed and their recurrence prevented by the use of PGE1 and PGE2 analogues. All the prostaglandin analogues investigated to date in humans have the potential for inducing abortion, an important side effect which may limit their worldwide use. The optimal prostaglandin analogue for ulcer healing should not induce abortion and should be potently cytoprotective. The predominant damaging agent in the development of peptic ulcer disease is gastric hydrochloric acid. Thus, the worldwide established efficacy and safety of H2-receptor antagonists such as cimetidine, ranitidine, famotidine and most recently of roxatidine acetate suggest that these agents have become the standard by which other forms of anti-ulcer therapy should be judged. PMID:2905237

  19. Gastrointestinal manifestations in myotonic muscular dystrophy

    PubMed Central

    Bellini, Massimo; Biagi, Sonia; Stasi, Cristina; Costa, Francesco; Mumolo, Maria Gloria; Ricchiuti, Angelo; Marchi, Santino

    2006-01-01

    Myotonic dystrophy (MD) is characterized by myotonic phenomena and progressive muscular weakness. Involvement of the gastrointestinal tract is frequent and may occur at any level. The clinical manifestations have previously been attributed to motility disorders caused by smooth muscle damage, but histologic evidence of alterations has been scarce and conflicting. A neural factor has also been hypothesized. In the upper digestive tract, dysphagia, heartburn, regurgitation and dyspepsia are the most common complaints, while in the lower tract, abdominal pain, bloating and changes in bowel habits are often reported. Digestive symptoms may be the first sign of dystrophic disease and may precede the musculo-skeletal features. The impairment of gastrointestinal function may be sometimes so gradual that the patients adapt to it with little awareness of symptoms. In such cases routine endoscopic and ultrasonographic evaluations are not sufficient and targeted techniques (electrogastrography, manometry, electromyography, functional ultrasonography, scintigraphy, etc.) are needed. There is a low correlation between the degree of skeletal muscle involvement and the presence and severity of gastrointestinal disturbances whereas a positive correlation with the duration of the skeletal muscle disease has been reported. The drugs recommended for treating the gastrointestinal complaints such as prokinetic, anti-dyspeptic drugs and laxatives, are mainly aimed at correcting the motility disorders. Gastrointestinal involvement in MD remains a complex and intriguing condition since many important problems are still unsolved. Further studies concentrating on genetic aspects, early diagnostic techniques and the development of new therapeutic strategies are needed to improve our management of the gastrointestinal manifestations of MD. PMID:16609987

  20. Neuropsychological profile of duchenne muscular dystrophy.

    PubMed

    Perumal, Anna Roshini; Rajeswaran, Jamuna; Nalini, Atchayaram

    2015-01-01

    Duchenne muscular dystrophy (DMD) is an inherited myogenic disorder characterized by progressive muscle wasting. DMD is a fatal X-linked recessive disorder with an estimated prevalence of 1 in 3,500 male live births. This disease has long been associated with intellectual impairment. Research has shown that boys with DMD have variable intellectual performance, indicating the presence of specific cognitive deficits. The aim of the study was to use a battery of intelligence, learning, and memory tests to identify a neuropsychological profile in boys with DMD. A total of 22 boys diagnosed with DMD in the age range of 6 to 10 years old were evaluated using the Wechsler Intelligence Scale for Children-Third Edition, Rey's Auditory Verbal Learning Test, and the Memory for Designs Test. The data were interpreted using means, standard deviations, percentages, and percentiles. Normative data were also used for further interpretation. The results showed that boys with DMD had a significantly lower IQ (88.5). Verbal IQ (86.59) was found to be lower than Performance IQ (92.64). There was evidence of impaired performance on the Processing Speed, Freedom From Distractibility, and Verbal Comprehension Indexes. Specific deficits in information processing, complex attention, immediate verbal memory span, verbal working memory, verbal comprehension, vocabulary, visuoconstruction ability, and verbal learning and encoding were observed. However, perceptional organization, general fund of information, abstract reasoning, visual discrimination and acuity, visual learning and memory, and verbal memory were adequate. The neuropsychological findings support the hypothesis that these children have specific cognitive deficits as opposed to a global intellectual deficit. PMID:24279481

  1. Duchenne Muscular Dystrophy: From Diagnosis to Therapy.

    PubMed

    Falzarano, Maria Sofia; Scotton, Chiara; Passarelli, Chiara; Ferlini, Alessandra

    2015-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked inherited neuromuscular disorder due to mutations in the dystrophin gene. It is characterized by progressive muscle weakness and wasting due to the absence of dystrophin protein that causes degeneration of skeletal and cardiac muscle. The molecular diagnostic of DMD involves a deletions/duplications analysis performed by quantitative technique such as microarray-based comparative genomic hybridization (array-CGH), Multiple Ligation Probe Assay MLPA. Since traditional methods for detection of point mutations and other sequence variants require high cost and are time consuming, especially for a large gene like dystrophin, the use of next-generation sequencing (NGS) has become a useful tool available for clinical diagnosis. The dystrophin gene is large and finely regulated in terms of tissue expression, and RNA processing and editing includes a variety of fine tuned processes. At present, there are no effective treatments and the steroids are the only fully approved drugs used in DMD therapy able to slow disease progression. In the last years, an increasing variety of strategies have been studied as a possible therapeutic approach aimed to restore dystrophin production and to preserve muscle mass, ameliorating the DMD phenotype. RNA is the most studied target for the development of clinical strategies and Antisense Oligonucleotides (AONs) are the most used molecules for RNA modulation. The identification of delivery system to enhance the efficacy and to reduce the toxicity of AON is the main purpose in this area and nanomaterials are a very promising model as DNA/RNA molecules vectors. Dystrophinopathies therefore represent a pivotal field of investigation, which has opened novel avenues in molecular biology, medical genetics and novel therapeutic options. PMID:26457695

  2. The burden of Duchenne muscular dystrophy

    PubMed Central

    Landfeldt, Erik; Lindgren, Peter; Bell, Christopher F.; Schmitt, Claude; Guglieri, Michela; Straub, Volker; Lochmüller, Hanns

    2014-01-01

    Objective: The objective of this study was to estimate the total cost of illness and economic burden of Duchenne muscular dystrophy (DMD). Methods: Patients with DMD from Germany, Italy, United Kingdom, and United States were identified through Translational Research in Europe–Assessment & Treatment of Neuromuscular Diseases registries and invited to complete a questionnaire online together with a caregiver. Data on health care use, quality of life, work status, informal care, and household expenses were collected to estimate costs of DMD from the perspective of society and caregiver households. Results: A total of 770 patients (173 German, 122 Italian, 191 from the United Kingdom, and 284 from the United States) completed the questionnaire. Mean per-patient annual direct cost of illness was estimated at between $23,920 and $54,270 (2012 international dollars), 7 to 16 times higher than the mean per-capita health expenditure in these countries. Indirect and informal care costs were substantial, each constituting between 18% and 43% of total costs. The total societal burden was estimated at between $80,120 and $120,910 per patient and annum, and increased markedly with disease progression. The corresponding household burden was estimated at between $58,440 and $71,900. Conclusions: We show that DMD is associated with a substantial economic burden. Our results underscore the many different costs accompanying a rare condition such as DMD and the considerable economic burden carried by affected families. Our description of the previously unknown economic context of a rare disease serves as important intelligence input to health policy evaluations of intervention programs and novel therapies, financial support schemes for patients and their families, and the design of future cost studies. PMID:24991029

  3. Antischizophrenic drugs of the diphenylbutylpiperidine type act as calcium channel antagonists.

    PubMed Central

    Gould, R J; Murphy, K M; Reynolds, I J; Snyder, S H

    1983-01-01

    Antischizophrenic neuroleptic drugs of the diphenylbutylpiperidine class, which includes pimozide, fluspirilene, penfluridol, and clopimozide, inhibit [3H]nitrendipine binding with IC50 values of 13-30 nM. This inhibition involves receptors for the verapamil/prenylamine class of calcium channel antagonists. These diphenylbutylpiperidines also inhibit potassium-induced calcium-dependent contractions of rat vas deferens at concentrations of 40-350 nM. Other phenothiazine and butyrophenone neuroleptics lack such potent calcium-antagonist actions. Diphenylbutylpiperidines also differ from other neuroleptics in their ability to relieve negative symptoms of schizophrenia, such as emotional withdrawal, as well as the positive symptoms which respond to all neuroleptics. We suggest that these unique antischizophrenic actions are related to a blockade by diphenylbutylpiperidines of voltage-operated calcium channels. PMID:6136040

  4. Intrathecal Injections in Children With Spinal Muscular Atrophy

    PubMed Central

    Swoboda, Kathryn J.; Sethna, Navil; Farrow-Gillespie, Alan; Khandji, Alexander; Xia, Shuting; Bishop, Kathie M.

    2016-01-01

    Nusinersen (ISIS-SMNRx or ISIS 396443) is an antisense oligonucleotide drug administered intrathecally to treat spinal muscular atrophy. We summarize lumbar puncture experience in children with spinal muscular atrophy during a phase 1 open-label study of nusinersen and its extension. During the studies, 73 lumbar punctures were performed in 28 patients 2 to 14 years of age with type 2/3 spinal muscular atrophy. No complications occurred in 50 (68%) lumbar punctures; in 23 (32%) procedures, adverse events were attributed to lumbar puncture. Most common adverse events were headache (n = 9), back pain (n = 9), and post–lumbar puncture syndrome (n = 8). In a subgroup analysis, adverse events were more frequent in older children, children with type 3 spinal muscular atrophy, and with a 21- or 22-gauge needle compared to a 24-gauge needle or smaller. Lumbar punctures were successfully performed in children with spinal muscular atrophy; lumbar puncture–related adverse event frequency was similar to that previously reported in children. PMID:26823478

  5. Neurocognitive Profiles in Duchenne Muscular Dystrophy and Gene Mutation Site

    PubMed Central

    D’Angelo, Maria Grazia; Lorusso, Maria Luisa; Civati, Federica; Comi, Giacomo Pietro; Magri, Francesca; Del Bo, Roberto; Guglieri, Michela; Molteni, Massimo; Turconi, Anna Carla; Bresolin, Nereo

    2011-01-01

    The presence of nonprogressive cognitive impairment is recognized as a common feature in a substantial proportion of patients with Duchenne muscular dystrophy. To investigate the possible role of mutations along the dystrophin gene affecting different brain dystrophin isoforms and specific cognitive profiles, 42 school-age children affected with Duchenne muscular dystrophy, subdivided according to sites of mutations along the dystrophin gene, underwent a battery of tests tapping a wide range of intellectual, linguistic, and neuropsychologic functions. Full-scale intelligence quotient was approximately 1 S.D. below the population average in the whole group of dystrophic children. Patients with Duchenne muscular dystrophy and mutations located in the distal portion of the dystrophin gene (involving the 140-kDa brain protein isoform, called Dp140) were generally more severely affected and expressed different patterns of strengths and impairments, compared with patients with Duchenne muscular dystrophy and mutations located in the proximal portion of the dystrophin gene (not involving Dp140). Patients with Duchenne muscular dystrophy and distal mutations demonstrated specific impairments in visuospatial functions and visual memory (which seemed intact in proximally mutated patients) and greater impairment in syntactic processing. PMID:22000308

  6. Azines as histamine H4 receptor antagonists.

    PubMed

    Lazewska, Dorota; Kiec-Kononowicz, Katarzyna

    2012-01-01

    Since 2000, when the histamine H4 receptor (H4R) was cloned, it has constituted an interesting target for drug development. Pharmacological studies suggest the potential utility of histamine H4R antagonists/inverse agonists in the treatment of inflammatory diseases, e.g. allergic rhinitis, asthma, atopic dermatitis, colitis, or pruritus. The first H4R ligands were non-selective compounds, but intensive chemical and pharmacological work has led to the discovery of highly potent and selective H4R antagonists (e.g. JNJ7777120, CZC-13788, PF-2988403, A-940894, A-987306). The first compound (UR-63325) has finally entered into clinical studies for the treatment of allergic respiratory diseases (completing the phase I ascending dose trial) and has been found to be safe and well tolerated. The number of scientific publications and patent applications in the H4 field is increasing annually. Among the diverse chemical structures of the H4R antagonists described a 2-aminopyrimidine scaffold is repeatedly found. This review looked at recent advances in the search for H4R antagonists as reflected in patent applications/patents and peer-reviewed publications over the last two years. The work concerns azines (mono-, di-, triazines) and their fused analogues. The chemistry and pharmacology has been described. PMID:22202103

  7. Oxazolidinones as novel human CCR8 antagonists.

    PubMed

    Jin, Jian; Wang, Yonghui; Wang, Feng; Kerns, Jeffery K; Vinader, Victoria M; Hancock, Ashley P; Lindon, Matthew J; Stevenson, Graeme I; Morrow, Dwight M; Rao, Parvathi; Nguyen, Cuc; Barrett, Victoria J; Browning, Chris; Hartmann, Guido; Andrew, David P; Sarau, Henry M; Foley, James J; Jurewicz, Anthony J; Fornwald, James A; Harker, Andy J; Moore, Michael L; Rivero, Ralph A; Belmonte, Kristen E; Connor, Helen E

    2007-03-15

    High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series that led to the identification of SB-649701 (1a), are described. PMID:17267215

  8. Design and synthesis of an orally active GPIIb/IIIa antagonist based on a phenylpiperazine scaffold.

    PubMed

    van Maarseveen, J H; den Hartog, J A; Tipker, K; Reinders, J H; Brakkee, J; Schön, U; Kehrbach, W; Kruse, C G

    1998-06-16

    The design and synthesis of an orally active LMW non-peptide GPIIb/IIIa antagonist, based on a N,N'-bisphenylpiperazine scaffold, is described. The optimal compound showed a high in vitro binding potency (pIC50 = 8.7) in combination with potent oral antithrombotic activity (30-40% inhibition of thrombus growth at 0.3-3 mg/kg) with a duration of action of > 90 min. in a hamster cheek pouch model. PMID:9873384

  9. Choosing Actions

    PubMed Central

    Rosenbaum, David A.; Chapman, Kate M.; Coelho, Chase J.; Gong, Lanyun; Studenka, Breanna E.

    2013-01-01

    Actions that are chosen have properties that distinguish them from actions that are not. Of the nearly infinite possible actions that can achieve any given task, many of the unchosen actions are irrelevant, incorrect, or inappropriate. Others are relevant, correct, or appropriate but are disfavored for other reasons. Our research focuses on the question of what distinguishes actions that are chosen from actions that are possible but are not. We review studies that use simple preference methods to identify factors that contribute to action choices, especially for object-manipulation tasks. We can determine which factors are especially important through simple behavioral experiments. PMID:23761769

  10. A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy.

    PubMed

    Mendell, Jerry R; Sahenk, Zarife; Malik, Vinod; Gomez, Ana M; Flanigan, Kevin M; Lowes, Linda P; Alfano, Lindsay N; Berry, Katherine; Meadows, Eric; Lewis, Sarah; Braun, Lyndsey; Shontz, Kim; Rouhana, Maria; Clark, Kelly Reed; Rosales, Xiomara Q; Al-Zaidy, Samiah; Govoni, Alessandra; Rodino-Klapac, Louise R; Hogan, Mark J; Kaspar, Brian K

    2015-01-01

    Becker muscular dystrophy (BMD) is a variant of dystrophin deficiency resulting from DMD gene mutations. Phenotype is variable with loss of ambulation in late teenage or late mid-life years. There is currently no treatment for this condition. In this BMD proof-of-principle clinical trial, a potent myostatin antagonist, follistatin (FS), was used to inhibit the myostatin pathway. Extensive preclinical studies, using adeno-associated virus (AAV) to deliver follistatin, demonstrated an increase in strength. For this trial, we used the alternatively spliced FS344 to avoid potential binding to off target sites. AAV1.CMV.FS344 was delivered to six BMD patients by direct bilateral intramuscular quadriceps injections. Cohort 1 included three subjects receiving 3 × 10(11) vg/kg/leg. The distance walked on the 6MWT was the primary outcome measure. Patients 01 and 02 improved 58 meters (m) and 125 m, respectively. Patient 03 showed no change. In Cohort 2, Patients 05 and 06 received 6 × 10(11) vg/kg/leg with improved 6MWT by 108 m and 29 m, whereas, Patient 04 showed no improvement. No adverse effects were encountered. Histological changes corroborated benefit showing reduced endomysial fibrosis, reduced central nucleation, more normal fiber size distribution with muscle hypertrophy, especially at high dose. The results are encouraging for treatment of dystrophin-deficient muscle diseases. PMID:25322757

  11. Evidence of muscular adaptations within four weeks of barbell training in women.

    PubMed

    Stock, Matt S; Olinghouse, Kendra D; Drusch, Alexander S; Mota, Jacob A; Hernandez, Jennah M; Akalonu, Chibuzo C; Thompson, Brennan J

    2016-02-01

    We investigated the time course of neuromuscular and hypertrophic adaptations associated with only four weeks of barbell squat and deadlift training. Forty-seven previously untrained women (mean±SD, age=21±3years) were randomly assigned to low volume training (n=15), moderate volume training (n=16), and control (n=16) groups. The low and moderate volume training groups performed two and four sets, respectively, of five repetitions per exercise, twice a week. Testing was performed weekly, and included dual X-ray absorptiometry and vastus lateralis and rectus femoris B-mode ultrasonography. Bipolar surface electromyographic (EMG) signals were detected from the vastus lateralis and biceps femoris during isometric maximal voluntary contractions of the leg extensors. Significant increases in lean mass for the combined gynoid and leg regions for the low (+0.68kg) and moderate volume (+0.47kg) groups were demonstrated within three weeks. Small-to-moderate effect sizes were shown for leg lean mass, vastus lateralis thickness and pennation angle, and peak torque, but EMG amplitude was unaffected. These findings demonstrated rapid muscular adaptations in response to only eight sessions of back squat and deadlift training in women despite the absence of changes in agonist-antagonist EMG amplitude. PMID:26583966

  12. CSF cytokine profile distinguishes multifocal motor neuropathy from progressive muscular atrophy

    PubMed Central

    Furukawa, Takahiro; Fujita, Koji; Nodera, Hiroyuki; Shimizu, Fumitaka; Miyamoto, Katsuichi; Takahashi, Yukitoshi; Kanda, Takashi; Kusunoki, Susumu; Izumi, Yuishin; Kaji, Ryuji

    2015-01-01

    Objective: We aimed to compare the cytokine and chemokine profiles of patients with multifocal motor neuropathy (MMN) with those of patients with progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS) to investigate immunologic differences in the CNS. Methods: CSF from 12 patients with MMN, 8 with PMA, 26 with sporadic ALS, and 10 with other noninflammatory neurologic disorders was analyzed for 27 cytokines and chemokines using the multiplex bead array assay. Cytokine titers of the 4 groups were compared, and correlations between the titers of relevant cytokines and clinical parameters were evaluated. Results: There were no obvious intrathecal changes except for interleukin (IL)-1 receptor antagonist in patients with MMN. In contrast, IL-4, IL-7, IL-17, eotaxin/CCL11, fibroblast growth factor-2 (FGF-2), granulocyte colony-stimulating factor (G-CSF), and platelet-derived growth factor BB titers were significantly elevated in patients with PMA and ALS; of these, FGF-2 and G-CSF titers were elevated compared with those in patients with MMN. IL-4 and IL-10 titers were high in patients with ALS, particularly patients with possible ALS presenting with a slowly progressive course or mild symptoms. Conclusions: The CSF cytokine profile of patients with MMN is distinct from that of patients with PMA and ALS. The similarity of the cytokine profiles between patients with PMA and ALS suggests that PMA shares common immunologic features with ALS in the CNS, even without clinical evidence of upper motor neuron involvement. PMID:26280014

  13. Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype.

    PubMed

    Vieira, Natassia M; Elvers, Ingegerd; Alexander, Matthew S; Moreira, Yuri B; Eran, Alal; Gomes, Juliana P; Marshall, Jamie L; Karlsson, Elinor K; Verjovski-Almeida, Sergio; Lindblad-Toh, Kerstin; Kunkel, Louis M; Zatz, Mayana

    2015-11-19

    Duchenne muscular dystrophy (DMD), caused by mutations at the dystrophin gene, is the most common form of muscular dystrophy. There is no cure for DMD and current therapeutic approaches to restore dystrophin expression are only partially effective. The absence of dystrophin in muscle results in dysregulation of signaling pathways, which could be targets for disease therapy and drug discovery. Previously, we identified two exceptional Golden Retriever muscular dystrophy (GRMD) dogs that are mildly affected, have functional muscle, and normal lifespan despite the complete absence of dystrophin. Now, our data on linkage, whole-genome sequencing, and transcriptome analyses of these dogs compared to severely affected GRMD and control animals reveals that increased expression of Jagged1 gene, a known regulator of the Notch signaling pathway, is a hallmark of the mild phenotype. Functional analyses demonstrate that Jagged1 overexpression ameliorates the dystrophic phenotype, suggesting that Jagged1 may represent a target for DMD therapy in a dystrophin-independent manner. PAPERCLIP. PMID:26582133

  14. Gene Therapy for Muscular Dystrophy: Moving the Field Forward

    PubMed Central

    Al-Zaidy, Samiah; Rodino-Klapac, Louise; Mendell, Jerry R

    2014-01-01

    Gene therapy for the muscular dystrophies has evolved as a promising treatment for this progressive group of disorders. While corticosteroids and/or supportive treatments remain standard of care for Duchenne muscular dystrophy (DMD), loss of ambulation, respiratory failure and compromised cardiac function is the inevitable outcome. Recent developments in genetically mediated therapies have allowed for personalized treatments that strategically target individual muscular dystrophy subtypes based on disease pathomechanism and phenotype. In this review, we highlight therapeutic progress with emphasis on evolving pre-clinical data and our own experience in completed clinical trials, and others currently underway. We also discuss the lessons we have learned along the way and the strategies developed to overcome limitations and obstacles in this field. PMID:25439576

  15. The effect of light color on muscular strength and power.

    PubMed

    Crane, Daniel K; Hensarling, Robert W; Jung, Alan P; Sands, Charles D; Petrella, John K

    2008-06-01

    The purpose of this study was to assess the effect of the color of light in a room on muscular strength and power. A convenience sample of 18 men (M age = 20.4 yr., SD = 1.2) performed a modified Wingate Anaerobic Cycle Test for muscular power and a hand grip strength test in each of the following conditions: red, blue, and white (neutral) ambient light. A repeated-measures multivariate analysis of variance indicated that average muscular power was significantly higher when performing the test in the room with red light compared to rooms lit with blue light or white light. The results also indicated that grip strength was significantly higher in the room lit with white light as compared to the room lit with blue light. PMID:18712217

  16. Recapitulation of developing artery muscularization in pulmonary hypertension.

    PubMed

    Sheikh, Abdul Q; Lighthouse, Janet K; Greif, Daniel M

    2014-03-13

    Excess smooth muscle accumulation is a key component of many vascular disorders, including atherosclerosis, restenosis, and pulmonary artery hypertension, but the underlying cell biological processes are not well defined. In pulmonary artery hypertension, reduced pulmonary artery compliance is a strong independent predictor of mortality, and pathological distal arteriole muscularization contributes to this reduced compliance. We recently demonstrated that embryonic pulmonary artery wall morphogenesis consists of discrete developmentally regulated steps. In contrast, poor understanding of distal arteriole muscularization in pulmonary artery hypertension severely limits existing therapies that aim to dilate the pulmonary vasculature but have modest clinical benefit and do not prevent hypermuscularization. Here, we show that most pathological distal arteriole smooth muscle cells, but not alveolar myofibroblasts, derive from pre-existing smooth muscle. Furthermore, the program of distal arteriole muscularization encompasses smooth muscle cell dedifferentiation, distal migration, proliferation, and then redifferentiation, thereby recapitulating many facets of arterial wall development. PMID:24582963

  17. [Muscular power of masticating muscles and mandibular osteoporosis].

    PubMed

    Morii, Hirotoshi; Takaishi, Yoshitomo

    2006-02-01

    Whereas the most powerful stimuli for bone formation is supposed to be a stretching of muscles, Frost HM classified the effect of muscle on bone mineral density (BMD) into various types: 1. age-related loss of bone mineral density (BMD) is partly due to loss of muscular wasting, 2. the increase of BMD in obesity is due to the increase in muscular power to support the increased body weight and 3. the decrease of BMD in chronic wasting disease is partly due to the decrease in muscular power. Likewise, the decrease in BMD in mandibular alveolar bones will be partly due to the decrease in the power of masticating muscles, if such exists. A case report of mitochondrial encephalo-myopathy associated with impaired function of cranial nerves involving trigeminus nerves and impaired function of masticating muscles and dysphagia. This patient showed decrease in alveolar BMD and atrophy of mandibular. PMID:16465028

  18. Effect of metals and their antagonists on the radical intensity and cytotoxicity of ascorbates.

    PubMed

    Satoh, K; Ida, Y; Kochi, M; Tajima, M; Kashimata, M; Sakagami, H

    1997-01-01

    Five heavy metal antagonists were compared for their specificity of chelating action against copper (CuCl, CuCl2) and iron (FeCl2, FeCl3). ESR spectroscopy showed that both copper and iron significantly enhanced the radical intensity of ascorbate and sodium 5,6-benzylidene-L-ascorbate (SBA). Equimolar concentrations of dimercaprol efficiently chelated all these metals, thus significantly reducing their stimulation effects. On the other hand, the chelating action of penicillamine, ethylenediaminetetraacetic acid and diethylenetriaminepentaacetic acid was limited to CuCl and CuCl2 whereas deferoxamine mesylate (DFO) was a specific iron chelator. The cytotoxic activity of sodium ascorbate was augmented by DFO, but diminished by FeCl3. The simultaneous addition of DFO and FeCl3 counteracted each other, thus neutralizing their individual effects. The cytotoxic activity of both sodium ascorbate and SBA was significantly enhanced by CuCl2 and this stimulation effect of CuCl2 was effectively chelated by DTPA. The present study demonstrates the specificity of the chelating action of these five antagonists, suggesting the possible application of these different types of antagonists for the prevention of the pathogenic diseases catalyzed by the corresponding metals. PMID:9413172

  19. The effects of bepridil compared with calcium antagonists on rat and rabbit aorta.

    PubMed

    Winslow, E; Farmer, S; Martorana, M; Marshall, R J

    1986-11-19

    The vasodilator (relaxant) action of the antianginal agent bepridil was compared with that of drugs known to either block membrane calcium channels, to be calmodulin antagonists or to inhibit intracellular calcium flux using rat and rabbit aortic strips. IC50 values were obtained for relaxation of tonic contractions induced by either potassium (K+) or phenylephrine (PE). The order of relaxant specificity against K+ compared with PE in both rabbit and rat tissue preparations was nisoldipine = nifedipine greater than diltiazem greater than verapamil greater than bepridil greater than PrMDI greater than W7 greater than TFP greater than phentolamine. The ratio for flunarizine equalled that of bepridil in rabbit and that of verapamil in rat. The calmodulin antagonist TFP showed additional alpha-adrenoceptor blocking properties. Analysis of concentration response curves to the antagonists together with PE/K+ ratios revealed a different profile for each drug tested on rabbit aorta. The range of PE/K+ ratios was much wider in rabbit compared to rat. The results suggest that, with the method used, rabbit aortic strips offer a simple technique for drug profiling and allows a clearer differentiation between membrane active and intracellularly acting drugs than does rat aorta. The profile of bepridil resembled more that of intracellularly acting drugs suggesting that intracellular actions (possibly calmodulin inhibition) may play a substantial role in its dilator actions on vascular smooth muscle. PMID:3493158

  20. Experimental Treatment for Duchenne Muscular Dystrophy Gets Boost from Existing Medication

    MedlinePlus

    ... 2013 March 2013 (historical) Experimental Treatment for Duchenne Muscular Dystrophy Gets Boost from Existing Medication A readily available ... effects of a promising experimental treatment for Duchenne muscular dystrophy (DMD), according to research partially funded by the ...

  1. NIH study shows increased risk for two types of myotonic muscular dystrophy

    Cancer.gov

    Adults with a form of muscular dystrophy called myotonic muscular dystrophy (MMD) may be at increased risk of developing cancer, according to a study by investigators at the National Cancer Institute (NCI), part of the National Institutes of Health.

  2. Discovery of novel and potent CRTH2 antagonists.

    PubMed

    Ito, Shinji; Terasaka, Tadashi; Zenkoh, Tatsuya; Matsuda, Hiroshi; Hayashida, Hisashi; Nagata, Hiroshi; Imamura, Yoshimasa; Kobayashi, Miki; Takeuchi, Makoto; Ohta, Mitsuaki

    2012-01-15

    High throughput screening of our chemical library for CRTH2 antagonists provided a lead compound 1a. Initial optimization of the lead led to the discovery of a novel, potent and orally bioavailable CRTH2 antagonist 17. PMID:22178554

  3. The pharmacological properties of a novel MCH1 receptor antagonist isolated from combinatorial libraries

    PubMed Central

    Nagasaki, Hiroshi; Chung, Shinjae; Dooley, Colette T.; Wang, Zhiwei; Li, Chunying; Saito, Yumiko; Clark, Stewart D; Houghten, Richard A.; Civelli, Olivier

    2009-01-01

    Melanin-concentrating hormone (MCH) is a neuropeptide that exhibits potent orexigenic activity. In rodents, it exerts its actions by interacting with one receptor, MCH1 receptor which is expressed in many parts of the central nervous system (CNS). To study the physiological implications of the MCH system, we need to be able to block it locally and acutely. This necessitates the use of MCH1 receptor antagonists. While MCH1 receptor antagonists have been previously reported, they are mainly not accessible to academic research. We apply here a strategy that leads to the isolation of a high affinity and selective MCH1 receptor antagonist amenable to in vivo analyses without further chemical modifications. This antagonist, TPI 1361-17, was identified through the screening of multiple non-peptide positional scanning synthetic combinatorial libraries (PS-SCL) totaling more than eight hundred thousand compounds in conditions that allow for the identification of only high-affinity compounds. TPI 1361-17 exhibited an IC50 value of 6.1 nM for inhibition of 1 nM MCH-induced Ca2+ mobilization and completely displaced the binding of [125I] MCH to rat MCH1 receptor. TPI 1361-17 was found specific, having no affinity for a variety of other G-protein coupled receptors and channels. TPI 1361-17 was found active in vivo since it blocked MCH-induced food intake by 75 %. Our results indicate that TPI 1361-17 is a novel and selective MCH1 receptor antagonist and is an effective tool to study the physiological functions of the MCH system. These results also illustrate the successful application of combinatorial library screening to identify specific surrogate antagonists in an academic setting. PMID:19041642

  4. 5-HT6 Receptor Antagonists: Potential Efficacy for the Treatment of Cognitive Impairment in Schizophrenia.

    PubMed

    de Bruin, Natasja M W J; Kruse, Chris G

    2015-01-01

    5-hydroxytryptamine6 receptor (5-HT6R) antagonists have shown efficacy in animal models for cognitive impairment in multiple cognitive domains relevant for schizophrenia. Improvements were found with 5-HT6R antagonists in preclinical tests for episodic memory, social cognition, executive function, working memory and several other tests for both learning and memory. In contrast, there is little evidence for efficacy on attention. It will be interesting to further investigate 5-HT6R antagonists in neurodevelopmental animal models which are based on prenatal exposure to specific environmental insults, and are characterized by a high level of face, construct and predictive validity for cognitive impairments associated with schizophrenia. It is also important to do more add-on preclinical studies of 5-HT6 antagonists with antipsychotics. Possible mechanisms of action to improve cognition have been described. 5-HT6R antagonists decrease GABA release and GABAergic interneuron excitability, which subsequently disinhibits glutamate and/or acetylcholine release and results in enhancement of synaptic plasticity. Furthermore, cognition could be improved by 5-HT6R antagonists, because these compounds increase the number of NCAM PSA-immunoreactive neurons in the dendate gyrus, inhibit mTOR and Fyn-tyrosine kinase and interact with DARPP-32. Interestingly, there is increasing preclinical evidence that could support additional benefits of 5-HT6R ligandson comorbid conditions in schizophrenia such as drug abuse, depression, anxiety, obesity andantipsychotic-induced EPS. Finally, we briefly give an overview of the 5-HT6R compounds that are currently in clinical development for the treatment of cognitive impairment in both schizophrenia and Alzheimer's disease. PMID:26044973

  5. NOP receptor mediates anti-analgesia induced by agonist-antagonist opioids.

    PubMed

    Gear, R W; Bogen, O; Ferrari, L F; Green, P G; Levine, J D

    2014-01-17

    Clinical studies have shown that agonist-antagonist opioid analgesics that produce their analgesic effect via action on the kappa-opioid receptor, produce a delayed-onset anti-analgesia in men but not women, an effect blocked by co-administration of a low dose of naloxone. We now report the same time-dependent anti-analgesia and its underlying mechanism in an animal model. Using the Randall-Selitto paw-withdrawal assay in male rats, we found that nalbuphine, pentazocine, and butorphanol each produced analgesia during the first hour followed by anti-analgesia starting at ∼90min after administration in males but not females, closely mimicking its clinical effects. As observed in humans, co-administration of nalbuphine with naloxone in a dose ratio of 12.5:1 blocked anti-analgesia but not analgesia. Administration of the highly selective kappa-opioid receptor agonist U69593 produced analgesia without subsequent anti-analgesia, and confirmed by the failure of the selective kappa antagonist nor-binaltorphimine to block nalbuphine-induced anti-analgesia, indicating that anti-analgesia is not mediated by kappa-opioid receptors. We therefore tested the role of other receptors in nalbuphine anti-analgesia. Nociceptin/orphanin FQ (NOP) and sigma-1 and sigma-2 receptors were chosen on the basis of their known anti-analgesic effects and receptor binding studies. The selective NOP receptor antagonists, JTC801, and J-113397, but not the sigma receptor antagonist, BD 1047, antagonized nalbuphine anti-analgesia. Furthermore, the NOP receptor agonist NNC 63-0532 produced anti-analgesia with the same delay in onset observed with the three agonist-antagonists, but without producing preceding analgesia and this anti-analgesia was also blocked by naloxone. These results strongly support the suggestion that clinically used agonist-antagonists act at the NOP receptor to produce anti-analgesia. PMID:24188792

  6. "The sixth sense": towards a history of muscular sensation.

    PubMed

    Smith, Roger

    2011-01-01

    This paper outlines the history of knowledge about the muscular sense and provides a bibliographic resource for further research. A range of different topics, questions and approaches have interrelated throughout this history, and the discussion clarifies this rather than presenting detailed research in any one area. Part I relates the origin of belief in a muscular sense to empiricist accounts of the contribution of the senses to knowledge from Locke, via the iddologues and other authors, to the second half of the nineteenth century. Analysis paid much attention to touch, first in the context of the theory of vision and then in its own right, which led to naming a distinct muscular sense. From 1800 to the present, there was much debate, the main lines of which this paper introduces, about the nature and function of what turned out to be a complex sense. A number of influential psycho-physiologists, notably Alexander Bain and Herbert Spencer, thought this sense the most primitive and primary of all, the origin of knowledge of world, causation and self as an active subject. Part II relates accounts of the muscular sense to the development of nervous physiology and of psychology. In the decades before 1900, the developing separation of philosophy, psychology and physiology as specialised disciplines divided up questions which earlier writers had discussed under the umbrella heading of muscular sensation. The term'kinaesthesia' came in 1880 and 'proprio-ception' in 1906. There was, all the same, a lasting interest in the argument that touch and muscular sensation are intrinsic to the existence of embodied being in the way the other senses are not. In the wider culture--the arts, sport, the psychophysiology of labour and so on--there were many ways in which people expressed appreciation of the importance of what the anatomist Charles Bell had called 'the sixth sense'. PMID:22822610

  7. Energy Expenditure Ranges and Muscular Work Grades

    PubMed Central

    Brown, J. R.; Crowden, G. P.

    1963-01-01

    This paper is based on the findings of a field study which was planned to ascertain by metabolic measurement the rates of energy expenditure of men and women on productive effort at work in modern factories. The investigation which is described was carried out during a period of peace-time full employment, mainly in factories associated with the Slough Industrial Health Service in which a nutritional survey of the calorie intake of male operatives had been made by the Ministry of Health and the Medical Research Council in 1952. The rates of energy expenditure of 70 men and 54 women in 27 occupational groups were measured by indirect calorimetric methods. On the basis of the criteria for the classification of work according grades to its heaviness, adopted by the Factory Department of the Ministry of Labour, muscular work grades have been ascribed to the occupations studied. From the distribution of 390 metabolic measurements, ranges of energy expenditure have been computed for occupations classed as sedentary, light, moderate, heavy, or very heavy, Observation of recurrent phase variations in types of productive effort in the work-cycle indicated that wider work grades, such as light-to-moderate or moderate-to-heavy, are needed to cover the energy expenditure rates of men and women in many occupations. The data obtained in this study have enabled a table termed the “Slough Scales” to be compiled giving ranges of energy expenditure and pulmonary ventilation rates for the various work grades ascribed to occupations. The mean rates of energy expenditure of 257 workers (in industries in different parts of England and Scotland) which have been calculated from data published by other investigators have been found to fall within the ranges specified in these scales for the work grades of their occupations. It is felt, therefore, that the Slough Scales represent a reasonably true appraisal of the relation between the Ministry of Labour occupational work grades and the

  8. Intentional Action and Action Slips.

    ERIC Educational Resources Information Center

    Heckhausen, Heinz; Beckmann, Jurgen

    1990-01-01

    An explanation of action slips is offered that examines controlled actions in the context of an intentional behavior theory. Actions are considered guided by mentally represented intentions, subdivided into goal intentions and contingent instrumental intentions. Action slips are categorized according to problem areas in the enactment of goal…

  9. Immobility reduces muscle fiber necrosis in dystrophin deficient muscular dystrophy.

    PubMed

    Kimura, S; Ikezawa, M; Nomura, K; Ito, K; Ozasa, S; Ueno, H; Yoshioka, K; Yano, S; Yamashita, T; Matuskura, M; Miike, T

    2006-08-01

    Duchenne/Becker muscular dystrophy is a progressive muscle disease, which is caused by the abnormality of dystrophin. Spina bifida is characterized by paralysis of the feet, with most of the upper extremities not being affected. We report here on the first case of Becker muscular dystrophy coinciding with spina bifida. The muscle biopsy specimens of the patient showed dystrophic changes in upper extremities, but clearly less in lower extremities. The results show that the restriction of excessive exercise is important for dystrophin deficiency disease. PMID:16516424

  10. Determinants of the incidence of Duchenne muscular dystrophy

    PubMed Central

    2015-01-01

    Duchenne muscular dystrophy (DMD), an X-linked disorder, is the most common muscular dystrophy with an incidence in boys of about 200 per million births. It presents in early childhood leading to death in early teens. Its relatively high incidence and severity have stimulated many studies from epidemiological to curative. Recent advances in molecular biology have opened up the possibility of carrier identification and potential reduction of the incidence of cases. This paper gives a population genetics model which can be used to predict the reduction in incidence. PMID:26697447

  11. Respiratory management of spinal muscular atrophy type 2.

    PubMed

    Gormley, Maurade C

    2014-12-01

    Respiratory insufficiency is the primary cause of morbidity and mortality among patients with spinal muscular atrophy type 2. The primary complications include ineffective cough with decreased airway clearance, nocturnal hypoventilation, diminished lung and chest wall development, and increased risk for pulmonary infection. Respiratory devices including mechanical insufflator-exsufflator and bilevel positive airway pressure are the primary devices of respiratory maintenance and treatment and are associated with decreased morbidity and fewer hospital admissions. This article discusses the primary respiratory complications of spinal muscular atrophy type 2 and the role of respiratory interventions to promote growth and development, improve cough efficacy, reverse nocturnal hypoventilation, and prevent and treat pulmonary infection. PMID:25365058

  12. The efficacy of balloon dilation in achalasia is the result of stretching of the lower esophageal sphincter, not muscular disruption.

    PubMed

    Borhan-Manesh, F; Kaviani, M J; Taghavi, A R

    2016-04-01

    Pneumatic dilation (PD) of the lower esophageal sphincter (LES) in achalasia is a major palliative treatment. It is generally believed, although never substantiated, that therapeutic efficacy of ballooning in achalasia is the result of the disruption and tearing of the muscular layers of the LES. To clarify this issue, we investigated the frequency of muscular disruption at the LES, 24 hours after PD, by employing the endoscopic ultrasound (EUS), in a group of 43 consented patients with achalasia. Between July 2009 and March2012, 51 consecutive adult patients with tentative diagnosis of achalasia, some with recurrence of symptoms after an earlier treatment with balloon dilation, were evaluated and underwent PD, using Rigiflex balloon without major adverse effect. Out of the 51 evaluated, 43 eligible and consenting patients who underwent EUS, 24 hours after PD, using Olympus GF-UE 160 echoendoscope and an Aloka Prosound probe at 7.5 MHZ, are the subjects of this study. The EUS in 43 eligible patients revealed an intact LES in 36 (83.7%), small area of muscular disruption in 5 (11.6%) and small hematoma in 2 patients (4.6%). Our data convincingly demonstrate that the clinical effectiveness of balloon dilation in achalasia is not the result of muscular disruption, but of circumferential stretching of the LES. Our findings on the mechanism of action of PD in achalasia could result in modifying the current method of dilation for a safer procedure, by slowing the rate of inflation and allowing the sphincter to slowly stretch itself to the distending balloon. PMID:25765473

  13. An Exploration of the Drive for Muscularity in Adolescent Boys and Girls.

    ERIC Educational Resources Information Center

    McCreary, Donald R.; Sasse, Doris K.

    2000-01-01

    Investigated the drive for muscularity among high school adolescents using the Drive for Muscularity Scale. Results indicated that the scale was reliable. High-drive students were mainly boys trying to gain weight and muscle mass. Drive related to poor self-esteem and higher depression levels among boys, but not girls. Drive for muscularity was…

  14. Inducible Nitric Oxide Inhibitors Block NMDA Antagonist-Stimulated Motoric Behaviors and Medial Prefrontal Cortical Glutamate Efflux

    PubMed Central

    Bergstrom, Hadley C.; Darvesh, Altaf S.; Berger, S. P.

    2015-01-01

    Nitric oxide (NO) plays a critical role in the motoric and glutamate releasing action of N-methyl-D-aspartate (NMDA)-antagonist stimulants. Earlier studies utilized neuronal nitric oxide synthase inhibitors (nNOS) for studying the neurobehavioral effects of non-competitive NMDA-antagonist stimulants such as dizocilpine (MK-801) and phencyclidine (PCP). This study explores the role of the inducible nitric oxide synthase inhibitors (iNOS) aminoguanidine (AG) and (-)-epigallocatechin-3-gallate (EGCG) in NMDA-antagonist induced motoric behavior and prefrontal cortical glutamate efflux. Adult male rats were administered a dose range of AG, EGCG, or vehicle prior to receiving NMDA antagonists MK-801, PCP, or a conventional psychostimulant (cocaine) and tested for motoric behavior in an open arena. Glutamate in the medial prefrontal cortex (mPFC) was measured using in vivo microdialysis after a combination of AG or EGCG prior to MK-801. Acute administration of AG or EGCG dose-dependently attenuated the locomotor and ataxic properties of MK-801 and PCP. Both AG and EGCG were unable to block the motoric effects of cocaine, indicating the acute pharmacologic action of AG and EGCG is specific to NMDA antagonism and not generalizable to all stimulant class drugs. AG and EGCG normalized MK-801-stimulated mPFC glutamate efflux. These data demonstrate that AG and EGCG attenuates NMDA antagonist-stimulated motoric behavior and cortical glutamate efflux. Our results suggest that EGCG-like polyphenol nutraceuticals (contained in “green tea” and chocolate) may be clinically useful in protecting against the adverse behavioral dissociative and cortical glutamate stimulating effects of NMDA antagonists. Medications that interfere with NMDA antagonists such as MK-801 and PCP have been proposed as treatments for schizophrenia. PMID:26696891

  15. Calcium antagonists. A role in the management of cyanide poisoning

    SciTech Connect

    Maduh, E.U.; Porter, D.W.; Baskin, S.I.

    1993-12-31

    The physiological role of calcium was demonstrated by Ringer (1883) when he linked the omission of calcium (Ca++) from the bathing medium to the induction of cardiac arrest in the isolated frog heart. This observation established that Ca++ controlled muscle contraction but it was not until the autumn of 1963 that the specific pharmacological significance of this contribution was realised by Fleckenstein (1964), leading to the development of Ca++ antagonism as a concept in drug action (Fleckenstein 1977). Identifying the precise role of Ca++ ions in toxic cell injury and tissue death attributable to drug and chemical intoxication has lagged behind developments in Ca++ physiology and pharmacology and to date, much remains to be learned, although studies aimed at characterising the role of Ca++ in cytotoxic cell injury are receiving intense attention (Bondy Komulainen 1988; Maduh et al. l988a, l99Oa,b; Orrenius et al. 1989; Trump et al. 1989). On the other hand, the importance of cyanide as a poison has been known from antiquity (for references to earlier literature see Baskin Fricke 1992; Solomonson 1981). In experimental cyanide poisoning, recent studies have examined alterations in cell Ca++ and the influence of Ca++ antagonists in the management of this chemical toxicological emergency. These efforts have principally focused on the cellular Ca++ homeostasis system, its interrelationship with cellular components, and its susceptibility to cyanide action.

  16. Calcium channel antagonists decrease the ethanol withdrawal syndrome.

    PubMed

    Little, H J; Dolin, S J; Halsey, M J

    1986-12-01

    Withdrawal from chronic ethanol intake results in a syndrome of tremor and hyperexcitability, which can progress to seizures and death. Drugs used therapeutically to alleviate the syndrome have sedative actions and dependence liability of their own. The basis of the syndrome is unclear, although ethanol affects many neuronal functions, including membrane calcium conductance. Calcium channel blocking drugs have been used in cardiovascular disorders; they bind to high affinity sites in the brain but have few overt actions on the central nervous system. We have tested the effects of four calcium channel antagonists on the ethanol withdrawal syndrome in rats. Nitrendipine and nimodipine abolished all spontaneous seizures and prevented or reduced seizures following an audiogenic stimulus, and mortality. Verapamil significantly decreased seizure incidence and both it and flunarizine lowered mortality. The dihydropyridines were considerably more effective than diazepam in the withdrawal syndrome but had little effect on pentylenetetrazol seizures, against which diazepam gave good protection. The calcium channel inhibitors showed no sedative activity in normal animals. The results provide evidence that alterations in calcium conductance may be involved in the ethanol withdrawal syndrome and offer possibilities for the development of non-sedative therapeutic treatment of this syndrome. PMID:3784769

  17. Fluorescent Human EP3 Receptor Antagonists.

    PubMed

    Tomasch, Miriam; Schwed, J Stephan; Kuczka, Karina; Meyer Dos Santos, Sascha; Harder, Sebastian; Nüsing, Rolf M; Paulke, Alexander; Stark, Holger

    2012-09-13

    Exchange of the lipophilc part of ortho-substituted cinnamic acid lead structures with different small molecule fluorophoric moieties via a dimethylene spacer resulted in hEP3R ligands with affinities in the nanomolar concentration range. Synthesized compounds emit fluorescence in the blue, green, and red range of light and have been tested concerning their potential as a pharmacological tool. hEP3Rs were visualized by confocal laser scanning microscopy on HT-29 cells, on murine kidney tissues, and on human brain tissues and functionally were characterized as antagonists on human platelets. Inhibition of PGE2 and collagen-induced platelet aggregation was measured after preincubation with novel hEP3R ligands. The pyryllium-labeled ligand 8 has been shown as one of the most promising structures, displaying a useful fluorescence and highly affine hEP3R antagonists. PMID:24900547

  18. Vasopressin receptor antagonists: Characteristics and clinical role.

    PubMed

    Rondon-Berrios, Helbert; Berl, Tomas

    2016-03-01

    Hyponatremia, the most common electrolyte disorder in hospitalized patients is associated with increased risk of mortality even when mild and apparently asymptomatic. Likewise morbidity manifested as attention deficits, gait disturbances, falls, fractures, and osteoporosis is more prevalent in hyponatremic subjects. Hyponatremia also generates a significant financial burden. Therefore, it is important to explore approaches that effectively and safely treat hyponatremia. Currently available strategies are physiologically sound and affordable but lack evidence from clinical trials and are limited by variable efficacy, slow response, and/or poor compliance. The recent emergence of vasopressin receptor antagonists provides a class of drugs that target the primary pathophysiological mechanism, namely vasopressin mediated impairment of free water excretion. This review summarizes the historical development, pharmacology, clinical trials supporting efficacy and safety, shortcomings, as well as practical suggestions for the use of vasopressin receptor antagonists. PMID:27156765

  19. Improvement of Cold Tolerance by Selective A1 Adenosine Receptor Antagonists in Rats

    PubMed Central

    Lee, T. F.; Li, D. J.; Jacobson, K. A.; Wang, L. C. H.

    2015-01-01

    Previously we have shown that the improvement of cold tolerance by theophylline is due to antagonism at adenosine receptors rather than inhibition of phosphodiesterase. Since theophylline is a nonselective adenosine receptor antagonist for both A1 and A2 receptors, the present study investigated the adenosine receptor subtype involved in theophylline’s action. Acute systemic injection of selective A1 receptor antagonists (1,3-dialkyl-8-aryl or 1,3-dialkyl-8-cyclopentyl xanthine derivatives) significantly increased both the total and maximal heat production as well as cold tolerance. In contrast, injection of a relatively selective A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (compound No. 19), failed to significantly alter the thermogenic response of the rat under cold exposure. Further, the relative effectiveness of these compounds in increasing total thermogenesis was positively correlated with their potency in blocking the A1 adenosine receptor (r= .52, p<0.01), but not in A2 adenosine receptor (r= .20, p<0.2). It is likely that the thermally beneficial effects of adenosine A1 antagonists are due to their attenuation of the inhibitory effects of endogenously released adenosine on lipolysis and glucose utilization, resulting in increased substrate mobilization and utilization for enhanced thermogenesis. PMID:2263650

  20. Homology modeling and antagonist binding site study of the human histamine H2 receptor.

    PubMed

    Zhang, Jing; Qi, Tao; Wei, Jing

    2012-11-01

    On the basis of the high resolution crystal structures of bovine rhodopsin, human beta2-adrenergic receptor and human A(2a) adenosine receptor, three-dimensional structure of the human histamine H2 receptor (HHR2) was developed by homology modeling. Results of the evaluations suggest that a high quality homology model for HHR2 has been obtained. Three antagonists, cimetidine, ranitidine and nizatidine, were applied to binding site study with this model through molecular docking, molecular dynamics simulations and the molecular mechanics-Poisson-Boltzmann surface area calculations. One aspartic acid, Asp98 in transmembrane domain 7 (TM3), has been identified as major contributors to ligand binding by H-bond interactions. Asn159 in TM4 and Asp186 in TM5 are of great importance in stabilizing HHR2- antagonist complexes. Two hydrophobic sites especially two residues, Val99 in TM3 and Phe254 in TM6, were identified to be essential for their strong hydrophobic interactions with antagonists. The findings reported here are in agreement with available experimental mutagenesis data. This study should be very helpful for a better understanding of the action mode of the antagonist and for guiding further drug design and mutagenesis studies. PMID:22779803

  1. Preclinical pharmacology of alpha1-adrenoceptor antagonists.

    PubMed

    Martin, D J

    1999-01-01

    The implication of a single adrenoceptor subtype in the contractility of prostatic and urethral smooth muscle cells led to the concept that drugs with selectivity for this subtype may exhibit functional uroselectivity. Comparison of the affinities of the alpha1-adrenoceptor antagonists revealed that few compounds show selectivity for one of the three cloned alpha1-adrenoceptor subtypes (alpha1a/A, alpha1b/B, alpha1d/D) whereas most of them had a similar affinity for the three subtypes. Moreover, data supporting a relationship between selectivity for the alpha1a/A-adrenoceptor subtype and functional uroselectivity are still lacking and recent data challenged the relevance of the selectivity for a given cloned alpha1-adrenoceptor subtype in predicting functional uroselectivity. In vivo data showed that alpha1-adrenoceptor antagonists without adrenoceptor subtype selectivity, like alfuzosin or to a minor extent doxazosin, showed functional uroselectivity whereas prazosin and terazosin were not shown to be uroselective. Compounds considered to be selective for the alpha1a/A-adrenoceptor, like tamsulosin or 5-Me-urapidil, did not show functional uroselectivity since they modified urethral and blood pressures in a manner which was not correlated to their selectivity for the cloned alpha1-adrenoceptor subtypes. Meanwhile, the identification in prostatic tissue, of a new sub-family of alpha1-adrenoceptors with low affinity for prazosin and denominated alpha1L gave rise to numerous studies. However, its functional role as well as the affinity of the known antagonists for this receptor subtype remains to be clarified. In conclusion, the existing alpha1-adrenoceptor antagonists have different pharmacological profiles in vivo which are yet not predictable from their receptor pharmacology based on the actual state of knowledge of the alpha1-adrenoceptor classification. PMID:10393471

  2. Molecular genetics of facioscapulohumeral muscular dystrophy (FSHD).

    PubMed

    Fisher, J; Upadhyaya, M

    1997-01-01

    Facioscapulohumeral muscular dystrophy (FSHD; MIM 158900), is an autosomal dominant neuromuscular disorder. The disease is characterized by the weakness of the muscles of the face, upper-arm and shoulder girdle. The gene for FSHD has been mapped to 4q35 (FSHD1A) and is closely linked to D4F1O4S1, which detects two highly polymorphic loci (located at 4q35 and 10q26), with restriction enzyme EcoRI. The polymorphic EcoRI fragment detected with D4F1O4S1 is composed almost entirely of D4Z4 (3.3 kb) tandem repeats. In FSHD patients a deletion of the integral number of D4Z4 repeats generates a fragment which is usually smaller than 35 kb, whereas in normal controls, the size usually ranges from 50 to 300 kb. These 'small' EcoRI fragments segregate with FSHD in families but appear as de novo deletions in the majority of sporadic cases. Each 3.3 kb repeat contains two homeobox domains neither of which has yet been proven to encode a protein. D4Z4 is located adjacent to the 4q telomere and cross hybridizes to several different regions of the genome. Although D4Z4 probably does not encode a protein with any direct association to FSHD, a clear correlation has been shown between the deletion size at this locus and the age at onset of the disease in FSHD patients. In approximately 5-10% of FSHD families the disease locus is unlinked to 4q35 (locus designated FSHD1B), however, none of the non 4q35 loci for FSHD have yet been chromosomally located. Thus so far, only one gene, FRG1 (FSHD region gene 1) has been identified from the FSHD candidate region on 4q35. The apparent low level of expressed sequences from within this region, the integral deletions of D4Z4 repeats observed in FSHD patients and the close proximity of these repeats to the 4q telomere, all suggest that the disease may be the result of position effect variegation. To date, the molecular diagnosis of FSHD with D4F104S1 has been most secure in those families which are linked to other 4q35 markers. Recent studies

  3. Phonological Awareness Skills in Young Boys with Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    Waring, Phoebe; Woodyatt, Gail

    2011-01-01

    Substantial research has detailed the reading deficits experienced by children with Duchenne muscular dystrophy (DMD). Although phonological awareness (PA) is vital in reading development, little is known about PA in the DMD population. This pilot study describes the PA abilities of a group of five young children with DMD, comparing the results…

  4. Neural Issues in the Control of Muscular Strength

    ERIC Educational Resources Information Center

    Kamen, Gary

    2004-01-01

    During the earliest stages of resistance exercise training, initial muscular strength gains occur too rapidly to be explained solely by muscle-based mechanisms. However, increases in surface-based EMG amplitude as well as motor unit discharge rate provide some insight to the existence of neural mechanisms in the earliest phases of resistance…

  5. P21 Deficiency Delays Regeneration of Skeletal Muscular Tissue

    PubMed Central

    Chinzei, Nobuaki; Hayashi, Shinya; Ueha, Takeshi; Fujishiro, Takaaki; Kanzaki, Noriyuki; Hashimoto, Shingo; Sakata, Shuhei; Kihara, Shinsuke; Haneda, Masahiko; Sakai, Yoshitada; Kuroda, Ryosuke; Kurosaka, Masahiro

    2015-01-01

    The potential relationship between cell cycle checkpoint control and tissue regeneration has been indicated. Despite considerable research being focused on the relationship between p21 and myogenesis, p21 function in skeletal muscle regeneration remains unclear. To clarify this, muscle injury model was recreated by intramuscular injection of bupivacaine hydrochloride in the soleus of p21 knockout (KO) mice and wild type (WT) mice. The mice were sacrificed at 3, 14, and 28 days post-operation. The results of hematoxylin-eosin staining and immunofluorescence of muscle membrane indicated that muscle regeneration was delayed in p21 KO mice. Cyclin D1 mRNA expression and both Ki-67 and PCNA immunohistochemistry suggested that p21 deficiency increased cell cycle and muscle cell proliferation. F4/80 immunohistochemistry also suggested the increase of immune response in p21 KO mice. On the other hand, both the mRNA expression and western blot analysis of MyoD, myogenin, and Pax7 indicated that muscular differentiation was delayed in p21KO mice. Considering these results, we confirmed that muscle injury causes an increase in cell proliferation. However, muscle differentiation in p21 KO mice was inhibited due to the low expression of muscular synthesis genes, leading to a delay in the muscular regeneration. Thus, we conclude that p21 plays an important role in the in vivo healing process in muscular injury. PMID:25942471

  6. Muscle Weakness and Speech in Oculopharyngeal Muscular Dystrophy

    ERIC Educational Resources Information Center

    Neel, Amy T.; Palmer, Phyllis M.; Sprouls, Gwyneth; Morrison, Leslie

    2015-01-01

    Purpose: We documented speech and voice characteristics associated with oculopharyngeal muscular dystrophy (OPMD). Although it is a rare disease, OPMD offers the opportunity to study the impact of myopathic weakness on speech production in the absence of neurologic deficits in a relatively homogeneous group of speakers. Methods: Twelve individuals…

  7. Advances in genetic therapeutic strategies for Duchenne muscular dystrophy

    PubMed Central

    Guiraud, Simon; Chen, Huijia; Burns, David T.

    2015-01-01

    New Findings What is the topic of this review? This review highlights recent progress in genetically based therapies targeting the primary defect of Duchenne muscular dystrophy. What advances does it highlight? Over the last two decades, considerable progress has been made in understanding the mechanisms underlying Duchenne muscular dystrophy, leading to the development of genetic therapies. These include manipulation of the expression of the gene or related genes, the splicing of the gene and its translation, and replacement of the gene using viral approaches. Duchenne muscular dystrophy is a lethal X‐linked disorder caused by mutations in the dystrophin gene. In the absence of the dystrophin protein, the link between the cytoskeleton and extracellular matrix is destroyed, and this severely compromises the strength, flexibility and stability of muscle fibres. The devastating consequence is progressive muscle wasting and premature death in Duchenne muscular dystrophy patients. There is currently no cure, and despite exhaustive palliative care, patients are restricted to a wheelchair by the age of 12 years and usually succumb to cardiac or respiratory complications in their late 20s. This review provides an update on the current genetically based therapies and clinical trials that target or compensate for the primary defect of this disease. These include dystrophin gene‐replacement strategies, genetic modification techniques to restore dystrophin expression, and modulation of the dystrophin homologue, utrophin, as a surrogate to re‐establish muscle function. PMID:26140505

  8. Muscular, cardiorespiratory and thermal strain of mast and pole workers.

    PubMed

    Oksa, Juha; Hosio, Sanna; Mäkinen, Tero; Lindholm, Harri; Rintamäki, Hannu; Rissanen, Sirkka; Latvala, Jari; Vaara, Kimmo; Oksa, Panu

    2014-01-01

    This field study evaluated the level of muscular, cardiorespiratory and thermal strain of mast and pole workers. We measured the muscular strain using electromyography (EMG), expressed as a percentage in relation to maximal EMG activity (%MEMG). Oxygen consumption (VO2) was indirectly estimated from HR measured during work and expressed as a percentage of maximum VO2 (%VO2max). Skin and deep body temperatures were measured to quantify thermal strain. The highest average muscular strain was found in the wrist flexor (24 ± 1.5%MEMG) and extensor (21 ± 1.0%MEMG) muscles, exceeding the recommendation of 14%MEMG. Average cardiorespiratory strain was 48 ± 3%VO2max. Nearly half (40%) of the participants exceeded the recommended 50%VO2max level. The core body temperature varied between 36.8°C and 37.6°C and mean skin temperature between 28.6°C and 33.4°C indicating possible occasional superficial cooling. Both muscular and cardiorespiratory strain may pose a risk of local and systemic overloading and thus reduced work efficiency. Thermal strain remained at a tolerable level. PMID:24655301

  9. Dasatinib as a treatment for Duchenne muscular dystrophy

    PubMed Central

    Lipscomb, Leanne; Piggott, Robert W.; Emmerson, Tracy; Winder, Steve J.

    2016-01-01

    Identification of a systemically acting and universal small molecule therapy for Duchenne muscular dystrophy would be an enormous advance for this condition. Based on evidence gained from studies on mouse genetic models, we have identified tyrosine phosphorylation and degradation of β-dystroglycan as a key event in the aetiology of Duchenne muscular dystrophy. Thus, preventing tyrosine phosphorylation and degradation of β-dystroglycan presents itself as a potential therapeutic strategy. Using the dystrophic sapje zebrafish, we have investigated the use of tyrosine kinase and other inhibitors to treat the dystrophic symptoms in this model of Duchenne muscular dystrophy. Dasatinib, a potent and specific Src tyrosine kinase inhibitor, was found to decrease the levels of β-dystroglycan phosphorylation on tyrosine and to increase the relative levels of non-phosphorylated β-dystroglycan in sapje zebrafish. Furthermore, dasatinib treatment resulted in the improved physical appearance of the sapje zebrafish musculature and increased swimming ability as measured by both duration and distance of swimming of dasatinib-treated fish compared with control animals. These data suggest great promise for pharmacological agents that prevent the phosphorylation of β-dystroglycan on tyrosine and subsequent steps in the degradation pathway as therapeutic targets for the treatment of Duchenne muscular dystrophy. PMID:26604135

  10. Duchenne muscular dystrophy: CRISPR/Cas9 treatment.

    PubMed

    Mendell, Jerry R; Rodino-Klapac, Louise R

    2016-05-01

    A novel approach to gene correction by genome editing shows great promise as a treatment for Duchenne muscular dystrophy (DMD). CRISPR/Cas9 delivered by adeno-associated virus to a mouse model for DMD demonstrated improvement in function and histology. PMID:26926391

  11. Poor Facial Affect Recognition among Boys with Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    Hinton, V. J.; Fee, R. J.; De Vivo, D. C.; Goldstein, E.

    2007-01-01

    Children with Duchenne or Becker muscular dystrophy (MD) have delayed language and poor social skills and some meet criteria for Pervasive Developmental Disorder, yet they are identified by molecular, rather than behavioral, characteristics. To determine whether comprehension of facial affect is compromised in boys with MD, children were given a…

  12. Phosphorylation of intact erythrocytes in human muscular dystrophy

    SciTech Connect

    Johnson, R.M.; Nigro, M.

    1986-04-01

    The uptake of exogenous /sup 32/Pi into the membrane proteins of intact erythrocytes was measured in 8 patients with Duchenne muscular dystrophy. No abnormalities were noted after autoradiographic analysis. This contrasts with earlier results obtained when isolated membranes were phosphorylated with gamma-(/sup 32/P)ATP, and suggests a possible reinterpretation of those experiments.

  13. Occupational Potential in a Population with Duchenne Muscular Dystrophy.

    ERIC Educational Resources Information Center

    Schkade, Janette K.; And Others

    1987-01-01

    Twenty-five males with Duchenne muscular dystrophy were tested to assess their potential for occupational activity. Tests measured possible sensory deficits, strength, endurance, and fatigue in response to sustained fine motor activity. Results indicate that, within limitations, persons with this diagnosis can engage in activity leading to skill…

  14. The Child with Muscular Dystrophy in School. Revised.

    ERIC Educational Resources Information Center

    Schock, Nancy C.

    Practical information on children with muscular dystrophy is intended to help parents and teachers facilitate their inclusion in mainstreamed classrooms. Major topics addressed include the following: transportation arrangements; providing full information to the teacher regarding the child's specific abilities and physical limitations;…

  15. Swallow Characteristics in Patients with Oculopharyngeal Muscular Dystrophy

    ERIC Educational Resources Information Center

    Palmer, Phyllis M.; Neel, Amy T.; Sprouls, Gwyneth; Morrison, Leslie

    2010-01-01

    Purpose: This prospective investigation evaluates oral weakness and its impact on swallow function, weight, and quality of life in patients with oculopharyngeal muscular dystrophy (OPMD). Method: Intraoral pressure, swallow pressure, and endurance were measured using an Iowa Oral Performance Instrument in participants with OPMD and matched…

  16. The Assessment of Intelligence in Boys with Duchenne Muscular Dystrophy.

    ERIC Educational Resources Information Center

    Mearig, Judith S.

    1979-01-01

    Challenges assumptions and research procedures leading to the position that below-average intellectual potential is an integral part of Duchenne muscular dystrophy. A study of 58 boys (ages 5 to 18) from urban, suburban, and rural settings indicated IQ range of 59 to 131 and no evidence of significant verbal deficit (reported in earlier studies).…

  17. Instructions to Adopt an External Focus Enhance Muscular Endurance

    ERIC Educational Resources Information Center

    Marchant, David C.; Greig, Matt; Bullough, Jonathan; Hitchen, Daniel

    2011-01-01

    The influence of internal (movement focus) and external (outcome focus) attentional-focusing instructions on muscular endurance were investigated using three exercise protocols with experienced exercisers. Twenty-three participants completed a maximal repetition, assisted bench-press test on a Smith's machine. An external focus of attention…

  18. Environmental Action.

    ERIC Educational Resources Information Center

    Lott, Jesse; Allen, Rodney F.

    This booklet, a general guide to citizen eco-action, discusses a plan of action on community environmental problems. It offers factors to be considered in any community eco-action situation, but it is not a rigid set of rules. An overview identifies seven key ideas of environmental issues, including the universal participation of all humans in the…

  19. Medicinal chemistry of competitive kainate receptor antagonists.

    PubMed

    Larsen, Ann M; Bunch, Lennart

    2011-02-16

    Kainic acid (KA) receptors belong to the group of ionotropic glutamate receptors and are expressed throughout in the central nervous system (CNS). The KA receptors have been shown to be involved in neurophysiological functions such as mossy fiber long-term potentiation (LTP) and synaptic plasticity and are thus potential therapeutic targets in CNS diseases such as schizophrenia, major depression, neuropathic pain and epilepsy. Extensive effort has been made to develop subtype-selective KA receptor antagonists in order to elucidate the physiological function of each of the five subunits known (GluK1-5). However, to date only selective antagonists for the GluK1 subunit have been discovered, which underlines the strong need for continued research in this area. The present review describes the structure-activity relationship and pharmacological profile for 10 chemically distinct classes of KA receptor antagonists comprising, in all, 45 compounds. To the medicinal chemist this information will serve as reference guidance as well as an inspiration for future effort in this field. PMID:22778857

  20. The Sexually Antagonistic Genes of Drosophila melanogaster

    PubMed Central

    Innocenti, Paolo; Morrow, Edward H.

    2010-01-01

    When selective pressures differ between males and females, the genes experiencing these conflicting evolutionary forces are said to be sexually antagonistic. Although the phenotypic effect of these genes has been documented in both wild and laboratory populations, their identity, number, and location remains unknown. Here, by combining data on sex-specific fitness and genome-wide transcript abundance in a quantitative genetic framework, we identified a group of candidate genes experiencing sexually antagonistic selection in the adult, which correspond to 8% of Drosophila melanogaster genes. As predicted, the X chromosome is enriched for these genes, but surprisingly they represent only a small proportion of the total number of sex-biased transcripts, indicating that the latter is a poor predictor of sexual antagonism. Furthermore, the majority of genes whose expression profiles showed a significant relationship with either male or female adult fitness are also sexually antagonistic. These results provide a first insight into the genetic basis of intralocus sexual conflict and indicate that genetic variation for fitness is dominated and maintained by sexual antagonism, potentially neutralizing any indirect genetic benefits of sexual selection. PMID:20305719

  1. The behavioural properties of CI-988, a selective cholecystokininB receptor antagonist.

    PubMed Central

    Singh, L.; Field, M. J.; Hughes, J.; Menzies, R.; Oles, R. J.; Vass, C. A.; Woodruff, G. N.

    1991-01-01

    1. The behavioural effects of a selective cholecystokininB (CCKB) receptor antagonist CI-988 were investigated in rodents. 2. In three rodent tests of anxiety (rat elevated X-maze, rat social interaction test and mouse light/dark box) CI-988 over the dose range 0.001-10.0 mg kg-1, (i.p.) produced an anxiolytic-like action. The magnitude of this effect was similar to that of chlordiazepoxide (CDP). In contrast, the selective CCKA receptor antagonist, devazepide, was inactive. CI-988 also showed anxiolytic-like action in the rat conflict test but the magnitude of this effect was about 2.5 fold less than that of CDP. 3. Central but not peripheral administration of the selective CCKB receptor agonist, pentagastrin, like FG 7142, produced an anxiogenic-like action. 4. The pentagastrin-induced anxiety was dose-dependently antagonized by CI-988, whereas devazepide was inactive. However, ten times higher doses of CI-988 were required to block a similar action of FG 7142. 5. In contrast to CDP, CI-988 up to 3000 fold higher doses than those inducing anxiolysis was inactive in tests measuring sedation and ataxia. It also failed to antagonize pentylenetetrazol-induced tonic seizures. Furthermore, CI-988 did not interact with alcohol or barbiturates. Thus, CI-988 appears to be an anxioselective compound. 6. The anxiolytic-like action of CDP in the rat elevated X-maze was dose-dependently antagonized by flumazenil. In contrast, the benzodiazepine receptor antagonist failed to block a similar effect of CI-988. 7. Thus, CI-988 shows anxiolytic-like activity in several animal models of anxiety.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1686205

  2. Functionalized Congeners of P2Y1 Receptor Antagonists:

    SciTech Connect

    de Castro, Sonia; Maruoka, Hiroshi; Hong, Kunlun; Kilbey, II, S Michael; Costanzi, Stefano; Hechler, Béatrice; Gachet, Christian; Harden, T. Kendall; Jacobson, Kenneth A.

    2010-01-01

    The P2Y{sub 1} receptor is a prothrombotic G protein-coupled receptor (GPCR) activated by ADP. Preference for the North (N) ring conformation of the ribose moiety of adenine nucleotide 3',5'-bisphosphate antagonists of the P2Y{sub 1} receptor was established by using a ring-constrained methanocarba (a bicyclo[3.1.0]hexane) ring as a ribose substitute. A series of covalently linkable N{sup 6}-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphates containing extended 2-alkynyl chains was designed, and binding affinity at the human (h) P2Y{sub 1} receptor determined. The chain of these functionalized congeners contained hydrophilic moieties, a reactive substituent, or biotin, linked via an amide. Variation of the chain length and position of an intermediate amide group revealed high affinity of carboxylic congener 8 (K{sub i} 23 nM) and extended amine congener 15 (K{sub i} 132 nM), both having a 2-(1-pentynoyl) group. A biotin conjugate 18 containing an extended {epsilon}-aminocaproyl spacer chain exhibited higher affinity than a shorter biotinylated analogue. Alternatively, click coupling of terminal alkynes of homologous 2-dialkynyl nucleotide derivatives to alkyl azido groups produced triazole derivatives that bound to the P2Y{sub 1} receptor following deprotection of the bisphosphate groups. The preservation of receptor affinity of the functionalized congeners was consistent with new P2Y{sub 1} receptor modeling and ligand docking. Attempted P2Y{sub 1} antagonist conjugation to PAMAM dendrimer carriers by amide formation or palladium-catalyzed reaction between an alkyne on the dendrimer and a 2-iodopurine-derivatized nucleotide was unsuccessful. A dialkynyl intermediate containing the chain length favored in receptor binding was conjugated to an azide-derivatized dendrimer, and the conjugate inhibited ADP-promoted human platelet aggregation. This is the first example of attaching a strategically functionalized P2Y receptor antagonist to a PAMAM dendrimer to

  3. N-Benzylpiperidine Derivatives as α7 Nicotinic Receptor Antagonists.

    PubMed

    Criado, Manuel; Mulet, José; Sala, Francisco; Sala, Salvador; Colmena, Inés; Gandía, Luis; Bautista-Aguilera, Oscar M; Samadi, Abdelouahid; Chioua, Mourad; Marco-Contelles, José

    2016-08-17

    A series of multitarget directed propargylamines, as well as other differently susbstituted piperidines have been screened as potential modulators of neuronal nicotinic acetylcholine receptors (nAChRs). Most of them showed antagonist actions on α7 nAChRs. Especially, compounds 13, 26, and 38 displayed submicromolar IC50 values on homomeric α7 nAChRs, whereas they were less effective on heteromeric α3β4 and α4β2 nAChRs (up to 20-fold higher IC50 values in the case of 13). Antagonism was concentration dependent and noncompetitive, suggesting that these compounds behave as negative allosteric modulators of nAChRs. Upon the study of a series of less complex derivatives, the N-benzylpiperidine motif, common to these compounds, was found to be the main pharmacophoric group. Thus, 2-(1-benzylpiperidin-4-yl)-ethylamine (48) showed an inhibitory potency comparable to the one of the previous compounds and also a clear preference for α7 nAChRs. In a neuroblastoma cell line, representative compounds 13 and 48 also inhibited, in a concentration-dependent manner, cytosolic Ca(2+) signals mediated by nAChRs. Finally, compounds 38 and 13 inhibited 5-HT3A serotonin receptors whereas they had no effect on α1 glycine receptors. Given the multifactorial nature of many pathologies in which nAChRs are involved, these piperidine antagonists could have a therapeutic potential in cases where cholinergic activity has to be negatively modulated. PMID:27254782

  4. GABAA receptor modulating steroid antagonists (GAMSA) are functional in vivo.

    PubMed

    Johansson, Maja; Strömberg, Jessica; Ragagnin, Gianna; Doverskog, Magnus; Bäckström, Torbjörn

    2016-06-01

    GABAA receptor modulating steroid antagonists (GAMSA) selectively inhibit neurosteroid-mediated enhancement of GABA-evoked currents at the GABAA receptor. 3α-hydroxy-neurosteroids, notably allopregnanolone and tetrahydrodeoxycorticosterone (THDOC), potentiate GABAA receptor-mediated currents. On the contrary, various 3β-hydroxy-steroids antagonize this positive neurosteroid-mediated modulation. Importantly, GAMSAs are specific antagonists of the positive neurosteroid-modulation of the receptor and do not inhibit GABA-evoked currents. Allopregnanolone and THDOC have both negative and positive actions. Allopregnanolone can impair encoding/consolidation and retrieval of memories. Chronic administration of a physiological allopregnanolone concentration reduces cognition in mice models of Alzheimer's disease. In humans an allopregnanolone challenge impairs episodic memory and in hepatic encephalopathy cognitive deficits are accompanied by increased brain ammonia and allopregnanolone. Hippocampal slices react in vitro to ammonia by allopregnanolone synthesis in CA1 neurons, which blocks long-term potentiation (LTP). Thus, allopregnanolone may impair learning and memory by interfering with hippocampal LTP. Contrary, pharmacological treatment with allopregnanolone can promote neurogenesis and positively influence learning and memory of trace eye-blink conditioning in mice. In rat the GAMSA UC1011 inhibits an allopregnanolone-induced learning impairment and the GAMSA GR3027 restores learning and motor coordination in rats with hepatic encephalopathy. In addition, the GAMSA isoallopregnanolone antagonizes allopregnanolone-induced anesthesia in rats, and in humans it antagonizes allopregnanolone-induced sedation and reductions in saccadic eye velocity. 17PA is also an effective GAMSA in vivo, as it antagonizes allopregnanolone-induced anesthesia and spinal analgesia in rats. In vitro the allopregnanolone/THDOC-increased GABA-mediated GABAA receptor activity is antagonized

  5. From the Cover: Glutamate antagonists limit tumor growth

    NASA Astrophysics Data System (ADS)

    Rzeski, Wojciech; Turski, Lechoslaw; Ikonomidou, Chrysanthy

    2001-05-01

    Neuronal progenitors and tumor cells possess propensity to proliferate and to migrate. Glutamate regulates proliferation and migration of neurons during development, but it is not known whether it influences proliferation and migration of tumor cells. We demonstrate that glutamate antagonists inhibit proliferation of human tumor cells. Colon adenocarcinoma, astrocytoma, and breast and lung carcinoma cells were most sensitive to the antiproliferative effect of the N-methyl-D-aspartate antagonist dizocilpine, whereas breast and lung carcinoma, colon adenocarcinoma, and neuroblastoma cells responded most favorably to the -amino-3-hydroxy-5-methyl-4-isoxazole-propionate antagonist GYKI52466. The antiproliferative effect of glutamate antagonists was Ca2+ dependent and resulted from decreased cell division and increased cell death. Morphological alterations induced by glutamate antagonists in tumor cells consisted of reduced membrane ruffling and pseudopodial protrusions. Furthermore, glutamate antagonists decreased motility and invasive growth of tumor cells. These findings suggest anticancer potential of glutamate antagonists.

  6. Glycosylation defects: a new mechanism for muscular dystrophy?

    PubMed

    Grewal, Prabhjit K; Hewitt, Jane E

    2003-10-15

    Recently, post-translational modification of proteins has been defined as a new area of focus for muscular dystrophy research by the identification of a group of disease genes that encode known or putative glycosylation enzymes. Walker-Warburg Syndrome (WWS) and muscle-eye-brain disease (MEB) are caused by mutations in two genes involved in O-mannosylation, POMT1 and POMGnT1, respectively. Fukuyama muscular dystrophy (FCMD) is due to mutations in fukutin, a putative phospholigand transferase. Congenital muscular dystrophy type 1C and limb girdle muscular dystrophy type 2I are allelic, both being due to mutations in the gene-encoding fukutin-related protein (FKRP). Finally, the causative gene in the myodystrophy (myd) mouse is a putative bifunctional glycosyltransferase (Large). WWS, MEB, FCMD and the myd mouse are also associated with neuronal migration abnormalities (often type II lissencephaly) and ocular or retinal defects. A deficiency in post-translational modification of alpha-dystroglycan is a common feature of all these muscular dystrophies and is thought to involve O-glycosylation pathways. This abnormally modified alpha-dystroglycan is deficient in binding to extracellular matrix ligands, including laminin and agrin. Selective deletion of dystroglycan in the central nervous system (CNS) produces brain abnormalities with striking similarities to WWS, MEB, FCMD and the myd mouse. Thus, impaired dystroglycan function is strongly implicated in these diseases. However, it is unlikely that these five glycosylation enzymes only have a role in glycosylation of alpha-dystroglycan and it is important that other protein targets are identified. PMID:12925572

  7. Management of calcium channel antagonist overdose.

    PubMed

    Salhanick, Steven D; Shannon, Michael W

    2003-01-01

    Calcium channel antagonists are used primarily for the treatment of hypertension and tachyarrhythmias. Overdose of calcium channel antagonists can be lethal. Calcium channel antagonists act at the L-type calcium channels primarily in cardiac and vascular smooth muscle preventing calcium influx into cells with resultant decreases in vascular tone and cardiac inotropy and chronotropy. The L-type calcium channel is a complex structure and is thus affected by a large number of structurally diverse antagonists. In the setting of overdose, patients may experience vasodilatation and bradycardia leading to a shock state. Patients may also be hyperglycaemic and acidotic due to the blockade of L-type calcium channels in the pancreatic islet cells that affect insulin secretion. Aggressive therapy is warranted in the setting of toxicity. Gut decontamination with charcoal, or whole bowel irrigation or multiple-dose charcoal in the setting of extended-release products is indicated. Specific antidotes include calcium salts, glucagon and insulin. Calcium salts may be given in bolus doses or may be employed as a continuous infusion. Care should be exercised to avoid the administration of calcium in the setting of concomitant digoxin toxicity. Insulin administration has been used effectively to increase cardiac inotropy and survival. The likely mechanism involves a shift to carbohydrate metabolism in the setting of decreased availability of carbohydrates due to decreased insulin secretion secondary to blockade of calcium channels in pancreatic islet cells. Glucose should be administered as well to maintain euglycaemia. Supportive care including the use of phosphodiesterase inhibitors, adrenergic agents, cardiac pacing, balloon pump or extracorporeal bypass is frequently indicated if antidotal therapy is not effective. Careful evaluation of asymptomatic patients, including and electrocardiogram and a period of observation, is indicated. Patients ingesting a nonsustained

  8. Detachment of glycolytic enzymes from cytoskeleton of melanoma cells induced by calmodulin antagonists.

    PubMed

    Glass-Marmor, L; Beitner, R

    1997-06-11

    Glycolysis, which is the primary energy source in cancer cells, is known to be controlled by allosteric regulators, as well as by reversible binding of glycolytic enzymes to cytoskeleton. We have previously found that different calmodulin antagonists decrease the levels of allosteric activators of glycolysis, and reduce ATP content and cell viability in B16 melanoma cells. Here we report of a novel, additional, mechanism of action of calmodulin antagonists in melanoma cells. We show that these drugs cause a detachment of the glycolytic enzymes, phosphofructokinase (ATP: D-fructose-6-phosphate 1-phosphotransferase, EC 2.7.1.11) and aldolase (D-fructose-1,6-bisphosphate D-glyceraldehyde-3-phosphate-lyase, EC 4.1.2.13), from cytoskeleton of B16 melanoma cells. This effect was dose- and time-dependent, and preceded the decrease in cell viability. The detachment of glycolytic enzymes from cytoskeleton would reduce the provision of local ATP, in the vicinity of the cytoskeleton-membrane and would affect cytoskeleton structure. Since the cytoskeleton is being recognized as an important modulator of cell function, proliferation, differentiation and neoplasia, detachment of the glycolytic enzymes from cytoskeleton induced by calmodulin antagonists, as well as their reported inhibitory action on cell proliferation, make these drugs most promising agents in treatment of cancer. PMID:9218707

  9. Effects of N-methyl-D-aspartate antagonists on different measures of motion sickness in cats.

    PubMed

    Lucot, J B

    1998-11-15

    Because N-methyl-D-aspartate (NMDA) antagonists prevent cisplatin-induced emesis and NMDA receptors are in both emetic pathways and structures associated with the final common pathway for vomiting, they have the potential to be broad-spectrum antiemetics. This was evaluated by determining their effects on motion sickness in cats. The measures included the number vomiting, the number of symptom points, which reflect activity early in the final common path and the duration of the retch/vomit sequence, which reflects activity late in the path. Dextrorphan, ketamine and dextromethorphan decreased the number vomiting with the same rank order of potency as at NMDA receptors. Additional studies with 1,3-dio-tolylguaninidine (DTG) and haloperidol ruled out a role for sigma receptors. The NMDA antagonists produced a nonsignificant dose-dependent decrease in symptoms and had no effects on the duration of vomiting. They also produced motor abnormalities at the highest doses. The competitive antagonist LY 233053 also decreased the number vomiting without altering the duration. It produced a nonsignificant non-dose-dependent decrease in symptoms and had no effects on gross motor output. The results are consistent with a broad spectrum of antiemetic efficacy with at least a part of its action in the early to middle portions of the final common pathway for vomiting. Additional actions on the vestibular nuclei are possible. PMID:10052568

  10. Evaluation of muscular lesions in connective tissue diseases: thallium 201 muscular scans

    SciTech Connect

    Guillet, G.; Guillet, J.; Sanciaume, C.; Maleville, J.; Geniaux, M.; Morin, P.

    1988-04-01

    We performed thallium 201 muscle scans to assess muscular involvement in 40 patients with different connective tissue diseases (7 with dermatomyositis, 7 with systemic lupus erythematosus, 12 with progressive systemic scleroderma, 2 with calcinosis, Raynaud's phenomenon, esophageal involvement, sclerodactyly, and telangiectasia (CREST) syndrome, 3 with monomelic scleroderma, 6 with morphea, and 3 with Raynaud's disease). Only 12 of these patients complained of fatigability and/or myalgia. Electromyography was performed and serum levels of muscle enzymes were measured in all patients. Comparison of thallium 201 exercise recording with the other tests revealed that scan sensitivity is greater than electromyographic and serum muscle enzymes levels. Thallium 201 scans showed abnormal findings in 32 patients and revealed subclinical lesions in 18 patients, while electromyography findings were abnormal in 25 of these 32 patients. Serum enzyme levels were raised in only 8 patients. Thallium 201 scanning proved to be a useful guide for modifying therapy when laboratory data were conflicting. It was useful to evaluate treatment efficacy. Because our data indicate a 100% positive predictive value, we believe that thallium 201 scanning should be advised for severe systemic connective tissue diseases with discordant test results.

  11. Antagonistic effects of Streptomyces violaceusniger strain G10 on Fusarium oxysporum f.sp. cubense race 4: indirect evidence for the role of antibiosis in the antagonistic process.

    PubMed

    Getha, K; Vikineswary, S

    2002-06-01

    Fusarium oxysporum f.sp. cubense is the causal pathogen of wilt disease of banana. A cost-effective measure of control for this disease is still not available. Streptomyces violaceusniger strain G10 acts as an antifungal agent antagonistic towards many different phytopathogenic fungi, including different pathogenic races of the Fusarium wilt pathogen. In an attempt to understand the mode of action of this antagonist in nature, the interaction between S. violaceusniger strain G10 and F. oxysporum f.sp. cubense was first studied by paired incubation on agar plates. Evidence for the in vitro antibiosis of strain G10 was demonstrated by inhibition zones in the "cross-plug" assay plates. Microscopic observations showed lysis of hyphal ends in the inhibited fungal colonies. Culture of strain G10 in liquid media produces antifungal metabolites, which showed in vitro antagonistic effects against F. oxysporum f.sp. cubense such as swelling, distortion and excessive branching of hyphae, and inhibition of spore germination. An indirect method was used to show that antibiosis is one of the mechanisms of antagonism by which strain G10 acts against F. oxysporun f.sp. cubense in soil. This study suggests the potential of developing strain G10 for the biological control of Fusarium wilt disease of banana. PMID:12032802

  12. A Prospective Investigation of Interpersonal Influences on the Pursuit of Muscularity in Late Adolescent Boys and Girls

    PubMed Central

    Shomaker, Lauren B.; Furman, Wyndol

    2010-01-01

    This project examined whether interpersonal pressure to be muscular predicted late adolescents’ pursuit of muscularity. Participants were 199 adolescents (16–19 years), mothers (n=175), and friends (n=159), assessed at two annual times. Pressure to be muscular was assessed with adolescents’, mothers’, and friends’ reports of their relationships. Adolescents reported pressure from fathers and romantic partners, appearance satisfaction, disordered eating, and pursuit of muscularity. Adolescents,’ mothers’, and friends’ reports of pressure related to pursuit of muscularity at both times. Adolescents’ perceptions and mothers’ reports prospectively predicted pursuit of muscularity. Findings highlight the relevance of relationships to pursuit of muscularity in late adolescents. PMID:20348360

  13. Classification of dopamine, serotonin, and dual antagonists by decision trees.

    PubMed

    Kim, Hye-Jung; Choo, Hyunah; Cho, Yong Seo; Koh, Hun Yeong; No, Kyoung Tai; Pae, Ae Nim

    2006-04-15

    Dopamine antagonists (DA), serotonin antagonists (SA), and serotonin-dopamine dual antagonists (Dual) are being used as antipsychotics. A lot of dopamine and serotonin antagonists reveal non-selective binding affinity against these two receptors because the antagonists share structurally common features originated from conserved residues of binding site of the aminergic receptor family. Therefore, classification of dopamine and serotonin antagonists into their own receptors can be useful in the designing of selective antagonist for individual therapy of antipsychotic disorders. Data set containing 1135 dopamine antagonists (D2, D3, and D4), 1251 serotonin antagonists (5-HT1A, 5-HT2A, and 5-HT2C), and 386 serotonin-dopamine dual antagonists was collected from the MDDR database. Cerius2 descriptors were employed to develop a classification model for the 2772 compounds with antipsychotic activity. LDA (linear discriminant analysis), SIMCA (soft independent modeling of class analogy), RP (recursive partitioning), and ANN (artificial neural network) algorithms successfully classified the active class of each compound at the average 73.6% and predicted at the average 69.8%. The decision trees from RP, the best model, were generated to identify and interpret those descriptors that discriminate the active classes more easily. These classification models could be used as a virtual screening tool to predict the active class of new candidates. PMID:16387502

  14. Human trabecular meshwork cells express BMP antagonist mRNAs and proteins.

    PubMed

    Tovar-Vidales, Tara; Fitzgerald, Ashley M; Clark, Abbot F

    2016-06-01

    Glaucoma patients have elevated aqueous humor and trabecular meshwork (TM) levels of transforming growth factor-beta2 (TGF-β2). TGF-β2 has been associated with increased extracellular matrix (ECM) deposition (i.e. fibronectin), which is attributed to the increased resistance of aqueous humor outflow through the TM. We have previously demonstrated that bone morphogenetic protein (BMP) 4 selectively counteracts the profibrotic effect of TGF-β2 with respect to ECM synthesis in the TM, and this action is reversed by the BMP antagonist gremlin. Thus, the BMP and TGF-β signaling pathways antagonize each other's antifibrotic and profibrotic roles. The purpose of this study was to determine whether cultured human TM cells: (a) express other BMP antagonists including noggin, chordin, BMPER, BAMBI, Smurf1 and 2, and (b) whether expression of these proteins is regulated by exogenous TGF-β2 treatment. Primary human trabecular meshwork (TM) cells were grown to confluency and treated with TGF-β2 (5 ng/ml) for 24 or 48 h in serum-free medium. Untreated cell served as controls. qPCR and Western immunoblots (WB) determined that human TM cells expressed mRNAs and proteins for the BMP antagonist proteins: noggin, chordin, BMPER, BAMBI, and Smurf1/2. Exogenous TGF-β2 decreased chordin, BMPER, BAMBI, and Smurf1 mRNA and protein expression. In contrast, TGF-β2 increased secreted noggin and Smurf2 mRNA and protein levels. BMP antagonist members are expressed in the human TM. These molecules may be involved in the normal function of the TM as well as TM pathogenesis. Altered expression of BMP antagonist members may lead to functional changes in the human TM. PMID:27167364

  15. Lower urinary tract symptoms suggestive of benign prostatic hyperplasia: latest update on alpha-adrenoceptor antagonists.

    PubMed

    Milani, Shirin; Djavan, Bob

    2005-06-01

    An update of a systematic review of alpha1-adrenoceptor (AR) antagonists in the treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) showed that these agents have comparable efficacy. The total symptom score is improved by 30-45% and maximum urinary flow rate by 15-30% vs baseline. alpha1-AR antagonists that can be started at their therapeutic dose have a more rapid onset of action than alpha1-AR antagonists that have to be titrated. alpha1-AR antagonists can be differentiated according to their tolerability. Alfuzosin (especially the 10 mg once daily dose) and tamsulosin (especially the 0.4 mg once daily dose) are better tolerated than doxazosin and terazosin. However, alfuzosin might induce more cardiovascular adverse events (AEs) in the elderly and/or patients with cardiovascular comorbidity and/or comedication. Tamsulosin tends to interfere less with blood pressure regulation and induce less vasodilatory AEs than alfuzosin, especially in the elderly, and is well tolerated in patients with cardiovascular comorbidity and/or comedication. Cardiovascular AEs might lead to potentially serious complications such as falls, fractures and institutionalization. Abnormal ejaculation has mainly been reported in placebo-controlled trials with tamsulosin but in direct comparative trials its rate with tamsulosin 0.4 mg was similar to, or only slightly higher than, the rate with alfuzosin. In addition, abnormal ejaculation is not reported as bothersome by the patient or associated with serious complications. It can be concluded that an alpha1-AR antagonist with a low potential to interfere with blood pressure regulation and to induce cardiovascular AEs, also in patients with cardiovascular comorbidity and/or comedication, can be considered a first-choice treatment option in LUTS/BPH. PMID:15871733

  16. Species differences in the effects of the κ-opioid receptor antagonist zyklophin.

    PubMed

    Sirohi, Sunil; Aldrich, Jane V; Walker, Brendan M

    2016-03-01

    We have shown that dysregulation of the dynorphin/kappa-opioid receptor (DYN/KOR) system contributes to escalated alcohol self-administration in alcohol dependence and that KOR antagonists with extended durations of action selectively reduce escalated alcohol consumption in alcohol-dependent animals. As KOR antagonism has gained widespread attention as a potential therapeutic target to treat alcoholism and multiple neuropsychiatric disorders, we tested the effect of zyklophin (a short-acting KOR antagonist) on escalated alcohol self-administration in rats made alcohol-dependent using intermittent alcohol vapor exposure. Following dependence induction, zyklophin was infused centrally prior to alcohol self-administration sessions and locomotor activity tests during acute withdrawal. Zyklophin did not impact alcohol self-administration or locomotor activity in either exposure condition. To investigate the neurobiological basis of this atypical effect for a KOR antagonist, we utilized a κ-, μ-, and δ-opioid receptor agonist-stimulated GTPyS coupling assay to examine the opioid receptor specificity of zyklophin in the rat brain and mouse brain. In rats, zyklophin did not affect U50488-, DAMGO-, or DADLE-stimulated GTPyS coupling, whereas the prototypical KOR antagonist nor-binaltorphimine (norBNI) attenuated U50488-induced stimulation in the rat brain tissue at concentrations that did not impact μ- and δ-receptor function. To reconcile the discrepancy between the present rat data and published mouse data, comparable GTPyS assays were conducted using mouse brain tissue; zyklophin effects were consistent with KOR antagonism in mice. Moreover, at higher concentrations, zyklophin exhibited agonist properties in rat and mouse brains. These results identify species differences in zyklophin efficacy that, given the rising interest in the development of short-duration KOR antagonists, should provide valuable information for therapeutic development efforts. PMID:26992699

  17. Opioid antagonists for pharmacological treatment of alcohol dependence - a critical review.

    PubMed

    Soyka, Michael; Rösner, Susanne

    2008-11-01

    Alcohol dependence is a widespread psychiatric disorder. While relapse prevention therapy in alcoholism was exclusively dominated by social and psychological treatments for many years, in the last decades the benefits of pharmacological agents for the rehabilitation treatment in alcoholism have become increasingly evident. Naltrexone, an opiate receptor antagonist, blocks the pleasant and reinforcing effects of alcohol by preventing the stimulation of opioid receptors and the reduction of dopamine release in the ventral tegmental area (VTA). Clinical evidence about the effectiveness of the substance is not always consistent, but meta-analyses confirm naltrexone's effect on the risk of heavy drinking. Evidence about the abstinence-maintaining effects of the substance comes from a relatively small database and needs further investigation. The evaluation of differential effects of naltrexone depending on biological or psychological profiles, which could further enhance the effectiveness of treatments for alcohol dependence, remains a challenge. Nalmefene, another opioid antagonist, as well as naltrexone depot, a sustained release formulation of naltrexone, are further promising strategies for the treatment of alcohol dependence. The review at hand gives on overview of the current evidence on opioid antagonists for the treatment of alcohol dependence regarding the possible mechanism of action, the substances' safety profiles and their effectiveness. The corresponding evidence is critically reviewed taking into consideration the influence of the study design on the magnitude and consistency of effect sizes as well the impact of patient characteristics on the response to the treatment with opioid antagonists. Future studies on the role of different subtypes of alcoholics according to their genetic or psychological profile to explain or even predict the effects of opioid antagonists in the treatment of alcohol dependence are needed. PMID:19630726

  18. Functional antagonistic properties of clozapine at the 5-HT3 receptor.

    PubMed

    Hermann, B; Wetzel, C H; Pestel, E; Zieglgänsberger, W; Holsboer, F; Rupprecht, R

    1996-08-23

    The atypical neuroleptic clozapine is thought to exert its psychopharmacological actions through a variety of neurotransmitter receptors. It binds preferentially to D4 and 5-HT2 receptors; however, little is known on it's interaction with the 5-HT3 receptor. Using a cell line stably expressing the 5-HT3 receptor, whole-cell voltage-clamp analysis revealed functional antagonistic properties of clozapine at low nanomolar concentrations in view of a binding affinity in the upper nanomolar range. Because the concentration of clozapine required for an interaction with the 5-HT3 receptor can be achieved with therapeutical doses, functional antagonistic properties at this ligand-gated ion channel may contribute to its unique psychopharmacological profile. PMID:8780717

  19. Novel paramagnetic AT1 receptor antagonists.

    PubMed

    Tan, Nichole P H; Taylor, Michelle K; Bottle, Steven E; Wright, Christine E; Ziogas, James; White, Jonathan M; Schiesser, Carl H; Jani, Nitya V

    2011-11-28

    Novel paramagnetic selective angiotensin AT(1) receptor antagonists (sartans) bearing nitroxides (3, 4) have been prepared and their pharmacology evaluated in vitro as well as in vivo. Compounds 3, 4 proved to be effective sartans with pK(B) estimates in the range 6.2-9.1. In addition, the sodium salt (11) of 4 (R = Bu) is able to protect against vascular injury in hypertensive rats as determined by its ability to attenuate the development of intimal thickening caused by balloon injury of the carotid artery. PMID:21963998

  20. Mineralocorticoid receptor antagonists and endothelial function

    PubMed Central

    Maron, Bradley A.; Leopold, Jane A.

    2010-01-01

    Hyperaldosteronism has been associated with endothelial dysfunction and impaired vascular reactivity in patients with hypertension or congestive heart failure. The mineralocorticoid receptor (MR) antagonists spironolactone and eplerenone have been shown to reduce morbidity and mortality, in part, by ameliorating the adverse effects of aldosterone on vascular function. Although spironolactone and eplerenone are increasingly utilized in patients with cardiovascular disease, widespread clinical use is limited by the development of gynecomastia with spironolactone and hyperkalemia with both agents. This suggests that the development of newer agents with favorable side effect profiles is warranted. PMID:18729003

  1. Agonists and antagonists for P2 receptors

    PubMed Central

    Jacobson, Kenneth A.; Costanzi, Stefano; Joshi, Bhalchandra V.; Besada, Pedro; Shin, Dae Hong; Ko, Hyojin; Ivanov, Andrei A.; Mamedova, Liaman

    2015-01-01

    Recent work has identified nucleotide agonists selective for P2Y1, P2Y2 and P2Y6 receptors and nucleotide antagonists selective for P2Y1, P2Y12 and P2X1 receptors. Selective non-nucleotide antagonists have been reported for P2Y1, P2Y2, P2Y6, P2Y12, P2Y13, P2X2/3/P2X3 and P2X7 receptors. For example, the dinucleotide INS 37217 (Up4dC) potently activates the P2Y2 receptor, and the non-nucleotide antagonist A-317491 is selective for P2X2/3/P2X3 receptors. Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems, including conformation-ally locked moieties, have been synthesized as ligands for P2Y receptors. The focus on conformational factors of the ribose-like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity. At P2Y1,2,4,11 receptors, there is a preference for the North conformation as indicated with (N)-methanocarba analogues. The P2Y1 antagonist MRS2500 inhibited ADP-induced human platelet aggregation with an IC50 of 0.95 nM. MRS2365, an (N)-methanocarba analogue of 2-MeSADP, displayed potency (EC50) of 0.4 nM at the P2Y1 receptor, with >10 000-fold selectivity in comparison to P2Y12 and P2Y13 receptors. At P2Y6 receptors there is a dramatic preference for the South conformation. Three-dimensional structures of P2Y receptors have been deduced from structure activity relationships (SAR), mutagenesis and modelling studies. Detailed three-dimensional structures of P2X receptors have not yet been proposed. PMID:16805423

  2. Negative regulation of TGFβ-induced lens epithelial to mesenchymal transition (EMT) by RTK antagonists.

    PubMed

    Zhao, Guannan; Wojciechowski, Magdalena C; Jee, Seonah; Boros, Jessica; McAvoy, John W; Lovicu, Frank J

    2015-03-01

    An eclectic range of ocular growth factors with differing actions are present within the aqueous and vitreous humors that bathe the lens. Growth factors that exert their actions via receptor tyrosine kinases (RTKs), such as FGF, play a normal regulatory role in lens; whereas other factors, such as TGFβ, can lead to an epithelial to mesenchymal transition (EMT) that underlies several forms of cataract. The respective downstream intracellular signaling pathways of these factors are in turn tightly regulated. One level of negative regulation is thought to be through RTK-antagonists, namely, Sprouty (Spry), Sef and Spred that are all expressed in the lens. In this study, we tested these different negative regulators and compared their ability to block TGFβ-induced EMT in rat lens epithelial cells. Spred expression within the rodent eye was confirmed using RT-PCR, western blotting and immunofluorescence. Rat lens epithelial explants were used to examine the morphological changes associated with TGFβ-induced EMT over 3 days of culture, as well as α-smooth muscle actin (α-sma) immunolabeling. Cells in lens epithelial explants were transfected with either a reporter (EGFP) vector (pLXSG), or with plasmids also coding for different RTK-antagonists (i.e. pLSXG-Spry1, pLSXG-Spry2, pLXSG-Sef, pLSXG-Spred1, pLSXG-Spred2, pLSXG-Spred3), before treating with TGFβ for up to 3 days. The percentages of transfected cells that underwent TGFβ-induced morphological changes consistent with an EMT were determined using cell counts and validated with a paired two-tailed t-test. Explants transfected with pLXSG demonstrated a distinct transition in cell morphology after TGFβ treatment, with ∼60% of the cells undergoing fibrotic-like cell elongation. This percentage was significantly reduced in cells overexpressing the different antagonists, indicative of a block in lens EMT. Of the antagonists tested under these in vitro conditions, Spred1 was the most potent demonstrating the

  3. Rational discovery of novel nuclear hormone receptor antagonists

    NASA Astrophysics Data System (ADS)

    Schapira, Matthieu; Raaka, Bruce M.; Samuels, Herbert H.; Abagyan, Ruben

    2000-02-01

    Nuclear hormone receptors (NRs) are potential targets for therapeutic approaches to many clinical conditions, including cancer, diabetes, and neurological diseases. The crystal structure of the ligand binding domain of agonist-bound NRs enables the design of compounds with agonist activity. However, with the exception of the human estrogen receptor-, the lack of antagonist-bound "inactive" receptor structures hinders the rational design of receptor antagonists. In this study, we present a strategy for designing such antagonists. We constructed a model of the inactive conformation of human retinoic acid receptor- by using information derived from antagonist-bound estrogen receptor-α and applied a computer-based virtual screening algorithm to identify retinoic acid receptor antagonists. Thus, the currently available crystal structures of NRs may be used for the rational design of antagonists, which could lead to the development of novel drugs for a variety of diseases.

  4. Systemic Vascular Function Is Associated with Muscular Power in Older Adults

    PubMed Central

    Heffernan, Kevin S.; Chalé, Angela; Hau, Cynthia; Cloutier, Gregory J.; Phillips, Edward M.; Warner, Patrick; Nickerson, Heather; Reid, Kieran F.; Kuvin, Jeffrey T.; Fielding, Roger A.

    2012-01-01

    Age-associated loss of muscular strength and muscular power is a critical determinant of loss of physical function and progression to disability in older adults. In this study, we examined the association of systemic vascular function and measures of muscle strength and power in older adults. Measures of vascular endothelial function included brachial artery flow-mediated dilation (FMD) and the pulse wave amplitude reactive hyperemia index (PWA-RHI). Augmentation index (AIx) was taken as a measure of systemic vascular function related to arterial stiffness and wave reflection. Measures of muscular strength included one repetition maximum (1RM) for a bilateral leg press. Peak muscular power was measured during 5 repetitions performed as fast as possible for bilateral leg press at 40% 1RM. Muscular power was associated with brachial FMD (r = 0.43, P < 0.05), PWA-RHI (r = 0.42, P < 0.05), and AIx (r = −0.54, P < 0.05). Muscular strength was not associated with any measure of vascular function. In conclusion, systemic vascular function is associated with lower-limb muscular power but not muscular strength in older adults. Whether loss of muscular power with aging contributes to systemic vascular deconditioning or vascular dysfunction contributes to decrements in muscular power remains to be determined. PMID:22966457

  5. Satellite Cells in Muscular Dystrophy - Lost in Polarity.

    PubMed

    Chang, Natasha C; Chevalier, Fabien P; Rudnicki, Michael A

    2016-06-01

    Recent findings employing the mdx mouse model for Duchenne muscular dystrophy (DMD) have revealed that muscle satellite stem cells play a direct role in contributing to disease etiology and progression of DMD, the most common and severe form of muscular dystrophy. Lack of dystrophin expression in DMD has critical consequences in satellite cells including an inability to establish cell polarity, abrogation of asymmetric satellite stem-cell divisions, and failure to enter the myogenic program. Thus, muscle wasting in dystrophic mice is not only caused by myofiber fragility but is exacerbated by intrinsic satellite cell dysfunction leading to impaired regeneration. Despite intense research and clinical efforts, there is still no effective cure for DMD. In this review we highlight recent research advances in DMD and discuss the current state of treatment and, importantly, how we can incorporate satellite cell-targeted therapeutic strategies to correct satellite cell dysfunction in DMD. PMID:27161598

  6. Relation of gamma oscillations in scalp recordings to muscular activity.

    PubMed

    Pope, Kenneth J; Fitzgibbon, Sean P; Lewis, Trent W; Whitham, Emma M; Willoughby, John O

    2009-06-01

    We recorded scalp electrical activity before and after full neuro-muscular paralysis in 5 volunteers and determined differences due to elimination of muscular activity on several standard applications of EEG. Due to paralysis, there were reductions in 'noisiness' of the standard scalp recordings which were maximal over the peripheral scalp, not explained by abolition of movement artefact, and best accounted for by sustained EMG activity in resting individuals. There was a corresponding reduction in spectral power in the gamma range. In central leads, the extent of gamma frequency coherence during a non-time-locked mental task (1 s epochs) was reduced by paralysis, likely due to a reduction in gamma-frequency coherence in widely arising EMG signals. In a time-locked mental task (auditory oddball), evoked responses were qualitatively unaffected by paralysis but 3 of 4 induced gamma responses were obscured by EMG. PMID:19229605

  7. Gene Therapy for Muscular Dystrophies: Progress and Challenges

    PubMed Central

    Oh, Donghoon

    2010-01-01

    Muscular dystrophies are groups of inherited progressive diseases of the muscle caused by mutations of diverse genes related to normal muscle function. Although there is no current effective treatment for these devastating diseases, various molecular strategies have been developed to restore the expressions of the associated defective proteins. In preclinical animal models, both viral and nonviral vectors have been shown to deliver recombinant versions of defective genes. Antisense oligonucleotides have been shown to modify the splicing mechanism of mesenger ribonucleic acid to produce an internally deleted but partially functional dystrophin in an experimental model of Duchenne muscular dystrophy. In addition, chemicals can induce readthrough of the premature stop codon in nonsense mutations of the dystrophin gene. On the basis of these preclinical data, several experimental clinical trials are underway that aim to demonstrate efficacy in treating these devastating diseases. PMID:20944811

  8. The importance of genetic diagnosis for Duchenne muscular dystrophy

    PubMed Central

    Aartsma-Rus, Annemieke; Ginjaar, Ieke B; Bushby, Kate

    2016-01-01

    Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy are caused by mutations in the dystrophin-encoding DMD gene. Large deletions and duplications are most common, but small mutations have been found as well. Having a correct diagnosis is important for family planning and providing proper care to patients according to published guidelines. With mutation-specific therapies under development for DMD, a correct diagnosis is now also important for assessing whether patients are eligible for treatments. This review discusses different mutations causing DMD, diagnostic techniques available for making a genetic diagnosis for children suspected of DMD and the importance of having a specific genetic diagnosis in the context of emerging genetic therapies for DMD. PMID:26754139

  9. [Electrical properties of limb muscular tissue in acute circulatory hypoxia].

    PubMed

    Kolchev, A I; Nasonkin, O S

    1994-01-01

    The study was undertaken to examine dispersion of the complex electric resistance and capacitive impedance of limb muscular tissue in the frequency range of 1 to 100 kHz in acute circulatory hypoxia caused by blood exfusion from the common carotid artery at 10-50% of the circulatory blood volume (CBV) at the same time local blood flow and oxygen tension in muscles were measured. Blood loss of 10-30% of CBV resulted in increased muscular tissue electric conductivity. Decompensated blood loss was characterized by a steady growth of complex electric resistance and capacitive impedance. There were the greatest changes in electric conductivity in the frequency range of 1-10 kHz. PMID:7824348

  10. Emery-Dreifuss muscular dystrophy: the most recognizable laminopathy.

    PubMed

    Madej-Pilarczyk, A; Kochański, A

    2016-01-01

    Emery-Dreifuss muscular dystrophy (EDMD), a rare inherited disease, is characterized clinically by humero-peroneal muscle atrophy and weakness, multijoint contractures, spine rigidity and cardiac insufficiency with conduction defects. There are at least six types of EDMD known so far, of which five have been associated with mutations in genes encoding nuclear proteins. The majority of the EDMD cases described so far are of the emerinopathy (EDMD1) kind, with a recessive X-linked mode of inheritance, or else laminopathy (EDMD2), with an autosomal dominant mode of inheritance. In the work described here, the authors have sought to describe the history by which EDMD came to be distinguished as a separate entity, as well as the clinical and genetic characteristics of the disease, the pathophysiology of lamin-related muscular diseases and, finally, therapeutic issues, prevention and ethical aspects. PMID:27179216

  11. The importance of genetic diagnosis for Duchenne muscular dystrophy.

    PubMed

    Aartsma-Rus, Annemieke; Ginjaar, Ieke B; Bushby, Kate

    2016-03-01

    Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy are caused by mutations in the dystrophin-encoding DMD gene. Large deletions and duplications are most common, but small mutations have been found as well. Having a correct diagnosis is important for family planning and providing proper care to patients according to published guidelines. With mutation-specific therapies under development for DMD, a correct diagnosis is now also important for assessing whether patients are eligible for treatments. This review discusses different mutations causing DMD, diagnostic techniques available for making a genetic diagnosis for children suspected of DMD and the importance of having a specific genetic diagnosis in the context of emerging genetic therapies for DMD. PMID:26754139

  12. Cell transplantation and gene therapy in muscular dystrophy.

    PubMed

    Morgan, J E; Partridge, T A

    1992-09-01

    Duchenne's muscular dystrophy (DMD), which affects 1/3500 live male births, involves a progressive degeneration of skeletal and cardiac muscle, leading to early death. The protein dystrophin is lacking in DMD and present, but defective, in the allelic, less severe, Becker muscular dystrophy and is also missing in the mdx mouse. Experiments on the mdx mouse have suggested two possible therapies for these myopathies. Implantation of normal muscle precursor cells (mpc) into mdx skeletal muscle leads to the conversion of dystrophin-negative fibres to -positive, with consequent improvement in muscle histology. Direct injection of dystrophin cDNA into skeletal or cardiac muscle also gives rise to dystrophin-positive fibres. Although both appear promising, there are a number of questions to be answered and refinements to be made before either technique could be considered possible as treatments for myopathies in man. PMID:1365921

  13. [DIAGNOSTIC VARIATIONS OF X-LINKED MUSCULAR DYSTROPHY WITH CONTRACTURES].

    PubMed

    Kvirkvelia, N; Shakarishvili, R; Gugutsidze, D; Khizanishvili, N

    2015-01-01

    Case report with review describes X-linked muscular dystrophy with contractures in 28 years old man and his cousin. The disease revealed itself in an early stage (age 5-10), the process was progressing with apparent tendons retraction and contraction, limited movement in the areas of the neck and back of spine, atrophy of shoulder and pelvic yard and back muscles. Intellect was intact. Cardyomyopathy was exhibited. CK was normal. EMG showed classic myopathic features. Muscle biopsy showed different caliber groups of muscle fibers, growth of endo-perimesial connective tissue. Clinical manifestations together with electrophysiological and histological data suggest consistency with Rotthauwe-Mortier-Bayer X-linked muscular dystrophy. PMID:26177134

  14. Fibrogenic Cell Plasticity Blunts Tissue Regeneration and Aggravates Muscular Dystrophy.

    PubMed

    Pessina, Patrizia; Kharraz, Yacine; Jardí, Mercè; Fukada, So-ichiro; Serrano, Antonio L; Perdiguero, Eusebio; Muñoz-Cánoves, Pura

    2015-06-01

    Preservation of cell identity is necessary for homeostasis of most adult tissues. This process is challenged every time a tissue undergoes regeneration after stress or injury. In the lethal Duchenne muscular dystrophy (DMD), skeletal muscle regenerative capacity declines gradually as fibrosis increases. Using genetically engineered tracing mice, we demonstrate that, in dystrophic muscle, specialized cells of muscular, endothelial, and hematopoietic origins gain plasticity toward a fibrogenic fate via a TGFβ-mediated pathway. This results in loss of cellular identity and normal function, with deleterious consequences for regeneration. Furthermore, this fibrogenic process involves acquisition of a mesenchymal progenitor multipotent status, illustrating a link between fibrogenesis and gain of progenitor cell functions. As this plasticity also was observed in DMD patients, we propose that mesenchymal transitions impair regeneration and worsen diseases with a fibrotic component. PMID:25981413

  15. Biomechanical analysis of the muscular power of martial arts athletes.

    PubMed

    Machado, S M; Osório, R A L; Silva, N S; Magini, M

    2010-06-01

    This study analyzes the performance of knee extension and flexion of Taekwondo and Kickboxing athletes. The power values were extracted through electromyography obtained by an isokinetic dynamometer at 60 degrees per second. These values are resulted from the square of the electromyography signal. The analysis of kick power was made using a modified wavelet algorithm considering values with 95% significance. Both groups presented equivalent power and torque capacity with different training times and experience, on the other hand, the wavelet analysis showed better results in muscular recruitment performance in athletes with more experience, in other words, power is not only performance but also power plus recruitment produces better results. This study uniquely showed that muscular enhancement capacity is not only related to the power capacity of contraction but also to motor coordination. PMID:20390460

  16. Bimaxillary Osteotomy for Jaw Deformity With Facioscapulohumeral Muscular Dystrophy.

    PubMed

    Kawasaki, Takako; Ohba, Seigo; Fujimura, Yuji; Asahina, Izumi

    2016-05-01

    Facioscapulohumeral muscular dystrophy (FSHD) is a subtype of muscular dystrophies which reduces the muscle strength, especially the regions of scapular, shoulder, and upper arms, progressively. According to progressive muscle weakness in FSHD, postoperative stability of patient with FSHD after orthognathic surgery is not reliably acquired same as healthy subjects. A 32-year-old woman with FSHD underwent orthodontic and orthognathic surgical treatment due to jaw deformity. She has been followed up more than 3 years after surgery and acquired skeletal stability. This patient is the first report that showed long-term skeletal stability after orthognathic surgery in patient with FSHD. This patient report suggests that it is possible to apply orthognathic surgical treatment to patients with FSHD. PMID:27054436

  17. GluN2B subunit-containing NMDA receptor antagonists prevent Abeta-mediated synaptic plasticity disruption in vivo.

    PubMed

    Hu, Neng-Wei; Klyubin, Igor; Anwyl, Roger; Anwy, Roger; Rowan, Michael J

    2009-12-01

    Currently, treatment with the relatively low-affinity NMDA receptor antagonist memantine provides limited benefit in Alzheimer's disease (AD). One probable dose-limiting factor in the use of memantine is the inhibition of NMDA receptor-dependent synaptic plasticity mechanisms believed to underlie certain forms of memory. Moreover, amyloid-beta protein (Abeta) oligomers that are implicated in causing the cognitive deficits of AD potently inhibit this form of plasticity. Here we examined if subtype-preferring NMDA receptor antagonists could preferentially protect against the inhibition of NMDA receptor-dependent plasticity of excitatory synaptic transmission by Abeta in the hippocampus in vivo. Using doses that did not affect control plasticity, antagonists selective for NMDA receptors containing GluN2B but not other GluN2 subunits prevented Abeta(1-42) -mediated inhibition of plasticity. Evidence that the proinflammatory cytokine TNFalpha mediates this deleterious action of Ass was provided by the ability of TNFalpha antagonists to prevent Abeta(1-42) inhibition of plasticity and the abrogation of a similar disruptive effect of TNFalpha using a GluN2B-selective antagonist. Moreover, at nearby synapses that were resistant to the inhibitory effect of TNFalpha, Abeta(1-42) did not significantly affect plasticity. These findings suggest that preferentially targeting GluN2B subunit-containing NMDARs may provide an effective means of preventing cognitive deficits in early Alzheimer's disease. PMID:19918059

  18. Receptor residence time trumps drug-likeness and oral bioavailability in determining efficacy of complement C5a antagonists.

    PubMed

    Seow, Vernon; Lim, Junxian; Cotterell, Adam J; Yau, Mei-Kwan; Xu, Weijun; Lohman, Rink-Jan; Kok, W Mei; Stoermer, Martin J; Sweet, Matthew J; Reid, Robert C; Suen, Jacky Y; Fairlie, David P

    2016-01-01

    Drug discovery and translation are normally based on optimizing efficacy by increasing receptor affinity, functional potency, drug-likeness (rule-of-five compliance) and oral bioavailability. Here we demonstrate that residence time of a compound on its receptor has an overriding influence on efficacy, exemplified for antagonists of inflammatory protein complement C5a that activates immune cells and promotes disease. Three equipotent antagonists (3D53, W54011, JJ47) of inflammatory responses to C5a (3nM) were compared for drug-likeness, receptor affinity and antagonist potency in human macrophages, and anti-inflammatory efficacy in rats. Only the least drug-like antagonist (3D53) maintained potency in cells against higher C5a concentrations and had a much longer duration of action (t1/2 ~ 20 h) than W54011 or JJ47 (t1/2 ~ 1-3 h) in inhibiting macrophage responses. The unusually long residence time of 3D53 on its receptor was mechanistically probed by molecular dynamics simulations, which revealed long-lasting interactions that trap the antagonist within the receptor. Despite negligible oral bioavailability, 3D53 was much more orally efficacious than W54011 or JJ47 in preventing repeated agonist insults to induce rat paw oedema over 24 h. Thus, residence time on a receptor can trump drug-likeness in determining efficacy, even oral efficacy, of pharmacological agents. PMID:27094554

  19. Receptor residence time trumps drug-likeness and oral bioavailability in determining efficacy of complement C5a antagonists

    PubMed Central

    Seow, Vernon; Lim, Junxian; Cotterell, Adam J.; Yau, Mei-Kwan; Xu, Weijun; Lohman, Rink-Jan; Kok, W. Mei; Stoermer, Martin J.; Sweet, Matthew J.; Reid, Robert C.; Suen, Jacky Y.; Fairlie, David P.

    2016-01-01

    Drug discovery and translation are normally based on optimizing efficacy by increasing receptor affinity, functional potency, drug-likeness (rule-of-five compliance) and oral bioavailability. Here we demonstrate that residence time of a compound on its receptor has an overriding influence on efficacy, exemplified for antagonists of inflammatory protein complement C5a that activates immune cells and promotes disease. Three equipotent antagonists (3D53, W54011, JJ47) of inflammatory responses to C5a (3nM) were compared for drug-likeness, receptor affinity and antagonist potency in human macrophages, and anti-inflammatory efficacy in rats. Only the least drug-like antagonist (3D53) maintained potency in cells against higher C5a concentrations and had a much longer duration of action (t1/2 ~ 20 h) than W54011 or JJ47 (t1/2 ~ 1–3 h) in inhibiting macrophage responses. The unusually long residence time of 3D53 on its receptor was mechanistically probed by molecular dynamics simulations, which revealed long-lasting interactions that trap the antagonist within the receptor. Despite negligible oral bioavailability, 3D53 was much more orally efficacious than W54011 or JJ47 in preventing repeated agonist insults to induce rat paw oedema over 24 h. Thus, residence time on a receptor can trump drug-likeness in determining efficacy, even oral efficacy, of pharmacological agents. PMID:27094554

  20. Receptor residence time trumps drug-likeness and oral bioavailability in determining efficacy of complement C5a antagonists

    NASA Astrophysics Data System (ADS)

    Seow, Vernon; Lim, Junxian; Cotterell, Adam J.; Yau, Mei-Kwan; Xu, Weijun; Lohman, Rink-Jan; Kok, W. Mei; Stoermer, Martin J.; Sweet, Matthew J.; Reid, Robert C.; Suen, Jacky Y.; Fairlie, David P.

    2016-04-01

    Drug discovery and translation are normally based on optimizing efficacy by increasing receptor affinity, functional potency, drug-likeness (rule-of-five compliance) and oral bioavailability. Here we demonstrate that residence time of a compound on its receptor has an overriding influence on efficacy, exemplified for antagonists of inflammatory protein complement C5a that activates immune cells and promotes disease. Three equipotent antagonists (3D53, W54011, JJ47) of inflammatory responses to C5a (3nM) were compared for drug-likeness, receptor affinity and antagonist potency in human macrophages, and anti-inflammatory efficacy in rats. Only the least drug-like antagonist (3D53) maintained potency in cells against higher C5a concentrations and had a much longer duration of action (t1/2 ~ 20 h) than W54011 or JJ47 (t1/2 ~ 1–3 h) in inhibiting macrophage responses. The unusually long residence time of 3D53 on its receptor was mechanistically probed by molecular dynamics simulations, which revealed long-lasting interactions that trap the antagonist within the receptor. Despite negligible oral bioavailability, 3D53 was much more orally efficacious than W54011 or JJ47 in preventing repeated agonist insults to induce rat paw oedema over 24 h. Thus, residence time on a receptor can trump drug-likeness in determining efficacy, even oral efficacy, of pharmacological agents.

  1. Comparison of the effects of eleven histamine H1-receptor antagonists on monoamine turnover in the mouse brain.

    PubMed

    Oishi, R; Shishido, S; Yamori, M; Saeki, K

    1994-02-01

    To compare in vivo effects of eleven compounds of different classes of histamine H1-receptor antagonists (alcoholamines: diphenhydramine, carbinoxamine, and clemastine; ethylenediamines: mepyramine, tripelennamine, and clemizole; alkylamines: triprolidine and chlorpheniramine; piperazines: meclizine and homochlorcyclizine; phenothiazines: promethazine) on neuronal uptake of dopamine (DA), noradrenaline (NA), and 5-hydroxytryptamine (5-HT), the effects on the turnover of these monoamines were examined in the mouse brain, based on the alpha-methyl-p-tyrosine-induced depletion of DA and NA or probenecid-induced accumulation of 5-hydroxyindoleacetic acid. The DA turnover was reduced remarkably by diphenhydramine, tripelennamine, and promethazine, and also significantly by chlorpheniramine, mepyramine, clemizole, and homochlorcyclizine, at doses used in the ordinary animal experiments. The 5-HT turnover was reduced markedly by mepyramine, tripelennamine, and chlorpheniramine. In contrast, the NA turnover was increased by promethazine and homochlorcyclizine, possibly due to their antagonistic effects on alpha-adrenoceptors. These results suggest that (1) the degree of inhibition of the uptake of DA and 5-HT by histamine H1-receptor antagonists is considerably different, (2) most H1-antagonists have little influence on NA uptake and some compounds enhance NA release, and that (3) carbinoxamine, clemastine, triprolidine, and meclizine have comparatively weak influences on monoamine metabolism. These effects on brain monoamine systems may be related to some central actions of histamine H1-receptor antagonists, such as an addiction to these compounds combined with opioids. PMID:7513381

  2. POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking.

    PubMed

    Schindler, Roland F R; Scotton, Chiara; Zhang, Jianguo; Passarelli, Chiara; Ortiz-Bonnin, Beatriz; Simrick, Subreena; Schwerte, Thorsten; Poon, Kar-Lai; Fang, Mingyan; Rinné, Susanne; Froese, Alexander; Nikolaev, Viacheslav O; Grunert, Christiane; Müller, Thomas; Tasca, Giorgio; Sarathchandra, Padmini; Drago, Fabrizio; Dallapiccola, Bruno; Rapezzi, Claudio; Arbustini, Eloisa; Di Raimo, Francesca Romana; Neri, Marcella; Selvatici, Rita; Gualandi, Francesca; Fattori, Fabiana; Pietrangelo, Antonello; Li, Wenyan; Jiang, Hui; Xu, Xun; Bertini, Enrico; Decher, Niels; Wang, Jun; Brand, Thomas; Ferlini, Alessandra

    2016-01-01

    The Popeye domain-containing 1 (POPDC1) gene encodes a plasma membrane-localized cAMP-binding protein that is abundantly expressed in striated muscle. In animal models, POPDC1 is an essential regulator of structure and function of cardiac and skeletal muscle; however, POPDC1 mutations have not been associated with human cardiac and muscular diseases. Here, we have described a homozygous missense variant (c.602C>T, p.S201F) in POPDC1, identified by whole-exome sequencing, in a family of 4 with cardiac arrhythmia and limb-girdle muscular dystrophy (LGMD). This allele was absent in known databases and segregated with the pathological phenotype in this family. We did not find the allele in a further screen of 104 patients with a similar phenotype, suggesting this mutation to be family specific. Compared with WT protein, POPDC1(S201F) displayed a 50% reduction in cAMP affinity, and in skeletal muscle from patients, both POPDC1(S201F) and WT POPDC2 displayed impaired membrane trafficking. Forced expression of POPDC1(S201F) in a murine cardiac muscle cell line (HL-1) increased hyperpolarization and upstroke velocity of the action potential. In zebrafish, expression of the homologous mutation (popdc1(S191F)) caused heart and skeletal muscle phenotypes that resembled those observed in patients. Our study therefore identifies POPDC1 as a disease gene causing a very rare autosomal recessive cardiac arrhythmia and LGMD, expanding the genetic causes of this heterogeneous group of inherited rare diseases. PMID:26642364

  3. Cuttlefish skin papilla morphology suggests a muscular hydrostatic function for rapid changeability.

    PubMed

    Allen, Justine J; Bell, George R R; Kuzirian, Alan M; Hanlon, Roger T

    2013-06-01

    Coleoid cephalopods adaptively change their body patterns (color, contrast, locomotion, posture, and texture) for camouflage and signaling. Benthic octopuses and cuttlefish possess the capability, unique in the animal kingdom, to dramatically and quickly change their skin from smooth and flat to rugose and three-dimensional. The organs responsible for this physical change are the skin papillae, whose biomechanics have not been investigated. In this study, small dorsal papillae from cuttlefish (Sepia officinalis) were preserved in their retracted or extended state, and examined with a variety of histological techniques including brightfield, confocal, and scanning electron microscopy. Analyses revealed that papillae are composed of an extensive network of dermal erector muscles, some of which are arranged in concentric rings while others extend across each papilla's diameter. Like cephalopod arms, tentacles, and suckers, skin papillae appear to function as muscular hydrostats. The collective action of dermal erector muscles provides both movement and structural support in the absence of rigid supporting elements. Specifically, concentric circular dermal erector muscles near the papilla's base contract and push the overlying tissue upward and away from the mantle surface, while horizontally arranged dermal erector muscles pull the papilla's perimeter toward its center and determine its shape. Each papilla has a white tip, which is produced by structural light reflectors (leucophores and iridophores) that lie between the papilla's muscular core and the skin layer that contains the pigmented chromatophores. In extended papillae, the connective tissue layer appeared thinner above the papilla's apex than in surrounding areas. This result suggests that papilla extension might create tension in the overlying connective tissue and chromatophore layers, storing energy for elastic retraction. Numerous, thin subepidermal muscles form a meshwork between the chromatophore layer

  4. POPDC1S201F causes muscular dystrophy and arrhythmia by affecting protein trafficking

    PubMed Central

    Schindler, Roland F.R.; Scotton, Chiara; Zhang, Jianguo; Passarelli, Chiara; Ortiz-Bonnin, Beatriz; Simrick, Subreena; Schwerte, Thorsten; Poon, Kar-Lai; Fang, Mingyan; Rinné, Susanne; Froese, Alexander; Nikolaev, Viacheslav O.; Grunert, Christiane; Müller, Thomas; Tasca, Giorgio; Sarathchandra, Padmini; Drago, Fabrizio; Dallapiccola, Bruno; Rapezzi, Claudio; Arbustini, Eloisa; Di Raimo, Francesca Romana; Neri, Marcella; Selvatici, Rita; Gualandi, Francesca; Fattori, Fabiana; Pietrangelo, Antonello; Li, Wenyan; Jiang, Hui; Xu, Xun; Bertini, Enrico; Decher, Niels; Wang, Jun; Brand, Thomas; Ferlini, Alessandra

    2015-01-01

    The Popeye domain–containing 1 (POPDC1) gene encodes a plasma membrane–localized cAMP-binding protein that is abundantly expressed in striated muscle. In animal models, POPDC1 is an essential regulator of structure and function of cardiac and skeletal muscle; however, POPDC1 mutations have not been associated with human cardiac and muscular diseases. Here, we have described a homozygous missense variant (c.602C>T, p.S201F) in POPDC1, identified by whole-exome sequencing, in a family of 4 with cardiac arrhythmia and limb-girdle muscular dystrophy (LGMD). This allele was absent in known databases and segregated with the pathological phenotype in this family. We did not find the allele in a further screen of 104 patients with a similar phenotype, suggesting this mutation to be family specific. Compared with WT protein, POPDC1S201F displayed a 50% reduction in cAMP affinity, and in skeletal muscle from patients, both POPDC1S201F and WT POPDC2 displayed impaired membrane trafficking. Forced expression of POPDC1S201F in a murine cardiac muscle cell line (HL-1) increased hyperpolarization and upstroke velocity of the action potential. In zebrafish, expression of the homologous mutation (popdc1S191F) caused heart and skeletal muscle phenotypes that resembled those observed in patients. Our study therefore identifies POPDC1 as a disease gene causing a very rare autosomal recessive cardiac arrhythmia and LGMD, expanding the genetic causes of this heterogeneous group of inherited rare diseases. PMID:26642364

  5. Synthesis of actively adjustable springs by antagonistic redundant actuation

    NASA Technical Reports Server (NTRS)

    Yi, Byung-Ju; Freeman, Robert A.

    1992-01-01

    A methodology for active spring generation is presented based on antagonistic redundant actuation. Antagonistic properties are characterized using an effective system stiffness. 'Antagonistic stiffness' is generated by preloading a closed-chain (parallel) linkage system. Internal load distribution is investigated along with the necessary conditions for spring synthesis. The performance and stability of a proposed active spring are shown by simulation, and applications are discussed.

  6. Action Learning.

    ERIC Educational Resources Information Center

    1996

    These four papers were presented at a symposium on action learning moderated by Lex Dilworth at the 1996 conference of the Academy of Human Resource Development. "Developing an Infrastructure for Individual and Organizational Change: Transfer of Learning from an Action Reflection Learning (ARL) Program" (ARL Inquiry) reports findings from a study…

  7. Caffeine and anaerobic performance: ergogenic value and mechanisms of action.

    PubMed

    Davis, J K; Green, J Matt

    2009-01-01

    large role. Additionally, enhanced Na+/K+ pump activity has been proposed to potentially enhance excitation contraction coupling with caffeine. A more favourable hypothesis seems to be that caffeine stimulates the CNS. Caffeine acts antagonistically on adenosine receptors, thereby inhibiting the negative effects adenosine induces on neurotransmission, arousal and pain perception. The hypoalgesic effects of caffeine have resulted in dampened pain perception and blunted perceived exertion during exercise. This could potentially have favourable effects on negating decreased firing rates of motor units and possibly produce a more sustainable and forceful muscle contraction. The exact mechanisms behind caffeine's action remain to be elucidated. PMID:19757860

  8. [Clinicopathological study of a case of oculopharyngeal muscular dystrophy].

    PubMed

    Moreno Martínez, J M; Martín Araguz, A; García de la Rocha, M L; Masjuán Vallejo, J; Barón Rubio, M; Ginel Feito, M D

    1991-01-01

    One case of oculopharyngeal muscular dystrophy is reported, in a 75 year old white male with manifest family history of palpebral ptosis. He displayed bilateral ptosis and dysphagia. Diagnosis was carried out after clinical, electrical and bioptic procedures. Data obtained have been discussed with previous reports in the literature. It was necessary to perform a cricopharyngeal myotomy to overcome the malnutrition secondary to his swallowing problem. PMID:1804038

  9. Dominant spinal muscular atrophy with lower extremity predominance

    PubMed Central

    Harms, M.B.; Allred, P.; Gardner, R.; Fernandes Filho, J.A.; Florence, J.; Pestronk, A.; Al-Lozi, M.; Baloh, R.H.

    2010-01-01

    Objective: Spinal muscular atrophies (SMAs) are hereditary disorders characterized by weakness from degeneration of spinal motor neurons. Although most SMA cases with proximal weakness are recessively inherited, rare families with dominant inheritance have been reported. We aimed to clinically, pathologically, and genetically characterize a large North American family with an autosomal dominant proximal SMA. Methods: Affected family members underwent clinical and electrophysiologic evaluation. Twenty family members were genotyped on high-density genome-wide SNP arrays and linkage analysis was performed. Results: Ten affected individuals (ages 7–58 years) showed prominent quadriceps atrophy, moderate to severe weakness of quadriceps and hip abductors, and milder degrees of weakness in other leg muscles. Upper extremity strength and sensation was normal. Leg weakness was evident from early childhood and was static or very slowly progressive. Electrophysiology and muscle biopsies were consistent with chronic denervation. SNP-based linkage analysis showed a maximum 2-point lod score of 5.10 (θ = 0.00) at rs17679127 on 14q32. A disease-associated haplotype spanning from 114 cM to the 14q telomere was identified. A single recombination narrowed the minimal genomic interval to Chr14: 100,220,765–106,368,585. No segregating copy number variations were found within the disease interval. Conclusions: We describe a family with an early onset, autosomal dominant, proximal SMA with a distinctive phenotype: symptoms are limited to the legs and there is notable selectivity for the quadriceps. We demonstrate linkage to a 6.1-Mb interval on 14q32 and propose calling this disorder spinal muscular atrophy–lower extremity, dominant. GLOSSARY lod = logarithm of the odds; SMA = spinal muscular atrophy; SMA-LED = spinal muscular atrophy–lower extremity, dominant; SNP = single-nucleotide polymorphism. PMID:20697106

  10. Revised genetic classification of Limb Girdle Muscular Dystrophies.

    PubMed

    Magri, F; Brajkovic, S; Govoni, A; Brusa, R; Comi, G P

    2014-10-10

    Limb girdle muscular dystrophies (LGMD) are a heterogeneous group of inherited progressive muscle disorders affecting predominantly the shoulder and pelvic girdle muscles. They present both with autosomal dominant and autosomal recessive patterns of inheritance. Recent development, including results from Next Generation Sequencing technology, expanded the number of recognised forms. Therefore a revised genetic classification that takes into account the novel entities is needed, allowing clinicians and researchers to refer to a common nomenclature for diagnostic and research purposes. PMID:25323878

  11. Muscular Strength and Incident Hypertension in Normotensive and Prehypertensive Men

    PubMed Central

    Maslow, Andréa L.; Sui, Xuemei; Colabianchi, Natalie; Hussey, Jim; Blair, Steven N.

    2009-01-01

    The protective effects of cardiorespiratory fitness (CRF) on hypertension (HTN) are well known; however, the association between muscular strength and incidence of HTN has yet to be examined. Purpose This study evaluated the strength-HTN association with and without accounting for CRF. Methods Participants were 4147 men (20–82 years) in the Aerobics Center Longitudinal Study for whom an age-specific composite muscular strength score was computed from measures of a 1-repetition maximal leg and a 1-repetition maximal bench press. CRF was quantified by maximal treadmill exercise test time in minutes. Cox proportional hazards regression analysis was used to estimate hazard ratios (HRs) and 95% confidence intervals of incident HTN events according to exposure categories. Results During a mean follow-up of 19 years, there were 503 incident HTN cases. Multivariable-adjusted (excluding CRF) HRs of hypertension in normotensive men comparing middle and high strength thirds to the lowest third were not significant at 1.17 and 0.84, respectively. Multivariable-adjusted (excluding CRF) HRs of hypertension in baseline prehypertensive men comparing middle and high strength thirds to the lowest third were significant at 0.73 and 0.72 (p=.01 each), respectively. The association between muscular strength and incidence of HTN in baseline prehypertensive men was no longer significant after control for CRF (p=.26). Conclusions The study indicated that middle and high levels of muscular strength were associated with a reduced risk of HTN in prehypertensive men only. However, this relationship was no longer significant after controlling for CRF. PMID:19927030

  12. Sexually antagonistic selection in human male homosexuality.

    PubMed

    Camperio Ciani, Andrea; Cermelli, Paolo; Zanzotto, Giovanni

    2008-01-01

    Several lines of evidence indicate the existence of genetic factors influencing male homosexuality and bisexuality. In spite of its relatively low frequency, the stable permanence in all human populations of this apparently detrimental trait constitutes a puzzling 'Darwinian paradox'. Furthermore, several studies have pointed out relevant asymmetries in the distribution of both male homosexuality and of female fecundity in the parental lines of homosexual vs. heterosexual males. A number of hypotheses have attempted to give an evolutionary explanation for the long-standing persistence of this trait, and for its asymmetric distribution in family lines; however a satisfactory understanding of the population genetics of male homosexuality is lacking at present. We perform a systematic mathematical analysis of the propagation and equilibrium of the putative genetic factors for male homosexuality in the population, based on the selection equation for one or two diallelic loci and Bayesian statistics for pedigree investigation. We show that only the two-locus genetic model with at least one locus on the X chromosome, and in which gene expression is sexually antagonistic (increasing female fitness but decreasing male fitness), accounts for all known empirical data. Our results help clarify the basic evolutionary dynamics of male homosexuality, establishing this as a clearly ascertained sexually antagonistic human trait. PMID:18560521

  13. Sexually Antagonistic Selection in Human Male Homosexuality

    PubMed Central

    Camperio Ciani, Andrea; Cermelli, Paolo; Zanzotto, Giovanni

    2008-01-01

    Several lines of evidence indicate the existence of genetic factors influencing male homosexuality and bisexuality. In spite of its relatively low frequency, the stable permanence in all human populations of this apparently detrimental trait constitutes a puzzling ‘Darwinian paradox’. Furthermore, several studies have pointed out relevant asymmetries in the distribution of both male homosexuality and of female fecundity in the parental lines of homosexual vs. heterosexual males. A number of hypotheses have attempted to give an evolutionary explanation for the long-standing persistence of this trait, and for its asymmetric distribution in family lines; however a satisfactory understanding of the population genetics of male homosexuality is lacking at present. We perform a systematic mathematical analysis of the propagation and equilibrium of the putative genetic factors for male homosexuality in the population, based on the selection equation for one or two diallelic loci and Bayesian statistics for pedigree investigation. We show that only the two-locus genetic model with at least one locus on the X chromosome, and in which gene expression is sexually antagonistic (increasing female fitness but decreasing male fitness), accounts for all known empirical data. Our results help clarify the basic evolutionary dynamics of male homosexuality, establishing this as a clearly ascertained sexually antagonistic human trait. PMID:18560521

  14. Small molecule TSHR agonists and antagonists.

    PubMed

    Neumann, S; Gershengorn, M C

    2011-04-01

    TSH activates the TSH receptor (TSHR) thereby stimulating the function of thyroid follicular cells (thyrocytes) leading to biosynthesis and secretion of thyroid hormones. Because TSHR is involved in several thyroid pathologies, there is a strong rationale for the design of small molecule "drug-like" ligands. Recombinant human TSH (rhTSH, Thyrogen(®)) has been used in the follow-up of patients with thyroid cancer to increase the sensitivity for detection of recurrence or metastasis. rhTSH is difficult to produce and must be administered by injection. A small molecule TSHR agonist could produce the same beneficial effects as rhTSH but with greater ease of oral administration. We developed a small molecule ligand that is a full agonist at TSHR. Importantly for its clinical potential, this agonist elevated serum thyroxine and stimulated thyroidal radioiodide uptake in mice after its absorption from the gastrointestinal tract following oral administration. Graves' disease (GD) is caused by persistent, unregulated stimulation of thyrocytes by thyroid-stimulating antibodies (TSAbs) that activate TSHR. We identified the first small molecule TSHR antagonists that inhibited TSH- and TSAb-stimulated signalling in primary cultures of human thyrocytes. Our results provide proof-of-principle for effectiveness of small molecule agonists and antagonists for TSHR. We suggest that these small molecule ligands are lead compounds for the development of higher potency ligands that can be used as probes of TSHR biology with therapeutic potential. PMID:21511239

  15. Antagonistic coevolution between quantitative and Mendelian traits.

    PubMed

    Yamamichi, Masato; Ellner, Stephen P

    2016-03-30

    Coevolution is relentlessly creating and maintaining biodiversity and therefore has been a central topic in evolutionary biology. Previous theoretical studies have mostly considered coevolution between genetically symmetric traits (i.e. coevolution between two continuous quantitative traits or two discrete Mendelian traits). However, recent empirical evidence indicates that coevolution can occur between genetically asymmetric traits (e.g. between quantitative and Mendelian traits). We examine consequences of antagonistic coevolution mediated by a quantitative predator trait and a Mendelian prey trait, such that predation is more intense with decreased phenotypic distance between their traits (phenotype matching). This antagonistic coevolution produces a complex pattern of bifurcations with bistability (initial state dependence) in a two-dimensional model for trait coevolution. Furthermore, with eco-evolutionary dynamics (so that the trait evolution affects predator-prey population dynamics), we find that coevolution can cause rich dynamics including anti-phase cycles, in-phase cycles, chaotic dynamics and deterministic predator extinction. Predator extinction is more likely to occur when the prey trait exhibits complete dominance rather than semidominance and when the predator trait evolves very rapidly. Our study illustrates how recognizing the genetic architectures of interacting ecological traits can be essential for understanding the population and evolutionary dynamics of coevolving species. PMID:27009218

  16. Cognitive and Neurobehavioral Profile in Boys With Duchenne Muscular Dystrophy.

    PubMed

    Banihani, Rudaina; Smile, Sharon; Yoon, Grace; Dupuis, Annie; Mosleh, Maureen; Snider, Andrea; McAdam, Laura

    2015-10-01

    Duchenne muscular dystrophy is a progressive neuromuscular condition that has a high rate of cognitive and learning disabilities as well as neurobehavioral disorders, some of which have been associated with disruption of dystrophin isoforms. Retrospective cohort of 59 boys investigated the cognitive and neurobehavioral profile of boys with Duchenne muscular dystrophy. Full-scale IQ of < 70 was seen in 27%; learning disability in 44%, intellectual disability in 19%; attention-deficit/hyperactivity disorder in 32%; autism spectrum disorders in 15%; and anxiety in 27%. Mutations affecting Dp260 isoform and 5'untranslated region of Dp140 were observed in 60% with learning disability, 50% intellectual disability, 77% with autism spectrum disorders, and 94% with anxiety. No statistically significant correlation was noted between comorbidities and dystrophin isoforms; however, there is a trend of cumulative loss of dystrophin isoforms with declining full-scale IQ. Enhanced psychology testing to include both cognitive and neurobehavioral disorders is recommended for all individuals with Duchenne muscular dystrophy. PMID:25660133

  17. Genetic Engineering of Dystroglycan in Animal Models of Muscular Dystrophy

    PubMed Central

    Sciandra, Francesca; Bigotti, Maria Giulia; Giardina, Bruno; Bozzi, Manuela; Brancaccio, Andrea

    2015-01-01

    In skeletal muscle, dystroglycan (DG) is the central component of the dystrophin-glycoprotein complex (DGC), a multimeric protein complex that ensures a strong mechanical link between the extracellular matrix and the cytoskeleton. Several muscular dystrophies arise from mutations hitting most of the components of the DGC. Mutations within the DG gene (DAG1) have been recently associated with two forms of muscular dystrophy, one displaying a milder and one a more severe phenotype. This review focuses specifically on the animal (murine and others) model systems that have been developed with the aim of directly engineering DAG1 in order to study the DG function in skeletal muscle as well as in other tissues. In the last years, conditional animal models overcoming the embryonic lethality of the DG knock-out in mouse have been generated and helped clarifying the crucial role of DG in skeletal muscle, while an increasing number of studies on knock-in mice are aimed at understanding the contribution of single amino acids to the stability of DG and to the possible development of muscular dystrophy. PMID:26380289

  18. The quality of life in boys with Duchenne muscular dystrophy.

    PubMed

    Zamani, Gholamreza; Heidari, Morteza; Azizi Malamiri, Reza; Ashrafi, Mahmoud Reza; Mohammadi, Mahmoud; Shervin Badv, Reza; Hosseini, Seyed Ahmad; Salehi, Soodeh; Shahrokhi, Amin; Qorbani, Mostafa; Fathi, Mohammad Reza

    2016-07-01

    We conducted a study to evaluate the quality of life in boys with Duchenne muscular dystrophy aged 8-18 years, compared with that in matched healthy controls. A total of 85 boys with Duchenne muscular dystrophy aged 8-18 years and 136 age, sex and living place matched healthy controls were included in this study. Patients and one of their parents separately completed the 27-item Persian version of KIDSCREEN questionnaire (child and adolescent version and parent version). From the children's perspective, the quality of life in patients was found to be lower in two subclasses: "physical activities and health" (p < 0.001) and "friends" (p = 0.005). Parental estimation of their sick child's quality of life was significantly lower than children's own assessment in two subclasses: "physical activities and health" (p < 0.001) and "general mood and feelings" (p < 0.001). Our results indicate that boys with Duchenne muscular dystrophy have quite a satisfactory quality of life. A happier and more hopeful life can be promoted through increasing social support and improving the parental knowledge regarding their child's more positive life perspective. PMID:27234309

  19. Differential isoform expression and selective muscle involvement in muscular dystrophies.

    PubMed

    Huovinen, Sanna; Penttilä, Sini; Somervuo, Panu; Keto, Joni; Auvinen, Petri; Vihola, Anna; Huovinen, Sami; Pelin, Katarina; Raheem, Olayinka; Salenius, Juha; Suominen, Tiina; Hackman, Peter; Udd, Bjarne

    2015-10-01

    Despite the expression of the mutated gene in all muscles, selective muscles are involved in genetic muscular dystrophies. Different muscular dystrophies show characteristic patterns of fatty degenerative changes by muscle imaging, even to the extent that the patterns have been used for diagnostic purposes. However, the underlying molecular mechanisms explaining the selective involvement of muscles are not known. To test the hypothesis that different muscles may express variable amounts of different isoforms of muscle genes, we applied a custom-designed exon microarray containing probes for 57 muscle-specific genes to assay the transcriptional profiles in sets of human adult lower limb skeletal muscles. Quantitative real-time PCR and whole transcriptome sequencing were used to further analyze the results. Our results demonstrate significant variations in isoform and gene expression levels in anatomically different muscles. Comparison of the known patterns of selective involvement of certain muscles in two autosomal dominant titinopathies and one autosomal dominant myosinopathy, with the isoform and gene expression results, shows a correlation between the specific muscles involved and significant differences in the level of expression of the affected gene and exons in these same muscles compared with some other selected muscles. Our results suggest that differential expression levels of muscle genes and isoforms are one determinant in the selectivity of muscle involvement in muscular dystrophies. PMID:26269091

  20. Gay male attraction toward muscular men: does mating context matter?

    PubMed

    Varangis, Eleanna; Lanzieri, Nicholas; Hildebrandt, Tom; Feldman, Matthew

    2012-03-01

    The purpose of this study was to examine gay men's perceived attractiveness of male figures based on short-term and long-term partner contexts. A sample of 190 gay adult men rated the attractiveness of line-drawings depicting male figures varying systematically in muscularity and body fat percentage in both short-term and long-term dating contexts. Mixed effects modeling was used to estimate the effects of figure (muscularity and body fat), dating context (short-term vs. long-term), and individual rater characteristics on attractiveness ratings. Results indicated that figure muscularity and body-fat had significant non-linear (i.e., quadratic) relationships with attractiveness ratings, and short-term dating context was associated with more discriminating ratings of attractiveness. Interactions between individual characteristics and figure characteristics indicated that the more available the individual and lower body fat, the more discriminating they were in ratings of attractiveness. The implications for future investigations considering both object and observer characteristics of attractiveness preferences are discussed. PMID:22342537

  1. Computational modeling of muscular thin films for cardiac repair

    NASA Astrophysics Data System (ADS)

    Böl, Markus; Reese, Stefanie; Parker, Kevin Kit; Kuhl, Ellen

    2009-03-01

    Motivated by recent success in growing biohybrid material from engineered tissues on synthetic polymer films, we derive a computational simulation tool for muscular thin films in cardiac repair. In this model, the polydimethylsiloxane base layer is simulated in terms of microscopically motivated tetrahedral elements. Their behavior is characterized through a volumetric contribution and a chain contribution that explicitly accounts for the polymeric microstructure of networks of long chain molecules. Neonatal rat ventricular cardiomyocytes cultured on these polymeric films are modeled with actively contracting truss elements located on top of the sheet. The force stretch response of these trusses is motivated by the cardiomyocyte force generated during active contraction as suggested by the filament sliding theory. In contrast to existing phenomenological models, all material parameters of this novel model have a clear biophyisical interpretation. The predictive features of the model will be demonstrated through the simulation of muscular thin films. First, the set of parameters will be fitted for one particular experiment documented in the literature. This parameter set is then used to validate the model for various different experiments. Last, we give an outlook of how the proposed simulation tool could be used to virtually predict the response of multi-layered muscular thin films. These three-dimensional constructs show a tremendous regenerative potential in repair of damaged cardiac tissue. The ability to understand, tune and optimize their structural response is thus of great interest in cardiovascular tissue engineering.

  2. Respiratory dysfunction in unsedated dogs with golden retriever muscular dystrophy.

    PubMed

    DeVanna, Justin C; Kornegay, Joe N; Bogan, Daniel J; Bogan, Janet R; Dow, Jennifer L; Hawkins, Eleanor C

    2014-01-01

    Golden retriever muscular dystrophy (GRMD) is a well-established model of Duchenne muscular dystrophy. The value of this model would be greatly enhanced with practical tools to monitor progression of respiratory dysfunction during treatment trials. Arterial blood gas analysis, tidal breathing spirometry, and respiratory inductance plethysmography (RIP) were performed to determine if quantifiable abnormalities could be identified in unsedated, untrained, GRMD dogs. Results from 11 dogs with a mild phenotype of GRMD and 11 age-matched carriers were compared. Arterial blood gas analysis was successfully performed in all dogs, spirometry in 21 of 22 (95%) dogs, and RIP in 18 of 20 (90%) dogs. Partial pressure of carbon dioxide and bicarbonate concentration were higher in GRMD dogs. Tidal breathing peak expiratory flows were markedly higher in GRMD dogs. Abnormal abdominal motion was present in 7 of 10 (70%) GRMD dogs. Each technique provided objective, quantifiable measures that will be useful for monitoring respiratory function in GRMD dogs during clinical trials while avoiding the influence of sedation on results. Increased expiratory flows and the pattern of abdominal breathing are novel findings, not reported in people with Duchenne muscular dystrophy, and might be a consequence of hyperinflation. PMID:24295812

  3. RESPIRATORY DYSFUNCTION IN UNSEDATED DOGS WITH GOLDEN RETRIEVER MUSCULAR DYSTROPHY

    PubMed Central

    DeVanna, Justin C.; Kornegay, Joe N.; Bogan, Daniel J.; Bogan, Janet R.; Dow, Jennifer L.; Hawkins, Eleanor C.

    2013-01-01

    Golden retriever muscular dystrophy (GRMD) is a well-established model of Duchenne muscular dystrophy. The value of this model would be greatly enhanced with practical tools to monitor progression of respiratory dysfunction during treatment trials. Arterial blood gas analysis, tidal breathing spirometry, and respiratory inductance plethysmography (RIP) were performed to determine if quantifiable abnormalities could be identified in unsedated, untrained, GRMD dogs. Results from 11 dogs with a mild phenotype of GRMD and 11 age-matched carriers were compared. Arterial blood gas analysis was successfully performed in all dogs, spirometry in 21 of 22 (95%) dogs, and RIP in 18 of 20 (90%) dogs. Partial pressure of carbon dioxide and bicarbonate concentration were higher in GRMD dogs. Tidal breathing peak expiratory flows were markedly higher in GRMD dogs. Abnormal abdominal motion was present in 7 of 10 (70%) GRMD dogs. Each technique provided objective, quantifiable measures that will be useful for monitoring respiratory function in GRMD dogs during clinical trials while avoiding the influence of sedation on results. Increased expiratory flows and the pattern of abdominal breathing are novel findings, not reported in people with Duchenne muscular dystrophy, and might be a consequence of hyperinflation. PMID:24295812

  4. Molecular Signatures of Membrane Protein Complexes Underlying Muscular Dystrophy.

    PubMed

    Turk, Rolf; Hsiao, Jordy J; Smits, Melinda M; Ng, Brandon H; Pospisil, Tyler C; Jones, Kayla S; Campbell, Kevin P; Wright, Michael E

    2016-06-01

    Mutations in genes encoding components of the sarcolemmal dystrophin-glycoprotein complex (DGC) are responsible for a large number of muscular dystrophies. As such, molecular dissection of the DGC is expected to both reveal pathological mechanisms, and provides a biological framework for validating new DGC components. Establishment of the molecular composition of plasma-membrane protein complexes has been hampered by a lack of suitable biochemical approaches. Here we present an analytical workflow based upon the principles of protein correlation profiling that has enabled us to model the molecular composition of the DGC in mouse skeletal muscle. We also report our analysis of protein complexes in mice harboring mutations in DGC components. Bioinformatic analyses suggested that cell-adhesion pathways were under the transcriptional control of NFκB in DGC mutant mice, which is a finding that is supported by previous studies that showed NFκB-regulated pathways underlie the pathophysiology of DGC-related muscular dystrophies. Moreover, the bioinformatic analyses suggested that inflammatory and compensatory mechanisms were activated in skeletal muscle of DGC mutant mice. Additionally, this proteomic study provides a molecular framework to refine our understanding of the DGC, identification of protein biomarkers of neuromuscular disease, and pharmacological interrogation of the DGC in adult skeletal muscle https://www.mda.org/disease/congenital-muscular-dystrophy/research. PMID:27099343

  5. Development of peripheral opioid antagonists' new insights into opioid effects.

    PubMed

    Moss, Jonathan; Rosow, Carl E

    2008-10-01

    The recent approval by the US Food and Drug Administration of 2 medications--methylnaltrexone and alvimopan--introduces a new class of therapeutic entities to clinicians. These peripherally acting mu-opioid receptor antagonists selectively reverse opioid actions mediated by receptors outside the central nervous system, while preserving centrally mediated analgesia. Methylnaltrexone, administered subcutaneously, has been approved in the United States, Europe, and Canada. In the United States, it is indicated for the treatment of opioid-induced constipation in patients with advanced illness (eg, cancer, AIDS) who are receiving palliative care, when response to laxative therapy has not been sufficient. Alvimopan, an orally administered medication, has been approved in the United States to facilitate recovery of gastrointestinal function after bowel resection and primary anastomosis. Clinical and laboratory studies performed during the development of these drugs have indicated that peripheral receptors mediate other opioid effects, including decreased gastric emptying, nausea and vomiting, pruritus, and urinary retention. Laboratory investigations with these compounds suggest that opioids affect fundamental cellular processes through mechanisms that were previously unknown. These mechanisms include modifications of human immunodeficiency virus penetration, tumor angiogenesis, vascular permeability, and bacterial virulence. PMID:18828971

  6. Vasopressin receptor antagonists and their role in clinical medicine

    PubMed Central

    Narayen, Girish; Mandal, Surya Narayan

    2012-01-01

    Hyponatremia is the most common electrolyte abnormality in hospitalized patients. Its treatment is based not only on extracellular fluid volume status of patients but also on its pathogenetic mechanisms. Conventional treatment of hyponatremia like fluid restriction, which is useful in euvolemic and hypervolemic hyponatremia, has very poor patient compliance over long term. Vasopressin receptor antagonists (Vaptans) are a new group of nonpeptide drugs which have been used in various clinical conditions with limited success. Whereas conivaptan is to be administered intravenously, the other vaptans like tolvaptan, lixivaptan, and satavaptan are effective as oral medication. They produce aquaresis by their action on vasopressin type 2 (V2R) receptors in the collecting duct and thus increase solute free water excretion. Vaptans are being used as an alternative to fluid restriction in euvolemic and hypervolemic hyponatremic patients. Efficacy of vaptans is now well accepted for management of correction of hyponatremia over a short period. However, its efficacy in improving the long-term morbidity and mortality in patients with chronic hyponatremia due to cirrhosis and heart failure is yet to be established. Vaptans have not become the mainstay treatment of hyponatremia yet. PMID:22470853

  7. Antagonistic Activity of Lactobacillus Isolates against Salmonella typhi In Vitro

    PubMed Central

    Abdel-Daim, Amira; Hassouna, Nadia; Hafez, Mohamed; Ashor, Mohamed Seif Aldeen; Aboulwafa, Mohammad M.

    2013-01-01

    Background. Enteric fever is a global health problem, and rapidly developing resistance to various drugs makes the situation more alarming. The potential use of Lactobacillus to control typhoid fever represents a promising approach, as it may exert protective actions through various mechanisms. Methods. In this study, the probiotic potential and antagonistic activities of 32 Lactobacillus isolates against Salmonella typhi were evaluated. The antimicrobial activity of cell free supernatants of Lactobacillus isolates, interference of Lactobacillus isolates with the Salmonella adherence and invasion, cytoprotective effect of Lactobacillus isolates, and possibility of concurrent use of tested Lactobacillus isolates and antibiotics were evaluated by testing their susceptibilities to antimicrobial agents, and their oxygen tolerance was also examined. Results. The results revealed that twelve Lactobacillus isolates could protect against Salmonella typhi infection through interference with both its growth and its virulence properties, such as adherence, invasion, and cytotoxicity. These Lactobacillus isolates exhibited MIC values for ciprofloxacin higher than those of Salmonella typhi and oxygen tolerance and were identified as Lactobacillus plantarum. Conclusion. The tested Lactobacillus plantarum isolates can be introduced as potential novel candidates that have to be subjected for in vivo and application studies for treatment and control of typhoid fever. PMID:24191248

  8. Rap1 and Rap2 Antagonistically Control Endothelial Barrier Resistance

    PubMed Central

    Pannekoek, Willem-Jan; Linnemann, Jelena R.; Brouwer, Patricia M.; Bos, Johannes L.; Rehmann, Holger

    2013-01-01

    Rap1 and Rap2 are closely related proteins of the Ras family of small G-proteins. Rap1 is well known to regulate cell-cell adhesion. Here, we have analysed the effect of Rap-mediated signalling on endothelial permeability using electrical impedance measurements of HUVEC monolayers and subsequent determination of the barrier resistance, which is a measure for the ease with which ions can pass cell junctions. In line with its well-established effect on cell-cell junctions, depletion of Rap1 decreases, whereas activation of Rap1 increases barrier resistance. Despite its high sequence homology with Rap1, depletion of Rap2 has an opposite, enhancing, effect on barrier resistance. This effect can be mimicked by depletion of the Rap2 specific activator RasGEF1C and the Rap2 effector MAP4K4, establishing Rap2 signalling as an independent pathway controlling barrier resistance. As simultaneous depletion or activation of both Rap1 and Rap2 results in a barrier resistance comparable to control cells, Rap1 and Rap2 control barrier resistance in a reciprocal manner. This Rap1-antagonizing effect of Rap2 is established independent of junctional actin formation. These data establish that endothelial barrier resistance is determined by the combined antagonistic actions of Rap1 and Rap2. PMID:23469100

  9. Mineralocorticoid Receptor Antagonists for Treatment of Hypertension and Heart Failure

    PubMed Central

    Sica, Domenic A.

    2015-01-01

    Spironolactone and eplerenone are both mineralocorticoid-receptor antagonists. These compounds block both the epithelial and nonepithelial actions of aldosterone, with the latter assuming increasing clinical relevance. Spironolactone and eplerenone both affect reductions in blood pressure either as mono- or add-on therapy; moreover, they each afford survival benefits in diverse circumstances of heart failure and the probability of renal protection in proteinuric chronic kidney disease. However, as use of mineralocorticoid-blocking agents has expanded, the hazards inherent in taking such drugs have become more apparent. Whereas the endocrine side effects of spironolactone are in most cases little more than a cosmetic annoyance, the potassium-sparing effects of both spironolactone and eplerenone can prove disastrous, even fatal, if sufficient degrees of hyperkalemia emerge. For most patients, however, the risk of developing hyperkalemia in and of itself should not discourage the sensible clinician from bringing these compounds into play. Hyperkalemia should always be considered a possibility in patients receiving either of these medications; therefore, anticipatory steps should be taken to minimize the likelihood of its occurrence if long-term therapy of these agents is being considered. PMID:27057293

  10. Prospective cohort study of spinal muscular atrophy types 2 and 3

    PubMed Central

    Kaufmann, Petra; McDermott, Michael P.; Darras, Basil T.; Finkel, Richard S.; Sproule, Douglas M.; Kang, Peter B.; Oskoui, Maryam; Constantinescu, Andrei; Gooch, Clifton L.; Foley, A. Reghan; Yang, Michele L.; Tawil, Rabi; Chung, Wendy K.; Martens, William B.; Montes, Jacqueline; Battista, Vanessa; O'Hagen, Jessica; Dunaway, Sally; Flickinger, Jean; Quigley, Janet; Riley, Susan; Glanzman, Allan M.; Benton, Maryjane; Ryan, Patricia A.; Punyanitya, Mark; Montgomery, Megan J.; Marra, Jonathan; Koo, Benjamin

    2012-01-01

    Objective: To characterize the natural history of spinal muscular atrophy type 2 and type 3 (SMA 2/3) beyond 1 year and to report data on clinical and biological outcomes for use in trial planning. Methods: We conducted a prospective observational cohort study of 79 children and young adults with SMA 2/3 who participated in evaluations for up to 48 months. Clinically, we evaluated motor and pulmonary function, quality of life, and muscle strength. We also measured SMN2 copy number, hematologic and biochemical profiles, muscle mass by dual x-ray absorptiometry (DXA), and the compound motor action potential (CMAP) in a hand muscle. Data were analyzed for associations between clinical and biological/laboratory characteristics cross-sectionally, and for change over time in outcomes using all available data. Results: In cross-sectional analyses, certain biological measures (specifically, CMAP, DXA fat-free mass index, and SMN2 copy number) and muscle strength measures were associated with motor function. Motor and pulmonary function declined over time, particularly at time points beyond 12 months of follow-up. Conclusion: The intermediate and mild phenotypes of SMA show slow functional declines when observation periods exceed 1 year. Whole body muscle mass, hand muscle compound motor action potentials, and muscle strength are associated with clinical measures of motor function. The data from this study will be useful for clinical trial planning and suggest that CMAP and DXA warrant further evaluation as potential biomarkers. PMID:23077013

  11. Morpho-functional relationship between muscular architecture and proportion of myofiber types in ovine antebrachial musculature.

    PubMed

    Konno, Toshihiro; Watanabe, Kouichi

    2012-01-01

    The antebrachium of domestic animals supports the trunk against gravity and generates propulsive force. The antigravity action of antebrachium is attributed to the contraction of flexor muscles of the carpal and digital joints. Mammalian skeletal muscles consist of myofibers, which are histochemically classified into type I, type IIA, and type IIB myofibers, of which composition reflects the proportional involvement of the muscle in varying function, such as posture maintenance and locomotion. The physiological cross-sectional area (PCSA), which are calculated from muscle volume, myofiber length, and pennation angle, reflects the maximum force of muscle. In the present study, we evaluated the PCSA of myofiber types in the antebrachial musculature and determined the magnitude of contribution from individual muscles toward varying actions of carpal and digital joints. The extensor carpi ulnaris and flexor digitorum superficialis muscles possessed a large proportional PCSA of type I myofibers, indicating the role for these muscles in maintaining a standing posture. The additional force required for walking/running was primarily provided by the flexor digitorum profundus caput humerale and extensor carpi radialis muscles. The proportional PCSA of myofiber types reflected the force generated for varying muscular function and provided insights into the dynamics of carpal and digital joints. PMID:23117305

  12. Cardiac electrophysiologic effects of a new calcium antagonist, lacidipine.

    PubMed

    Cerbai, E; DeBonfioli Cavalcabó, P; Masini, I; Visentin, S; Giotti, A; Mugelli, A

    1990-04-01

    Lacidipine is a new 1,4-dihydropyridine derivative with potent and long-lasting antihypertensive activity. We used intracellular microelectrodes to characterize the electrophysiologic properties of lacidipine on different cardiac preparations. Lacidipine (10(-8) -10(-6) M) dose-dependently decreased contractility of driven sheep Purkinje fibers. For concentrations less than or equal to 10(-7) M, this effect was associated with a selective decrease of the plateau height. Higher concentrations (3 X 10(-7) and 10(-6) M), however, affected action potential amplitude, overshoot, and maximum rate of depolarization. In the same range of concentrations, lacidipine did not affect normal automaticity of guinea-pig sinus node and sheep Purkinje fibers. Lacidipine (10(-6) M) consistently blocked barium-induced abnormal automaticity in Purkinje fibers and reduced the amplitude and Vmax of the slow action potentials induced by histamine (10(-5) M) in guinea pig papillary muscle depolarized by potassium (22 mM). The effect of lacidipine on the slow inward current (Isi) was studied in shortened Purkinje fibers under voltage-clamp conditions. Lacidipine (10(-7)-10(-6) M) reduced the Isi without affecting the I-V relationship. None of the effects of lacidipine was reversed by 2-h washout. The results indicate that lacidipine has calcium-antagonistic properties in cardiac tissues. Its cardiac effects occur at concentrations 100 times higher than those active in the vascular smooth muscle. The lack of recovery of the lacidipine effects suggests that its interaction with the calcium channel may occur at an inner site of the cell membrane. PMID:1691391

  13. Novel Use of Tolvaptan in a Pediatric Patient With Congestive Heart Failure Due to Duchenne Muscular Dystrophy and Congenital Adrenal Hyperplasia

    PubMed Central

    Sami, Sarah A.; Moffett, Brady S.; Karlsten, Melissa L.; Cabrera, Antonio G.; Price, Jack F.; Dreyer, William J.; Denfield, Susan W.

    2015-01-01

    Successful management of hyponatremia in heart failure patients requires a multifaceted approach in order to preserve end-organ function. We describe the novel use of a selective vasopressin receptor antagonist, tolvaptan, for management of hyponatremia in a 17-year-old Caucasian male with severe Duchenne muscular dystrophy, congestive heart failure (CHF), and congenital adrenal hyperplasia. The medical history was significant for recurrent admissions for hyponatremia secondary to adrenal crises, which was also exacerbated by his CHF. After initiation of tolvaptan and its extended administration, he had no further hyponatremia-related admissions and no adverse reactions. The complexity of this combination of conditions is presented, and the efficacy of the drug and the rationale behind the treatment approach is discussed. PMID:26472954

  14. Emerging role of orexin antagonists in insomnia therapeutics: An update on SORAs and DORAs.

    PubMed

    Kumar, Anil; Chanana, Priyanka; Choudhary, Supriti

    2016-04-01

    The pharmacological management of insomnia has lately become a challenge for researchers worldwide. As per the third International Classification of Sleep disorders (ICSD-3) insomnia can be defined as a state with repeated difficulty in sleep initiation, duration, consolidation, or quality that occurs despite adequate opportunity and circumstances for sleep, and results in some form of daytime impairment. The conventional treatments approved for management of insomnia were benzodiazepines (BZDs) (estazolam, quazepam, triazolam, flurazepam and temazepam) and non-BZDs, also known as z-drugs (zaleplon, zolpidem, and eszopiclone), tricyclic antidepressant (TCA) doxepin as well as melatonin agonists, e.g. ramelteon. But the potential of these agents to address sleep problems has been limited due to substantial side effects associated with them like hangover, dependence and tolerance, rebound insomnia, muscular atonia, inhibition of respiratory system, cognitive dysfunctions, and increased anxiety. Recently, orexin neuropeptides have been identified as regulators of transition between wakefulness and sleep and documented to aid an initial transitory effect towards wakefulness by activating cholinergic/monoaminergic neural pathways of the ascending arousal system. This has led to the development of orexin peptides and receptors, as possible therapeutic targets for the treatment of sleep disorders with the advantage of having lesser side effects as compared to conventional treatments. The present review focuses on the orexin peptides and receptors signifying their physiological profile as well as the development of orexin receptor antagonists as novel strategies in sleep medicine. PMID:26922522

  15. Drive for muscularity and disordered eating among French adolescent boys: a sociocultural model.

    PubMed

    Rodgers, Rachel F; Ganchou, Camille; Franko, Debra L; Chabrol, Henri

    2012-06-01

    The pursuit of muscularity is an important body image concern among boys which has been described within sociocultural models of risk for eating disorders. This study explored a sociocultural model of disordered eating in which drive for thinness and pursuit of muscularity were both pathways to disordered eating among French adolescent boys. A sample of 146 adolescents completed a questionnaire assessing drive for thinness, drive for muscularity, media-ideal internalization, appearance comparison, and sociocultural pressure. The model was a good fit to the data and both drive for thinness and the pursuit of muscularity were related to disordered eating. Furthermore, internalization and appearance comparison mediated the relationships between pressure to increase muscle and both drive for muscularity and drive for thinness. Longitudinal research could help clarify the role of the pursuit of muscularity in the development of disordered eating and extreme body shape changing behaviors. PMID:22494958

  16. Mechanisms of disease: congenital muscular dystrophies-glycosylation takes center stage.

    PubMed

    Martin, Paul T

    2006-04-01

    Recent studies have defined a group of muscular dystrophies, now termed the dystroglycanopathies, as novel disorders of glycosylation. These conditions include Walker-Warburg syndrome, muscle-eye-brain disease, Fukuyama-type congenital muscular dystrophy, congenital muscular dystrophy types 1C and 1D, and limb-girdle muscular dystrophy type 2I. Although clinical findings can be highly variable, dystroglycanopathies are all characterized by cortical malformations and ocular defects at the more severe end of the clinical spectrum, in addition to muscular dystrophy. All of these disorders are defined by the underglycosylation of alpha-dystroglycan. Defective glycosylation of dystroglycan severs the link between this important cell adhesion molecule and the extracellular matrix, thereby contributing to cellular pathology. Recent experiments indicate that glycosylation might not only define forms of muscular dystrophy but also provide an avenue to the development of therapies for these disorders. PMID:16932553

  17. Corticospinal control of antagonistic muscles in the cat.

    PubMed

    Ethier, Christian; Brizzi, Laurent; Giguère, Dominic; Capaday, Charles

    2007-09-01

    We recently suggested that movement-related inter-joint muscle synergies are recruited by selected excitation and selected release from inhibition of cortical points. Here we asked whether a similar cortical mechanism operates in the functional linking of antagonistic muscles. To this end experiments were done on ketamine-anesthetized cats. Intracortical microstimulation (ICMS) and intramuscular electromyographic recordings were used to find and characterize wrist, elbow and shoulder antagonistic motor cortical points. Simultaneous ICMS applied at two cortical points, each evoking activity in one of a pair of antagonistic muscles, produced co-contraction of antagonistic muscle pairs. However, we found an obvious asymmetry in the strength of reciprocal inhibition; it was always significantly stronger on physiological extensors than flexors. Following intravenous injection of a single bolus of strychnine, a cortical point at which only a physiological flexor was previously activated also elicited simultaneous activation of its antagonist. This demonstrates that antagonistic corticospinal neurons are closely grouped, or intermingled. To test whether releasing a cortical point from inhibition allows it to be functionally linked with an antagonistic cortical point, one of three GABA(A) receptor antagonists, bicuculline, gabazine or picrotoxin, was injected iontophoretically at one cortical point while stimulation was applied to an antagonistic cortical point. This coupling always resulted in co-contraction of the represented antagonistic muscles. Thus, antagonistic motor cortical points are linked by excitatory intracortical connections held in check by local GABAergic inhibition, with reciprocal inhibition occurring at the spinal level. Importantly, the asymmetry of cortically mediated reciprocal inhibition would appear significantly to bias muscle maps obtained by ICMS in favor of physiological flexors. PMID:17880397

  18. A novel leptin antagonist peptide inhibits breast cancer growth in vitro and in vivo

    PubMed Central

    Catalano, Stefania; Leggio, Antonella; Barone, Ines; De Marco, Rosaria; Gelsomino, Luca; Campana, Antonella; Malivindi, Rocco; Panza, Salvatore; Giordano, Cinzia; Liguori, Alessia; Bonofiglio, Daniela; Liguori, Angelo; Andò, Sebastiano

    2015-01-01

    The role of the obesity cytokine leptin in breast cancer progression has raised interest in interfering with leptin's actions as a valuable therapeutic strategy. Leptin interacts with its receptor through three different binding sites: I–III. Site I is crucial for the formation of an active leptin–leptin receptor complex and in its subsequent activation. Amino acids 39-42 (Leu-Asp-Phe-Ile- LDFI) were shown to contribute to leptin binding site I and their mutations in alanine resulted in muteins acting as typical antagonists. We synthesized a small peptide based on the wild-type sequence of leptin binding site I (LDFI) and evaluated its efficacy in antagonizing leptin actions in breast cancer using in vitro and in vivo experimental models. The peptide LDFI abolished the leptin-induced anchorage-dependent and -independent growth as well as the migration of ERα-positive (MCF-7) and -negative (SKBR3) breast cancer cells. These results were well correlated with a reduction in the phosphorylation levels of leptin downstream effectors, as JAK2/STAT3/AKT/MAPK. Importantly, the peptide LDFI reversed the leptin-mediated up-regulation of its gene expression, as an additional mechanism able to enhance the peptide antagonistic activity. The described effects were specific for leptin signalling, since the developed peptide was not able to antagonize the other growth factors' actions on signalling activation, proliferation and migration. Finally, we showed that the LDFI pegylated peptide markedly reduced breast tumour growth in xenograft models. The unmodified peptide LDFI acting as a full leptin antagonist could become an attractive option for breast cancer treatment, especially in obese women. PMID:25721149

  19. Mutually-antagonistic interactions in baseball networks

    NASA Astrophysics Data System (ADS)

    Saavedra, Serguei; Powers, Scott; McCotter, Trent; Porter, Mason A.; Mucha, Peter J.

    2010-03-01

    We formulate the head-to-head matchups between Major League Baseball pitchers and batters from 1954 to 2008 as a bipartite network of mutually-antagonistic interactions. We consider both the full network and single-season networks, which exhibit structural changes over time. We find interesting structure in the networks and examine their sensitivity to baseball’s rule changes. We then study a biased random walk on the matchup networks as a simple and transparent way to (1) compare the performance of players who competed under different conditions and (2) include information about which particular players a given player has faced. We find that a player’s position in the network does not correlate with his placement in the random walker ranking. However, network position does have a substantial effect on the robustness of ranking placement to changes in head-to-head matchups.

  20. Different affinity states of alpha-1 adrenergic receptors defined by agonists and antagonists in bovine aorta plasma membranes

    SciTech Connect

    Jagadeesh, G.; Deth, R.C.

    1987-11-01

    Evidence for a nonlinear relationship between alpha-1 adrenergic receptor occupancy and tissue responses, together with the finding of different affinity states for agonist binding, has raised the possibility of functional heterogeneity of alpha-1 adrenergic receptors. We have conducted studies to examine: 1) binding characteristics of (/sup 3/H)prazosin, 2) competition of antagonists at these sites and 3) different affinity states of the receptor for agonists and modulation of these states by 5'-guanylylimidodiphosphate (Gpp(NH)p). A plasma membrane-enriched vesicular fraction (F2; 15%/33% sucrose interphase) was prepared from the muscular medial layer of bovine thoracic aorta. (/sup 3/H)Prazosin binding was characterized by a monophasic saturation isotherm (KD = 0.116 nM, Bmax = 112 fmol/mg of protein). Antagonist displacement studies yielded a relative potency order of prazosin greater than or equal to WB4104 much greater than phentolamine greater than corynanthine greater than yohimbine greater than or equal to idazoxan greater than rauwolscine. Competition curves for unlabeled prazosin, WB4101 (2-(2,6-dimethoxyphenoxyethyl)-aminomethyl-1,4 benzodioxane) and phentolamine were shallow and were best modeled to two binding sites with picomolar and nanomolar KD values. Gpp(NH)p was without effect on antagonist affinity. Agonist (epinephrine, norepinephrine and phenylephrine) competition with (/sup 3/H)prazosin binding was biphasic with pseudo-Hill slopes less than 1.0. Binding was best described by a two-site model in which the average contribution of high affinity sites was 23% of total binding. KD values for the high affinity site ranged from 2.9 to 18 nM, and 3.9 to 5.0 microM for the low affinity site.

  1. A Laboratory Experiment on Muscular Metabolism and Fatigue Using the Isolated Frog Muscle Preparation.

    ERIC Educational Resources Information Center

    Ianuzzo, C. David; And Others

    1987-01-01

    Describes an experiment which demonstrates the association of particular metabolic biochemical changes and muscular fatigue. Highlights applications related to cellular energy metabolism, metabolic regulation, and muscle energetics. (ML)

  2. A dual CCR2/CCR5 chemokine antagonist, BMS-813160? Evaluation of WO2011046916.

    PubMed

    Norman, Peter

    2011-12-01

    This application claims the dual CCR2/CCR5 antagonist (S)-1-[(1S,2R,4R)-4-isopropyl(methyl)amino)-2-propylcyclohexyl]-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one, crystalline form N-1, a process for its preparation and therapeutic uses of it. The compound is shown to be a potent, well-absorbed, drug with a good duration of action. It shows better properties than similar compounds previously claimed by Bristol-Myers Squibb and appears to be a clinical development candidate. PMID:21936726

  3. Dotarizine versus flunarizine as calcium antagonists in chromaffin cells.

    PubMed Central

    Villarroya, M; Gandía, L; Lara, B; Albillos, A; López, M G; García, A G

    1995-01-01

    1. Dotarizine is a novel piperazine derivative structurally related to flunarizine that is currently being evaluated in clinical trials for its antimigraine and antivertigo effects. This clinical profile may be related to its Ca2+ antagonist properties. Therefore, the actions of both compounds as calcium antagonists were compared in bovine chromaffin cells. 2. Dotarizine and flunarizine blocked 45Ca2+ uptake into K+ depolarized chromaffin cells (70 mM K+/0.5 mM Ca2+ for 60 s) in a concentration-dependent manner, with IC50s of 4.8 and 6.7 microM, respectively. 3. Dotarizine and flunarizine also inhibited the whole-cell Ca2+ and Ba2+ currents (ICa, IBa) in voltage-clamped chromaffin cells, induced by depolarizing test pulses to 0 mV, during 50 ms, from a holding potential of -80 mV. Blockade exhibited IC50s of 4 microM for dotarizine and 2.2 microM for flunarizine. Dotarizine increased the rate of inactivation of ICa and IBa; inhibition of whole-cell currents was use-dependent. 4. Transient increases of the cytosolic Ca2+ concentration, [Ca2+]i, produced by K+ stimulation (70 mM K+ for 5 s) of single fura-2-loaded chromaffin cells, were also inhibited by dotarizine and flunarizine with IC50s of 1.2 and 0.6 microM, respectively. Upon washout of dotarizine, the [Ca2+]i increases recovered fully after 5-10 min. In contrast, the responses remained largely inhibited 10 min after washing out flunarizine. 5. Catecholamine release induced by K+ stimulation (10-s pulses of 70 mM) was inhibited by dotarizine with an IC50 of 2.6 microM and by flunarizine with an IC50 of 1.2 microM. The blocking effects of both compounds developed slowly, and was fully established after 20-30 min of superfusion.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7881736

  4. Action perception predicts action performance

    PubMed Central

    Bailey, Heather R.; Kurby, Christopher A.; Giovannetti, Tania; Zacks, Jeffrey M.

    2013-01-01

    Everyday action impairments often are observed in demented older adults, and they are common potential barriers to functional independence. We evaluated whether the ability to segment and efficiently encode activities is related to the ability to execute activities. Further, we evaluated whether brain regions important for segmentation also were important for action performance. Cognitively healthy older adults and those with very mild or mild dementia of the Alzheimer's type watched and segmented movies of everyday activities and then completed the Naturalistic Action Test. Structural MRI was used to measure volume in the dorsolateral prefrontal cortex (DLPFC), medial temporal lobes (MTL), posterior cortex, and anterior cingulate cortex (ACC). Dementia status and the ability to segment everyday activities strongly predicted naturalistic action performance, and MTL volume largely accounted for this relationship. In addition, the current results supported the Omission-Commission Model: Different cognitive and neurological mechanisms predicted different types of action error. Segmentation, dementia severity, and MTL volume predicted everyday omission errors, DLPFC volume predicted commission errors, and ACC volume predicted action additions. These findings suggest that event segmentation may be critical for effective action production, and that the segmentation and production of activities may recruit the same event representation system. PMID:23851113

  5. ACTIONS OF TRIETHYLCHOLINE ON NEUROMUSCULAR TRANSMISSION

    PubMed Central

    Bowman, W C; Rand, M J

    1997-01-01

    The effects of the triethyl analogue of choline (triethyl 2-hydroxyethyl ammonium) on muscular activity have been studied in conscious rabbits, chicks, dogs and a cat. The contractions of the tibialis anticus and soleus muscles of cats under chloralose anaesthesia, and of the tibialis anticus muscle of rabbits under urethane anaesthesia and the isolated diaphragm preparation of the rat were also used. In conscious animals, triethylcholine caused a slowly developing muscular weakness which was more severe after exercise and which resembled the symptoms of myasthenia gravis. In nerve-muscle preparations triethylcholine had a selective action in reducing the contractions of muscles elicited by a high rate of nerve stimulation while leaving unaffected the contractions caused by slower rates of stimulation. During the paralysis of the tibialis muscle of the cat produced by triethylcholine, action potentials recorded from the motor nerve were unaffected and the muscle responded normally to injected acetylcholine and to direct electrical stimulation. The failure of neuromuscular transmission produced by triethylcholine was reversed by injection of choline, but anticholinesterases were ineffective. Choline reduced the toxicity of triethylcholine in mice. It is concluded that triethylcholine produces transmission failure at the neuromuscular junction by interfering with the ability of the nerve endings to synthesize acetylcholine. The possibility that triethylcholine is itself acetylated by the nerve endings and released as an inactive neurohormone is discussed. It was shown that triethylcholine was devoid of depolarizing action and curare-like blocking action. It possesses a transient ganglion blocking action of the tetraethylammonium-type as shown in experiments in which it caused a fall in blood pressure and blocked the response of the nictitating membrane to pre- but not to post-ganglionic stimulation of the cervical sympathetic nerve. PMID:9142408

  6. Scorpion venom-induced neutrophilia is inhibited by a PAF receptor antagonist in the rat.

    PubMed

    Borges, C M; Silveira, M R; Aparecida, M; Beker, C L; Freire-Maia, L; Teixeira, M M

    2000-04-01

    A dramatic blood neutrophilia is an important feature of the severe envenoming caused by the Brazilian scorpion Tityus serrulatus and may contribute to the development of lung injury in children. We examined the effects of an intravenous injection of T. serrulatus scorpion venom (TsV) on the total number of leukocytes and neutrophils in the blood of anesthetized rats. Injection of TsV (250 microg/kg) induces a significant leukocytosis 2 and 3 h after its injection, explained by an increase in the number of neutrophils. The release of catecholamines and action on adrenoceptors is responsible for most of the systemic manifestations of TsV. However, pretreatment with the beta-adrenoceptor antagonists metoprolol and propranolol or the alpha1-adrenoceptor antagonist prazosin (0.25 mg/kg) did not prevent TsV-induced neutrophilia. Blood neutrophilia induced by TsV occurred simultaneously with a significant reduction of mature neutrophils in bone marrow. Pretreatment with the platelet-activating factor (PAF) receptor antagonists UK-74505 or WEB-2086 prevented TsV-induced increase in blood neutrophils and reduction in the number of neutrophils in the bone marrow. It is concluded that scorpion venom induces blood neutrophilia in rats, explained by a PAF receptor-dependent mobilization of neutrophils from the bone marrow. PMID:10770284

  7. Stress tolerance and biocontrol performance of the yeast antagonist, Candida diversa, change with morphology transition.

    PubMed

    Li, Guangkun; Chi, Mengshan; Chen, Huizhen; Sui, Yuan; Li, Yan; Liu, Yongsheng; Zhang, Xiaojing; Sun, Zhiqiang; Liu, Guoqing; Wang, Qi; Liu, Jia

    2016-02-01

    As an eco-friendly management method, biological control of postharvest diseases, utilizing antagonistic yeasts, is a research topic receiving considerable attention. Detailed knowledge on the biology of yeast antagonists is crucial when considering their potential application and development as biocontrol products. Changes in the growth form, such as single-cell to pseudohyphae, have been associated with the mode of action in postharvest biocontrol yeasts. In this study, the antagonistic yeast, Candida diversa, reversibly shifted from a single-cell morphology on yeast peptone dextrose (YPD) medium with 2 % agar to a pseudohyphal morphology on YPD with 0.3 % agar. The tolerance of the pseudohyphal form to heat and oxidative stresses, as well as the biocontrol efficacy against Botrytis cinerea on apple and kiwifruit stored at 25 and 4 °C, was significantly higher as compared to the single-cell form. This study provides new information on the ability of C. diversa to change its morphology and the impact of the morphology shift on stress tolerance and biocontrol performance. PMID:26637302

  8. Biological Control of Patulin by Antagonistic Yeast: A case study and possible model.

    PubMed

    Mahunu, Gustav Komla; Zhang, Hongyin; Yang, Qiya; Li, Chaolan; Zheng, Xiangfeng

    2016-08-01

    The occurrence of patulin in fresh apples and apple products is a great burden from health, safety and economic perspectives. Attempts to prevent patulin accumulation in fruits might lead to the excessive use of fungicides. Therefore, guaranteeing the safety of apple foods is crucial for the international apple industry. Recently, literature revealed that application of antagonistic yeasts and other BCAs have been able to disrupt the process of fungal infection and patulin production in apples. Although, over the years the effect of interaction between BCAs and fungi on patulin production has been reported, the exact mechanism(s) of their action remain unclear. Here, the review focused on toxicology and occurrence of PAT; research advances made over the past few years on the interaction between antagonistic yeast, fruits and patulin-producing fungi; the prevalence of patulin in apple fruits and products and the implications of synthetic-fungicide applications. In addition, attention was focused on the mechanism(s) and the enhancement of the biocontrol efficacy of antagonistic for patulin control. PMID:25845381

  9. Antagonistic toxicity of arsenate and cadmium in a freshwater amphipod (Gammarus pulex).

    PubMed

    Vellinger, Céline; Parant, Marc; Rousselle, Philippe; Usseglio-Polatera, Philippe

    2012-10-01

    Because toxicants rarely occur alone in the environment, a major challenge in risk assessment is to address the combined effects of chemicals on aquatic organisms. This work is aimed at investigating the joint toxicity action of binary mixtures of cadmium and arsenate on Gammarus pulex. Individuals were exposed during 240 h to four single arsenate or cadmium concentrations and binary mixtures of these metals according to a complete factorial plane. Observed mortality in binary mixtures was compared to observed mortality in single arsenate or cadmium exposures. In addition, interactive effects (antagonistic, additive or synergistic) were evaluated using a predictive model for the theoretically expected interactive effect of chemicals. For all the tested concentration combinations, we observed an antagonist 'between-metals' interaction on G. pulex mortality. This antagonistic effect was more marked for the lowest than for the highest (i.e. 1502.0 μg(AsV) L(-1) and 28.5 μg(Cd) L(-1)) tested concentrations of individual metals in binary mixtures. Metal concentrations in body tissues were evaluated and were significantly lower in binary mixtures than in single metal exposures at similar concentration, especially for combinations corresponding to the highest concentrations of both metals (1502.0 μg(AsV) L(-1) and 28.5 μg(Cd) L(-1)). Results were discussed in terms of (1) mechanisms of uptake and bioconcentration and (2) relationships between metal concentration in gammarid body and observed toxicity. PMID:22535317

  10. Effects of P2Y12 receptor antagonists beyond platelet inhibition - comparison of ticagrelor with thienopyridines.

    PubMed

    Nylander, Sven; Schulz, Rainer

    2016-04-01

    The effect and clinical benefit of P2Y12 receptor antagonists may not be limited to platelet inhibition and the prevention of arterial thrombus formation. Potential additional effects include reduction of the pro-inflammatory role of activated platelets and effects related to P2Y12 receptor inhibition on other cells apart from platelets. P2Y12 receptor antagonists, thienopyridines and ticagrelor, differ in their mode of action being prodrugs instead of direct acting and irreversibly instead of reversibly binding to P2Y12 . These key differences may provide different potential when it comes to additional effects. In addition to P2Y12 receptor blockade, ticagrelor is unique in having the only well-documented additional target of inhibition, the equilibrative nucleoside transporter 1. The current review will address the effects of P2Y12 receptor antagonists beyond platelets and the protection against arterial thrombosis. The discussion will include the potential for thienopyridines and ticagrelor to mediate anti-inflammatory effects, to conserve vascular function, to affect atherosclerosis, to provide cardioprotection and to induce dyspnea. PMID:26758983

  11. Plant growth-promoting rhizobacteria (PGPR): Their potential as antagonists and biocontrol agents

    PubMed Central

    Beneduzi, Anelise; Ambrosini, Adriana; Passaglia, Luciane M.P.

    2012-01-01

    Bacteria that colonize plant roots and promote plant growth are referred to as plant growth-promoting rhizobacteria (PGPR). PGPR are highly diverse and in this review we focus on rhizobacteria as biocontrol agents. Their effects can occur via local antagonism to soil-borne pathogens or by induction of systemic resistance against pathogens throughout the entire plant. Several substances produced by antagonistic rhizobacteria have been related to pathogen control and indirect promotion of growth in many plants, such as siderophores and antibiotics. Induced systemic resistance (ISR) in plants resembles pathogen-induced systemic acquired resistance (SAR) under conditions where the inducing bacteria and the challenging pathogen remain spatially separated. Both types of induced resistance render uninfected plant parts more resistant to pathogens in several plant species. Rhizobacteria induce resistance through the salicylic acid-dependent SAR pathway, or require jasmonic acid and ethylene perception from the plant for ISR. Rhizobacteria belonging to the genera Pseudomonas and Bacillus are well known for their antagonistic effects and their ability to trigger ISR. Resistance-inducing and antagonistic rhizobacteria might be useful in formulating new inoculants with combinations of different mechanisms of action, leading to a more efficient use for biocontrol strategies to improve cropping systems. PMID:23411488

  12. Structure of the BTB Domain of Keap1 and Its Interaction with the Triterpenoid Antagonist CDDO

    PubMed Central

    Cleasby, Anne; Yon, Jeff; Day, Philip J.; Richardson, Caroline; Tickle, Ian J.; Williams, Pamela A.; Callahan, James F.; Carr, Robin; Concha, Nestor; Kerns, Jeffrey K.; Qi, Hongwei; Sweitzer, Thomas; Ward, Paris; Davies, Thomas G.

    2014-01-01

    The protein Keap1 is central to the regulation of the Nrf2-mediated cytoprotective response, and is increasingly recognized as an important target for therapeutic intervention in a range of diseases involving excessive oxidative stress and inflammation. The BTB domain of Keap1 plays key roles in sensing environmental electrophiles and in mediating interactions with the Cul3/Rbx1 E3 ubiquitin ligase system, and is believed to be the target for several small molecule covalent activators of the Nrf2 pathway. However, despite structural information being available for several BTB domains from related proteins, there have been no reported crystal structures of Keap1 BTB, and this has precluded a detailed understanding of its mechanism of action and interaction with antagonists. We report here the first structure of the BTB domain of Keap1, which is thought to contain the key cysteine residue responsible for interaction with electrophiles, as well as structures of the covalent complex with the antagonist CDDO/bardoxolone, and of the constitutively inactive C151W BTB mutant. In addition to providing the first structural confirmation of antagonist binding to Keap1 BTB, we also present biochemical evidence that adduction of Cys 151 by CDDO is capable of inhibiting the binding of Cul3 to Keap1, and discuss how this class of compound might exert Nrf2 activation through disruption of the BTB-Cul3 interface. PMID:24896564

  13. Antagonistic and Bargaining Games in Optimal Marketing Decisions

    ERIC Educational Resources Information Center

    Lipovetsky, S.

    2007-01-01

    Game theory approaches to find optimal marketing decisions are considered. Antagonistic games with and without complete information, and non-antagonistic games techniques are applied to paired comparison, ranking, or rating data for a firm and its competitors in the market. Mix strategy, equilibrium in bi-matrix games, bargaining models with…

  14. Microbial antagonists of Verticillium dahliae colonize cotton root system

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Verticillium wilt remains one of the most severe diseases affecting cotton production in Uzbekistan. We are investigating microbial antagonist to control this pathogen. To this end, we have identified several antagonists of Verticillium dahliae (Bacillus sp. 234, Bacillus sp. 3, Streptomyces roseofl...

  15. Early gonadotropin-releasing hormone antagonist start improves follicular synchronization and pregnancy outcome as compared to the conventional antagonist protocol

    PubMed Central

    Park, Chan Woo; Hwang, Yu Im; Koo, Hwa Seon; Kang, Inn Soo; Yang, Kwang Moon

    2014-01-01

    Objective To assess whether an early GnRH antagonist start leads to better follicular synchronization and an improved clinical pregnancy rate (CPR). Methods A retrospective cohort study. A total of 218 infertile women who underwent IVF between January 2011 and February 2013. The initial cohort (Cohort I) that underwent IVF between January 2011 and March 2012 included a total of 68 attempted IVF cycles. Thirty-four cycles were treated with the conventional GnRH antagonist protocol, and 34 cycles with an early GnRH antagonist start protocol. The second cohort (Cohort II) that underwent IVF between June 2012 and February 2013 included a total of 150 embryo-transfer (ET) cycles. Forty-three cycles were treated with the conventional GnRH antagonist protocol, 34 cycles with the modified early GnRH antagonist start protocol using highly purified human menopause gonadotropin and an addition of GnRH agonist to the luteal phase support, and 73 cycles with the GnRH agonist long protocol. Results The analysis of Cohort I showed that the number of mature oocytes retrieved was significantly higher in the early GnRH antagonist start cycles than in the conventional antagonist cycles (11.9 vs. 8.2, p=0.04). The analysis of Cohort II revealed higher but non-significant CPR/ET in the modified early GnRH antagonist start cycles (41.2%) than in the conventional antagonist cycles (30.2%), which was comparable to that of the GnRH agonist long protocol cycles (39.7%). Conclusion The modified early antagonist start protocol may improve the mature oocyte yield, possibly via enhanced follicular synchronization, while resulting in superior CPR as compared to the conventional antagonist protocol, which needs to be studied further in prospective randomized controlled trials. PMID:25599038

  16. Increased activity of antagonists of growth hormone-releasing hormone substituted at positions 8, 9, and 10

    PubMed Central

    Varga, Jozsef L.; Schally, Andrew V.; Horvath, Judit E.; Kovacs, Magdolna; Halmos, Gabor; Groot, Kate; Toller, Gabor L.; Rekasi, Zoltan; Zarandi, Marta

    2004-01-01

    Antagonists of human growth hormone-releasing hormone (hGHRH) with increased potency and improved enzymatic and chemical stability are needed for potential clinical applications. We synthesized 21 antagonistic analogs of hGHRH(1-29)NH2, substituted at positions 8, 9, and 10 of the common core sequence {phenylacetyl-Tyr1, d-Arg2,28, para-chloro-phenylalanine 6, Arg9/homoarginine 9, Tyr10/O-methyltyrosine 10, α-aminobutyric acid 15, norleucine 27, Har29} hGHRH(1-29)NH2. Inhibitory effects on hGHRH-induced GH release were evaluated in vitro in a superfused rat pituitary system, as well as in vivo after i.v. injection into rats. The binding affinities of the peptides to pituitary GHRH receptors were also determined. Introduction of para-amidinophenylalanine 10 yielded antagonists JV-1-62 and -63 with the highest activities in vitro and lowest receptor dissociation constants (Ki = 0.057-0.062 nM). Antagonists JV-1-62 and -63 also exhibited the strongest effect in vivo, significantly (P < 0.05-0.001) inhibiting hGHRH-induced GH release for at least 1 h. Para-aminophenylalanine 10 and O-ethyltyrosine 10 substitutions yielded antagonists potent in vitro, but His10, 3,3′-diphenylalanine 10, 2-naphthylalanine 10, and cyclohexylalanine 10 modifications were detrimental. Antagonists containing citrulline 9 (in MZ-J-7-72), amidinophenylalanine 9 (in JV-1-65), His9, d-Arg9, citrulline 8, Ala8, d-Ala8, or α-aminobutyric acid 8 substituents also had high activity and receptor affinity in vitro. However, in vitro potencies of analogs with substitution in position 9 correlated poorly with acute endocrine effects in vivo, as exemplified by the weak and/or short inhibitory actions of antagonists JV-1-65 and MZ-J-7-72 on GH release in vivo. Nevertheless, antagonist JV-1-65 was more potent than JV-1-63 in tests on inhibition of the growth of human prostatic and lung cancer lines xenografted into nude mice. This indicates that oncological activity may be based on several mechanisms

  17. Pharmacokinetic interactions with calcium channel antagonists (Part I).

    PubMed

    Schlanz, K D; Myre, S A; Bottorff, M B

    1991-11-01

    Calcium channel antagonists are a diverse class of drugs widely used in combination with other therapeutic agents. The potential exists for many clinically significant pharmacokinetic interactions between these and other concurrently administered drugs. The mechanisms of calcium channel antagonist-induced changes in drug metabolism include altered hepatic blood flow and impaired hepatic enzyme metabolising activity. Increases in serum concentrations and/or reductions in clearance have been reported for several drugs used with a number of calcium channel antagonists. A number of reports and studies of calcium channel antagonist interactions have yielded contradictory results and the clinical significance of pharmacokinetic changes seen with these agents is ill-defined. The first part of this article deals with interactions between calcium antagonists and marker compounds, theophylline, midazolam, lithium, doxorubicin, oral hypoglycaemics and cardiac drugs. PMID:1773549

  18. Characterization of protoberberine analogs employed as novel human P2X{sub 7} receptor antagonists

    SciTech Connect

    Lee, Ga Eun; Lee, Won-Gil; Lee, Song-Yi; Lee, Cho-Rong; Park, Chul-Seung; Chang, Sunghoe; Park, Sung-Gyoo; Song, Mi-Ryoung; Kim, Yong-Chul

    2011-04-15

    The P2X{sub 7} receptor (P2X{sub 7}R), a member of the ATP-gated ion channel family, is regarded as a promising target for therapy of immune-related diseases including rheumatoid arthritis and chronic pain. A group of novel protoberberine analogs (compounds 3-5), discovered by screening of chemical libraries, was here investigated with respect to their function as P2X{sub 7}R antagonists. Compounds 3-5 non-competitively inhibited BzATP-induced ethidium ion influx into hP2X{sub 7}-expressing HEK293 cells, with IC{sub 50} values of 100-300 nM. This antagonistic action on the channel further confirmed that both BzATP-induced inward currents and Ca{sup 2+} influx were strongly inhibited by compounds 3-5 in patch-clamp and Ca{sup 2+} influx assays. The antagonists also effectively suppressed downstream signaling of P2X{sub 7} receptors including IL-1{beta} release and phosphorylation of ERK1/2 and p38 proteins in hP2X{sub 7}-expressing HEK293 cells or in differentiated human monocytes (THP-1 cells). Moreover, IL-2 secretion from CD3/CD28-stimulated Jurkat T cell was also dramatically inhibited by the antagonist. These results imply that novel protoberberine analogs may modulate P2X{sub 7} receptor-mediated immune responses by allosteric inhibition of the receptor. - Graphical abstract: Display Omitted

  19. An Autoinflammatory Disease with Deficiency of the Interleukin-1–Receptor Antagonist

    PubMed Central

    Aksentijevich, Ivona; Masters, Seth L.; Ferguson, Polly J.; Dancey, Paul; Frenkel, Joost; van Royen-Kerkhoff, Annet; Laxer, Ron; Tedgård, Ulf; Cowen, Edward W.; Pham, Tuyet-Hang; Booty, Matthew; Estes, Jacob D.; Sandler, Netanya G.; Plass, Nicole; Stone, Deborah L.; Turner, Maria L.; Hill, Suvimol; Butman, John A.; Schneider, Rayfel; Babyn, Paul; El-Shanti, Hatem I.; Pope, Elena; Barron, Karyl; Bing, Xinyu; Laurence, Arian; Lee, Chyi-Chia R.; Chapelle, Dawn; Clarke, Gillian I.; Ohson, Kamal; Nicholson, Marc; Gadina, Massimo; Yang, Barbara; Korman, Benjamin D.; Gregersen, Peter K.; van Hagen, P. Martin; Hak, A. Elisabeth; Huizing, Marjan; Rahman, Proton; Douek, Daniel C.; Remmers, Elaine F.; Kastner, Daniel L.; Goldbach-Mansky, Raphaela

    2010-01-01

    Background Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1–receptor antagonist, with prominent involvement of skin and bone. Methods We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1–receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1–pathway genes including IL1RN. Results We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from the Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1–family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1β stimulation. Patients treated with anakinra responded rapidly. Conclusions We propose the term deficiency of the interleukin-1–receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1–receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.) PMID:19494218

  20. Kinetic properties of "dual" orexin receptor antagonists at OX1R and OX2R orexin receptors.

    PubMed

    Callander, Gabrielle E; Olorunda, Morenike; Monna, Dominique; Schuepbach, Edi; Langenegger, Daniel; Betschart, Claudia; Hintermann, Samuel; Behnke, Dirk; Cotesta, Simona; Fendt, Markus; Laue, Grit; Ofner, Silvio; Briard, Emmanuelle; Gee, Christine E; Jacobson, Laura H; Hoyer, Daniel

    2013-01-01

    Orexin receptor antagonists represent attractive targets for the development of drugs for the treatment of insomnia. Both efficacy and safety are crucial in clinical settings and thorough investigations of pharmacokinetics and pharmacodynamics can predict contributing factors such as duration of action and undesirable effects. To this end, we studied the interactions between various "dual" orexin receptor antagonists and the orexin receptors, OX1R and OX2R, over time using saturation and competition radioligand binding with [(3)H]-BBAC ((S)-N-([1,1'-biphenyl]-2-yl)-1-(2-((1-methyl-1H-benzo[d]imidazol-2-yl)thio)acetyl)pyrrolidine-2-carboxamide). In addition, the kinetics of these compounds were investigated in cells expressing human, mouse and rat OX1R and OX2R using FLIPR® assays for calcium accumulation. We demonstrate that almorexant reaches equilibrium very slowly at OX2R, whereas SB-649868, suvorexant, and filorexant may take hours to reach steady state at both orexin receptors. By contrast, compounds such as BBAC or the selective OX2R antagonist IPSU ((2-((1H-Indol-3-yl)methyl)-9-(4-methoxypyrimidin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one) bind rapidly and reach equilibrium very quickly in binding and/or functional assays. Overall, the "dual" antagonists tested here tend to be rather unselective under non-equilibrium conditions and reach equilibrium very slowly. Once equilibrium is reached, each ligand demonstrates a selectivity profile that is however, distinct from the non-equilibrium condition. The slow kinetics of the "dual" antagonists tested suggest that in vitro receptor occupancy may be longer lasting than would be predicted. This raises questions as to whether pharmacokinetic studies measuring plasma or brain levels of these antagonists are accurate reflections of receptor occupancy in vivo. PMID:24376396

  1. Kinetic properties of “dual” orexin receptor antagonists at OX1R and OX2R orexin receptors

    PubMed Central

    Callander, Gabrielle E.; Olorunda, Morenike; Monna, Dominique; Schuepbach, Edi; Langenegger, Daniel; Betschart, Claudia; Hintermann, Samuel; Behnke, Dirk; Cotesta, Simona; Fendt, Markus; Laue, Grit; Ofner, Silvio; Briard, Emmanuelle; Gee, Christine E.; Jacobson, Laura H.; Hoyer, Daniel

    2013-01-01

    Orexin receptor antagonists represent attractive targets for the development of drugs for the treatment of insomnia. Both efficacy and safety are crucial in clinical settings and thorough investigations of pharmacokinetics and pharmacodynamics can predict contributing factors such as duration of action and undesirable effects. To this end, we studied the interactions between various “dual” orexin receptor antagonists and the orexin receptors, OX1R and OX2R, over time using saturation and competition radioligand binding with [3H]-BBAC ((S)-N-([1,1′-biphenyl]-2-yl)-1-(2-((1-methyl-1H-benzo[d]imidazol-2-yl)thio)acetyl)pyrrolidine-2-carboxamide). In addition, the kinetics of these compounds were investigated in cells expressing human, mouse and rat OX1R and OX2R using FLIPR® assays for calcium accumulation. We demonstrate that almorexant reaches equilibrium very slowly at OX2R, whereas SB-649868, suvorexant, and filorexant may take hours to reach steady state at both orexin receptors. By contrast, compounds such as BBAC or the selective OX2R antagonist IPSU ((2-((1H-Indol-3-yl)methyl)-9-(4-methoxypyrimidin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one) bind rapidly and reach equilibrium very quickly in binding and/or functional assays. Overall, the “dual” antagonists tested here tend to be rather unselective under non-equilibrium conditions and reach equilibrium very slowly. Once equilibrium is reached, each ligand demonstrates a selectivity profile that is however, distinct from the non-equilibrium condition. The slow kinetics of the “dual” antagonists tested suggest that in vitro receptor occupancy may be longer lasting than would be predicted. This raises questions as to whether pharmacokinetic studies measuring plasma or brain levels of these antagonists are accurate reflections of receptor occupancy in vivo. PMID:24376396

  2. Time-Referenced Effects of an Internal vs. External Focus of Attention on Muscular Activity and Compensatory Variability

    PubMed Central

    Hossner, Ernst-Joachim; Ehrlenspiel, Felix

    2010-01-01

    The paralysis-by-analysis phenomenon, i.e., attending to the execution of one's movement impairs performance, has gathered a lot of attention over recent years (see Wulf, 2007, for a review). Explanations of this phenomenon, e.g., the hypotheses of constrained action (Wulf et al., 2001) or of step-by-step execution (Masters, 1992; Beilock et al., 2002), however, do not refer to the level of underlying mechanisms on the level of sensorimotor control. For this purpose, a “nodal-point hypothesis” is presented here with the core assumption that skilled motor behavior is internally based on sensorimotor chains of nodal points, that attending to intermediate nodal points leads to a muscular re-freezing of the motor system at exactly and exclusively these points in time, and that this re-freezing is accompanied by the disruption of compensatory processes, resulting in an overall decrease of motor performance. Two experiments, on lever sequencing and basketball free throws, respectively, are reported that successfully tested these time-referenced predictions, i.e., showing that muscular activity is selectively increased and compensatory variability selectively decreased at movement-related nodal points if these points are in the focus of attention. PMID:21833285

  3. Tracking the Development of Muscular Myoglobin Stores in Mysticete Calves.

    PubMed

    Cartwright, Rachel; Newton, Cori; West, Kristi M; Rice, Jim; Niemeyer, Misty; Burek, Kathryn; Wilson, Andrew; Wall, Alison N; Remonida-Bennett, Jean; Tejeda, Areli; Messi, Sarah; Marcial-Hernandez, Lila

    2016-01-01

    For marine mammals, the ability to tolerate apnea and make extended dives is a defining adaptive trait, facilitating the exploitation of marine food resources. Elevated levels of myoglobin within the muscles are a consistent hallmark of this trait, allowing oxygen collected at the surface to be stored in the muscles and subsequently used to support extended dives. In mysticetes, the largest of marine predators, details on muscular myoglobin levels are limited. The developmental trajectory of muscular myoglobin stores has yet to be documented and any physiological links between early behavior and the development of muscular myoglobin stores remain unknown. In this study, we used muscle tissue samples from stranded mysticetes to investigate these issues. Samples from three different age cohorts and three species of mysticetes were included (total sample size = 18). Results indicate that in mysticete calves, muscle myoglobin stores comprise only a small percentage (17-23%) of conspecific adult myoglobin complements. Development of elevated myoglobin levels is protracted over the course of extended maturation in mysticetes. Additionally, comparisons of myoglobin levels between and within muscles, along with details of interspecific differences in rates of accumulation of myoglobin in very young mysticetes, suggest that levels of exercise may influence the rate of development of myoglobin stores in young mysticetes. This new information infers a close interplay between the physiology, ontogeny and early life history of young mysticetes and provides new insight into the pressures that may shape adaptive strategies in migratory mysticetes. Furthermore, the study highlights the vulnerability of specific age cohorts to impending changes in the availability of foraging habitat and marine resources. PMID:26788728

  4. New aspects on patients affected by dysferlin deficient muscular dystrophy

    PubMed Central

    Klinge, Lars; Aboumousa, Ahmed; Eagle, Michelle; Hudson, Judith; Sarkozy, Anna; Vita, Gianluca; Charlton, Richard; Roberts, Mark; Straub, Volker; Barresi, Rita; Lochmüller, Hanns

    2009-01-01

    Mutations in the dysferlin gene lead to limb girdle muscular dystrophy 2B, Miyoshi myopathy and distal anterior compartment myopathy. A cohort of 36 patients affected by dysferlinopathy is described, in the first UK study of clinical, genetic, pathological and biochemical data. The diagnosis was established by reduction of dysferlin in the muscle biopsy and subsequent mutational analysis of the dysferlin gene. Seventeen mutations were novel; the majority of mutations were small deletions/insertions, and no mutational hotspots were identified. Sixty-one per cent of patients (22 patients) initially presented with limb girdle muscular dystrophy 2B, 31% (11 patients) with a Miyoshi phenotype, one patient with proximodistal mode of onset, one patient with muscle stiffness after exercise and one patient as a symptomatic carrier. A wider range of age of onset was noted than previously reported, with 25% of patients having first symptoms before the age of 13 years. Independent of the initial mode of presentation, in our cohort of patients the gastrocnemius muscle was the most severely affected muscle leading to an inability to stand on tiptoes, and lower limbs were affected more severely than upper limbs. As previous anecdotal evidence on patients affected by dysferlinopathy suggests good muscle prowess before onset of symptoms, we also investigated pre-symptomatic fitness levels of the patients. Fifty-three per cent of the patients were very active and sporty before the onset of symptoms which makes the clinical course of dysferlinopathy unusual within the different forms of muscular dystrophy and provides a challenge to understanding the underlying pathomechanisms in this disease. PMID:19528035

  5. Muscle exercise in limb girdle muscular dystrophies: pitfall and advantages.

    PubMed

    Siciliano, Gabriele; Simoncini, Costanza; Giannotti, Stefano; Zampa, Virna; Angelini, Corrado; Ricci, Giulia

    2015-05-01

    Different genetic mutations underlying distinct pathogenic mechanisms have been identified as cause of muscle fibers degeneration and strength loss in limb girdle muscular dystrophies (LGMD). As a consequence, exercise tolerance is affected in patients with LGMD, either as a direct consequence of the loss of muscle fibers or secondary to the sedentary lifestyle due to the motor impairment. It has been debated for many years whether or not muscle exercise is beneficial or harmful for patients with myopathic disorders. In fact, muscular exercise would be considered in helping to hinder the loss of muscle tissue and strength. On the other hand, muscle structural defects in LGMD can result in instability of the sarcolemma, making it more likely to induce muscle damage as a consequence of intense muscle contraction, such as that performed during eccentric training. Several reports have suggested that supervised aerobic exercise training is safe and may be considered effective in improving oxidative capacity and muscle function in patients with LGMD, such as LGMD2I, LGMD2L, LGMD2A. More or less comfortable investigation methods applied to assess muscle function and structure can be useful to detect the beneficial effects of supervised training in LGMD. However, it is important to note that the available trials assessing muscle exercise in patients with LGMD have often involved a small number of patients, with a wide clinical heterogeneity and a different experimental design. Based on these considerations, resistance training can be considered part of the rehabilitation program for patients with a limb-girdle type of muscular dystrophy, but it should be strictly supervised to assess its effects and prevent possible development of muscle damage. PMID:26155063

  6. Muscular nitric oxide synthase (muNOS) and utrophin.

    PubMed

    Chaubourt, Emmanuel; Voisin, Vincent; Fossier, Philippe; Baux, Gérard; Israël, Maurice; De La Porte, Sabine

    2002-01-01

    Duchenne muscular dystrophy (DMD), the severe X-linked recessive disorder which results in progressive muscle degeneration, is due to a lack of dystrophin, a membrane cytoskeletal protein. Three types of treatment are envisaged: pharmacological (glucocorticoid), myoblast transplantation, and gene therapy. An alternative to the pharmacological approach is to compensate for dystrophin loss by the upregulation of another cytoskeletal protein, utrophin. Utrophin and dystrophin are part of a complex of proteins and glycoproteins, which links the basal lamina to the cytoskeleton, thus ensuring the stability of the muscle membrane. One protein of the complex, syntrophin, is associated with a muscular isoform of the neuronal nitric oxide synthase (nNOS). We have demonstrated an overexpression of utrophin, visualised by immunofluorescence and quantified by Western blotting, in normal myotubes and in mdx (the animal model of DMD) myotubes, as in normal (C57) and mdx mice, both treated with nitric oxide (NO) donor or L-arginine, the NOS substrate. There is evidence that utrophin may be capable of performing the same cellular functions as dystrophin and may functionally compensate for its lack. Thus, we propose to use NO donors, as palliative treatment of Duchenne and Becker muscular dystrophies, pending, or in combination with, gene and/or cellular therapy. Discussion has focussed on the various isoforms of NOS that could be implicated in the regeneration process. Dystrophic and healthy muscles respond to treatment, suggesting that although NOS is delocalised in the cytoplasm in the case of DMD, it conserves substantial activity. eNOS present in mitochondria and iNOS present in cytoplasm and the neuromuscular junction could also be activated. Lastly, production of NO by endothelial NOS of the capillaries would also be beneficial through increased supply of metabolites and oxygen to the muscles. PMID:11755782

  7. Tracking the Development of Muscular Myoglobin Stores in Mysticete Calves

    PubMed Central

    Cartwright, Rachel; Newton, Cori; West, Kristi M.; Rice, Jim; Niemeyer, Misty; Burek, Kathryn; Wilson, Andrew; Wall, Alison N.; Remonida-Bennett, Jean; Tejeda, Areli; Messi, Sarah; Marcial-Hernandez, Lila

    2016-01-01

    For marine mammals, the ability to tolerate apnea and make extended dives is a defining adaptive trait, facilitating the exploitation of marine food resources. Elevated levels of myoglobin within the muscles are a consistent hallmark of this trait, allowing oxygen collected at the surface to be stored in the muscles and subsequently used to support extended dives. In mysticetes, the largest of marine predators, details on muscular myoglobin levels are limited. The developmental trajectory of muscular myoglobin stores has yet to be documented and any physiological links between early behavior and the development of muscular myoglobin stores remain unknown. In this study, we used muscle tissue samples from stranded mysticetes to investigate these issues. Samples from three different age cohorts and three species of mysticetes were included (total sample size = 18). Results indicate that in mysticete calves, muscle myoglobin stores comprise only a small percentage (17–23%) of conspecific adult myoglobin complements. Development of elevated myoglobin levels is protracted over the course of extended maturation in mysticetes. Additionally, comparisons of myoglobin levels between and within muscles, along with details of interspecific differences in rates of accumulation of myoglobin in very young mysticetes, suggest that levels of exercise may influence the rate of development of myoglobin stores in young mysticetes. This new information infers a close interplay between the physiology, ontogeny and early life history of young mysticetes and provides new insight into the pressures that may shape adaptive strategies in migratory mysticetes. Furthermore, the study highlights the vulnerability of specific age cohorts to impending changes in the availability of foraging habitat and marine resources. PMID:26788728

  8. Immunohistochemical localization of the calcitonin gene-related peptide binding site in the primate trigeminovascular system using functional antagonist antibodies.

    PubMed

    Miller, Silke; Liu, Hantao; Warfvinge, Karin; Shi, Licheng; Dovlatyan, Mary; Xu, Cen; Edvinsson, Lars

    2016-07-22

    Calcitonin gene-related peptide (CGRP) is a potent vasodilator and a neuromodulator implicated in the pathophysiology of migraine. It binds to the extracellular domains of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein (RAMP) 1 that together form the CGRP receptor. Antagonist antibodies against CGRP and its binding site at the receptor are clinically effective in preventing migraine attacks. The blood-brain barrier penetration of these antagonist antibodies is limited, suggesting that a potential peripheral site of action is sufficient to prevent migraine attacks. To further understand the sites of CGRP-mediated signaling in migraine, we used immunohistochemical staining with recently developed antagonist antibodies specifically recognizing a fusion protein of the extracellular domains of RAMP1 and CLR that comprise the CGRP binding pocket at the CGRP receptor in monkey and man. We confirmed binding of the antagonist antibodies to human vascular smooth muscle cells (VSMCs) of dural meningeal arteries and neurons in the trigeminal ganglion, both of which are likely sites of action for therapeutic antibodies in migraine patients. We further used one of these antibodies for detailed mapping on cynomolgus monkey tissue and found antagonist antibody binding sites at multiple levels in the trigeminovascular system: in the dura mater VSMCs, in neurons and satellite glial cells in the trigeminal ganglion, and in neurons in the spinal trigeminal nucleus caudalis. These data reinforce and clarify our understanding of CGRP receptor localization in a pattern consistent with a role for CGRP receptors in trigeminal sensitization and migraine pathology. PMID:27155150

  9. Action, human.

    PubMed

    Russo, M T

    2010-01-01

    The term "human action" designates the intentional and deliberate movement that is proper and exclusive to mankind. Human action is a unified structure: knowledge, intention or volition, deliberation, decision or choice of means and execution. The integration between these dimensions appears as a task that demands strength of will to achieve the synthesis of self-possession and self-control that enables full personal realisation. Recently, the debate about the dynamism of human action has been enriched by the contribution of neurosciences. Thanks to techniques of neuroimaging, neurosciences have expanded the field of investigation to the nature of volition, to the role of the brain in decision-making processes and to the notion of freedom and responsibility. PMID:20393686

  10. Management of Cardiac Involvement in NeuroMuscular Diseases: Review

    PubMed Central

    Bouhouch, Rachida; Elhouari, Tarik; Oukerraj, Latifa; Fellat, Ibtissam; Zarzur, Jamila; Bennani, Rajaa; Arharbi, Mhamed

    2008-01-01

    Neuromuscular Diseases are a heterogeneous molecular, clinical and prognosis group. Progress has been achieved in the understanding and classification of these diseases. Cardiac involvement in neuromuscular diseases namely conduction disorders, ventricular dilatation and dilated cardiomyopathy with its impact on prognosis, is often dissociated from the peripheral myopathy. Therefore, close surveillance is mandatory in the affected patients. In this context, preventive therapy (beta-blockers and angiotensin converting enzyme inhibitors) has been recently recommended in the most common Neuromuscular Diseases, Duchenne Muscular Dystrophy and Myotonic Dystrophy. PMID:19337361

  11. Histone deacetylase inhibitors as potential treatment for spinal muscular atrophy

    PubMed Central

    Mohseni, Jafar; Zabidi-Hussin, Z.A.M.H.; Sasongko, Teguh Haryo

    2013-01-01

    Histone acetylation plays an important role in regulation of transcription in eukaryotic cells by promoting a more relaxed chromatin structure necessary for transcriptional activation. Histone deacetylases (HDACs) remove acetyl groups and suppress gene expression. HDAC inhibitors (HDACIs) are a group of small molecules that promote gene transcription by chromatin remodeling and have been extensively studied as potential drugs for treating of spinal muscular atrophy. Various drugs in this class have been studied with regard to their efficacy in increasing the expression of survival of motor neuron (SMN) protein. In this review, we discuss the current literature on this topic and summarize the findings of the main studies in this field. PMID:24130434

  12. Fasciculations masquerading as minipolymyoclonus in bulbospinal muscular atrophy

    PubMed Central

    Bhat, Sushanth; Ma, Wei; Kozochonok, Elena; Chokroverty, Sudhansu

    2015-01-01

    Minipolymyoclonus has been described in both anterior horn cell disorders and central nervous system degenerative conditions. While its etiology remains unclear and speculative, a central generator has been previously proposed. We describe a case of bulbospinal muscular atrophy (Kennedy's disease), where minipolymyoclonus-like movements corresponded to fasciculations in neurophysiological studies. Our novel finding suggests that the etiologies of minipolymyoclonus in central and peripheral nervous system disorders are distinct, despite outward clinical similarity. The term “minipolyfasciculations” may be more reflective of the underlying process causing minipolymyoclonus-like movements in lower motor neuron disorders. PMID:26019432

  13. Cell and gene therapy in Duchenne muscular dystrophy.

    PubMed

    Morgan, J E

    1994-02-01

    Experiments in mice have supported the idea of treating Duchenne muscular dystrophy (DMD) by implanting normal muscle precursor cells into dystrophin-deficient muscles. However, similar experiments on DMD patients have had little success. Gene therapy for DMD, by introducing dystrophin constructs via retroviral or adenoviral vectors, has been shown to be possible in the mouse, but the efficiency and safety aspects of this technique will have to be carefully examined before similar experiments can be attempted in man. Direct injection of dystrophin cDNA constructs into mdx muscles has given rise to very low levels of dystrophin and this may be a possibility for the treatment of heart muscle. PMID:7514447

  14. Fasciculations masquerading as minipolymyoclonus in bulbospinal muscular atrophy.

    PubMed

    Bhat, Sushanth; Ma, Wei; Kozochonok, Elena; Chokroverty, Sudhansu

    2015-01-01

    Minipolymyoclonus has been described in both anterior horn cell disorders and central nervous system degenerative conditions. While its etiology remains unclear and speculative, a central generator has been previously proposed. We describe a case of bulbospinal muscular atrophy (Kennedy's disease), where minipolymyoclonus-like movements corresponded to fasciculations in neurophysiological studies. Our novel finding suggests that the etiologies of minipolymyoclonus in central and peripheral nervous system disorders are distinct, despite outward clinical similarity. The term "minipolyfasciculations" may be more reflective of the underlying process causing minipolymyoclonus-like movements in lower motor neuron disorders. PMID:26019432

  15. Antisense mediated exon skipping therapy for duchenne muscular dystrophy (DMD).

    PubMed

    Brolin, Camilla; Shiraishi, Takehiko

    2011-01-01

    Duchenne Muscular Dystrophy (DMD) is a lethal disease caused by mutations in the dystrophin gene (DMD) that result in the absence of essential muscle protein dystrophin. Among many different approaches for DMD treatment, exon skipping, mediated by antisense oligonucleotides, is one of the most promising methods for restoration of dystrophin expression. This approach has been tested extensively targeting different exons in numerous models both in vitro and in vivo. During the past 10 years, there has been a considerable progress by using DMD animal models involving three types of antisense oligonucleotides (2'-O-methyl phosphorothioate (2OME-PS), phosphorodiamidate morpholino oligomer (PMO)) and peptide nucleic acid (PNA). PMID:21686247

  16. Late onset GM2 gangliosidosis mimicking spinal muscular atrophy.

    PubMed

    Jamrozik, Z; Lugowska, A; Gołębiowski, M; Królicki, L; Mączewska, J; Kuźma-Kozakiewicz, M

    2013-09-25

    A case of late onset GM2 gangliosidodis with spinal muscular atrophy phenotype followed by cerebellar and extrapyramidal symptoms is presented. Genetic analysis revealed compound heterozygous mutation in exon 10 of the HEXA gene. Patient has normal intelligence and emotional reactivity. Neuroimaging tests of the brain showed only cerebellar atrophy consistent with MR spectroscopy (MRS) abnormalities. (18)F-fluorodeoxyglucose positron emission tomography (18)F-FDG PET/CT of the brain revealed glucose hypometabolism in cerebellum and in temporal and occipital lobes bilaterally. PMID:23820084

  17. Corticosteroid Treatment Impact on Spinal Deformity in Duchenne Muscular Dystrophy

    PubMed Central

    Sanzarello, Ilaria; Merlini, Luciano; Traina, Francesco; Rosa, Michele Attilio; Faldini, Cesare

    2014-01-01

    Duchenne muscular dystrophy is a progressive disease with loss of ambulation at around 9-10 years of age, followed, if untreated, by development of scoliosis, respiratory insufficiency, and death in the second decade of life. This review highlights the natural history of the disease, in particular, with regard to the development of the spinal deformity and how this complication has been modified by surgical interventions and overall by corticosteroid treatment. The beneficial effect of corticosteroids may have also an impact on the clinical trial design of the new emerging causative therapies.

  18. Non-equivalence of Key Positively Charged Residues of the Free Fatty Acid 2 Receptor in the Recognition and Function of Agonist Versus Antagonist Ligands*

    PubMed Central

    Sergeev, Eugenia; Hansen, Anders Højgaard; Pandey, Sunil K.; MacKenzie, Amanda E.; Hudson, Brian D.; Ulven, Trond; Milligan, Graeme

    2016-01-01

    Short chain fatty acids (SCFAs) are produced in the gut by bacterial fermentation of poorly digested carbohydrates. A key mediator of their actions is the G protein-coupled free fatty acid 2 (FFA2) receptor, and this has been suggested as a therapeutic target for the treatment of both metabolic and inflammatory diseases. However, a lack of understanding of the molecular determinants dictating how ligands bind to this receptor has hindered development. We have developed a novel radiolabeled FFA2 antagonist to probe ligand binding to FFA2, and in combination with mutagenesis and molecular modeling studies, we define how agonist and antagonist ligands interact with the receptor. Although both agonist and antagonist ligands contain negatively charged carboxylates that interact with two key positively charged arginine residues in transmembrane domains V and VII of FFA2, there are clear differences in how these interactions occur. Specifically, although agonists require interaction with both arginine residues to bind the receptor, antagonists require an interaction with only one of the two. Moreover, different chemical series of antagonist interact preferentially with different arginine residues. A homology model capable of rationalizing these observations was developed and provides a tool that will be invaluable for identifying improved FFA2 agonists and antagonists to further define function and therapeutic opportunities of this receptor. PMID:26518871

  19. Non-equivalence of Key Positively Charged Residues of the Free Fatty Acid 2 Receptor in the Recognition and Function of Agonist Versus Antagonist Ligands.

    PubMed

    Sergeev, Eugenia; Hansen, Anders Højgaard; Pandey, Sunil K; MacKenzie, Amanda E; Hudson, Brian D; Ulven, Trond; Milligan, Graeme

    2016-01-01

    Short chain fatty acids (SCFAs) are produced in the gut by bacterial fermentation of poorly digested carbohydrates. A key mediator of their actions is the G protein-coupled free fatty acid 2 (FFA2) receptor, and this has been suggested as a therapeutic target for the treatment of both metabolic and inflammatory diseases. However, a lack of understanding of the molecular determinants dictating how ligands bind to this receptor has hindered development. We have developed a novel radiolabeled FFA2 antagonist to probe ligand binding to FFA2, and in combination with mutagenesis and molecular modeling studies, we define how agonist and antagonist ligands interact with the receptor. Although both agonist and antagonist ligands contain negatively charged carboxylates that interact with two key positively charged arginine residues in transmembrane domains V and VII of FFA2, there are clear differences in how these interactions occur. Specifically, although agonists require interaction with both arginine residues to bind the receptor, antagonists require an interaction with only one of the two. Moreover, different chemical series of antagonist interact preferentially with different arginine residues. A homology model capable of rationalizing these observations was developed and provides a tool that will be invaluable for identifying improved FFA2 agonists and antagonists to further define function and therapeutic opportunities of this receptor. PMID:26518871

  20. Antagonist Targeting microRNA-155 Protects against Lithium-Pilocarpine-Induced Status Epilepticus in C57BL/6 Mice by Activating Brain-Derived Neurotrophic Factor

    PubMed Central

    Cai, Zhengxu; Li, Song; Li, Sheng; Song, Fan; Zhang, Zhen; Qi, Guanhua; Li, Tianbai; Qiu, Juanjuan; Wan, Jiajia; Sui, Hua; Guo, Huishu

    2016-01-01

    Epilepsy is a severe brain disorder affecting numerous patients. Recently, it is inferred that modulation of microRNA-155 (miR-155) could serve as a promising treatment of mesial temporal lobe epilepsy. In the current study, the therapeutic potential of miR-155 antagonist against temporal lobe epilepsy (TLE) was evaluated and the underlying mechanism involved in this regulation was explored. TLE model was induced by lithium-pilocarpine method. The effect of miR-155 antagonist on epilepticus symptoms of TLE mice was assessed using Racine classification and electroencephalogram (EEG) recordings. The expression of brain-derived neurotrophic factor (BDNF) and its association with miR-155 were also assessed with a series of experiments. Our results showed that level of miR-155 was significantly up-regulated after induction of TLE model. Based on the results of EEG and behavior analyses, seizures in mice were alleviated by miR-155 antagonist. Moreover, administration of miR-155 antagonist also significantly increased the level of BDNF. The results of dual luciferase assay and Western blotting showed that miR-155 antagonist exerted its action on status epilepticus by directly regulating the activity of BDNF. Taken all the information together, our results demonstrated that miR-155 antagonist might firstly induce the expression of BDNF, which then contributed to the alleviation of epilepsy in the current study. PMID:27303295

  1. Investigation of Poor Academic Achievement in Children with Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    Hinton, V. J.; De Vivo, D. C.; Fee, R.; Goldstein, E.; Stern, Y.

    2004-01-01

    Duchenne Muscular Dystrophy (DMD) is a neurogenetic developmental disorder that presents with progressive muscular weakness. It is caused by a mutation in a gene that results in the absence of specific products that normally localize to muscle cells and the central nervous system (CNS). The majority of affected individuals have IQs within the…

  2. The Relationship between Selected Body Composition Variables and Muscular Endurance in Women

    ERIC Educational Resources Information Center

    Esco, Michael R.; Olson, Michele S.; Williford, Henry N.

    2010-01-01

    The primary purpose of this study was to determine if muscular endurance is affected by referenced waist circumference groupings, independent of body mass and subcutaneous abdominal fat, in women. This study also explored whether selected body composition measures were associated with muscular endurance. Eighty-four women were measured for height,…

  3. Tongue fasciculations in an infant with spinal muscular atrophy type 1

    PubMed Central

    Giannopoulou, Eleni Z; Martin, Thomas; Wirth, Brunhilde; Yilmaz, Umut; Gortner, Ludwig; Meyer, Sascha

    2015-01-01

    Key Clinical Message Muscular hypotonia in infants may be associated with several conditions, such as spinal muscular atrophy (SMA). We report on an infant with tongue fasciculations and a rare mutation of the SMN1 gene. The presence of tongue fasciculations in combination with a thorough history may be suggestive of SMA. PMID:26509018

  4. Effects of Three Resistance Training Programs on Muscular Strength and Absolute and Relative Endurance.

    ERIC Educational Resources Information Center

    Anderson, Tim; Kearney, Jay T.

    1982-01-01

    The effects of three resistance training programs on male college students' muscular strength and absolute and relative muscular endurance were investigated. Results show that human skeletal muscle makes both general and specific adaptations to a training stimulus, and that the balance of these adaptations is to some extent dependent upon the…

  5. Meeting the Assistive Technology Needs of Students with Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    Heller, Kathryn Wolff; Mezei, Peter J.; Avant, Mary Jane Thompson

    2009-01-01

    Students with Duchenne muscular dystrophy (DMD) have a degenerative disease that requires ongoing changes in assistive technology (AT). The AT team needs to be knowledgeable about the disease and its progression in order to meet these students' changing needs in a timely manner. The unique needs of students with Duchenne muscular dystrophy in…

  6. Some Dynamics of Personality Development in Boys Suffering from Muscular Dystrophy

    ERIC Educational Resources Information Center

    Mearig, Judith S.

    1973-01-01

    Discussed are personality aspects of Duchenne or pseudohypertrophic muscular dystrophy, a progressive wasting of muscular tissue, which afflicts only boys, and usually has its noticeable onset before the age of 6 years; and described is the development of three male dystrophic siblings. (DB)

  7. Effects of Passive Physical Exercise on Peripheral Vision in Muscular Dystrophic Children.

    ERIC Educational Resources Information Center

    Eickelberg, Warren; And Others

    1983-01-01

    The effects of passive exercise of the extremities on peripheral vision of muscular dystrophic children aged 9 to 13 years was investigated. Compared to control subjects, those who experienced six minutes of passive exercise evidenced increased peripheral vision. Curriculum revisions for muscular dystrophic children indicate the importance of…

  8. Scalpel or Straitjacket: CRISPR/Cas9 Approaches for Muscular Dystrophies.

    PubMed

    Himeda, Charis L; Jones, Takako I; Jones, Peter L

    2016-04-01

    Versatility of CRISPR/Cas9-based platforms makes them promising tools for the correction of diverse genetic/epigenetic disorders. Here we contrast the use of these genome editing tools in two myopathies with very different molecular origins: Duchenne muscular dystrophy, a monogenetic disease, and facioscapulohumeral muscular dystrophy, an epigenetic disorder with unique therapeutic challenges. PMID:26917062

  9. Structure of REV-ERBβ Ligand-binding Domain Bound to a Porphyrin Antagonist*

    PubMed Central

    Matta-Camacho, Edna; Banerjee, Subhashis; Hughes, Travis S.; Solt, Laura A.; Wang, Yongjun; Burris, Thomas P.; Kojetin, Douglas J.

    2014-01-01

    REV-ERBα and REV-ERBβ are members of the nuclear receptor (NR) superfamily of ligand-regulated transcription factors that play important roles in the regulation of circadian physiology, metabolism, and immune function. Although the REV-ERBs were originally characterized as orphan receptors, recent studies have demonstrated that they function as receptors for heme. Here, we demonstrate that cobalt protoporphyrin IX (CoPP) and zinc protoporphyrin IX (ZnPP) are ligands that bind directly to the REV-ERBs. However, instead of mimicking the agonist action of heme, CoPP and ZnPP function as antagonists of REV-ERB function. This was unexpected because the only distinction between these ligands is the metal ion that is coordinated. To understand the structural basis by which REV-ERBβ can differentiate between a porphyrin agonist and antagonist, we characterized the interaction between REV-ERBβ with heme, CoPP, and ZnPP using biochemical and structural approaches, including x-ray crystallography and NMR. The crystal structure of CoPP-bound REV-ERBβ indicates only minor conformational changes induced by CoPP compared with heme, including the porphyrin ring of CoPP, which adopts a planar conformation as opposed to the puckered conformation observed in the heme-bound REV-ERBβ crystal structure. Thus, subtle changes in the porphyrin metal center and ring conformation may influence the agonist versus antagonist action of porphyrins and when considered with other studies suggest that gas binding to the iron metal center heme may drive alterations in REV-ERB activity. PMID:24872411

  10. Action Research

    ERIC Educational Resources Information Center

    Milton-Brkich, Katie Lynn; Shumbera, Kristen; Beran, Becky

    2010-01-01

    Defined as "any systemic inquiry conducted by teachers... for the purpose of gathering information about how their particular schools operate, how they teach, and how their students learn" (Mertler, 2009), "action research" is empowering and professional research done by teachers to inform and improves their own practices. Although there are many…

  11. Verapamil as an apparent competitive antagonist of the serotonin receptor of rabbit isolated aorta.

    PubMed

    Auguet, M; Delaflotte, S; Clostre, F; DeFeudis, F V

    1986-01-01

    The actions of four Ca2+-antagonists (verapamil, diltiazem, nifedipine and flunarizine) were tested on serotonin- (5-HT-) induced contraction of rabbit isolated aorta. Verapamil produced a dose-dependent, parallel shift to the right of the concentration-response curve for 5-HT (pA2 approximately equal to 7.13; Schild slope approximately equal to 1.01), indicative of competitive antagonism. The effects of diltiazem, nifedipine and flunarizine were much less pronounced and best characterized as non-competitive interactions. The effect of verapamil, which likely involves its antagonism of smooth muscle 5-HT2-receptors, might be useful in explaining its therapeutic actions and/or its side-effects. PMID:3699438

  12. Nalmefene: radioimmunoassay for a new opioid antagonist.

    PubMed

    Dixon, R; Hsiao, J; Taaffe, W; Hahn, E; Tuttle, R

    1984-11-01

    A specific radioimmunoassay (RIA) has been developed for the quantitation of a new opioid antagonist, nalmefene, in human plasma. The method employs a rabbit antiserum to an albumin conjugate of naltrexone-6-(O-carboxymethyl)oxime and [3H]naltrexone as the radioligand. Assay specificity was achieved by extraction of nalmefene from plasma at pH 9 into ether prior to RIA. The procedure has a limit of sensitivity of 0.2 ng/mL of nalmefene using a 0.5-mL sample of plasma for analysis. The intra- and interassay coefficients of variation did not exceed 5.6 and 11%, respectively. The specificity of the RIA was established by demonstrating excellent agreement (r = 0.99) with a less sensitive and more time consuming HPLC procedure in the analysis of clinical plasma samples. The use of the RIA for the pharmacokinetic evaluation of nalmefene is illustrated with plasma concentration profiles of the drug in humans following intravenous and oral administration. PMID:6520774

  13. Endothelin receptor antagonists in pulmonary arterial hypertension.

    PubMed

    Dupuis, J; Hoeper, M M

    2008-02-01

    The endothelin (ET) system, especially ET-1 and the ET(A) and ET(B) receptors, has been implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Together with prostanoids and phosphodiesterase 5 inhibitors, ET receptor antagonists have become mainstays in the current treatment of PAH. Three substances are currently available for the treatment of PAH. One of these substances, bosentan, blocks both ET(A) and ET(B) receptors, whereas the two other compounds, sitaxsentan and ambrisentan, are more selective blockers of the ET(A) receptor. There is ongoing debate as to whether selective or nonselective ET receptor blockade is advantageous in the setting of PAH, although there is no clear evidence that receptor selectivity is relevant with regard to the clinical effects of these drugs. For the time being, other features, such as safety profiles and the potential for pharmacokinetic interactions with other drugs used in the treatment of PAH, may be more important than selectivity or nonselectivity when selecting treatments for individual patients. PMID:18238950

  14. Indole-like Trk receptor antagonists.

    PubMed

    Tammiku-Taul, Jaana; Park, Rahel; Jaanson, Kaur; Luberg, Kristi; Dobchev, Dimitar A; Kananovich, Dzmitry; Noole, Artur; Mandel, Merle; Kaasik, Allen; Lopp, Margus; Timmusk, Tõnis; Karelson, Mati

    2016-10-01

    The virtual screening for new scaffolds for TrkA receptor antagonists resulted in potential low molecular weight drug candidates for the treatment of neuropathic pain and cancer. In particular, the compound (Z)-3-((5-methoxy-1H-indol-3-yl)methylene)-2-oxindole and its derivatives were assessed for their inhibitory activity against Trk receptors. The IC50 values were computationally predicted in combination of molecular and fragment-based QSAR. Thereafter, based on the structure-activity relationships (SAR), a series of new compounds were designed and synthesized. Among the final selection of 13 compounds, (Z)-3-((5-methoxy-1-methyl-1H-indol-3-yl)methylene)-N-methyl-2-oxindole-5-sulfonamide showed the best TrkA inhibitory activity using both biochemical and cellular assays and (Z)-3-((5-methoxy-1-methyl-1H-indol-3-yl)methylene)-2-oxindole-5-sulfonamide was the most potent inhibitor of TrkB and TrkC. PMID:27318978

  15. Antagonists for acute oral cadmium chloride intoxication

    SciTech Connect

    Basinger, M.A.; Jones, M.M.; Holscher, M.A.; Vaughn, W.K.

    1988-01-01

    An examination has been carried out on the relative efficacy of a number of chelating agents when acting as antagonists for oral cadmium chloride intoxication in mice. The compounds were administered orally after the oral administration of cadmium chloride at 1 mmol/kg. Of the compounds examined, several were useful in terms of enhancing survival, but by far the most effective in both enhancing survival and leaving minimal residual levels of cadmium in the liver and the kidney, was meso-2,3-dimercaptosuccinic acid (DMSA). Several polyaminocarboxylic acids also enhanced survival. The most effective of these in reducing liver and kidney levels of cadmium were diethylenetriaminepentaacetic acid (DTPA), trans-1,2-diaminocyclohexane-N,N,N'N'-tetraacetic acid (CDTA), and triethylenetetraminehexaacetic acid (TTHA). D-Penicillamine (DPA) was found to promote survival but also led to kidney cadmium levels higher than those found in the controls. Sodium 2,3-dimercaptopropane-1-sulfonate (DMPS) was as effective in promoting survival as DMSA but left levels of cadmium in the kidney and liver that were approximately four times greater than those found with DMSA.

  16. Calcium antagonist properties of the bisbenzylisoquinoline alkaloid cycleanine.

    PubMed

    Martínez, J A; Bello, A; Rubio, L L; Rodríguez, C; Galán, L; Caudales, E; Alvarez, J L

    1998-01-01

    The alkaloid cycleanine ([12aR-(12aR,24aR)]-2,3,12a,13,14,15,24,24a-octa hydro-5,6,17,18- tetramethoxy-1,13-dimethyl-8, 11:20,23-dietheno-1H,12H [1,10]dioxacyclooctadecino[2,3,4-ij:11,12,13-i'j']diisoquinolin e) was extracted from the bulbs of Stephania glabra (Roxb) Miers and its effects on cardiac and smooth muscle preparations were studied and compared to those of nifedipine (1,4-dihydro-2, 6-dimethyl-4-(2-nitrophenyl)-3,5-pyridine dicarboxylic acid dimethylesther). Cycleanine inhibited the KCl-induced contraction of rabbit aortic rings with higher potency than nifedipine. IC50s for cycleanine and nifedipine were 0.8 and 7.10(-9) M respectively. Cycleanine had minor effects on the norepinephrine-induced contraction of rabbit aortic rings. Cycleanine and nifedipine also depressed the contraction of rat ventricular preparations but with lower potency (IC50 = 3 and 0.03.10(-6) M respectively). Action potential duration of rat right ventricular strips was decreased by both compounds. L-type Ca-current (ICaL) of single rat ventricular cardiomyocytes was inhibited by cycleanine in a voltage- and frequency-dependent manner. With a higher potency nifedipine inhibited ICaL in a tonic and almost frequency-independent manner. The results suggest that cycleanine can act as a potent vascular selective Ca-antagonist. PMID:9565772

  17. Antagonistic interaction between Trichoderma asperellum and Phytophthora capsici in vitro*

    PubMed Central

    Jiang, Heng; Zhang, Liang; Zhang, Jing-ze; Ojaghian, Mohammad Reza; Hyde, Kevin D.

    2016-01-01

    Phytophthora capsici is a phytopathogen that causes a destructive pepper blight that is extremely difficult to control. Using a fungicide application against the disease is costly and relatively ineffective and there is also a huge environmental concern about the use of such chemicals. The genus Trichoderma has been known to have a potential biocontrol issue. In this paper we investigate the mechanism for causing the infection of T. asperellum against P. capsici. Trichoderma sp. (isolate CGMCC 6422) was developed to have a strong antagonistic action against hyphae of P. capsici through screening tests. The strain was identified as T. asperellum through using a combination of morphological characteristics and molecular data. T. asperellum was able to collapse the mycelium of the colonies of the pathogen through dual culture tests by breaking down the pathogenic hyphae into fragments. The scanning electron microscope showed that the hyphae of T. asperellum surrounded and penetrated the pathogens hyphae, resulting in hyphal collapse. The results show that seven days after inoculation, the hyphae of the pathogen were completely degraded in a dual culture. T. asperellum was also able to enter the P. capsici oospores through using oogonia and then developed hyphae and produced conidia, leading to the disintegration of the oogonia and oospores. Seven days after inoculation, an average 10.8% of the oospores were infected, but at this stage, the structures of oospores were still intact. Subsequently, the number of infected oospores increased and the oospores started to collapse. Forty-two days after inoculation, almost all the oospores were infected, with 9.3% of the structures of the oospores being intact and 90.7% of the oospores having collapsed.

  18. Cell type-dependent agonist/antagonist activities of polybrominated diphenyl ethers.

    PubMed

    Nakamura, N; Matsubara, K; Sanoh, S; Ohta, S; Uramaru, N; Kitamura, S; Yamaguchi, M; Sugihara, K; Fujimoto, N

    2013-11-25

    There have been many concerns expressed regarding the possible adverse effects of thyroid hormone-disrupting chemicals including polychlorinated biphenyls and polybrominated diphenyl ethers (PBDEs), since thyroid hormones play crucial roles in normal vertebrate development. A vast amount of PBDEs have been used as flame retardants for the last two decades and our environment has been contaminated with them. Some PBDEs, especially hydroxylated PBDEs, reportedly show an affinity to the thyroid hormone receptor (TR) and act as thyroid hormone agonists, but in other studies they were reported to inhibit the actions of thyroid hormones. Therefore, in the present study, we investigated the binding affinities of PBDEs and their metabolites to TR and their ability to induce thyroid hormone-responsive transcription using luciferase reporter gene assays in two different cell lines, a pituitary cell line, MtT/E-2, and Chinese hamster ovary (CHO) cells. The binding assay showed that many of the examined PBDEs have significant affinity to TR. Interestingly, some of these PBDEs, such as 4'-OH-BDE-17 and 2'-OH-BDE-28, acted as agonists in the reporter gene assay in MtT/E-2 cells, while they acted as antagonists in CHO cells. Our results demonstrated that whether PBDEs and their metabolites are TR agonists or antagonists depends on the cell type used in the assay, which may suggest that the thyroid hormone-disrupting actions of PBDEs differ among target tissues or species. PMID:24076165

  19. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists

    PubMed Central

    Khanfar, Mohammad A.; Affini, Anna; Lutsenko, Kiril; Nikolic, Katarina; Butini, Stefania; Stark, Holger

    2016-01-01

    With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures. PMID:27303254

  20. Endothelin receptor antagonists in the treatment of pulmonary arterial hypertension.

    PubMed

    Langleben, David

    2007-03-01

    The recognition that endothelin-1 contributes to the pathogenesis of pulmonary arterial hypertension has led to the development of clinically useful endothelin receptor antagonists that improve symptoms and functional capacity and alter the natural history of the disease in a beneficial way. The antagonists have varying degrees of selectivity for the two classes of endothelin receptor, termed ETA and ETB, and the varying degrees may translate into clinical differences. Endothelin receptor antagonists have become an integral part of therapy for pulmonary arterial hypertension, and the indications for their use are expanding. PMID:17338931

  1. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists.

    PubMed

    Khanfar, Mohammad A; Affini, Anna; Lutsenko, Kiril; Nikolic, Katarina; Butini, Stefania; Stark, Holger

    2016-01-01

    With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures. PMID:27303254

  2. Mechanisms and assessment of statin-related muscular adverse effects

    PubMed Central

    Moßhammer, Dirk; Schaeffeler, Elke; Schwab, Matthias; Mörike, Klaus

    2014-01-01

    Statin-associated muscular adverse effects cover a wide range of symptoms, including asymptomatic increase of creatine kinase serum activity and life-threatening rhabdomyolysis. Different underlying pathomechanisms have been proposed. However, a unifying concept of the pathogenesis of statin-related muscular adverse effects has not emerged so far. In this review, we attempt to categorize these mechanisms along three levels. Firstly, among pharmacokinetic factors, it has been shown for some statins that inhibition of cytochrome P450-mediated hepatic biotransformation and hepatic uptake by transporter proteins contribute to an increase of systemic statin concentrations. Secondly, at the myocyte membrane level, cell membrane uptake transporters affect intracellular statin concentrations. Thirdly, at the intracellular level, inhibition of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase results in decreased intracellular concentrations of downstream metabolites (e.g. selenoproteins, ubiquinone, cholesterol) and alteration of gene expression (e.g. ryanodine receptor 3, glycine amidinotransferase). We also review current recommendations for prescribers. PMID:25069381

  3. Juvenile spinal muscular atrophy: a new hexosaminidase deficiency phenotype.

    PubMed

    Johnson, W G; Wigger, H J; Karp, H R; Glaubiger, L M; Rowland, L P

    1982-01-01

    A 24-year-old Ashkenazi Jewish man was evaluated for a nine-year history of progressive leg weakness with fasciculations. Electromyography, nerve conduction velocities, muscle biopsy, and serum creatine kinase were consistent with anterior horn cell disease. On rectal biopsy, ganglion cells were filled with membranous cytoplasmic bodies and an unusual submucosal layer of periodic acid-Schiff positive histiocytes filled with granules was seen. Hexosaminidase A in serum and leukocytes was severely decreased in the patient and partially decreased in parents and a brother. A paternal relative had classic infantile Tay-Sachs disease. Juvenile spinal muscular atrophy in this patient, closely resembling the Kugelberg-Welander phenotype, resulted from an alpha-locus hexosaminidase deficiency disorder, possibly a genetic compound of HEX alpha 2 and a milder hexosaminidase alpha-locus allele. Other cases of hexosaminidase deficiency have included anterior horn cell disease as part of a more complex disorder, but this is the first case, to our knowledge, of a hexosaminidase deficiency disorder presenting as spinal muscular atrophy. PMID:6460466

  4. Morphometric studies of the muscular branch of the median nerve.

    PubMed

    Olave, E; Prates, J C; Gabrielli, C; Pardi, P

    1996-10-01

    The branch from the median nerve to the thenar muscles has a proximal and lateral (recurrent) course and is vulnerable to lesions that affect these muscles. Because of its anatomical-clinical importance, this branch was studied in 60 palmar regions from 30 cadavers of adult individuals of both sexes, aged between 23 and 77 y. It arose from the lateral branch of the median nerve in 83.3% of the cases. Its origin was distal to the flexor retinaculum in 48.3%, at the distal margin of the retinaculum in 31.6%, in the carpal tunnel in 18.3% and proximal to the retinaculum in 1.7%; it pierced the retinaculum in 15%. The point of recurrence of the branch was localised topographically to 34.6 +/- 3.6 mm from the distal wrist crease; the angle between its recurrent course and the longitudinal axis of the hand averaged 66.8 degrees. In 50% of the cases the muscular branch innervated abductor pollicis brevis (APB), opponens pollicis (OP) and the superficial head of flexor pollicis brevis (FPB), in 40% it supplied only APB and OP, and in 10% a short muscular branch gave rise to independent branches in the palm and which supplied APB, OP and the superficial head of FPB. The so called "accessory thenar branch' was found in 38.3%. PMID:8886966

  5. [Central Nervous Involvement in Patients with Fukuyama Congenital Muscular Dystrophy].

    PubMed

    Ishigaki, Keiko

    2016-02-01

    Fukuyama congenital muscular dystrophy (FCMD), the second most common muscular dystrophy in the Japanese population, is an autosomal recessive disorder caused by mutations in the fukutin (FKTN) gene. The main features of FCMD are a combination of infantile-onset hypotonia, generalized muscle weakness, eye abnormalities and central nervous system involvement with mental retardation and seizures associated with cortical migration defects. The FKTN gene product is thought to be necessary for maintaining migrating neurons in an immature state during migration, and for supporting migration via α-dystroglycan in the central nervous system. Typical magnetic resonance imaging findings in FCMD patients are cobblestone lissencephaly and cerebellar cystic lesions. White matter abnormalities with hyperintensity on T(2)-weighted images are seen especially in younger patients and those with severe phenotypes. Most FCMD patients are mentally retarded and the level is moderate to severe, with IQs ranging from 30 to 50. In our recent study, 62% of patients developed seizures. Among them, 71% had only febrile seizures, 6% had afebrile seizures from the onset, and 22% developed afebrile seizures following febrile seizures. Most patients had seizures that were controllable with just 1 type of antiepileptic drug, but 18% had intractable seizures that must be treated with 3 medications. PMID:26873231

  6. Nitric oxide synthase deficiency and the pathophysiology of muscular dystrophy

    PubMed Central

    Tidball, James G; Wehling-Henricks, Michelle

    2014-01-01

    The secondary loss of neuronal nitric oxide synthase (nNOS) that occurs in dystrophic muscle is the basis of numerous, complex and interacting features of the dystrophic pathology that affect not only muscle itself, but also influence the interaction of muscle with other tissues. Many mechanisms through which nNOS deficiency contributes to misregulation of muscle development, blood flow, fatigue, inflammation and fibrosis in dystrophic muscle have been identified, suggesting that normalization in NO production could greatly attenuate diverse aspects of the pathology of muscular dystrophy through multiple regulatory pathways. However, the relative importance of the loss of nNOS from the sarcolemma versus the importance of loss of total nNOS from dystrophic muscle remains unknown. Although most current evidence indicates that nNOS localization at the sarcolemma is not required to achieve NO-mediated reductions of pathology in muscular dystrophy, the question remains open concerning whether membrane localization would provide a more efficient rescue from features of the dystrophic phenotype. PMID:25194047

  7. Reassessing the improbability of a muscular crinoid stem

    PubMed Central

    Gorzelak, Przemysław; Głuchowski, Edward; Salamon, Mariusz A.

    2014-01-01

    Muscular articulations in modern stalked crinoids are only present in the arms. Although it has been suggested that certain coiled-stemmed fossil taxa may have been functionally adapted to utilize muscles, evidence supporting this interpretation is lacking. Here, we use cathodoluminescence and SEM to reveal the skeletal microstructure of the enigmatic coiled-stemmed taxon Ammonicrinus (Flexibilia). Based on the well-established link between skeletal microstructure and the nature of infilling soft tissues in modern echinoderms, we reconstructed the palaeoanatomy of the Middle Devonian ammonicrinids. We show that their median columnals with elongated lateral columnal enclosure extensions (LCEE) have stereom microstructure unexpectedly resembling that in the crinoid muscular arm plates. In particular, large ligamentary facets, that are present on each side of a transverse ridge, are mainly comprised of fine galleried stereom that is indicative of the mutable collagenous tissues. In contrast, fine labyrinthic stereom, commonly associated with muscles, is situated in the periphery on each side of the surface of elongated LCEE. Our findings thus strongly suggest that the muscles may have also been present in the stem of ammonicrinids. These results reassess the previous hypotheses about evolution of muscles in crinoids and provide new insights into the mode of life of Ammonicrinus. PMID:25116414

  8. Neurotrophins, cytokines, oxidative parameters and funcionality in Progressive Muscular Dystrophies.

    PubMed

    Comim, Clarissa M; Mathia, Gisiane B; Hoepers, Andreza; Tuon, Lisiane; Kapczinski, Flávio; Dal-Pizzol, Felipe; Quevedo, João; Rosa, Maria I

    2015-09-01

    We investigated the levels of brain derived-neurotrophic factor (BDNF), cytokines and oxidative parameters in serum and tried to correlate them with the age and functionality of patients with Progressive Muscle Dystrophies (PMD). The patients were separated into six groups (case and controls pared by age and gender), as follows: Duchenne Muscular Dystrophy (DMD); Steinert Myotonic Dystrophy (SMD); and Limb-girdle Muscular Dystrophy type-2A (LGMD2A). DMD patients (± 17.9 years old) had a decrease of functionality, an increase in the IL-1β and TNF-α levels and a decrease of IL-10 levels and superoxide dismutase activity in serum. SMD patients (± 25.8 years old) had a decrease of BDNF and IL-10 levels and superoxide dismutase activity and an increase of IL-1β levels in serum. LGMD2A patients (± 27.7 years old) had an decrease only in serum levels of IL-10. This research showed the first evidence of BDNF involvement in the SMD patients and a possible unbalance between pro-inflammatory and anti-inflammatory cytokine levels, along with decreased superoxide dismutase activity in serum of DMD and SMD patients. PMID:25910175

  9. Dystrophin in frameshift deletion patients with Becker Muscular Dystrophy

    SciTech Connect

    Gangopadhyay, S.B.; Ray, P.N.; Worton, R.G.; Sherratt, T.G.; Heckmatt, J.Z.; Dubowitz, V.; Strong, P.N.; Miller, G. ); Shokeir, M. )

    1992-09-01

    In a previous study the authors identified 14 cases with Duchenne muscular dystrophy (DMD) or its milder variant, Becker muscular dystrophy (BMD), with a deletion of exons 3-7, a deletion that would be expected to shift the translational reading frame of the mRNA and give a severe phenotype. They have examined dystrophin and its mRNA from muscle biopsies of seven cases with either mild or intermediate phenotypes. In all cases they detected slightly lower-molecular-weight dystrophin in 12%-15% abundance relative to the normal. By sequencing amplified mRNA they have found that exon 2 is spliced to exon 8, a splice that produces a frameshifted mRNA, and have found no evidence for alternate splicing that might be involved in restoration of dystrophin mRNA reading frame in the patients with a mild phenotype. Other transcriptional and posttranscriptional mechanisms such as cryptic promoter, ribosomal frameshifting, and reinitiation are suggested that might play some role in restoring the reading frame. 34 refs., 5 figs. 1 tab.

  10. Congenital Muscular Dystrophy and Generalized Epilepsy Caused by GMPPB Mutations

    PubMed Central

    Raphael, Alya R.; Couthouis, Julien; Sakamuri, Sarada; Siskind, Carly; Vogel, Hannes; Day, John W.; Gitler, Aaron D.

    2014-01-01

    The alpha-dystroglycanopathies are genetically heterogeneous muscular dystrophies that result from hypoglycosylation of alpha-dystroglycan (α-DG). Alpha-dystroglycan is an essential link between the extracellular matrix and the muscle fiber sarcolemma, and proper glycosylation is critical for its ability to bind to ligands in the extracellular matrix. We sought to identify the genetic basis of alpha-dystroglycanopathy in a family wherein the affected individuals presented with congenital muscular dystrophy, brain abnormalities and generalized epilepsy. We performed whole exome sequencing and identified compound heterozygous GMPPB mutations in the affected children. GMPPB is an enzyme in the glycosylation pathway, and GMPPB mutation were recently linked to eight cases of alpha-dystroglycanopathy with a range of symptoms. We identified a novel mutation in GMPPB (p.I219T) as well as a previously published mutation (p.R287Q). Thus, our work further confirms a role for GMPPB defects in alpha-dystroglycanopathy, and suggests that glycosylation may play a role in the neuronal membrane channels or networks involved in the physiology of generalized epilepsy syndromes. PMID:24780531

  11. Gaming magazines and the drive for muscularity in preadolescent boys: a longitudinal examination.

    PubMed

    Harrison, Kristen; Bond, Bradley J

    2007-09-01

    The development of a drive for muscularity among boys has been linked to various cultural influences, one of which is exposure to mass media depicting the muscular male body ideal. We sought to determine whether self-reported exposure to four ideal-body magazine genres (health/fitness, fashion, sports, and gaming) predicted an increased drive for muscularity 1 year later. A sample of 104 Black and 77 White preadolescent boys (mean age 8.77) participated in a 2-wave longitudinal panel study. Controlling Wave 1 grade, perceived thinness/adiposity, and drive for muscularity, exposure to video gaming magazines predicted a significant increase in Wave 2 drive for muscularity, but only for White boys. Discussion calls for the inclusion of video gaming magazine exposure measures in future research on print media and male body ideals, along with empirical exploration of racial themes in gaming magazines. PMID:18089273

  12. Independent mobility after early introduction of a power wheelchair in spinal muscular atrophy.

    PubMed

    Dunaway, Sally; Montes, Jacqueline; O'Hagen, Jessica; Sproule, Douglas M; Vivo, Darryl C De; Kaufmann, Petra

    2013-05-01

    Weakness resulting from spinal muscular atrophy causes severe limitations in functional mobility. The early introduction of power mobility has potential to enhance development and mitigate disability. These outcomes are achieved by simulating normal skill acquisition and by promoting motor learning, visuospatial system development, self-exploration, cognition, and social development. There are few reports on early power mobility in spinal muscular atrophy, and it is typically not prescribed until school age. The authors evaluated 6 children under age 2 years with neuromuscular disease (5 spinal muscular atrophy, 1 congenital muscular dystrophy) for power mobility. Parents recorded the practice hours necessary to achieve independence using the Power Mobility Skills Checklist. Four children achieved independence in all items on the checklist by 7.9 months (range: 73-458 days). Introduction of early power mobility is feasible in spinal muscular atrophy patients under age 2 years and should be introduced in late infancy when children typically acquire locomotor skills. PMID:22772161

  13. Amelioration of Muscular Dystrophy by Transgenic Expression of Niemann-Pick C1

    PubMed Central

    Steen, Michelle S.; Adams, Marvin E.; Tesch, Yan

    2009-01-01

    Duchenne muscular dystrophy (DMD) and other types of muscular dystrophies are caused by the loss or alteration of different members of the dystrophin protein complex. Understanding the molecular mechanisms by which dystrophin-associated protein abnormalities contribute to the onset of muscular dystrophy may identify new therapeutic approaches to these human disorders. By examining gene expression alterations in mouse skeletal muscle lacking α-dystrobrevin (Dtna−/−), we identified a highly significant reduction of the cholesterol trafficking protein, Niemann-Pick C1 (NPC1). Mutations in NPC1 cause a progressive neurodegenerative, lysosomal storage disorder. Transgenic expression of NPC1 in skeletal muscle ameliorates muscular dystrophy in the Dtna−/− mouse (which has a relatively mild dystrophic phenotype) and in the mdx mouse, a model for DMD. These results identify a new compensatory gene for muscular dystrophy and reveal a potential new therapeutic target for DMD. PMID:18946078

  14. [Calpain-3 gene defect causing limb gird muscular dystrophy in a Hungarian family].

    PubMed

    Horváth, Rita; Walter, Maggie C; Lochmüller, Hanns; Hübner, Angela; Karcagi, Veronika; Pikó, Henriett; Timár, László; Komoly, Sámuel

    2005-01-20

    Limb gird muscular dystrophies (LGMD2) are a clinically and genetically heterogeneous group of hereditary diseases with autosomal recessive trait, characterized by progressive atrophy and weakness predominantly in the proximal limb muscles. The authors present clinical, histological, immunohistochemical and immunoblot results of two sisters suffering from so far unclassified autosomal recessive limb girdle muscular dystrophy. Haplotype analysis for genes possibly involved in autosomal recessive limb girdle muscular dystrophies was performed in the genetically informative family. All of the results pointed to a molecular genetic defect of the calpain-3 (CAPN3) gene. Direct sequencing of the CAPN3 gene revealed compound heterozygous state for two mutations previously described in association with limb girdle muscular dystrophy, proving pathogenicity. The authors would like to emphasize the importance of the above described combined strategy in diagnosing limb girdle muscular dystrophies. PMID:15884399

  15. Analysis of the effects of alpha 1-adrenoceptor antagonists on noradrenaline-mediated contraction of rat small mesenteric artery.

    PubMed Central

    Van der Graaf, P. H.; Shankley, N. P.; Black, J. W.

    1996-01-01

    1. In this study, we examined the interaction between noradrenaline (NA) and phenylephrine (PE) with seven antagonists (prazosin, tamsulosin, phentolamine, WB-4101, 5-methylurapidil, spiperone and HV 723) in an attempt to characterize the alpha 1-adrenoceptor population of the rat isolated small mesenteric artery (SMA) preparation. 2. Six of the seven antagonists investigated produced concentration-dependent, parallel, rightward shift of the NA concentration-effect (E/[A]) curves. The exception was tamsulosin, which produced significant decrease of the upper asymptote. In the case of 5-methylurapidil and HV723, the Schild plot slope parameters were not significantly different from unity over the range of concentrations used. However, the Schild plot slopes obtained for the other antagonists were all significantly greater than unity, inconsistent with expectations for simple competitive antagonism. 3. HV723, prazosin and tamsulosin were also tested using PE as an agonist. All three antagonists produced concentration-dependent, parallel, rightward shifts of the PE curves and Schild analysis yielded slope parameters not significantly different from unity. The pKB estimates obtained for tamsulosin and prazosin were not significantly different from the pA2 values obtained when NA was used as agonist. In the case of HV723, the 95% confidence intervals for the pKB values yielded with NA and PE did not overlap (pKB = 8.80-9.13 and 8.15-8.77 for NA and PE, respectively). 4. In the absence of evidence to indicate that the steep Schild plots were due to failure to satisfy the basic criteria for quantitative analysis in a one-receptor system, we considered the possibility that the complexity was caused by an action of NA at inhibitory D1 receptors. The selective D1 receptor antagonists, SCH-23390 (10 nM), had no significant effect on the NA E/[A] control curve, but the apparent potency of 100 nM prazosin was reduced by approximately 3.5 fold. 5. This study indicates that the

  16. The muscarinic antagonists scopolamine and atropine are competitive antagonists at 5-HT3 receptors.

    PubMed

    Lochner, Martin; Thompson, Andrew J

    2016-09-01

    Scopolamine is a high affinity muscarinic antagonist that is used for the prevention of post-operative nausea and vomiting. 5-HT3 receptor antagonists are used for the same purpose and are structurally related to scopolamine. To examine whether 5-HT3 receptors are affected by scopolamine we examined the effects of this drug on the electrophysiological and ligand binding properties of 5-HT3A receptors expressed in Xenopus oocytes and HEK293 cells, respectively. 5-HT3 receptor-responses were reversibly inhibited by scopolamine with an IC50 of 2.09 μM. Competitive antagonism was shown by Schild plot (pA2 = 5.02) and by competition with the 5-HT3 receptor antagonists [(3)H]granisetron (Ki = 6.76 μM) and G-FL (Ki = 4.90 μM). The related molecule, atropine, similarly inhibited 5-HT evoked responses in oocytes with an IC50 of 1.74 μM, and competed with G-FL with a Ki of 7.94 μM. The reverse experiment revealed that granisetron also competitively bound to muscarinic receptors (Ki = 6.5 μM). In behavioural studies scopolamine is used to block muscarinic receptors and induce a cognitive deficit, and centrally administered concentrations can exceed the IC50 values found here. It is therefore possible that 5-HT3 receptors are also inhibited. Studies that utilise higher concentrations of scopolamine should be mindful of these potential off-target effects. PMID:27108935

  17. Single exposure of dopamine D1 antagonist prevents and D2 antagonist attenuates methylphenidate effect

    PubMed Central

    Claussen, Catherine M; Witte, Lindsey J; Dafny, Nachum

    2015-01-01

    Methylphenidate (MPD) is a readily prescribed drug for the treatment of attention deficit hyperactivity disorder (ADHD) and moreover is used illicitly by youths for its cognitive-enhancing effects and recreation. MPD exposure in rodents elicits increased locomotor activity. Repetitive MPD exposure leads to further augmentation of their locomotor activity. This behavioral response is referred to as behavioral sensitization. Behavioral sensitization is used as an experimental marker for a drug’s ability to elicit dependence. There is evidence that dopamine (DA) is a key player in the acute and chronic MPD effect; however, the role of DA in the effects elicited by MPD is still debated. The objective of this study was to investigate the role of D1 and/or D2 DA receptors in the acute and chronic effect of MPD on locomotor activity. The study lasted for 12 consecutive days. Seven groups of male Sprague Dawley® rats were used. A single D1 or D2 antagonist was given before and after acute and chronic MPD administration. Single injection of D1 DA antagonist was able to significantly attenuate the locomotor activity when given prior to the initial MPD exposure and after repetitive MPD exposure, while the D2 DA antagonist partially attenuated the locomotor activity only when given before the second MPD exposure. The results show the role, at least in part, of the D1 DA receptor in the mechanism of behavioral sensitization, whereas the D2 DA receptor only partially modulates the response to acute and chronic MPD. PMID:27186140

  18. Effects of beta-adrenoceptor antagonists on Ca(2+)-overload induced by lysophosphatidylcholine in rat isolated cardiomyocytes.

    PubMed Central

    Chen, M.; Hashizume, H.; Abiko, Y.

    1996-01-01

    1. The effects of beta-adrenoceptor antagonists including (-)- and (+)-propranolol, (-)- and (+)-penbutolol, timolol, pindolol, atenolol, acebutolol and practolol on the Ca(2+)-overload induced by lysophosphatidylcholine (LPC) were examined in isolated cardiomyocytes of the rat. 2. Fura-2 was used for measurement of the intracellular calcium concentration ([Ca2+]i). LPC (15 microM) produced a rapid increase in [Ca2+]i from 72 +/- 5 to 3042 +/- 431 nM which coincided with a decrease in the percentage of rod-shaped cells from 69 +/- 2 to 5 +/- 2%. 3. Preincubation with (-)-propranolol (20 microM), (+)-propranolol (50 microM), or (-)- or (+)-penbutolol (20 microM), the lipophilicity of which is higher than other beta-adrenoceptor antagonists, significantly inhibited both the increase in [Ca2+]i and the cell-shape change induced by 15 microM LPC. The inhibitory effects of the four drugs on the LPC-induced increase in [Ca2+]i and cell-shape change were concentration-dependent. The IC50S of (-)-propranolol, (+)-propranolol, (-)- and (+)-penbutolol for the increase in [Ca2+]i were 1.28, 10.50, 0.67 and 0.76 microM, respectively. 4. Pretreatment with pindolol, timolol, acebutolol, practolol, atenolol or lignocaine did not inhibit the increase in [Ca2+]i and the morphological change induced by LPC. 5. LPC markedly increased the release of creatine phosphokinase from 9 +/- 1 to 45 +/- 2% which could be significantly reduced by (-)- or (+)-propranolol but not by acebutolol or timolol. 6. The protective effects of (-)- and (+)-propranolol, (-)- and (+)-penbutolol against the Ca(2+)-overload induced by LPC were not associated with the beta-adrenoceptor antagonistic action, but probably with an unknown action which is related to the preservation of membrane integrity. Further studies are necessary to clarify the exact mechanisms of the protective action of these beta-adrenoceptor antagonists against the Ca(2+)-overload induced by LPC. PMID:8799555

  19. Developmental Defects in a Zebrafish Model for Muscular Dystrophies Associated with the Loss of Fukutin-Related Protein (FKRP)

    ERIC Educational Resources Information Center

    Thornhill, Paul; Bassett, David; Lochmuller, Hanns; Bushby, Kate; Straub, Volker

    2008-01-01

    A number of muscular dystrophies are associated with the defective glycosylation of [alpha]-dystroglycan and many are now known to result from mutations in a number of genes encoding putative or known glycosyltransferases. These diseases include severe forms of congenital muscular dystrophy (CMD) such as Fukuyama type congenital muscular dystrophy…

  20. [Therapeutic readthrough strategy for suppression of nonsense mutations in duchenne muscular dystrophy].

    PubMed

    Shiozuka, Masataka; Matsuda, Ryoichi

    2011-11-01

    Effective treatment for Duchenne muscular dystrophy (DMD) is currently unavailable. Readthrough of disease-causing premature termination codons might alleviate the symptoms of genetic diseases caused by nonsense mutations. Several ribosome-binding compounds, including selective antibiotics and synthetic novel small molecules, induce translational readthrough, restoring full-length functional proteins. Here in this innovative therapeutic strategy has been summarized with a focus on DMD. We have previously reported that negamycin restored dystrophin expression with less toxicity than gentamicin in mdx mice. To explore more potent readthrough inducers, we established the transgenic mouse called READ (readthrough evaluation and assessment by dural receptor) for readthrough-specific detection. Using READ mice, we discovered drug candidates, including sterically negamycin-like small molecules and aminoglycoside derivatives. The newly developed small molecules induced dose-dependent readthrough with greater potency than ataluren in vitro and promoted the expression of dystrophin and reduction in serum creatine kinase activity in mdx mice. Moreover, the aminoglycoside derivative restored both dystrophin protein and contractile function of mdx skeletal muscles with appreciably higher readthrough activity and lower toxicity than that of gentamicin. Furthermore, we confirmed the efficacy of a thioglycolate-based depilatory agent to enhance the topical delivery of skin-impermeable drugs, including aminoglycosides. These promising new chemotherapeutic agents with beneficial effects on readthrough action, lower toxicity, and transdermal delivery may have significant value in treating or preventing genetic diseases caused by nonsense mutations. PMID:22068478

  1. Does cheating pay: the role of externally supplied momentum on muscular force in resistance exercise.

    PubMed

    Arandjelović, Ognjen

    2013-01-01

    Our work investigates the use of "external momentum" in the context of hypertrophy-oriented training. This is momentum supplied to the load (such as a dumbbell) used in an exercise by means of action of muscles not inherently involved in the exercise. We challenge the general consensus that the use of such momentum often described as "cheating" is counterproductive. We focus on the use of external momentum in the shoulder lateral raise and adopt a framework whereby exercise execution is simulated on a computer. This is achieved using a physical model of motion which is combined with anthropomorphic measurements and empirical data of muscular recruitment from previous work. The introduction of moderate momentum (producing initial angular velocities around 57.5° s(-1)) increases the torque of the target muscles even without an increase in the load used. A moderate increase in the load and the use of momentum allows the torque to be increased even further. In contrast, excessive use of momentum results in lower demands on the target muscles, while an excessive increase of the load reduces the total hypertrophy stimulus by virtue of the decreased number of repetitions which can be performed successfully and thus the dramatically shortened time under tension. Our results disprove the conventional belief that the use of external momentum necessarily reduces the overload of the target muscles. A moderate use of external momentum increases both the per-repetition peak torque and the total hypertrophy stimulus in a set. PMID:22615008

  2. [Anesthetic Management of a Patient with Facioscapulohumeral Muscular Dystrophy: Importance of Monitoring Neuromuscular Function at Multiple Sites].

    PubMed

    Matsui, Shuhei; Tanaka, Satoshi; Kiyosawa, Kenkichi; Tanaka, Toshiyuki; Kawamata, Mikito

    2015-12-01

    A 39-year-old female with facioscapulohumeral muscular dystrophy (FSHD) was scheduled for thoracoscopic resection of an anterior mediastinal tumor. She had slowly progressive weakness and atrophy in the fascial and shoulder girdle muscles. General anesthesia was induced and maintained with propofol, remifentanil, and fentanyl combined with thoracic paravertebral block. Rocuronium-induced neuromuscular blockade was evaluated with acceleromyography at the corrugator supercilii, masseter, and adductor pollicis muscles. There was no reaction at the atrophic corrugator supercilii muscle in response to train-of-four (TOF) stimulation even before rocuronium administration. In contrast twitch responses at the masseter and adductor pollicis muscles to TOF stimulation could be evoked and the duration of action of rocuronium was found to be similar to that of the normal population. The perioperative course was uneventful. Neuromuscular monitoring sites should be carefully selected in FSHD patients because of possible inability to monitor neuromuscular function at the atrophic muscles. PMID:26790332

  3. Biomolecular recognition of antagonists by α7 nicotinic acetylcholine receptor: Antagonistic mechanism and structure-activity relationships studies.

    PubMed

    Peng, Wei; Ding, Fei

    2015-08-30

    As the key constituent of ligand-gated ion channels in the central nervous system, nicotinic acetylcholine receptors (nAChRs) and neurodegenerative diseases are strongly coupled in the human species. In recently years the developments of selective agonists by using nAChRs as the drug target have made a large progress, but the studies of selective antagonists are severely lacked. Currently these antagonists rest mainly on the extraction of partly natural products from some animals and plants; however, the production of these crude substances is quite restricted, and artificial synthesis of nAChR antagonists is still one of the completely new research fields. In the context of this manuscript, our primary objective was to comprehensively analyze the recognition patterns and the critical interaction descriptors between target α7 nAChR and a series of the novel compounds with potentially antagonistic activity by means of virtual screening, molecular docking and molecular dynamics simulation, and meanwhile these recognition reactions were also compared with the biointeraction of α7 nAChR with a commercially natural antagonist - methyllycaconitine. The results suggested clearly that there are relatively obvious differences of molecular structures between synthetic antagonists and methyllycaconitine, while the two systems have similar recognition modes on the whole. The interaction energy and the crucially noncovalent forces of the α7 nAChR-antagonists are ascertained according to the method of Molecular Mechanics/Generalized Born Surface Area. Several amino acid residues, such as B/Tyr-93, B/Lys-143, B/Trp-147, B/Tyr-188, B/Tyr-195, A/Trp-55 and A/Leu-118 played a major role in the α7 nAChR-antagonist recognition processes, in particular, residues B/Tyr-93, B/Trp-147 and B/Tyr-188 are the most important. These outcomes tally satisfactorily with the discussions of amino acid mutations. Based on the explorations of three-dimensional quantitative structure

  4. Citizen's actions

    NASA Technical Reports Server (NTRS)

    1975-01-01

    The role played by individual citizens as consumers of energy was examined, with emphasis on studying ways in which their action could result in energy conservation. It was shown that there are ways that energy can be conserved in this way, with citizens acting either individually or in groups. The potential savings are significant, but the actual savings may be quite small. The citizens need to be motivated to save and to believe in a conservation ethic; developing such an ethic is difficult, and perhaps not responsive to the shotgun approach now being attempted. The true course of action may be to synthesize new societal structures that provide the maximum evolution of culture within the limitation of scarce energy resources.

  5. Air stacking: effects on pulmonary function in patients with spinal muscular atrophy and in patients with congenital muscular dystrophy*,**

    PubMed Central

    Marques, Tanyse Bahia Carvalho; Neves, Juliana de Carvalho; Portes, Leslie Andrews; Salge, João Marcos; Zanoteli, Edmar; Reed, Umbertina Conti

    2014-01-01

    OBJECTIVE: Respiratory complications are the main causes of morbidity and mortality in patients with neuromuscular disease (NMD). The objectives of this study were to determine the effects that routine daily home air-stacking maneuvers have on pulmonary function in patients with spinal muscular atrophy (SMA) and in patients with congenital muscular dystrophy (CMD), as well as to identify associations between spinal deformities and the effects of the maneuvers. METHODS: Eighteen NMD patients (ten with CMD and eight with SMA) were submitted to routine daily air-stacking maneuvers at home with manual resuscitators for four to six months, undergoing pulmonary function tests before and after that period. The pulmonary function tests included measurements of FVC; PEF; maximum insufflation capacity (MIC); and assisted and unassisted peak cough flow (APCF and UPCF, respectively) with insufflations. RESULTS: After the use of home air-stacking maneuvers, there were improvements in the APCF and UPCF. In the patients without scoliosis, there was also a significant increase in FVC. When comparing patients with and without scoliosis, the increases in APCF and UPCF were more pronounced in those without scoliosis. CONCLUSIONS: Routine daily air-stacking maneuvers with a manual resuscitator appear to increase UPCF and APCF in patients with NMD, especially in those without scoliosis. PMID:25410841

  6. Actionable Nuggets

    PubMed Central

    McColl, Mary Ann; Aiken, Alice; Smith, Karen; McColl, Alexander; Green, Michael; Godwin, Marshall; Birtwhistle, Richard; Norman, Kathleen; Brankston, Gabrielle; Schaub, Michael

    2015-01-01

    Abstract Objective To present the results of a pilot study of an innovative methodology for translating best evidence about spinal cord injury (SCI) for family practice. Design Review of Canadian and international peer-reviewed literature to develop SCI Actionable Nuggets, and a mixed qualitative-quantitative evaluation to determine Nuggets’ effect on physician knowledge of and attitudes toward patients with SCI, as well as practice accessibility. Setting Ontario, Newfoundland, and Australia. Participants Forty-nine primary care physicians. Methods Twenty Actionable Nuggets (pertaining to key health issues associated with long-term SCI) were developed. Nugget postcards were mailed weekly for 20 weeks to participating physicians. Prior knowledge of SCI was self-rated by participants; they also completed an online posttest to assess the information they gained from the Nugget postcards. Participants’ opinions about practice accessibility and accommodations for patients with SCI, as well as the acceptability and usefulness of Nuggets, were assessed in interviews. Main findings With Actionable Nuggets, participants’ knowledge of the health needs of patients with SCI improved, as knowledge increased from a self-rating of fair (58%) to very good (75%) based on posttest quiz results. The mean overall score for accessibility and accommodations in physicians’ practices was 72%. Participants’ awareness of the need for screening and disease prevention among this population also increased. The usefulness and acceptability of SCI Nugget postcards were rated as excellent. Conclusion Actionable Nuggets are a knowledge translation tool designed to provide family physicians with concise, practical information about the most prevalent and pressing primary care needs of patients with SCI. This evidence-based resource has been shown to be an excellent fit with information consumption processes in primary care. They were updated and adapted for distribution by the Canadian

  7. Complications of TNF-α antagonists and iron homeostasis

    EPA Science Inventory

    TNF-α is a central regulator of inflammation and its blockade downregulates other proinflammatory cytokines, chemokines, and growth factors. Subsequently, TNF-α antagonists are currently used in treatment regimens directed toward several inflammatory diseases. Despite a beneficia...

  8. Androgen action.

    PubMed

    Werner, Ralf; Holterhus, Paul-Martin

    2014-01-01

    Androgens are important for male sex development and physiology. Their actions are mediated by the androgen receptor (AR), a ligand-dependent nuclear transcription factor. The activity of the AR is controlled at multiple stages due to ligand binding and induced structural changes assisted by the foldosome, compartmentalization, recruitment of coregulators, posttranslational modifications and chromatin remodeling, leading to subsequent transcription of androgen-responsive target genes. Beside these short-term androgen actions, there is phenomenological and experimental evidence of long-term androgen programming in mammals and in the human during sensitive programming time windows, both pre- and postnatally. At the molecular level, research into androgen insensitivity syndrome has unmasked androgen programming at the transcriptome level, in genital fibroblasts and peripheral blood mononuclear cells, and at the epigenome level. Androgens are crucial for male sex development and physiology during embryogenesis, at puberty and in adult life. Testosterone and its more potent metabolite, dihydrotestosterone, which is converted from testosterone within the target cell by 5α-reductase II, are the main androgens involved in male sex differentiation. Androgen action is mediated by a single AR. The AR belongs to the nuclear receptor 3 group C, composed of the glucocorticoid receptor (NR3C1), mineralocorticoid receptor (NR3C2), progesterone receptor (NR3C3) and AR (NR3C4), and acts as a ligand-dependent transcription factor. PMID:25247642

  9. The influence of 5-HT2 and 5-HT4 receptor antagonists to modify drug induced disinhibitory effects in the mouse light/dark test

    PubMed Central

    Costall, Brenda; Naylor, Robert J

    1997-01-01

    The ability of 5-HT2 and 5-HT4 receptor antagonists to modify the disinhibitory profile of diazepam and other agents was investigated in male BKW mice in the light/dark test box. The 5-HT2A/2B/2C receptor antagonists ritanserin, MDL11939 and RP62203 and also methysergide, which failed to modify mouse behaviour when administered alone, caused dose-related enhancements (4 to 8 fold) in the potency of diazepam to disinhibit behavioural responding to the aversive situation of the test box. Ritanserin was shown to enhance the disinhibitory potency of other benzodiazepines, chlordiazepoxide (4 fold), temazepam (10 fold) and lorazepam (10 fold), the 5-HT1A receptor ligands, 8-OH-DPAT (25 fold), buspirone (100 fold) and lesopitron (500 fold), the 5-HT3 receptor antagonists, ondansetron (100 fold) R(+)-zacopride (100 fold) and S(−)-zacopride (greater than a 1000 fold), the substituted benzamides, sulpiride (10 fold) and tiapride (5 to 10 fold) and the cholecystokinin (CCK)A receptor antagonist, devazepide (100 fold). It also reduced the onset of action of disinhibition following treatment with the 5-HT synthesis inhibitor parachlorophenylalanine. Ritanserin failed to enhance the disinhibitory effects of the CCKB receptor antagonist CI-988, the angiotensin AT1 receptor antagonist losarten or the angiotensin converting enzyme inhibitor ceranapril. The 5-HT4 receptor antagonists SDZ205-557, GR113808 and SB204070 caused dose-related reductions in the disinhibitory effect of diazepam, returning values to those shown in vehicle treated controls. The antagonists failed to modify mouse behaviour when administered alone. GR113808 was also shown to cause a dose-related antagonism of the disinhibitory effects of chlordiazepoxide, lorazepam, 8-OH-DPAT, buspirone, lesopitron, ondansetron, R(+)-zacopride, sulpiride, tiapride, devazepide, CI-988, losarten, ceranapril and parachlorophenylalanine. It was concluded that in BKW mice (a) the failure of 5-HT2 and 5-HT4 receptor antagonists

  10. Anthropomorphic finger antagonistically actuated by SMA plates.

    PubMed

    Engeberg, Erik D; Dilibal, Savas; Vatani, Morteza; Choi, Jae-Won; Lavery, John

    2015-10-01

    Most robotic applications that contain shape memory alloy (SMA) actuators use the SMA in a linear or spring shape. In contrast, a novel robotic finger was designed in this paper using SMA plates that were thermomechanically trained to take the shape of a flexed human finger when Joule heated. This flexor actuator was placed in parallel with an extensor actuator that was designed to straighten when Joule heated. Thus, alternately heating and cooling the flexor and extensor actuators caused the finger to flex and extend. Three different NiTi based SMA plates were evaluated for their ability to apply forces to a rigid and compliant object. The best of these three SMAs was able to apply a maximum fingertip force of 9.01N on average. A 3D CAD model of a human finger was used to create a solid model for the mold of the finger covering skin. Using a 3D printer, inner and outer molds were fabricated to house the actuators and a position sensor, which were assembled using a multi-stage casting process. Next, a nonlinear antagonistic controller was developed using an outer position control loop with two inner MOSFET current control loops. Sine and square wave tracking experiments demonstrated minimal errors within the operational bounds of the finger. The ability of the finger to recover from unexpected disturbances was also shown along with the frequency response up to 7 rad s(-1). The closed loop bandwidth of the system was 6.4 rad s(-1) when operated intermittently and 1.8 rad s(-1) when operated continuously. PMID:26292164

  11. Suppressing antagonistic bioengineering feedbacks doubles restoration success.

    PubMed

    Suykerbuyk, Wouter; Bouma, Tjeerd J; van der Heide, Tjisse; Faust, Cornelia; Govers, Laura L; Giesen, Wim B J T; de Jong, Dick J; van Katwijk, Marieke M

    2012-06-01

    In a seagrass restoration project, we explored the potential for enhancing the restoration process by excluding antagonistic engineering interactions (i.e., biomechanical warfare) between two ecosystem engineers: the bioturbating lugworm Arenicola marina and the sediment-stabilizing seagrass Zostera noltii Hornem. Applying a shell layer underneath half of our seagrass transplants successfully reduced adult lugworm density by over 80% and reduced lugworm-induced microtopography (a proxy for lugworm disturbance) at the wave-sheltered site. At the wave-exposed site adult lugworm densities and microtopography were already lower than at the sheltered site but were further reduced in the shell-treated units. Excluding lugworms and their bioengineering effects corresponded well with a strongly enhanced seagrass growth at the wave-sheltered site, which was absent at the exposed site. Enhanced seagrass growth in the present study was fully assigned to the removal of lugworms' negative engineering effects and not to any (indirect) evolving effects such as an altered biogeochemistry or sediment-stabilizing effects by the shell layer. The context-dependency implies that seagrass establishment at the exposed site is not constrained by negative ecosystem-engineering interactions only, but also by overriding physical stresses causing poor growth conditions. Present findings underline that, in addition to recent emphasis on considering positive (facilitating) interactions in ecological theory and practice, it is equally important to consider negative engineering interactions between ecosystem-engineering species. Removal of such negative interactions between ecosystem-engineering species can give a head start to the target species at the initial establishment phase, when positive engineering feedbacks by the target species on itself are still lacking. Though our study was carried out in a marine environment with variable levels of wave disturbance, similar principles may be

  12. P2X1 Receptor Antagonists Inhibit HIV-1 Fusion by Blocking Virus-Coreceptor Interactions

    PubMed Central

    Giroud, Charline; Marin, Mariana; Hammonds, Jason; Spearman, Paul

    2015-01-01

    receptor antagonist, NF279, is due to the blocking of virus interactions with both the CXCR4 and CCR5 coreceptors. The ability of NF279 to abrogate cellular calcium signaling induced by the respective chemokines showed that this compound acts as a dual-coreceptor antagonist. P2X1 receptor antagonists could thus represent a new class of dual-coreceptor inhibitors with a structure and a mechanism of action that are distinct from those of known HIV-1 coreceptor antagonists. PMID:26136569

  13. Functional potencies of dopamine agonists and antagonists at human dopamine D₂ and D₃ receptors.

    PubMed

    Tadori, Yoshihiro; Forbes, Robert A; McQuade, Robert D; Kikuchi, Tetsuro

    2011-09-01

    We measured the functional agonist potencies of dopamine agonists including antiparkinson drugs, and functional antagonist potencies of antipsychotics at human dopamine D(2) and D(3) receptors. In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cells expressing low and high densities of human dopamine D(2L) and D(2S) receptors (hD(2L)-Low, hD(2L)-High, hD(2S)-Low and hD(2S)-High, respectively) and human dopamine D(3) Ser-9 and D(3) Gly-9 receptors (hD(3)-Ser-9 and hD(3)-Gly-9, respectively). Cabergoline, bromocriptine, pergolide, (±)-7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), talipexole, pramipexole, R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-olhydrochloride (PD128907) and ropinirole behaved as dopamine D(2) and D(3) receptor full agonists and showed higher potencies in hD(2L)-High and hD(2S)-High compared to hD(2L)-Low and hD(2S)-Low. In hD(3)-Ser-9 and hD(3)-Gly-9 compared to hD(2L)-Low and hD(2S)-Low, dopamine, ropinirole, PD128907, and pramipexole potencies were clearly higher; talipexole and 7-OH-DPAT showed slightly higher potencies; pergolide showed slightly lower potency; and, cabergoline and bromocriptine potencies were lower. Aripiprazole acted as an antagonist in hD(2L)-Low; a low intrinsic activity partial agonist in hD(2S)-Low; a moderate partial agonist in hD(3)-Ser-9 and hD(3)-Gly-9; a robust partial agonist in hD(2L)-High; and a full agonist in hD(2S)-High. Amisulpride, sulpiride and perphenazine behaved as preferential antagonists; and chlorpromazine and asenapine behaved as modest preferential antagonists; whereas fluphenazine, haloperidol, and blonanserin behaved as non-preferential antagonists in hD(2S)-Low and hD(2S)-High compared to hD(3)-Ser-9 and hD(3)-Gly-9. These findings may help to elucidate the basis of therapeutic benefit observed with these drugs, with

  14. Azogabazine; a photochromic antagonist of the GABAA receptor.

    PubMed

    Huckvale, Rosemary; Mortensen, Martin; Pryde, David; Smart, Trevor G; Baker, James R

    2016-07-12

    The design and synthesis of azogabazine is described, which represents a highly potent (IC50 = 23 nM) photoswitchable antagonist of the GABAA receptor. An azologization strategy is adopted, in which a benzyl phenyl ether in a high affinity gabazine analogue is replaced by an azobenzene, with resultant retention of antagonist potency. We show that cycling from blue to UV light, switching between trans and cis isomeric forms, leads to photochemically controlled antagonism of the GABA ion channel. PMID:27327397

  15. Identification of M-CSF agonists and antagonists

    DOEpatents

    Pandit, Jayvardhan; Jancarik, Jarmila; Kim, Sung-Hou; Koths, Kirston; Halenbeck, Robert; Fear, Anna Lisa; Taylor, Eric; Yamamoto, Ralph; Bohm, Andrew

    2000-02-15

    The present invention is directed to methods for crystallizing macrophage colony stimulating factor. The present invention is also directed to methods for designing and producing M-CSF agonists and antagonists using information derived from the crystallographic structure of M-CSF. The invention is also directed to methods for screening M-CSF agonists and antagonists. In addition, the present invention is directed to an isolated, purified, soluble and functional M-CSF receptor.

  16. Deficiency of interleukin-1 receptor antagonist responsive to anakinra.

    PubMed

    Schnellbacher, Charlotte; Ciocca, Giovanna; Menendez, Roxanna; Aksentijevich, Ivona; Goldbach-Mansky, Raphaela; Duarte, Ana M; Rivas-Chacon, Rafael

    2013-01-01

    We describe a 3-month-old infant who presented to our institution with interleukin (IL)-1 receptor antagonist deficiency (DIRA), which consists of neutrophilic pustular dermatosis, periostitis, aseptic multifocal osteomyelitis, and persistently high acute-phase reactants. Skin findings promptly improved upon initiation of treatment with anakinra (recombinant human IL-1 receptor antagonist), and the bony lesions and systemic inflammation resolved with continued therapy. PMID:22471702

  17. Bradykinin antagonists modified with dipeptide mimetic beta-turn inducers.

    PubMed

    Alcaro, Maria C; Vinci, Valerio; D'Ursi, Anna M; Scrima, Mario; Chelli, Mario; Giuliani, Sandro; Meini, Stefania; Di Giacomo, Marcello; Colombo, Lino; Papini, Anna Maria

    2006-05-01

    Bradykinin (BK) is involved in a wide variety of pathophysiological processes. Potent BK peptide antagonists can be developed introducing constrained unnatural amino acids, necessary to force the secondary structure of the molecule. In this paper, we report a structure-activity relationship study of two peptide analogues of the potent B2 antagonist HOE 140 by replacing the D-Tic-Oic dipeptide with conformationally constrained dipeptide mimetic beta-turn inducers. PMID:16504505

  18. [Aran-Duchenne? Duchenne-Aran? The quarrel around progressive muscular atrophy].

    PubMed

    Bonduelle, M

    1990-01-01

    A description of progressive muscular atrophy, the first item in neuro-muscular nosography, figures in the memoir published by F.A. Aran in 1850. There, all the essential features of the disease can be found: its usual onset at the distal end of the upper limbs, its slowly progressive worsening, with muscular atrophy sparing certain muscles or muscular fascicles, its peculiar "claw hand", its muscular "fasciculations" and cramps, with untouched sensitivity. After praising Aran's "beautiful description", G.B. Duchenne de Boulogne subsequently persisted in claiming paternity, untiringly referring to a memoir on "muscular atrophy with fatty transformation" said to have been submitted to the Académie des Sciences in 1849. There is no trace of this memoir, and while it is true that the "localized electrisation" technique was applied by Duchenne to all the patients in Aran's memoir, and that he was the sole author of two of his observations, it is Aran who must be credited with the clinical description, the synthetic presentation and the appellation of "progressive muscular atrophy". Initially, this term covered a number of disparate facts which were later identified and put in their proper nosological place, even though this dismemberment left standing what Charcot called "Duchenne-Aran disease" before the Aran-Duchenne denomination prevailed. This denomination is now customary, and rightly so. PMID:2181591

  19. Independent Association of Muscular Strength and Carotid Intima-Media Thickness in Children.

    PubMed

    Melo, X; Santa-Clara, H; Santos, D A; Pimenta, N M; Minderico, C S; Fernhall, B; Sardinha, L B

    2015-07-01

    The aim of this cross-sectional study was to examine the influence of muscular strength on carotid intima-media thickness (cIMT) in children, controlling for the effect of cardiorespiratory fitness (CRF) and central adiposity and to examine if differences among muscular strength tertiles translate to physiological differences. We assessed cIMT of the common carotid artery in 366 children between 11-12 years of age (191 girls). Measures included cIMT assessed with high-resolution ultrasonography, a maximal handgrip strength test, body fat mass and lean mass from DXA and CRF determined using a maximal cycle ergometer test. Association between muscular strength and cIMT adjusted for CRF and central adiposity, as measured by trunk fat, was tested with multiple linear regression analysis. Differences in risk factors among muscular strength groups were tested with ANOVA. The Muscular Strength Index (MSI) was inversely associated with cIMT independently of CRF and central adiposity (p<0.05). The low MSI group had the highest values of cIMT, waist circumference and systolic blood pressure and the lowest CRF (p<0.05). There was an inverse and independent association between muscular strength and cIMT. Low muscular strength was associated with higher levels of cardiovascular disease risk factors in children. PMID:25875317

  20. CXCR3 antagonist VUF10085 binds to an intrahelical site distinct from that of the broad spectrum antagonist TAK–779

    PubMed Central

    Nedjai, Belinda; Viney, Jonathan M; Li, Hubert; Hull, Caroline; Anderson, Caroline A; Horie, Tomoki; Horuk, Richard; Vaidehi, Nagarajan; Pease, James E

    2015-01-01

    Background and Purpose The chemokine receptor CXCR3 is implicated in a variety of clinically important diseases, notably rheumatoid arthritis and atherosclerosis. Consequently, antagonists of CXCR3 are of therapeutic interest. In this study, we set out to characterize binding sites of the specific low MW CXCR3 antagonist VUF10085 and the broad spectrum antagonist TAK-779 which blocks CXCR3 along with CCR2 and CCR5. Experimental Approach Molecular modelling of CXCR3, followed by virtual ligand docking, highlighted several CXCR3 residues likely to contact either antagonist, notably a conserved aspartate in helix 2 (Asp-1122:63), which was postulated to interact with the quaternary nitrogen of TAK-779. Validation of modelling was carried out by site-directed mutagenesis of CXCR3, followed by assays of cell surface expression, ligand binding and receptor activation. Key Results Mutation of Asn-1323.33, Phe-207 and Tyr-2716.51 within CXCR3 severely impaired both ligand binding and chemotactic responses, suggesting that these residues are critical for maintenance of a functional CXCR3 conformation. Contrary to our hypothesis, mutation of Asp-1122:63 had no observable effects on TAK-779 activity, but clearly decreased the antagonist potency of VUF 10085. Likewise, mutations of Phe-1313.32, Ile-2796.59 and Tyr-3087.43 were well tolerated and were critical for the antagonist activity of VUF 10085 but not for that of TAK-779. Conclusions and Implications This more detailed definition of a binding pocket within CXCR3 for low MW antagonists should facilitate the rational design of newer CXCR3 antagonists, with obvious clinical potential. PMID:25425280