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Sample records for antagonistic muscular actions

  1. Muscarinic antagonists microinjected into the subthalamic nucleus decrease muscular rigidity in reserpinized rats.

    PubMed

    Hernández-López, S; Flores, G; Rosales, M G; Sierra, A; Martínez-Fong, D; Aceves, J

    1996-08-09

    The ability of anticholinergic agents microinjected into the subthalamic nucleus to reduce reserpine-induced muscular rigidity was assessed in rats. The electromyographical activity of the gastrocnemius-soleus muscle was used as a parameter of muscular rigidity. Reserpine (5 mg/kg i.p.) produced the appearance of electromyographical activity. The muscarinic antagonists M3 (1.27 nmol of 4-DAMP) and M1 (2.36 nmol of pirenzepine) markedly reduced the reserpine-induced electromyographical activity, whereas the M2 antagonist AFDX-116 (2.37 nmol) had no effect. These results suggest that a high cholinergic tone in the subthalamic nucleus is associated with the reserpine-induced muscular rigidity. Moreover, the M3 muscarinic antagonist is more effective than the M1 muscarinic antagonist in reducing the muscular rigidity in reserpinized rats, a model of Parkinson's disease, by blocking the high cholinergic tone in the subthalamic nucleus.

  2. Antianginal Actions of Beta-Adrenoceptor Antagonists

    PubMed Central

    2007-01-01

    Angina pectoris is usually the first clinical sign of underlying myocardial ischemia, which results from an imbalance between oxygen supply and oxygen demand in the heart. This report describes the pharmacology of β-adrenoceptor antagonists as it relates to the treatment of angina. The β-adrenoceptor antagonists are widely used in long-term maintenance therapy to prevent acute ischemic episodes in patients with chronic stable angina. Beta-adrenoceptor antagonists competitively inhibit the binding of endogenous catecholamines to β1-adrenoceptors in the heart. Their anti-ischemic effects are due primarily to a reduction in myocardial oxygen demand. By decreasing heart rate, myocardial contractility and afterload, β-adrenoceptor antagonists reduce myocardial workload and oxygen consumption at rest as well as during periods of exertion or stress. Predictable adverse effects include bradycardia and cardiac depression, both of which are a direct result of the blockade of cardiac β1-adrenoceptors, but adverse effects related to the central nervous system (eg, lethargy, sleep disturbances, and depression) may also be bothersome to some patients. Beta-adrenoceptor antagonists must be used cautiously in patients with diabetes mellitus, peripheral vascular disease, heart failure, and asthma or other obstructive airway diseases. Beta-adrenoceptor antagonists may be used in combination with nitrates or calcium channel blockers, which takes advantage of the diverse mechanisms of action of drugs from each pharmacologic category. Moreover, concurrent use of β-adrenoceptor antagonists may alleviate the reflex tachycardia that sometimes occurs with other antianginal agents. PMID:17998992

  3. An electrophysiological analysis of the effects of noradrenaline and alpha-receptor antagonists on neuromuscular transmission in mammalian muscular arteries.

    PubMed

    Holman, M E; Surprenant, A

    1980-01-01

    1 The effects of exogenously applied noradrenaline (NA) and alpha-adrenoceptor antagonists on the mechanical and intracellularly recorded responses to perivascular nerve stimulation were examined in the rabbit ear artery, rabbit saphenous artery and rat tail artery. 2 Excitatory junction potentials (e.j.ps) and action potentials recorded from these smooth muscles were not blocked or depressed by phentolamine, phenoxybenzamine, prazosin, or labetolol in concentrations as high as 10 microgram/ml. Phentolamine (1 to 10 microgram/ml) depressed neurally-evoked contractions of the ear and saphenous, but not the tail artery, and also depressed the contractions produced by direct muscle stimulation in the ear and saphenous arteries. Prazosin and labetolol (0.1 to 10 microgram/ml) had no effect on the neurally evoked contractile response in any of the arteries examined. 3 The amplitude of the steady-state e.j.p. during repetitive stimulation at 0.45 to 2 Hz was increased by phentolamine or phenoxybenzamine but not by prazosin or labetolol. Phentolamine and phenoxybenzamine also increased the amplitude of the e.j.p. evoked by a single stimulus in the majority of the preparations. 4 Concentrations of NA greater than or equal to 1 microgram/ml depolarized the smooth muscle while concentrations greater than or equal to 0.5 microgram/ml depressed the amplitude of the e.j.ps recorded from these arteries. alpha-Antagonists did not suppress either the NA-induced membrane depolarization or depression of e.j.ps. 5 These observations call into question the physiological relevance of both pre- and postsynaptic alpha-receptors in regard to adrenergic neuromuscular transmission in muscular arteries.

  4. The interference effect of men's handling of muscular action figures on a lexical decision task.

    PubMed

    Barlett, Christopher P; Smith, Sara J; Harris, Richard J

    2006-12-01

    It has been shown in previous work [Action figures and men. Sex Roles 53, 877-885] that male participants who handled extremely muscular action figures had lower body esteem than those who did not handle action figures or a Ken doll. However, the internal mechanisms that dictated this effect are unclear. Therefore, the current study extended this previous work by having male participants handle action figures of varying muscularity and completing a lexical decision task with target words that consisted of both positive and negative body words and feeling words in order to determine if males would be primed to think negatively about their bodies and self or if positive thoughts about their bodies and self would be interfered with. The results show that those participants who handled the extremely muscular action figures responded significantly more slowly to feeling positive words (e.g., content, confident) and marginally more slowly to body positive words (e.g., muscle, bicep) than those who did not handle any action figures. Overall, this suggests that the interference of positive words, not the priming of negative words, is the internal mechanism that produces the decreased body image satisfaction after exposure to muscular stimuli. Implications and future research are discussed.

  5. Angiotensin II type 1 receptor antagonists alleviate muscle pathology in the mouse model for laminin-α2-deficient congenital muscular dystrophy (MDC1A)

    PubMed Central

    2012-01-01

    Background Laminin-α2-deficient congenital muscular dystrophy (MDC1A) is a severe muscle-wasting disease for which no curative treatment is available. Antagonists of the angiotensin II receptor type 1 (AT1), including the anti-hypertensive drug losartan, have been shown to block also the profibrotic action of transforming growth factor (TGF)-β and thereby ameliorate disease progression in mouse models of Marfan syndrome. Because fibrosis and failure of muscle regeneration are the main reasons for the severe disease course of MDC1A, we tested whether L-158809, an analog derivative of losartan, could ameliorate the dystrophy in dyW/dyW mice, the best-characterized model of MDC1A. Methods L-158809 was given in food to dyW/dyW mice at the age of 3 weeks, and the mice were analyzed at the age of 6 to 7 weeks. We examined the effect of L-158809 on muscle histology and on muscle regeneration after injury as well as the locomotor activity and muscle strength of the mice. Results We found that TGF-β signaling in the muscles of the dyW/dyW mice was strongly increased, and that L-158809 treatment suppressed this signaling. Consequently, L-158809 reduced fibrosis and inflammation in skeletal muscle of dyW/dyW mice, and largely restored muscle regeneration after toxin-induced injury. Mice showed improvement in their locomotor activity and grip strength, and their body weight was significantly increased. Conclusion These data provide evidence that AT1 antagonists ameliorate several hallmarks of MDC1A in dyW/dyW mice, the best-characterized mouse model for this disease. Because AT1 antagonists are well tolerated in humans and widely used in clinical practice, these results suggest that losartan may offer a potential future treatment of patients with MDC1A. PMID:22943509

  6. 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…

  7. 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…

  8. Muscular proprioception contributes to the control of interceptive actions.

    PubMed

    Bastin, Julien; Calvin, Sarah; Montagne, Gilles

    2006-08-01

    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 information specify this angle, the contribution of proprioceptive information has not been directly tested. In this study, the authors used a virtual reality setup to study the role of proprioception when intercepting a moving target. In a series of experiments, the authors manipulated proprioceptive information by using the tendon vibration paradigm. The results revealed that proprioception is crucial not only to locate a moving target with respect to the body but also, and more importantly, to produce online displacement velocity changes to intercept a moving target. These findings emphasize the importance of proprioception in the control of interceptive action and illustrate the relevance of our model to account for the regulations produced by the participants.

  9. Antagonistic action of pitrazepin on human and rat GABAA receptors

    PubMed Central

    Demuro, Angelo; Martinez-Torres, Ataulfo; Francesconi, Walter; Miledi, Ricardo

    1999-01-01

    Pitrazepin, 3-(piperazinyl-1)-9H-dibenz(c,f) triazolo(4,5-a)azepin is a piperazine antagonist of GABA in a variety of electrophysiological and in vitro binding studies involving GABA and glycine receptors. In the present study we have investigated the effects of pitrazepin, and the GABAA antagonist bicuculline, on membrane currents elicited by GABA in Xenopus oocytes injected with rat cerebral cortex mRNA or cDNAs encoding α1β2 or α1β2γ2S human GABAA receptor subunits.The three types of GABAA receptors expressed were reversibly antagonized by bicuculline and pitrazepin in a concentration-dependent manner. GABA dose-current response curves for the three types of receptors were shifted to the right, in a parallel manner, by increasing concentrations of pitrazepin.Schild analyses gave pA2 values of 6.42±0.62, n=4, 6.41±1.2, n=5 and 6.21±1.24, n=6, in oocytes expressing rat cerebral cortex, α1β2 or α1β2γ2S human GABAA receptors respectively (values are given as means±s.e.mean), and the Hill coefficients were all close to unity. All this is consistent with the notion that pitrazepin acts as a competitive antagonist of these GABAA receptors; and that their antagonism by pitrazepin is not strongly dependent on the subunit composition of the receptors here studied.Since pitrazepin has been reported to act also at the benzodiazepine binding site, we studied the effect of the benzodiazepine antagonist Ro 15-1788 (flumazenil) on the inhibition of α1β2γ2S receptors by pitrazepin. Co-application of Ro 15-1788 did not alter the inhibiting effect of pitrazepin. Moreover, pitrazepin did not antagonize the potentiation of GABA-currents by flunitrazepam. All this suggests that pitrazepin does not affect the GABA receptor-chloride channel by interacting with the benzodiazepine receptor site. PMID:10369456

  10. 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.

  11. Mechanism of action of species-selective P2X7 receptor antagonists

    PubMed Central

    Michel, Anton D; Ng, Sin-Wei; Roman, Shilina; Clay, William C; Dean, David K; Walter, Daryl S

    2009-01-01

    Background and purpose: AZ11645373 and N-{2-methyl-5-[(1R, 5S)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylcarbonyl]phenyl}-2-tricyclo[3.3.1.13,7]dec-1-ylacetamide hydrochloride (compound-22) are recently described P2X7 receptor antagonists. In this study we have further characterized these compounds to determine their mechanism of action and interaction with other species orthologues. Experimental approach: Antagonist effects at recombinant and chimeric P2X7 receptors were assessed by ethidium accumulation and radioligand-binding studies. Key results: AZ11645373 and compound-22 were confirmed as selective non-competitive antagonists of human or rat P2X7 receptors respectively. Both compounds were weak antagonists of the mouse and guinea-pig P2X7 receptors and, for each compound, their potency estimates at human and dog P2X7 receptors were similar. The potency of compound-22 was moderately temperature-dependent while that of AZ11645373 was not. The antagonist effects of both compounds were slowly reversible and were not prevented by decavanadate, suggesting that they were allosteric antagonists. Indeed, the compounds competed for binding sites labelled by an allosteric radio-labelled P2X7 receptor antagonist. The species selectivity of AZ11645373, but not compound-22, was influenced by the nature of the amino acid at position 95 of the P2X7 receptor. N2-(3,4-difluorophenyl)-N1-[2-methyl-5-(1-piperazinylmethyl)phenyl]glycinamide dihydrochloride, a positive allosteric modulator of the rat receptor, reduced the potency of compound-22 at the rat receptor but had little effect on the actions of AZ11645373. Conclusions: AZ11645373 and compound-22 are allosteric antagonists of human and rat P2X7 receptors respectively. The differential interaction of the two compounds with the receptor suggests there may be more than one allosteric regulatory site on the P2X7 receptor at which antagonists can bind and affect receptor function. PMID:19309360

  12. 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.

  13. A novel human-based receptor antagonist of sustained action reveals body weight control by endogenous GLP-1.

    PubMed

    Patterson, James T; Ottaway, Nickki; Gelfanov, Vasily M; Smiley, David L; Perez-Tilve, Diego; Pfluger, Paul T; Tschöp, Matthias H; Dimarchi, Richard D

    2011-02-18

    Ex-4 (9-39)a is a well characterized GLP-1 receptor antagonist that suffers from two notable limitations, its nonhuman amino acid sequence and its relatively short in vivo duration of action. Comparable N-terminal shortening of human GLP-1 lessens agonism but does not provide a high potency antagonist. Through a series of GLP-1/Ex-4 hybrid peptides, the minimal structural changes required to generate a pure GLP-1-based antagonist were identified as Glu16, Val19, and Arg20, yielding an antagonist of approximately 3-fold greater in vitro potency compared with Ex-4 (9-39)a. The structural basis of antagonism appears to result from stabilization of the α helix combined with enhanced electrostatic and hydrophobic interactions with the extracellular domain of the receptor. Site-specific acylation of the human-based antagonist yielded a peptide of increased potency as a GLP-1 receptor antagonist and 10-fold greater selectivity relative to the GIP receptor. The acylated antagonist demonstrated sufficient duration of action to maintain inhibitory activity when administered as a daily subcutaneous injection. The sustained pharmacokinetics and enhanced human sequence combine to form an antagonist optimized for clinical study. Daily administration of this antagonist by subcutaneous injection to diet-induced obese mice for 1 week caused a significant increase in food intake, body weight, and glucose intolerance, demonstrating endogenous GLP-1 as a relevant hormone in mammalian energy balance in the obese state.

  14. Effects of calcium antagonists on central actions of ethanol: comparative studies with nifedipine, verapamil and cinnarizine.

    PubMed

    Czarnecka, E; Kubik-Bogucka, E

    1993-11-01

    The effects of nifedipine (17.5 and 50 mg/kg), verapamil (5 and 15 mg/kg) and cinnarizine (75 and 200 mg/kg) on acute toxicity and central actions of ethanol (i.e. ethanol-induced sleep and hypothermia, disturbances of rota-rod performance and spontaneous activity) were investigated in mice. Additionally, effects of these drugs on the development of tolerance to hypothermic and sleep-inducing action of ethanol were studied in rats. Calcium antagonists were given acutely 30 min before ethanol administration, or chronically once daily (lower dose) for 10 days, and on the 11th day the animals received an ethanol injection. Single doses of nifedipine increased the acute toxicity of ethanol and potentiated its central effects. After long-term administration of nifedipine no significant alterations in the central actions of ethanol were observed. Verapamil and cinnarizine antagonized the ethanol-induced sleep and impairment of locomotor activity. Nifedipine did not affect the development of tolerance to hypnotic and hypothermic action of ethanol. Verapamil prevents the development of tolerance to hypnotic action of ethanol, whereas cinnarizine prevents the development of tolerance to the hypnotic and hypothermic action of ethanol.

  15. The action of acetylcholine antagonists on amino acid responses in the frog spinal cord in vitro.

    PubMed Central

    Nicoll, R A

    1975-01-01

    1 The isolated hemisected frog spinal cord has been used to study the action of acetylcholine antagonists on amino acid responses by means of sucrose gap recording. 2 Primary afferents and motoneurones were shown to contain few, if any, cholinoceptors, since acetylcholine and carbachol responses were essentially abolished when synaptic transmission was blocked with magnesium ions or when action potentials were blocked by tetrodotoxin. 3 Curare antagonized the gamma-aminobutyric acid (GABA) and beta-alanine depolarizations of primary afferents and hyperpolarizing action of these amino acids on motoneurones. Nicotine also antagonized beta-alanine depolarizations and to a small extent GABA depolarizations of primary afferents. These actions are similar to but weaker than those obtained previously with picrotoxin. 4 Atropine selectively antagonized beta-alanine depolarizations of primary afferents and blocked beta-alanine and glycine hyperpolarizations of motoneurones. GABA responses were entirely resistant to the action of atropine. These actions are similar to but 50 times weaker than those obtained previously with strychnine. 5 Dihydro-beta-erythroidine, tetraethylammonium, and gallamine were entirely ineffective in antagonizing amino acid responses. Since these agents are known to block the dorsal root potential elicited by ventral root stimulation but have no effect on the amino acid responses of primary afferents, it is evident that a cholinergic step is involved in this pathway. PMID:1082355

  16. Identification and mechanism of action of the acylguanidine MRT-83, a novel potent Smoothened antagonist.

    PubMed

    Roudaut, Hermine; Traiffort, Elisabeth; Gorojankina, Tatiana; Vincent, Ludwig; Faure, Helene; Schoenfelder, Angele; Mann, Andre; Manetti, Fabrizio; Solinas, Antonio; Taddei, Maurizio; Ruat, Martial

    2011-03-01

    There is a clear need to develop novel pharmacological tools to improve our understanding of Smoothened (Smo) function in normal and pathological states. Here, we report the discovery, the mechanism of action, and the in vivo activity of N-(2-methyl-5-(3-(3,4,5-trimethoxybenzoyl)guanidino)phenyl)biphenyl-4-carboxamide (MRT-83), a novel potent antagonist of Smo that belongs to the acylguanidine family of molecules. MRT-83 fits to a proposed pharmacophoric model for Smo antagonists with three hydrogen bond acceptor groups and three hydrophobic regions. MRT-83 blocks Hedgehog (Hh) signaling in various assays with an IC50 in the nanomolar range, showing greater potency than the reference Smo antagonist cyclopamine. MRT-83 inhibits Bodipy-cyclopamine binding to human and mouse Smo but does not modify Wnt signaling in human embryonic kidney 293 transiently transfected with a Tcf/Lef-dependent Firefly luciferase reporter together with a Renilla reniformis luciferase control reporter. MRT-83 abrogates the agonist-induced trafficking of endogenous mouse or human Smo to the primary cilium of C3H10T1/2 or NT2 cells that derive from a pluripotent testicular carcinoma. Stereotaxic injection into the lateral ventricle of adult mice of MRT-83 but not of a structurally related compound inactive at Smo abolished up-regulation of Patched transcription induced by Sonic Hedgehog in the neighboring subventricular zone. These data demonstrate that MRT-83 efficiently antagonizes Hh signaling in vivo. All together, these molecular, functional and biochemical studies provide evidence that MRT-83 interacts with Smo. Thus, this novel Smo antagonist will be useful for manipulating Hh signaling and may help develop new therapies against Hh-pathway related diseases.

  17. 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

    2014-04-05

    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.

  18. 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

  19. Anti free radical action of calcium antagonists and H1 and H2 receptors antagonists in neoplastic disease.

    PubMed

    della Rovere, F; Broccio, M; Granata, A; Zirilli, A; Brugnano, L; Artemisia, A; Broccio, G

    1996-01-01

    The blood of the subjects suffering from Neoplastic Disease (ND) shows phenomena of membrane peroxidation due to the presence of Free Radicals (FRs), in a quantity much greater than the one observed in the blood of healthy subjects. This can be detected either by calculating the time necessary for the formation of "Heinz bodies" (Hbs), (p < 0.00001) after oxidative stress of the blood in vitro with acetylphenylidrazine (APH), or by calculating the methemoglobin (metHb) quantity that forms after the same treatment (P < 0.00001). The statistical analyses we carried out showed that metHb formation was not affected by age, sex, smoking habits, red blood cell number, Hb, Ht or tumor staging. In this study, by using equal parameters of investigation, we noted that the blood of the subjects with ND who were previously treated with calcium-antagonists drugs and with antagonists of H1 and H2 receptors, gave results completely superimposable on the results obtained from healthy subjects, implying that the treatment had avoided the increase of FRs. Therefore we concluded that calcium-antagonists and the antagonists of the H1 and H2 receptors behave as antioxidant substances, having decreased the FRs damaging activity on the cellular membranes, thus controlling, although to a limited degree, the pejorative evolution of the disease. It is also important to remember that investigations into the ND, even possible screenings, must take into account the above said data, submitting the subjects under investigation to a pharmacological wash out, particularly with those substances which, are considered to be scavengers of FRs. Some of these substances are investigated in this work.

  20. Effect of the 5-HT(6) serotonin antagonist MS-245 on the actions of (-)nicotine.

    PubMed

    Young, Richard; Bondareva, Tatiana; Wesolowska, Anna; Young, Shawquia; Glennon, Richard A

    2006-09-01

    The 5-HT(6) serotonin receptor antagonist MS-245 neither substitutes for nor antagonizes the discriminative stimulus effects of (-)nicotine. However, MS-245 was shown to enhance the potency of (-)nicotine in Sprague-Dawley rats trained to discriminate 0.6 mg/kg of (-)nicotine from saline vehicle in a typical two-lever drug discrimination paradigm such that a combination of MS-245 (5.0 mg/kg) plus the ED(50) dose of (-)nicotine caused the animals to respond as if they had received the training dose of (-)nicotine. MS-245 also potentiated the hypolocomotor actions, but not the antinociceptive effects, of (-)nicotine in mice. The results suggest possible involvement of serotonin-regulated signaling mechanisms in certain behavioral effects of nicotine.

  1. 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

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

    PubMed Central

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

    2013-01-01

    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

  3. Differential time course of the vasodilator action of various calcium antagonists.

    PubMed

    van der Lee, R; Kam, K L; Pfaffendorf, M; van Zwieten, P A

    1998-01-01

    It is rather the rate of the vasodilator effect than its magnitude which determines the triggering of reflex tachycardia associated with dihydropyridine calcium antagonists (DHP-CA). We therefore compared the rate of the vasodilator effects of a series of CA (both DHP and non-DHP) in rat isolated mesenteric artery preparations (size 256 +/- 3 microns, length 2 mm) from male Wistar rats (weighing 300-350 g) in an isolated wire myograph according to Mulvany and Halpern [12]. The mean force of the KCl-induced contraction amounted to 2.3 +/- 0.1 mN/mm. Potency (given as IC50-values), differential time course of action and recovery of the contractile response of the vessels after wash-out were established. These three parameters adhere to the following sequences: (1. potency) barnidipine [corrected] > (S)-lercanidipine > barnidipine racemate [corrected]> amlodipine > nifedipine, lacidipine > (R)-lercanidipine > verapamil, mibefradil; (2. differential time course) lacidipine, amlodipine > (S)- and (R)-lercanidipine, barnidipine [corrected], barnidipine racemate [corrected] > mibefradil, verapamil, nifedipine; (3. recovery) nifedipine > verapamil, barnidipine [corrected], amlodipine > barnidipine, lacidipine > mibefradil, (R)-lercanidipine > (S)-lercanidipine. In conclusion, barnidipine [corrected] proved to be the most potent vasodilator agent; interestingly, barnidipine was 20 times less potent when applied as a racemic mixture. A slow onset of action in DHP is a very important mechanism in preventing reflex tachycardia. For non-DHP (verapamil, mibefradil) reflex tachycardia probably is prevented by a direct effect on the conductive tissue in the myocardium.

  4. Reserpine has a direct action as a calcium antagonist on mammalian smooth muscle cells.

    PubMed Central

    Casteels, R; Login, I S

    1983-01-01

    The effects of reserpine on excitation-contraction coupling and 45Ca exchange of smooth muscle cells of the rabbit ear artery and the guinea-pig taenia coli have been studied. Reserpine inhibited the spontaneous mechanical activity of the taenia coli and the force development induced by 59 mM-external K or 10(-5) M-carbachol. In the ear artery reserpine blocked the K-induced contraction but its effect on the contraction elicited by noradrenaline was smaller. At 0.2 mM-Ca, the inhibition of the tonic component of the noradrenaline-induced contraction was more pronounced than that of the phasic component. This reserpine action was fully reversible for the noradrenaline stimulus in the ear artery but less so for K-induced contractions. The inhibitory action on contractions induced in taenia coli by K-rich solution and by carbachol was even less reversible. The analysis of the effect of reserpine on the 45Ca exchange in the ear artery has revealed that it inhibits the increase of the fractional loss induced by K depolarization, but that it does not exert a significant effect on the increased fractional loss induced by 10(-5) M-noradrenaline. Reserpine slows down the filling with 45Ca of the agonist-sensitive store without affecting the steady-state amount of Ca taken up by the store. A study of the degree of filling of the store by measuring the force development and the 45Ca release elicited by noradrenaline in Ca-free medium, reveals that the force development after loading in a reserpine-containing medium remains less than the control, although the same amount of Ca is released from the store. It was shown by using tetrabenazine that the inhibitory action of reserpine on the Ca exchange and the force development is not due to an interaction of reserpine with the receptor molecules that are responsible for its depleting action on aminergic granules. These results strongly suggest that reserpine exerts a Ca antagonistic action on smooth muscle whereby it blocks the

  5. Probing biochemical mechanisms of action of muscarinic M3 receptor antagonists with label-free whole cell assays.

    PubMed

    Deng, Huayun; Wang, Chaoming; Su, Ming; Fang, Ye

    2012-10-02

    Binding kinetics of drugs is increasingly recognized to be important for their in vivo efficacy and safety profiles. However, little is known about the effect of drug binding kinetics on receptor signaling in native cells. Here we used label-free whole cell dynamic mass redistribution (DMR) assays under persistent and duration-controlled stimulation conditions to investigate the influence of the binding kinetics of four antagonists on the signaling of endogenous muscarinic M3 receptor in native HT-29 cells. Results showed that DMR assays under different conditions differentiated the biochemical mechanisms of action of distinct M3 antagonists. When co-stimulated with acetylcholine, tiotropium, a relatively slow binding antagonist, was found to selectively block the late signaling of the receptor, suggesting that acetylcholine attains its binding equilibrium faster than tiotropium does, thereby still being able to initiate its rapid response until the antagonist draws up and fully blocks the signaling. Furthermore, DMR assays under microfluidics allowed estimation of the residence times of these antagonists acting at the receptor in native cells, which were found to be the determining factor for the blockage efficiency of M3 receptor signaling under duration-controlled conditions. This study demonstrates that DMR assays can be used to elucidate the functional consequence of kinetics-driven antagonist occupancy in native cells.

  6. The action of the cholecystokinin-A receptor antagonist, devazepide, on the digestive system of the chicken.

    PubMed

    Furuse, M; Choi, Y H; Satoh, S; Okumura, J

    1996-04-15

    The influence of the cholecystokinin (CCK)-A receptor antagonist, devazepide (DVZ), on the chicken digestive tract was investigated. The passage of food from the crops of birds treated with DVZ was not significantly different from that of the control. DVZ treatment did not inhibit the biliary flow stimulated by the CCK analogue, caerulein. Dispersed chicken pancreatic acini stimulated with CCK were treated with various concentrations of DVZ. At 10-5 M, DVZ completely inhibited amylase release; this concentration was much higher than those reported to have similar effects in mammals. The results suggest that the action DVZ as a CCK antagonist in the chicken is very weak.

  7. Antagonistic effects of fluconazole and 5-fluorocytosine on candidacidal action of amphotericin B in human serum.

    PubMed Central

    Martin, E; Maier, F; Bhakdi, S

    1994-01-01

    This study addressed the effects of fluconazole and 5-fluorocytosine on the candidacidal activity of amphotericin B in the presence of human serum. A Candida albicans isolate that was susceptible to all three agents according to standard testing procedures was employed. Fungicidal activity was estimated by using a flow cytometric procedure that exploited the fact that yeast cells killed by amphotericin B diminish in size and take up propidium iodide. The following findings were made. (i) Fluconazole and 5-fluorocytosine each failed to inhibit pseudohyphal formation and cell aggregation even when applied at 10 and 50 micrograms/ml, respectively, for up to 10 h. Hence, these agents were not fungistatic when tested in the presence of serum. (ii) Simultaneous application of 5-fluorocytosine had neither enhancing nor inhibitory effects on the fungicidal activity of amphotericin B. However, yeasts that were preincubated for 20 h with 5-fluorocytosine became less susceptible to killing by amphotericin B. (iii) Fluconazole exerted a frank antagonistic effect on the fungicidal activity of amphotericin B. Thus, under our in vitro conditions, both fluconazole and 5-fluorocytosine can overtly antagonize the candidacidal action of amphotericin B. PMID:8092834

  8. Aldosterone receptor antagonists--how cardiovascular actions may explain their beneficial effects in heart failure.

    PubMed

    Ovaert, P; Elliott, J; Bernay, F; Guillot, E; Bardon, T

    2010-04-01

    Historically, aldosterone receptor antagonists (ARA) have been classified as 'potassium sparing diuretics'. However, the positive effect of spironolactone, the most extensively studied ARA, on morbidity and mortality observed in humans suffering cardiac insufficiency could not be explained by the renal effect of the drug alone, and a pivotal clinical study has led to extensive research. Many experimental studies have demonstrated that ARA have previously unexpected beneficial effects on the cardiovascular system including reduction in remodelling of the vascular smooth muscle cells and myocytes and improvement of endothelial cell dysfunction in heart failure. These effects improve vascular compliance and slow down the progression of left ventricular dysfunction and end-organ damage. Furthermore, aldosterone receptor blockade also restores the baroreceptor reflex, improving heart rate variability in heart failure in humans. Some of these effects have been demonstrated in dog models of cardiac disease and so justified further investigation of the potential benefit of ARA in dogs with congestive heart failure (CHF). Positive effects of spironolactone on morbidity and mortality appear to have been seen in studies conducted in dogs suffering from naturally occurring CHF. In addition, eplerenone has been shown to have benefits in canine models of heart failure. The precise mechanisms by which ARA produce these beneficial effects in dogs remain to be determined but this group of drugs clearly provide therapeutic actions out-with their diuretic effects.

  9. Muscular Dystrophy

    MedlinePlus

    ... depending on the type of muscular dystrophy. Duchenne muscular dystrophy About half of people with muscular dystrophy have ... muscles Muscle pain and stiffness Learning disabilities Becker muscular dystrophy Signs and symptoms are similar to those of ...

  10. Effects of ONO-1101, a novel beta-antagonist, on action potential and membrane currents in cardiac muscle.

    PubMed

    Muraki, K; Nakagawa, H; Nagano, N; Henmi, S; Kawasumi, H; Nakanishi, T; Imaizumi, K; Tokuno, T; Atsuki, K; Imaizumi, Y; Watanabe, M

    1996-08-01

    Direct effects of ONO-1101 ¿(-)-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl-3-[4-[(S) -2-hydroxy-3-(2-morpholino carbonylamino)ethylamino] propoxy]phenylpropionate monohydrochloride), a novel beta-antagonist, on action potential parameters and membrane currents, and its beta adrenoceptor antagonism were examined in cardiac muscle. Action potential-parameters in papillary muscle of reserpinized animals and membrane currents recorded from single myocytes obtained from guinea pig and rabbit hearts were not affected by 1 to 100 microM ONO-1101. On the other hand, ONO-1101 markedly inhibited the potentiation of Ca current by isoproterenol in single cardiac myocytes of the guinea pig. The concentration-response relationship of Ca current for isoproterenol was shifted to the right. This effect resembled that of esmolol, which is also a beta adrenoceptor antagonist. A Schild plot analysis revealed the slope and pA2 value of each antagonist (ONO-1101, 0.94, 8.0; and esmolol, 0.98, 7.3, respectively) and demonstrated that ONO-1101 is about 5 times more potent than esmolol as a beta-antagonist. Two other effects of isoproterenol: 1) potentiation of delayed rectifier K current and 2) activation of chloride current, were also inhibited by ONO-1101. The time required for 50% removal of beta-antagonism of ONO-1101 and esmolol after the washout was estimated as 4 and 6 min, respectively, in depolarized papillary muscle. These results suggest that ONO-1101 is a potent beta-antagonist whose effects were removed quickly by washout. When applied at what is thought to be a clinical dosage, ONO-1101 had no direct effects on action potential-parameters and membrane currents in cardiac muscle. These characteristics of ONO-1101 suggest that this agent may be effective in clinical use.

  11. Action of AT1 receptor antagonists on angiotensin II-induced tone in human isolated subcutaneous resistance arteries.

    PubMed

    Garcha, R S; Sever, P S; Hughes, A D

    1999-08-01

    1. Human isolated subcutaneous arteries were studied under isometric conditions in a myograph. 2. Addition of angiotensin II (AII) induced a concentration-dependent increase in tone in isolated arteries. The active metabolite of candesartan (CV 11974), losartan and the active metabolite of losartan, E-3174 antagonized AII-induced tone in a non-competitive manner, but the AT2 selective antagonist, PD123319, was without effect on responses to AII. The effects of candesartan, losartan and E-3174 were analysed using a classical model of non-competitive antagonism and a two-state receptor model. 3. Mechanical removal of the endothelium; pre-incubation with Nomega-nitro-L-arginine methyl ester hydrochloride (L-NAME); pre-incubation with indomethacin, a cyclo-oxygenase inhibitor; or pre-incubation with BQ 485, an endothelin antagonist; had no significant effect on contractions induced by AII. 4. Our results suggest AII contracts human isolated resistance arteries by an action on AT1 receptors and does not involve release of endothelial factors. Use of a two-state receptor model successfully described the action of the AT1 antagonists without sacrificing assumptions regarding the competitive nature of binding of these antagonists.

  12. Acetylcholinesterase antagonist potentiated insulin action in fed but not fasted state.

    PubMed

    Schafer, Joshua; Legare, Dallas J; Lautt, W Wayne

    2010-05-01

    The glucose disposal effect of insulin is doubled in response to a meal. This meal-induced insulin sensitization results from insulin acting on the liver, in the presence of a permissive hepatic parasympathetic feeding signal and elevated hepatic glutathione (GSH), to release hepatic insulin-sensitizing substance (HISS), a hormone that acts selectively on skeletal muscle to stimulate insulin-mediated glucose uptake. Blockade of the parasympathetic feeding signal to the liver, either through surgical denervation or atropine-mediated antagonism of hepatic muscarinic receptors, eliminates the HISS response, resulting in HISS-dependent insulin resistance (HDIR) and decreasing the response to insulin by approximately 55% in the fed state. Insulin action in Sprague-Dawley rats, as determined with a rapidly sampled, transient euglycemic clamp in response to insulin (50 mU/kg), is decreased in a dose-dependent manner by atropine. In this study, we have used the ED75 atropine-induced model of HDIR. After a submaximal dose of atropine, potentiation of the remaining parasympathetic effect with the acetylcholinesterase antagonist neostigmine significantly restored postprandial insulin sensitization in a dose-dependent manner with peak effect at 0.1 microg/kg/min. Neostigmine reversed the insulin resistance induced by partial fasting and partial muscarinic inhibition (hepatic GSH levels are at fed levels), but not that induced by surgical hepatic denervation (GSH normal, no nerve signal) or 24-h fasting (low GSH). No potentiation of the response to insulin by neostigmine occurred in normal, fed rats. The data suggest the use of either direct or indirectly acting cholinergic agonists for the treatment of impaired postprandial insulin sensitization.

  13. Preventing the stress-induced shift from goal-directed to habit action with a β-adrenergic antagonist.

    PubMed

    Schwabe, Lars; Höffken, Oliver; Tegenthoff, Martin; Wolf, Oliver T

    2011-11-23

    Stress modulates instrumental action in favor of habit processes that encode the association between a response and preceding stimuli and at the expense of goal-directed processes that learn the association between an action and the motivational value of the outcome. Here, we asked whether this stress-induced shift from goal-directed to habit action is dependent on noradrenergic activation and may therefore be blocked by a β-adrenoceptor antagonist. To this end, healthy men and women were administered a placebo or the β-adrenoceptor antagonist propranolol before they underwent a stress or a control procedure. Shortly after the stress or control procedure, participants were trained in two instrumental actions that led to two distinct food outcomes. After training, one of the food outcomes was selectively devalued by feeding participants to satiety with that food. A subsequent extinction test indicated whether instrumental behavior was goal-directed or habitual. As expected, stress after placebo rendered participants' behavior insensitive to the change in the value of the outcome and thus habitual. After propranolol intake, however, stressed participants behaved, same as controls, goal-directed, suggesting that propranolol blocked the stress-induced bias toward habit behavior. Our findings show that the shift from goal-directed to habitual control of instrumental action under stress necessitates noradrenergic activation and could have important clinical implications, particularly for addictive disorders.

  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.

  15. Spontaneous mobility of GABAA receptor M2 extracellular half relative to noncompetitive antagonist action.

    PubMed

    Chen, Ligong; Durkin, Kathleen A; Casida, John E

    2006-12-15

    The gamma-aminobutyric acid type A receptor beta(3) homopentamer is spontaneously open and highly sensitive to many noncompetitive antagonists(NCAs) and Zn(2+). Our earlier study of the M2 cytoplasmic half (-1' to 10') established a model in which NCAs bind at pore-lining residues Ala(2)', Thr(6)', and Leu(9)'. To further define transmembrane 2 (M2) structure relative to NCA action, we extended the Cys scanning to the extra cellular half of the beta(3) homopentamer (11' to 20'). Spontaneous disulfides formed with T13'C, L18'C, and E20'C from M2/M2 cross-linking and with I14'C (weak), H17'C, and R19'Con bridging M2/M3 intersubunits, based on single (M2 Cys only) and dual (M2 Cys plus M3 C289S) mutations. Induced disulfides also formed with T16'C, but there were few or none with M11'C, T12'C, and N15'C. These findings show conformational flexibility/mobility in the M2 extracellular half 17' to 20' region interpreted as a deformed beta-like conformation in the open channel. The NCA radioligands used were [(3)H]1-(4-ethynylphenyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane ([(3)H]EBOB) and [(3)H]3,3-bis-trifluoromethylbicyclo[2.2.1]heptane-2,2-dicarbonitrile with essentially the same results. NCA binding was disrupted by individual Cys substitutions at 13',14',16',17', and 19'. The inactivity of T13'C/T13'S may have been due to disturbance of the channel gate; I14'S and T16'S showed much better binding activity than their Cys counterparts, and the low activities of H17'C and R19'C were reversed by dithiothreitol. Zn(2+) potency for inhibition of [(3)H]EBOB binding was lowered 346-fold by the mutation H17'A. We propose that NCAs enter their binding site both directly, through the channel pore, and indirectly, through the water cavity of adjacent subunits.

  16. Dual action of neurokinin-1 antagonists on Mas-related GPCRs

    PubMed Central

    Azimi, Ehsan; Reddy, Vemuri B.; Shade, Kai-Ting C.; Anthony, Robert M.; Pereira, Paula Juliana Seadi; Lerner, Ethan A.

    2016-01-01

    The challenge of translating findings from animal models to the clinic is well known. An example of this challenge is the striking effectiveness of neurokinin-1 receptor (NK-1R) antagonists in mouse models of inflammation coupled with their equally striking failure in clinical investigations in humans. Here, we provide an explanation for this dichotomy: Mas-related GPCRs (Mrgprs) mediate some aspects of inflammation that had been considered mediated by NK-1R. In support of this explanation, we show that conventional NK-1R antagonists have off-target activity on the mouse receptor MrgprB2 but not on the homologous human receptor MRGPRX2. An unrelated tripeptide NK-1R antagonist has dual activity on MRGPRX2. This tripeptide both suppresses itch in mice and inhibits degranulation from the LAD-2 human mast cell line elicited by basic secretagogue activation of MRGPRX2. Antagonists of Mrgprs may fill the void left by the failure of NK-1R antagonists. PMID:27734033

  17. 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.

  18. Dopamine receptor antagonists as new mode-of-action insecticide leads for control of Aedes and Culex mosquito vectors.

    PubMed

    Nuss, Andrew B; Ejendal, Karin F K; Doyle, Trevor B; Meyer, Jason M; Lang, Emma G; Watts, Val J; Hill, Catherine A

    2015-03-01

    New mode-of-action insecticides are sought to provide continued control of pesticide resistant arthropod vectors of neglected tropical diseases (NTDs). We previously identified antagonists of the AaDOP2 D1-like dopamine receptor (DAR) from the yellow fever mosquito, Aedes aegypti, with toxicity to Ae. aegypti larvae as leads for novel insecticides. To extend DAR-based insecticide discovery, we evaluated the molecular and pharmacological characteristics of an orthologous DAR target, CqDOP2, from Culex quinquefasciatus, the vector of lymphatic filariasis and West Nile virus. CqDOP2 has 94.7% amino acid identity to AaDOP2 and 28.3% identity to the human D1-like DAR, hD1. CqDOP2 and AaDOP2 exhibited similar pharmacological responses to biogenic amines and DAR antagonists in cell-based assays. The antagonists amitriptyline, amperozide, asenapine, chlorpromazine and doxepin were between 35 to 227-fold more selective at inhibiting the response of CqDOP2 and AaDOP2 in comparison to hD1. Antagonists were toxic to both C. quinquefasciatus and Ae. aegypti larvae, with LC50 values ranging from 41 to 208 μM 72 h post-exposure. Orthologous DOP2 receptors identified from the African malaria mosquito, Anopheles gambiae, the sand fly, Phlebotomus papatasi and the tsetse fly, Glossina morsitans, had high sequence similarity to CqDOP2 and AaDOP2. DAR antagonists represent a putative new insecticide class with activity against C. quinquefasciatus and Ae. aegypti, the two most important mosquito vectors of NTDs. There has been limited change in the sequence and pharmacological properties of the DOP2 DARs of these species since divergence of the tribes Culicini and Aedini. We identified antagonists selective for mosquito versus human DARs and observed a correlation between DAR pharmacology and the in vivo larval toxicity of antagonists. These data demonstrate that sequence similarity can be predictive of target potential. On this basis, we propose expanded insecticide discovery around

  19. Dopamine Receptor Antagonists as New Mode-of-Action Insecticide Leads for Control of Aedes and Culex Mosquito Vectors

    PubMed Central

    Nuss, Andrew B.; Ejendal, Karin F. K.; Doyle, Trevor B.; Meyer, Jason M.; Lang, Emma G.; Watts, Val J.; Hill, Catherine A.

    2015-01-01

    Background New mode-of-action insecticides are sought to provide continued control of pesticide resistant arthropod vectors of neglected tropical diseases (NTDs). We previously identified antagonists of the AaDOP2 D1-like dopamine receptor (DAR) from the yellow fever mosquito, Aedes aegypti, with toxicity to Ae. aegypti larvae as leads for novel insecticides. To extend DAR-based insecticide discovery, we evaluated the molecular and pharmacological characteristics of an orthologous DAR target, CqDOP2, from Culex quinquefasciatus, the vector of lymphatic filariasis and West Nile virus. Methods/Results CqDOP2 has 94.7% amino acid identity to AaDOP2 and 28.3% identity to the human D1-like DAR, hD1. CqDOP2 and AaDOP2 exhibited similar pharmacological responses to biogenic amines and DAR antagonists in cell-based assays. The antagonists amitriptyline, amperozide, asenapine, chlorpromazine and doxepin were between 35 to 227-fold more selective at inhibiting the response of CqDOP2 and AaDOP2 in comparison to hD1. Antagonists were toxic to both C. quinquefasciatus and Ae. aegypti larvae, with LC50 values ranging from 41 to 208 μM 72 h post-exposure. Orthologous DOP2 receptors identified from the African malaria mosquito, Anopheles gambiae, the sand fly, Phlebotomus papatasi and the tsetse fly, Glossina morsitans, had high sequence similarity to CqDOP2 and AaDOP2. Conclusions DAR antagonists represent a putative new insecticide class with activity against C. quinquefasciatus and Ae. aegypti, the two most important mosquito vectors of NTDs. There has been limited change in the sequence and pharmacological properties of the DOP2 DARs of these species since divergence of the tribes Culicini and Aedini. We identified antagonists selective for mosquito versus human DARs and observed a correlation between DAR pharmacology and the in vivo larval toxicity of antagonists. These data demonstrate that sequence similarity can be predictive of target potential. On this basis, we propose

  20. Muscular Dystrophy

    MedlinePlus

    ... Devices The Search for a Cure en español Distrofia muscular About MD Muscular dystrophy (MD) is a ... muscles and cause different degrees of muscle weakness. Duchenne muscular dystrophy is the most common and the ...

  1. Nitric oxide-dependent antiplatelet action of AT1-receptor antagonists in a pulmonary thromboembolism in mice.

    PubMed

    Matys, Tomasz; Kucharewicz, Iwona; Pawlak, Robert; Chabielska, Ewa; Domaniewski, Tomasz; Buczko, Wlodzimierz

    2003-12-01

    The aim of this study was to determine whether AT1-receptor antagonists could inhibit platelet activation-dependent pulmonary thromboembolism in mice and to investigate the involvement of nitric oxide in this action. Losartan, its active metabolite EXP3174, and valsartan given intraperitoneally 1 hour before the thrombotic challenge (in doses of 3, 10, or 30 mg/kg) protected mice from death or hind-limb paralysis in response to intravenous injection of a mixture of collagen and epinephrine; losartan was effective in all doses used, whereas EXP3174 and valsartan reduced mortality only in the two higher doses. The protective action of EXP3174 and valsartan was abolished when nitric oxide synthase was inhibited with l-NAME, whereas that of losartan was only partially reduced. Moreover, only losartan protected mice from death caused by intravenous injection of the thromboxane A2 mimetic U46619 and this action was preserved in l-NAME-pretreated animals. Our results demonstrate the ability of AT1-receptor antagonists to inhibit platelet activation in vivo in a nitric oxide-dependent mechanism. Stronger antiplatelet activity of losartan, most likely due to its blockade of thromboxane A2/prostaglandin H2 receptor, could be of potential clinical relevance, particularly in conditions in which synthesis of endogenous nitric oxide is impaired.

  2. Scalability of the muscular action in a parametric 3D model of the index finger.

    PubMed

    Sancho-Bru, Joaquín L; Vergara, Margarita; Rodríguez-Cervantes, Pablo-Jesús; Giurintano, David J; Pérez-González, Antonio

    2008-01-01

    A method for scaling the muscle action is proposed and used to achieve a 3D inverse dynamic model of the human finger with all its components scalable. This method is based on scaling the physiological cross-sectional area (PCSA) in a Hill muscle model. Different anthropometric parameters and maximal grip force data have been measured and their correlations have been analyzed and used for scaling the PCSA of each muscle. A linear relationship between the normalized PCSA and the product of the length and breadth of the hand has been finally used for scaling, with a slope of 0.01315 cm(-2), with the length and breadth of the hand expressed in centimeters. The parametric muscle model has been included in a parametric finger model previously developed by the authors, and it has been validated reproducing the results of an experiment in which subjects from different population groups exerted maximal voluntary forces with their index finger in a controlled posture.

  3. Superagonist, Full Agonist, Partial Agonist, and Antagonist Actions of Arylguanidines at 5-Hydroxytryptamine-3 (5-HT3) Subunit A Receptors.

    PubMed

    Alix, Katie; Khatri, Shailesh; Mosier, Philip D; Casterlow, Samantha; Yan, Dong; Nyce, Heather L; White, Michael M; Schulte, Marvin K; Dukat, Małgorzata

    2016-11-16

    Introduction of minor variations to the substitution pattern of arylguanidine 5-hydroxytryptamine-3 (5-HT3) receptor ligands resulted in a broad spectrum of functionally-active ligands from antagonist to superagonist. For example, (i) introduction of an additional Cl-substituent(s) to our lead full agonist N-(3-chlorophenyl)guanidine (mCPG, 2; efficacy % = 106) yielded superagonists 7-9 (efficacy % = 186, 139, and 129, respectively), (ii) a positional isomer of 2, p-Cl analog 11, displayed partial agonist actions (efficacy % = 12), and (iii) replacing the halogen atom at the meta or para position with an electron donating OCH3 group or a stronger electron withdrawing (i.e., CF3) group resulted in antagonists 13-16. We posit based on combined mutagenesis, crystallographic, and computational analyses that for the 5-HT3 receptor, the arylguanidines that are better able to simultaneously engage the primary and complementary subunits, thus keeping them in close proximity, have greater agonist character while those that are deficient in this ability are antagonists.

  4. Distinct Actions of Endothelin A-Selective Versus Combined Endothelin A/B Receptor Antagonists in Early Diabetic Kidney Disease

    PubMed Central

    Saleh, Mohamed A.; Pollock, Jennifer S.

    2011-01-01

    Selective endothelin A (ETA) and combined ETA and ETB receptor antagonists are being investigated for use in treating diabetic nephropathy. However, the receptor-specific mechanisms responsible for producing the potential benefits have not been discerned. Thus, we determined the actions of ETA and ETB receptors on measures of glomerular function and renal inflammation in the early stages of diabetic renal injury in rats through the use of selective and combined antagonists. Six weeks after streptozotocin (STZ)-induced hyperglycemia, rats were given 2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid (ABT-627) (5 mg/kg/day), a selective ETA antagonist; (2R,3R,4S)-4-(benzo[d][1,3]dioxol-5-yl)-2-(3-fluoro-4-methoxyphenyl)-1-(2-(N-propylpentylsulfonamido)ethyl)pyrrolidine-3-carboxylic acid hydrochloride (A-182086) (10 mg/kg/day), a combined ETA/B antagonist; or vehicle for 1 week. Sham controls received STZ vehicle (saline). Hyperglycemia led to significant proteinuria, increased glomerular permeability to albumin (Palb), nephrinuria, and an increase in total matrix metalloprotease (MMP) and transforming growth factor-β1 (TGF-β1) activities in glomeruli. Plasma and glomerular soluble intercellular adhesion molecule-1 (sICAM-1) and monocyte chemoattractant protein-1 (MCP-1) were elevated after 7 weeks of hyperglycemia. Daily administration of both ABT-627 and A-182086 for 1 week significantly attenuated proteinuria, the increase in Palb, nephrinuria, and total MMP and TGF-β1 activity. However, glomerular sICAM-1 and MCP-1 expression was attenuated with ABT-627, but not A-182086, treatment. In summary, both selective ETA and combined ETA/B antagonists reduced proteinuria and glomerular permeability and restored glomerular filtration barrier component integrity, but only ETA-selective blockade had anti-inflammatory and antifibrotic effects. We conclude that selective ETA antagonists are more likely to be

  5. Excitatory actions of mushroom poison (acromelic acid) on unmyelinated muscular afferents in the rat.

    PubMed

    Taguchi, Toru; Tomotoshi, Kimihiko; Mizumura, Kazue

    2009-06-05

    Ingestion of a poisonous mushroom, Clitocybe acromelalga, results in strong and long-lasting allodynia, burning pain, redness and swelling in the periphery of the body. Acromelic acid (ACRO), a kainate analogue isolated from the mushroom, is assumed to be involved in the poisoning. ACRO has two isomers, ACRO-A and ACRO-B. The potency of ACRO-A is a million times higher than that of ACRO-B for induction of allodynia when intrathecally administered in mice. The effect of ACRO on the primary afferents of somatic tissues remains largely unknown. The aim of the present study was to examine the effect of ACRO-A on the response behavior of unmyelinated afferents in the skeletal muscle. For this purpose single fiber recordings of C-afferents were made from rat extensor digitorum longus (EDL) muscle-common peroneal nerve preparations in vitro. Intramuscular injections of ACRO-A at three different concentrations (10(-12), 10(-10) and 10(-8)M, 5 microl over 5s) near the receptive field in the EDL muscle elicited excitation of C-afferents (12%, 50% and 44%, respectively). ACRO-A at the concentration of 10(-10)M induced the strongest excitation. The incidence of ACRO-A responsive fibers at the concentration of 10(-10) and 10(-8)M was significantly higher than that at 10(-12)M. The responses to mechanical and heat stimulations did not differ between ACRO-A sensitive and insensitive fibers. These results clearly demonstrated the powerful excitatory action of ACRO-A on mechanosensitive unmyelinated afferents in the rat skeletal muscle.

  6. Antagonistic and cooperative actions of Kif7 and Sufu define graded intracellular Gli activities in Hedgehog signaling.

    PubMed

    Law, Kelvin King Lo; Makino, Shigeru; Mo, Rong; Zhang, Xiaoyun; Puviindran, Vijitha; Hui, Chi-Chung

    2012-01-01

    Graded Hedgehog (Hh) signaling governs the balance of Gli transcriptional activators and repressors to specify diverse ventral cell fates in the spinal cord. It remains unclear how distinct intracellular Gli activity is generated. Here, we demonstrate that Sufu acts universally as a negative regulator of Hh signaling, whereas Kif7 inhibits Gli activity in cooperation with, and independent of, Sufu. Together, they deter naïve precursors from acquiring increasingly ventral identity. We show that Kif7 is also required to establish high intracellular Gli activity by antagonizing the Sufu-inhibition of Gli2. Strikingly, by abolishing the negative regulatory action of Sufu, diverse ventral cell fates can be specified in the absence of extracellular Hh signaling. These data suggest that Sufu is the primary regulator of graded Hh signaling and establish that the antagonistic and cooperative actions of Kif7 and Sufu are responsible for setting up distinct Gli activity in ventral cell fate specification.

  7. In the amygdala anxiolytic action of mGlu5 receptors antagonist MPEP involves neuropeptide Y but not GABAA signaling.

    PubMed

    Wierońska, Joanna M; Smiałowska, Maria; Brański, Piotr; Gasparini, Fabrizio; Kłodzińska, Aleksandra; Szewczyk, Bernadeta; Pałucha, Agnieszka; Chojnacka-Wójcik, Ewa; Pilc, Andrzej

    2004-03-01

    Several lines of evidence indicate that inhibition of the metabotropic glutamate (mGlu) receptor 5 produces anxiolytic-like effects in rodents. Peptide neurotransmitter neuropeptide Y (NPY) produces an anxiolytic effect in rats after intraventricular or intra-amygdalar administration. Many classes of anxiolytic drugs exert their effect through the GABA-benzodiazepine (BZD) receptor complex. Therefore, in the present study we have investigated whether the anxiolytic action of MPEP (2-methyl-6-(phenylethynyl)pyridyne), an mGlu5 receptor antagonist, is mediated by a mechanism involving either the GABA-BZD receptor complex or NPY receptor. In the behavioral studies, the anxiolytic activity of MPEP (10 mg/kg, i.p.) was examined using plus-maze test. The BZD antagonist flumazenil (10 mg/kg, i.p.) was given to one group of rats and Y1 receptor antagonist BIBO 3304 (((R)-N-[[4-(aminocarbonylaminomethyl) phenyl] methyl]-N2-(diphenylacetyl)-argininamide trifluoroacetate)3304) (200 pmol/site, intra-amygdala) to the other. It was found that anxiolytic effects of MPEP were not changed by flumazenil, but were abolished by BIBO 3304. Immunohistochemical studies showed a high density of mGlu5 receptor immunoreactivity (IR) in the amygdala. The effect of MPEP on NPY expression in the amygdala was studied using immunohistochemistry (IH) and radioimmunoassay (RIA). Both methods showed a diminution of NPY IR expression, to about 43% (IH) or 81% (RIA) of the control level after multiple administrations, but we observed an increase up to 148% of the control after single MPEP administration. These effects may suggest a release of NPY from nerve terminals after MPEP administration. Our results indicate that the anxiolytic action of MPEP is conveyed through NPY neurons with the involvement of Y1 receptors in the amygdala and that BZD receptors do not significantly contribute to these effects.

  8. 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.

  9. Inhibitory action of forearm flexor muscle afferents on corticospinal outputs to antagonist muscles in humans

    PubMed Central

    Bertolasi, Laura; Priori, Alberto; Tinazzi, Michele; Bertasi, Valeria; Rothwell, John C

    1998-01-01

    To find out whether muscle afferents influence the excitability of corticospinal projections to antagonist muscles, we studied sixteen healthy subjects and one patient with a focal brain lesion. Using transcranial magnetic and electrical brain stimulation we tested the excitability of corticomotoneuronal connections to right forearm muscles at rest after conditioning stimulation of the median nerve at the elbow. Somatosensory potentials evoked by median nerve stimulation were also recorded in each subject. Test stimuli delivered at 13–19 ms after median nerve stimulation significantly inhibited EMG responses elicited in forearm extensor muscles by transcranial magnetic stimulation, but did not inhibit responses to electrical stimulation. In contrast, magnetically and electrically elicited responses in forearm flexor muscles were suppressed to the same extent. The higher the intensity of the test shocks, the smaller was the amount of median nerve-elicited inhibition. Inhibition in extensor muscles was also smaller during tonic wrist extension, or if the induced electrical stimulating current in the brain flowed from posterior to anterior over the motor strip rather than vice versa. Test responses evoked by magnetic transcranial stimulation in the first dorsal interosseous and in brachioradialis muscles were not inhibited after median nerve stimulation at the elbow. Stimulation of digital nerves failed to inhibit motor potentials in extensor muscles. Test stimuli delivered at 15 and 17 ms after radial nerve stimulation significantly inhibited EMG responses elicited in forearm flexor muscles by magnetic transcranial stimulation. In the patient with a focal thalamic lesion, who had dystonic postures and an absent N20 component of the somatosensory-evoked potentials but normal strength, median nerve stimulation failed to inhibit magnetically evoked responses in forearm extensor muscles. We propose that activation of median nerve muscle afferents can suppress the

  10. X-ray structures define human P2X3 receptor gating cycle and antagonist action

    NASA Astrophysics Data System (ADS)

    Mansoor, Steven E.; Lü, Wei; Oosterheert, Wout; Shekhar, Mrinal; Tajkhorshid, Emad; Gouaux, Eric

    2016-10-01

    P2X receptors are trimeric, non-selective cation channels activated by ATP that have important roles in the cardiovascular, neuronal and immune systems. Despite their central function in human physiology and although they are potential targets of therapeutic agents, there are no structures of human P2X receptors. The mechanisms of receptor desensitization and ion permeation, principles of antagonism, and complete structures of the pore-forming transmembrane domains of these receptors remain unclear. Here we report X-ray crystal structures of the human P2X3 receptor in apo/resting, agonist-bound/open-pore, agonist-bound/closed-pore/desensitized and antagonist-bound/closed states. The open state structure harbours an intracellular motif we term the ‘cytoplasmic cap’, which stabilizes the open state of the ion channel pore and creates lateral, phospholipid-lined cytoplasmic fenestrations for water and ion egress. The competitive antagonists TNP-ATP and A-317491 stabilize the apo/resting state and reveal the interactions responsible for competitive inhibition. These structures illuminate the conformational rearrangements that underlie P2X receptor gating and provide a foundation for the development of new pharmacological agents.

  11. X-ray structures define human P2X3 receptor gating cycle and antagonist action

    PubMed Central

    Mansoor, Steven E.; Lü, Wei; Oosterheert, Wout; Shekhar, Mrinal; Tajkhorshid, Emad; Gouaux, Eric

    2016-01-01

    Summary P2X receptors are trimeric, non-selective cation channels activated by ATP that play important roles in cardiovascular, neuronal and immune systems. Despite their central function in human physiology and as potential targets of therapeutic agents, there are no structures of human P2X receptors. Mechanisms of receptor desensitization and ion permeation, principles of antagonism, and complete structure of the pore-forming transmembrane domains remain unclear. We report x-ray crystal structures of human P2X3 receptor in apo/resting, agonist-bound/open-pore, agonist-bound/desensitized and antagonist-bound closed states. The open state structure harbors an intracellular motif we term the “cytoplasmic cap”, that stabilizes the open state of the ion channel pore and creates lateral, phospholipid-lined cytoplasmic fenestrations for water and ion egress. Competitive antagonists TNP-ATP and A-317491 stabilize the apo/resting state and reveal the interactions responsible for competitive inhibition. These structures illuminate the conformational rearrangements underpinning P2X receptor gating and provide a foundation for development of new pharmacologic agents. PMID:27626375

  12. New adenosine A2A receptor antagonists: actions on Parkinson's disease models.

    PubMed

    Pinna, Annalisa; Volpini, Rosaria; Cristalli, Gloria; Morelli, Micaela

    2005-04-11

    The 8-substituted 9-ethyladenine derivatives: 8-bromo-9-ethyladenine (ANR 82), 8-ethoxy- 9-ethyladenine (ANR 94), and 8-furyl-9-ethyladenine (ANR 152) have been characterized in vitro as adenosine receptor antagonists. Adenosine is deeply involved in the control of motor behaviour and substantial evidences indicate that adenosine A(2A) receptor antagonists improve motor deficits in animal models of Parkinson's disease. On this basis, the efficacy of ANR 82, ANR 94, and ANR 152 in rat models of Parkinson's disease was evaluated. All compounds tested reversed the catalepsy induced by haloperidol. However, in unilaterally 6-hydroxydopamine-lesioned rats, only ANR 94 and ANR 152 potentiated l-dihydroxy-phenylalanine (l-DOPA) effect on turning behaviour and induced contralateral turning behaviour in rats sensitised to l-DOPA. Taken together the results of this study indicate that some 8-substituted 9-ethyladenine derivatives ameliorate motor deficits in rat models of Parkinson's disease, suggesting a potential therapeutic role of these compounds.

  13. Effects of the putative antagonist NCS382 on the behavioral pharmacological actions of gammahydroxybutyrate in mice.

    PubMed

    Cook, Charles D; Aceto, Mario D; Coop, Andrew; Beardsley, Patrick M

    2002-02-01

    Gammahydroxybutyrate (GHB) is an endogenous chemical found in the human brain that when administered systemically readily crosses the blood-brain barrier and produces behavioral effects. Some previously reported observations, including reports of specific antagonism by NCS382 (6,7,8,9-tetrahydro-5-[H]-benzocycloheptene-5- ol-4-ylidene acetic acid), support the hypothesis that GHB is a neurotransmitter with its own receptor system. In addition to its uncertain physiological role, the recent interest in GHB has been engendered by its illicit use and abuse. To further characterize the behavioral effects of GHB and to evaluate NCS382 for its potential antagonistic effects. Following the administration of GHB alone and in combination with NCS382, mice were tested in a Functional Observational Battery (FOB) and for their effects on locomotor activity and on schedule-maintained behavior. Additionally, spontaneous and NCS382-precipitated withdrawal in rats chronically treated with GHB was examined. In the FOB, GHB generally produced depressant-like effects that were generally not reversed by NCS382. GHB also dose dependently reduced locomotor activity and rates of operant behavior, which were generally not reversed by co-administrations with NCS382. Neither spontaneous nor NCS382-precipitated signs of physical dependence were observed following chronic GHB administration. GHB dose dependently produced depressant-like effects on learned and unlearned behavior. The putative GHB antagonist NCS382 failed to convincingly antagonize these effects. Physical dependence was not evident following spontaneous withdrawal or NCS382 challenge. Taken together, these results suggest that NCS382's ability to antagonize GHB's effects may be very limited.

  14. A molecular graphics study on structure-action relationships of calcium-antagonistic and agonistic 1,4-dihydropyridines

    NASA Astrophysics Data System (ADS)

    Höltje, H.-D.; Marrer, S.

    1987-04-01

    Based on force field and quantum chemical calculations a hypothesis on the molecular mechanism of Ca channel-modulating 1,4-dihydropyridines (DHPs) has been developed. A careful investigation of the molecular electrostatic fields of the compounds led to the discovery of a unique area of the molecular potentials where Ca agonists and antagonists possess potentials with opposite sign. It is further demonstrated that the molecular potential of a simple receptor site model is reduced by interaction with Ca channel-activating DHPs and on the contrary increased by Ca channel-blocking DHPs. It is concluded that these effects could be the basis for opposite actions of 1,4-dihydropyridine enantiomers at the potential-dependent Ca channels.

  15. Pharmacological Actions of NGB 2904, a Selective Dopamine D3 Receptor Antagonist, in Animal Models of Drug Addiction

    PubMed Central

    Xi, Zheng-Xiong; Gardner, Eliot L.

    2013-01-01

    As a continuation of our work with SB-277011A, we have examined the effects of another highly elective dopamine (DA) D3 receptor antagonist, N-(4-[4-{2,3-dichlorophenyl}-1-piperazinyl]butyl)-2-fluorenylcarboxamide (NGB 2904), in animal models of addiction. Our results indicate that by systemic administration, NGB 2904 inhibits intravenous cocaine self-administration maintained under a progressive-ratio (PR) reinforcement schedule, cocaine-or cocaine cue–induced reinstatement of cocaine-seeking behavior, and cocaine- or other addictive drug-enhanced brain stimulation reward (BSR). The action of NGB 2904 on PR cocaine self-administration was long-lasting (1–2 days) after a single injection, supporting its potential use in treatment of cocaine addiction. The effects of NGB 2904 in the BSR paradigm were dose-dependent for both NGB 2904 and cocaine; that is, only lower doses of NGB 2904 were effective, and their putative antiaddiction effect could be overcome by increasing the doses of cocaine or other addictive drugs. A dopamine-dependent mechanism is proposed to explain the effects of NGB 2904 on cocaine’s actions in these animal models of drug addiction. The data reviewed in this paper suggest that NGB 2904 or other D3-selective antagonists may have potential in controlling motivation for drug-taking behavior or relapse to drug-seeking behavior, but may have a limited role in antagonizing the acute rewarding effects produced by cocaine or other addictive drugs. In addition, NGB 2904 may also act as a useful tool to study the role of D3 receptors in drug addiction. PMID:17627675

  16. 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

  17. Photoinduced removal of nifedipine reveals mechanisms of calcium antagonist action on single heart cells

    PubMed Central

    1985-01-01

    The currents through voltage-activated calcium channels in heart cell membranes are suppressed by dihydropyridine calcium antagonists such as nifedipine. Nifedipine is photolabile, and the reduction of current amplitude by this drug can be reversed within a few milliseconds after a 1-ms light flash. The blockade by nifedipine and its removal by flashes were studied in isolated myocytes from neonatal rat heart using the whole-cell clamp method. The results suggest that nifedipine interacts with closed, open, and inactivated calcium channels. It is likely that at the normal resting potential of cardiac cells, the suppression of current amplitude arises because nifedipine binds to and stabilizes channels in the resting, closed state. Inhibition is enhanced at depolarized membrane potentials, where interaction with inactivated channels may also become important. Additional block of open channels is suggested when currents are carried by Ba2+ but is not indicated with Ca2+ currents. Numerical simulations reproduce the experimental observations with molecular dissociation constants on the order of 10(-7) M for closed and open channels and 10(-8) M for inactivated channels. PMID:2414392

  18. The role of renal hemodynamics in the antihypertensive action of mepirodipine, a new calcium antagonist.

    PubMed

    Noda, H; Fujita, T; Ogata, E

    1992-01-01

    To evaluate the role of regional hemodynamics in the anti-hypertensive effect of mepirodipine, a new dihydropyridine-derivative calcium antagonist, we measured systemic, renal, hepatic, and forearm hemodynamics in 10 patients with essential hypertension treated with mepirodipine (15 mg/day) for 4 weeks. After the administration of mepirodipine, a significant decline in mean blood pressure (-13.8 +/- 2.3%, p less than 0.01) accompanied by a decrease in systemic vascular resistance (-21.1 +/- 2.6%, p less than 0.01) was observed. Although forearm vascular resistance did not change significantly, both renal (-19.2 +/- 6.7%, p less than 0.01) and hepatic vascular resistance (-17.6 +/- 3.8%, p less than 0.01) decreased considerably. The decrements of mean blood pressure with mepirodipine did not correlate with those of hepatic or forearm vascular resistance but correlated positively with those of renal vascular resistance (r = 0.699, p less than 0.05). Moreover, the increment of renal blood flow with mepirodipine was negatively correlated with the pretreatment level of renal blood flow (r = -0.670, p less than 0.05); renal blood flow increased to a greater extent in patients with lower pretreatment renal blood flow. These findings suggest that the oral administration of mepirodipine in patients with essential hypertension can produce selective vasodilation in the renal vasculature, which may play an important role in the relatively long-term antihypertensive effect of this drug.

  19. 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 ...

  20. 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 ...

  1. Muscular Dystrophy

    MedlinePlus

    ... It Like for Teens With MD? en español Distrofia muscular Aside from seeing the telethon on Labor ... which weakens different muscle groups in various ways: Duchenne (pronounced: due-SHEN) muscular dystrophy (DMD) , the most ...

  2. [Mechanism of the protective action of acetylcholine and serotonin against their cytotoxic antagonists].

    PubMed

    Buznikov, G A; Manukhin, B N; Rakic, L; Aroyan, A A; Kycherov, N F; Suvorov, N N

    1975-01-01

    By means of biological testing on supersensitive embryos of the sea-urchin Arbacia lixula, it has been shown that the eggs and embryos of the sea-urchin Paracentrotus lividus incubated in solutions of cytotoxic neuropharmacological drugs (cholino- and serotoninolytics), accumulate the latter. During the first (rapid) stage of binding, a level is reached which is 2-6 times higher than the external concentration; during the second stage of binding, this level gradually increases up to the values which are 8-12 times higher than the external concentration. The protecting action of exogenous acetylcholine and serotonin against the drugs studied does not inhibit their accumulation in embryonic cells. Therefore this protecting action is due to the decrease in the sensitivity of embryos to neurophysiological drugs. The protecting effect of endogenous factor produced by eggs and embryos is associated with the inhibition or abolition of the second stage of binding of cytotoxic neuropharmacological drugs.

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

    PubMed Central

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

    1998-01-01

    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

  4. Voltage-dependent antagonist/agonist actions of taurine on Ca(2+)-activated potassium channels of rat skeletal muscle fibers.

    PubMed

    Tricarico, D; Barbieri, M; Conte Camerino, D

    2001-09-01

    Emerging evidence supports the idea that taurine exerts some of its actions through inhibition of inward rectifier K(+) channels, ATP-sensitive K(+) channels, and voltage-dependent K(+) channels. However, to date not much is known about the effects of this sulfonic amino acid on Ca(2+)-activated K(+) (K(Ca(2+))) channels, which are widely expressed in various tissues, including skeletal muscle. In the present work, the effects of taurine on K(Ca(2+)) channels of rat skeletal muscle fibers were investigated using the patch-clamp technique. The application of the amino acid to the internal side of the excised macropatches induced a dose-dependent decrease in the outward K(Ca(2+)) currents recorded at positive membrane potentials in the presence of 8 to 16 microM concentrations of free Ca(2+) ions in the bath with an IC(50) of 31.9. 10(-3) +/- 1 M (slope factor = 1.2) (n = 11 patches). In contrast, at negative membrane potentials taurine caused an enhancement of the muscular inward K(Ca(2+)) currents with a DE(50) (drug concentration needed to enhance the current by 50%) of 46.7. 10(-3) +/- 2 M (slope factor = 1.3) (n = 9 patches). Single channel analysis revealed that this effect was mediated by changes in the reversal potential of the K(Ca(2+)) channel for K(+) ions with no changes in the gating properties or in the sensitivity of the channel to Ca(2+) ions. Taurine also did not affect the single channel conductance. In conclusion, taurine shows a voltage-dependent dualistic action on K(Ca(2+)) channels, being an inhibitor of the channel at positive membrane potentials and an activator at negative membrane potentials.

  5. Actions of amphetamine and antagonists on pupil diameter in the chronic sympathectomized dog.

    PubMed

    Sharpe, L G; Pickworth, W B; Martin, W R

    1977-07-18

    The left superior cervical ganglia were removed from 5 dogs. Beginning 30 days postoperatively, epinephrine (10 microgram/kg/min), norepinephrine (10 microgram/kg/min), and d-amphetamine (1.0 mg/kg) were infused i.v. for 10 min following either vehicle, phenoxybenzamine, pimozide, or haloperidol. Epinephrine and norepinephrine dilated the pupil and retracted the nictitating membrane of the denervated side, whereas amphetamine dilated both pupils and retracted both nictitating membranes. Phenoxybenzamine (4 mg/kg) constricted primarily the pupil of the innervated iris and completely antagonized the effects of the catecholamines on the irides and amphetamine on the nictitating membranes, but only partially antagonized amphetamine-induced mydriasis. Haloperidol (1.0 mg/kg) constricted both pupils, possessed only modest alpha-adrenergic blocking activity, and was as effective as phenoxybenzamine in antagonizing amphetamine-induced mydriasis. Pimozide (0.1 mg/kg) constricted both pupils, had no significant alpha-adrenergic blocking activity, and did not antagonize amphetamine-induced mydriasis. Pimozide and haloperidol, but not phenoxybenzamine, blocked amphetamine-induced stereotyped head bobbing. These results suggest that amphetamine produces mydriasis in the dog through a peripheral sympathetic action and also through a central mechanism involving inhibition of the oculomotor nucleus. However, the role of dopamine is not clear.

  6. Does the benzodiazepine antagonist Ro 15-1788 antagonize the action of ethanol?

    PubMed

    Klotz, U; Ziegler, G; Rosenkranz, B; Mikus, G

    1986-11-01

    Ethanol aggravates benzodiazepine-induced central nervous depression by pharmacokinetic and/or pharmacodynamic interactions and Ro 15-1788 reverses promptly the hypnotic effects of benzodiazepines. We therefore studied the acute effects of Ro 15-1788 on the ethanol-induced sedation in six healthy male subjects. Subsequently to an oral loading dose (0.54 g ethanol kg-1) ethanol was infused for 4 h (0.15 g ethanol kg-1 h-1) and steady state blood levels between 0.9 to 1.2 g l-1 were reached within 2 h. At steady state and during the elimination phase of ethanol an intravenous bolus of 0.5 mg Ro 15-1788 or placebo was administered in a randomized, double-blind crossover fashion. The marked sedative effects of ethanol as assessed by visual analogue scales (2 to 6 fold increase in the sedation index), and choice reaction time (25 to 40% prolongation) were not affected by Ro 15-1788. However, the pharmaco-EEG indicated that Ro 15-1788 seems to reverse transiently the ethanol-induced changes in total alpha, delta, and slow alpha bands. There was no pharmacokinetic interaction between both agents since elimination of Ro 15-1788 (t1/2 = 1.2 +/- 0.7 h) and of ethanol (0.17 +/- 0.02 g l-1 h-1) were in good agreement with control values. Thus, it could be concluded that Ro 15-1788 might affect for a short while the action of ethanol by interfering with the benzodiazepine receptors.

  7. Differential blocking action of dihydropyridine Ca2+ antagonists on a T-type Ca2+ channel (alpha1G) expressed in Xenopus oocytes.

    PubMed

    Furukawa, Taiji; Nukada, Toshihide; Miura, Reiko; Ooga, Kyoji; Honda, Mituyoshi; Watanabe, Suguru; Koganesawa, Satoshi; Isshiki, Takaaki

    2005-03-01

    Recent reports show that efonidipine, a dihydropyridine Ca2+ antagonist, has blocking action on T-type Ca2+ channels, which may produce favorable actions on cardiovascular systems. However, the effects of other dihydropyridine Ca2+ antagonists on T-type Ca2+ channels have not been investigated yet. Therefore, in this study, we examined the effects of dihydropyridine compounds clinically used for treatment of hypertension on a T-type Ca2+ channel subtype, alpha1G, expressed in Xenopus oocytes. These effects were compared with those on T-type Ca2+ channel. Rabbit L-type (alpha1Calpha2/deltabeta1a) or rat T-type (alpha1G) Ca2+ channel was expressed in Xenopus oocytes by injection of cRNA for each subunit. The Ba currents through expressed channels were measured by conventional 2-microelectrode voltage-clamp methods. Twelve DHPs (amlodipine, barnidipine, benidipine, cilnidipine, efonidipine, felodipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nitrendipine) and mibefradil were tested. Cilnidipine, felodipine, nifedipine, nilvadipine, minodipine, and nitrendipine had little effect on the T-type channel. The blocks by drugs at 10 microM were less than 10% at a holding potential of -100 mV. The remaining 6 drugs had blocking action on the T-type channel comparable to that on the L-type channel. The blocking actions were also comparable to that by mibefradil. These results show that many dihydropyridine Ca2+ antagonists have blocking action on the alpha1G channel subtype. The action of dihydropyridine Ca2+ antagonists in clinical treatment should be evaluated on the basis of subtype selectivity.

  8. 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

  9. 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 ...

  10. Muscular Dystrophy

    MedlinePlus

    ... affects about 1 out of every 3,500 boys. (Girls can carry the gene that causes the disease, ... and heart problems. Limb-girdle muscular dystrophy affects boys and girls equally. Symptoms usually start when kids are between ...

  11. 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 ...

  12. Inhibitory action of betaxolol, a beta 1-selective adrenoceptor antagonist, on voltage-dependent calcium channels in guinea-pig artery and vein.

    PubMed Central

    Setoguchi, M.; Ohya, Y.; Abe, I.; Fujishima, M.

    1995-01-01

    1. The effects of betaxolol, (+/-)-1-[4-[2-(cyclopropylmethoxy) ethyl] phenoxy]-3-(isopropylamino)-2-propanol hydrochloride, a beta 1-selective adrenoceptor antagonist, on voltage-dependent Ca2+ channels were investigated in single smooth muscle cells from guinea-pig mesenteric artery and portal vein using a whole-cell variant of the patch-clamp technique. Ca2+ channel currents were recorded with bath solutions contained 10 mM Ba2+ for arterial cells and 2 mM Ca2+ for venous cells. 2. Betaxolol inhibited Ca2+ channel currents dose-dependently in both mesenteric artery cells and portal vein cells. The two isomers, (+)-betaxolol and (-)-betaxolol (relative beta-antagonistic efficacies of 0.1 and 1, respectively), had similar potencies for inhibiting Ca2+ channel currents in portal vein cells. Propranolol did not inhibit the currents. Thus the inhibitory action of betaxolol on Ca2+ channel currents was independent of the beta-adrenoceptor. 3. The inhibitory action of betaxolol on Ca2+ channel currents was compared with that of diltiazem and of nifedipine in mesenteric artery cells. The current inhibition depended on the stimulation frequency with all drugs (use-dependent block). All drugs also accelerated the current decay and shifted the voltage-dependent inactivation curve in a negative direction. 4. In conclusion, betaxolol inhibited Ca2+ channel currents in vascular smooth muscle cells. The mode of inhibitory action was similar to that of diltiazem and nifedipine. Our results suggest that betaxolol is a unique beta-adrenoceptor antagonist that has a direct inhibitory action on voltage-dependent Ca2+ channels in vascular smooth muscle cells. PMID:7647977

  13. Pharmacology of the inhibitory glycine receptor: agonist and antagonist actions of amino acids and piperidine carboxylic acid compounds.

    PubMed

    Schmieden, V; Betz, H

    1995-11-01

    To define structure-activity relations for ligands binding to the inhibitory glycine receptor (GlyR), the agonistic and antagonistic properties of alpha- and beta-amino acids were analyzed at the recombinant human alpha 1 GlyR expressed in Xenopus oocytes. The agonistic activity of alpha-amino acids exhibited a marked stereoselectivity and was highly susceptible to substitutions at the C alpha-atom. In contrast, alpha-amino acid antagonism was not enantiomer dependent and was influenced little by C alpha-atom substitutions. The beta-amino acids taurine, beta-aminobutyric acid (beta-ABA), and beta-aminoisobutyric acid (beta-AIBA) are partial agonists at the GlyR. Low concentrations of these compounds competitively inhibited glycine responses, whereas higher concentrations elicited a significant membrane current. Nipecotic acid, which contains a trans-beta-amino acid configuration, behaved as purely competitive GlyR antagonist. Our data are consistent with the existence of a common binding site for all amino acid agonists and antagonists, at which the functional consequences of binding depend on the particular conformation a given ligand adopts within the binding pocket. In the case of beta-amino acids, the trans conformation appears to mediate antagonistic receptor binding, and the cis conformation appears to mediate agonistic receptor binding. This led us to propose that the partial agonist activity of a given beta-amino acid is determined by the relative mole fractions of the respective cis/trans conformers.

  14. Actions of novel agonists, antagonists and antipsychotic agents at recombinant rat 5-HT6 receptors: a comparative study of coupling to G alpha s.

    PubMed

    Dupuis, Delphine S; Mannoury la Cour, Clotilde; Chaput, Christine; Verrièle, Laurence; Lavielle, Gilbert; Millan, Mark J

    2008-07-07

    Though 5-HT6 receptors are targets for the treatment of schizophrenia and other psychiatric disorders, the influence of drugs upon signal transduction has not been extensively characterized. Herein, we employed a Scintillation Proximity Assay (SPA)/antibody-immunocapture procedure of coupling to G alpha s to evaluate the interaction of a broad range of novel agonists, antagonists and antipsychotics at rat 5-HT(6) receptors stably expressed in HEK293 cells. Serotonin (pEC(50), 7.7) increased [35S]GTP gamma S binding to G alpha s by ca 2-fold without affecting binding to Gi/o or Gq. LSD (9.2), 5-MeODMT (7.9), 5-CT (7.0) and tryptamine (6.1) were likewise full agonists. In contrast, the novel sulfonyl derivatives, WAY181,187 (9.1) and WAY208,466 (7.8), behaved as partial agonists and attenuated the actions of 5-HT. SB271,046 and SB258,585 abolished activation of G alpha s by 5-HT with pKb values of 10.2 and 9.9, respectively, actions mimicked by the novel antagonist, SB399,885 (10.9). SB271,046 likewise blocked partial agonist properties of WAY181,187 and WAY208,466 with pKb values of 9.8 and 9.0, respectively. 5-HT-stimulated [35S]GTP gamma S binding to G alpha s was antagonised by various antipsychotics including olanzapine (7.8), asenapine (9.1) and SB737,050 (7.8), whereas aripiprazole and bifeprunox were inactive. Further, antagonist properties of clozapine (8.0) were mimicked by its major metabolite, N-desmethylclozapine (7.9). In conclusion, the novel ligands, WAY208,466 and WAY181,187, behaved as partial agonists at 5-HT6 receptors coupled to G alpha s, while SB399,885 was a potent antagonist. Though 5-HT6 receptor blockade is not indispensable for therapeutic efficacy, it may well play a role in the functional actions of certain antipsychotic agents.

  15. Actions of two new antagonists showing selectivity for different sub-types of metabotropic glutamate receptor in the neonatal rat spinal cord.

    PubMed Central

    Jane, D. E.; Jones, P. L.; Pook, P. C.; Tse, H. W.; Watkins, J. C.

    1994-01-01

    1. The presynaptic depressant action of L-2-amino-4-phosphonobutyrate (L-AP4) on the monosynaptic excitation of neonatal rat motoneurones has been differentiated from the similar effects produced by (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate ((1S,3R)-ACPD), (1S,3S)-ACPD and (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine (L-CCG-I), and from the postsynaptic motoneuronal depolarization produced by (1S,3R)-ACPD, by the actions of two new antagonists, alpha-methyl-L-AP4 (MAP4) and alpha-methyl-L-CCG-I (MCCG). Such selectivity was not seen with a previously reported antagonist, (+)-alpha-methyl-4-carboxyphenylglycine (MCPG). 2. MAP4 selectively and competitively antagonized the depression of monosynaptic excitation produced by L-AP4 (KD 22 microM). At ten fold higher concentrations, MAP4 also antagonized synaptic depression produced by L-CCG-I but in an apparently non-competitive manner. MAP4 was virtually without effect on depression produced by (1S,3R)- or (1S,3S)-ACPD. 3. MCCG differentially antagonized the presynaptic depression produced by the range of agonists used. This antagonist had minimal effect on L-AP4-induced depression. The antagonism of the synaptic depression effected by (1S,3S)-ACPD and L-CCG-I was apparently competitive in each case but of varying effectiveness, with apparent KD values for the interaction between MCCG and the receptors activated by the two depressants calculated as 103 and 259 microM, respectively. MCCG also antagonized the presynaptic depression produced by (1S,3R)-ACPD. 4. Neither MAP4 nor MCCG (200-500 microM) significantly affected motoneuronal depolarizations produced by (1S,3R)-ACPD.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7921606

  16. Screening and modes of action of antagonistic bacteria to control the fungal pathogen Phaeomoniella chlamydospora involved in grapevine trunk diseases.

    PubMed

    Haidar, Rana; Roudet, Jean; Bonnard, Olivier; Dufour, Marie Cécile; Corio-Costet, Marie France; Fert, Mathieu; Gautier, Thomas; Deschamps, Alain; Fermaud, Marc

    2016-11-01

    The antagonistic activity of 46 bacterial strains isolated from Bordeaux vineyards were evaluated against Phaeomoniella chlamydospora, a major grapevine pathogen involved in Esca. The reduction of the necrosis length of stem cuttings ranged between 31.4% and 38.7% for the 8 most efficient strains. Two in planta trials allowed the selection of the two best strains, Bacillus pumilus (S32) and Paenibacillus sp. (S19). Their efficacy was not dependent on application method; co-inoculation, prevention in the wood and soil inoculation were tested. The involvement of antibiosis by the secretion of diffusible and/or volatile compounds in the antagonistic capacity of these two strains was assessed in vitro. Volatile compounds secreted by B. pumilus (S32) and Paenibacillus sp. (S19) were identified by gas chromatography/mass spectroscopy (GC/MS). The volatile compounds 1-octen-3-ol and 2,5-dimethyl pyrazine were obtained commercially and tested, and they showed strong antifungal activity against P. chlamydospora, which suggested that these compounds may play an important role in the bacterial antagonistic activity in planta. Furthermore, the expression of 10 major grapevine defense genes was quantified by real-time polymerase chain reaction, which demonstrated that the two strains significantly affected the grapevine transcripts four days after their application on the plants. High expression levels of different genes associated with P. chlamydospora infection in B. pumilus pre-treated plants suggests that this strain induces systemic resistance in grapevine. For the first time, we demonstrated the ability of two bacterial strains, B. pumilus and Paenibacillus sp., isolated from grapevine wood, to control P. chlamydospora via direct and/or indirect mechanisms. Copyright © 2016 Elsevier GmbH. All rights reserved.

  17. Volatile organic compounds: a potential direct long-distance mechanism for antagonistic action of Fusarium oxysporum strain MSA 35.

    PubMed

    Minerdi, Daniela; Bossi, Simone; Gullino, Maria Lodovica; Garibaldi, Angelo

    2009-04-01

    Fusarium oxysporum MSA35 [wild-type (WT) strain] is an antagonistic Fusarium that lives in association with a consortium of bacteria belonging to the genera Serratia, Achromobacter, Bacillus and Stenotrophomonas in an Italian soil suppressive to Fusarium wilt. Typing experiments and virulence tests provided evidence that the F. oxysporum isolate when cured of the bacterial symbionts [the cured (CU) form], is pathogenic, causing wilt symptoms identical to those caused by F. oxysporum f. sp. lactucae. Here, we demonstrate that small volatile organic compounds (VOCs) emitted from the WT strain negatively influence the mycelial growth of different formae speciales of F. oxysporum. Furthermore, these VOCs repress gene expression of two putative virulence genes in F. oxysporum lactucae strain Fuslat10, a fungus against which the WT strain MSA 35 has antagonistic activity. The VOC profile of the WT and CU fungus shows different compositions. Sesquiterpenes, mainly caryophyllene, were present in the headspace only of WT MSA 35. No sesquiterpenes were found in the volatiles of ectosymbiotic Serratia sp. strain DM1 and Achromobacter sp. strain MM1. Bacterial volatiles had no effects on the growth of the different ff. spp. of F. oxysporum examined. Hyphae grownwithVOCfrom WT F. oxysporum f. sp. lactucae strain MSA 35 were hydrophobic whereas those grown without VOCs were not, suggesting a correlation between the presence of volatiles in the atmosphere and the phenotype of the mycelium. This is the first report of VOC production by antagonistic F. oxysporum MSA35 and their effects on pathogenic F. oxysporum. The results obtained in this work led us to propose a new potential direct long-distance mechanism for antagonism by F. oxysporum MSA 35 mediated by VOCs. Antagonism could be the consequence of both reduction of pathogen mycelial growth and inhibition of pathogen virulence gene expression.

  18. Hippocampal-Dependent Antidepressant Action of the H3 Receptor Antagonist Clobenpropit in a Rat Model of Depression

    PubMed Central

    Femenía, Teresa; Magara, Salvatore; DuPont, Caitlin M.

    2015-01-01

    Background: Histamine is a modulatory neurotransmitter regulating neuronal activity. Antidepressant drugs target modulatory neurotransmitters, thus ultimately regulating glutamatergic transmission and plasticity. Histamine H3 receptor (H3R) antagonists have both pro-cognitive and antidepressant effects; however, the mechanism by which they modulate glutamate transmission is not clear. We measured the effects of the H3R antagonist clobenpropit in the Flinders Sensitive Line (FSL), a rat model of depression with impaired memory and altered glutamatergic transmission. Methods: Behavioral tests included the forced swim test, memory tasks (passive avoidance, novel object recognition tests), and anxiety-related paradigms (novelty suppressed feeding, social interaction, light/dark box tests). Hippocampal protein levels were detected by Western blot. Hippocampal plasticity was studied by in slice field recording of CA3-CA1 long-term synaptic potentiation (LTP), and glutamatergic transmission by whole-cell patch clamp recording of excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons. Results: Clobenpropit, administered systemically or directly into the hippocampus, decreased immobility during the forced swim test; systemic injections reversed memory deficits and increased hippocampal GluN2A protein levels. FSL rats displayed anxiety-related behaviors not affected by clobenpropit treatment. Clobenpropit enhanced hippocampal plasticity, but did not affect EPSCs. H1R and H2R antagonists prevented the clobenpropit-induced increase in LTP and, injected locally into the hippocampus, blocked clobenpropit’s effect in the forced swim test. Conclusions: Clobenpropit’s antidepressant effects and the enhanced synaptic plasticity require hippocampal H1R and H2R activation, suggesting that clobenpropit acts through disinhibition of histamine release. Clobenpropit reverses memory deficits and increases hippocampal GluN2A expression without modifying anxiety

  19. Control of retinoic acid receptor heterodimerization by ligand-induced structural transitions. A novel mechanism of action for retinoid antagonists.

    PubMed

    Depoix, C; Delmotte, M H; Formstecher, P; Lefebvre, P

    2001-03-23

    Heterodimerization of retinoic acid receptors (RARs) with 9-cis-retinoic receptors (RXRs) is a prerequisite for binding of RXR.RAR dimers to DNA and for retinoic acid-induced gene regulation. Whether retinoids control RXR/RAR solution interaction remains a debated question, and we have used in vitro and in vivo protein interaction assays to investigate the role of ligand in modulating RXR/RAR interaction in the absence of DNA. Two-hybrid assay in mammalian cells demonstrated that only RAR agonists were able to increase significantly RAR interaction with RXR, whereas RAR antagonists inhibited RXR binding to RAR. Quantitative glutathione S-transferase pull-down assays established that there was a strict correlation between agonist binding affinity for the RAR monomer and the affinity of RXR for liganded RAR, but RAR antagonists were inactive in inducing RXR recruitment to RAR in vitro. Alteration of coactivator- or corepressor-binding interfaces of RXR or RAR did not alter ligand-enhanced dimerization. In contrast, preventing the formation of a stable holoreceptor structure upon agonist binding strongly altered RXR.RAR dimerization. Finally, we observed that RAR interaction with RXR silenced RXR ligand-dependent activation function. We propose that ligand-controlled dimerization of RAR with RXR is an important step in the RXR.RAR activation process. This interaction is dependent upon adequate remodeling of the AF-2 structure and amenable to pharmacological inhibition by structurally modified retinoids.

  20. CD40 agonist converting CTL exhaustion via the activation of the mTORC1 pathway enhances PD-1 antagonist action in rescuing exhausted CTLs in chronic infection.

    PubMed

    Xu, Aizhang; Wang, Rong; Freywald, Andrew; Stewart, Kristoffor; Tikoo, Suresh; Xu, Jianqing; Zheng, Changyu; Xiang, Jim

    2017-03-11

    Expansion of PD-1-expressing CD8(+) cytotoxic T lymphocytes (CTLs) and associated CTL exhaustion are chief issues for ineffective virus-elimination in chronic infectious diseases. PD-1 blockade using antagonistic anti-PD-L1 antibodies results in a moderate conversion of CTL exhaustion. We previously demonstrated that CD40L signaling of ovalbumin (OVA)-specific vaccine, OVA-Texo, converts CTL exhaustion via the activation of the mTORC1 pathway in OVA-expressing adenovirus (AdVova)-infected B6 mice showing CTL inflation and exhaustion. Here, we developed AdVova-infected B6 and transgenic CD11c-DTR (termed AdVova-B6 and AdVova-CD11c-DTR) mice with chronic infection, and assessed a potential effect of CD40 agonist on the conversion of CTL exhaustion and on a potential enhancement of PD-1 antagonist action in rescuing exhausted CTLs in our chronic infection models. We demonstrate that a single dose of anti-CD40 alone can effectively convert CTL exhaustion by activating the mTORC1 pathway, leading to CTL proliferation, up-regulation of an effector-cytokine IFN-γ and the cytolytic effect in AdVova-B6 mice. Using anti-CD4 antibody and diphtheria toxin (DT) to deplete CD4(+) T-cells and dendritic cells (DCs), we discovered that the CD40 agonist-induced conversion in AdVova-B6 and AdVova-CD11c-DTR mice is dependent upon host CD4(+) T-cell and DC involvements. Moreover, CD40 agonist significantly enhances PD-1 antagonist effectiveness in rescuing exhausted CTLs in chronic infection. Taken together, our data demonstrate the importance of CD40 signaling in the conversion of CTL exhaustion and its ability to enhance PD-1 antagonist action in rescuing exhausted CTLs in chronic infection. Therefore, our findings may positively impact the design of new therapeutic strategies for chronic infectious diseases.

  1. Assessment in pig coronary artery of long-lasting and potent calcium antagonistic actions of the novel dihydropyridine derivative mepirodipine hydrochloride.

    PubMed

    Nakayama, K; Kashiwabara, T; Yamada, S; Tanaka, Y

    1989-01-01

    Ca antagonistic properties of mepirodipine hydrochloride [+)-(3'S,4S)-3-(1'-benzyl-3'-pyrrolidinyl methyl 2,6-dimethyl-4- (m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride, YM-09730-5) were assessed by studying the pharmacological actions and binding characteristics of the drug in the stem coronary artery. IC50 values of YM-09730-5 (3.5 x 10(-10) mol/l) and nifedipine (6.6 x 10(-9) mol/l) for 40 mmol/l K-induced tonic contraction of pig coronary artery indicated that YM-09730-5 was about 20 times more potent than nifedipine in Ca antagonistic action. However, YM-09730-5 showed an onset of inhibitory action 3 to 5 times slower than nifedipine. A 40-min preincubation of the target tissue with YM-09730-5 also inhibited the contractions produced by acetylcholine, histamine, 5-hydroxytryptamine, and high Ca, and pD2' values were between 8.0 and 7.0; while nifedipine was less potent. The specific binding of [3H]nitrendipine to the membrane of pig coronary artery was inhibited by YM-09730-5, thereby indicating that [3H]nitrendipine and YM-09730-5 compete for the similar receptor sites of dihydropyridine-sensitive Ca channels. Suppression of high K-, Ca- and agonist-induced contractions by YM-09730-5 (3 x 10(-9) mol/l-10(-7) mol/l) remained even after washings at 20-min intervals for more than 3 h; and, in particular at a high concentration of YM-09730-5, the suppression was slightly antagonized by excess Ca or a Ca-agonist. The contraction inhibited by nifedipine, on the other hand, was readily restored by several washings.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Agonist versus antagonist action of ATP at the P2Y4 receptor is determined by the second extracellular loop.

    PubMed

    Herold, Christopher L; Qi, Ai-Dong; Harden, T Kendall; Nicholas, Robert A

    2004-03-19

    UTP is a potent full agonist at both the human P2Y(4) (hP2Y(4)) and rat P2Y(4) (rP2Y(4)) receptor. In contrast, ATP is a potent full agonist at the rP2Y(4) receptor but is a similarly potent competitive antagonist at the hP2Y(4) receptor. To delineate the structural determinants of agonism versus antagonism in these species homologues, we expressed a series of human/rat P2Y(4) receptor chimeras in 1321N1 human astrocytoma cells and assessed the capacity of ATP and UTP to mobilize intracellular Ca(2+). Replacement of the NH(2) terminus of the hP2Y(4) receptor with the corresponding region of the rP2Y(4) receptor resulted in a receptor that was activated weakly by ATP, whereas replacement of the second extracellular loop (EL2) of the hP2Y(4) receptor with that of the rP2Y(4) receptor yielded a chimeric receptor that was activated fully by UTP and near fully by ATP, albeit with lower potencies than those observed at the rP2Y(4) receptor. These potencies were increased, and ATP was converted to a full agonist by replacing both the NH(2) terminus and EL2 in the hP2Y(4) receptor with the corresponding regions from the rP2Y(4) receptor. Mutational analysis of the five divergent amino acids in EL2 between the two receptors revealed that three amino acids, Asn-177, Ile-183, and Leu-190, contribute to the capacity of EL2 to impart ATP agonism. Taken together, these results suggest that the second extracellular loop and the NH(2) terminus form a functional motif that plays a key role in determining whether ATP functions as an agonist or antagonist at mammalian P2Y(4) receptors.

  3. 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

  4. 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

  5. The SnRK2-APC/C(TE) regulatory module mediates the antagonistic action of gibberellic acid and abscisic acid pathways.

    PubMed

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

    2015-08-14

    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/C(TE) 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/C(TE) 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/C(TE)-mediated degradation of OsPYL/RCARs. Thus, we propose that the SnRK2-APC/C(TE) regulatory module represents a regulatory hub underlying the antagonistic action of GA and ABA in plants.

  6. 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.

  7. 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.

  8. 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. ...

  9. ORA59 and EIN3 interaction couples jasmonate-ethylene synergistic action to antagonistic salicylic acid regulation of PDF expression.

    PubMed

    He, Xiang; Jiang, Jishan; Wang, Changquan; Dehesh, Katayoon

    2017-02-07

    Hormonal crosstalk is central for tailoring plant responses to the nature of challenges encountered. The role of antagonism between the two major defense hormones, salicylic acid (SA) and jasmonic acid (JA), and modulation of this interplay by ethylene (ET) in favor of JA signaling pathway in plant stress responses is well recognized, but the underlying mechanism is not fully understood. Here, we show the opposing function of two transcription factors, ethylene insensitive3 (EIN3) and EIN3-Like1 (EIL1), in SA-mediated suppression and JA-mediated activation of PLANT DEFENSIN1.2 (PDF1.2). This functional duality is mediated via their effect on protein, not transcript levels of the PDF1.2 transcriptional activator octadecanoid-responsive arabidopsis59 (ORA59). Specifically, JA induces ORA59 protein levels independently of EIN3/EIL1, whereas SA reduces the protein levels dependently of EIN3/EIL1. Co-infiltration assays revealed nuclear co-localization of ORA59 and EIN3, and split-luciferase together with yeast-two-hybrid assays established their physical interaction. The functional ramification of the physical interaction is EIN3-dependent degradation of ORA59 by the 26S proteasome. These findings allude to SA-responsive reduction of ORA59 levels mediated by EIN3 binding to and targeting of ORA59 for degradation, thus nominating ORA59 pool as a coordination node for the antagonistic function of ET/JA and SA.

  10. A 5-HT3 receptor antagonist potentiates the behavioral, neurochemical and electrophysiological actions of an SSRI antidepressant.

    PubMed

    Bétry, C; Overstreet, D; Haddjeri, N; Pehrson, A L; Bundgaard, C; Sanchez, C; Mørk, A

    2015-04-01

    More effective treatments for major depression are needed. We studied if the selective 5-HT3 receptor antagonist ondansetron can potentiate the antidepressant potential of the selective serotonin (5-HT) reuptake inhibitor (SSRI) paroxetine using behavioral, neurochemical and electrophysiological methods. Flinders Sensitive Line (FSL) rats, treated with ondansetron, and/or a sub-effective dose of paroxetine, were assessed in the forced swim test. The effects of an acute intravenous administration of each compound alone and in combination were evaluated with respect to 5-HT neuronal firing rate in the dorsal raphe nucleus (DRN). Effects of s.c. administration of the compounds alone and in combination on extracellular levels of 5-HT were assessed in the ventral hippocampus of freely moving rats by microdialysis. The results showed that ondansetron enhanced the antidepressant activity of paroxetine in the forced swim test. It partially prevented the suppressant effect of paroxetine on DRN 5-HT neuronal firing and enhanced the paroxetine-induced increase of hippocampal extracellular 5-HT release. These findings indicate that 5-HT3 receptor blockade potentiates the antidepressant effects of SSRIs. Since both paroxetine and ondansetron are used clinically, it might be possible to validate this augmentation strategy in depressed patients.

  11. Learning about Spinal Muscular Atrophy

    MedlinePlus

    ... Disorders 2003 News Release Fischbeck Group Learning About Spinal Muscular Atrophy What is spinal muscular atrophy? What are the ... Additional Resources for Spinal Muscular Atrophy What is spinal muscular atrophy? Spinal muscular atrophy is a group of inherited ...

  12. Antagonist action of progesterone at σ-receptors in the modulation of voltage-gated sodium channels

    PubMed Central

    Johannessen, Molly; Fontanilla, Dominique; Mavlyutov, Timur; Ruoho, Arnold E.

    2011-01-01

    σ-Receptors are integral membrane proteins that have been implicated in a number of biological functions, many of which involve the modulation of ion channels. A wide range of synthetic ligands activate σ-receptors, but endogenous σ-receptor ligands have proven elusive. One endogenous ligand, dimethyltryptamine (DMT), has been shown to act as a σ-receptor agonist. Progesterone and other steroids bind σ-receptors, but the functional consequences of these interactions are unclear. Here we investigated progesterone binding to σ1- and σ2-receptors and evaluated its effect on σ-receptor-mediated modulation of voltage-gated Na+ channels. Progesterone binds both σ-receptor subtypes in liver membranes with comparable affinities and blocks photolabeling of both subtypes in human embryonic kidney 293 cells that stably express the human cardiac Na+ channel Nav1.5. Patch-clamp recording in this cell line tested Na+ current modulation by the σ-receptor ligands ditolylguanidine, PB28, (+)SKF10047, and DMT. Progesterone inhibited the action of these ligands to varying degrees, and some of these actions were reduced by σ1-receptor knockdown with small interfering RNA. Progesterone inhibition of channel modulation by drugs was consistent with stronger antagonism of σ2-receptors. By contrast, progesterone inhibition of channel modulation by DMT was consistent with stronger antagonism of σ1-receptors. Progesterone binding to σ-receptors blocks σ-receptor-mediated modulation of a voltage-gated ion channel, and this novel membrane action of progesterone may be relevant to changes in brain and cardiovascular function during endocrine transitions. PMID:21084640

  13. Antagonist action of progesterone at σ-receptors in the modulation of voltage-gated sodium channels.

    PubMed

    Johannessen, Molly; Fontanilla, Dominique; Mavlyutov, Timur; Ruoho, Arnold E; Jackson, Meyer B

    2011-02-01

    σ-Receptors are integral membrane proteins that have been implicated in a number of biological functions, many of which involve the modulation of ion channels. A wide range of synthetic ligands activate σ-receptors, but endogenous σ-receptor ligands have proven elusive. One endogenous ligand, dimethyltryptamine (DMT), has been shown to act as a σ-receptor agonist. Progesterone and other steroids bind σ-receptors, but the functional consequences of these interactions are unclear. Here we investigated progesterone binding to σ(1)- and σ(2)-receptors and evaluated its effect on σ-receptor-mediated modulation of voltage-gated Na(+) channels. Progesterone binds both σ-receptor subtypes in liver membranes with comparable affinities and blocks photolabeling of both subtypes in human embryonic kidney 293 cells that stably express the human cardiac Na(+) channel Na(v)1.5. Patch-clamp recording in this cell line tested Na(+) current modulation by the σ-receptor ligands ditolylguanidine, PB28, (+)SKF10047, and DMT. Progesterone inhibited the action of these ligands to varying degrees, and some of these actions were reduced by σ(1)-receptor knockdown with small interfering RNA. Progesterone inhibition of channel modulation by drugs was consistent with stronger antagonism of σ(2)-receptors. By contrast, progesterone inhibition of channel modulation by DMT was consistent with stronger antagonism of σ(1)-receptors. Progesterone binding to σ-receptors blocks σ-receptor-mediated modulation of a voltage-gated ion channel, and this novel membrane action of progesterone may be relevant to changes in brain and cardiovascular function during endocrine transitions.

  14. Characterization of CRF1 receptor antagonists with differential peripheral vs central actions in CRF challenge in rats.

    PubMed

    Tanaka, Maiko; Tomimatsu, Yoshiro; Sakimura, Katsuya; Ootani, Yoshikazu; Sako, Yuu; Kojima, Takuto; Aso, Kazuyoshi; Yano, Takahiko; Hirai, Keisuke

    2017-09-01

    The aim of this study was to investigate peripheral and central roles of corticotropin-releasing factor (CRF) in endocrinological and behavioral changes. Plasma adrenocorticotropin (ACTH) concentration was measured as an activity of hypothalamic-pituitary-adrenal (HPA) axis. As behavioral changes, locomotion and anxiety behavior were measured after CRF challenge intravenously (i.v.) for the peripheral administration or intracerebroventricularly (i.c.v.) for the central administration. Plasma ACTH concentration was significantly increased by both administration routes of CRF; however, hyperlocomotion and anxiety behavior were induced only by the i.c.v. administration. In the drug discovery of CRF1 receptor antagonists, we identified two types of compounds, Compound A and Compound B, which antagonized peripheral CRF-induced HPA axis activation to the same extent, but showed different effects on the central CRF signal. These had similar in vitro CRF1 receptor binding affinities (15 and 10nM) and functional activities in reporter gene assay (15 and 9.5nM). In the ex vivo binding assays using tissues of the pituitary, oral treatment with Compound A and Compound B at 10mg/kg inhibited [(125)I]-CRF binding, whereas in the assay using tissues of the frontal cortex, treatment of Compound A but not Compound B inhibited [(125)I]-CRF binding, indicating that only Compound A inhibited central [(125)I]-CRF binding. In the peripheral CRF challenge, increase in plasma ACTH concentration was significantly suppressed by both Compound A and Compound B. In contrast, Compound A inhibited the increase in locomotion induced by the central CRF challenge while Compound B did not. Compound A also reduced central CRF challenge-induced anxiety behavior and c-fos immunoreactivity in the cortex and the hypothalamic paraventricular nucleus. These results indicate that the central CRF signal, rather than the peripheral CRF signal would be related to anxiety and other behavioral changes, and CRF1

  15. Advantages of an antagonist: bicuculline and other GABA antagonists

    PubMed Central

    Johnston, Graham AR

    2013-01-01

    The convulsant alkaloid bicuculline continues to be investigated more than 40 years after the first publication of its action as an antagonist of receptors for the inhibitory neurotransmitter GABA. This historical perspective highlights key aspects of the discovery of bicuculline as a GABA antagonist and the sustained interest in this and other GABA antagonists. The exciting advances in the molecular biology, pharmacology and physiology of GABA receptors provide a continuing stimulus for the discovery of new antagonists with increasing selectivity for the myriad of GABA receptor subclasses. Interesting GABA antagonists not structurally related to bicuculline include gabazine, salicylidene salicylhydrazide, RU5135 and 4-(3-biphenyl-5-(4-piperidyl)-3-isoxazole. Bicuculline became the benchmark antagonist for what became known as GABAA receptors, but not all ionotropic GABA receptors are susceptible to bicuculline. In addition, not all GABAA receptor antagonists are convulsants. Thus there are still surprises in store as the study of GABA receptors evolves. PMID:23425285

  16. Effect of the calcium antagonists bepridil (CERM-1978) and verapamil on Ca++-dependent slow action potentials in frog skeletal muscle.

    PubMed

    Kerr, L M; Sperelakis, N

    1982-07-01

    The calcium slow channels found in cardiac and smooth muscle are blocked by calcium-antagonistic agents. In the present study, the effects of the Ca++-antagonistic drugs bepridil and verapamil on the slow action potentials (APs) found in the frog skeletal muscle were examined. Slow APs were induced in Cl-- free (acetate substituted), Na+-free (sucrose substituted), high K+ (25 mM)media. A conventional two-microelectrode recording technique was used. Amplitude of the slow APs increases linearly with log [Ca]o with a slope of 28.2 mV/decade, suggesting that Ca++ is the major inward current carrier because this value approaches the theoretical slope of 29 mV/decade (at 21 degrees C) predicted by the Nernst equation for a divalent cation. Duration also increases with increases in [Ca]o. The slow APs were abolished by glycerol shock treatment, which disconnects the T-tubules from the surface membrane, suggesting that the slow APs originate in the T-tubules. Verapamil and bepridil depress the amplitude of the slow APs in a use-dependent manner at concentrations of 5 X 10-9 to 1 X 10-6 M and abolish the slow APs at 5 X 10-6 M. These drugs also decrease the rates of rise of the slow APs. Bepridil decreases the duration of the slow APs, whereas verapamil has little effect, suggesting that bepridil, in addition to blocking the slow channels, might also increase gk. Thus, the slow channels found in the T-tubular system of frog skeletal muscle have some of the same properties of slow channels in vascular smooth muscle and cardiac muscle.

  17. Spinal Muscular Atrophy

    MedlinePlus

    ... here Home » Disorders » Patient & Caregiver Education » Fact Sheets Spinal Muscular Atrophy Fact Sheet What is spinal muscular atrophy? What ... Where can I get more information? What is spinal muscular atrophy? Spinal muscular atrophy (SMA) is one of several ...

  18. Molecular basis determining inhibition/activation of nociceptive receptor TRPA1 protein: a single amino acid dictates species-specific actions of the most potent mammalian TRPA1 antagonist.

    PubMed

    Banzawa, Nagako; Saito, Shigeru; Imagawa, Toshiaki; Kashio, Makiko; Takahashi, Kenji; Tominaga, Makoto; Ohta, Toshio

    2014-11-14

    The transient receptor potential ankyrin 1 (TRPA1) is a Ca(2+)-permeable, nonselective cation channel mainly expressed in a subset of nociceptive neurons. TRPA1 functions as a cellular sensor detecting mechanical, chemical, and thermal stimuli. Because TRPA1 is considered to be a key player in nociception and inflammatory pain, TRPA1 antagonists have been developed as analgesic agents. Recently, by utilizing species differences, we identified the molecular basis of the antagonistic action of A967079, one of the most potent mammalian TRPA1 antagonists. Here, we show a unique effect of A967079 on TRPA1 from diverse vertebrate species, i.e. it acts as an agonist but not as an antagonist for chicken and frog TRPA1s. By characterizing chimeric channels of human and chicken TRPA1s, as well as point mutants, we found that a single specific amino acid residue located within the putative fifth transmembrane domain was involved in not only the stimulatory but also the inhibitory actions of A967079. AP18, structurally related to A967079, exerted similar pharmacological properties to A967079. Our findings and previous reports on species differences in the sensitivity to TRPA1 antagonists supply useful information in the search for novel analgesic medicines targeting TRPA1.

  19. 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.

  20. Supplementation action with ascorbic acid in the morphology of the muscular layer and reactive acetylcholinesterase neurons of ileum of mdx mice.

    PubMed

    Lisboa, Marcelo José Santiago; De Oliveira Lima, Marília Fabiana; Stabille, Sandra Regina; Zanoni, Jacqueline Nelisis; Gagliardo, Karina Martinez; Souto, Melyna Soares; Souza, Renivaldo; Da Silva, Jodonai Barbosa; De Almeida Yokomizo, Sônia Regina; Liberti, Edson Aparecido; Clebis, Naianne Kelly

    2017-07-01

    The Duchenne Muscular Dystrophy (DMD) is a genetic disorder characterized by the absence of dystrophin protein, causing severe myopathy from increases of oxidative stress. Injuries of intestinal muscle can compromise the myenteric plexus. This study aimed to evaluate the disorders occurred in the muscular layer and in the acetylcholinesterase myenteric neurons (ACHE-r) of ileum of mdx mice, and the effects of supplementation with ascorbic acid (AA) in both components. 30 male mice C57BL/10, and 30 male mice C57BL/10Mdx were separated according to the age and treatment (n=10/group): 30-days-old control group (C30); 30-days-old dystrophic group (D30); 60-days-old control group (C60); 60-days-old dystrophic group (D60); 60-days-old control group supplemented with AA (CS60); and 60-days-old dystrophic group supplemented with AA (DS60). The animals were euthanized and the ileum was collected and processed. Semi-serial sections were stained by Masson's trichrome, and acetylcholinesterase histochemical technique in whole-mounts preparations to identify the myenteric neurons. The muscular layer thickness and the area of smooth muscle of ileum were lower in dystrophic groups, especially in D30 group. The DS60 group showed the muscular layer thickness similar to C60. The density of ACHE-r neurons of myenteric plexus of ileum was lower in D30 animals; however, it was similar in animals of 60-days-old without treatment (C60 and D60) and, higher in DS60. The cell body profile area of ACHE-r neurons was similar in C30-D30 and C60-D60; however, it was higher in DS60. DMD caused damage to the ileum's musculature and myenteric plexus, and the AA prevented the ACHE-r neuronal loss. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Influence of MPEP (a selective mGluR5 antagonist) on the anticonvulsant action of novel antiepileptic drugs against maximal electroshock-induced seizures in mice.

    PubMed

    Zolkowska, Dorota; Kondrat-Wrobel, Maria W; Florek-Luszczki, Magdalena; Luszczki, Jarogniew J

    2016-02-04

    The aim of this study was to determine the effects of 2-methyl-6-(phenylethynyl)pyridine (MPEP - a selective antagonist for the glutamate metabotropic receptor subtype mGluR5) on the protective action of some novel antiepileptic drugs (lamotrigine, oxcarbazepine, pregabalin and topiramate) against maximal electroshock-induced seizures in mice. Brain concentrations of antiepileptic drugs were measured to determine whether MPEP altered pharmacokinetics of antiepileptic drugs. Intraperitoneal injection of 1.5 and 2mg/kg of MPEP significantly elevated the threshold for electroconvulsions in mice, whereas MPEP at a dose of 1mg/kg considerably enhanced the anticonvulsant activity of pregabalin and topiramate, but not that of lamotrigine or oxcarbazepine in the maximal electroshock-induced seizures in mice. Pharmacokinetic results revealed that MPEP (1mg/kg) did not alter total brain concentrations of pregabalin and topiramate, and the observed effect in the mouse maximal electroshock seizure model was pharmacodynamic in nature. Collectively, our preclinical data suggest that MPEP may be a safe and beneficial adjunct to the therapeutic effects of antiepileptic drugs in human patients. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Actions of Agonists and Antagonists of the ghrelin/GHS-R Pathway on GH Secretion, Appetite, and cFos Activity

    PubMed Central

    Hassouna, Rim; Labarthe, Alexandra; Zizzari, Philippe; Videau, Catherine; Culler, Michael; Epelbaum, Jacques; Tolle, Virginie

    2012-01-01

    The stimulatory effects of ghrelin, a 28-AA acylated peptide originally isolated from stomach, on growth hormone (GH) secretion and feeding are exclusively mediated through the growth hormone secretagogue 1a receptor (GHS-R1a), the only ghrelin receptor described so far. Several GHS-R1a agonists and antagonists have been developed to treat metabolic or nutritional disorders but their mechanisms of action in the central nervous system remain poorly understood. In the present study, we compared the activity of BIM-28163, a GHS-R1a antagonist, and of several agonists, including native ghrelin and the potent synthetic agonist, BIM-28131, to modulate food intake, GH secretion, and cFos activity in arcuate nucleus (ArcN), nucleus tractus solitarius (NTS), and area postrema (AP) in wild-type and NPY-GFP mice. BIM-28131 was as effective as ghrelin in stimulating GH secretion, but more active than ghrelin in inducing feeding. It stimulated cFos activity similarly to ghrelin in the NTS and AP but was more powerful in the ArcN, suggesting that the super-agonist activity of BIM-28131 is mostly mediated in the ArcN. BIM-28163 antagonized ghrelin-induced GH secretion but not ghrelin-induced food consumption and cFos activation, rather it stimulated food intake and cFos activity without affecting GH secretion. The level of cFos activation was dependent on the region considered: BIM-28163 was as active as ghrelin in the NTS, but less active in the ArcN and AP. All compounds also induced cFos immunoreactivity in ArcN NPY neurons but BIM-28131 was the most active. In conclusion, these data demonstrate that two peptide analogs of ghrelin, BIM-28163, and BIM-28131, are powerful stimulators of appetite in mice, acting through pathways and key brain regions involved in the control of appetite that are only partially superimposable from those activated by ghrelin. A better understanding of the molecular pathways activated by these compounds could be useful in devising future therapeutic

  3. Antimuscarinic, calcium channel blocker and tachykinin NK2 receptor antagonist actions of otilonium bromide in the circular muscle of guinea-pig colon.

    PubMed

    Santicioli, P; Zagorodnyuk, V; Renzetti, A R; Maggi, C A

    1999-05-01

    ]substance P-sulphone and [betaAla8]neurokinin A (4-10) (IC50 60 microM and 54 microM, respectively). In radioligand binding experiments otilonium bromide produced a concentration-dependent inhibition of the binding of both an agonist ([125I]neurokinin A, Ki 7.2 microM) and an antagonist ([3H]SR 48968, Ki 2.2 microM) to membranes of Chinese hamster ovary cells transfected with the human tachykinin NK2 receptor. In conclusion, the present findings demonstrate that, in the microM range of concentrations, otilonium bromide acts as a muscarinic and tachykinin NK2 receptor antagonist and as a calcium channel blocker. The latter property is likely to account for its ability to suppress contraction initiated by the tachykinin NK1 receptor agonist. Therefore multiple mechanisms of action account for the ability of otilonium bromide to reduce stimulated motility of intestinal smooth muscle.

  4. Kisspeptin antagonists.

    PubMed

    Roseweir, Antonia Kathryn; Millar, Robert P

    2013-01-01

    Kisspeptin is now known to be an important regulator of the hypothalamic--pituitary-gonadal axis and is the target of a range of regulators, such as steroid hormone feedback, nutritional and metabolic regulation. Kisspeptin binds to its cognate receptor, KISS1R (also called GPR54), on GnRH neurons and stimulates their activity, which in turn provides an obligatory signal for GnRH secretion-thus gating down-stream events supporting reproduction. The development of peripherally active kisspeptin antagonists could offer a unique therapeutic agent for treating hormone-dependent disorders of reproduction, including precocious puberty, endometriosis, and metastatic prostate cancer. The following chapter discusses the advances made in the search for both peptide and small molecule kisspeptin antagonists and their use in delineating the role of kisspeptin within the reproductive system. To date, four peptide antagonists and one small molecule antagonist have been designed.

  5. 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)

  6. 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)

  7. Spinal muscular atrophy

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/000996.htm Spinal muscular atrophy To use the sharing features on this page, please enable JavaScript. Spinal muscular atrophy is a group of disorders of the motor ...

  8. Spinal Muscular Atrophy (SMA)

    MedlinePlus

    ... Habits for TV, Video Games, and the Internet Spinal Muscular Atrophy (SMA) KidsHealth > For Parents > Spinal Muscular Atrophy (SMA) Print ... treatment for the disease's most troubling symptoms. About SMA Normally, healthy nerve cells in the brain called ...

  9. Different action of a specific NR2B/NMDA antagonist Ro 25-6981 on cortical evoked potentials and epileptic afterdischarges in immature rats.

    PubMed

    Szczurowska, Ewa; Mareš, Pavel

    2015-02-01

    . The modification of ADs, i.e. stimulations with stepwise increasing intensities (10 min intervals) was used to demonstrate possible dependence on activity. The Ro 25-6981 was administered immediately after the 4-mA stimulation (i.e. when rats experienced six ADs on the average). The 3-mg/kg dose resulted in shorter ADs after high stimulation intensities in P12. There were no significant effects in older animals, only a tendency to ADs shortening was observed in P25 rats. In conclusion, our results indicate that Ro 25-6981 as a selective antagonist of NR2B/NMDARs exhibit age- and activation-dependent anticonvulsant action at early postnatal development. In contrast, the influence of Ro 25-6981 on physiological excitability induced by single pulse stimulation of sensorimotor cortex does not depend on age. This compound may thus represent a useful antiepileptic agent in immature brain since its action against ADs prolongation can be observed even 110 min after the single administration of the drug.

  10. Meaning of Muscular Dystrophy

    MedlinePlus

    ... MD Living With MD en español Qué significa distrofia muscular What Is Muscular Dystrophy? Muscular dystrophy (say: MUS- ... blood test if a kid has Becker or Duchenne MD. Or the doctor might take a small piece of the muscle and look at it under a microscope to ...

  11. [Updates in muscular dystrophies].

    PubMed

    Erazo-Torricelli, R

    Advances in molecular genetics on lasts 15 years had modified profoundly our knowledge about muscular dystrophies. The pathogenia, caused by defectives proteins which disrupt dystrophin-associated-protein complex in most of the dystrophies, has generate a new classification based in protein and genomic defects. In this review, clinical, genetic, diagnostic and therapeutic aspects of the main muscular dystrophies are described. Limb girdle muscular dystrophies with Duchenne-like phenotype (sarcoglycanopathies), are identified by immunohistochemistry, as X-linked Emery-Dreifuss muscular dystrophy (emerin deficit), and classical congenital muscular dystrophy (merosine depletion). The others limb girdle muscular dystrophies, an heterogeneous phenotypical group, are detected by Western blot (mainly calpainopathies), or inmunohistochemistry in muscle (caveolinopathies) and blood (dysferlinopathies). Congenital muscular dystrophies with brain malformations: Fukuyama, muscle-eye-brain, and Walker-Warburg syndrome; and fukutin-related protein dystrophy, only may be differentiated by genetic analysis. All them shows alpha-dystroglican depletion. Autosomal dominant Emery-Dreifuss muscular dystrophy and facioscapulohumeral dystrophy are exclusively identified by DNA study. Finally, Duchenne/Becker muscular dystrophies are diagnosed by immunohistochemistry, Western blot and/or DNA analysis. Treatment of muscular dystrophies is based in physiotherapy, ventilatory support, surgery and drugs (mainly steroids, effective in Duchenne/Becker muscular dystrophies). Genic and cellular therapy are yet on experimental field, and are matter of the future. Now, accurate diagnosis is important for therapeutic management, prognosis and genetic counseling.

  12. Statistical insights into major human muscular diseases.

    PubMed

    Gupta, Shakti; Kim, Sung-Min; Wang, Yu; Dinasarapu, Ashok Reddy; Subramaniam, Shankar

    2014-07-15

    Muscular diseases lead to muscle fiber degeneration, impairment of mobility, and in some cases premature death. Many of these muscular diseases are largely idiopathic. The goal of this study was to identify biomarkers based on their functional role and possible mechanisms of pathogenesis, specific to individual muscular disease. We analyzed the muscle transcriptome from five major muscular diseases: acute quadriplegic myopathy (AQM), amyotrophic lateral sclerosis (ALS), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), dermatomyositis (DM) and polymyositis (PM) using pairwise statistical comparison to identify uniquely regulated genes in each muscular disease. The genome-wide information encoded in the transcriptome provided biomarkers and functional insights into dysregulation in each muscular disease. The analysis showed that the dysregulation of genes in forward membrane pathway, responsible for transmitting action potential from neural excitation, is unique to AQM, while the dysregulation of myofibril genes, determinant of the mechanical properties of muscle, is unique to ALS, dysregulation of ER protein processing, responsible for correct protein folding, is unique to DM, and upregulation of immune response genes is unique to PM. We have identified biomarkers specific to each muscular disease which can be used for diagnostic purposes.

  13. The effect of the DcpS inhibitor D156844 on the protective action of follistatin in mice with spinal muscular atrophy.

    PubMed

    Harris, Ashlee W; Butchbach, Matthew E R

    2015-09-01

    Spinal muscular atrophy (SMA), a leading genetic cause of pediatric death in the world, is an early-onset disease affecting the motor neurons in the anterior horn of the spinal cord. This degeneration of motor neurons leads to loss of muscle function. At the molecular level, SMA results from the loss of or mutation in the survival motor neuron 1 (SMN1) gene. The number of copies of the nearly duplicated gene SMN2 modulates the disease severity in humans as well as in transgenic mouse models for SMA. Most preclinical therapeutic trials focus on identifying ways to increase SMN2 expression and to alter its splicing. Other therapeutic strategies have investigated compounds which protect affected motor neurons and their target muscles in an SMN-independent manner. In the present study, the effect of a combination regimen of the SMN2 inducer D156844 and the protectant follistatin on the disease progression and survival was measured in the SMNΔ7 SMA mouse model. The D156844/follistatin combination treatment improved the survival of, delayed the end stage of disease in and ameliorated the growth rate of SMNΔ7 SMA mice better than follistatin treatment alone. The D156844/follistatin combination treatment, however, did not provide additional benefit over D156844 alone with respect to survival and disease end stage even though it provided some additional therapeutic benefit over D156844 alone with respect to motor phenotype. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. 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

  15. Differential modulatory actions of GABAA agonists on susceptibility to GABAA antagonists-induced seizures in morphine dependent rats: possible mechanisms in seizure propensity.

    PubMed

    Joukar, Siyavash; Atapour, Nafiseh; Kalantaripour, Tajpari; Bashiri, Hamideh; Shahidi, Alireza

    2011-07-01

    In order to clarify the mechanisms involved in the susceptibility to GABA(A) antagonists-induced seizures in morphine dependent rats, we investigated how GABA(A) agonists modulate this vulnerability. Seizures were induced to animals by infusion of GABA(A) antagonists: pentylenetetrazole (PTZ), picrotoxin (PIC) and bicuculline (BIC). GABA(A) agonists, muscimol (MUS) and 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridin-3-ol (THIP), were administered intravenous (i.v.) before antagonists. Morphine-dependence significantly decreased the PTZ threshold dose (19.16±1.89 versus 25.74±1.25mg/kg) while, it had no effect on PIC induced seizures. BIC doses for both threshold and tonic-clonic seizures induction were significantly lower in morphine dependent rats (0.10±0.01 and 0.12±0.02 versus 0.25±0.02 and 0.39±0.07mg/kg respectively). In morphine-dependence, although pre-treatment with MUS significantly increased the required dose of PTZ for seizures threshold, THIP significantly decreased the required dose of PTZ for tonic-clonic convulsion. Moreover, MUS pretreatment completely recovered the effect of morphine dependency on BIC seizure activity. The results suggest that the capability of GABA(A) agonists on modulation of propensity to seizures induced by different antagonists in morphine-dependence is dissimilar. Therefore, it seems that long-term morphine alters some properties of GABA system so that the responsive rate of GABA(A) receptors not only to its antagonists, but also to its agonists will change differently.

  16. Regulation of vascular tone and pulse wave velocity in human muscular conduit arteries: selective effects of nitric oxide donors to dilate muscular arteries relative to resistance vessels.

    PubMed

    Fok, Henry; Jiang, Benyu; Clapp, Brian; Chowienczyk, Phil

    2012-11-01

    Arterial tone in muscular conduit arteries may influence pressure wave reflection through changes in diameter and pulse wave velocity. We examined the relative specificity of vasodilator drugs for radial artery and forearm resistance vessels during intrabrachial arterial infusion. The nitric oxide (NO) donors, nitroglycerine and nitroprusside, and brain natriuretic peptide were compared with the α-adrenergic antagonist phentolamine, calcium-channel antagonist verapamil, and hydralazine. Radial artery diameter was measured by high resolution ultrasound, forearm blood flow by strain gauge plethysmography, and pulse wave velocity by pressure recording cuffs placed over the distal brachial and radial arteries. Norepinephrine was used to constrict the radial artery to generate a greater range of vasodilator tone when examining pulse wave velocity. Despite dilating resistance vasculature, phentolamine and verapamil had little effect on radial artery diameter (mean dilation <9%). By contrast, for comparable actions on resistance vessels, nitroglycerine and nitroprusside but not brain natriuretic peptide had powerful actions to dilate the radial artery (dilations of 31.3 ± 3.6%, 23.6 ± 3.1%, and 9.8 ± 2.0% for nitroglycerine, nitroprusside, and brain natriuretic peptide, respectively). Changes in pulse wave velocity followed those in arterial diameter irrespective of the signaling pathway used to modulate arterial tone (R=-0.89, P<0.05). Basal tone in human muscular arteries is relatively unaffected by α-adrenergic or calcium-channel blockade, but is functionally or directly antagonized by NO donors. The differential response to NO donors suggests that there is potential to manipulate the downstream pathway to confer greater specificity for large arteries with a resultant decrease in pressure wave reflection and systolic blood pressure.

  17. [Respiratory management in muscular dystrophies].

    PubMed

    Kuru, Satoshi

    2011-11-01

    Respiratory failure is a major contributor to immobility and mortality in progressive muscular dystrophies. The severity of pulmonary impairment and the stage at which it develops differ according to the type of muscular dystrophy. Appropriate respiratory management for each type should be considered. In Duchenne muscular dystrophy (DMD), respiratory impairment manifests in the late teens, and assisted mechanical ventilation is administered. Noninvasive positive-pressure ventilation (NIPPV) has increased the median survival of patients with DMD by 10 year and improved quality of life. In myotonic dystrophy (MyD), the causes of respiratory failure can involve both the central and the peripheral nervous systems in addition to respiratory muscles. Nocturnal desaturation is more severe in MyD than in other muscular dystrophies with similar degrees of respiratory muscle weakness. Cognitive impairment should be taken into account in the management of MyD patients. NIPPV does not appear to improve survival of MyD. Guidelines for DMD have been published. Respiratory function should be assessed serially by measuring forced vital capacity, oxyhemoglobin saturation, peak cough flow, and end-tidal CO2 level. A respiratory action plan should be enacted with increasing disease severity. Therapeutic measures comprise airway clearance, respiratory muscle training, noninvasive nocturnal ventilation, daytime noninvasive ventilation, and continuous invasive ventilation. At the advanced stage of respiratory failure, attention should be paid to complications related to long-term mechanical ventilation, such as pneumothorax and tracheal hemorrhage. Discussing about end-of-life care among the patient, family, and physician is important before mechanical ventilatory support is required.

  18. Comparison of mechanisms of action of luteinizing hormone-releasing hormone (LHRH) antagonist cetrorelix and LHRH agonist triptorelin on the gene expression of pituitary LHRH receptors in rats

    PubMed Central

    Kovacs, Magdolna; Schally, Andrew V.

    2001-01-01

    The mechanisms through which luteinizing hormone (LH)-releasing hormone (LHRH) antagonists suppress pituitary gonadotroph functions and LHRH-receptor (LHRH-R) expression are incompletely understood. Consequently, we investigated the direct effect of LHRH antagonist cetrorelix in vitro on the expression of the pituitary LHRH-R gene and its ability to counteract the exogenous LHRH and the agonist triptorelin in the regulation of this gene. We also compared the effects of chronic administration of cetrorelix and triptorelin on the LHRH-R mRNA level and gonadotropin secretion in ovariectomized (OVX) and normal female rats. The exposure of pituitary cells in vitro to 3-min pulses of 1 nM LHRH or 0.1 nM triptorelin for 5 h increased the LHRH-R mRNA level by 77–88%. Continuous perfusion of the cells with 50 nM cetrorelix did not cause any significant changes, but prevented the stimulatory effect of LHRH pulses on the receptor mRNA expression. In OVX rats, 10 days after administration of a depot formulation of cetrorelix, releasing 100 μg of peptide daily, the elevated LHRH-R mRNA level was decreased by 73%, whereas daily injection of 100 μg of triptorelin caused a 41% suppression. In normal female rats, cetrorelix treatment suppressed the LHRH-R mRNA level by 33%, but triptorelin increased it by 150%. The highly elevated serum LH levels in OVX rats and the normal LH concentration of cycling rats were rapidly and completely suppressed by cetrorelix. Triptorelin decreased the serum LH in OVX rats to the precastration level, but had no effect on basal LH in normal rats. Our results confirm that LHRH antagonists, such as cetrorelix, inhibit the gene expression of pituitary LHRH-R indirectly, by counteracting the stimulatory effect of LHRH. A rapid suppression of serum LH by LHRH antagonists would be advantageous in the treatment of sex hormone-dependent tumors and other conditions. PMID:11593037

  19. Preparation of leptin antagonists by site-directed mutagenesis of human, ovine, rat, and mouse leptin's site III: implications on blocking undesired leptin action in vivo.

    PubMed

    Solomon, Gili; Niv-Spector, Leonora; Gonen-Berger, Dana; Callebaut, Isabelle; Djiane, Jean; Gertler, Arieh

    2006-12-01

    Six muteins of human, ovine, rat, and mouse leptins mutated to Ala in amino acids 39-41 or 39-42 were prepared by site-directed mutagenesis of the putative site III, which does not affect binding but is necessary for receptor activation, then expressed, solubilized in 4.5 M urea, at pH 11.3 in presence of cysteine, refolded and purified to homogeneity by anion-exchange chromatography on Q-Sepharose or combination of anion-exchange chromatography followed by gel filtration. The overall yields were 400-800 mg from 5 L of fermentation. All proteins were >98% pure as evidenced by SDS-PAGE and contained at least 95% monomers as documented by gel-filtration chromatography under nondenaturing conditions. Circular dichroism analysis revealed that all six muteins have identical secondary structure characteristic of nonmutated leptins, namely 52-63% of alpha helix content. All muteins formed a 1:1 complex with chicken leptin binding domain, (chLBD) and bound chLBD or membrane-embedded leptin receptor with affinity identical to WT leptins. Muteins were devoid of any biological activity in several bioassays but were potent competitive antagonists. Some muteins were pegylated using 40 kDa PEG. Although pegylation decreased the in vitro activity, increasing circulation half-life can recompensate this deficit, so pegylated antagonists are expected to be more potent in vivo.

  20. 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

  1. Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Registry

    ClinicalTrials.gov

    2017-08-11

    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

  2. Short Communication: Inhibition of DC-SIGN-Mediated HIV-1 Infection by Complementary Actions of Dendritic Cell Receptor Antagonists and Env-Targeting Virus Inactivators.

    PubMed

    Pustylnikov, Sergey; Dave, Rajnish S; Khan, Zafar K; Porkolab, Vanessa; Rashad, Adel A; Hutchinson, Matthew; Fieschi, Frank; Chaiken, Irwin; Jain, Pooja

    2016-01-01

    The DC-SIGN receptor on human dendritic cells interacts with HIV gp120 to promote both infection of antigen-presenting cells and transinfection of T cells. We hypothesized that in DC-SIGN-expressing cells, both DC-SIGN ligands such as dextrans and gp120 antagonists such as peptide triazoles would inhibit HIV infection with potential complementary antagonist effects. To test this hypothesis, we evaluated the effects of dextran (D66), isomaltooligosaccharides (D06), and several peptide triazoles (HNG156, K13, and UM15) on HIV infection of B-THP-1/DC-SIGN cells. In surface plasmon resonance competition assays, D66 (IC50 = 35.4 μM) and D06 (IC50 = 3.4 mM) prevented binding of soluble DC-SIGN to immobilized mannosylated bovine serum albumin (BSA). An efficacious dose-dependent inhibition of DC-SIGN-mediated HIV infection in both pretreatment and posttreatment settings was observed, as indicated by inhibitory potentials (EC50) [D66 (8 μM), D06 (48 mM), HNG156 (40 μM), UM15 (100 nM), and K13 (25 nM)]. Importantly, both dextrans and peptide triazoles significantly decreased HIV gag RNA levels [D66 (7-fold), D06 (13-fold), HNG156 (7-fold), K-13 (3-fold), and UM15 (6-fold)]. Interestingly, D06 at the highest effective concentration showed a 14-fold decrease of infection, while its combination with 50 μM HNG156 showed a 26-fold decrease. Hence, these compounds can combine to inactivate the viruses and suppress DC-SIGN-mediated virus-cell interaction that as shown earlier leads to dendritic cell HIV infection and transinfection dependent on the DC-SIGN receptor.

  3. Levobetaxolol (Betaxon) and other beta-adrenergic antagonists: preclinical pharmacology, IOP-lowering activity and sites of action in human eyes.

    PubMed

    Sharif, N A; Xu, S X; Crider, J Y; McLaughlin, M; Davis, T L

    2001-08-01

    The pharmacological characteristics of levobetaxolol, a single active isomer of betaxolol, were determined and compared with activities of other beta-adrenoceptor antagonists. Levobetaxolol (43-fold beta1-selective) exhibited a higher affinity at cloned human beta1 (Ki = 0.76 nM) than at beta2 (Ki = 32.6 nM) receptors, while dextrobetaxolol was much weaker at both receptors. Levobetaxolol potently antagonized functional activities at cloned human beta1 and beta2 receptors, and also at guinea pig atrial beta1, tracheal beta2 and rat colonic beta3 receptors (IC50s = 33.2 nM, 2970 nM and 709 nM, respectively). Thus, levobetaxolol was 89-times beta1-selective (vs beta2). Levobetaxolol (Ki = 16.4 nM) was more potent than dextrobetaxolol (Ki = 2.97 microM) at inhibiting isoproterenol-induced cAMP production in human non-pigmented ciliary epithelial cells. Levobunolol and (l)-timolol had high affinities at beta1 and beta2 receptors but were considerably less beta1-selective than levobetaxolol. Levo-, dextro- and racemic-betaxolol exhibited little or no affinity, except at sigma sites and Ca2+-channels (IC50s > 1 microM), at 89 other receptor/ligand binding sites. Levobetaxolol exhibited a micromolar affinity for L-type Ca2+-channels. In conscious ocular hypertensive cynomolgus monkeys, levobetaxolol was more potent than dextrobetaxolol, reducing intraocular pressure by 25.9+/-3.2% at a dose of 150 microg/eye (n = 15-30). Quantitative [3H]-levobetaxolol autoradiography revealed high levels of binding to human ciliary processes, iris, choroid/retina, and ciliary muscles. In conclusion, levobetaxolol is a potent, high affinity and beta1-selective IOP-lowering beta-adrenoceptor antagonist.

  4. Renal actions of endothelin-1 in newborn piglets: dose-effect relation and the effects of receptor antagonist (BQ-123) and cyclooxygenase inhibitor (indomethacin).

    PubMed

    Bhat, R; John, E; Chari, G; Shankararao, R; Fornell, L; Gulati, A; Vidyasagar, D

    1995-11-01

    Although the effects of endothelin-1 (ET-1) on intact or perfused adult kidney are well understood, its effects in the fetus and the newborn have not been well studied. We examined the effects of infusions of 25, 50, and 100 ng/kg of ET-1 per minute on mean blood pressure (MBP), cardiac index (CI), renal blood flow (RBF), glomerular filtration rate (GFR), and urine volume (UV) in 7- to 10-day-old piglets (n = 24). In addition, the effects of pretreatment with a receptor antagonist (BQ-123) and with a cyclooxygenase inhibitor (indomethacin) were studied in 12 separate piglets. ET-1 produced a dose- and level-dependent decrease in CI (60%), RBF (50% to 75%), GFR (66% to 80%) and MBP 15% to 17%. These changes returned to 75% to 80% of baseline 60 minutes after discontinuation of ET-1. Low-dose infusion (25 ng/kg) did not result in any changes in systemic or renal hemodynamics. Plasma half-life of ET-1 in piglets was 2.1 +/- 0.4 minutes. Pretreatment with the specific ETA receptor antagonist BQ-123 completely blocked the ET-1-induced systemic and renal hemodynamic changes. Indomethacin blocked the ET-1-induced rise in MBP but failed to block any renal changes. In fact, indomethacin accentuated the changes induced by ET-1, especially the changes in RBF, RVR, and GFR. Studies of receptor binding in the renal cortex and medulla showed that, in the cortex, the Ki value for ET-1 was 6.32 +/- 1.57, and for ET-3 it was 20.05 +/- 4.38 (p < 0.05); in the medulla, the Ki values were similar for both ET-1 and ET-3. These results indicate that in piglets the renal vascular bed is highly sensitive to ET-1, and its effects are predominantly mediated through ETA receptors.

  5. 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

  6. Insights into the influence of 5-HT2c aminoacidic variants with the inhibitory action of serotonin inverse agonists and antagonists.

    PubMed

    Galeazzi, Roberta; Massaccesi, Luca; Piva, Francesco; Principato, Giovanni; Laudadio, Emilioano

    2014-03-01

    Specific modulation of serotonin 5-HT(2C) G protein-coupled receptors may be therapeutic for obesity and neuropsychiatric disorders. The different efficacy of drugs targeting these receptors are due to the presence of genetic variants in population and this variability is still hard to predict. Therefore, in order to administer the more suitable drug, taking into account patient genotype, it is necessary to know the molecular effects of its gene nucleotide variations. In this work, starting from an accurate 3D model of 5-HT(2C), we focus on the prediction of the possible effect of some single nucleotide polymorphisms (SNPs) producing amino acidic changes in proximity of the 5-HT(2C) ligand binding site. Particularly we chose a set of 5-HT(2C) inverse agonists and antagonists which have high inhibitory activity. After prediction of the structures of the receptor-ligand complexes using molecular docking tools, we performed full atom molecular dynamics simulations in explicit lipid bilayer monitoring the interactions between ligands and trans-membrane helices of the receptor, trying to infer relations with their biological activity. Serotonin, as the natural ligand was chosen as reference compound to advance a hypothesis able to explain the receptor inhibition mechanism. Indeed we observed a different behavior between the antagonists and inverse agonist with respect to serotonin or unbounded receptor, which could be responsible, even if not directly, of receptor's inactivation. Furthermore, we analyzed five aminoacidic variants of 5HT(2C) receptor observing alterations in the interactions between ligands and receptor which give rise to changes of free energy values for every complex considered.

  7. Effect of the non peptide angiotensin II antagonist, GR117289C on the vasoconstrictor actions of angiotensin II in the human forearm

    PubMed Central

    Lyons, D.; Webster, J.; Nixon, A.; Young, M. M. R.; Smith, J.; Benjamin, N.

    1997-01-01

    AIMS: GR117289C is a non peptide, selective angiotensin (AT1) receptor antagonist. The purpose of this study was to determine whether this agent, given orally, could attenuate the vasoconstrictor effects of angiotensin II(AII) infused locally into the forearm circulation in man. METHODS: Eight healthy male subjects were studied on four occasions in a randomized, double-blind, placebo controlled, crossover study. Five hours (approximate time of peak dynamic effect) following dosing with GR117289C (300 mg, 100 mg, 10 mg or placebo), A II was infused in incremental doses (0, 0.1, 0.4, 1.6, 6.2, 25 and 100 pmol min-1) into the left brachial artery, each for 10 min. Forearm blood flow was measured using venous occlusion plethysmography. RESULTS: GR117289C inhibits the vasoconstrictor effects of A II in a dose dependent manner. The active treatment: placebo ratios of forearm blood flow in the infused arm during the highest dose of AII (100 pmol min-1) were: GR117289C 10 mg, 1.12 (95% C.I. 0.81-1.55; P = 0.478), 100 mg, 1.43 (95% C.I. 1.01-2.01; P = 0.042) and 300 mg, 1.62 (95% C.I. 1.17-2.24; P = 0.006). There was no significant difference in blood pressure between each of the treatment groups and placebo. CONCLUSIONS: GR117289C is a pharmacologically active, oral A II antagonist in healthy men. PMID:9088589

  8. Evidence for an extra-abdominal site of action for the 5-HT3 receptor antagonist BRL24924 in the inhibition of radiation-evoked emesis in the ferret.

    PubMed

    Andrews, P L; Hawthorn, J

    1987-09-01

    Recent studies have implicated 5-HT3(5-HT-M) receptors in the genesis of retching and vomiting evoked by antineoplastic agents. Such receptors have so far only been located peripherally, notably on the vagus. Therefore, the effects of bilateral abdominal vagotomy and antagonism of 5-HT3 receptors have been investigated on retching and vomiting induced by radiation. The gastrokinetic substituted benzamide BRL24924, (Beecham Pharmaceuticals) which has 5-HT3 receptor antagonist properties, was used. Using the ferret, it was shown that whole body x-radiation produced retching and vomiting, which was most severe during the 30 min following irradiation, and continued for at least 90 min. Abdominal vagotomy almost totally abolished the retching and vomiting, occurring during the 30 min immediately after irradiation. The following 60 min period was similar to that of control animals. This would suggest that the emetic events can be divided into a vagally-dependent and independent phase. In a small dose, BRL 24924 mimicked abdominal vagtotomy, in a larger dose, it almost totally abolished the retching and vomiting throughout the entire 90 min period. These results suggest that 5-HT3 receptor antagonists are capable of ameliorating radiation-induced retching and vomiting and that, while an important site of their action could be the abdominal vagi, other areas are probably also involved.

  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.

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

    PubMed Central

    Kinnaird, Catherine R.; Ferris, Daniel P.

    2013-01-01

    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

  11. Antagonistic action on NMDA/GluN2B mediated currents of two peptides that were conantokin-G structure-based designed.

    PubMed

    Reyes-Guzman, Edwin A; Vega-Castro, Nohora; Reyes-Montaño, Edgar A; Recio-Pinto, Esperanza

    2017-05-16

    The GluN2B subunit of the N-methyl-D-aspartate receptor (NMDAr) modulates many physiological processes including learning, memory, and pain. Excessive increase in NMDAr/GluN2B activity has been associated with various disorders such neuropathic pain and neuronal death following hypoxia. Thus there is an interest in identifying NMDAr antagonists that interact specifically with the GluN2B subunit. Recently based on structural analysis between the GluN2B subunit and conantokin-G, a toxin that interacts selectively with the GluN2B subunit, we designed various peptides that are predicted to act as NMDAr antagonists by interacting with the GluN2B subunit. In this study we tested this prediction for two of these peptides EAR16 and EAR18. The effects of EAR16 and EAR18 in NMDA-evoked currents were measured in cultured rat embryonic hippocampal neurons and in HEK-293 cells expressing recombinant NMDAr comprised of GluN1a-GluN2A or GluN1a-GluN2B subunits. In hippocampal neurons, EAR16 and EAR18 reduced the NMDA-evoked calcium currents in a dose-dependent and reversible manner with comparable IC50 (half maximal inhibitory concentration) values of 241 and 176 µM, respectively. At 500 µM, EAR16 blocked more strongly the NMDA-evoked currents mediated by the GluN1a-GluN2B (84%) than those mediated by the GluN1a-GluN2A (50%) subunits. At 500 µM, EAR18 blocked to a similar extent the NMDA-evoked currents mediated by the GluN1a-GluN2B (62%) and the GluN1a-GluN2A (55%) subunits. The newly designed EAR16 and EAR18 peptides were shown to block in reversible manner NMDA-evoked currents, and EAR16 showed a stronger selectivity for GluN2B than for GluN2A.

  12. Rapid and Sustained Antidepressant Action of the mGlu2/3 Receptor Antagonist MGS0039 in the Social Defeat Stress Model: Comparison with Ketamine

    PubMed Central

    Dong, Chao; Zhang, Ji-chun; Yao, Wei; Ren, Qian; Ma, Min; Yang, Chun; Chaki, Shigeyuki

    2017-01-01

    Abstract Background: Similar to the N-methyl-D-aspartate receptor antagonist ketamine, the metabotropic glutamate 2/3 receptor antagonist, MGS0039, shows antidepressant effects. However, there are no reports comparing these 2 compounds in the social defeat stress model of depression. Methods: We examined the effects of MGS0039 (1 mg/kg) and ketamine (10 mg/kg) on depression-like behavior in susceptible mice after repeated social defeat stress. Protein levels of brain-derived neurotrophic factor, TrkB, phospho-TrkB, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (GluA1), postsynaptic density protein 95, and dendritic spine density in selected brain regions were measured. Results: In the tail suspension and forced swimming tests, both MGS0039 and ketamine significantly attenuated the increased immobility time observed in susceptible mice, compared with vehicle-treated animals, 1 or 2 days after a single dose of drug. In the sucrose preference test, both compounds significantly improved the reduced preference typically seen in susceptible mice at 3 to 7 days after a single dose of drug. Western-blot analyses showed that similar to ketamine, MGS0039 significantly attenuated the reduced brain-derived neurotrophic factor, phospho-TrkB/TrkB ratio, GluA1 and postsynaptic density protein 95 seen in the prefrontal cortex, dentate gyrus, and CA3 of the hippocampus from susceptible mice, 8 days after a single dose. Again, in a similar manner to ketamine, MGS0039 significantly attenuated the reduction of spine density in the prelimbic regions of the medial prefrontal cortex, dentate gyrus, and CA3 of the hippocampus, but not infralimbic regions of the medial prefrontal cortex and CA1, in susceptible mice 8 days after a single dose. In contrast, neither drug elicited an effect on altered brain-derived neurotrophic factor-TrkB signaling, GluA1, and postsynaptic density protein 95 levels and did not increase spine density observed in the nucleus accumbens of

  13. Soluble interleukin-1 receptor accessory protein ameliorates collagen-induced arthritis by a different mode of action from that of interleukin-1 receptor antagonist.

    PubMed

    Smeets, R L; Joosten, L A B; Arntz, O J; Bennink, M B; Takahashi, N; Carlsen, H; Martin, M U; van den Berg, W B; van de Loo, F A J

    2005-07-01

    To discern the mode of interleukin-1 (IL-1) inhibition of soluble IL-1 receptor accessory protein (sIL-1RAcP) by comparison with IL-1 receptor antagonist (IL-1Ra) in arthritis. Adenoviral vectors encoding either sIL-1RAcP or IL-1Ra were administered systemically before onset of collagen-induced arthritis in DBA/1 mice. Anti-bovine type II collagen IgG and IL-6 were quantified in serum. Proliferative response of splenic T cells was determined in the presence of sIL-1RAcP or IL-1Ra. The effect on IL-1 inhibition of recombinant sIL-1RAcP and IL-1Ra was further examined in vitro, using NF-kappaB luciferase reporter cell lines. Quantitative polymerase chain reaction was used to determine the relative messenger RNA expression of the IL-1 receptors. Adenoviral overexpression of both sIL-1RAcP and IL-1Ra resulted in amelioration of the collagen-induced arthritis. Both IL-1 antagonists reduced the circulating levels of antigen-specific IgG2a antibodies, but only IL-1Ra was able to inhibit lymphocyte proliferation. By using purified lymphocyte populations derived from NF-kappaB reporter mice, we showed that sIL-1RAcP inhibits IL-1-induced NF-kappaB activity in B cells but not T cells, whereas IL-1Ra inhibited IL-1 on both cell types. A study in a panel of NF-kappaB luciferase reporter cells showed that the sIL-1RAcP inhibits IL-1 signaling on cells expressing either low levels of membrane IL-1RAcP or high levels of IL-1RII. We show that the sIL-1RAcP ameliorated experimental arthritis without affecting T cell immunity, in contrast to IL-1Ra. Our results provide data in support of receptor competition by sIL-1RAcP as an explanation for the different mode of IL-1 antagonism in comparison with IL-1Ra.

  14. A Negative Allosteric Modulator for α5 Subunit-Containing GABA Receptors Exerts a Rapid and Persistent Antidepressant-Like Action without the Side Effects of the NMDA Receptor Antagonist Ketamine in Mice

    PubMed Central

    Nelson, Mackenzie E.; Krimmel, Samuel R.; Georgiou, Polymnia; Gould, Todd D.

    2017-01-01

    Abstract New antidepressant pharmacotherapies that provide rapid relief of depressive symptoms are needed. The NMDA receptor antagonist ketamine exerts rapid antidepressant actions in depressed patients but also side effects that complicate its clinical utility. Ketamine promotes excitatory synaptic strength, likely by producing high-frequency correlated activity in mood-relevant regions of the forebrain. Negative allosteric modulators of GABA-A receptors containing α5 subunits (α5 GABA-NAMs) should also promote high-frequency correlated electroencephalogram (EEG) activity and should therefore exert rapid antidepressant responses. Because α5 subunits display a restricted expression in the forebrain, we predicted that α5 GABA-NAMs would produce activation of principle neurons but exert fewer side effects than ketamine. We tested this hypothesis in male mice and observed that the α5 GABA-NAM MRK-016 exerted an antidepressant-like response in the forced swim test at 1 and 24 h after administration and an anti-anhedonic response after chronic stress in the female urine sniffing test (FUST). Like ketamine, MRK-016 produced a transient increase in EEG γ power, and both the increase in γ power and its antidepressant effects in the forced swim test were blocked by prior administration of the AMPA-type glutamate receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX). Unlike ketamine, however, MRK-016 produced no impairment of rota-rod performance, no reduction of prepulse inhibition (PPI), no conditioned-place preference (CPP), and no change in locomotion. α5 GABA-NAMs, thus reproduce the rapid antidepressant-like actions of ketamine, perhaps via an AMPA receptor (AMPAR)-dependent increase in coherent neuronal activity, but display fewer potential negative side effects. These compounds thus demonstrate promise as clinically useful fast-acting antidepressants. PMID:28275719

  15. Use of aldosterone antagonists at discharge after myocardial infarction: results from the National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network (ACTION) Registry-Get with the Guidelines (GWTG).

    PubMed

    Rao, Krishnasree K; Enriquez, Jonathan R; de Lemos, James A; Alexander, Karen P; Chen, Anita Y; McGuire, Darren K; Fonarow, Gregg C; Das, Sandeep R

    2013-10-01

    Aldosterone antagonists (AldA) improve survival after myocardial infarction (MI) in patients with left ventricular systolic dysfunction (ejection fraction [EF] <40%) concomitant with either clinical heart failure (HF) or diabetes mellitus (DM). Although current American College of Cardiology/American Heart Association guidelines provide a class I recommendation for AldA therapy in such patients, how US practice reflects these recommendations is unclear. Using data from the National Cardiovascular Data Registry ACTION Registry-GWTG, we describe contemporary discharge AldA prescription patterns among 202,213 patients discharged after acute MI from 526 US sites participating in ACTION Registry-GWTG between January 2007 and March 2011. Overall, 10.0% of patients were eligible for AldA without documented contraindication, with only 14.5% of eligible patients receiving AldA at discharge. Among the subset of AldA-eligible patients discharged on otherwise optimal medical therapy (68.9%), AldAs were prescribed to 16.1%. Aldosterone antagonist use was higher in patients with EF <40% and clinical HF with or without DM (17.7% and 16.6%, respectively), compared with patients with EF <40% and DM without clinical HF (7.8%, P < .001 for each). Fewer than 2% of participating centers used AldA in ≥50% of eligible patients. Despite clinical outcome evidence and class I guideline recommendations, AldAs are underused in the United States, with only 1 in 7 eligible patients prescribed AldA at discharge after MI. This contrasts with high use of other evidence-based post-MI medications and identifies a specific gap in translation of evidence into clinical practice. © 2013.

  16. Light-Dependent Regulation of DEL1 Is Determined by the Antagonistic Action of E2Fb and E2Fc1[W][OA

    PubMed Central

    Berckmans, Barbara; Lammens, Tim; Van Den Daele, Hilde; Magyar, Zoltan; Bögre, Laszlo; De Veylder, Lieven

    2011-01-01

    Endoreduplication represents a variation on the cell cycle in which multiple rounds of DNA replication occur without subsequent chromosome separation and cytokinesis, thereby increasing the cellular DNA content. It is known that the DNA ploidy level of cells is controlled by external stimuli such as light; however, limited knowledge is available on how environmental signals regulate the endoreduplication cycle at the molecular level. Previously, we had demonstrated that the conversion from a mitotic cell cycle into an endoreduplication cycle is controlled by the atypical E2F transcription factor, DP-E2F-LIKE1 (DEL1), that represses the endocycle onset. Here, the Arabidopsis (Arabidopsis thaliana) DEL1 gene was identified as a transcriptional target of the classical E2Fb and E2Fc transcription factors that antagonistically control its transcript levels through competition for a single E2F cis-acting binding site. In accordance with the reported opposite effects of light on the protein levels of E2Fb and E2Fc, DEL1 transcription depended on the light regime. Strikingly, modified DEL1 expression levels uncoupled the link between light and endoreduplication in hypocotyls, implying that DEL1 acts as a regulatory connection between endocycle control and the photomorphogenic response. PMID:21908689

  17. Beta-CCT, a selective BZ-omega1 receptor antagonist, blocks the anti-anxiety but not the amnesic action of chlordiazepoxide in mice.

    PubMed

    Belzung, C; Le Guisquet, A M; Griebel, G

    2000-04-01

    The aim of this study was to test further the hypothesis that different benzodiazepine (BZ-omega) receptor subtypes may mediate anxiolytic and amnesic effects of BZ agonists, using the selective BZ-omega1 receptor antagonist beta-CCT (beta-carboline-3-carboxylate t-butyl-ester). Experiments were performed in Swiss mice using the elevated plus-maze anxiety test and two learning tasks - passive avoidance and the radial arm maze. In the elevated plus-maze test, beta-CCT (30 mg/kg, i.p.) completely abolished the increase in open-arm entries induced by the BZ chlordiazepoxide (5mg/kg, i.p.). Chlordiazepoxide decreased retention latency in the passive avoidance step-through procedure, and increased the number of errors in the radial arm maze. These effects were not modified by beta-CCT. Except for a slight, albeit significant, amnesic effect in the passive avoidance test, beta-CCT was devoid of intrinsic activity when administered alone. These results are in agreement with previous studies using selective BZ-omega1 agonists, and thus provide further evidence that BZ-omega1 receptors may be involved in the anxiolytic but not in the amnesic effects of BZ agonists.

  18. 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)

  19. Facioscapulohumeral muscular dystrophy.

    PubMed

    Statland, Jeffrey; Tawil, Rabi

    2014-08-01

    Facioscapulohumeral muscular dystrophy (FSHD) is a common type of adult muscular dystrophy and is divided into types 1 and 2 based on genetic mutation. Clinically, both FSHD types often show asymmetric and progressive muscle weakness affecting initially the face, shoulder, and arms followed by the distal then proximal lower extremities. Approximately 95% of patients, termed FSHD1, have a deletion of a key number of repetitive elements on chromosome 4q35. The remaining 5%, termed FSHD2, have no deletion on chromosome 4q35. Nevertheless, both types share a common downstream mechanism, making it possible for future disease-directed therapies to be effective for both FSHD types.

  20. 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.

  1. 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

  2. Spinal Muscular Atrophy

    MedlinePlus

    ... are most often affected. Complications include scoliosis and chronic shortening of muscles or tendons around joints. × Definition Spinal Muscular Atrophy (SMA) Types I, II, and III belong to a group of hereditary diseases that cause weakness and wasting of the voluntary muscles in the arms and ...

  3. Meaning of Muscular Dystrophy

    MedlinePlus

    ... MD Living With MD en español Qué significa distrofia muscular Over Labor Day, just as you're ... grown-up. This article talks about two types: Duchenne and Becker MD. Generally, only boys get Duchenne ...

  4. The role of external Ca²⁺ in the action of Ca²⁺-channel agonists and antagonists on isolated human thoracic arteries.

    PubMed

    Garaliene, V; Barsys, V; Giedraitis, S; Benetis, R; Krauze, A

    2014-02-01

    In systemic atherosclerosis develops the abnormal vascular tone which is associated with elevated calcium influx into smooth muscle cells and their calcification that may be proportional to the extent and severity of atherosclerotic disease. The goal of the present study was to investigate the responses of isolated human arterial samples to Ca²⁺-channel agonists and antagonists by varying the external Ca²⁺ concentration. Two dihydropyridine type calcium-channel blockers, amlodipine and cerebrocrast, were used in this study. The benzodiazepine-type calcium-channel blocker diltiazem, the benzimidazole derivative 1-acetyl-5,6-dimethoxy-2-methylthiobenzimidazole and 3,4'-bipyridine derivative milrinone were also used. Experiments were carried out on isolated human thoracic artery samples obtained from 74 patients, aged 38-88 years, during conventional myocardial revascularisation operations. The contraction of artery samples was recorded using an iFOT10 force transducer. Cumulative concentration-contraction curves of the tested agents (10⁻⁷ to 10⁻⁴ M) were established by varying the external Ca²⁺ concentration from 0.9 mM to 2.7 mM. Cerebrocrast, regardless of the Ca²⁺ concentration significantly increased arterial contraction, particularly at the lower Ca²⁺ (≈77%). Diltiazem, the benzimidazole derivative and milrinone caused the artery samples to relax at 10⁻⁴ M concentrations by 55%, 55% and 44%, respectively, when the external Ca²⁺ corresponded to the physiological standard. Shifting to lower or higher Ca²⁺ concentrations significantly altered the response of vessel samples by increasing their contraction. In conclusion, the present study shows that the response of isolated human thoracic artery samples to both the slow calcium channel suppressant diltiazem and to agonists of that channel (milrinone and the benzimidazole derivative) is regulated by the amount of calcium present in the physiological solution. Treatment with a slow

  5. Effects of the chronic ingestion of therapeutic doses of chlorimipramine on the behavioral action of agonists and antagonists of serotonin in male rats.

    PubMed

    Rodríguez Echandía, E L; Broitman, S T; Fóscolo, M R

    1983-08-01

    Locomotor activity and hole-board exploration (frequency and time spent head-dipping) were impaired in male rats by injecting IP the 5-HT agonists, fluoxetine and 5-HTP. This treatment produced also myoclonus and increased the time spent resting during trials. The chronic ingestion of chlorimipramine (CIM) or the injection of the 5-HT receptor blocker, methysergide (15 mg/kg) prevented the action of the 5-HT agonists on locomotion and resting and blocked the appearance of myoclonus. Both CIM and methysergide prevented to a minor degree the fluoxetine-5-HTP-induced decrease of exploration. The chronic ingestion of CIM clearly potentiated the effects of methysergide on hole-board exploration. Results suggest that the chronic treatment with therapeutic doses of CIM reduces the functional activity of some 5-HT systems in the brain of the rat, probably by blockade of post-synaptic 5-HT receptors. This does not preclude, however, that CIM may also alter some NA systems.

  6. Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy

    ClinicalTrials.gov

    2017-07-11

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

  7. Facioscapulohumeral muscular dystrophy.

    PubMed

    Tawil, Rabi

    2008-10-01

    Facioscapulohumeral muscular dystrophy (FSHD), a dominantly inherited disorder, is the third most common dystrophy after Duchenne and myotonic muscular dystrophy. No known effective treatments exist for FSHD. The lack of an understanding of the underlying pathophysiology remains an obstacle in the development of targeted therapeutic interventions. The genetic defect is a loss of a critical number of a repetitive element (D4Z4) in the 4q subtelomeric region. The loss of the repeats results in specific changes in chromatin structure, although neither the molecular nor the cellular consequences of this change are known. Nevertheless, these epigenetic changes in chromatin structure offer a potential therapeutic target. This review discusses current management strategies in FSHD as well as potential therapeutic interventions to slow down or reverse the progressive muscle atrophy and weakness.

  8. Ago-antagonist theory in Darwinian evolution.

    PubMed

    Bazzani, Armando; Freguglia, Paolo

    2013-01-01

    In this paper we discuss a proposal on the essential structural aspects of Darwinian Evolution Theory. Using this point of view we apply a mathematical ago-antagonist theory inspired by Y. Cherruault's (1998) ideas, which we have extended. In the ago-antagonist model, the phenotype characters measure the individual propensity to perform an innovative x(t) (agonist) or conservative y(t) (antagonist) action with respect to mutation and to speciation process. We have mathematically introduced the conflict concept and we present a model that takes into account the environmental effects by means of a stochastic multiplicative process. We shortly discuss the properties of the related stochastic differential equations.

  9. 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.

  10. Translational Research for Muscular Dystrophy

    DTIC Science & Technology

    2012-05-01

    REPORT TYPE Annual 3. DATES COVERED 1 MAR 2011 - 30 APR 2012 4. TITLE AND SUBTITLE Translational Research for Muscular Dystrophy 5a. CONTRACT...SUPPLEMENTARY NOTES 14. ABSTRACT The goal of this work is to increase the availability of critical mouse models of human muscular dystrophy (MD...3 W81XWH-11-1-0330 Cox, Gregory A 4 4 11 11 12 Translational Research for Muscular Dystrophy W81XWH-11-1-0330 Gregory A

  11. 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

  12. 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.

  13. Spinal Muscular Atrophy.

    PubMed

    Kolb, Stephen J; Kissel, John T

    2015-11-01

    Spinal muscular atrophy is an autosomal-recessive disorder characterized by degeneration of motor neurons in the spinal cord and caused by mutations in the survival motor neuron 1 gene, SMN1. The severity of SMA is variable. The SMN2 gene produces a fraction of the SMN messenger RNA (mRNA) transcript produced by the SMN1 gene. There is an inverse correlation between SMN2 gene copy number and clinical severity. Clinical management focuses on multidisciplinary care. Preclinical models of SMA have led to an explosion of SMA clinical trials that hold great promise of effective therapy in the future. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Therapeutic advances in muscular dystrophy

    PubMed Central

    Leung, Doris G; Wagner, Kathryn R

    2013-01-01

    The muscular dystrophies comprise a heterogeneous group of genetic disorders that produce progressive skeletal muscle weakness and wasting. There has been rapid growth and change in our understanding of these disorders in recent years, and advances in basic science are being translated into increasing numbers of clinical trials. This review will discuss therapeutic developments in 3 of the most common forms of muscular dystrophy: Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, and myotonic dystrophy. Each of these disorders represents a different class of genetic disease (monogenic, epigenetic, and repeat expansion disorders), and the approach to therapy addresses the diverse and complex molecular mechanisms involved in these diseases. The large number of novel pharmacologic agents in development with good biologic rationale and strong proof of concept suggests there will be an improved quality of life for individuals with muscular dystrophy. PMID:23939629

  15. [Duchenne muscular dystrophy pathophysiology].

    PubMed

    Péréon, Y; Mercier, S; Magot, A

    2015-12-01

    Dystrophin is a large cytoskeletal protein located at the plasma membrane in both muscle and non-muscle tissues, which mediates interactions between the cytoskeleton, cell membrane, and extracellular matrix. Dystrophin is a key component of multiprotein complexes (dystrophin- associated glycoprotein complex, or DGC). It is also involved in many intracellular cascades affecting membrane proteins such as calcium channels, or various signalisation pathways. In Duchenne Muscular Dystrophy, both dystrophin and DGC proteins are missing. This induces excessive membrane fragility and permeability, dysregulation of calcium homeostasis, oxidative damage, which in turn favour muscle cell necrosis. The latter is initially followed by regeneration. With age, the regenerative capacity of the muscles appears to be exhausted and muscle fibres are gradually replaced by connective and adipose tissue. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  16. Vasopressin-receptor antagonist therapy in patients with hyponatraemia.

    PubMed

    Vachharajani, Tushar; Vachharajani, Vidula

    2007-07-01

    Hyponatraemia often complicates the treatment of underlying conditions in patients who are seriously ill. Arginine vasopressin receptor antagonists block the action of arginine vasopressin and correct sodium and water imbalance in patients with euvolaemic or hypervolaemic hyponatraemia.

  17. 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

  18. 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

  19. 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

  20. 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.

  1. Ageing with Muscular Disease

    PubMed Central

    Martinsen, Bente; Dreyer, Pia

    2016-01-01

    Background: The demographic development with an ageing population is predicted to be the next global public health challenge. Advances in medicine and the socioeconomic development have reduced mortality and morbidity due to infectious conditions and non-communicable diseases. The increase in longevity will not be restricted to healthy people. Objective: To understand how people with muscular diseases experience ageing. Method: A literature review was conducted using the Matrix Method developed by Garrard (2007). This systematic method was used to identify, describe and interpret studies, irrespective of the methods applied. To avoid the exclusion of important sources, experiences and topics, we chose an integrative approach that accommodates the inclusion of studies with different methodologies. People with MD have gradually extended their life expectancy during the last 30 years. Thus, we reviewed the literature regarding MD and ageing without time limit. Results: We identified three themes: 1) Slowing down early 2) Accepting lifelong deterioration and 3) Striving for normality. Conclusion: People with MD live in a field of tension between a feeling of autonomy and normality and difficulties coping with reduced physical abilities. Getting older accentuates this tension since the physical strength diminishes and it is harder to maintain autonomy. The bodily challenges may coincide with the end of the rehabilitation people living with MD have received. Seemingly, no age-related rehabilitation is offered, and people living with MD are thus at risk of an unnecessarily passive life. PMID:28144383

  2. Spinal muscular atrophies.

    PubMed

    Viollet, Louis; Melki, Judith

    2013-01-01

    Spinal muscular atrophies (SMA) are genetic disorders characterized by degeneration of lower motor neurons. The most frequent form is caused by mutations of the survival motor neuron 1 gene (SMN1). The identification of this gene greatly improved diagnostic testing and family-planning options of SMA families. SMN plays a key role in metabolism of RNA. However, the link between RNA metabolism and motor neuron degeneration remains unknown. A defect in mRNA processing likely generates either a loss of function of some critical RNA or abnormal transcripts with toxic property for motor neurons. Mutations of SMN in various organisms highlighted an essential role of SMN in motor axon and neuromuscular junction development or maintenance. The quality of life of patients has greatly improved over recent decades through the improvement of care and management of patients. In addition, major advances in translational research have been made in the field of SMA. Various therapeutic strategies have been successfully developed aiming at acting on SMN2, a partially functional copy of the SMN1 gene which remains present in patients. Drugs have been identified and some are already at preclinical stages. Identifying molecules involved in the SMA degenerative process should represent additional attractive targets for therapeutics in SMA. Copyright © 2013 Elsevier B.V. All rights reserved.

  3. Antioxidant effects of calcium antagonists in rat brain homogenates.

    PubMed

    Yao, K; Ina, Y; Nagashima, K; Ohmori, K; Ohno, T

    2000-06-01

    We studied the antioxidant activities of calcium antagonists against autoxidation in rat brain homogenates. The homogenates were incubated for 30 min at 37 degrees C with or without a calcium antagonist and subsequently assayed for lipid peroxide content. Percent inhibition of the lipid peroxidation was used as an index of the antioxidant effect. Dihydropyridine calcium antagonists exhibited concentration-dependent (3-300 micromol/l) inhibitory effects against lipid peroxidation. The relative order of antioxidant potency and associated IC50 values (micromol/l) of the calcium antagonists for inhibition of the lipid peroxidation were as follows: nifedipine (51.5)>barnidipine (58.6)>benidipine (71.2)>nicardipine (129.3)>amlodipine (135.5)>nilvadipine (167.3)>nitrendipine (252.1)> diltiazem (>300)=verapamil (>300). These results suggest that some dihydropyridine calcium antagonists show antioxidant properties. The antioxidant effects of the calcium antagonists may contribute to their pharmacological actions.

  4. Muscarinic Receptor Antagonists.

    PubMed

    Matera, Maria Gabriella; Cazzola, Mario

    2017-01-01

    Parasympathetic activity is increased in patients with chronic obstructive pulmonary disease (COPD) and asthma and appears to be the major reversible component of airway obstruction. Therefore, treatment with muscarinic receptor antagonists is an effective bronchodilator therapy in COPD and also in asthmatic patients. In recent years, the accumulating evidence that the cholinergic system controls not only contraction by airway smooth muscle but also the functions of inflammatory cells and airway epithelial cells has suggested that muscarinic receptor antagonists could exert other effects that may be of clinical relevance when we must treat a patient suffering from COPD or asthma. There are currently six muscarinic receptor antagonists licenced for use in the treatment of COPD, the short-acting muscarinic receptor antagonists (SAMAs) ipratropium bromide and oxitropium bromide and the long-acting muscarinic receptor antagonists (LAMAs) aclidinium bromide, tiotropium bromide, glycopyrronium bromide and umeclidinium bromide. Concerns have been raised about possible associations of muscarinic receptor antagonists with cardiovascular safety, but the most advanced compounds seem to have an improved safety profile. Further beneficial effects of SAMAs and LAMAs are seen when added to existing treatments, including LABAs, inhaled corticosteroids and phosphodiesterase 4 inhibitors. The importance of tiotropium bromide in the maintenance treatment of COPD, and likely in asthma, has spurred further research to identify new LAMAs. There are a number of molecules that are being identified, but only few have reached the clinical development.

  5. 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.

  6. 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.

  7. Muscular dystrophy in a dog resembling human becker muscular dystrophy.

    PubMed

    Baroncelli, A B; Abellonio, F; Pagano, T B; Esposito, I; Peirone, B; Papparella, S; Paciello, O

    2014-05-01

    A 3-year-old, male Labrador retriever dog was presented with clinical signs of progressive exercise intolerance, bilateral elbow extension, rigidity of the forelimbs, hindlimb flexion and kyphosis. Microscopical examination of muscle tissue showed marked variability in myofibre size, replacement of muscle with mature adipose tissue and degeneration/regeneration of muscle fibres, consistent with muscular dystrophy. Immunohistochemical examination for dystrophin showed markedly reduced labelling with monoclonal antibodies specific for the rod domain and the carboxy-terminal of dystrophin, while expression of β-sarcoglycan, γ-sarcoglycan and β-dystroglycan was normal. Immunoblotting revealed a truncated dystrophin protein of approximately 135 kDa. These findings supported a diagnosis of congenital canine muscular dystrophy resembling Becker muscular dystrophy in man.

  8. Third Generation Mineralocorticoid Receptor Antagonists; Why We Need a Fourth

    PubMed Central

    Gomez-Sanchez, Elise

    2015-01-01

    The first mineralocorticoid receptor (MR) antagonist, spironolactone, was developed almost 60 years ago to treat primary aldosteronism and pathological edema. Its use waned in part due to its lack of selectivity. Subsequently knowledge of the scope of MR function was expanded along with clinical evidence of the therapeutic importance of MR antagonists to prevent the ravages of inappropriate MR activation. Forty-two years elapsed between the first and MR-selective second generation of MR antagonists. Fifteen years later, despite serious shortcomings of the existing antagonists, a third generation antagonist has yet to be marketed. Progress has been slowed by the lack of appreciation of the large variety of cell types that express the MR and its diverse cell-type-specific actions, as well as its uniquely complex interactions actions at the molecular level. New MR antagonists should preferentially target the inflammatory and fibrotic effects of MR and perhaps its excitatory effects on sympathetic nervous system, but not the renal tubular epithelium or neurons of the cortex and hippocampus. This review briefly describes efforts to develop a third generation MR antagonist and why fourth generation antagonists and selective agonists based on structural determinants of tissue and ligand-specific MR activation should be contemplated. PMID:26466326

  9. 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.

  10. 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

  11. Spinal muscular atrophy.

    PubMed

    D'Amico, Adele; Mercuri, Eugenio; Tiziano, Francesco D; Bertini, Enrico

    2011-11-02

    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

  12. 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.

  13. CCR2 antagonists.

    PubMed

    Struthers, Mary; Pasternak, Alexander

    2010-01-01

    Inhibition of CCR2 has been considered as a target for multiple therapeutic diseases including autoimmune disease, atherosclerosis, pain, and metabolic disease, based in part on the critical role this receptor plays on monocyte migration. Numerous companies have reported programs to identify CCR2 antagonists. Common challenges to the development of CCR2 agents have included poor activity at the rodent receptor and selectivity for both other chemokine receptors and ion channels. This review summarizes the rationale for targeting CCR2 in disease, the recent progress in the identification of potent and select CCR2 antagonists, and the current status of clinical trials for CCR2 agents.

  14. Trainability of Muscular Activity Level during Maximal Voluntary Co-Contraction: Comparison between Bodybuilders and Nonathletes

    PubMed Central

    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. 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…

  16. 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…

  17. Porcine models of muscular dystrophy

    USDA-ARS?s Scientific Manuscript database

    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...

  18. 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.

  19. 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

  20. [Research progress of selective mGluR1 antagonists].

    PubMed

    Yang, Yi-lei; Sun, Wei; Peng, Cheng; Zhang, Xiao-ye; Yang, Xiao-hong

    2011-10-01

    As an important member of metabotropic glutamate receptors (mGluR), metabotropic glutamate receptor 1 (mGluR1) plays an important role in the signal transduction of central nervous system. Selective mGluR1 antagonists can block the signaling pathway activated by mGluR1 and exert a series of physiological actions including analgesia, antianxiety, antidepression, etc. Currently, the discovery and modification of selective mGluR1 antagonists have become a hot research focus. This paper reviews the structural catalogs of selective mGluR1 antagonists and their structure-activity relationships in the last decade.

  1. Myeloid cells are capable of synthesizing aldosterone to exacerbate damage in muscular dystrophy.

    PubMed

    Chadwick, Jessica A; Swager, Sarah A; Lowe, Jeovanna; Welc, Steven S; Tidball, James G; Gomez-Sanchez, Celso E; Gomez-Sanchez, Elise P; Rafael-Fortney, Jill A

    2016-12-01

    FDA-approved mineralocorticoid receptor (MR) antagonists are used to treat heart failure. We have recently demonstrated efficacy of MR antagonists for skeletal muscles in addition to heart in Duchenne muscular dystrophy mouse models and that mineralocorticoid receptors are present and functional in skeletal muscles. The goal of this study was to elucidate the underlying mechanisms of MR antagonist efficacy on dystrophic skeletal muscles. We demonstrate for the first time that infiltrating myeloid cells clustered in damaged areas of dystrophic skeletal muscles have the capacity to produce the natural ligand of MR, aldosterone, which in excess is known to exacerbate tissue damage. Aldosterone synthase protein levels are increased in leukocytes isolated from dystrophic muscles compared with controls and local aldosterone levels in dystrophic skeletal muscles are increased, despite normal circulating levels. All genes encoding enzymes in the pathway for aldosterone synthesis are expressed in muscle-derived leukocytes. 11β-HSD2, the enzyme that inactivates glucocorticoids to increase MR selectivity for aldosterone, is also increased in dystrophic muscle tissues. These results, together with the demonstrated preclinical efficacy of antagonists, suggest MR activation is in excess of physiological need and likely contributes to the pathology of muscular dystrophy. This study provides new mechanistic insight into the known contribution of myeloid cells to muscular dystrophy pathology. This first report of myeloid cells having the capacity to produce aldosterone may have implications for a wide variety of acute injuries and chronic diseases with inflammation where MR antagonists may be therapeutic. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  2. Indications for Opioid Antagonists.

    PubMed

    Coppes, O J Michael; Sang, Christine N

    2017-06-01

    As opioids have become more common in clinical practice for the treatment of both acute and chronic pain, so too has the need for a deeper understanding of the clinical applications of opioid antagonists. The purpose of this review is to present both the longstanding and potential new indications for the use of drugs that block the effects of opioid receptors. There is a growing body of data demonstrating the modulation of pain by opioid antagonists. Additional clinical studies that show their direct antinociceptive effects and/or enhancement of the analgesic potency of opioid agonists are warranted. We briefly discuss the well-established role that these agents play in the reversal of life-threatening opioid toxicity and explore both existing and expanding clinical applications, including their apparent paradox that they may themselves be associated with analgesia.

  3. alpha2-Adrenoreceptor antagonists.

    PubMed

    Mayer, P; Imbert, T

    2001-06-01

    A review of the literature relating to the therapeutic potential of alpha2-adrenoceptor antagonists published between 1990 and 2000 is presented. Although extensively studied since the early 1970s in a wide spectrum of therapeutic applications, the distinction of alpha2-adrenoceptor subtypes and some emerging evidence concerning new applications in neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases, obesity and schizophrenia, have refreshed an interest in this class of agents.

  4. Calcium antagonists and vasospasm.

    PubMed

    Meyer, F B

    1990-04-01

    A critical review of the clinical data supports the conclusion that nimodipine decreases the severity of neurologic deficits and improves outcome after subarachnoid hemorrhage. The mechanisms by which mortality and morbidity are reduced are still controversial. First, the frequency of vasospasm is not altered (Figs. 5 and 6). Second, the consistent reversal of vasospasm once present has not been demonstrated either angiographically or by noninvasive cerebral blood flow studies. These observations suggest that there is either modification of microcirculatory flow (i.e., dilation of pial conducting vessels or decreased platelet aggregation) or a direct neuronal protective effect. As suggested previously, support for either mechanism is not resolute, and further investigation is necessary. Currently, nimodipine has been the most thoroughly investigated calcium antagonist both from an experimental and clinical perspective. Oral administration has had few reported complications. Therefore, the benefit/risk ratio clearly supports the prophylactic use of this calcium antagonist in patients of all clinical grades after subarachnoid hemorrhage. Evidence also indicates that starting nimodipine after the onset of delayed ischemic deficits is of benefit. Finally, it can be predicted that in the future additional calcium antagonists with more selective vascular or neuronal effects will be developed for use in neurologic disorders.

  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. 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.

  7. 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

  8. Side-effects of mixed agonist-antagonist analgesics used in sequential anaesthesia

    PubMed Central

    Devaux, C.; Schoepffler, P.; Gauthier-Lafaye, J. P.

    1979-01-01

    1 Mixed agonist-antagonist analgesics have analgesic action but also possess a range of side-effects. 2 Narcotic antagonists do not reverse the non-specific effects of opiates. 3 Under certain circumstances the effects of agonists and mixed agonist-antagonists can be additive. 4 Chronic dosage of mixed agonist-antagonists leads to a lower level of dependence than that observed with the standard narcotics. 5 Mixed agonist-antagonists may not antagonize the respiratory effects of narcotics and may result in potentiation of such depression. PMID:465294

  9. [Fractures in spinal muscular atrophy].

    PubMed

    Febrer, Anna; Vigo, Meritxell; Rodríguez, Natalia; Medina, Julita; Colomer, Jaume; Nascimento, Andrés

    2013-09-01

    Objetivo. Determinar la frecuencia de fracturas en pacientes con atrofia muscular espinal, mecanismo de produccion, edad de aparicion y repercusion funcional. Pacientes y metodos. Se estudian 65 pacientes con atrofia muscular espinal. Se recogen las fracturas diagnosticadas mediante radiografia y se analizan los siguientes parametros: tipo de atrofia muscular espinal, marcha, edad en el momento de la fractura, mecanismo de produccion, localizacion, tratamiento aplicado y repercusion funcional. Resultados. Presentaron fracturas 13 pacientes (20%), con un total de 20 (cuatro presentaron dos o mas fracturas). La edad media fue de 6,35 años. La localizacion fue en su mayoria en el femur y el mecanismo de produccion, en 12 casos por caidas y en 8 por traumatismo menor. No detectamos ninguna fractura vertebral. Todas se trataron de manera conservadora. El unico paciente ambulante que presento una fractura dejo de caminar despues de la inmovilizacion. Conclusiones. La existencia de fracturas en estos pacientes interfiere en su calidad de vida y en el nivel funcional. Es importante la prevencion de las mismas en el manejo del paciente y vigilando la correcta postura en la silla de ruedas con sistemas de sujecion Deberian emprenderse mas estudios sobre la perdida de densidad mineral osea en estos pacientes y su posible relacion con las fracturas.

  10. Halofuginone promotes satellite cell activation and survival in muscular dystrophies.

    PubMed

    Barzilai-Tutsch, Hila; Bodanovsky, Anna; Maimon, Hadar; Pines, Mark; Halevy, Orna

    2016-01-01

    Halofuginone is a leading agent in preventing fibrosis and inflammation in various muscular dystrophies. We hypothesized that in addition to these actions, halofuginone directly promotes the cell-cycle events of satellite cells in the mdx and dysf(-/-) mouse models of early-onset Duchenne muscular dystrophy and late-onset dysferlinopathy, respectively. In both models, addition of halofuginone to freshly prepared single gastrocnemius myofibers derived from 6-week-old mice increased BrdU incorporation at as early as 18h of incubation, as well as phospho-histone H3 (PHH3) and MyoD protein expression in the attached satellite cells, while having no apparent effect on myofibers derived from wild-type mice. BrdU incorporation was abolished by an inhibitor of mitogen-activated protein kinase/extracellular signal-regulated protein kinase, suggesting involvement of this pathway in mediating halofuginone's effects on cell-cycle events. In cultures of myofibers and myoblasts isolated from dysf(-/-) mice, halofuginone reduced Bax and induced Bcl2 expression levels and induced Akt phosphorylation in a time-dependent manner. Addition of an inhibitor of the phosphinositide-3-kinase/Akt pathway reversed the halofuginone-induced cell survival, suggesting this pathway's involvement in mediating halofuginone's effects on survival. Thus, in addition to its known role in inhibiting fibrosis and inflammation, halofuginone plays a direct role in satellite cell activity and survival in muscular dystrophies, regardless of the mutation. These actions are of the utmost importance for improving muscle pathology and function in muscular dystrophies.

  11. Tetrahydroindolizinone NK1 antagonists.

    PubMed

    Bao, Jianming; Lu, Huagang; Morriello, Gregori J; Carlson, Emma J; Wheeldon, Alan; Chicchi, Gary G; Kurtz, Marc M; Tsao, Kwei-Lan C; Zheng, Song; Tong, Xinchun; Mills, Sander G; DeVita, Robert J

    2010-04-01

    A new class of potent NK(1) receptor antagonists with a tetrahydroindolizinone core has been identified. This series of compounds demonstrated improved functional activities as compared to previously identified 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core is discussed in detail. A number of compounds displayed high NK(1) receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK(1) binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P(450) inhibition and hPXR induction profiles. 2010 Elsevier Ltd. All rights reserved.

  12. Rare Muscular Dystrophies: Congenital, Distal, Emery-Dreifuss and Oculopharyngeal Muscular Dystrophies

    MedlinePlus

    ... 14 CMD, DD, EDMD and OPMD • ©2011 MDA Classification of Congenital Muscular Dystrophies Type of CMD Merosin- ... Chromosome 1 gene, recessive See illustration, page 5. Classification of Distal Muscular Dystrophies Type of CMD Welander’s ...

  13. 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

  14. Pharmacological and clinical importance of narcotic antagonists and mixed antagonists — use in cardiology

    PubMed Central

    Coltart, D. John; Malcolm, Alasdair D.

    1979-01-01

    1 The treatment of pain of cardiac origin requires a knowledge of the haemodynamic action of the analgesic agents used. 2 The haemodynamic effects of morphine, diamorphine, pavaveretum, pethidine and pentazocine are reviewed. 3 Clinical experience with the new antagonist analgesic buprenorphine is reported. 4 These studies indicate that buprenorphine may be the agent of choice for the relief of severe pain in patients with unstable circulation. PMID:465292

  15. Compression garment promotes muscular strength recovery after resistance exercise.

    PubMed

    Goto, Kazushige; Morishima, Takuma

    2014-12-01

    This study aimed to investigate the effects of wearing a compression garment (CG) for 24 h on changes in muscular strength and blood parameters over time after resistance exercise. Nine trained men conducted resistance exercises (10 repetitions of 3-5 sets at 70% of one-repetition maximum (1RM) for nine exercises) in two trials, wearing either a CG or a normal garment (CON) for 24 h after exercise. Recovery of muscular strength, blood parameters, muscle soreness, and upper arm and thigh circumference were compared between the trials. Both trials showed decreases in maximal strength after the exercise (P < 0.05). However, the CG trial showed faster recovery of one-repetition maximum for the chest press from 3 to 8 h after exercise (P < 0.05). Recovery of maximal knee extension strength was also improved in the CG trial 24 h after exercise (P < 0.05). The CG trial was associated with lower muscle soreness and subjective fatigue scores the following morning (P < 0.05). The upper arm and thigh circumferences were significantly higher during the recovery period in the CON trial, whereas no change was observed in the CG trial. Blood lactate, insulin like growth factor-1, free testosterone, myoglobin, creatine kinase, interleukin 6, and interleukin 1 receptor antagonist concentrations for 24 h after exercise were similar in both trials. Wearing a CG after resistance exercise facilitates the recovery of muscular strength. Recovery for upper body muscles significantly improved within 3-8 h after exercise. However, facilitation of recovery of lower limb muscles by wearing the CG took a longer time.

  16. 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.…

  17. 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.…

  18. 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)

  19. 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)

  20. Muscular abnormalities in children with muscular hypotonia and cerebral damage.

    PubMed

    Porro, G; Carboni, P; Spagnoli, L G; Palmieri, G

    1987-01-01

    Forty children with hypotonia and non progressive cerebral impairment were observed. In all cases muscle morpho-histometric and ultrastructural studies were performed, in 13 cases muscular acetylcholinesterase study was carried out. The Authors pointed out the high frequency (92% of cases) of muscle abnormalities: histochemical alteration of fibre type distribution (type 1 or type 2 fibres prevalence, type 2C persistence), diameter change (hypertrophy or hypotrophy of the fibres). In 37.5% of the cases, randomly distributed, were also present myofibrillar degeneration, Z band streaming, desalignment or marked destructuration of the sarcomeres. The muscular acetylcholinesterase study showed the same anomalous pattern of molecular forms (11 out of 13 cases), with increase of light (6S, 4S) and disappearance of heavy (16S) and medium forms (13S, 10S), without significant change of enzymatic activity. The possible alterated influence of CNS on muscle fibre differentiation and growth because of abnormal neural control is discussed. This hypothesis even if could be related with abnormal fibre typing and diameter, do not seem to explain the ultrastructural and biochemical abnormalities observed.

  1. Translational Research for Muscular Dystrophy

    DTIC Science & Technology

    2014-05-01

    JAX stock 18018: B10ScSn.Cg-Prkdcscid Dmdmdx/J Like human patients who suffer from one of the most common neuromuscular diseases, Duchenne muscular...overt phenotype in BL10.mdx mice. However, the muscle wasting and kyphosis of the D2.mdx mouse is evident at this early adult age. Figure 3...and whe antitative is a very e. Our atic loss X mice train at any re shown ness is total force per eakness ch earlier in, the of

  2. Bioisosteres of 9-carboxymethyl-4-oxo-imidazo[1,2-a]indeno-[1,2-e]pyrazin-2-carboxylic acid derivatives. Progress towards selective, potent in vivo AMPA antagonists with longer durations of action.

    PubMed

    Jimonet, P; Bohme, G A; Bouquerel, J; Boireau, A; Damour, D; Debono, M W; Genevois-Borella, A; Hardy, J C; Hubert, P; Manfré, F; Nemecek, P; Pratt, J; Randle, J C; Ribeill, Y; Stutzmann, J M; Vuilhorgne, M; Mignani, S

    2001-01-22

    A novel series of 2- and 9-disubstituted heterocyclic-fused 4-oxo-indeno[1,2-e]pyrazin derivatives was synthesized. One of them, the 9-(1H-tetrazol-5-ylmethyl)-4-oxo-5,10-dihydroimidazo[1,2-a]indeno[1,2-e]pyrazin-2-yl phosphonic acid 4i exhibited a strong and a selective binding affinity for the AMPA receptor (IC50 = 13 nM) and demonstrated potent antagonist activity (IC50 = 6nM) at the ionotropic AMPA receptor. This compound also displayed good anticonvulsant properties against electrically-induced convulsions after ip and iv administration with ED50 values between 0.8 and 1 mg/kg. Furthermore, a strong increase in potency was observed when given iv 3 h before test (ED50 = 3.5 instead of 25.6 mg/kg for the corresponding 9-carboxymethyl-2-carboxylic acid analogue). These data confirmed that there is an advantage in replacing the classical carboxy substituents by their bioisosteres such as tetrazole or phosphonic acid groups.

  3. Antagonistic Activity and Mode of Action of Phenazine-1-Carboxylic Acid, Produced by Marine Bacterium Pseudomonas aeruginosa PA31x, Against Vibrio anguillarum In vitro and in a Zebrafish In vivo Model

    PubMed Central

    Zhang, Linlin; Tian, Xueying; Kuang, Shan; Liu, Ge; Zhang, Chengsheng; Sun, Chaomin

    2017-01-01

    Phenazine and its derivatives are very important secondary metabolites produced from Pseudomonas spp. and have exhibited broad-spectrum antifungal and antibacterial activities. However, till date, there are few reports about marine derived Pseudomonas and its production of phenazine metabolites. In this study, we isolated a marine Pseudomonas aeruginosa strain PA31x which produced natural product inhibiting the growth of Vibrio anguillarum C312, one of the most serious bacterial pathogens in marine aquaculture. Combining high-resolution electro-spray-ionization mass spectroscopy and nuclear magnetic resonance spectroscopy analyses, the functional compound against V. anguillarum was demonstrated to be phenazine-1-carboxylic acid (PCA), an important phenazine derivative. Molecular studies indicated that the production of PCA by P. aeruginosa PA31x was determined by gene clusters phz1 and phz2 in its genome. Electron microscopic results showed that treatment of V. anguillarum with PCA developed complete lysis of bacterial cells with fragmented cytoplasm being released to the surrounding environment. Additional evidence indicated that reactive oxygen species generation preceded PCA-induced microbe and cancer cell death. Notably, treatment with PCA gave highly significant protective activities against the development of V. anguillarum C312 on zebrafish. Additionally, the marine derived PCA was further found to effectively inhibit the growth of agricultural pathogens, Acidovorax citrulli NP1 and Phytophthora nicotianae JM1. Taken together, this study reveals that marine Pseudomonas derived PCA carries antagonistic activities against both aquacultural and agricultural pathogens, which broadens the application fields of PCA. PMID:28289406

  4. Antagonistic Activity and Mode of Action of Phenazine-1-Carboxylic Acid, Produced by Marine Bacterium Pseudomonas aeruginosa PA31x, Against Vibrio anguillarum In vitro and in a Zebrafish In vivo Model.

    PubMed

    Zhang, Linlin; Tian, Xueying; Kuang, Shan; Liu, Ge; Zhang, Chengsheng; Sun, Chaomin

    2017-01-01

    Phenazine and its derivatives are very important secondary metabolites produced from Pseudomonas spp. and have exhibited broad-spectrum antifungal and antibacterial activities. However, till date, there are few reports about marine derived Pseudomonas and its production of phenazine metabolites. In this study, we isolated a marine Pseudomonas aeruginosa strain PA31x which produced natural product inhibiting the growth of Vibrio anguillarum C312, one of the most serious bacterial pathogens in marine aquaculture. Combining high-resolution electro-spray-ionization mass spectroscopy and nuclear magnetic resonance spectroscopy analyses, the functional compound against V. anguillarum was demonstrated to be phenazine-1-carboxylic acid (PCA), an important phenazine derivative. Molecular studies indicated that the production of PCA by P. aeruginosa PA31x was determined by gene clusters phz1 and phz2 in its genome. Electron microscopic results showed that treatment of V. anguillarum with PCA developed complete lysis of bacterial cells with fragmented cytoplasm being released to the surrounding environment. Additional evidence indicated that reactive oxygen species generation preceded PCA-induced microbe and cancer cell death. Notably, treatment with PCA gave highly significant protective activities against the development of V. anguillarum C312 on zebrafish. Additionally, the marine derived PCA was further found to effectively inhibit the growth of agricultural pathogens, Acidovorax citrulli NP1 and Phytophthora nicotianae JM1. Taken together, this study reveals that marine Pseudomonas derived PCA carries antagonistic activities against both aquacultural and agricultural pathogens, which broadens the application fields of PCA.

  5. A novel antihypertension agent, sargachromenol D from marine brown algae, Sargassum siliquastrum, exerts dual action as an L-type Ca(2+) channel blocker and endothelin A/B2 receptor antagonist.

    PubMed

    Park, Byong-Gon; Shin, Woon-Seob; Oh, Sangtae; Park, Gab-Man; Kim, Nam Ik; Lee, Seokjoon

    2017-09-01

    We isolated the novel vasoactive marine natural products, (5E,10E)-14-hydroxy-2,6,10-trimethylpentadeca-5,10-dien-4-one (4) and sargachromenol D (5), from Sargassum siliquastrum collected from the coast of the East Sea in South Korea by using activity-guided HPLC purification. The compounds effectively dilated depolarization (50mMK(+))-induced basilar artery contraction with EC50 values of 3.52±0.42 and 1.62±0.63μM, respectively, but only sargachromenol D (5) showed a vasodilatory effect on endothelin-1 (ET-1)-induced basilar artery contraction (EC50=9.8±0.6μM). These results indicated that sargachromenol D (5) could act as a dual antagonist of l-type Ca(2+) channel and endothelin A/B2 receptors. Moreover, sargachromenol D (5) lowered blood pressure in spontaneous hypertensive rats (SHRs) 2h after oral treatment at a dose of 80mg/kg dose and the effect was maintained for 24h. Based on our ex vivo and in vivo experiments, we propose that sargachromenol D (5) is a strong candidate for the treatment of hypertension that is not controlled by conventional drugs, in particular, severe-, type II diabetes-, salt-sensitive, and metabolic disease-induced hypertension. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. [Muscular disorders associated with ankylosing spondylitis and their correction with the help of whole body cryotherapy].

    PubMed

    Kulikov, A G; Tabiev, V I; Rassulova, M A

    2015-01-01

    The objective of the present study was to evaluate the possibilities for the correction of muscular disorders associated with ankylosing spondylitis and their correction with the help of whole body cryotherapy. The study included 55 patients randomly allocated to two groups. Group 1 was comprised of the patients treated with the use of the common mineral baths, physiotherapy, therapeutic physical exercises, spinal massage, and whole body air-cryotherapy. Group 2 contained the patients who were treated in a similar way with the exception of whole body cryotherapy; they served as controls. Muscular disorders were diagnosed by means of functional muscular testing. The study has demonstrated the high prevalence of muscular disorders in the patients suffering from ankylosing spondylitis. Moreover, it revealed the profile of such disorders associated with ankylosing spondylitis and showed significant correlation between the results of functional muscular testing, BASMI and BASFI indices as well as characteristics of chest excursions (p<0.01). The analysis of the results of the treatment gave evidence of the higher effectiveness of the combined treatment including whole body cryotherapy in comparison with the alternative therapeutic modalities employed in the present study. This therapeutic modality ensured the statistically more pronounced improvement of functional muscular testing parameters (p<0.05), muscle strength and extensibility, as well as certain other clinical and functional characteristics. The groups of muscles most susceptible to cryogenic therapy have been identified. The data obtained in the present study shed light on some specific features of the action of whole body cryotherapy accounting for its corrective influence on the muscular disorders in the patients presenting with ankylosing spondylitis. It is concluded that the proposed approach can be recommended for the introduction in the combined therapeutic and rehabilitative treatment of muscular

  7. 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.

  8. Antistress Effects of Rosa rugosa Thunb. on Total Sleep Deprivation-Induced Anxiety-Like Behavior and Cognitive Dysfunction in Rat: Possible Mechanism of Action of 5-HT6 Receptor Antagonist.

    PubMed

    Na, Ju-Ryun; Oh, Dool-Ri; Han, SeulHee; Kim, Yu-Jin; Choi, EunJin; Bae, Donghyuck; Oh, Dong Hwan; Lee, Yoo-Hyun; Kim, Sunoh; Jun, Woojin

    2016-09-01

    Our previous results suggest that the Rosa rugosa Thunb. (family Rosaceae) alleviates endurance exercise-induced stress by decreasing oxidative stress levels. This study aimed to screen and identify the physiological antistress effects of an extract of R. rugosa (RO) on sleep deprivation-induced anxiety-like behavior and cognitive tests (in vivo) and tested for hippocampal CORT and monoamine levels (ex vivo), corticosterone (CORT)-induced injury, N-methyl-d-aspartate (NMDA) receptor, and serotonin 6 (5-hydroxytryptamine 6, 5-HT6) receptor activities (in vitro) in search of active principles and underlying mechanisms of action. We confirmed the antistress effects of RO in a sleep-deprived stress model in rat and explored the underlying mechanisms of its action. In conclusion, an R. rugosa extract showed efficacy and potential for use as an antistress therapy to treat sleep deprivation through its antagonism of the 5-HT6 receptor and resulting inhibition of cAMP activity.

  9. Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis.

    PubMed

    Janero, David R; Makriyannis, Alexandros

    2009-03-01

    pharmacological profiling, as the prelude to first-in-man testing of CB1 receptor antagonists with unique modes of targeting/pharmacological action, represents an exciting translational frontier in the critical path to CB receptor blockers as medicines.

  10. Pharmacological analysis of calcium antagonist receptors

    SciTech Connect

    Reynolds, I.J.

    1987-01-01

    This work focuses on two aspects of the action of calcium antagonist drugs, namely, the interaction of drugs with receptors for verapamil-like calcium antagonists, and the interactions of drugs with voltage-sensitive calcium fluxes in rat brain synaptosomes. From binding studies I have found that the ligand of choice for labeling the verapamil receptor is (-)(/sup 3/H)desmethoxy-verapamil. This drug labels potently, reversibly and stereoselectively two receptors in membranes prepared from rat brain and rabbit skeletal muscle tissues. In equilibrium studies dihydropyridine calcium antagonists interact in a non-competitive fashion, while many non-DHPs are apparently competitive. In-depth kinetic studies in skeletal muscle membranes indicate that the two receptors are linked in a negative heterotropic fashion, and that low-affinity binding of (-) (/sup 3/H)desmethoxy-verapamil may be to the diltiazem receptor. However, these studies were not able to distinguish between the hypothesis that diltiazem binds to spatially separate, allosterically coupled receptors, and the hypothesis that diltiazem binds to a subsite of the verapamil receptor.

  11. [Congenital muscular dystrophies in children].

    PubMed

    Scavone-Mauro, Cristina; Barros, Graciela

    2013-09-06

    From the clinical and genetic point of view, congenital muscular dystrophies (CMD) are a heterogenic group of diseases within neuromuscular pathologies. The best known forms are: merosin deficiency CMD, collagen VI deficiency CMD, LMNA-related CMD, selenoprotein-related CMD (SEPN1) and alpha-dystroglycan-related CMD. They present with a broad spectrum of clinical phenotypes. Most of them are transmitted by recessive autosomal inheritance. The initial manifestations very often begin in infancy or in the neonatal period. There are clinical suspicions of the existence of hypotonia and paresis, and they are characterised by a dystrophic pattern in the muscular biopsy (muscle replaced by fibroadipose tissue, with necrosis and cell regeneration). Advances in the understanding of the molecular pathogenesis of CMD have made it possible to make further progress in the classification of the different subtypes. The aim of this review is to comment on the advances made in recent years as regards the classification of CMD in terms of genetics, the proteins involved and their clinical presentation.

  12. Selective activation of α7 nicotinic acetylcholine receptor (nAChRα7) inhibits muscular degeneration in mdx dystrophic mice.

    PubMed

    Leite, Paulo Emílio Correa; Gandía, Luís; de Pascual, Ricardo; Nanclares, Carmen; Colmena, Inés; Santos, Wilson C; Lagrota-Candido, Jussara; Quirico-Santos, Thereza

    2014-07-21

    Amount evidence indicates that α7 nicotinic acetylcholine receptor (nAChRα7) activation reduces production of inflammatory mediators. This work aimed to verify the influence of endogenous nAChRα7 activation on the regulation of full-blown muscular inflammation in mdx mouse with Duchenne muscular dystrophy. We used mdx mice with 3 weeks-old at the height myonecrosis, and C57 nAChRα7(+/+) wild-type and nAChRα7(-/-) knockout mice with muscular injury induced with 60µL 0.5% bupivacaine (bp) in the gastrocnemius muscle. Pharmacological treatment included selective nAChRα7 agonist PNU282987 (0.3mg/kg and 1.0mg/kg) and the antagonist methyllycaconitine (MLA at 1.0mg/kg) injected intraperitoneally for 7 days. Selective nAChRα7 activation of mdx mice with PNU282987 reduced circulating levels of lactate dehydrogenase (LDH, a marker of cell death by necrosis) and the area of perivascular inflammatory infiltrate, and production of inflammatory mediators TNFα and metalloprotease MMP-9 activity. Conversely, PNU282987 treatment increased MMP-2 activity, an indication of muscular tissue remodeling associated with regeneration, in both mdx mice and WTα7 mice with bp-induced muscular lesion. Treatment with PNU282987 had no effect on α7KO, and MLA abolished the nAChRα7 agonist-induced anti-inflammatory effect in both mdx and WT. In conclusion, nAChRα7 activation inhibits muscular inflammation and activates tissue remodeling by increasing muscular regeneration. These effects were not accompanied with fibrosis and/or deposition of non-functional collagen. The nAChRα7 activation may be considered as a potential target for pharmacological strategies to reduce inflammation and activate mechanisms of muscular regeneration.

  13. Spinal muscular atrophy disease: a literature review for therapeutic strategies.

    PubMed

    Stavarachi, M; Apostol, P; Toma, M; Cimponeriu, D; Gavrila, L

    2010-01-01

    Currently, there is no cure for the treatment of spinal muscular atrophy (SMA). Based on the available clinical and molecular findings, different therapeutic strategies were tested in vitro and in vivo and clinical trials are ongoing. The main therapeutic direction is focused on the enhancement of SMN expression by increasing the full-length (fl) SMN2 transcript levels, preventing the SMN exon 7 from skipping or from protein stabilizing. In addition, the action of neurotrophic, neuroprotective or anabolic agents is tested and stem cell and gene therapy approaches are in a promising development.

  14. Opposing local effects of endocannabinoids on the activity of noradrenergic neurons and release of noradrenaline: relevance for their role in depression and in the actions of CB(1) receptor antagonists.

    PubMed

    Kirilly, E; Hunyady, L; Bagdy, G

    2013-01-01

    There is strong evidence that endocannabinoids modulate signaling of serotonin and noradrenaline, which play key roles in the pathophysiology and treatment of anxiety and depression. Most pharmacological and genetic, human and rodent studies suggest that the presence of under-functioning endocannabinoid type-1 (CB(1)) receptors is associated with increased anxiety and elevated extracellular serotonin concentration. In contrast, noradrenaline is presumably implicated in the mediation of depression-type symptoms of CB(1) receptor antagonists. Evidence shows that most CB(1) receptors located on axons and terminals of GABA-ergic, serotonergic or glutamatergic neurons stimulate the activity of noradrenergic neurons. In contrast, those located on noradrenergic axons and terminals inhibit noradrenaline release efficiently. In this latter process, excitatory ionotropic or G protein-coupled receptors, such as the NMDA, alpha1 and beta1 adrenergic receptors, activate local endocannabinoid synthesis at postsynaptic sites and stimulate retrograde endocannabinoid neurotransmission acting on CB(1) receptors of noradrenergic terminals. The underlying mechanisms include calcium signal generation, which activates enzymes that increase the synthesis of both anandamide and 2-arachidonoylglycerol, while G(q/11) protein activation also increases the formation of 2-arachidonoylglycerol from diacylglycerol during the signaling process. In addition, other non-CB(1) receptor endocannabinoid targets such as CB(2), transient receptor potential vanilloid subtype, peroxisome proliferator-activated receptor-alpha and possibly GPR55 can also mediate some of the endocannabinoid effects. In conclusion, both neuronal activation and neurotransmitter release depend on the in situ synthesized endocannabinoids and thus, local endocannabinoid concentrations in different brain areas may be crucial in the net effect, namely in the regulation of neurons located postsynaptically to the noradrenergic synapse.

  15. Prevention of thrombosis and rethrombosis and enhancement of the thrombolytic actions of recombinant tissue-type plasminogen activator in the canine heart by DMP728, a glycoprotein IIb/IIIa antagonist.

    PubMed Central

    Lucchessi, B R; Rote, W E; Driscoll, E M; Mu, D X

    1994-01-01

    1. We studied DMP728, a non-peptide glycoprotein (GP) IIb/IIIa receptor antagonist, for prevention of coronary artery thrombosis or rethrombosis in a chronic canine model subjected to arterial injury. 2. In protocol I, DMP728 (1.0 mg kg-1, i.v., n = 8) or saline (n = 8) was administered and a 150 microA anodal current was applied to the intimal surface of the left circumflex coronary artery (LCX). Dogs were monitored for 6 h and again on each of 5 subsequent days. 3. Ex vivo platelet aggregation was inhibited but returned to baseline 1 day after drug administration. Thrombus weight was reduced (saline, 20.7 +/- 5.0 mg; DMP728 1.7 +/- 0.4 mg; P < 0.05), as was infarct size [saline, 27.5 +/- 4.3; DMP728, 1.6 +/- 0.7 (per cent left ventricle); P < 0.05]. All control animals died by day 3, while all but one of the treated dogs survived the entire protocol (P < 0.05). 4. In protocol II, an LCX thrombus was induced and thrombolytic therapy was initiated 30 min later. DMP728 (1.0 mg kg-1, i.v., n = 8) or saline (n = 8) was administered 5 min after recombinant tissue-type plasminogen activator infusion had begun. The incidence of reocclusion was reduced by DMP728 (saline, 4/8; DMP728, 1/8). One day after thrombolysis, 7/8 DMP728-treated animals were alive compared with 1/8 in the control group (P = 0.01). 5. DMP728 inhibited ex vivo platelet aggregation, prevented primary and secondary occlusive thrombus formation, reduced thrombus weight and infarct size and increased survival in a chronic canine model of coronary artery thrombus formation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7889289

  16. 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

  17. [Autosomal recessive limb-girdle muscular dystrophy].

    PubMed

    Hernández-Caballero, Marta E; Miranda-Duarte, Antonio; Escobar-Cedillo, Rosa E; Villegas-Castrejon, Hilda

    2010-10-16

    Muscular dystrophies are a heterogeneous group of hereditary diseases characterized by loss of muscle and weakness of non neurogenic origin. They are caused by mutations in one or more genes involved in the formation of muscle cells. The discovery of several proteins in the muscle began with the discovery of dystrophin, 130 years after the clinical description of muscular dystrophy. Currently, due to a better understanding of the biology of normal and diseased muscle, has achieved a classification at the molecular level of different types of muscular dystrophies, according to the protein that is affected. This has been particularly important for limb girdle muscular dystrophies, which present clinical features that can lead to confusion with Duchenne muscular dystrophy. Moreover, in recent years has encouraged the development of therapies in the near future could provide a solution for restoring the function of the muscle fiber.

  18. Dysregulation of calcium homeostasis in muscular dystrophies.

    PubMed

    Vallejo-Illarramendi, Ainara; Toral-Ojeda, Ivan; Aldanondo, Garazi; López de Munain, Adolfo

    2014-10-08

    Muscular dystrophies are a group of diseases characterised by the primary wasting of skeletal muscle, which compromises patient mobility and in the most severe cases originate a complete paralysis and premature death. Existing evidence implicates calcium dysregulation as an underlying crucial event in the pathophysiology of several muscular dystrophies, such as dystrophinopathies, calpainopathies or myotonic dystrophy among others. Duchenne muscular dystrophy is the most frequent myopathy in childhood, and calpainopathy or LGMD2A is the most common form of limb-girdle muscular dystrophy, whereas myotonic dystrophy is the most frequent inherited muscle disease worldwide. In this review, we summarise recent advances in our understanding of calcium ion cycling through the sarcolemma, the sarcoplasmic reticulum and mitochondria, and its involvement in the pathogenesis of these dystrophies. We also discuss some of the clinical implications of recent findings regarding Ca2+ handling as well as novel approaches to treat muscular dystrophies targeting Ca2+ regulatory proteins.

  19. Carrier testing for spinal muscular atrophy

    PubMed Central

    Gitlin, Jonathan M.; Fischbeck, Kenneth; Crawford, Thomas O.; Cwik, Valerie; Fleischman, Alan; Gonye, Karla; Heine, Deborah; Hobby, Kenneth; Kaufmann, Petra; Keiles, Steven; MacKenzie, Alex; Musci, Thomas; Prior, Thomas; Lloyd-Puryear, Michele; Sugarman, Elaine A.; Terry, Sharon F.; Urv, Tiina; Wang, Ching; Watson, Michael; Yaron, Yuval; Frosst, Phyllis; Howell, R. Rodney

    2014-01-01

    Spinal muscular atrophy is the most common fatal hereditary disease among newborns and infants. There is as yet no effective treatment. Although a carrier test is available, currently there is disagreement among professional medical societies who proffer standards of care as to whether or not carrier screening for spinal muscular atrophy should be offered as part of routine reproductive care. This leaves health care providers without clear guidance. In fall 2009, a meeting was held by National Institutes of Health to examine the scientific basis for spinal muscular atrophy carrier screening and to consider the issues that accompany such screening. In this article, the meeting participants summarize the discussions and conclude that pan-ethnic carrier screening for spinal muscular atrophy is technically feasible and that the specific study of implementing a spinal muscular atrophy carrier screening program raises broader issues about determining the scope and specifics of carrier screening in general. PMID:20808230

  20. Small Molecule CXCR3 Antagonists.

    PubMed

    Andrews, Stephen P; Cox, Rhona J

    2016-04-14

    Chemokines and their receptors are known to play important roles in disease. More than 40 chemokine ligands and 20 chemokine receptors have been identified, but, to date, only two small molecule chemokine receptor antagonists have been approved by the FDA. The chemokine receptor CXCR3 was identified in 1996, and nearly 20 years later, new areas of CXCR3 disease biology continue to emerge. Several classes of small molecule CXCR3 antagonists have been developed, and two have shown efficacy in preclinical models of inflammatory disease. However, only one CXCR3 antagonist has been evaluated in clinical trials, and there remain many opportunities to further investigate known classes of CXCR3 antagonists and to identify new chemotypes. This Perspective reviews the known CXCR3 antagonists and considers future opportunities for the development of small molecules for clinical evaluation.

  1. Lower limb examinations for muscular tension estimation methods for each muscle group based on functionally different effective muscle theory.

    PubMed

    Nishii, Taiki; Komada, Satoshi; Yashiro, Daisuke; Hirai, Junji

    2013-01-01

    Conventional estimation methods distribute tension to muscles by solving optimization problems, because the system is redundant. The theory of functionally different effective muscle, based on 3 antagonistic pairs of muscle groups in limbs, has enabled to calculate the maximum joint torque of each pair, i.e. functionally different effective muscle force. Based on this theory, a method to estimate muscular tension has been proposed, where joint torque of each muscle group is derived by multiplying functionally different effective muscle force, the muscular activity of muscular activity pattern for direction of tip force, and ratio of tip force to maximum output force. The estimation of this method is as good as Crowninshield's method, moreover this method also reduce the computation time if the estimation concerns a selected muscle group.

  2. Physiology of respiratory disturbances in muscular dystrophies

    PubMed Central

    Lo Mauro, Antonella

    2016-01-01

    Muscular dystrophy is a group of inherited myopathies characterised by progressive skeletal muscle wasting, including of the respiratory muscles. Respiratory failure, i.e. when the respiratory system fails in its gas exchange functions, is a common feature in muscular dystrophy, being the main cause of death, and it is a consequence of lung failure, pump failure or a combination of the two. The former is due to recurrent aspiration, the latter to progressive weakness of respiratory muscles and an increase in the load against which they must contract. In fact, both the resistive and elastic components of the work of breathing increase due to airway obstruction and chest wall and lung stiffening, respectively. The respiratory disturbances in muscular dystrophy are restrictive pulmonary function, hypoventilation, altered thoracoabdominal pattern, hypercapnia, dyspnoea, impaired regulation of breathing, inefficient cough and sleep disordered breathing. They can be present at different rates according to the type of muscular dystrophy and its progression, leading to different onset of each symptom, prognosis and degree of respiratory involvement. Key points A common feature of muscular dystrophy is respiratory failure, i.e. the inability of the respiratory system to provide proper oxygenation and carbon dioxide elimination. In the lung, respiratory failure is caused by recurrent aspiration, and leads to hypoxaemia and hypercarbia. Ventilatory failure in muscular dystrophy is caused by increased respiratory load and respiratory muscles weakness. Respiratory load increases in muscular dystrophy because scoliosis makes chest wall compliance decrease, atelectasis and fibrosis make lung compliance decrease, and airway obstruction makes airway resistance increase. The consequences of respiratory pump failure are restrictive pulmonary function, hypoventilation, altered thoracoabdominal pattern, hypercapnia, dyspnoea, impaired regulation of breathing, inefficient cough and

  3. [Congenital unilateral muscular hyperplasia of the hand - a rare malformation].

    PubMed

    Pillukat, T; Lanz, U

    2004-01-01

    This is a report on eight cases of a rare congenital malformation in the upper extremity, consisting of a unilateral muscular hyperplasia. In addition to the hand, all segments of the upper extremity may be affected. The hyperplasia is always unilateral, preferably on the right hand side, in combination with accessory muscles. Hereditary dependence or association with other malformations has not been observed. Six of eight patients were male. Shoulder and arm function were normal in all cases. Ulnar drift of the fingers in the metacarpophalangeal joints (six of eight patients), flexion contractures of the metacarpophalangeal joints (six of eight patients) and extension contractures of the wrist (three of eight patients) to various degrees were seen. A prominence of the second and third metacarpal head with an enlarged space between them gave the affected hands a very typical appearance (six of eight patients). Deformities and functional limitations requiring surgical treatment were present in six patients. In all cases, accessory muscles were found intraoperatively and resected. The macroscopic and microscopic appearance of the muscle specimen did not differ from normal muscular tissue. In all cases, additional procedures were necessary to improve the overall function. Nevertheless, the reconstructive efforts did not lead to an entirely normal hand function or appearance. The malformation we describe can clearly be distinguished from other malformations such as arthrogryposis multiplex congenita, Freeman-Sheldon syndrome or macrodactyly. Up to now, only two other reports were found in the literature showing characteristics similar to those in our own cases. Four similar cases were observed by Benatar. From a pathomechanical point of view, a disturbance in the muscular balance seems to cause the deformities and functional limitations. This imbalance could be related to accessory muscles which are not opposed by defined antagonists or to an unbalanced hyperplasia of

  4. Cannabinoids and muscular pain. Effectiveness of the local administration in rat.

    PubMed

    Sánchez Robles, E Ma; Bagües Arias, A; Martín Fontelles, Ma I

    2012-09-01

    Pain associated with musculoskeletal disorders can be difficult to control and the incorporation of new approaches for its treatment is an interesting challenge. Activation of cannabinoid (CB) receptors decreases nociceptive transmission in acute, inflammatory and neuropathic pain states; however, although the use of cannabis derivatives has been recently accepted as a useful alternative for the treatment of spasticity and pain in patients with multiple sclerosis, the effects of CB receptor agonists in muscular pain have hardly been studied. Here, we characterized the antinociceptive effect of non selective and selective CB agonists by systemic and local administration, in two muscular models of pain, masseter and gastrocnemius, induced by hypertonic saline (HS) injection. Drugs used were: the non-selective agonist WIN 55,212-2 and two selective agonists, ACEA (CB 1) and JWH 015 (CB 2); AM 251 (CB 1) and AM 630 (CB 2) were used as selective antagonists. In the masseter pain model, both systemic (intraperitoneal) and local (intramuscular) administration of CB 1 and CB 2 agonists reduced the nociceptive behaviour induced by HS, whereas in the gastrocnemius model the local administration was more effective than systemic. Our results provide evidence that both, CB 1 and CB 2 receptors can contribute to muscular antinociception and, interestingly, suggest that the local administration of CB agonists could be a new and useful pharmacological strategy in the treatment of muscular pain, avoiding adverse effects induced by systemic administration. © 2012 European Federation of International Association for the Study of Pain Chapters.

  5. Global muscular dystrophy research: A 25-year bibliometric perspective.

    PubMed

    Ram, Shri

    2017-01-01

    Muscular dystrophy is a genetic disorder leading to progressive weakness of muscles caused due to dysfunction in or lack of protein in muscle cells. The prevalence of muscular dystrophy has been observed globally and is becoming a critical area of study for better health services. The purpose of the study is to analyze the research strength of muscular dystrophy using bibliographic literature. A quantitative literature analysis was carried out on muscular dystrophy from 1991 to 2015 for assessing the global research trends. This literature-based study was conducted using the documents retrieved from the Science Citation Index using the keywords: Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), Congenital Muscular Dystrophy (CMD), Myotonic Dystrophy, Emery-Dreifuss Muscular Dystrophy, Facioscapulohumeral Muscular Dystrophy, Oculopharyngeal Muscular Dystrophy, and Limb-Girdle Muscular Dystrophy. Analysis was done for annual productivity of publication, authorship, collaboration, country performance, citation frequency, characteristics of most cited document, journal productivity, etc.

  6. Osteoprotegerin protects against muscular dystrophy.

    PubMed

    Dufresne, Sébastien S; Dumont, Nicolas A; Bouchard, Patrice; Lavergne, Éliane; Penninger, Josef M; Frenette, Jérôme

    2015-04-01

    Receptor-activator of NF-κB, its ligand RANKL, and the soluble decoy receptor osteoprotegerin are the key regulators of osteoclast differentiation and bone remodeling. Although there is a strong association between osteoporosis and skeletal muscle atrophy/dysfunction, the functional relevance of a particular biological pathway that synchronously regulates bone and skeletal muscle physiopathology still is elusive. Here, we show that muscle cells can produce and secrete osteoprotegerin and pharmacologic treatment of dystrophic mdx mice with recombinant osteoprotegerin muscles. (Recombinant osteoprotegerin-Fc mitigates the loss of muscle force in a dose-dependent manner and preserves muscle integrity, particularly in fast-twitch extensor digitorum longus.) Our data identify osteoprotegerin as a novel protector of muscle integrity, and it potentially represents a new therapeutic avenue for both muscular diseases and osteoporosis.

  7. 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

  8. Neuronal death enhanced by N-methyl-d-aspartate antagonists

    PubMed Central

    Ikonomidou, Chrysanthy; Stefovska, Vanya; Turski, Lechoslaw

    2000-01-01

    Glutamate promotes neuronal survival during brain development and destroys neurons after injuries in the mature brain. Glutamate antagonists are in human clinical trials aiming to demonstrate limitation of neuronal injury after head trauma, which consists of both rapid and slowly progressing neurodegeneration. Furthermore, glutamate antagonists are considered for neuroprotection in chronic neurodegenerative disorders with slowly progressing cell death only. Therefore, humans suffering from Huntington's disease, characterized by slowly progressing neurodegeneration of the basal ganglia, are subjected to trials with glutamate antagonists. Here we demonstrate that progressive neurodegeneration in the basal ganglia induced by the mitochondrial toxin 3-nitropropionate or in the hippocampus by traumatic brain injury is enhanced by N-methyl-d-aspartate antagonists but ameliorated by α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate antagonists. These observations reveal that N-methyl-d-aspartate antagonists may increase neurodestruction in mature brain undergoing slowly progressing neurodegeneration, whereas blockade of the action of glutamate at α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors may be neuroprotective. PMID:11058158

  9. Porcine models of muscular dystrophy.

    PubMed

    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.

  10. 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.

  11. NK-1 receptor antagonists: a new paradigm in pharmacological therapy.

    PubMed

    Muñoz, M; Coveñas, R

    2011-01-01

    The neuropeptide substance P (SP) shows a widespread distribution in both the central and peripheral nervous systems and it is known that after binding to the neurokinin-1 (NK-1) receptors, SP regulates many biological functions in the central nervous system such as emotional behaviour, stress, depression, anxiety, emesis, migraine, alcohol addiction and neurodegeneration. SP has been also implicated in pain, inflammation, hepatotoxicity and in virus proliferation, and it plays an important role in cancer (e.g., tumour cell proliferation, angiogenesis, and the migration of tumour cells for invasion and metastasis). By contrast, it is known that after binding to NK-1 receptors, NK-1 receptor antagonists specifically inhibit the above-mentioned biological functions mediated by SP. Thus, these antagonists exert an anxyolitic, antidepressant, antiemetic, antimigraine, antialcohol addiction or neuroprotector effect in the central nervous system, and they play a role in analgesic, antiinflammatory, hepatoprotector processes and in antivirus proliferation. Regarding cancer, NK-1 receptor antagonists exert an antitumour action (inducing tumour cell death by apoptosis), and induce antiangiogenesis and inhibit the migration of tumour cells. It is also known that NK-1 receptors have a widespread distribution and that they are overexpressed in tumour cells. Thus, NK-1 receptor antagonists are molecularly targeted agents. In general, current drugs have a single therapeutic effect, although less commonly they may exert several. However, the data reported above indicate that NK-1 receptor antagonists are promising drugs, exerting many therapeutic effects (the action of such antagonists is dose-dependent and, depending on the concentration, has more positive effects). In this review, we update the multiple therapeutic effects exerted by NK-1 receptor antagonists.

  12. 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

  13. In Silico Discovery of Androgen Receptor Antagonists with Activity in Castration Resistant Prostate Cancer

    PubMed Central

    Shen, Howard C.; Shanmugasundaram, Kumaran; Simon, Nicholas I.; Cai, Changmeng; Wang, Hongyun; Chen, Sen; Rigby, Alan C.

    2012-01-01

    Previously available androgen receptor (AR) antagonists (bicalutamide, flutamide, and nilutamide) have limited activity against AR in prostate cancers that relapse after castration [castration resistant prostate cancer (CRPC)]. However, recent AR competitive antagonists such as MDV3100, generated through chemical modifications to the current AR ligands, appear to have increased activity in CRPC and have novel mechanisms of action. Using pharmacophore models and a refined homology model of the antagonist-liganded AR ligand binding domain, we carried out in silico screens of small molecule libraries and report here on the identification of a series of structurally distinct nonsteroidal small molecule competitive AR antagonists. Despite their unique chemical architectures, compounds representing each of six chemotypes functioned in vitro as pure AR antagonists. Moreover, similarly to MDV3100 and in contrast to previous AR antagonists, these compounds all prevented AR binding to chromatin, consistent with each of the six chemotypes stabilizing a similar AR antagonist conformation. Additional studies with the lead chemotype (chemotype A) showed enhanced AR protein degradation, which was dependent on helix 12 in the AR ligand binding domain. Significantly, chemotype A compounds functioned as AR antagonists in vivo in normal male mice and suppressed AR activity and tumor cell proliferation in human CRPC xenografts. These data indicate that certain ligand-induced structural alterations in the AR ligand binding domain may both impair AR chromatin binding and enhance AR degradation and support continued efforts to develop AR antagonists with unique mechanisms of action and efficacy in CRPC. PMID:23023563

  14. In silico discovery of androgen receptor antagonists with activity in castration resistant prostate cancer.

    PubMed

    Shen, Howard C; Shanmugasundaram, Kumaran; Simon, Nicholas I; Cai, Changmeng; Wang, Hongyun; Chen, Sen; Balk, Steven P; Rigby, Alan C

    2012-11-01

    Previously available androgen receptor (AR) antagonists (bicalutamide, flutamide, and nilutamide) have limited activity against AR in prostate cancers that relapse after castration [castration resistant prostate cancer (CRPC)]. However, recent AR competitive antagonists such as MDV3100, generated through chemical modifications to the current AR ligands, appear to have increased activity in CRPC and have novel mechanisms of action. Using pharmacophore models and a refined homology model of the antagonist-liganded AR ligand binding domain, we carried out in silico screens of small molecule libraries and report here on the identification of a series of structurally distinct nonsteroidal small molecule competitive AR antagonists. Despite their unique chemical architectures, compounds representing each of six chemotypes functioned in vitro as pure AR antagonists. Moreover, similarly to MDV3100 and in contrast to previous AR antagonists, these compounds all prevented AR binding to chromatin, consistent with each of the six chemotypes stabilizing a similar AR antagonist conformation. Additional studies with the lead chemotype (chemotype A) showed enhanced AR protein degradation, which was dependent on helix 12 in the AR ligand binding domain. Significantly, chemotype A compounds functioned as AR antagonists in vivo in normal male mice and suppressed AR activity and tumor cell proliferation in human CRPC xenografts. These data indicate that certain ligand-induced structural alterations in the AR ligand binding domain may both impair AR chromatin binding and enhance AR degradation and support continued efforts to develop AR antagonists with unique mechanisms of action and efficacy in CRPC.

  15. A nonsteroidal glucocorticoid receptor antagonist.

    PubMed

    Miner, Jeffrey N; Tyree, Curtis; Hu, Junlian; Berger, Elaine; Marschke, Keith; Nakane, Masaki; Coghlan, Michael J; Clemm, Dave; Lane, Ben; Rosen, Jon

    2003-01-01

    Selective intracellular receptor antagonists are used clinically to ameliorate hormone-dependent disease states. Patients with Cushing's syndrome have high levels of the glucocorticoid, cortisol, and suffer significant consequences from this overexposure. High levels of this hormone are also implicated in exacerbating diabetes and the stress response. Selectively inhibiting this hormone may have clinical benefit in these disease states. To this end, we have identified the first selective, nonsteroidal glucocorticoid receptor (GR) antagonist. This compound is characterized by a tri-aryl methane core chemical structure. This GR-specific antagonist binds with nanomolar affinity to the GR and has no detectable binding affinity for the highly related receptors for mineralocorticoids, androgens, estrogens, and progestins. We demonstrate that this antagonist inhibits glucocorticoid-mediated transcriptional regulation. This compound binds competitively with steroids, likely occupying a similar site within the ligand-binding domain. Once bound, however, the compound fails to induce critical conformational changes in the receptor necessary for agonist activity.

  16. Characteristics of diffuse muscular coactivation (DMC) in persons with fibromyalgia -- part 2.

    PubMed

    Donaldson, C C S; MacInnis, A L; Snelling, L S; Sella, G E; Mueller, H H

    2002-01-01

    This study examined the electrical characteristics (Root Mean Square -- RMS and median frequency) of Diffuse Muscular Coactivation (DMC) associated with the tender points of fibromyalgia. DMC is defined as an increase from resting levels (tonus) in the electrical activity of any muscle during a movement which does not involve that muscle and is not part of the agonist -- antagonist unit. The results show an increase in RMS in fibromyalgia sufferers as compared to controls. Coactivation was stronger proximal to the neck and decreased in intensity as the area recorded moved distally. Median frequency changed over time but not significantly between groups. Possible neurological mechanisms are discussed.

  17. Targeting latent TGFβ release in muscular dystrophy.

    PubMed

    Ceco, Ermelinda; Bogdanovich, Sasha; Gardner, Brandon; Miller, Tamari; DeJesus, Adam; Earley, Judy U; Hadhazy, Michele; Smith, Lucas R; Barton, Elisabeth R; Molkentin, Jeffery D; McNally, Elizabeth M

    2014-10-22

    Latent transforming growth factor-β (TGFβ) binding proteins (LTBPs) bind to inactive TGFβ in the extracellular matrix. In mice, muscular dystrophy symptoms are intensified by a genetic polymorphism that changes the hinge region of LTBP, leading to increased proteolytic susceptibility and TGFβ release. We have found that the hinge region of human LTBP4 was also readily proteolysed and that proteolysis could be blocked by an antibody to the hinge region. Transgenic mice were generated to carry a bacterial artificial chromosome encoding the human LTBP4 gene. These transgenic mice displayed larger myofibers, increased damage after muscle injury, and enhanced TGFβ signaling. In the mdx mouse model of Duchenne muscular dystrophy, the human LTBP4 transgene exacerbated muscular dystrophy symptoms and resulted in weaker muscles with an increased inflammatory infiltrate and greater LTBP4 cleavage in vivo. Blocking LTBP4 cleavage may be a therapeutic strategy to reduce TGFβ release and activity and decrease inflammation and muscle damage in muscular dystrophy.

  18. Genetics Home Reference: tibial muscular dystrophy

    MedlinePlus

    ... more common in particular ethnic groups? Genetic Changes Mutations in the TTN gene cause tibial muscular dystrophy . ... in chemical signaling and in assembling new sarcomeres. Mutations in the TTN gene alter the structure and ...

  19. 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. Published by Elsevier Ltd.

  20. How Do People Cope with Muscular Dystrophy?

    MedlinePlus

    ... section. How do people cope with muscular dystrophy (MD)? Although MD presents many challenges in many different aspects of daily life, those with MD enjoy full lives. Advances in drug therapies, physical ...

  1. [Muscular strength development by electromagnetic stimulation].

    PubMed

    Gorodnichev, R M; Beliaev, A G; Pivovarova, E A; Shliakhtov, V N

    2014-01-01

    A new tool for muscular strength development by electromagnetic stimulation (MS) of muscular during voluntary contraction has been described. 18 healthy subjects (men) took part in the research. They were devided into two groups--control (CG) and experimental (EG). Subjects of CG and EG have equal muscular strength parameters. M. gastrocnemius of subjects in EG was exposed to MS (1.8 T, 5 Hz) during training exercises (plantar foot flection). The subjects of CG did not receive MS. The torque of plantar foot flection of EG subjects increased significantly (24%) during 10 days training. The torque of plantar foot flection of CG subjects did not change significantly. We hypothesize increasing of muscular strength of EG subjects was result of high-threshold motor units activation under MS.

  2. [Ceruloplasmin in patients with Duchenne muscular dystrophy].

    PubMed

    Reyes, J; Holmgren, J; Colombo, M

    1991-03-01

    Duchenne muscular dystrophy is a well defined form of sex linked inherited muscular disease. Approximately 1/3 of cases are the product of a new mutation. We studied 20 patients with this disease and 19 heterozygous females. Ceruloplasmin levels were significantly higher in patients compared to controls. A possible protective role of this enzyme against oxydating agents may help prevent peroxydation of lipids from the smooth muscle cell membrane.

  3. Duchenne muscular dystrophy: the management of scoliosis

    PubMed Central

    Gardner, Adrian C.; Roper, Helen P.; Chikermane, Ashish A.; Tatman, Andrew J.

    2016-01-01

    This study summaries the current management of scoliosis in patients with Duchenne Muscular Dystrophy. A literature review of Medline was performed and the collected articles critically appraised. This literature is discussed to give an overview of the current management of scoliosis within Duchenne Muscular Dystrophy. Importantly, improvements in respiratory care, the use of steroids and improving surgical techniques have allowed patients to maintain quality of life and improved life expectancy in this patient group. PMID:27757431

  4. 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

  5. Platelet-activating factor antagonists.

    PubMed

    Negro Alvarez, J M; Miralles López, J C; Ortiz Martínez, J L; Abellán Alemán, A; Rubio del Barrio, R

    1997-01-01

    Platelet-activating factor (PAF), identified as 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine, exhibits potent proinflammatory properties. PAF is produced by numerous cell types, including endothelial cells, neutrophils, monocytes, macrophages, basophils, eosinophils and mastocytes. Since the discovery and identification of the chemical structure of PAF, a large variety of specific PAF-receptor antagonists, both natural and synthetic compounds, have been described. Intensive research has been conducted and development programs set up by more 25 pharmaceutical companies world-wide, studying the therapeutic interest of more than 50 PAF-receptors antagonists in various pathophysiological conditions. Medline (1966-1996), Embase (Excerpta Medica; 1974-1996), and other biomedical and drug directory databases were searched to identify English-language articles (basic science, clinical trial research, and review articles) and abstracts of conference proceedings on PAF receptor antagonists and related terms. The most important PAF receptor antagonists are reviewed with their effectiveness in various experimental tests. Fundamentally, PAF antagonists may be divided in two groups: natural and synthetic compounds. Natural (Ginkgolides, Kadsurenone, Chantancin, Phomactin, Swietemohonin A, Prehispalone, THC-7-oic acid, Aglafoline, FR 900452, PCA 4248 and SCH 37370), and synthetic antagonists (CV-3988, CV-6209, SRI 63-072, SRI 63-441, UR-10324, UR-11353, E-5880, CL 184005, 6-Mono and Bis-aryl phosphate antagonists, TCV-309, Ro-74719, WEB 2086, Y 24180, BN 50726, BN 50727, BN 50730, BN 50739, Ro 24-4736, Ro 24-0238, RP 55778, RP 59227, RP 66681, YM 264, YM 461, SM 10661, SR 27417, UK 74505, BB 182, BB 823, BB 654, SDZ 64-412, SDZ 65-123, L 652731, L 659898, L 668750, L 671284, L680573, L 680574, CIS 19, ABT-299 and Pinusolide) have a great variability in their chemical structure that might have importance in their different pharmacological profile. The great majority of these

  6. Mixed antagonistic effects of bilobalide at rho1 GABAC receptor.

    PubMed

    Huang, S H; Duke, R K; Chebib, M; Sasaki, K; Wada, K; Johnston, G A R

    2006-01-01

    Bilobalide was found to be a moderately potent antagonist with a weak use-dependent effect at recombinant human rho(1) GABA(C) receptors expressed in Xenopus oocytes using two-electrode voltage clamp methodology. Antagonism of bilobalide at homomeric rho(1) GABA(C) receptors appeared to be mixed. At low concentration, bilobalide (3 microM) caused a parallel right shift and surmountable GABA maximal response of the GABA dose-response curve characteristic of a competitive antagonist. At high concentrations, bilobalide (10-100 microM) caused nonparallel right shifts and reduced maximal GABA responses of GABA dose-response curves characteristic of a noncompetitive antagonist. The potency of bilobalide appears to be dependent on the concentrations of GABA and was more potent at lower GABA concentrations. The mechanism of action of bilobalide at rho(1) GABA(C) receptors appears to be similar to that of the chloride channel blocker picrotoxinin.

  7. Therapeutics in duchenne muscular dystrophy.

    PubMed

    Strober, Jonathan B

    2006-04-01

    Duchenne muscular dystrophy (DMD) is a fatal disorder affecting approximately 1 in 3,500 live born males, characterized by progressive muscle weakness. Several different strategies are being investigated in developing a cure for this disorder. Until a cure is found, therapeutic and supportive care is essential in preventing complications and improving the afflicted child's quality of life. Currently, corticosteroids are the only class of drug that has been extensively studied in this condition, with controversy existing over the use of these drugs, especially in light of the multiple side effects that may occur. The use of nutritional supplements has expanded in recent years as researchers improve our abilities to use gene and stem cell therapies, which will hopefully lead to a cure soon. This article discusses the importance of therapeutic interventions in children with DMD, the current debate over the use of corticosteroids to treat this disease, the growing use of natural supplements as a new means of treating these boys and provides an update on the current state of gene and stem cell therapies.

  8. Muscular fatigue: considerations for dance.

    PubMed

    Wyon, Matthew A; Koutedakis, Yiannis

    2013-01-01

    Muscular fatigue can be defined as the failure to maintain an expected power output. It is a multifaceted phenomenon that incorporates metabolic, neural and neuromuscular components, among others. Metabolic causes of fatigue are associated with the ability to maintain energy supply during exercise, the speed at which homeostasis is achieved post-exercise, and the effects of high intensity exercise by-products on the peripheral neuromuscular system. Research has indicated that the central nervous system plays a protective role in preventing catastrophic muscle damage by reducing the intensity and frequency of propagation founded on biofeedback from the muscle cells. The duration and particularly the type of physical activity play a role in the development of muscle fatigue, with impact or weightbearing exercises, such as dance, producing increased symptoms compared to non-impact or non-weightbearing equivalents. The effects of prolonged exercise and the associated increased levels of muscle fatigue that may lead to compromises in neuromuscular propagation need to be considered in dance.

  9. Bone and Spinal Muscular Atrophy.

    PubMed

    Vai, Silvia; Bianchi, Maria Luisa; Moroni, Isabella; Mastella, Chiara; Broggi, Francesca; Morandi, Lucia; Arnoldi, Maria Teresa; Bussolino, Chiara; Baranello, Giovanni

    2015-10-01

    Spinal Muscular Atrophy (SMA) is an autosomal recessive neuromuscular disease, leading to progressive denervation atrophy in the involved skeletal muscles. Bone status has been poorly studied. We assessed bone metabolism, bone mineral density (BMD) and fractures in 30 children (age range 15-171 months) affected by SMA types 2 and 3. Eighteen children (60%) had higher than normal levels of CTx (bone resorption marker); 25-OH vitamin D was in the lower range of normal (below 20 ng/ml in 9 children and below 12 ng/ml in 2). Lumbar spine BMAD (bone mineral apparent density) Z-score was below -1.5 in 50% of children. According to clinical records, four children had sustained four peripheral fractures; on spine X-rays, we observed 9 previously undiagnosed vertebral fractures in 7 children. There was a significant inverse regression between PTH and 25-OH D levels, and a significant regression between BMC and BMAD values and the scores of motor-functional tests. Even if this study could not establish the pathogenesis of bone derangements in SMA, its main findings - reduced bone density, low 25OH vitamin D levels, increased bone resorption markers and asymptomatic vertebral fractures also in very young patients - strongly suggest that even young subjects affected by SMA should be considered at risk of osteopenia and even osteoporosis and fractures. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. The pharmacological properties of lipophilic calcium antagonists.

    PubMed

    van Zwieten, P A

    1998-01-01

    Several types of calcium antagonists (CA) (verapamil, diltiazem, nifedipine and related drugs) may be used as antihypertensives. In practice, the dihydropyridines (nifedipine and related drugs) are the CA used most frequently as antihypertensives. Apart from the lowering of blood pressure CA may lead to other, theoretically beneficial, effects: regression of left ventricular and vascular hypertrophy, renal protection, weak natriuretic, weak antiplatelet, anti-ischaemic and antiatherogenic activity. Several new dihydropyridine CA have been introduced in recent years. The advantages of the newer compounds, such as amlodipine, felodipine, isradipine, lacidipine and lercanidipine, may include: vasoselectivity, hence little or no cardiodepressant activity; an improved kinetic profile, resulting in a slow onset and long duration of action, fewer side-effects such as reflex tachycardia and headache, owing to the slow onset of the antihypertensive action. For a few newer CA a predominant effect on specialized circulatory beds (renal, coronary and cerebral) has been claimed. The new CA, which are clearly lipophilic, deserve special attention. Owing to the lipophilic character of such compounds considerable concentration occurs in lipid-containing membrane depots. The CA thus concentrated are slowly released from these depots and, subsequently, reach their targets, the L-type calcium channels. This phenomenon explains both the slow onset and the long duration of action of these CA. Owing to the slow onset of action reflex tachycardia is virtually absent. The long duration of action allows satisfactory control of blood pressure in hypertensives by means of a single daily dose. A few lipophilic dihydropyridine CA are vasoselective. This property implies that at therapeutic, vasodilatory dosages no cardiodepressant activity occurs. Lercanidipine is a recently introduced example of a lipophilic and vasoselective dihydropyridine CA. It is an effective vasodilator

  11. Muscarinic agonists and antagonists: effects on the urinary bladder.

    PubMed

    Sellers, Donna J; Chess-Williams, Russ

    2012-01-01

    Voiding of the bladder is the result of a parasympathetic muscarinic receptor activation of the detrusor smooth muscle. However, the maintenance of continence and a normal bladder micturition cycle involves a complex interaction of cholinergic, adrenergic, nitrergic and peptidergic systems that is currently little understood. The cholinergic component of bladder control involves two systems, acetylcholine (ACh) released from parasympathetic nerves and ACh from non-neuronal cells within the urothelium. The actions of ACh on the bladder depend on the presence of muscarinic receptors that are located on the detrusor smooth muscle, where they cause direct (M₃) and indirect (M₂) contraction; pre-junctional nerve terminals where they increase (M₁) or decrease (M₄) the release of ACh and noradrenaline (NA); sensory nerves where they influence afferent nerve activity; umbrella cells in the urothelium where they stimulate the release of ATP and NO; suburothelial interstitial cells with unknown function; and finally, other unidentified sites in the urothelium from where prostaglandins and inhibitory/relaxatory factors are released. Thus, the actions of muscarinic receptor agonists and antagonists on the bladder may be very complex even when considering only local muscarinic actions. Clinically, muscarinic antagonists remain the mainstay of treatment for the overactive bladder (OAB), while muscarinic agonists have been used to treat hypoactive bladder. The antagonists are effective in treating OAB, but their precise mechanisms and sites of action (detrusor, urothelium, and nerves) have yet to be established. Potentially more selective agents may be developed when the cholinergic systems within the bladder are more fully understood.

  12. Dysfunction of axonal membrane conductances in adolescents and young adults with spinal muscular atrophy

    PubMed Central

    Vucic, Steve; Lin, Cindy S.-Y.; Park, Susanna B.; Johnston, Heather M.; du Sart, Desirée; Bostock, Hugh; Kiernan, Matthew C.

    2011-01-01

    Spinal muscular atrophy is distinct among neurodegenerative conditions of the motor neuron, with onset in developing and maturing patients. Furthermore, the rate of degeneration appears to slow over time, at least in the milder forms. To investigate disease pathophysiology and potential adaptations, the present study utilized axonal excitability studies to provide insights into axonal biophysical properties and explored correlation with clinical severity. Multiple excitability indices (stimulus–response curve, strength–duration time constant, threshold electrotonus, current–threshold relationship and recovery cycle) were investigated in 25 genetically characterized adolescent and adult patients with spinal muscular atrophy, stimulating the median motor nerve at the wrist. Results were compared with 50 age-matched controls. The Medical Research Council sum score and Spinal Muscular Atrophy Functional Rating Scale were used to define the strength and motor functional status of patients with spinal muscular atrophy. In patients with spinal muscular atrophy, there were reductions in compound muscle action potential amplitude (P < 0.0005) associated with reduction in stimulus response slope (P < 0.0005), confirming significant axonal loss. In the patients with mild or ambulatory spinal muscular atrophy, there was reduction of peak amplitude without alteration in axonal excitability; in contrast, in the non-ambulatory or severe spinal muscular atrophy cohort prominent changes in axonal function were apparent. Specifically, there were steep changes in the early phase of hyperpolarization in threshold electrotonus (P < 0.0005) that correlated with clinical severity. Additionally, there were greater changes in depolarizing threshold electrotonus (P < 0.0005) and prolongation of the strength-duration time constant (P = 0.001). Mathematical modelling of the excitability changes obtained in patients with severe spinal muscular atrophy supported a

  13. Role of concentric force in limiting improvement in muscular strength.

    PubMed

    Hortobágyi, T; Katch, F I

    1990-02-01

    We hypothesized that resistance training with combined eccentric and concentric actions, and concentric action only, should yield similar changes in muscular strength. Subjects in a free weight group trained three times a week for 12 wk with eccentric and concentric actions (FW, n = 16), a second group trained with concentric-only contractions using hydraulic resistance (HY; n = 12), and a control group did not train (n = 11). Training for FW and HY included five sets of supine bench press and upright squat at an intensity of 1-6 repetition maximum (RM) plus five supplementary exercises at 5-10 RM for a total of 20 sets per session for approximately 50 min. Testing at pre-, mid-, and posttraining included 1) 1 RM bench press and squat with and 2) without prestretch using free weights; 3)isokinetic peak force and power for bench press and squat at 5 degrees/s, and isotonic peak velocity and power for bench press with 20-kg load and squat with 70-kg load; 4) hydraulic peak bench press force and power, and peak knee extension torque and power at fast and slow speeds; and 5) surface anthropometry (fatfolds and girths to estimate upper arm and thigh volume and muscle area). Changes in overall fatness, muscularity, and muscle + bone cross-sectional area of the limbs did not differ between groups (P greater than 0.05). Improvements in free weight bench press and squat were similar (P greater than 0.05) in FW (approximately 24%) and HY (approximately 22%, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

  14. Cannabinoid Discrimination and Antagonism by CB1 Neutral and Inverse Agonist Antagonists

    PubMed Central

    Delatte, Marcus S.; Vemuri, V. Kiran; Thakur, Ganesh A.; Nikas, Spyridon P.; Subramanian, Kumara V.; Shukla, Vidyanand G.; Makriyannis, Alexandros; Bergman, Jack

    2013-01-01

    Cannabinoid receptor 1 (CB1) inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications. Recent laboratory studies suggest that the effects of CB1 neutral antagonists differ from those of such inverse agonists, raising the possibility of improved clinical utility. However, little is known regarding the antagonist properties of neutral antagonists. In the present studies, the CB1 inverse agonist SR141716A (rimonabant) and the CB1 neutral antagonist AM4113 were compared for their ability to modify CB1 receptor–mediated discriminative stimulus effects in nonhuman primates trained to discriminate the novel CB1 full agonist AM4054. Results indicate that AM4054 serves as an effective CB1 discriminative stimulus, with an onset and time course of action comparable with that of the CB1 agonist Δ9-tetrahydrocannabinol, and that the inverse agonist rimonabant and the neutral antagonist AM4113 produce dose-related rightward shifts in the AM4054 dose-effect curve, indicating that both drugs surmountably antagonize the discriminative stimulus effects of AM4054. Schild analyses further show that rimonabant and AM4113 produce highly similar antagonist effects, as evident in comparable pA2 values (6.9). Taken together with previous studies, the present data suggest that the improved safety profile suggested for CB1 neutral antagonists over inverse agonists is not accompanied by a loss of antagonist action at CB1 receptors. PMID:23287700

  15. Cannabinoid discrimination and antagonism by CB(1) neutral and inverse agonist antagonists.

    PubMed

    Kangas, Brian D; Delatte, Marcus S; Vemuri, V Kiran; Thakur, Ganesh A; Nikas, Spyridon P; Subramanian, Kumara V; Shukla, Vidyanand G; Makriyannis, Alexandros; Bergman, Jack

    2013-03-01

    Cannabinoid receptor 1 (CB(1)) inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications. Recent laboratory studies suggest that the effects of CB(1) neutral antagonists differ from those of such inverse agonists, raising the possibility of improved clinical utility. However, little is known regarding the antagonist properties of neutral antagonists. In the present studies, the CB(1) inverse agonist SR141716A (rimonabant) and the CB(1) neutral antagonist AM4113 were compared for their ability to modify CB(1) receptor-mediated discriminative stimulus effects in nonhuman primates trained to discriminate the novel CB(1) full agonist AM4054. Results indicate that AM4054 serves as an effective CB(1) discriminative stimulus, with an onset and time course of action comparable with that of the CB(1) agonist Δ(9)-tetrahydrocannabinol, and that the inverse agonist rimonabant and the neutral antagonist AM4113 produce dose-related rightward shifts in the AM4054 dose-effect curve, indicating that both drugs surmountably antagonize the discriminative stimulus effects of AM4054. Schild analyses further show that rimonabant and AM4113 produce highly similar antagonist effects, as evident in comparable pA(2) values (6.9). Taken together with previous studies, the present data suggest that the improved safety profile suggested for CB(1) neutral antagonists over inverse agonists is not accompanied by a loss of antagonist action at CB(1) receptors.

  16. Muscular strength and physical function.

    PubMed

    Brill, P A; Macera, C A; Davis, D R; Blair, S N; Gordon, N

    2000-02-01

    The purpose of this study was to evaluate the potential association of muscular strength and endurance at baseline with the prevalence of functional limitations at follow-up. Study participants were 3,069 men and 589 women (30-82 yr) who received a clinical examination including a strength evaluation at the Cooper Clinic between 1980 and 1989 and responded to a 1990 mail-back survey. Participants also had to achieve at least 85% of their age-predicted maximal heart rate on a maximal exercise treadmill test and have no history of heart attack, stroke, diabetes, high blood pressure, cancer, or arthritis at their first visit. A strength index composite score (0-6) was calculated using age- and sex-specific tertiles from bench press, leg press, and sit-up tests. Those scoring 5 or 6 were categorized in the high strength group. Functional health status was assessed by responses to questions about the participant's ability to perform light, moderate, and strenuous recreational, household, daily living, and personal care tasks. After an average follow-up of 5 yr, 7% of men and 12% of women reported at least one functional limitation. A logistic regression model including age, aerobic fitness, body mass index, and new health problems at follow-up found that, relative to those with lower levels of strength, the odds of reporting functional limitations at follow-up in men and women categorized as having higher levels of strength were 0.56 (95%CI = 0.34, 0.93) and 0.54 (95%CI = 0.21, 1.39), respectively. These findings, if replicated in other populations, suggest that maintenance of strength throughout the lifespan may reduce the prevalence of functional limitations.

  17. Antagonists of IAP proteins as cancer therapeutics.

    PubMed

    Dynek, Jasmin N; Vucic, Domagoj

    2013-05-28

    Inhibitor of apoptosis (IAP) proteins play pivotal roles in cellular survival by blocking apoptosis, modulating signal transduction, and affecting cellular proliferation. Through their interactions with inducers and effectors of apoptosis IAP proteins can effectively suppress apoptosis triggered by diverse stimuli including death receptor signaling, irradiation, chemotherapeutic agents, or growth factor withdrawal. Evasion of apoptosis, in part due to the action of IAP proteins, enhances resistance of cancer cells to treatment with chemotherapeutic agents and contributes to tumor progression. Additionally, IAP genes are known to be subject to amplification, mutation, and chromosomal translocation in human malignancies and autoimmune diseases. In this review we will discuss the role of IAP proteins in cancer and the development of antagonists targeting IAP proteins for cancer treatment.

  18. Circulating Biomarkers for Duchenne Muscular Dystrophy

    PubMed Central

    Aartsma-Rus, Annemieke; Spitali, Pietro

    2015-01-01

    Abstract Duchenne muscular dystrophy is the most common form of muscular dystrophy. Genetic and biochemical research over the years has characterized the cause, pathophysiology and development of the disease providing several potential therapeutic targets and/or biomarkers. High throughput – omic technologies have provided a comprehensive understanding of the changes occurring in dystrophic muscles. Murine and canine animal models have been a valuable source to profile muscles and body fluids, thus providing candidate biomarkers that can be evaluated in patients. This review will illustrate known circulating biomarkers that could track disease progression and response to therapy in patients affected by Duchenne muscular dystrophy. We present an overview of the transcriptomic, proteomic, metabolomics and lipidomic biomarkers described in literature. We show how studies in muscle tissue have led to the identification of serum and urine biomarkers and we highlight the importance of evaluating biomarkers as possible surrogate endpoints to facilitate regulatory processes for new medicinal products. PMID:27858763

  19. Job rotation: Effects on muscular activity variability.

    PubMed

    Rodriguez, Andres C; Barrero, Lope H

    2017-04-01

    Job rotation strategies have been used for years as an administrative intervention to reduce the risk of musculoskeletal disorders. The benefits of job rotation have been hypothesized to occur via changes in muscular activity variability (MAV). However, the effect of job rotation on MAV has not been fully analyzed in a literature review. A wide search was conducted to identify studies testing the effect of different job rotation strategies on MAV. Twenty-six studies of acceptable quality were included. Several studies on different types of tasks supported the view that job rotation can increase muscular activity variability, particularly with strategies such as alternating tasks and pace changes. However, it remains uncertain whether such variability changes immediately translate into benefits for the worker because little evidence was found that showed simultaneous changes in different muscular groups. Additionally, variability was occasionally achieved at the expense of average activity in the assessed muscles. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Feline Muscular Dystrophy with Dystrophin Deficiency

    PubMed Central

    Carpenter, James L.; Hoffman, Eric P.; Romanul, Flaviu C. A.; Kunkel, Louis M.; Rosales, Remedios K.; Ma, Nancy S. F.; Dasbach, James J.; Rae, John F.; Moore, Frances M.; McAfee, Mary B.; Pearce, Laurie K.

    1989-01-01

    This is the first description of a dystrophin-Deficient muscular dystrophy in domestic cats. The disorder appears to be of X-linked inheritance because it affected both males of a litter of four kittens. Immunoblotting and immunofluorescent detection of dystrophin showed dystrophin present in control cat muscle but no detectable dystrophin in either affected cat. The feline muscular dystrophy was progressive and histopathologically resembled human Duchenne/Becker muscular dystrophy except for the lack of fat infiltration and the presence of prominent hypertrophy of both muscle fibers and muscles groups in the feline disorder. ImagesFigure 1Figure 2Figure 3Figure 4Figure 5Figure 6Figure 7Figure 8Figure 9 PMID:2683799

  1. Effect of Lumbar Progressive Resistance Exercise on Lumbar Muscular Strength and Core Muscular Endurance in Soldiers.

    PubMed

    Mayer, John M; Childs, John D; Neilson, Brett D; Chen, Henian; Koppenhaver, Shane L; Quillen, William S

    2016-11-01

    Low back pain is common, costly, and disabling for active duty military personnel and veterans. The evidence is unclear on which management approaches are most effective. The purpose of this study was to assess the effectiveness of lumbar extensor high-intensity progressive resistance exercise (HIPRE) training versus control on improving lumbar extension muscular strength and core muscular endurance in soldiers. A randomized controlled trial was conducted with active duty U.S. Army Soldiers (n = 582) in combat medic training at Fort Sam Houston, Texas. Soldiers were randomized by platoon to receive the experimental intervention (lumbar extensor HIPRE training, n = 298) or control intervention (core stabilization exercise training, n = 284) at one set, one time per week, for 11 weeks. Lumbar extension muscular strength and core muscular endurance were assessed before and after the intervention period. At 11-week follow-up, lumbar extension muscular strength was 9.7% greater (p = 0.001) for HIPRE compared with control. No improvements in core muscular endurance were observed for HIPRE or control. Lumbar extensor HIPRE training is effective to improve isometric lumbar extension muscular strength in U.S. Army Soldiers. Research is needed to explore the clinical relevance of these gains. Reprint & Copyright © 2016 Association of Military Surgeons of the U.S.

  2. 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 ...

  3. Genetics Home Reference: spinal and bulbar muscular atrophy

    MedlinePlus

    ... MedlinePlus (2 links) Encyclopedia: Muscle Atrophy Health Topic: Spinal Muscular Atrophy Genetic and Rare Diseases Information Center (1 link) ... Patient Support and Advocacy Resources (5 links) Cure SMA Kennedy's Disease Association Muscular Dystrophy Association National Organization ...

  4. 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

  5. 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

  6. [5-HT3 receptor antagonist als analgetics in rheumatic diseases].

    PubMed

    Müller, W; Fiebich, B L; Stratz, T

    2006-10-01

    Various rheumatic diseases like fibromyalgia, systemic inflammatory rheumatic disorders and localized diseases, such as arthritides and activated arthroses, tendinopathies and periarthropathies, as well as trigger points can be improved considerably by treatment with the 5-HT3 receptor antagonist tropisetron. Particularly in the latter group of diseases, local injections have done surprisingly rapid analgesic action. This effect matches that of local anesthetics, but lasts considerably longer and is comparable to local injections of local anesthetics combined with corticosteroids. The action of the 5-HT3 receptor antagonists can be attributed to an antinociceptive effect that occurs at the same time as an antiphlogistic and probably also an immunosuppressive effect. Whereas an inhibited release of substance P from the nociceptors, and possibly some other neurokins as well, seems to be the most likely explanation for the antinociceptive action, the antiphlogistic effect is primarily due to an inhibited formation of various different phlogistic substances; in some conditions, like systemic inflammatory rheumatic diseases, for example, the 5-HT3 receptor antagonists may exert an immunosuppressive effect in addition to this.

  7. Action of the thiamine antagonist bacimethrin on thiamine biosynthesis.

    PubMed

    Zilles, J L; Croal, L R; Downs, D M

    2000-10-01

    Bacimethrin is an analog of the 4-amino-5-hydroxymethyl-2-methylpyrimidine (HMP) moiety of thiamine and inhibits the growth of Salmonella enterica serovar Typhimurium on a defined medium. Two classes of mutants that had increased bacimethrin resistance were isolated and characterized. Results showed that overexpression of the thi operon or specific lesions in thiD resulted in a bacimethrin-resistant phenotype. Phenotypic analyses of the thiD mutants suggested that they had a specific defect in one of the two kinase activities associated with this gene product and, further, that ThiD and not PdxK was primarily responsible for salvage of HMP from the medium.

  8. Design and synthesis of peripherally restricted transient receptor potential vanilloid 1 (TRPV1) antagonists.

    PubMed

    Tamayo, Nuria; Liao, Hongyu; Stec, Markian M; Wang, Xianghong; Chakrabarti, Partha; Retz, Dan; Doherty, Elizabeth M; Surapaneni, Sekhar; Tamir, Rami; Bannon, Anthony W; Gavva, Narender R; Norman, Mark H

    2008-05-08

    Transient receptor potential vanilloid 1 (TRPV1) channel antagonists may have clinical utility for the treatment of chronic nociceptive and neuropathic pain. We recently advanced a TRPV1 antagonist, 3 (AMG 517), into clinical trials as a new therapy for the treatment of pain. However, in addition to the desired analgesic effects, this TRPV1 antagonist significantly increased body core temperature following oral administration in rodents. Here, we report one of our approaches to eliminate or minimize the on-target hyperthermic effect observed with this and other TRPV1 antagonists. Through modifications of our clinical candidate, 3 a series of potent and peripherally restricted TRPV1 antagonists have been prepared. These analogues demonstrated on-target coverage in vivo but caused increases in body core temperature, suggesting that peripheral restriction was not sufficient to separate antagonism mediated antihyperalgesia from hyperthermia. Furthermore, these studies demonstrate that the site of action for TRPV1 blockade elicited hyperthermia is outside the blood-brain barrier.

  9. 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...

  10. The influence of geographic variations on the muscular activity in selected sports movements.

    PubMed

    Clarys, J P; Alewaeters, K; Zinzen, E

    2001-12-01

    Surface EMG (SEMG) has been used frequently to study motion techniques or skills, body positions, material or equipment used, training-methodology and learning processes in sports and ergonomics. Little if any information is available on the effect of the geographical environment on the neuromuscular control of an athlete or workman during his/her performance or effort. Motions were chosen in Alpine skiing and cycling. Thirty-one certified ski instructors and twelve professional road cyclists participated in the study of geographical variance and its impact on muscle activity. SEMG was measured from the agonists and antagonists of the upper- and lower limb. Skiers were measured on downhill slopes ranging from 19 to 51% while the cyclists performed with different saddle positions on 2, 7 and 12% slope inclinations, respectively. Verification of the variation of muscular intensity (IEMG) over the slope inclination during a simulated giant slalom indicated that the muscular activity increased with increasing slope angle and decreased with decreasing slope angle, while heart rate measured with short-range radio telemetry increased at a constant rate between start and finish independent of the geographical variations. In a direct descent on different slopes % levels the integrated EMG is well related to the inclination (r=0.82) confirming the findings of the giant slalom. In cycling we found that, regardless of the pelvis position, the muscular intensity of lower limb muscles increased with increasing slope inclination, while the muscular intensity of the arms decreased with the same increasing slope inclination. In addition the decreased intensity of the arm muscles remained significantly higher with the pelvis (saddle) fully forward. The geography of the terrain did influence the neuromuscular work and therewith probably the performance also. The influence however, varies with specific circumstances and is coupled with items of variability of the equipment used and

  11. The neuromuscular impact of symptomatic SMN restoration in a mouse model of spinal muscular atrophy

    PubMed Central

    Arnold, W. David; McGovern, Vicki L.; Sanchez, Benjamin; Li, Jia; Corlett, Kaitlyn M.; Kolb, Stephen J.; Rutkove, Seward B.; Burghes, Arthur H.

    2016-01-01

    Background Significant advances in the development of SMN-restoring therapeutics have occurred since 2010 when very effective biological treatments were reported in mouse models of spinal muscular atrophy. As these treatments are applied in human clinical trials, there is pressing need to define quantitative assessments of disease progression, treatment stratification, and therapeutic efficacy. The electrophysiological measures Compound Muscle Action Potential and Motor Unit Number Estimation are reliable measures of nerve function. In both the SMNΔ7 mouse and a pig model of spinal muscular atrophy, early SMN restoration results in preservation of electrophysiological measures. Currently, clinical trials are underway in patients at post-symptomatic stages of disease progression. In this study, we present results from both early and delayed SMN restoration using clinically-relevant measures including electrical impedance myography, compound muscle action potential, and motor unit number estimation to quantify the efficacy and time-sensitivity of SMN-restoring therapy. Methods SMAΔ7 mice were treated via intracerebroventricular injection with antisense oligonucleotides targeting ISS-N1 to increase SMN protein from the SMN2 gene on postnatal day 2, 4, or 6 and compared with sham-treated spinal muscular atrophy and control mice. Compound muscle action potential and motor unit number estimation of the triceps surae muscles were performed at day 12, 21, and 30 by a single evaluator blinded to genotype and treatment. Similarly, electrical impedance myography was measured on the biceps femoris muscle at 12 days for comparison. Results Electrophysiological measures and electrical impedance myography detected significant differences at 12 days between control and late-treated (4 or 6 days) and sham-treated spinal muscular atrophy mice, but not in mice treated at 2 days(p<0.01). EIM findings paralleled and correlated with compound muscle action potential and motor unit

  12. The neuromuscular impact of symptomatic SMN restoration in a mouse model of spinal muscular atrophy.

    PubMed

    Arnold, W; McGovern, Vicki L; Sanchez, Benjamin; Li, Jia; Corlett, Kaitlyn M; Kolb, Stephen J; Rutkove, Seward B; Burghes, Arthur H

    2016-03-01

    Significant advances in the development of SMN-restoring therapeutics have occurred since 2010 when very effective biological treatments were reported in mouse models of spinal muscular atrophy. As these treatments are applied in human clinical trials, there is pressing need to define quantitative assessments of disease progression, treatment stratification, and therapeutic efficacy. The electrophysiological measures Compound Muscle Action Potential and Motor Unit Number Estimation are reliable measures of nerve function. In both the SMN∆7 mouse and a pig model of spinal muscular atrophy, early SMN restoration results in preservation of electrophysiological measures. Currently, clinical trials are underway in patients at post-symptomatic stages of disease progression. In this study, we present results from both early and delayed SMN restoration using clinically-relevant measures including electrical impedance myography, compound muscle action potential, and motor unit number estimation to quantify the efficacy and time-sensitivity of SMN-restoring therapy. SMA∆7 mice were treated via intracerebroventricular injection with antisense oligonucleotides targeting ISS-N1 to increase SMN protein from the SMN2 gene on postnatal day 2, 4, or 6 and compared with sham-treated spinal muscular atrophy and control mice. Compound muscle action potential and motor unit number estimation of the triceps surae muscles were performed at day 12, 21, and 30 by a single evaluator blinded to genotype and treatment. Similarly, electrical impedance myography was measured on the biceps femoris muscle at 12days for comparison. Electrophysiological measures and electrical impedance myography detected significant differences at 12days between control and late-treated (4 or 6days) and sham-treated spinal muscular atrophy mice, but not in mice treated at 2days (p<0.01). EIM findings paralleled and correlated with compound muscle action potential and motor unit number estimation (r=0.61 and r

  13. 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…

  14. Peyronie disease: surgical treatment with muscular aponeurosis.

    PubMed

    Bruschini, H; Mitre, A I

    1979-05-01

    A new method for surgical correction of Peyronie disease by grafting autologous muscular aponeurosis was tried in 4 patients. Early results were encouraging, with disappearance of penile curvature and of pain on erection. The urologist can perform the operation without the assistance a plastic surgeon must usually give when dermal grafts are used.

  15. 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…

  16. Respiratory function in facioscapulohumeral muscular dystrophy 1.

    PubMed

    Wohlgemuth, M; Horlings, C G C; van der Kooi, E L; Gilhuis, H J; Hendriks, J C M; van der Maarel, S M; van Engelen, B G M; Heijdra, Y F; Padberg, G W

    2017-06-01

    To test the hypothesis that wheelchair dependency and (kypho-)scoliosis are risk factors for developing respiratory insufficiency in facioscapulohumeral muscular dystrophy, we examined 81 patients with facioscapulohumeral muscular dystrophy 1 of varying degrees of severity ranging from ambulatory patients to wheelchair-bound patients. We examined the patients neurologically and by conducting pulmonary function tests: Forced Vital Capacity, Forced Expiratory Volume in 1 second, and static maximal inspiratory and expiratory mouth pressures. We did not find pulmonary function test abnormalities in ambulant facioscapulohumeral muscular dystrophy patients. Even though none of the patients complained of respiratory dysfunction, mild to severe respiratory insufficiency was found in more than one third of the wheelchair-dependent patients. Maximal inspiratory pressures and maximal expiratory pressures were decreased in most patients, with a trend that maximal expiratory pressures were more affected than maximal inspiratory pressures. Wheelchair-dependent patients with (kypho-)scoliosis showed the most restricted lung function. Wheelchair-dependent patients with (kypho-)scoliosis are at risk for developing respiratory function impairment. We advise examining this group of facioscapulohumeral muscular dystrophy patients periodically, even in the absence of symptoms of respiratory insufficiency, given its frequency and impact on daily life and the therapeutic consequences. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. [Muscular metastases. A case report (author's transl)].

    PubMed

    Trèves, R; Barruche, D; Desproges-Gotteron, R

    Muscular metastases are exceptionally reported. The authors present a case of crural neuralgia in relation with a localisation in the psoas iliacus of a gastric carcinoma. A review of literature defines the rarity of this facts (156 cases) the etiology (carcinome more often) and the explication who is still obscur.

  18. Complete atrioventricular block in Duchenne muscular dystrophy.

    PubMed

    Fayssoil, A; Orlikowski, D; Nardi, O; Annane, D

    2008-11-01

    Duchenne muscular dystrophy (DMD) is an inherited myogenic disorder due to mutations in the dystrophin gene on chromosome Xp21.1. It is characterized by progressive muscle wasting and weakness of variable distribution and severity. Heart is involved leading to heart failure. Conduction abnormalities are unusual. We report a case of complete atrio-ventricular block in a DMD patient.

  19. Coaction Effects on a Muscular Endurance Task

    ERIC Educational Resources Information Center

    Martens, Rainer; Landers, Daniel M.

    1969-01-01

    A common procedure in administering muscular endurance tests is to have several individuals perform the same task at the same time. A very old psychological concept known as social facilitation suggests that an individual's performance may be affected by the presence of others. (CK)

  20. Coaction Effects on a Muscular Endurance Task

    ERIC Educational Resources Information Center

    Martens, Rainer; Landers, Daniel M.

    1969-01-01

    A common procedure in administering muscular endurance tests is to have several individuals perform the same task at the same time. A very old psychological concept known as social facilitation suggests that an individual's performance may be affected by the presence of others. (CK)

  1. 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

  2. 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. © 2015 New York Academy of Sciences.

  3. Genetics Home Reference: oculopharyngeal muscular dystrophy

    MedlinePlus

    ... symptom in people with this disorder is usually droopy eyelids ( ptosis ), followed by difficulty swallowing (dysphagia). The swallowing difficulties ... 2 links) GeneReview: Oculopharyngeal Muscular Dystrophy MedlinePlus Encyclopedia: Ptosis General Information from MedlinePlus (5 links) Diagnostic Tests ...

  4. Tamoxifen resistant breast cancer: coregulators determine the direction of transcription by antagonist-occupied steroid receptors.

    PubMed

    Takimoto, G S; Graham, J D; Jackson, T A; Tung, L; Powell, R L; Horwitz, L D; Horwitz, K B

    1999-01-01

    Pharmacological antagonists of steroid receptor action had been thought to exert their effects by a passive mechanism driven principally by the ability of the antagonist to compete with agonist for the ligand binding site. However, recent analyses of antagonist-occupied receptor function suggest a more complex picture. Antagonists can be subdivided into two groups, type I, or pure antagonists, and type II, or mixed antagonists that can have variable transcriptional activity based upon differential dimerization and DNA binding properties. This led us to propose that receptor antagonism may not simply be a passive competition for the ligand binding site, but may, in some cases, involve active recruitment of corepressor or coactivator proteins to produce a mixed transcriptional phenotype. We used a yeast two-hybrid screen to identify proteins that interact specifically with antagonist-occupied receptors. Two proteins have been characterized: L7/SPA, a ribosome-associated protein that is localized in both the cytoplasm and nucleus, but with no known extranucleolar nuclear function; and hN-CoR, the human homolog of the mouse thyroid receptor corepressor mN-CoR. In in vivo transcription assays we show that L7/SPA enhances the partial agonist activity of type II mixed antagonists, and that N-CoR and the related corepressor, SMRT, suppresses it. The coregulators do not affect agonists or pure antagonists. Moreover, the net agonist activity seen with mixed antagonists is a function of the ratio of coactivator to corepressor. Based upon these results, we proposed that in breast tumors the inappropriate agonist activity seen with therapeutic antagonists such as tamoxifen is responsible for the hormone-resistant state. To confirm this, we are quantitating coactivator/corepressor ratios in breast tumor cells lines and clinical breast cancers. Results should provide new insights into the mechanisms underlying the progression of breast cancer to hormone resistance, and may

  5. Celiprolol, a potent cardioselective beta 1-adrenoceptor antagonist with mild alpha 2-adrenoceptor antagonist properties.

    PubMed

    Wolf, P S; Pruss, T P; Rand, M J; Smith, R D; Mann, W S; Romano, D V

    1985-12-01

    Celiprolol is a cardioselective beta-adrenoceptor antagonist, with interesting propranolol-insensitive cardiostimulatory, vasodilatory and bronchodilatory effects. Recent reports suggest that mild alpha 2-adrenoceptor antagonism may contribute to these effects. The present investigation further explored the alpha 2 effects of celiprolol. In isolated electrically-stimulated rat atria celiprolol (1.0 and 10 mumol/l) significantly increased the release of [3H]-norepinephrine, consistent with the blockade of pre-junctional alpha 2-adrenoceptors. Evidence for post-synaptic alpha 2-adrenoceptor antagonist activity was obtained in studies of the effects of celiprolol on the pressor response to clonidine and either phenylephrine or methoxamine in perfused hind-limbs of dogs (pretreated with mecamylamine and propranolol) and pithed rats. In the dog, celiprolol (10 mg/kg) significantly inhibited the vasoconstrictor response of clonidine while in the rat higher doses were required (> or = 12.5 mg/kg). Celiprolol did not affect the pressor response induced by alpha 1-agonists. We conclude that celiprolol possesses a mild alpha 2-adrenoceptor blocking action which may contribute to its unconventional profile.

  6. 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.

  7. Cannabinoid CB1 antagonists and dopamine antagonists produce different effects on a task involving response allocation and effort-related choice in food-seeking behavior.

    PubMed

    Sink, K S; Vemuri, V K; Olszewska, T; Makriyannis, A; Salamone, J D

    2008-03-01

    Cannabinoid CB1 antagonists/inverse agonists suppress food-motivated behaviors and are being evaluated as potential appetite suppressants. It has been suggested that the effects of CB1 antagonism on food motivation could be related to actions on mesolimbic dopamine (DA). If this were true, then the effects of interference with cannabinoid CB1 transmission should closely resemble the effects of interference with DA transmission. To directly compare the effects of DA antagonists with those of CB1 antagonists/inverse agonists, the present studies employed a concurrent lever-pressing/chow-intake procedure. With this task, interference with DA transmission shifts choice behavior such that lever pressing for a preferred food is decreased but chow intake is increased. Rats treated with IP injections of the DA D1 antagonist SCH39166 (ecopipam; 0.05-0.2 mg/kg) or the D2 antagonist eticlopride (0.025-0.1 mg/kg) showed substantial decreases in lever pressing and concomitant increases in chow consumption. In contrast, IP administration of the CB1 neutral antagonist AM4113 (4.0-16.0 mg/kg) or the CB1 antagonist/inverse agonist AM251 (2.0-8.0 mg/kg) decreased operant responding for pellets, but there was no corresponding increase in chow intake. These effects of CB1 antagonists/inverse agonists were similar to those produced by the appetite suppressant fenfluramine and by prefeeding. In contrast, low doses of DA antagonists leave primary food motivation intact, but shift behaviors toward food reinforcers that can be obtained with lower response costs. These results suggest that the effects of interference with CB1 transmission are readily distinguishable from those of reduced DA transmission.

  8. Non-antisecretory activities of H2 antagonists.

    PubMed

    Bertaccini, G; Coruzzi, G

    1986-01-01

    Besides the main effect of the H2 antagonists--that is, the inhibition of gastric acid secretion--these drugs possess several other pharmacological activities, which in most cases may be evident only for doses higher than those required to produce the H2 blockade. The non-secretory activities of the H2 antagonists may be classified into true side effects--that is, those independent of the primary action, which may or may not depend on the primary action. They concern the central and autonomic nervous systems, cardiovascular and endocrine systems, digestive system (gut, liver, pancreas), immune system, and so forth. It is obvious that when the actions of the different H2 blockers are completely at variance with regard to the same factor (cimetidine increase the TSH response to TRH, whereas ranitidine decreases it; ranitidine stimulates gastrointestinal motility, whereas oxmetidine inhibits it; ranitidine increases the exocrine pancreatic response to cholecystokinin, whereas oxmetidine decreases it; metiamide and cimetidine increase the activity of histamine methyltransferase, whereas burimamide decreases it), this is a clear demonstration that we are dealing with non-specific effects rather than with H2-receptor blockade. All these effects may be of interest because sometimes they may be useful in potentiating the primary action, and sometimes they may represent adverse reactions. In any case, they characterize pharmacologically the individual molecules of the family.

  9. The nitric oxide-donor molsidomine modulates the innate inflammatory response in a mouse model of muscular dystrophy.

    PubMed

    Zordan, Paola; Sciorati, Clara; Campana, Lara; Cottone, Lucia; Clementi, Emilio; Querini, Patrizia-Rovere; Brunelli, Silvia

    2013-09-05

    Inflammation plays a crucial role in muscle remodeling and repair after acute and chronic damage, in particular in muscular dystrophies, a heterogeneous group of genetic diseases leading to muscular degeneration. Defect of nitric oxide (NO) generation is a key pathogenic event in muscular dystrophies, thus NO donors have been explored as new therapeutics for this disease. We have investigated the immune-modulating effect of one of such drugs, molsidomine, able to slow the progression of muscular dystrophy in the α-Sarcoglican-null mice, a model for the limb girdle muscular dystrophy 2D, sharing several hallmarks of muscle degeneration with other muscular dystrophies. α-Sarcoglican-null mice were treated with molsidomine and drug effects on the inflammatory infiltrates and on muscle repair were assessed at selected time points. We found that molsidomine treatment modulates effectively the characteristics of the inflammatory infiltrate within dystrophic muscles, enhancing its healing function. Initially molsidomine amplified macrophage recruitment, promoting a more efficient clearance of cell debris and effective tissue regeneration. At a later stage molsidomine decreased significantly the extent of the inflammatory infiltrate, whose persistence exacerbates muscle damage: most of the remaining macrophages displayed characteristics of the transitional population, associated with reduced fibrosis and increased preservation of the muscle tissue. The dual action of molsidomine, the already known NO donation and the immunomodulatory function we now identified, suggests that it has a unique potential in tissue healing during chronic muscle damage. This, alongside its already approved use in human, makes molsidomine a drug with a significant therapeutic potential in muscular dystrophies.

  10. Neuronal involvement in muscular atrophy.

    PubMed

    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.

  11. Opioid antagonists for smoking cessation

    PubMed Central

    David, Sean P; Lancaster, Tim; Stead, Lindsay F; Evins, A. Eden; Prochaska, Judith J

    2014-01-01

    Background The reinforcing properties of nicotine may be mediated through release of various neurotransmitters both centrally and systemically. People who smoke report positive effects such as pleasure, arousal, and relaxation as well as relief of negative affect, tension, and anxiety. Opioid (narcotic) antagonists are of particular interest to investigators as potential agents to attenuate the rewarding effects of cigarette smoking. Objectives To evaluate the efficacy of opioid antagonists in promoting long-term smoking cessation. The drugs include naloxone and the longer-acting opioid antagonist naltrexone. Search methods We searched the Cochrane Tobacco Addiction Group Specialised Register for trials of naloxone, naltrexone and other opioid antagonists and conducted an additional search of MEDLINE using ’Narcotic antagonists’ and smoking terms in April 2013. We also contacted investigators, when possible, for information on unpublished studies. Selection criteria We considered randomised controlled trials comparing opioid antagonists to placebo or an alternative therapeutic control for smoking cessation. We included in the meta-analysis only those trials which reported data on abstinence for a minimum of six months. We also reviewed, for descriptive purposes, results from short-term laboratory-based studies of opioid antagonists designed to evaluate psycho-biological mediating variables associated with nicotine dependence. Data collection and analysis We extracted data in duplicate on the study population, the nature of the drug therapy, the outcome measures, method of randomisation, and completeness of follow-up. The main outcome measure was abstinence from smoking after at least six months follow-up in patients smoking at baseline. Abstinence at end of treatment was a secondary outcome. We extracted cotinine- or carbon monoxide-verified abstinence where available. Where appropriate, we performed meta-analysis, pooling risk ratios using a Mantel

  12. 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

  13. 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.

  14. Therapeutic antagonists and conformational regulation of integrin function.

    PubMed

    Shimaoka, Motomu; Springer, Timothy A

    2003-09-01

    Integrins are a structurally elaborate family of adhesion molecules that transmit signals bi-directionally across the plasma membrane by undergoing large-scale structural rearrangements. By regulating cell-cell and cell-matrix contacts, integrins participate in a wide range of biological processes, including development, tissue repair, angiogenesis, inflammation and haemostasis. From a therapeutic standpoint, integrins are probably the most important class of cell-adhesion receptors. Recent progress in the development of integrin antagonists has resulted in their clinical application and has shed new light on integrin biology. On the basis of their mechanism of action, small-molecule integrin antagonists fall into three different classes. Each of these classes affect the equilibria that relate integrin conformational states, but in different ways.

  15. Mineralcorticoid antagonists in heart failure.

    PubMed

    D'Elia, Emilia; Krum, Henry

    2014-10-01

    Mineralocorticoid receptor antagonists (MRAs) have become mandated therapy in patients with reduced ejection fraction (systolic) heart failure (HF) across all symptom classes. These agents should also be prescribed in the early post-myocardial infarction setting in those with reduced ejection fraction and either HF symptoms or diabetes. This article explores the pathophysiological role of aldosterone, an endogenous ligand for the mineralcorticoid receptor (MR), and summarizes the clinical data supporting guideline recommendations for these agents in systolic HF. The use of MRAs in novel areas beyond systolic HF ejection is also explored. Finally, the current status of newer agents will be examined.

  16. NK-1 Antagonists and Itch.

    PubMed

    Ständer, Sonja; Luger, Thomas A

    2015-01-01

    Substance P (SP) is an important mediator of pro-inflammatory mechanisms in the skin. It targets multiple cells such as keratinocytes, mast cells, and fibroblasts which are involved in the cutaneous generation of pruritus. This suggests that SP is an interesting target for therapy. In fact, in recent case reports and case series, SP antagonists demonstrated a significant antipruritic effect in acute and chronic pruritus such as drug-induced pruritus, paraneoplastic pruritus, prurigo nodularis, cutaneous T-cell lymphoma, and brachioradial pruritus.

  17. [Duchenne and Becker muscular dystrophy in Chile].

    PubMed

    Holmgren, J; Reyes, J; Colombo, M; Blanco, M A

    1992-03-01

    Duchenne muscular dystrophy is one of the best known forms of muscular dystrophy. The incidence in different countries varies from 130 to 390 per million male live births. Becker variety may be considered a mild form of Duchenne dystrophy, with an incidence 10 times lower. A sex linked recessive inheritance is involved in both forms, the affected gene is placed at locus X21. The incidence of both forms in Chile is similar to that reported worldwide, and has been increasing since 1950. Increased CK and LDH levels are confirmed in patients, and overall, they are also higher in female carriers. However only 26% of carriers have increased CK levels and 21% increased LDH levels, compared to normal subjects. Electromyograms show myopathic characteristics in all carrier women. The scope of a prospective clinical, genetic and epidemiologic study currently underway is discussed.

  18. Progress in therapy for Duchenne muscular dystrophy.

    PubMed

    Fairclough, Rebecca J; Bareja, Akshay; Davies, Kay E

    2011-11-01

    Duchenne muscular dystrophy is a devastating muscular dystrophy of childhood. Mutations in the dystrophin gene destroy the link between the internal muscle filaments and the extracellular matrix, resulting in severe muscle weakness and progressive muscle wasting. There is currently no cure and, whilst palliative treatment has improved, affected boys are normally confined to a wheelchair by 12 years of age and die from respiratory or cardiac complications in their twenties or thirties. Therapies currently being developed include mutation-specific treatments, DNA- and cell-based therapies, and drugs which aim to modulate cellular pathways or gene expression. This review aims to provide an overview of the different therapeutic approaches aimed at reconstructing the dystrophin-associated protein complex, including restoration of dystrophin expression and upregulation of the functional homologue, utrophin.

  19. The immediate effect of kinesiology taping on muscular imbalance for infants with congenital muscular torticollis.

    PubMed

    Öhman, Anna M

    2012-07-01

    To investigate the immediate effect of kinesiology taping (KT) on muscular imbalance in the lateral flexors of the neck. A retrospective study. Twenty-eight infants with congenital muscular torticollis and muscular imbalance in the lateral flexors of the neck were chosen consecutively. Data regarding the Muscle Function Scale (MFS) score before and after the first taping session were obtained from the records. A significant decrease in the difference between the MFS scores was found after KT was applied (P < .001). Significantly greater scores were noted on the unaffected side after KT (P = .02) and significantly lower scores were noted on the affected side after KT (P = .003). Multiple regression demonstrated that the MFS score on the unaffected side (P < .001) and use of the muscle-relaxing technique (P = .009) were significantly associated with a decrease in the difference between the MFS scores of the 2 sides. KT has an immediate effect on muscular imbalance in infants with congenital muscular torticollis. Copyright © 2012 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.

  20. Congenital muscular torticollis: experience of 14 cases.

    PubMed

    Das, B K; Matin, A; Hassan, G Z; Hossain, M Z; Zaman, M A

    2010-10-01

    Congenital Muscular Torticollis (CMT) is a postural deformity of head and neck detected at birth or shortly after birth, primarily resulting from unilateral shortening of Sternocleidomastoid Muscle (SCM). In neonates and infants, patient may cure conservatively by physiotherapy but surgery is the treatment of choice for children and adolescents. There are various techniques of surgery. Here we show our experience regarding management of congenital muscular torticollis. In the present retrospective case series, fourteen patients of congenital muscular torticollis were treated. The cases were enrolled between Nov' 2005 to Oct' 2007 in Bangabandhu Sheikh Mujib Medical University, Gonosasthaya Somaj Vittik Medical College Hospital, Dhaka and different private clinics of Dhaka city of Bangladesh. Neonates and infants were treated conservatively with physiotherapy and others treated surgically by transection of both sternal and clavicular head of SCM under general anesthesia. Operated patients were released on following post operative day with advised to do physiotherapy. Patients age range from 7 days to 15 years of which ten were female and four male. SCM was shortened in all cases (8 on right side and 6 on left side). Eleven were female and three male. Of 14 patients, 2 neonates, 7 infants and 5 were more than 1 year age. There was no associated anomaly. Out of 9 neonates and infants 8 cured conservatively with physiotherapy and another one significantly improved. Six were treated surgically including one failed physiotherapy. Post operative period was uneventful and there was no complication. Results were evaluated clinically and comments of peers. Most of the patient of congenital muscular torticollis can be treated conservatively during infancy. Division of both sternal and clavicular head of SCM is easy and safe surgical technique for the treatment of CMT of older children and adolescents.

  1. Very severe spinal muscular atrophy (Type 0).

    PubMed

    Al Dakhoul, Suleiman

    2017-01-01

    This case report describes a rare phenotype of very severe spinal muscular atrophy (SMA) in a newborn who presented with reduced fetal movements in utero and significant respiratory distress at birth. The patient was homozygously deleted for exon 7 and exon 8 of the survival motor neuron gene 1. Very severe SMA should be considered in the differential diagnosis of respiratory distress at birth, and more research should be dedicated to investigate the genetic determinants of its widely variable phenotypes.

  2. Very severe spinal muscular atrophy (Type 0)

    PubMed Central

    Al Dakhoul, Suleiman

    2017-01-01

    This case report describes a rare phenotype of very severe spinal muscular atrophy (SMA) in a newborn who presented with reduced fetal movements in utero and significant respiratory distress at birth. The patient was homozygously deleted for exon 7 and exon 8 of the survival motor neuron gene 1. Very severe SMA should be considered in the differential diagnosis of respiratory distress at birth, and more research should be dedicated to investigate the genetic determinants of its widely variable phenotypes. PMID:28182029

  3. Urological manifestations of Duchenne muscular dystrophy.

    PubMed

    Askeland, Eric J; Arlen, Angela M; Erickson, Bradley A; Mathews, Katherine D; Cooper, Christopher S

    2013-10-01

    Duchenne muscular dystrophy is a dystrophinopathy affecting males that is associated with multiple organ system complications. To our knowledge urological complications of Duchenne muscular dystrophy have been described only anecdotally to date. We reviewed the medical charts of 135 patients with Duchenne or Duchenne-Becker muscular dystrophy for demographics and disease progression, urological diagnoses, intervention and followup. Of 135 patients 67 (50%) had at least 1 documented urological diagnosis and 38 (28%) had multiple manifestations. Lower urinary tract symptoms were the most common urological diagnosis (32% of patients). Survival analysis revealed a median age at onset of lower urinary tract symptoms of 23 years (95% CI 17.7-23.9). Intervention was required in 12 patients (9%), most commonly due to nephrolithiasis. Urological morbidity increased with Duchenne muscular dystrophy progression when stratified by clinical progression. Lower urinary tract symptoms were more common in nonambulatory patients (40.7% vs 19%, p = 0.007), those with a diagnosis of scoliosis (44% vs 19.7%, p = 0.003) and/or scoliosis spine surgery (60% vs 22%, p <0.001), and those on invasive respiratory support (53% vs 29%, p = 0.046). Likewise, nephrolithiasis was more common in nonambulatory patients (10% vs 0%, p = 0.017), those with scoliosis (12% vs 0%, p = 0.004) and/or scoliosis spine surgery (20% vs 1%, p <0.001), and those on invasive respiratory support (29% vs 3%, p <0.001). Only 28% of patients with a urological manifestation were referred to urology. As these patients transition into adolescence and adulthood, the increased prevalence of urological manifestations warrants increased awareness and referral to urologists. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  4. Spinal muscular atrophy: molecular genetics and diagnostics.

    PubMed

    Ogino, Shuji; Wilson, Robert B

    2004-01-01

    Spinal muscular atrophy is one of the most common autosomal recessive diseases, affecting approximately one in 10,000 live births and with a carrier frequency of approximately one in 50. Spinal muscular atrophy is caused by a deficiency of the ubiquitous protein survival of motor neuron (SMN), which is encoded by the SMN genes, SMN1 and SMN2. Due to a single nucleotide polymorphism (840C>T), SMN2 produces less full-length transcript than SMN1 and cannot entirely prevent neuronal cell death at physiologic gene dosages. The 38-kDa SMN protein comprises 294 amino acids and is involved in the biogenesis of uridine-rich small nuclear ribonucleoproteins, facilitating their cytoplasmic assembly into the spliceosome. Various animal models have been developed to study the pathogenesis of spinal muscular atrophy, as well as to test novel therapeutics. Common PCR-restriction fragment length polymorphism assays can detect the homozygous absence of SMN1 in approximately 94% of patients with clinically typical spinal muscular atrophy. SMN gene dosage analysis can determine the copy number of SMN1 to detect carriers and patients heterozygous for the absence of SMN1. Due to the genetic complexity and the high carrier frequency, accurate risk assessment and genetic counseling are particularly important. Comprehensive SMA genetic testing, combined with appropriate genetic counseling and risk assessment, provides the most complete evaluation of patients and their families at this time. New technologies, such as monosomal analysis techniques, may be widely available in the future. Copyright Future Drugs Ltd.

  5. Dysferlin mediates membrane tubulation and links T-tubule biogenesis to muscular dystrophy.

    PubMed

    Hofhuis, Julia; Bersch, Kristina; Büssenschütt, Ronja; Drzymalski, Marzena; Liebetanz, David; Nikolaev, Viacheslav O; Wagner, Stefan; Maier, Lars S; Gärtner, Jutta; Klinge, Lars; Thoms, Sven

    2017-03-01

    The multi-C2 domain protein dysferlin localizes to the plasma membrane and the T-tubule system in skeletal muscle; however, its physiological mode of action is unknown. Mutations in the DYSF gene lead to autosomal recessive limb-girdle muscular dystrophy type 2B and Miyoshi myopathy. Here, we show that dysferlin has membrane tubulating capacity and that it shapes the T-tubule system. Dysferlin tubulates liposomes, generates a T-tubule-like membrane system in non-muscle cells, and links the recruitment of phosphatidylinositol 4,5-bisphosphate to the biogenesis of the T-tubule system. Pathogenic mutant forms interfere with all of these functions, indicating that muscular wasting and dystrophy are caused by the dysferlin mutants' inability to form a functional T-tubule membrane system. © 2017. Published by The Company of Biologists Ltd.

  6. Muscle MRI findings in facioscapulohumeral muscular dystrophy.

    PubMed

    Gerevini, Simonetta; Scarlato, Marina; Maggi, Lorenzo; Cava, Mariangela; Caliendo, Giandomenico; Pasanisi, Barbara; Falini, Andrea; Previtali, Stefano Carlo; Morandi, Lucia

    2016-03-01

    Facioscapulohumeral muscular dystrophy (FSHD) is characterized by extremely variable degrees of facial, scapular and lower limb muscle involvement. Clinical and genetic determination can be difficult, as molecular analysis is not always definitive, and other similar muscle disorders may have overlapping clinical manifestations. Whole-body muscle MRI examination for fat infiltration, atrophy and oedema was performed to identify specific patterns of muscle involvement in FSHD patients (30 subjects), and compared to a group of control patients (23) affected by other myopathies (NFSHD). In FSHD patients, we detected a specific pattern of muscle fatty replacement and atrophy, particularly in upper girdle muscles. The most frequently affected muscles, including paucisymptomatic and severely affected FSHD patients, were trapezius, teres major and serratus anterior. Moreover, asymmetric muscle involvement was significantly higher in FSHD as compared to NFSHD patients. In conclusion, muscle MRI is very sensitive for identifying a specific pattern of involvement in FSHD patients and in detecting selective muscle involvement of non-clinically testable muscles. Muscle MRI constitutes a reliable tool for differentiating FSHD from other muscular dystrophies to direct diagnostic molecular analysis, as well as to investigate FSHD natural history and follow-up of the disease. Muscle MRI identifies a specific pattern of muscle involvement in FSHD patients. Muscle MRI may predict FSHD in asymptomatic and severely affected patients. Muscle MRI of upper girdle better predicts FSHD. Muscle MRI may differentiate FSHD from other forms of muscular dystrophy. Muscle MRI may show the involvement of non-clinical testable muscles.

  7. Diagnostic approach to the congenital muscular dystrophies

    PubMed Central

    Bönnemann, Carsten G.; Wang, Ching H.; Quijano-Roy, Susana; Deconinck, Nicolas; Bertini, Enrico; Ferreiro, Ana; Muntoni, Francesco; Sewry, Caroline; Béroud, Christophe; Mathews, Katherine D.; Moore, Steven A.; Bellini, Jonathan; Rutkowski, Anne; North, Kathryn N.

    2017-01-01

    Congenital muscular dystrophies (CMDs) are early onset disorders of muscle with histological features suggesting a dystrophic process. The congenital muscular dystrophies as a group encompass great clinical and genetic heterogeneity so that achieving an accurate genetic diagnosis has become increasingly challenging, even in the age of next generation sequencing. In this document we review the diagnostic features, differential diagnostic considerations and available diagnostic tools for the various CMD subtypes and provide a systematic guide to the use of these resources for achieving an accurate molecular diagnosis. An International Committee on the Standard of Care for Congenital Muscular Dystrophies composed of experts on various aspects relevant to the CMDs performed a review of the available literature as well as of the unpublished expertise represented by the members of the committee and their contacts. This process was refined by two rounds of online surveys and followed by a three-day meeting at which the conclusions were presented and further refined. The combined consensus summarized in this document allows the physician to recognize the presence of a CMD in a child with weakness based on history, clinical examination, muscle biopsy results, and imaging. It will be helpful in suspecting a specific CMD subtype in order to prioritize testing to arrive at a final genetic diagnosis. PMID:24581957

  8. Diaphragmatic function in advanced Duchenne muscular dystrophy.

    PubMed

    Beck, Jennifer; Weinberg, Jan; Hamnegård, Carl-Hugo; Spahija, Jadranka; Olofson, Jan; Grimby, Gunnar; Sinderby, Christer

    2006-03-01

    The aim of this study was to assess diaphragm electrical activation and diaphragm strength in patients with advanced Duchenne muscular dystrophy during resting conditions. Eight patients with advanced Duchenne muscular dystrophy (age of 25 +/- 2 years) were studied during tidal breathing, maximal inspiratory capacity, maximal sniff inhalations, and magnetic stimulation of the phrenic nerves. Six patients were prescribed home mechanical ventilation (five non-invasive and one tracheotomy). Transdiaphragmatic pressure and diaphragm electrical activation were measured using an esophageal catheter. During tidal breathing (tidal volume 198 +/- 83 ml, breathing frequency 25 +/- 7), inspiratory diaphragm electrical activation was clearly detectable in seven out of eight patients and was 12 +/- 7 times above the noise level, and represented 45 +/- 19% of the maximum diaphragm electrical activation. Mean inspiratory transdiaphragmatic pressure during tidal breathing was 1.5 +/- 1.2 cmH2O, and during maximal sniff was 7.6 +/- 3.6 cmH2O. Twitch transdiaphragmatic pressure deflections could not be detected. This study shows that despite near complete loss of diaphragm strength in advanced Duchenne muscular dystrophy, diaphragm electrical activation measured with an esophageal electrode array remains clearly detectable in all but one patient.

  9. Immunodetection analysis of muscular dystrophies in Mexico.

    PubMed

    Gómez-Díaz, Benjamín; Rosas-Vargas, Haydeé; Roque-Ramírez, Bladimir; Meza-Espinoza, Pedro; Ruano-Calderón, Luis A; Fernández-Valverde, Francisca; Escalante-Bautista, Deyanira; Escobar-Cedillo, Rosa E; Sánchez-Chapul, Laura; Vargas-Cañas, Steven; López-Hernández, Luz B; Bahena-Martínez, Eliganty; Luna-Angulo, Alexandra B; Canto, Patricia; Coral-Vázquez, Ramón M

    2012-03-01

    The muscular dystrophies (MDs) result from perturbations in the myofibers. These alterations are induced in part by mechanical stress due to membrane cell fragility, disturbances in mechanotransduction pathways, muscle cell physiology, and metabolism. We analyzed 290 biopsies of patients with a clinical diagnosis of muscular dystrophy. Using immunofluorescence staining, we searched for primary and secondary deficiencies of 12 different proteins, including membrane, costamere, cytoskeletal, and nuclear proteins. In addition, we analyzed calpain-3 by immunoblot. We identified 212 patients with varying degrees of protein deficiencies, including dystrophin, sarcoglycans, dysferlin, caveolin-3, calpain-3, emerin, and merosin. Moreover, 78 biopsies showed normal expression of all investigated muscle proteins. The frequency rates of protein deficiencies were as follows: 52.36% dystrophinopathies; 18.40% dysferlinopathies; 14.15% sarcoglycanopathies; 11.32% calpainopathies; 1.89% merosinopathies; 1.42% caveolinopathies; and 0.47% emerinopathies. Deficiencies in lamin A/C and telethonin were not detected. We have described the frequency of common muscular dystrophies in Mexico. Copyright © 2011 Wiley Periodicals, Inc.

  10. Combined application of neuromuscular electrical stimulation and voluntary muscular contractions.

    PubMed

    Paillard, Thierry

    2008-01-01

    Electromyostimulation (EMS) and voluntary muscle contraction (VC) constitute different modes of muscle activation and induce different acute physiological effects on the neuromuscular system. Long-term application of each mode of muscle activation can produce different muscle adaptations. It seems theoretically possible to completely or partially cumulate the muscle adaptations induced by each mode of muscle activation applied separately. This work consisted of examining the literature concerning the muscle adaptations induced by long-term application of the combined technique (CT) [i.e. EMS is combined with VC - non-simultaneously] compared with VC and/or EMS alone in healthy subjects and/or athletes and in post-operative knee-injured subjects. In general, CT induced greater muscular adaptations than VC whether in sports training or rehabilitation. This efficiency would be due to the fact that CT can facilitate cumulative effects of training completely or partially induced by VC and EMS practiced alone. CT also provides a greater improvement of the performance of complex dynamic movements than VC. However, EMS cannot improve coordination between different agonistic and antagonistic muscles and thus does not facilitate learning the specific coordination of complex movements. Hence, EMS should be combined with specific sport training to generate neuromuscular adaptations, but also allow the adjustment of motor control during a voluntary movement. Likewise, in a therapeutic context, CT was particularly efficient to accelerate recovery of muscle contractility during a rehabilitation programme. Strength loss and atrophy inherent in a traumatism and/or a surgical operation would be more efficiently compensated with CT than with VC. Furthermore, CT also restored more functional abilities than VC. Finally, in a rehabilitation context, EMS is complementary to voluntary exercise because in the early phase of rehabilitation it elicits a strength increase, which is necessary

  11. Synthetic peptide antagonists of glucagon.

    PubMed Central

    Unson, C G; Andreu, D; Gurzenda, E M; Merrifield, R B

    1987-01-01

    Several glucagon analogs were synthesized in an effort to find derivatives that would bind with high affinity to the glucagon receptor of rat liver membranes but would not activate membrane-bound adenylate cyclase and, therefore, would serve as antagonists of the hormone. Measurements on a series of glucagon/secretin hybrids indicated that replacement of Asp9 in glucagon by Glu9, found in secretin, was the important sequence difference in the N terminus of the two hormones. Further deletion of His1 and introduction of a C-terminal amide resulted in des-His1-[Glu9]glucagon amide, which had a 40% binding affinity relative to that of native glucagon but caused no detectable adenylate cyclase activation in the rat liver membrane. This antagonist completely inhibited the effect of a concentration of glucagon that alone gave a full agonist response. It had an inhibition index of 12. The pA2 was 7.2. An attempt was made to relate conformation with receptor binding. The peptides were synthesized by solid-phase methods and purified to homogeneity by reverse-phase high-performance liquid chromatography on C18-silica columns. PMID:3035568

  12. Vitamin K antagonists: beyond bleeding.

    PubMed

    Krüger, Thilo; Floege, Jürgen

    2014-01-01

    Warfarin is the most widely used oral anticoagulant in clinical use today. Indications range from prosthetic valve replacement to recurrent thromboembolic events due to antiphospholipid syndrome. In hemodialysis (HD) patients, warfarin use is even more frequent than in the nonrenal population due to increased cardiovascular comorbidities. The use of warfarin in dialysis patients with atrial fibrillation requires particular caution because side effects may outweigh the assumed benefit of reduced stroke rates. Besides increased bleeding risk, coumarins exert side effects which are not in the focus of clinical routine, yet they deserve special consideration in dialysis patients and should influence the decision of whether or not to prescribe vitamin K antagonists in cases lacking clear guidelines. Issues to be taken into consideration in HD patients are the induction or acceleration of cardiovascular calcifications, a 10-fold increased risk of calciphylaxis and problems related to maintaining a target INR range. New anticoagulants like direct thrombin inhibitors are promising but have not yet been approved for ESRD patients. Here, we summarize the nontraditional side effects of coumarins and give recommendations about the use of vitamin K antagonists in ESRD patients.

  13. 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.

  14. Threatened masculinity and muscularity: an experimental examination of multiple aspects of muscularity in men.

    PubMed

    Hunt, Christopher John; Gonsalkorale, Karen; Murray, Stuart B

    2013-06-01

    Two studies examined the threatened masculinity theory of male body dissatisfaction, which posits that threats to masculinity result in increased muscle dissatisfaction. In Study 1, a masculinity threat was followed by tasks examining confidence in physical ability and perceptions of current and ideal body shapes. Results showed that men who experienced a masculinity threat reported lower confidence in their physical ability and perceived themselves as less muscular than men who experienced an affirmation of their masculinity. In Study 2, men were asked to report their intention to increase muscularity and their appearance anxiety following a threat to masculinity. Results showed that men reported lower appearance anxiety and drive for muscularity when their masculinity was threatened than when their masculinity was affirmed. This apparent contradiction can be explained by noting that men may be motivated to deny appearance concerns following a threat to masculinity, as such concerns are equated with femininity.

  15. 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

  16. 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.

  17. 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.

  18. Cholinergic antagonists in a solitary wasp venom.

    PubMed

    Piek, T; Mantel, P

    1986-01-01

    The venom of the solitary wasp Philanthus triangulum contains a cholinergic antagonist of the nicotinic receptor of the rectus abdominis muscle of the frog, Xenopus laevis. The venom of African P. triangulum contains two different cholinergic factors, a competitive and a non-competitive antagonist. The venom of the European P. triangulum may not contain a competitive antagonist of the nicotinic receptor of X. laevis, but only a very strong non-competitive antagonist. The possible non-synonymity of both groups of P. triangulum is discussed.

  19. Management of scoliosis in patients with Duchenne muscular dystrophy and spinal muscular atrophy: A literature review.

    PubMed

    Garg, Sumeet

    2016-01-01

    Scoliosis occurs in nearly all non-ambulatory children with spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). Non-operative treatments have not been shown to be effective at preventing progression of scoliosis. Progressive scoliosis can impact the ability of patients to sit comfortably, be cosmetically unappealing, and in severe cases exacerbate pulmonary disease. The main goal of operative treatment is to improve sitting balance and prevent progression of scoliosis. Complication rates are high and there is little data on effect of operative treatment on quality of life in children with SMA and DMD. Comprehensive multi-disciplinary pre-operative evaluations are vital to reduce the risks of operative treatment.

  20. Recent developments in the treatment of Duchenne muscular dystrophy and spinal muscular atrophy

    PubMed Central

    Liew, Wendy K. M.

    2013-01-01

    Pediatric neuromuscular disorders comprise a large variety of disorders that can be classified based on their neuroanatomical localization, patterns of weakness, and laboratory test results. Over the last decade, the field of translational research has been active with many ongoing clinical trials. This is particularly so in two common pediatric neuromuscular disorders: Duchenne muscular dystrophy and spinal muscular atrophy. Although no definitive therapy has yet been found, numerous active areas of research raise the potential for novel therapies in these two disorders, offering hope for improved quality of life and life expectancy for affected individuals. PMID:23634188

  1. Different positioning of the ligand-binding domain helix 12 and the F domain of the estrogen receptor accounts for functional differences between agonists and antagonists.

    PubMed Central

    Nichols, M; Rientjes, J M; Stewart, A F

    1998-01-01

    The estrogen receptor is capable of binding a diverse set of ligands that are broadly categorized as agonists or antagonists, depending on their abilities to induce or interfere with transcriptional responsiveness. We show, using a fusion protein assay for ligand-binding which does not rely on transcriptional responsiveness, that agonists and antagonists differently position the C-terminus of the ligand-binding domain (helix 12) and the F domain. Upon antagonist binding, the F domain interferes with the fusion protein activity. Mutational disruption of helix 12 alters the position of the F domain, imposing interference after agonist or antagonist binding. Genetically selected inversion mutations where only agonists, but not antagonists, induce interference are similarly reliant on helix 12 and F domain positioning. Our results demonstrate that agonists and antagonists differently position helix 12 and implicate the F domain in mechanisms of antagonist action. PMID:9451001

  2. Muscular strength, functional performances and injury risk in professional and junior elite soccer players.

    PubMed

    Lehance, C; Binet, J; Bury, T; Croisier, J L

    2009-04-01

    Muscle strength and anaerobic power of the lower extremities are neuromuscular variables that influence performance in many sports activities, including soccer. Despite frequent contradictions in the literature, it may be assumed that muscle strength and balance play a key role in targeted acute muscle injuries. The purpose of the present study was to provide and compare pre-season muscular strength and power profiles in professional and junior elite soccer players throughout the developmental years of 15-21. One original aspect of our study was that isokinetic data were considered alongside the past history of injury in these players. Fifty-seven elite and junior elite male soccer players were assigned to three groups: PRO, n=19; U-21, n=20 and U-17, n=18. Players benefited from knee flexor and extensor isokinetic testing consisting of concentric and eccentric exercises. A context of lingering muscle disorder was defined using statistically selected cut-offs. Functional performance was evaluated throughout a squat jump and 10 m sprint. The PRO group ran faster and jumped higher than the U-17 group (P<0.05). No significant difference in isokinetic muscle strength performance was observed between the three groups when considering normalized body mass parameters. Individual isokinetic profiles enabled the identification of 32/57 (56%) subjects presenting lower limb muscular imbalance. Thirty-six out of 57 players were identified as having sustained a previous major lower limb injury. Of these 36 players, 23 still showed significant muscular imbalance (64%). New trends in rational training could focus more on the risk of imbalance and implement antagonist strengthening aimed at injury prevention. Such an intervention would benefit not only athletes recovering from injury, but also uninjured players. An interdisciplinary approach involving trainers, a physical coach, and medical staff would be of interest to consider in implementing a prevention programme.

  3. 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.

  4. Evaluation of Toosendanin as a Botulinum Neurotoxin Antagonist

    DTIC Science & Technology

    2008-01-01

    an action resembling that of the aminopyridine class of potassium blockers (Simpson, 1986; Adler et al., 1995, 1996, 2000). In this study, we...Biol., Vol. 10, pp.13–18. Li, P.Z. and Sun, G.Z. (1983) ‘Antagonistic effect of toosendanin to botulinum toxins on neuromuscular preparations of mice...presynaptic neuromuscular blocking agent’, Acta Physiol. Sin., Vol. 32, pp.293–297. Shih, Y.L. and Hsu, K. (1983) ‘Anti-botulismic effect of toosendanin and

  5. Mineralocorticoid receptor antagonists attenuate pulmonary inflammation and bleomycin-evoked fibrosis in rodent models.

    PubMed

    Lieber, Gissela B; Fernandez, Xiomara; Mingo, Garfield G; Jia, Yanlin; Caniga, Michael; Gil, Malgorzata A; Keshwani, Shanil; Woodhouse, Janice D; Cicmil, Milenko; Moy, Lily Y; Kelly, Nancy; Jimenez, Johanna; Crawley, Yvette; Anthes, John C; Klappenbach, Joel; Ma, Yu-Lu; McLeod, Robbie L

    2013-10-15

    Accumulating evidence indicates protective actions of mineralocorticoid antagonists (MR antagonists) on cardiovascular pathology, which includes blunting vascular inflammation and myocardial fibrosis. We examined the anti-inflammatory and anti-fibrotic potential of MR antagonists in rodent respiratory models. In an ovalbumin allergic and challenged Brown Norway rat model, the total cell count in nasal lavage was 29,348 ± 5451, which was blocked by spironolactone (0.3-60 mg/kg, p.o.) and eplerenone (0.3-30 mg/kg, p.o.). We also found that MR antagonists attenuated pulmonary inflammation in the Brown Norway rat. A series of experiments were conducted to determine the actions of MR blockade in acute/chronic lung injury models. (1) Ex vivo lung slice rat experiments found that eplerenone (0.01 and 10 µM) and spironolactone (10 µM) diminished lung hydroxyproline concentrations by 55 ± 5, 122 ± 9, and 83 ± 8%. (2) In in vivo studies, MR antagonists attenuated the increases in bronchioalveolar lavage (BAL) neutrophils and macrophages caused by lung bleomycin exposure. In separate studies, bleomycin (4.0 U/kg, i.t.) increased lung levels of hydroxyproline by approximately 155%, which was blocked by spironolactone (10-60 mg/kg, p.o.). In a rat Lipopolysaccharide (LPS) model, spironolactone inhibited acute increases in BAL cytokines with moderate effects on neutrophils. Finally, we found that chronic LPS exposure significantly increased end expiratory lung and decreased lung elastance in the mouse. These functional effects of chronic LPS were improved by MR antagonists. Our results demonstrate that MR antagonists have significant pharmacological actions in the respiratory system.

  6. Discovery of new muscarinic acetylcholine receptor antagonists from Scopolia tangutica

    PubMed Central

    Du, Nana; Liu, Yanfang; Zhang, Xiuli; Wang, Jixia; Zhao, Jianqiang; He, Jian; Zhou, Han; Mei, Lijuan; Liang, Xinmiao

    2017-01-01

    Scopolia tangutica (S. tangutica) is a traditional Chinese medicinal plant used for antispasmodics, anesthesia, analgesia and sedation. Its pharmacological activities are mostly associated with the antagonistic activity at muscarinic acetylcholine receptors (mAchRs) of several known alkaloids such as atropine and scopolamine. With our recent identification of four hydroxycinnamic acid amides from S. tangutica, we hypothesized that this plant may contain previously unidentified alkaloids that may also contribute to its in vivo effect. Herein, we used a bioassay-guided multi-dimension separation strategy to discover novel mAchR antagonists from S. tangutica. The core of this approach is to use label-free cell phenotypic assay to first identify active fractions, and then to guide purification of active ligands. Besides four tropanes and six cinnamic acid amides that have been previously isolated from S. tangutica, we recently identified two new tropanes, one new cinnamic acid amide, and nine other compounds. Six tropane compounds purified from S. tangutica for the first time were confirmed to be competitive antagonists of muscarinic receptor 3 (M3), including the two new ones 8 and 12 with IC50 values of 1.97 μM and 4.47 μM, respectively. Furthermore, the cinnamic acid amide 17 displayed 15-fold selectivity for M1 over M3 receptors. These findings will be useful in designing lead compounds for mAchRs and elucidating mechanisms of action of S. tangutica. PMID:28387362

  7. 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

  8. Synergistic and antagonistic drug combinations depend on network topology.

    PubMed

    Yin, Ning; Ma, Wenzhe; Pei, Jianfeng; Ouyang, Qi; Tang, Chao; Lai, Luhua

    2014-01-01

    Drug combinations may exhibit synergistic or antagonistic effects. Rational design of synergistic drug combinations remains a challenge despite active experimental and computational efforts. Because drugs manifest their action via their targets, the effects of drug combinations should depend on the interaction of their targets in a network manner. We therefore modeled the effects of drug combinations along with their targets interacting in a network, trying to elucidate the relationships between the network topology involving drug targets and drug combination effects. We used three-node enzymatic networks with various topologies and parameters to study two-drug combinations. These networks can be simplifications of more complex networks involving drug targets, or closely connected target networks themselves. We found that the effects of most of the combinations were not sensitive to parameter variation, indicating that drug combinational effects largely depend on network topology. We then identified and analyzed consistent synergistic or antagonistic drug combination motifs. Synergistic motifs encompass a diverse range of patterns, including both serial and parallel combinations, while antagonistic combinations are relatively less common and homogenous, mostly composed of a positive feedback loop and a downstream link. Overall our study indicated that designing novel synergistic drug combinations based on network topology could be promising, and the motifs we identified could be a useful catalog for rational drug combination design in enzymatic systems.

  9. 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…

  10. Expression Profiling in the Muscular Dystrophies

    PubMed Central

    Chen, Yi-Wen; Zhao, Po; Borup, Rehannah; Hoffman, Eric P.

    2000-01-01

    We used expression profiling to define the pathophysiological cascades involved in the progression of two muscular dystrophies with known primary biochemical defects, dystrophin deficiency (Duchenne muscular dystrophy) and α-sarcoglycan deficiency (a dystrophin-associated protein). We employed a novel protocol for expression profiling in human tissues using mixed samples of multiple patients and iterative comparisons of duplicate datasets. We found evidence for both incomplete differentiation of patient muscle, and for dedifferentiation of myofibers to alternative lineages with advancing age. One developmentally regulated gene characterized in detail, α-cardiac actin, showed abnormal persistent expression after birth in 60% of Duchenne dystrophy myofibers. The majority of myofibers (∼80%) remained strongly positive for this protein throughout the course of the disease. Other developmentally regulated genes that showed widespread overexpression in these muscular dystrophies included embryonic myosin heavy chain, versican, acetylcholine receptor α-1, secreted protein, acidic and rich in cysteine/osteonectin, and thrombospondin 4. We hypothesize that the abnormal Ca2+ influx in dystrophin- and α-sarcoglycan–deficient myofibers leads to altered developmental programming of developing and regenerating myofibers. The finding of upregulation of HLA-DR and factor XIIIa led to the novel identification of activated dendritic cell infiltration in dystrophic muscle; these cells mediate immune responses and likely induce microenvironmental changes in muscle. We also document a general metabolic crisis in dystrophic muscle, with large scale downregulation of nuclear-encoded mitochondrial gene expression. Finally, our expression profiling results show that primary genetic defects can be identified by a reduction in the corresponding RNA. PMID:11121445

  11. Spinal and Bulbar Muscular Atrophy Overview

    PubMed Central

    Fischbeck, Kenneth H.

    2016-01-01

    Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by an expanded repeat in the androgen receptor gene. The mutant protein is toxic to motor neurons and muscle. The toxicity is ligand-dependent and likely involves aberrant interaction of the mutant androgen receptor with other nuclear factors leading to transcriptional dysregulation. Various therapeutic strategies have been effective in transgenic animal models, and the challenge now is to translate these strategies into safe and effective treatment in patients. PMID:26547319

  12. [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

  13. 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.

  14. Muscular cysticercosis: Case report and imaging findings.

    PubMed

    Olmo, Neide Regina Simões; Fiorio, Ulysses Ferreira; Bastos, Eder Amaral; Clemente, Marcel Andreazza; Mendes, Gustavo Gomes

    2016-11-01

    Cysticercosis is a parasitic disease caused by a worm of the Cestoda class. The most prevalent form affects the nervous system. This case report is from a 78-year-old female patient evaluated at Clínica Mult Imagem, in the city of Santos, Brazil, who presented a form of the disease that differed from the classic neurocysticercosis, in this case muscular cysticercosis. This and other forms of manifestation justify further studies to ensure adequate recognition, diagnosis and treatment of this parasitic disease.

  15. Resveratrol ameliorates muscular pathology in the dystrophic mdx mouse, a model for Duchenne muscular dystrophy.

    PubMed

    Hori, Yusuke S; Kuno, Atsushi; Hosoda, Ryusuke; Tanno, Masaya; Miura, Tetsuji; Shimamoto, Kazuaki; Horio, Yoshiyuki

    2011-09-01

    Muscular dystrophies are inherited myogenic disorders accompanied by progressive skeletal muscle weakness and degeneration. We previously showed that resveratrol (3,5,4'-trihydroxy-trans-stilbene), an antioxidant and activator of the NAD(+)-dependent protein deacetylase SIRT1, delays the progression of heart failure and prolongs the lifespan of δ-sarcoglycan-deficient hamsters. Because a defect of dystroglycan complex causes muscular dystrophies, and δ-sarcoglycan is a component of this complex, we hypothesized that resveratrol might be a new therapeutic tool for muscular dystrophies. Here, we examined resveratrol's effect in mdx mice, an animal model of Duchenne muscular dystrophy. mdx mice that received resveratrol in the diet for 32 weeks (4 g/kg diet) showed significantly less muscle mass loss and nonmuscle interstitial tissue in the biceps femoris compared with mdx mice fed a control diet. In the muscles of these mice, resveratrol significantly decreased oxidative damage shown by the immunostaining of nitrotyrosine and 8-hydroxy-2'-deoxyguanosine and suppressed the up-regulation of NADPH oxidase subunits Nox4, Duox1, and p47(phox). Resveratrol also reduced the number of α-smooth muscle actin (α-SMA)(+) myofibroblast cells and endomysial fibrosis in the biceps femoris, although the infiltration of CD45(+) inflammatory cells and increase in transforming growth factor-β1 (TGF-β1) were still observed. In C2C12 myoblast cells, resveratrol pretreatment suppressed the TGF-β1-induced increase in reactive oxygen species, fibronectin production, and expression of α-SMA, and SIRT1 knockdown blocked these inhibitory effects. SIRT1 small interfering RNA also increased the expression of Nox4, p47(phox), and α-SMA in C2C12 cells. Taken together, these findings indicate that SIRT1 activation may be a useful strategy for treating muscular dystrophies.

  16. 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

  17. Antagonist muscle co-activation of limbs in human infant crawling: A pilot study.

    PubMed

    Xiong, Qi L; Wu, Xiao Y; Xiao, Nong; Zeng, Si Y; Wan, Xiao P; Zheng, Xiao L; Hou, Wen S

    2015-01-01

    Muscle Co-activation (MCo) is the simultaneous muscular activation of agonist and antagonist muscle groups, which provides adequate joint stability, movement accuracy during movement. Infant crawling is an important stage of motor function development that manifests non-synchronization growth and development of upper and lower limbs due to the well-known gross motor development principle of head to toe. However, the effect of MCo level for agonist and antagonist muscle groups on motor function development of limbs has not been previously reported. In this paper, sEMG signals were collected from triceps brachii (TB) and biceps brachii (BB), quadriceps femoris (QF) and hamstrings (HS) of limbs when fourteen infants were crawling at their self-selected speed. Antagonist muscle co-activation was evaluated by measuring two common indexes (co-activation index and Pearson's correlation coefficient).A significant difference was observed between upper limbs and lower limbs, but the relationship between MCo and speed of crawling was poor. This study is an opening for further investigation including a longitudinal study and compare against infant with CNS disorders.

  18. 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…

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

    USDA-ARS?s Scientific Manuscript database

    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...

  20. Contingent muscular tension during a choice reaction task.

    PubMed

    Araki, Masanobu; Choshi, Koji

    2006-06-01

    This study examined the effects of contingent muscular tension on a choice reaction task, and especially, the effects various amounts of muscular tension have on the information processing of choice reaction time. The reactive movement task included a choice reaction task. Ten right-handed healthy men (ages 18 to 19 years) underwent trials with stimulus presentation probabilities of 50% and 20% on the muscular tension task and choice reaction tasks. The conditions for the muscular tension tasks were divided into seven different conditions: 0%, 10%, 20%, 30%, 40%, 50%, and 60% of maximum voluntary contraction. On these tasks, subjects performed isometric contraction of the biceps brachii. The choice reaction task was a rapid extension of the left or right knee as a choice reaction. Measures were choice reaction time, movement time, and total reaction time. Analysis indicated that shortening choice reaction time of the left and right feet was observed under 10% muscular tension of maximum strength. Muscular tension appreciably influenced information processing, including choice reaction time. Muscular tension did not affect movement time. Results are discussed with respect to previous research and the optimal muscular tension for best performance.

  1. 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…

  2. 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…

  3. Congenital muscular torticollis: evaluation and classification.

    PubMed

    Tatli, Burak; Aydinli, Nur; Caliskan, Mine; Ozmen, Meral; Bilir, Feride; Acar, Gonul

    2006-01-01

    In this investigation of congenital muscular torticollis, 311 infants treated consecutively for congenital torticollis over an 8-year period (1995-2003) at the Pediatric Neurology Clinic of Istanbul Medical Faculty, Istanbul University, Turkey were reviewed retrospectively. The clinical presentation, associated abnormalities, treatment, and outcomes of the overall group and of subgroups divided according to an ultrasonography-based classification were evaluated. All patients were evaluated using a standard approach: cervical ultrasonography was performed, and the patients were divided into two subgroups. Each group was scanned for other anomalies, and outcomes were compared. The mean age at diagnosis was 2.3 months; patients included in this study were 138 males and 173 females. Two clinical subgroups, comprised of sternomastoid tumors 85% and postural torticollis 15%, were identified. Passive range of motion was the initial treatment recommended for all of the patients. Follow-up data were available for all 311 patients; 95% experienced total resolution and 5% experienced subtotal resolution. We conclude that the majority of children with congenital muscular torticollis experience total resolution of symptoms. The success rate of conservative treatment is primarily dependent on the patients' age at the initiation of exercises and ultrasonographic findings.

  4. 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

  5. Sleep disordered breathing in facioscapulohumeral muscular dystrophy.

    PubMed

    Della Marca, Giacomo; Frusciante, Roberto; Dittoni, Serena; Vollono, Catello; Buccarella, Cristina; Iannaccone, Elisabetta; Rossi, Monica; Scarano, Emanuele; Pirronti, Tommaso; Cianfoni, Alessandro; Mazza, Salvatore; Tonali, Pietro A; Ricci, Enzo

    2009-10-15

    Facioscapulohumeral muscular dystrophy (FSHD) is one of the most frequent forms of muscular dystrophy. The aims of this study were: 1) to evaluate the prevalence of sleep disordered breathing (SDB) in patients with FSHD; 2) to define the sleep-related respiratory patterns in FSHD patients with SDB; and 3) to find the clinical predictors of SDB. Fifty-one consecutive FSHD patients were enrolled, 23 women, mean age 45.7+/-12.3 years (range: 26-72). The diagnosis of FSHD was confirmed by genetic tests. All patients underwent medical and neurological evaluations, subjective evaluation of sleep and full-night laboratory-based polysomnography. Twenty patients presented SDB: 13 presented obstructive apneas, four presented REM related oxygen desaturations and three showed a mixed pattern. Three patients needed positive airways pressure. SDB was not related to the severity of the disease. Body mass index, neck circumference and daytime sleepiness did not allow prediction of SDB. In conclusion, the results suggest a high prevalence of SDB in patients with FSHD. The presence of SDB does not depend on the clinical severity of the disease. SDB is often asymptomatic, and no clinical or physical measure can reliably predict its occurrence. A screening of SDB should be included in the clinical assessment of FSHD.

  6. [Cardiac involvement in Duchenne muscular dystrophy].

    PubMed

    Fayssoil, Abdallah; Orlikowski, David; Nardi, Olivier; Annane, Djillali

    2008-04-01

    Duchenne muscular dystrophy (DMD) is an X-linked hereditary dystrophinopathy due to the absence of dystrophin, a cytoskeleton protein; it is the most frequent of the dystrophinopathies. DMD affects one newborn boy in 3500. The disease locus is found on the short arm of the X chromosome (Xp21). Dystrophin plays an important role in the maintenance of the cellular architecture and permits signal transduction between the cytoskeleton and the extracellular matrix. Its absence is expressed by peripheral muscular damage, most often at the pelvic girdle, and sometimes associated with pseudohypertrophy of the calf. The disease is very often complicated by cardiac damage that develops towards the end of adolescence, together with restrictive lung disease that will usually end up requiring respiratory support. The prognosis is severe. Doppler examination of the myocardial tissue helps to screen for subclinical myocardial damage. Therapeutic management is multidisciplinary. Medical treatment of cardiac involvement relies on the drugs already proved effective in chronic heart failure. Ongoing research is currently studying gene therapy.

  7. The superhealing MRL background improves muscular dystrophy

    PubMed Central

    2012-01-01

    Background Mice from the MRL or “superhealing” strain have enhanced repair after acute injury to the skin, cornea, and heart. We now tested an admixture of the MRL genome and found that it altered the course of muscle pathology and cardiac function in a chronic disease model of skeletal and cardiac muscle. Mice lacking γ-sarcoglycan (Sgcg), a dystrophin-associated protein, develop muscular dystrophy and cardiomyopathy similar to their human counterparts with limb girdle muscular dystrophy. With disruption of the dystrophin complex, the muscle plasma membrane becomes leaky and muscles develop increased fibrosis. Methods MRL/MpJ mice were bred with Sgcg mice, and cardiac function was measured. Muscles were assessed for fibrosis and membrane leak using measurements of hydroxyproline and Evans blue dye. Quantitative trait locus mapping was conducted using single nucleotide polymorphisms distinct between the two parental strains. Results Introduction of the MRL genome reduced fibrosis but did not alter membrane leak in skeletal muscle of the Sgcg model. The MRL genome was also associated with improved cardiac function with reversal of depressed fractional shortening and the left ventricular ejection fraction. We conducted a genome-wide analysis of genetic modifiers and found that a region on chromosome 2 was associated with cardiac, diaphragm muscle and abdominal muscle fibrosis. Conclusions These data are consistent with a model where the MRL genome acts in a dominant manner to suppress fibrosis in this chronic disease setting of heart and muscle disease. PMID:23216833

  8. Elevated Expression of Moesin in Muscular Dystrophies.

    PubMed

    Pines, Mark; Levi, Oshrat; Genin, Olga; Lavy, Adi; Angelini, Corrado; Allamand, Valérie; Halevy, Orna

    2017-03-01

    Fibrosis is the main complication of muscular dystrophies. We identified moesin, a member of the ezrin-radixin-moesin family, in dystrophic muscles of mice representing Duchenne and congenital muscular dystrophies (DMD and CMD, respectively) and dysferlinopathy, but not in the wild type. High levels of moesin were also observed in muscle biopsy specimens from DMD, Ullrich CMD, and merosin-deficient CMD patients, all of which present high levels of fibrosis. The myofibroblasts, responsible for extracellular matrix protein synthesis, and the macrophages infiltrating the dystrophic muscles were the source of moesin. Moesin-positive cells were embedded within the fibrotic areas between the myofibers adjacent to the collagen type I fibers. Radixin was also synthesized by the myofibroblasts, whereas ezrin colocalized with the myofiber membranes. In animal models and patients' muscles, part of the moesin was in its active phosphorylated form. Inhibition of fibrosis by halofuginone, an antifibrotic agent, resulted in a major decrease in moesin levels in the muscles of DMD and CMD mice. In summary, the results of this study may pave the way for exploiting moesin as a novel target for intervention in MDs, and as part of a battery of biomarkers to evaluate treatment success in preclinical studies and clinical trials.

  9. Postactivation potentiation and muscular endurance training.

    PubMed

    Mettler, Joni A; Griffin, Lisa

    2012-03-01

    The aim of this study was to investigate muscle twitch force potentiation after voluntary conditioning contractions (CC) of various intensities and the CC duration necessary to achieve maximal potentiation before and after muscular endurance training. Fourteen healthy men and women (23.6 ± 0.96 years of age) performed repeated CCs of 25%, 50%, and 100% maximal voluntary contraction of the adductor pollicis muscle until maximal potentiation. CCs were followed by electrically evoked twitches. The training group performed a fatigue task and endurance trained for 8 weeks. Endurance time increased by 79.8 ± 22.5% posttraining. Potentiation occurred after all CC intensities and was greater after training. The CC duration needed to achieve maximal potentiation decreased as CC intensity increased. Potentiation was greater during the fatigue task after compared to before training and was correlated with endurance time. An increase in muscle force potentiation may function as a mechanism to prolong muscular endurance. Copyright © 2011 Wiley Periodicals, Inc.

  10. 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

  11. Establishing a standardized therapeutic testing protocol for spinal muscular atrophy.

    PubMed

    Tsai, Li-Kai; Tsai, Ming-Shung; Lin, Tzer-Bin; Hwu, Wuh-Liang; Li, Hung

    2006-11-01

    Several mice models have been created for spinal muscular atrophy (SMA); however, there is still no standard preclinical testing system for the disease. We previously generated type III-specific SMA model mice, which might be suitable for use as a preclinical therapeutic testing system for SMA. To establish such a system and test its applicability, we first created a testing protocol and then applied it as a means to investigate the use of valproic acid (VPA) as a possible treatment for SMA. These SMA mice revealed tail/ear/foot deformity, muscle atrophy, poorer motor performances, smaller compound muscle action potential and lower spinal motoneuron density at the age of 9 to 12 months in comparison with age-matched wild-type littermate mice. In addition, VPA attenuates motoneuron death, increases spinal SMN protein level and partially normalizes motor function in SMA mice. These results suggest that the testing protocol developed here is well suited for use as a standardized preclinical therapeutic testing system for SMA.

  12. Beneficial effects of penicillamine treatment on hereditary avian muscular dystrophy.

    PubMed

    Chou, T; Hill, E J; Bartle, E; Woolley, K; LeQuire, V; Olson, W; Roelofs, R; Park, J H

    1975-10-01

    Hereditary muscular dystrophy in chickens of the New Hampshire strain was treated with penicillamine from the 9th day after hatching to the 425th day. The adult maintenance dose for males was 50 mg/kg per day and for females, 13-65 mg/kg per day. In avian dystrophy, deterioration of the muscle fibers is evidenced in the 2nd mo by an inability of the birds to rise after falling on their backs and by a progressive rigidity of the wings. The drug delayed the onset of symptoms and partially alleviated the debilitating aspects of the disease. Penicillamine produced three major improvements: (a) better righting ability when birds were placed on their backs; (b) greater wing flexibility; (c) and suppression of plasma creatine phosphokinase activity. The results are statistically analyzed and discussed in relationship to Duchenne dystrophy. Normal birds were not affected by penicillamine as judged by these parameters. The rationale for using penicillamine, a sulfhydryl compound with reducing properties, was (a) to attempt to protect essential thiol enzymes in the anabolic and glycolytic pathways against inactivation and (b) to prevent collagen cross-linking and deposition in muscle. Although the precise mechanism of drug action has not been determined. the possible role of penicillamine in mitigating the symptoms of genetic dystrophy in man is under consideration. Further, penicillamine may have a more generalized application i the prevention of contractures in a variety of neuromuscular disorders.

  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. Spectrum of Neuropathophysiology in Spinal Muscular Atrophy Type I

    PubMed Central

    Harding, Brian N.; Kariya, Shingo; Monani, Umrao R.; Chung, Wendy K.; Benton, Maryjane; Yum, Sabrina W.; Tennekoon, Gihan; Finkel, Richard S.

    2014-01-01

    Neuropathological findings within the CNS and PNS in patients with spinal muscular atrophy type I (SMA-I) were examined in relation to genetic, clinical and electrophysiological features. Five infants representing the full clinical spectrum of SMAI were examined clinically for compound motor action potential amplitude and SMN2 gene copy number; morphologic analyses of postmortem CNS, neuromuscular junction and muscle tissue samples were performed and SMN protein was assessed in muscle samples. The 2 clinically most severely affected patients had a single copy of the SMN2 gene; in addition to anterior horn cells, dorsal root ganglia and thalamus, neuronal degeneration in them was widespread in cerebral cortex, basal ganglia, pigmented nuclei, brainstem and cerebellum. Two typical SMA-I patients and a milder case each had 2 copies of the SMN2 gene and more restricted neuropathological abnormalities. Maturation of acetylcholine receptor subunits was delayed and the neuromuscular junctions were abnormally formed in the SMA-1 patients. Thus, the neuropathological findings in human SMA-I are similar to many findings in animal models; factors other than SMN2 copy number modify disease severity. We present a pathophysiologic model for SMA-I as a protein deficiency disease affecting a neuronal network with variable clinical thresholds. Because new treatment strategies improve survival of infants with SMA-I, a better understanding of these factors will guide future treatments. PMID:25470343

  15. PROGRESSIVE MUSCULAR DYSTROPHY—A Preliminary Report on Treatment with Amino Acids, Folic Acid and Vitamins

    PubMed Central

    Van Meter, J. Ray

    1953-01-01

    Ten patients with progressive muscular dystrophy were given daily oral doses of amino acids, folic acid and selected vitamins. At the time of this report they had been treated by this means for periods varying from two months to one year. Only one had other therapy concurrently. Definite and progressive improvement, objective and subjective, occurred in all cases. Among objective changes noted—not all of them in all cases—were return of strength, increase in size and tonus of atrophic muscles, restoration of normal respiratory action and relief of depression. Patients reported a sense of well-being, increase in strength and a feeling of bodily warmth. PMID:13094541

  16. 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.

  17. Why is muscularity sexy? Tests of the fitness indicator hypothesis.

    PubMed

    Frederick, David A; Haselton, Martie G

    2007-08-01

    Evolutionary scientists propose that exaggerated secondary sexual characteristics are cues of genes that increase offspring viability or reproductive success. In six studies the hypothesis that muscularity is one such cue is tested. As predicted, women rate muscular men as sexier, more physically dominant and volatile, and less committed to their mates than nonmuscular men. Consistent with the inverted-U hypothesis of masculine traits, men with moderate muscularity are rated most attractive. Consistent with past research on fitness cues, across two measures, women indicate that their most recent short-term sex partners were more muscular than their other sex partners (ds = .36, .47). Across three studies, when controlling for other characteristics (e.g., body fat), muscular men rate their bodies as sexier to women (partial rs = .49-.62) and report more lifetime sex partners (partial rs = .20-.27), short-term partners (partial rs = .25-.28), and more affairs with mated women (partial r = .28).

  18. 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.

  19. Genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies.

    PubMed

    Hightower, Rylie M; Alexander, Matthew S

    2017-09-06

    Muscular dystrophy is defined as the progressive wasting of skeletal muscles that is caused by inherited or spontaneous genetic mutations. Next-generation sequencing has greatly improved the accuracy and speed of diagnosis for different types of muscular dystrophy. Advancements in depth of coverage, convenience, and overall reduced cost have led to the identification of genetic modifiers that are responsible for phenotypic variability in affected patients. These genetic modifiers have been postulated to explain key differences in disease phenotypes, including age of loss of ambulation, steroid responsiveness, and the presence or absence of cardiac defects in patients with the same form of muscular dystrophy. This review highlights recent findings on genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies based on animal and clinical studies. These genetic modifiers hold great promise to be developed into novel therapeutic targets for the treatment of muscular dystrophies. Muscle Nerve, 2017. © 2017 Wiley Periodicals, Inc.

  20. Spinal muscular atrophy with respiratory distress type 1 (SMARD1).

    PubMed

    Kaindl, Angela M; Guenther, Ulf-Peter; Rudnik-Schöneborn, Sabine; Varon, Raymonda; Zerres, Klaus; Schuelke, Markus; Hübner, Christoph; von Au, Katja

    2008-02-01

    Autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1), recently referred to as distal spinal muscular atrophy 1 (DSMA1; MIM#604320) and also known as distal hereditary motor neuropathy type 6 (dHMN6 or HMN6), results from mutations in the IGHMBP2 gene on chromosome 11q13.3 encoding the immunoglobulin micro-binding protein 2. In contrast to the infantile spinal muscular atrophy type 1 (SMA1; Werdnig-Hoffmann disease) with weakness predominantly of proximal muscles and bell-shaped thorax deformities due to intercostal muscle atrophy, infants with distal spinal muscular atrophy 1 usually present with distal muscle weakness, foot deformities, and sudden respiratory failure due to diaphragmatic paralysis that often requires urgent intubation. In this article, the authors review the clinical, neuropathological, and genetic aspects of distal spinal muscular atrophy 1 and discuss differential diagnoses.

  1. Consensus Statement on Standard of Care for Congenital Muscular Dystrophies

    PubMed Central

    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

    2016-01-01

    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

  2. Antagonistic coevolution accelerates molecular evolution

    PubMed Central

    Paterson, Steve; Vogwill, Tom; Buckling, Angus; Benmayor, Rebecca; Spiers, Andrew J.; Thomson, Nicholas R.; Quail, Mike; Smith, Frances; Walker, Danielle; Libberton, Ben; Fenton, Andrew; Hall, Neil; Brockhurst, Michael A.

    2013-01-01

    The Red Queen hypothesis proposes that coevolution of interacting species (such as hosts and parasites) should drive molecular evolution through continual natural selection for adaptation and counter-adaptation1–3. Although the divergence observed at some host-resistance4–6 and parasite-infectivity7–9 genes is consistent with this, the long time periods typically required to study coevolution have so far prevented any direct empirical test. Here we show, using experimental populations of the bacterium Pseudomonas fluorescens SBW25 and its viral parasite, phage Φ2 (refs 10, 11), that the rate of molecular evolution in the phage was far higher when both bacterium and phage coevolved with each other than when phage evolved against a constant host genotype. Coevolution also resulted in far greater genetic divergence between replicate populations, which was correlated with the range of hosts that coevolved phage were able to infect. Consistent with this, the most rapidly evolving phage genes under coevolution were those involved in host infection. These results demonstrate, at both the genomic and phenotypic level, that antagonistic coevolution is a cause of rapid and divergent evolution, and is likely to be a major driver of evolutionary change within species. PMID:20182425

  3. [Angiotensin II receptor antagonists: different or equivalent?].

    PubMed

    Mounier-Vehier, C; Devos, P

    ARA-II: Angiotensin II receptor antagonists (ARA-II) belong to a recent class of antihypertensive drugs whose mechanism of action is similar to converting enzyme inhibitors (CEI). ARA-II are particularly interesting due to the excellent clinical and biological tolerance, similar to placebo, and their antihypertensive efficacy, comparable with classical drug classes. PUBLISHED TRIALS: A meta-analysis, published by Conlin in the American Journal of Hypertension, suggests that ARA-II, specifically losartan, valsartan, irbesartan and candesartan, have an equipotent blood pressure lowering effect. The careful lecture of this meta-analysis however discloses a faulty methodology from which no valid conclusion can be drawn. Since this early publication, several other comparative studies have been published. These multicentric, randomized double-blind studies enrolled a sufficient number of patients and demonstrated a clinical difference between certain ARA-II at usual dosages. CLINICAL PRACTICE: These studies do have an impact on everyday practice. For the practitioner, the goal is to obtain and then maintain a long-term and optimal reduction in the blood pressure level (reduction or prevention of target-organ disorders and cardiovascular complications of high blood pressure). This reduction in the cardiovascular risk will also depend directly on tolerance and compliance to the antihypertensive treatment. This element must also be considered in assessing treatment efficacy, independent of the blood pressure lowering effect. The results of several other studies will be published in 2001-2003. These large-scale studies on ARA-II related morbidity and mortality will be most useful in determining the role of these drugs in different therapeutic strategies compared with other drug classes.

  4. NMDA receptor antagonists extend the sensitive period for imprinting.

    PubMed

    Parsons, C H; Rogers, L J

    2000-03-01

    Filial imprinting in the domestic chick occurs during a sensitive period of development. The exact timing of this period can vary according to the methods used to measure imprinting. Using our imprinting paradigm, we have shown that normal, dark-reared chicks lose the ability to imprint after the second day post-hatching. Further, we reported that chicks treated 10 h after hatching with a mixture of the noncompetitive NMDA receptor antagonist ketamine (55 mg/kg) and the alpha(2)-adrenergic receptor agonist xylazine (6 mg/kg) were able to imprint on day 8 after hatching, whereas controls treated with saline did not imprint. We now show that the effect of the ketamine-xylazine mixture can be mimicked by treating chicks with ketamine alone or with another noncompetitive NMDA receptor antagonist, MK-801 (5 mg/kg). Treating chicks with a single dose of ketamine (55 mg/kg) or with a single dose of xylazine (6 mg/kg) failed to produce the effect on the sensitive period. However, prolonging the action of ketamine by treating chicks with two doses of ketamine (at 10 and 12 h after hatching) did allow imprinting on day 8. In contrast, prolonging the action of xylazine had no effect on the sensitive period for imprinting. Chicks treated with MK-801 were also able to imprint on day 8. Thus, we have evidence that the NMDA receptor system is involved in the mechanisms that control the sensitive period for imprinting.

  5. 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.

  6. 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

  7. 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

  8. 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

    2015-04-09

    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.

  9. Action semantics modulate action prediction.

    PubMed

    Springer, Anne; Prinz, Wolfgang

    2010-11-01

    Previous studies have demonstrated that action prediction involves an internal action simulation that runs time-locked to the real action. The present study replicates and extends these findings by indicating a real-time simulation process (Graf et al., 2007), which can be differentiated from a similarity-based evaluation of internal action representations. Moreover, results showed that action semantics modulate action prediction accuracy. The semantic effect was specified by the processing of action verbs and concrete nouns (Experiment 1) and, more specifically, by the dynamics described by action verbs (Experiment 2) and the speed described by the verbs (e.g., "to catch" vs. "to grasp" vs. "to stretch"; Experiment 3). These results propose a linkage between action simulation and action semantics as two yet unrelated domains, a view that coincides with a recent notion of a close link between motor processes and the understanding of action language.

  10. Antagonists of the kappa opioid receptor.

    PubMed

    Urbano, Mariangela; Guerrero, Miguel; Rosen, Hugh; Roberts, Edward

    2014-05-01

    The research community has increasingly focused on the development of OPRK antagonists as pharmacotherapies for the treatment of depression, anxiety, addictive disorders and other psychiatric conditions produced or exacerbated by stress. Short-acting OPRK antagonists have been recently developed as a potential improvement over long-acting prototypic ligands including nor-BNI and JDTic. Remarkably the short-acting LY2456302 is undergoing phase II clinical trials for the augmentation of the antidepressant therapy in treatment-resistant depression. This Letter reviews relevant chemical and pharmacological advances in the identification and development of OPRK antagonists.

  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. Spinal Muscular Atrophy: The Development and Implementation of Potential Treatments Running Head: Spinal Muscular Atrophy

    PubMed Central

    Arnold, W. David; Burghes, Arthur H.M.

    2013-01-01

    In neurodegenerative disorders effective treatments are urgently needed, along with methods to detect that the treatment worked. In this review we discuss the rapid progress in the understanding of recessive proximal spinal muscular atrophy and how this is leading to exciting potential treatments of the disease. Spinal muscular atrophy is a caused by loss of the Survival Motor Neuron 1 (SMN1) gene and reduced levels of SMN protein. The critical downstream targets of SMN deficiency that result in motor neuron loss are not known. However, increasing SMN levels has a marked impact in mouse models, and these therapeutics are rapidly moving towards clinical trials. Promising preclinical therapies, the varying degree of impact on the mouse models, and potential measures of treatment effect are reviewed. One key issue discussed is the variable outcome of increasing SMN at different stages of disease progression. PMID:23939659

  13. Pain in adolescents with spinal muscular atrophy and Duchenne and Becker muscular dystrophy.

    PubMed

    Lager, Christina; Kroksmark, Anna-Karin

    2015-09-01

    The purpose of this study was to explore the prevalence, nature and scope of pain in adolescents with spinal muscular atrophy and Duchenne and Becker muscular dystrophy and whether the pain differs between diagnostic groups or between adolescents with different ambulation status. Furthermore to study the consequences of pain and to identify pain-exacerbating and pain-relieving factors. In a national survey, fifty-five adolescents with spinal muscular atrophy and dystrophinopathy completed a questionnaire assessing pain frequency, duration, location using a body map, intensity and discomfort using visual analogue scales, pain interference using a modified version of Brief Pain Inventory and factors exacerbating and relieving pain. Sixty-nine per cent of the adolescents reported pain during the past three months and 50% reported chronic pain. The pain prevalence did not differ significantly between diagnostic groups or between ambulators and non-ambulators. The average pain intensity was graded as mild and the worst pain as moderate. The pain typically occurred weekly, most frequently in the neck/back or legs. General activity and mood were the areas that were most affected by pain. Common pain-exacerbating factors were sitting, too much movement/activity and being lifted or transferred. Pain is a frequent problem in adolescents with spinal muscular atrophy and dystrophinopathy. The assessments used enable an understanding both of the nature and scope of pain and of the impact of pain in everyday life. The study highlights the importance of assessing pain in a systematic manner and offering an individual approach to interventions designed to reduce pain in this population. Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  14. 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.

  15. The Evolution of Sexually Antagonistic Phenotypes

    PubMed Central

    Perry, Jennifer C.; Rowe, Locke

    2015-01-01

    Sexual conflict occurs whenever there is sexually antagonistic selection on shared traits. When shared traits result from interactions (e.g., mating rate) and have a different genetic basis in each sex (i.e., interlocus conflict), then sex-specific traits that shift the value of these interaction traits toward the sex-specific optimum will be favored. Male traits can be favored that increase the fitness of their male bearers, but decrease the fitness of interacting females. Likewise, female traits that reduce the costs of interacting with harmful males may simultaneously impose costs on males. If the evolution of these antagonistic traits changes the nature of selection acting on the opposite sex, interesting coevolutionary dynamics will result. Here we examine three current issues in the study of sexually antagonistic interactions: the female side of sexual conflict, the ecological context of sexual conflict, and the strength of evidence for sexually antagonistic coevolution. PMID:26032715

  16. Emerging cardiovascular indications of mineralocorticoid receptor antagonists.

    PubMed

    Parviz, Yasir; Iqbal, Javaid; Pitt, Bertram; Adlam, David; Al-Mohammad, Abdallah; Zannad, Faiez

    2015-04-01

    Mineralocorticoid receptor (MR) antagonism is a well-established treatment modality for patients with hypertension, heart failure, and left ventricular systolic dysfunction (LVSD) post-myocardial infarction (MI). There are emerging data showing potential benefits of MR antagonists in other cardiovascular conditions. Studies have shown association between MR activation and the development of myocardial fibrosis, coronary artery disease, metabolic syndrome, and cerebrovascular diseases. This review examines the preclinical and clinical data of MR antagonists for novel indications including heart failure with preserved ejection fraction (HFPEF), pulmonary arterial hypertension (PAH), arrhythmia, sudden cardiac death, valvular heart disease, metabolic syndrome, renal disease, and stroke. MR antagonists are not licensed for these conditions yet; however, emerging data suggest that indication for MR antagonists are likely to broaden; further studies are warranted.

  17. Unprecedented NES non-antagonistic inhibitor for nuclear export of Rev from Sida cordifolia.

    PubMed

    Tamura, Satoru; Kaneko, Masafumi; Shiomi, Atsushi; Yang, Guang-Ming; Yamaura, Toshiaki; Murakami, Nobutoshi

    2010-03-15

    Bioassay-guided separation from the MeOH extract of the South American medicinal plant Sida cordifolia resulted in isolation of (10E,12Z)-9-hydroxyoctadeca-10,12-dienoic acid (1) as an unprecedented NES non-antagonistic inhibitor for nuclear export of Rev. This mechanism of action was established by competitive experiment by the biotinylated probe derived from leptomycin B, the known NES antagonistic inhibitor. Additionally, structure-activity relationship analysis by use of the synthesized analogs clarified cooperation of several functionalities in the Rev-export inhibitory activity of 1.

  18. 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).

  19. Limb-girdle muscular dystrophy in childhood.

    PubMed

    Bönnemann, Carsten G

    2005-07-01

    LGMD refers to a class of muscular dystrophies with onset in the proximal muscles. They are genetically heterogeneous, with both autosomal recessive and dominant forms. The autosomal recessive forms are more common and in general follow a more severe course compared to the dominant forms. It is important to reach a specific genetic diagnosis beyond making a group diagnosis of LGMD to provide adequate genetic counseling, to predict risks for the patient such as the development of cardiomyopathy, and to be able to take advantage of specific treatments when they become available. Establishing a specific diagnosis requires knowledge about the individual clinical features, expert analysis of the muscule biopsy, and the guided initiation of appropriate genetic testing.

  20. [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.

  1. Cardiac involvement in facioscapulohumeral muscular dystrophy.

    PubMed

    Finsterer, Josef; Stöllberger, Claudia; Meng, Gerhard

    2005-01-01

    Cardiac involvement (CI) in form of myocardial thickening in a patient with genetically confirmed facioscapulohumeral muscular dystrophy (FSHMD) has not been reported. The patient is a 50-year-old male with a tandem repeat size of 17 and 14 kb in the D4Z4 locus on chromosome 4q35. The clinical cardiologic investigation was normal. Blood pressure was 150/90 mm Hg. Funduscopy, 24-hour ambulatory ECG, and 24-hour blood pressure monitoring were normal. ECG showed incomplete right bundle branch block, ST elevation in V2-V4, tall T waves in V3-V5, and hypertrophy signs. Echocardiography revealed left ventricular myocardial thickening of the posterior wall (11.7 mm) and the septum (15.5 mm). In conclusion, CI in genetically confirmed FSHMD may manifest not only as ECG abnormalities but also as left ventricular myocardial thickening. Copyright 2005 S. Karger AG, Basel.

  2. [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.

  3. Neonatal muscular manifestations in mitochondrial disorders.

    PubMed

    Tulinius, Már; Oldfors, Anders

    2011-08-01

    During the last decade rapid development has occurred in defining nuclear gene mutations causing mitochondrial disease. Some of these newly defined gene mutations cause neonatal or early infantile onset of disease, often associated with severe progressive encephalomyopathy combined with other multi-organ involvement such as cardiomyopathy or hepatopathy and with early death. Findings suggesting myopathy in neonates are hypotonia, muscle weakness and wasting, and arthrogryposis. We aim to describe the clinical findings of patients with mitochondrial disease presenting with muscular manifestations in the neonatal period or in early infancy and in whom the genetic defect has been characterized. The majority of patients with neonatal onset of mitochondrial disease have mutations in nuclear genes causing dysfunction of the mitochondrial respiratory chain, leading to defective oxidative phosphorylation.

  4. Clinical trials in spinal muscular atrophy.

    PubMed

    Kaufmann, Petra; Iannaccone, Susan T

    2008-08-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by muscle atrophy and weakness due to degeneration of the anterior horn cells in the spinal cord. A great need exists for an effective treatment of SMA, a disease that often causes severe disability in patients who are cognitively intact and can have a normal life expectancy. Unlike many other neurologic diseases, SMA can be easily diagnosed through genetic testing. Also, preclinical progress over the last 2 decades has been major, with the discovery of the gene and of a "druggable" modifying gene that provides one of several promising targets for treatment. SMA is rare but is a common orphan disease, so trials should be feasible, raising the hope that we will find effective treatments for this disorder.

  5. Macrophages: micromanagers of antagonistic signaling nanoclusters.

    PubMed

    Eggeling, Christian; Davis, Simon J

    2017-04-03

    How cells integrate antagonistic receptor signaling events is enigmatic. Using superresolution optical microscopy, Lopes et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201608094) demonstrate the nanometer-scale molecular reorganization of antagonistic signaling receptors in macrophages, after engagement by the receptors of activating and inhibitory ligands. They propose that large-scale rearrangements of this type underpin decision-making by these cells.

  6. Effects of muscular strength on cardiovascular risk factors and prognosis.

    PubMed

    Artero, Enrique G; Lee, Duck-chul; Lavie, Carl J; España-Romero, Vanesa; Sui, Xuemei; Church, Timothy S; Blair, Steven N

    2012-01-01

    Physical fitness is one of the strongest predictors of individual future health status. Together with cardiorespiratory fitness (CRF), muscular strength has been increasingly recognized in the pathogenesis and prevention of chronic disease. We review the most recent literature on the effect of muscular strength in the development of cardiovascular disease, with special interest in elucidating its specific benefits beyond those from CRF and body composition. Muscular strength has shown an independent protective effect on all-cause and cancer mortality in healthy middle-aged men, as well as in men with hypertension and patients with heart failure. It has also been inversely associated with age-related weight and adiposity gains, risk of hypertension, and prevalence and incidence of the metabolic syndrome. In children and adolescents, higher levels of muscular fitness have been inversely associated with insulin resistance, clustered cardiometabolic risk, and inflammatory proteins. Generally, the influence of muscular fitness was weakened but remained protective after considering CRF. Also, interestingly, higher levels of muscular fitness seems to some extent counteract the adverse cardiovascular profile of overweight and obese individuals. As many of the investigations have been conducted with non-Hispanic white men, it is important to examine how race/ethnicity and gender may affect these relationships. To conclude, most important effects of resistance training are also summarized, to better understand how higher levels of muscular fitness may result in a better cardiovascular prognosis and survival.

  7. Respiratory muscle dysfunction in facioscapulohumeral muscular dystrophy.

    PubMed

    Santos, Dante Brasil; Boussaid, Ghilas; Stojkovic, Tanya; Orlikowski, David; Letilly, Nadege; Behin, Anthony; Butel, Sandrine; Lofaso, Frédéric; Prigent, Hélène

    2015-08-01

    Respiratory insufficiency in facioscapulohumeral muscular dystrophy has rarely been studied. We compared two age- and sex-matched groups of 29 patients, with and without respiratory dysfunction. Tests in the 29 patients with respiratory dysfunction suggested predominant expiratory muscle dysfunction, leading to ineffective cough in 17 patients. Supine and upright vital capacities were not different (P = 0.76), suggesting absence of diaphragmatic dysfunction. By stepwise regression, only expiratory reserve volume correlated with the Walton and Gardner-Medwin score (R(2) = 0.503; P = 0.001). Compared to controls, patients with respiratory dysfunction had higher values for the Walton and Gardner-Medwin score (6.1 ± 1.9 vs. 3.2 ± 1.2; P <0.0001) and body mass index (26.9 ± 6.0 vs. 22.9 ± 4.0 kg/m(2); P = 0.003) and a smaller number of D4Z4 allele repeats (4.8 ± 1.6 vs. 5.7 ± 1.8; P = 0.05). Mechanical ventilation was required eventually in 20 patients, including 14 who were wheelchair bound. Three patients had acute respiratory failure requiring mechanical ventilation; 16 patients had poor airway clearance, including 10 with sleep apnea syndrome, responsible in 7 for chronic hypercapnia. Two patients presented isolated severe sleep apnea syndrome. Respiratory dysfunction in facioscapulohumeral muscular dystrophy is predominantly related to expiratory muscle weakness. Respiratory function and cough effectiveness should especially be monitored in patients with severe motor impairment and high body mass index. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Determination of muscular fatigue in elite runners.

    PubMed

    Hanon, Christine; Thépaut-Mathieu, Chantalle; Vandewalle, Henry

    2005-05-01

    This study analyses the changes in the electromyographic activity (EMG) of six major muscles of the leg during an incremental running test carried out on a treadmill. These muscles, the gluteus maximus (GM), biceps femoris (BF), vastus lateralis (VL), rectus femoris (RF), tibialis anterior (TA) and gastrocnemius (Ga) are known to have quite different functions during running. The aim of this study was to develop a methodology adapted to the analysis of integrated EMG (iEMG) running results, and to test the chronology of the onset of fatigue of the major muscles involved in running. Nine well-trained subjects [VO(2max) 76 (2.9) ml.min(-1).kg(-1)] took part in this study. They completed a running protocol consisting of 4 min stages, incrementally increasing in speed until exhaustion. The EMG signal was recorded during ten bursts of activation analysed separately at 45 s and 3 min 40 s of each stage. During running, consideration of the alteration in stride frequency with either an increase in speed or the onset of fatigue appears to be an indispensable part of the assessment of muscular fatigue. This allows the comparison of muscular activation between the various stage speeds by the use of common working units. Distance seems to be the only working unit that allows this comparison and thus the determination of the appearance of fatigue during running. The biarticular hip-mobilising muscles (RF and BF), which present two different bursts of activation during one running cycle, are the muscles that show the earliest signs of fatigue.

  9. Contribution of trunk muscularity on sprint run.

    PubMed

    Kubo, T; Hoshikawa, Y; Muramatsu, M; Iida, T; Komori, S; Shibukawa, K; Kanehisa, H

    2011-03-01

    This study aimed to investigate how the trunk muscularity is related to sprint running performance. In 23 youth soccer players, the cross-sectional images at the mid level of each of L1-L2, L2-L3, L3-L4, L4-L5, and L5-S1 were obtained using magnetic resonance imaging to determine the cross-sectional areas (CSAs) of rectus abdominis, oblique, psoas major, quadratus lumborum and erector spinae muscles. The times taken to sprint over 20 m were measured, and the mean velocity of running was calculated for each of the 2 distances (V (10 m) and V (20 m)) and for the distance from 10 m to 20 m (V (10-20 m)). The CSA values of the 5 slice levels for all muscles except for the quadratus lumborum and those of the 3 slice levels (L1-L2, L2-L3 and L3-L4) for the quadratus lumborum were averaged and expressed relative to the two-third power of body mass (CSA/BM (2/3)). The CSA/BM (2/3) values of the erector spinae and quadratus lumborum were selected as significant contributors to predict V (10 m) ( R(2)=0.450), V (20 m) ( R(2)=0.504) and V (10-20 m) ( R(2)=0.420). The current results indicate that the muscularity of the erector spinae and quadratus lumborum contributes to achieving a high performance in sprint running over distances of less than 20 m.

  10. Action selection and action awareness.

    PubMed

    Wenke, Dorit; Waszak, Florian; Haggard, Patrick

    2009-07-01

    Human actions are often classified as either internally generated, or externally specified in response to environmental cues. These two modes of action selection have distinct neural bases, but few studies investigated how the mode of action selection affects the subjective experience of action. We measured the experience of action using the subjective compression of the interval between actions and their effects, known as 'temporal binding'. Participants performed either a left or a right key press, either in response to a specific cue, or as they freely chose. Moreover, the time of each key press could either be explicitly cued to occur in one of two designated time intervals, or participants freely chose in which interval to act. Each action was followed by a specific tone. Participants judged the time of their actions or the time of the tone. Temporal binding was found for both internally generated and for stimulus-based actions. However, the amount of binding depended on whether or not both the choice and the timing of action were selected in the same way. Stronger binding was observed when both action choice and action timing were internally generated or externally specified, compared to conditions where the two parameters were selected by different routes. Our result suggests that temporal action-effect binding depends on how actions are selected. Binding is strongest when actions result from a single mode of selection.

  11. 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

  12. The alpha7 nicotinic acetylcholine receptor-selective antagonist, methyllycaconitine, partially protects against beta-amyloid1-42 toxicity in primary neuron-enriched cultures.

    PubMed

    Martin, Shelley E; de Fiebre, Nancy Ellen C; de Fiebre, Christopher M

    2004-10-01

    Studies have suggested that the neuroprotective actions of alpha7 nicotinic agonists arise from activation of receptors and not from the extensive desensitization which rapidly follows activation. Here, we report that the alpha7-selective nicotinic antagonist, methyllycaconitine (MLA), protects against beta-amyloid-induced neurotoxicity; whereas the alpha4beta2-selective antagonist, dihydro-beta-erythroidine, does not. These findings suggest that neuroprotective actions of alpha7-acting agents arise from receptor inhibition/desensitization and that alpha7 antagonists may be useful neuroprotective agents.

  13. First and second generation H₁ histamine receptor antagonists produce different sleep-inducing profiles in rats.

    PubMed

    Unno, Katsuya; Ozaki, Tomoya; Mohammad, Shahid; Tsuno, Saki; Ikeda-Sagara, Masami; Honda, Kazuki; Ikeda, Masayuki

    2012-05-15

    First generation H₁ histamine receptor antagonists, such as d-chlorpheniramine (d-CPA) and diphenhydramine, produce drowsiness in humans. They are currently used as over-the-counter sleep aids. However, the mechanisms underlying drowsiness induced by these H₁ histamine receptor antagonists remain obscure because they produce heterogeneous receptor-independent actions. Ketotifen is a second generation H₁ histamine receptor antagonist which is more permeable to the brain than newer H₁ histamine receptor antagonists. Therefore, to access sleep-inducing profiles by H₁ histamine receptor blocking actions, the present study compared the dose-dependent effects of diphenhydramine and ketotifen (1-40 mg/kg, intraperitoneal injection at dark onset time) on daily sleep-wake patterns in rats. Ketotifen dose-dependently decreased rapid-eye-movement (REM) sleep and increased non-REM sleep by amplifying slow-wave electroencephalogram powers. Diphenhydramine at 4 mg/kg transiently increased non-REM sleep and reduced REM sleep similar to the effects of ketotifen. The larger injections of diphenhydramine (10-40 mg/kg), however, reduced non-REM sleep, abolished slow-wave enhancements and facilitated wakefulness. The bi-directional action of diphenhydramine on sleep is similar to our former results using d-CPA. Taken together, the arousal effects caused by over-dose administrations of the first generation H₁ histamine receptor antagonists may be mediated by H₁ histamine receptor-independent actions. To further examine the tolerance of ketotifen-induced sleep, 3 mg/kg ketotifen was injected daily for 5 days 3 h before light onset time. These experiments consistently enhanced non-REM-sleep at the end of the active phase of rats, suggesting that ketotifen may function as a desirable sleep aid although the coincidental REM sleep reduction requires attention. Copyright © 2012 Elsevier B.V. All rights reserved.

  14. Genetics and emerging treatments for Duchenne and Becker muscular dystrophy.

    PubMed

    Wein, Nicolas; Alfano, Lindsay; Flanigan, Kevin M

    2015-06-01

    Mutations in the DMD gene result in Duchenne or Becker muscular dystrophy due to absent or altered expression of the dystrophin protein. The more severe Duchenne muscular dystrophy typically presents around ages 2 to 5 with gait disturbance, and historically has led to the loss of ambulation by age 12. It is important for the practicing pediatrician, however, to be aware of other presenting signs, such as delayed motor or cognitive milestones, or elevated serum transaminases. Becker muscular dystrophy is milder, often presenting after age 5, with ambulation frequently preserved past 20 years and sometimes into late decades.

  15. Antiandrogen flutamide protects male mice from androgen-dependent toxicity in three models of spinal bulbar muscular atrophy.

    PubMed

    Renier, Kayla J; Troxell-Smith, Sandra M; Johansen, Jamie A; Katsuno, Masahisa; Adachi, Hiroaki; Sobue, Gen; Chua, Jason P; Sun Kim, Hong; Lieberman, Andrew P; Breedlove, S Marc; Jordan, Cynthia L

    2014-07-01

    Spinal and bulbar muscular atrophy (SBMA) is a late-onset, progressive neurodegenerative disease linked to a polyglutamine (polyQ) expansion in the androgen receptor (AR). Men affected by SBMA show marked muscle weakness and atrophy, typically emerging midlife. Given the androgen-dependent nature of this disease, one might expect AR antagonists to have therapeutic value for treating SBMA. However, current work from animal models suggests otherwise, raising questions about whether polyQ-expanded AR exerts androgen-dependent toxicity through mechanisms distinct from normal AR function. In this study, we asked whether the nonsteroidal AR antagonist flutamide, delivered via a time-release pellet, could reverse or prevent androgen-dependent AR toxicity in three different mouse models of SBMA: the AR97Q transgenic (Tg) model, a knock-in (KI) model, and a myogenic Tg model. We find that flutamide protects mice from androgen-dependent AR toxicity in all three SBMA models, preventing or reversing motor dysfunction in the Tg models and significantly extending the life span in KI males. Given that flutamide effectively protects against androgen-dependent disease in three different mouse models of SBMA, our data are proof of principle that AR antagonists have therapeutic potential for treating SBMA in humans and support the notion that toxicity caused by polyQ-expanded AR uses at least some of the same mechanisms as normal AR before diverging to produce disease and muscle atrophy.

  16. Guanidinoethyl sulphonate is a glycine receptor antagonist in striatum.

    PubMed

    Sergeeva, Olga A; Chepkova, Aisa N; Haas, Helmut L

    2002-11-01

    1. Guanidinoethyl sulphonate (GES) is an analogue of taurine and an inhibitor of taurine transport. Interactions of GES with GABA(A) and glycine receptors are studied by whole cell recording and fast drug application in isolated striatal neurons of the mouse. 2. We confirm that GES is a weak agonist at GABA(A) receptors, and is able to antagonize GABA-evoked responses. GES did not gate GlyR. 3. GES antagonized glycine responses in a concentration-dependent and surmountable manner. Glycine dose-response curves were shifted to the right by GES (0.5 mM), yielding EC(50)s and Hill coefficients of 62 micro M and 2.5 in control, 154 micro M and 1.3 in the presence of GES. 4. GlyR-mediated taurine responses were competitively antagonized by GES. Taurine dose-response curves, in contrast to the glycine dose-response curves were shifted by GES to the right in a parallel manner. 5. The GlyR-block by GES was not voltage-dependent. 6. In contrast to our findings in the mouse, in rat striatal neurons which lack expression of the alpha3 GlyR subunit, GES shifted the glycine dose-response curve to the right in a parallel way without affecting the maximal response. Subtype-specificity of the GES action at GlyR must await further investigation in artificial expression systems. 7. We conclude that GES is a competitive antagonist at GlyR. The antagonistic action of GES at inhibitory ionotropic receptors can explain its epileptogenic action. Care must be taken with the interpretation of data on GES evoked taurine release.

  17. Pediatric heart failure therapy with beta-adrenoceptor antagonists.

    PubMed

    Foerster, Susan R; Canter, Charles E

    2008-01-01

    Management of chronic heart failure in pediatrics has been altered by the adult literature showing improvements in mortality and hospitalization rates with the use of beta-adrenoceptor antagonists (beta-blockers) for routine therapy of all classes of ischemic and non-ischemic heart failure. Many pediatric heart failure specialists have incorporated these agents into their routine management of pediatric heart failure related to dilated cardiomyopathy or ventricular dysfunction in association with congenital heart disease. Retrospective and small prospective case series have shown encouraging improvements in cardiac function and symptoms, but interpretation has been complicated by the high rate of spontaneous recovery in pediatric patients. A recently completed pediatric double-blind, randomized, placebo-controlled clinical trial showed no difference between placebo and two doses of carvedilol over a 6-month period of follow-up, with significant improvement of all three groups over the course of evaluation. Experience with adults has suggested that only certain beta-blockers, including carvedilol, bisoprolol, nebivolol, and metoprolol succinate, should be used in the treatment of heart failure and that patients with high-grade heart failure may derive the most benefit. Other studies surmise that early or prophylactic use of these medications may alter the risk of disease progression in some high-risk subsets, such as patients receiving anthracyclines or those with muscular dystrophy. This article reviews these topics using experience as well as data from all the recent pediatric studies on the use of beta-blockers to treat congestive heart failure, especially when related to systolic ventricular dysfunction.

  18. Bound to Lose: Physical Incapacitation Increases the Conceptualized Size of an Antagonist in Men

    PubMed Central

    Fessler, Daniel M. T.; Holbrook, Colin

    2013-01-01

    Because decision-making in situations of potential conflict hinges on assessing many features of the self and the foe, this process can be facilitated by summarizing diverse attributes in a single heuristic representation. Physical size and strength are evolutionarily ancient determinants of victory in conflict, and their relevance is reinforced during development. Accordingly, size and muscularity constitute ready dimensions for a summary representation of relative formidability, a perspective paralleled by the notion that social power is represented using envisioned relative size. Physical incapacitation constitutes a significant tactical disadvantage, hence temporary incapacitation should increase the envisioned size and strength of an antagonist. In Study 1, being bound to a chair increased men’s estimates of the size of an angry man and decreased estimates of their own height. Study 2 conceptually replicated these effects: among men for whom standing on a balance board was challenging, the attendant experience of postural instability increased estimates of an angry man’s size and muscularity, with similar patterns occurring at a reduced level among all but those whose equilibrium was apparently unaffected by this task. PMID:23951126

  19. Calcium antagonists and atherosclerosis protection in hypertension.

    PubMed

    Hernández, Rafael Hernández; Armas-Hernández, María José; Velasco, Manuel; Israili, Zafar H; Armas-Padilla, María Cristina

    2003-01-01

    Calcium antagonists are effective in hypertensive patients of all ethnic groups, irrespective of age, dietary salt intake, salt-sensitivity status or plasma renin activity profile. Some prospective studies show that the calcium antagonists, nifedipine GITS and nitrendipine, reduce cardiovascular morbidity and mortality at least to the same extent as the diuretics. Other prospective studies are in progress to evaluate the effect of calcium antagonists on cardiovascular morbidity and mortality, and the progression of atherosclerosis in hypertensive patients. Calcium antagonists, especially the highly lipophilic amlodipine, lacidipine and nisoldipine, are shown to possess antioxidant properties. These drugs reduce the oxidation of LDL and its influx into the arterial wall, and reduce atherosclerotic lesions in animals. Platelet production of malondialdehyde, a marker of oxygen free radical formation, is suppressed by amlodipine, lacidipine or nifedipine in hypertensive patients. New evidence from long-term clinical trials of calcium antagonists indicates that these drugs can reduce the rate of progression of atherosclerosis in hypertensive and coronary heart disease patients. In the Regression Growth Evaluation Statin Study (REGRESS), co-administration of calcium antagonist, amlodipine or nifedipine with pravasatin caused a significant reduction in the appearance of new angiographic lesions. In the Verapamil in Hypertension and Atherosclerosis Study (VHAS), verapamil was more effective than chlorthalidone in promoting regression of thicker carotid lesions in parallel with a reduction in the incidence of cardiovascular events. In the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT), amlodipine slowed the progression of early coronary atherosclerosis in patients with coronary artery disease. In a subprotocol of the Intervention as a Goal in the Hypertension Treatment (INSIGHT) study, nifedipine GITS significantly decreased intima

  20. Influence of beta-adrenoceptor agonists and antagonists on baclofen-induced memory impairment in mice.

    PubMed

    Zarrindast, M R; Haidari, H; Jafari, M R; Djahanguiri, B

    2004-07-01

    Post-training administration of different doses of baclofen (a GABAB agonist) has been shown to impair memory retention, in a step-down passive avoidance test in mice. We have studied the effects of beta-adrenergic agonists and antagonists on baclofen-induced memory impairment in mice. Dobutamine (a beta 1-agonist) or salbutamol (a beta 2-agonist) reversed the memory impairment induced by baclofen without exhibiting intrinsic actions on memory when administered alone. The administration of atenolol (a beta 1-antagonist) or propranolol (a beta-antagonist) produced a memory impairment. When co-administered with baclofen, both atenolol and propranolol exacerbated the memory impairment induced by the GABAB agonist. It is concluded that beta-adrenergic mechanisms may be involved in the modulation of memory via GABAB receptors.

  1. Action physics

    NASA Astrophysics Data System (ADS)

    McGinness, Lachlan P.; Savage, C. M.

    2016-09-01

    More than a decade ago, Edwin Taylor issued a "call to action" that presented the case for basing introductory university mechanics teaching around the principle of stationary action [E. F. Taylor, Am. J. Phys. 71, 423-425 (2003)]. We report on our response to that call in the form of an investigation of the teaching and learning of the stationary action formulation of physics in a first-year university course. Our action physics instruction proceeded from the many-paths approach to quantum physics to ray optics, classical mechanics, and relativity. Despite the challenges presented by action physics, students reported it to be accessible, interesting, motivational, and valuable.

  2. 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.

  3. Genetics Home Reference: limb-girdle muscular dystrophy

    MedlinePlus

    ... a machine to help them breathe (mechanical ventilation). Intelligence is generally unaffected in limb-girdle muscular dystrophy ; ... qualified healthcare professional . About Selection Criteria for Links Data Files & API Site Map Customer Support USA.gov ...

  4. uPA deficiency exacerbates muscular dystrophy in MDX mice

    PubMed Central

    Suelves, Mònica; Vidal, Berta; Serrano, Antonio L.; Tjwa, Marc; Roma, Josep; López-Alemany, Roser; Luttun, Aernout; de Lagrán, María Martínez; Díaz, Maria Àngels; Jardí, Mercè; Roig, Manuel; Dierssen, Mara; Dewerchin, Mieke; Carmeliet, Peter; Muñoz-Cánoves, Pura

    2007-01-01

    Duchenne muscular dystrophy (DMD) is a fatal and incurable muscle degenerative disorder. We identify a function of the protease urokinase plasminogen activator (uPA) in mdx mice, a mouse model of DMD. The expression of uPA is induced in mdx dystrophic muscle, and the genetic loss of uPA in mdx mice exacerbated muscle dystrophy and reduced muscular function. Bone marrow (BM) transplantation experiments revealed a critical function for BM-derived uPA in mdx muscle repair via three mechanisms: (1) by promoting the infiltration of BM-derived inflammatory cells; (2) by preventing the excessive deposition of fibrin; and (3) by promoting myoblast migration. Interestingly, genetic loss of the uPA receptor in mdx mice did not exacerbate muscular dystrophy in mdx mice, suggesting that uPA exerts its effects independently of its receptor. These findings underscore the importance of uPA in muscular dystrophy. PMID:17785520

  5. A Stochastic Process Arising in the Study of Muscular Contraction

    DTIC Science & Technology

    1961-01-01

    effect a and (3 can be taken as velocity functions. REFERENCE [1] R. J. PODOLSKY, "The chemical thermodynamics and molecular mechanism of muscular contraction," Ann. New York Acad. Sci., Vol. 72 (1959), pp. 522-537.

  6. How Physicians Support Mothers of Children with Duchenne Muscular Dystrophy.

    PubMed

    Fujino, Haruo; Saito, Toshio; Matsumura, Tsuyoshi; Shibata, Saki; Iwata, Yuko; Fujimura, Harutoshi; Shinno, Susumu; Imura, Osamu

    2015-09-01

    Communicating about Duchenne muscular dystrophy and its prognosis can be difficult for affected children and their family. We focused on how physicians provide support to the mothers of children with Duchenne muscular dystrophy who have difficulty communicating about the condition with their child. The eligible participants were certified child neurologists of the Japanese Society of Child Neurology. Participants responded to questionnaires consisting of free descriptions of a vignette of a child with Duchenne muscular dystrophy and a mother. We analyzed 263 responses of the participants. We found 4 themes on advising mothers, involving encouraging communication, family autonomy, supporting family, and considering the child's concerns. These results provide a better understanding of the communication between physicians and family members who need help sharing information with a child with Duchenne muscular dystrophy. These findings will assist clinical practitioners in supporting families and the affected children throughout the course of their illness.

  7. Perspectives of stem cell therapy in Duchenne muscular dystrophy.

    PubMed

    Meregalli, Mirella; Farini, Andrea; Belicchi, Marzia; Parolini, Daniele; Cassinelli, Letizia; Razini, Paola; Sitzia, Clementina; Torrente, Yvan

    2013-09-01

    Muscular dystrophies are heritable and heterogeneous neuromuscular disorders characterized by the primary wasting of skeletal muscle, usually caused by mutations in the proteins forming the link between the cytoskeleton and the basal lamina. As a result of mutations in the dystrophin gene, Duchenne muscular dystrophy patients suffer from progressive muscle atrophy and an exhaustion of muscular regenerative capacity. No efficient therapies are available. The evidence that adult stem cells were capable of participating in the regeneration of more than their resident organ led to the development of potential stem cell treatments for degenerative disorder. In the present review, we describe the different types of myogenic stem cells and their possible use for the progression of cell therapy in Duchenne muscular dystrophy.

  8. Low-intensity exercise, vascular occlusion, and muscular adaptations.

    PubMed

    Teramoto, Masaru; Golding, Lawrence A

    2006-01-01

    The study investigated the effects of low-intensity exercise on muscular fitness when combined with vascular occlusion. Nineteen college male and female students performed two sets of a 5-min step exercise using a 12-inch bench three times per week for 5 weeks. During the step exercise, blood flow to one leg was restricted (vascular occlusion) with a blood pressure cuff, while the other leg was not occluded. Muscular strength of the occluded leg was significantly increased over the nonoccluded leg (p < 0. 05). Muscular endurance and muscle mass were improved after 5 weeks of training (p < 0.05); however, the changes between the two legs were not significantly different (p > 0.05). Exercise with vascular occlusion has the potential to be an alternative form of training to promote muscular strength.

  9. Perspectives on Clinical Trials in Spinal Muscular Atrophy

    PubMed Central

    Swoboda, Kathryn J.; Kissel, John T.; Crawford, Thomas O.; Bromberg, Mark B.; Acsadi, Gyula; D'Anjou, Guy; Krosschell, Kristin J.; Reyna, Sandra P.; Schroth, Mary K.; Scott, Charles B.; Simard, Louise R.

    2011-01-01

    Spinal muscular atrophy is one of the most heterogeneous of the single-gene neuromuscular disorders. The broad spectrum of severity, with onset from the prenatal period to adulthood, presents unique challenges in the design and implementation of clinical trials. The clinical classification of subjects into severe (type 1), intermediate (type 2), and mild (type 3) subtypes has proved useful both in enhancing communication among clinicians internationally and in forging the collaborative development of outcome measures for clinical trials. Ideally, clinical trial design in spinal muscular atrophy must take into account the spinal muscular atrophy type, patient age, severity-of-affection status, nature of the therapeutic approach, timing of the proposed intervention relative to disease progression, and relative homogeneity of the cohort to be studied. Following is an overview of the challenges and opportunities, current and future therapeutic strategies, and progress to date in clinical trials in spinal muscular atrophy. PMID:17761650

  10. Complementary actions.

    PubMed

    Sartori, Luisa; Betti, Sonia

    2015-01-01

    Complementary colors are color pairs which, when combined in the right proportions, produce white or black. Complementary actions refer here to forms of social interaction wherein individuals adapt their joint actions according to a common aim. Notably, complementary actions are incongruent actions. But being incongruent is not sufficient to be complementary (i.e., to complete the action of another person). Successful complementary interactions are founded on the abilities: (i) to simulate another person's movements, (ii) to predict another person's future action/s, (iii) to produce an appropriate incongruent response which differ, while interacting, with observed ones, and (iv) to complete the social interaction by integrating the predicted effects of one's own action with those of another person. This definition clearly alludes to the functional importance of complementary actions in the perception-action cycle and prompts us to scrutinize what is taking place behind the scenes. Preliminary data on this topic have been provided by recent cutting-edge studies utilizing different research methods. This mini-review aims to provide an up-to-date overview of the processes and the specific activations underlying complementary actions.

  11. Complementary actions

    PubMed Central

    Sartori, Luisa; Betti, Sonia

    2015-01-01

    Complementary colors are color pairs which, when combined in the right proportions, produce white or black. Complementary actions refer here to forms of social interaction wherein individuals adapt their joint actions according to a common aim. Notably, complementary actions are incongruent actions. But being incongruent is not sufficient to be complementary (i.e., to complete the action of another person). Successful complementary interactions are founded on the abilities: (i) to simulate another person’s movements, (ii) to predict another person’s future action/s, (iii) to produce an appropriate incongruent response which differ, while interacting, with observed ones, and (iv) to complete the social interaction by integrating the predicted effects of one’s own action with those of another person. This definition clearly alludes to the functional importance of complementary actions in the perception–action cycle and prompts us to scrutinize what is taking place behind the scenes. Preliminary data on this topic have been provided by recent cutting-edge studies utilizing different research methods. This mini-review aims to provide an up-to-date overview of the processes and the specific activations underlying complementary actions. PMID:25983717

  12. Short stature caused by a natural growth hormone antagonist.

    PubMed

    Chihara, K; Takahashi, Y; Kaji, H; Goji, K; Okimura, Y; Abe, H

    1998-01-01

    Severe short stature in a male child due to a single mutation in the GH-1 gene was first reported in 1996 by Takahashi et al. [N Engl J Med 1996;334:432-436]. This missense mutation was predicted to convert codon 77 from arginine (R) to cysteine (C). The child's chronological age was 4 years and 11 months, and his bone age 2 years and 6 months, i.e., equal to only 51% of his chronological age. Body proportions were normal except for the prominent forehead and saddle nose. Pituitary size was normal on magnetic resonance imaging examinations. Serum IGF-1, IGFBP-3 and GHBP were all decreased or at the lower limit of the normal range. Nocturnal urinary growth hormone (GH) excretion was high. Isoelectric focusing analysis revealed the presence of an abnormal GH peak in addition to the normal one. The R77C mutant GH possessed a 6 times greater affinity to GHBP than the wild-type GH, and inhibited tyrosine phosphorylation in IM-9 cells 10 times more potently than the wild-type GH, showing an antagonistic or a dominant negative action. In agreement with the antagonistic property of the mutant GH exhibited, the child did not show any increase in serum IGF-1 levels after exogenous hGH administration. It should be noted that the child in this study is not a typical case of Kowarski syndrome in which endogenous GH is found to be simply bioinactive, as in the patient we recently described elsewhere. Therefore, this patient's condition should be categorized as a new syndrome of short stature caused by a natural GH antagonist.

  13. Cardiovascular effects of ghrelin antagonist in conscious rats.

    PubMed

    Vlasova, Maria A; Järvinen, Kristiina; Herzig, Karl-Heinz

    2009-08-07

    Ghrelin, a 28 aa growth-hormone-releasing peptide, has been shown to increase food intake and decrease arterial pressure in animals and in humans. Recently, a ghrelin antagonist (GhA), [d-Lys-3]-GHRP-6, was demonstrated to decrease food intake in mice, but its cardiovascular actions have not been described. In the present study, the effects of the GhA on cardiovascular parameters in conscious rats were investigated and the involvement of the sympathetic nervous system evaluated. Mean arterial pressure (MAP) and heart rate (HR) measurements were assessed by radiotelemetry. GhA was administered in doses of 2, 4 and 6 mg/kg subcutaneously (s.c.). MAP as well as HR was dose-dependently elevated after sc application of GhA. Sympathetic blockade of alpha-adrenoreceptors with phentolamine (3 mg/kg, s.c.) and simultaneous antagonism of beta(1)-adrenoreceptors with atenolol (10 mg/kg, s.c.) abolished the increase in MAP and HR induced by GhA (4 mg/kg, s.c.). Administration of phentolamine alone inhibited the increase of MAP, but not HR; atenolol alone abolished the elevation of both MAP and HR evoked by GhA. These results suggest that the peripheral injection of ghrelin antagonist increases arterial pressure and heart rate, at least in part, through the activation of the sympathetic nervous system. Therefore, the use of the ghrelin antagonist system as a therapeutic target for reduction in food intake might lead to serious side effects like elevated blood pressure in humans mostly already having an elevated blood pressure as part of their metabolic syndrome.

  14. Embryo implantation and GnRH antagonists: embryo implantation: the Rubicon for GnRH antagonists.

    PubMed

    Hernandez, E R

    2000-06-01

    When gonadotrophin-releasing hormone (GnRH) was discovered, the agonist and antagonist of GnRH were developed to control the release of FSH and LH by the gonadotrophs. More than 10 years of research were needed to develop a GnRH antagonist free of histamine release. Recent studies have shown that these GnRH antagonists are effective in preventing a rise in LH during ovarian stimulation in IVF. However, a decrease in ongoing pregnancies seems to suggest that implantation rates per transferred embryo are reduced in GnRH antagonist-stimulated cycles. In my opinion, these data highlight an area less well known to clinicians: the role of the GnRH antagonist at the cellular level in extrapituitary tissues. There are sufficient data in the literature suggesting that GnRH antagonist is an inhibitor of the cell cycle by decreasing the synthesis of growth factors. Given that, for folliculogenesis, blastomere formation and endometrium development, mitosis is everything; the interaction between the GnRH antagonist and the GnRH receptor (present in all these cells and tissues) may compromise the mitotic programme of these cells. This is the Rubicon for the GnRH antagonist: to demonstrate irrevocably that, at the minimal doses necessary to suppress LH release, it does not affect processes such as implantation, embryo development and folliculogenesis.

  15. Pulmonary Endpoints in Duchenne Muscular Dystrophy. A Workshop Summary.

    PubMed

    Finder, Jonathan; Mayer, Oscar Henry; Sheehan, Daniel; Sawnani, Hemant; Abresch, R Ted; Benditt, Joshua; Birnkrant, David J; Duong, Tina; Henricson, Erik; Kinnett, Kathi; McDonald, Craig M; Connolly, Anne M

    2017-08-15

    Development of novel therapeutics for treatment of Duchenne muscular dystrophy (DMD) has led to clinical trials that include pulmonary endpoints that allow assessment of respiratory muscle status, especially in nonambulatory subjects. Parent Project Muscular Dystrophy (PPMD) convened a workshop in Bethesda, Maryland, on April 14 and 15, 2016, to summarize published respiratory data in DMD and give guidance to clinical researchers assessing the effect of interventions on pulmonary outcomes in DMD.

  16. [Antagonistic activity of novel green microalgae strain].

    PubMed

    Selivanova, E A; Ignatenko, M E; Nemtseva, N V

    2014-01-01

    Screening of novel microalgae strains for the presence of pronounced antagonistic (antibacterial) activity against opportunistic bacteria. 11 pure cultures of green unicellular algae isolated from fresh and salt basins of Orenburg region were studied for the presence of antagonistic activity against 4 test-strains of opportunistic bacteria by a photometric method. The effect of water extracts of microalgae Astermonas gracilis on the speed of self-purification of brine from Escherichia coli as well as antibacterial activity of peloid were evaluated under co-cultivation conditions. Pure cultures of green unicellular algae Scenedesmus obliquus (Turpin) Kütz, Scenedesmus magnus Meyen var. magnus, Pediastru duplex Meyen var. duplex, Chlorella vulgaris Bory, Monoraphidium arcuatum (Korschikov) Hindak (=Ankistrodesmus arcuatus Korschikov), Dictyosphaerium sp. had the most pronounced antagonistic activit against opportunistic bacteria. Water extract ofA. gracilis microalgae accelerated brine self-purification fro E. coli due to antibacterial effect. Peloid containing extracts of microorganism cells had a pronounced antibacterial effect against opportunistic bacteria. Antagonistic substances localized inside cells of microalgae increased the speed of allochthonic microorganism elimination that is one of the mechanisms of self-purification of a basin and antibacterial effect of peloid. The novel green microalgae strains studied due to the presence of pronounced antagonistic activity may have a wide practical application.

  17. From Chemotherapy-Induced Emesis to Neuroprotection: Therapeutic Opportunities for 5-HT3 Receptor Antagonists.

    PubMed

    Fakhfouri, Gohar; Mousavizadeh, Kazem; Mehr, Sharam Ejtemaei; Dehpour, Ahmad Reza; Zirak, Mohammad Reza; Ghia, Jean-Eric; Rahimian, Reza

    2015-12-01

    5-HT3 receptor antagonists are extensively used as efficacious agents in counteracting chemotherapy-induced emesis. Recent investigations have shed light on other potential effects (analgesic, anxiolytic, and anti-psychotic). Some studies have reported neuroprotective properties for the 5-HT3 receptor antagonists in vitro and in vivo. When administered to Aβ-challenged rat cortical neurons, 5-HT3 receptor antagonists substantially abated apoptosis, elevation of cytosolic Ca(2), glutamate release, reactive oxygen species (ROS) generation, and caspase-3 activity. In addition, in vivo studies show that 5-HT3 receptor antagonists possess, alongside their anti-emetic effects, notable immunomodulatory properties in CNS. We found that pretreatment with tropisetron significantly improved neurological deficits and diminished leukocyte transmigration into the brain, TNF-α level, and brain infarction in a murine model of embolic stroke. Our recent investigation revealed that tropisetron protects against Aβ-induced neurotoxicity in vivo through both 5-HT3 receptor-dependent and -independent pathways. Tropisetron, in vitro, was found to be an efficacious inhibitor of the signaling pathway leading to the activation of pro-inflammatory NF-κB, a transcription factor pivotal to the upregulation of several neuroinflammatory mediators in brain. This mini review summarizes novel evidence concerning effects of 5-HT3 antagonists and their possible mechanisms of action in ameliorating neurodegenerative diseases including Alzheimer, multiple sclerosis, and stroke. Further, we discuss some newly synthesized 5-HT3 receptor antagonists with dual properties of 5-HT3 receptor blockade/alpha-7 nicotinic receptor activator and their potential in management of memory impairment. Since 5-HT3 receptor antagonists possess a large therapeutic window, they can constitute a scaffold for design and synthesis of new neuroprotective medications.

  18. Histamine H4 receptor antagonists as potent modulators of mammalian vestibular primary neuron excitability

    PubMed Central

    Desmadryl, G; Gaboyard-Niay, S; Brugeaud, A; Travo, C; Broussy, A; Saleur, A; Dyhrfjeld-Johnsen, J; Wersinger, E; Chabbert, C

    2012-01-01

    BACKGROUND AND PURPOSE Betahistine, the main histamine drug prescribed to treat vestibular disorders, is a histamine H3 receptor antagonist. Here, we explored the potential for modulation of the most recently cloned histamine receptor (H4 receptor) to influence vestibular system function, using a selective H4 receptor antagonist JNJ 7777120 and the derivate compound JNJ 10191584. EXPERIMENTAL APPROACH RT-PCR was used to assess the presence of H4 receptors in rat primary vestibular neurons. In vitro electrophysiological recordings and in vivo behavioural approaches using specific antagonists were employed to examine the effect of H4 receptor modulation in the rat vestibular system. KEY RESULTS The transcripts of H4 and H3 receptors were present in rat vestibular ganglia. Application of betahistine inhibited the evoked action potential firing starting at micromolar range, accompanied by subsequent strong neuronal depolarization at higher concentrations. Conversely, reversible inhibitory effects elicited by JNJ 10191584 and JNJ 7777120 began in the nanomolar range, without inducing neuronal depolarization. This effect was reversed by application of the selective H4 receptor agonist 4-methylhistamine. Thioperamide, a H3/H4 receptor antagonist, exerted effects similar to those of H3 and H4 receptor antagonists, namely inhibition of firing at nanomolar range and membrane depolarization above 100 µM. H4 receptor antagonists significantly alleviated the vestibular deficits induced in rats, while neither betahistine nor thioperamide had significant effects. CONCLUSIONS AND IMPLICATIONS H4 receptor antagonists have a pronounced inhibitory effect on vestibular neuron activity. This result highlights the potential role of H4 receptors as pharmacological targets for the treatment of vestibular disorders. PMID:22624822

  19. Electrophysiological biomarkers in spinal muscular atrophy: proof of concept

    PubMed Central

    David Arnold, W; Porensky, Paul N; McGovern, Vicki L; Iyer, Chitra C; Duque, Sandra; Li, Xiaobai; Meyer, Kathrin; Schmelzer, Leah; Kaspar, Brian K; Kolb, Stephen J; Kissel, John T; Burghes, Arthur H M

    2014-01-01

    Objective Preclinical therapies that restore survival motor neuron (SMN) protein levels can dramatically extend survival in spinal muscular atrophy (SMA) mouse models. Biomarkers are needed to effectively translate these promising therapies to clinical trials. Our objective was to investigate electrophysiological biomarkers of compound muscle action potential (CMAP), motor unit number estimation (MUNE) and electromyography (EMG) using an SMA mouse model. Methods Sciatic CMAP, MUNE, and EMG were obtained in SMNΔ7 mice at ages 3–13 days and at 21 days in mice with SMN selectively reduced in motor neurons (ChATCre). To investigate these measures as biomarkers of treatment response, measurements were obtained in SMNΔ7 mice treated with antisense oligonucleotide (ASO) or gene therapy. Results CMAP was significantly reduced in SMNΔ7 mice at days 6–13 (P < 0.01), and MUNE was reduced at days 7–13 (P < 0.01). Fibrillations were present on EMG in SMNΔ7 mice but not controls (P = 0.02). Similar findings were seen at 21 days in ChATCre mice. MUNE in ASO-treated SMNΔ7 mice were similar to controls at day 12 and 30. CMAP reduction persisted in ASO-treated SMNΔ7 mice at day 12 but was corrected at day 30. Similarly, CMAP and MUNE responses were corrected with gene therapy to restore SMN. Interpretation These studies confirm features of preserved neuromuscular function in the early postnatal period and subsequent motor unit loss in SMNΔ7 mice. SMN restoring therapies result in preserved MUNE and gradual repair of CMAP responses. This provides preclinical evidence for the utilization of CMAP and MUNE as biomarkers in future SMA clinical trials. PMID:24511555

  20. Outside in: The matrix as a modifier of muscular dystrophy.

    PubMed

    Quattrocelli, Mattia; Spencer, Melissa J; McNally, Elizabeth M

    2017-03-01

    Muscular dystrophies are genetic conditions leading to muscle degeneration and often, impaired regeneration. Duchenne Muscular Dystrophy is a prototypical form of muscular dystrophy, and like other forms of genetically inherited muscle diseases, pathological progression is variable. Variability in muscular dystrophy can arise from differences in the manner in which the primary mutation impacts the affected protein's function; however, clinical heterogeneity also derives from secondary mutations in other genes that can enhance or reduce pathogenic features of disease. These genes, called genetic modifiers, regulate the pathophysiological context of dystrophic degeneration and regeneration. Understanding the mechanistic links between genetic modifiers and dystrophic progression sheds light on pathologic remodeling, and provides novel avenues to therapeutically intervene to reduce muscle degeneration. Based on targeted genetic approaches and unbiased genomewide screens, several modifiers have been identified for muscular dystrophy, including extracellular agonists of signaling cascades. This review will focus on identification and possible mechanisms of recently identified modifiers for muscular dystrophy, including osteopontin, latent TGFβ binding protein 4 (LTBP4) and Jagged1. Moreover, we will review the investigational approaches that aim to target modifier pathways and thereby counteract dystrophic muscle wasting.

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

    PubMed

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

    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. 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. 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.

  2. Prospect of gene therapy for cardiomyopathy in hereditary muscular dystrophy

    PubMed Central

    Yue, Yongping; Binalsheikh, Ibrahim M.; Leach, Stacey B.; Domeier, Timothy L.; Duan, Dongsheng

    2016-01-01

    Introduction Cardiac involvement is a common feature in muscular dystrophies. It presents as heart failure and/or arrhythmia. Traditionally, dystrophic cardiomyopathy is treated with symptom-relieving medications. Identification of disease-causing genes and investigation on pathogenic mechanisms have opened new opportunities to treat dystrophic cardiomyopathy with gene therapy. Replacing/repairing the mutated gene and/or targeting the pathogenic process/mechanisms using alternative genes may attenuate heart disease in muscular dystrophies. Areas covered Duchenne muscular dystrophy is the most common muscular dystrophy. Duchenne cardiomyopathy has been the primary focus of ongoing dystrophic cardiomyopathy gene therapy studies. Here, we use Duchenne cardiomyopathy gene therapy to showcase recent developments and to outline the path forward. We also discuss gene therapy status for cardiomyopathy associated with limb-girdle and congenital muscular dystrophies, and myotonic dystrophy. Expert opinion Gene therapy for dystrophic cardiomyopathy has taken a slow but steady path forward. Preclinical studies over the last decades have addressed many fundamental questions. Adeno-associated virus-mediated gene therapy has significantly improved the outcomes in rodent models of Duchenne and limb girdle muscular dystrophies. Validation of these encouraging results in large animal models will pave the way to future human trials. PMID:27340611

  3. 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

  4. How to measure muscular endurance in children: a new approach.

    PubMed

    Kević, Gordana; Siljeg, Klara; Mrgan, Josip; Sporis, Goran

    2013-06-01

    The aim of this study was primarily to determine the reliability and factor validity of four muscular endurance tests, and secondly, to identify gender differences in muscular endurance tests. For this purpose, a new muscular endurance test was constructed for pupils aged between seven and eight (CROCO). The research was done on a sample of 71 pupils aged between seven and eight (35 girls and 36 boys), their body height being 129.2 +/- 1.3 cm for boys and 127.1 +/- 1.4 cm for girls, body weight 29.3 +/- 7.2 kg for boys and 27.1 +/- 6.5 for girls. According to the results, all tests have shown a good level of reliability and factor validity. Also, the present study confirmed the expected gender differences (p < or = 0.05). In all muscular endurance tests, the boys were slightly better than girls (p < or = 0.05). The authors recommend the implementation of the CROCO test and other muscular endurance tests used in this study, both for the implementation in the primary school curricula and in sports because of these tests' satisfactory level of reliability and factor validity. The school curricula need to be adjusted to the age and gender differences of children in order to promote positive health behavior from the earliest age on the one hand, and on the other to be able to objectively measure muscular endurance.

  5. Two Potent OXE-R Antagonists: Assignment of Stereochemistry

    PubMed Central

    2014-01-01

    5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is formed by the oxidation of 5-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-HETE), which is a major metabolite of enzymatic oxidation of arachidonic acid (AA). 5-Oxo-ETE is the most potent lipid chemoattractant for human eosinophils. Its actions are mediated by the selective OXE receptor, which is therefore an attractive target in eosinophilic diseases such as allergic rhinitis and asthma. Recently, we have reported two excellent OXE receptor antagonists that have IC50 values at low nanomolar concentrations. Each of these antagonists has a chiral center, and the isolation of the individual enantiomers by chiral high-performance liquid chromatography (HPLC) revealed that in each case one enantiomer is over 300 times more potent than the other. To unambiguously assign the stereochemistry of these enantiomers and to provide access to larger amounts of the active compounds for biological testing, we report here their total synthesis. PMID:25050171

  6. Carbobenzoxy amino acids: Structural requirements for cholecystokinin receptor antagonist activity

    SciTech Connect

    Maton, P.N.; Sutliff, V.E.; Jensen, R.T.; Gardner, J.D.

    1985-04-01

    The authors used dispersed acini prepared from guinea pig pancreas to examine 28 carbobenzoxy (CBZ) amino acids for their abilities to function as cholecystokinin receptor antagonists. All amino acid derivatives tested, except for CBZ-alanine, CBZ-glycine, and N alpha-CBZ- lysine, were able to inhibit the stimulation of amylase secretion caused by the C-terminal octapeptide of cholecystokinin. In general, there was a good correlation between the ability of a carbobenzoxy amino acid to inhibit stimulated amylase secretion and the ability of the amino acid derivative to inhibit binding of /sup 125/I-cholecystokinin. The inhibition of cholecystokinin-stimulated amylase secretion was competitive, fully reversible, and specific for those secretagogues that interact with the cholecystokinin receptor. The potencies with which the various carbobenzoxy amino acids inhibited the action of cholecystokinin varied 100-fold and CBZ-cystine was the most potent cholecystokinin receptor antagonist. This variation in potency was primarily but not exclusively a function of the hydrophobicity of the amino acid side chain.

  7. Benzocyclobutane, benzocycloheptane and heptene derivatives as melatonin agonists and antagonists.

    PubMed

    Tsotinis, Andrew; Afroudakis, Pandelis A; Garratt, Peter J; Bocianowska-Zbrog, Alina; Sugden, David

    2014-10-01

    Two series of analogues were designed, synthesised and evaluated as potential human melatonin type 1 and 2 receptor (hMT1 and hMT2 ) ligands. Their biological effects were assessed by a well-established, specific model of melatonin action, the pigment response of Xenopus laevis melanophores. Compounds containing a benzocyclobutane scaffold and a methoxy group in the "melatonin" orientation were found to be potent agonists, with one of the analogues exhibiting activity comparable to melatonin. In contrast, analogues with a methoxy group in non-melatonin positions or with multiple methoxy groups showed either weaker agonist activity or were antagonists. Benzocycloheptene derivatives with one methoxy group are found to be weak agonists, whereas those with two methoxy groups were found to be antagonists, as were all of the benzocycloheptane derivatives evaluated. The most active compounds were assessed in a human receptor radio ligand binding assay but showed little discrimination between MT1 and MT2 . These results again show that the indole nitrogen of melatonin is not a necessary component for analogue activity and also illustrate that replacement of the indole ring with a 4-membered carbocycle can provide highly active compounds when the methoxy group is in the melatonin position. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Heterogeneity of binding of muscarinic receptor antagonists in rat brain homogenates

    SciTech Connect

    Lee, J.H.; el-Fakahany, E.E.

    1985-06-01

    The binding properties of (-)-(/sup 3/H)quinuclidinyl benzilate and (/sup 3/H) N-methylscopolamine to muscarinic acetylcholine receptors have been investigated in rat brain homogenates. The binding of both antagonists demonstrated high affinity and saturability. Analysis of the binding data resulted in linear Scatchard plots. However, (-)-(/sup 3/H)quinuclidinyl benzilate showed a significantly higher maximal binding capacity than that of (/sup 3/H)N-methylscopolamine. Displacement of both ligands with several muscarinic receptor antagonists resulted in competition curves in accordance with the law of mass-action for quinuclidinyl benzilate, atropine and scopolamine. A similar profile was found for the quaternary ammonium analogs of atropine and scopolamine when (/sup 3/H)N-methylscopolamine was used to label the receptors. However, when these hydrophilic antagonists were used to displace (-)-(/sup 3/H) quinuclidinyl benzilate binding, they showed interaction with high- and low-affinity binding sites. On the other hand, the nonclassical muscarinic receptor antagonist, pirenzepine, was able to displace both ligands from two binding sites. The present data are discussed in terms of the relationship of this anomalous heterogenity of binding of these hydrophilic muscarinic receptor antagonists and the proposed M1 and M2 receptor subtypes.

  9. Synthesis and biological activities of dynorphin A analogues with opioid antagonist properties.

    PubMed

    Gairin, J E; Mazarguil, H; Alvinerie, P; Saint-Pierre, S; Meunier, J C; Cros, J

    1986-10-01

    Dynorphin A, which displays a wide variety of physiological effects, binds to opioid receptors preferentially at the kappa receptor type. kappa-selective antagonists would be very useful as pharmacological and biochemical probes to study and better understand the action of dynorphin A at its preferred receptor. However, the development of such molecules has been elusive, and very few are known at this time. Taking these features into account, we have synthesized by the solid-phase procedure several analogues of dynorphin A containing various D-amino acid substitutions. The binding properties of the peptides have been examined at three main opioid binding sites (mu, delta, and kappa) and their kappa selectivity determined. Their biological activities have been tested in three specific pharmacological assays for agonist and/or antagonist properties. Introduction of D-Trp substitution leads to analogues, in particular [D- Trp2,8,D-Pro10]-, [D-Trp5,8,D-Pro10]-, and [D-Trp2,4,8,D-Pro10]dynorphin(1-11), showing antagonist properties in the isolated rabbit vas deferens preparation, a kappa specific bioassay. The antagonism against dynorphin A is weak, as indicated by the observed Ke values (433, 199, and 293 nM, respectively), and not very selective (kappa vs. mu). Such peptide analogues derived from the endogenous ligand and endowed with antagonist properties are the first ones reported to date and could open a promising way in designing more potent and selective kappa opioid antagonists.

  10. 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.

  11. Interaction of anisatin with rat brain gamma-aminobutyric acidA receptors: allosteric modulation by competitive antagonists.

    PubMed

    Kakemoto, E; Okuyama, E; Nagata, K; Ozoe, Y

    1999-08-15

    Anisatin, a toxic sesquiterpene isolated from the Japanese star anise (Illicium anisatum L.), competitively inhibited the specific binding of [3H]4'-ethynyl-4-n-propylbicycloorthobenzoate ([3H]EBOB), a non-competitive antagonist of gamma-aminobutyric acid (GABA)A receptors, to rat brain membranes with an IC50 value of 0.43 microM. R 5135, a competitive GABA antagonist, decreased the potency of anisatin in inhibiting [3H]EBOB binding in a negatively cooperative manner. Two other competitive antagonists, SR 95531 (gabazine) and (-)-bicuculline methiodide, had similar effects. On the other hand, R 5135 exerted little influence on the potencies of the other non-competitive antagonists tested: EBOB, picrotoxinin, isopropylbicyclophosphate, and dieldrin. Thus, anisatin was clearly different from the other non-competitive antagonists in responding to the action of competitive antagonists on (GABA)A receptors. These findings suggest that the binding region of anisatin might overlap with that of the other non-competitive antagonists, but that anisatin must interact with other specific region(s).

  12. Expression profiling of muscles from Fukuyama-type congenital muscular dystrophy and laminin-alpha 2 deficient congenital muscular dystrophy; is congenital muscular dystrophy a primary fibrotic disease?

    PubMed

    Taniguchi, Mariko; Kurahashi, Hiroki; Noguchi, Satoru; Sese, Jun; Okinaga, Takeshi; Tsukahara, Toshifumi; Guicheney, Pascale; Ozono, Keiichi; Nishino, Ichizo; Morishita, Shinichi; Toda, Tatsushi

    2006-04-07

    Fukuyama-type congenital muscular dystrophy (FCMD) and laminin-alpha2 deficient congenital muscular dystrophy (MDC1A) are congenital muscular dystrophies (CMDs) and they both are categorized into the same clinical entity of muscular dystrophy as Duchenne muscular dystrophy (DMD). All three disorders share a common etiologic defect in the dystrophin-glycoprotein complex, which connects muscle structural proteins with the extracellular basement membrane. To investigate the pathophysiology of these CMDs, we generated microarray gene expression profiles of skeletal muscle from patients in various clinical stages. Despite diverse pathological changes, the correlation coefficient of overall gene expression among these samples was considerably high. We performed a multi-dimensional statistical analysis, the Distillation, to extract determinant genes that distinguish CMD muscle from normal controls. Up-regulated genes were primarily extracellular matrix (ECM) components, whereas down-regulated genes included structural components of mature muscle. These observations reflect active interstitial fibrosis with less active regeneration of muscle cell components in the CMDs, characteristics that are clearly distinct from those of DMD. Although the severity of fibrosis varied among the specimens tested, ECM gene expression was consistently high without substantial changes through the clinical course. Further, in situ hybridization showed more prominent ECM gene expression on muscle cells than on interstitial tissue cells, suggesting that ECM components are induced by regeneration process rather than by 'dystrophy.' These data imply that the etiology of FCMD and MDC1A differs from that of the chronic phase of classical muscular dystrophy, and the major pathophysiologic change in CMDs might instead result from primary active fibrosis.

  13. High-affinity neuropeptide Y receptor antagonists.

    PubMed Central

    Daniels, A J; Matthews, J E; Slepetis, R J; Jansen, M; Viveros, O H; Tadepalli, A; Harrington, W; Heyer, D; Landavazo, A; Leban, J J

    1995-01-01

    Neuropeptide Y (NPY) is one of the most abundant peptide transmitters in the mammalian brain. In the periphery it is costored and coreleased with norepinephrine from sympathetic nerve terminals. However, the physiological functions of this peptide remain unclear because of the absence of specific high-affinity receptor antagonists. Three potent NPY receptor antagonists were synthesized and tested for their biological activity in in vitro, ex vivo, and in vivo functional assays. We describe here the effects of these antagonists inhibiting specific radiolabeled NPY binding at Y1 and Y2 receptors and antagonizing the effects of NPY in human erythroleukemia cell intracellular calcium mobilization perfusion pressure in the isolated rat kidney, and mean arterial blood pressure in anesthetized rats. PMID:7568074

  14. High-affinity neuropeptide Y receptor antagonists.

    PubMed

    Daniels, A J; Matthews, J E; Slepetis, R J; Jansen, M; Viveros, O H; Tadepalli, A; Harrington, W; Heyer, D; Landavazo, A; Leban, J J; Spaltenstein, A

    1995-09-26

    Neuropeptide Y (NPY) is one of the most abundant peptide transmitters in the mammalian brain. In the periphery it is costored and coreleased with norepinephrine from sympathetic nerve terminals. However, the physiological functions of this peptide remain unclear because of the absence of specific high-affinity receptor antagonists. Three potent NPY receptor antagonists were synthesized and tested for their biological activity in in vitro, ex vivo, and in vivo functional assays. We describe here the effects of these antagonists inhibiting specific radiolabeled NPY binding at Y1 and Y2 receptors and antagonizing the effects of NPY in human erythroleukemia cell intracellular calcium mobilization perfusion pressure in the isolated rat kidney, and mean arterial blood pressure in anesthetized rats.

  15. Throwing performance is associated with muscular power.

    PubMed

    Bourdin, M; Rambaud, O; Dorel, S; Lacour, J-R; Moyen, B; Rahmani, A

    2010-07-01

    The aim of the present study was to test the hypothesis that performance in throwing events is associated with muscular characteristics of both upper and lower limbs. Thirty-eight male throwers volunteered to participate. Bench press and half squat tests were conducted on a guided barbell. The barbell displacement signal was recorded using a kinematic system. Maximal power, corresponding optimal velocity and force (P(max)S, V(opt)S, F(opt)S and P(max)BP, V(opt)BP, F(opt)BP for half squat and bench press, respectively) were extrapolated from the power-velocity relationship. Lower limb stiffness (K) was determined during maximal hopping. The results demonstrated that P(max)S and P(max)BP were correlated with each thrower's season's best performance (SBP, R=0.54, P<0.01 and R=0.71, P<0.001, respectively). P(max)S expressed relative to body mass was not correlated with SBP. K was significantly correlated with SBP (R=0.66, P<0.001). The relationship between P (max)BP expressed relative to body mass and SBP remained significant ( R=0.54, P<0.001). The results of the study suggest that high strength and stiffness values for lower limbs and strength and velocity characteristics for upper limbs may be associated with athletic throwing performance.

  16. 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.

  17. 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.

  18. 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

  19. Muscular anatomy of the human ventricular folds.

    PubMed

    Moon, Jerald; Alipour, Fariborz

    2013-09-01

    Our purpose in this study was to better understand the muscular anatomy of the ventricular folds in order to help improve biomechanical modeling of phonation and to better understand the role of these muscles during phonatory and nonphonatory tasks. Four human larynges were decalcified, sectioned coronally from posterior to anterior by a CryoJane tape transfer system, and stained with Masson's trichrome. The total and relative areas of muscles observed in each section were calculated and used for characterizing the muscle distribution within the ventricular folds. The ventricular folds contained anteriorly coursing thyroarytenoid and ventricularis muscle fibers that were in the lower half of the ventricular fold posteriorly, and some ventricularis muscle was evident in the upper and lateral portions of the fold more anteriorly. Very little muscle tissue was observed in the medial half of the fold, and the anterior half of the ventricular fold was largely devoid of any muscle tissue. All 4 larynges contained muscle bundles that coursed superiorly and medially through the upper half of the fold, toward the lateral margin of the epiglottis. Although variability of expression was evident, a well-defined thyroarytenoid muscle was readily apparent lateral to the arytenoid cartilage in all specimens.

  20. 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

  1. 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

  2. Electrical impedance myography in facioscapulohumeral muscular dystrophy.

    PubMed

    Statland, Jeffrey M; Heatwole, Chad; Eichinger, Katy; Dilek, Nuran; Martens, William B; Tawil, Rabi

    2016-10-01

    In this study we determined the reliability and validity of electrical impedance myography (EIM) in facioscapulohumeral muscular dystrophy (FSHD). We performed a prospective study of EIM on 16 bilateral limb and trunk muscles in 35 genetically defined and clinically affected FSHD patients (reliability testing on 18 patients). Summary scores based on body region were derived. Reactance and phase (50 and 100 kHz) were compared with measures of strength, FSHD disease severity, and functional outcomes. Participants were mostly men, mean age 53.0 years, and included a full range of severity. Limb and trunk muscles showed good to excellent reliability [intraclass correlation coefficients (ICC) 0.72-0.99]. Summary scores for the arm, leg, and trunk showed excellent reliability (ICC 0.89-0.98). Reactance was the most sensitive EIM parameter to a broad range of FSHD disease metrics. EIM is a reliable measure of muscle composition in FSHD that offers the possibility to serially evaluate affected muscles. Muscle Nerve 54: 696-701, 2016. © 2016 Wiley Periodicals, Inc.

  3. Molecular diagnosis of Duchenne muscular dystrophy.

    PubMed

    Nallamilli, Babi Ramesh Reddy; Ankala, Arunkanth; Hegde, Madhuri

    2014-10-01

    Duchenne Muscular Dystrophy (DMD) is an X-linked inherited neuromuscular disorder caused by mutations in the dystrophin gene (DMD; locus Xp21.2). The mutation spectrum of DMD is unique in that 65% of causative mutations are intragenic deletions, with intragenic duplications and point mutations (along with other sequence variants) accounting for 6% to 10% and 30% to 35%, respectively. The strategy for molecular diagnostic testing for DMD involves initial screening for deletions/duplications using microarray-based comparative genomic hybridization (array-CGH) followed by full-sequence analysis of DMD for sequence variants. Recently, next-generation sequencing (NGS)-based targeted gene analysis has become clinically available for detection of point mutations and other sequence variants (small insertions, deletions, and indels). This unit initially discusses the strategic algorithm for establishing a molecular diagnosis of DMD and later provides detailed protocols of current molecular diagnostic methods for DMD, including array-CGH, PCR-based Sanger sequencing, and NGS-based sequencing assay.

  4. Limb-girdle muscular dystrophy 2A.

    PubMed

    Gallardo, Eduard; Saenz, Amets; Illa, Isabel

    2011-01-01

    Limb-girdle muscular dystrophy type 2A (LGMD2A) is caused by mutations in the gene CAPN3 located in the chromosome region 15q15.1-q21.1. To date more than 300 mutations have been described. This gene encodes for a 94-kDa nonlysosomal calcium-dependent cysteine protease and its function in skeletal muscle is not fully understood. It seems that calpain-3 has an unusual zymogenic activation that involves, among other substrates, cytoskeletal proteins. Calpain-3 is thought to interact with titin and dysferlin. Calpain-3 deficiency produces abnormal sarcomeres that lead eventually to muscle fiber death. Hip adductors and gluteus maximus are the earliest clinically affected muscles. No clinical differences have been reported depending on the type of mutation in the CAPN3 gene. The muscle biopsy shows variability of fiber size, interstitial fibrosis, internal nuclei, lobulated fibers, and, in some cases, presence of eosinophils. Recent gene expression profiling studies have shown upregulation of interleukin-32 and immunoglobulin genes, which may explain the eosinophilic infiltration. Two mouse knockout models of CAPN3 have been characterized. There are no curative treatments for this disease. However, experimental therapeutics using mouse models conclude that adeno-associated virus (AAV) vectors seem to be one of the best approaches because of their efficiency and persistency of gene transfer.

  5. Lipomatous muscular 'dystrophy' of Piedmontese cattle.

    PubMed

    Biasibetti, E; Amedeo, S; Brugiapaglia, A; Destefanis, G; Di Stasio, L; Valenza, F; Capucchio, M T

    2012-11-01

    Lipomatous myopathy is a degenerative muscle pathology characterized by the substitution of muscle cells with adipose tissue, sporadically reported in cattle, pigs, and rarely in sheep, horses and dogs. This study investigated the pathology of this myopathy in 40 muscle samples collected from regularly slaughtered Piedmontese cattle living in Piedmont region (Italy). None of the animals showed clinical signs of muscular disease. Muscle specimens were submitted to histological and enzymatic investigations. Gross pathology revealed a different grade of infiltration of adipose tissue, involving multiple or single muscles. The most affected regions were the ventral abdomen and the shoulders, especially the cutaneous muscles and the muscles of the thoracic group. Morphological staining revealed an infiltration of adipose tissue varying in distribution and severity, changes in muscle fibre size and increased number of fibres with centrally located nuclei, suggesting muscle degeneration-regeneration. Necrosis and non-suppurative inflammatory cells were also seen. Furthermore, proliferation of connective tissue and non-specific myopathic changes were present. Chemical and physical characteristics of the affected tissue were also evaluated. The authors discuss about the aetiopathogenesis and classification of this muscle disorder whose histological lesions were similar to those reported in human dystrophies.

  6. Cardiac asynchrony in Duchenne muscular dystrophy.

    PubMed

    Fayssoil, Abdallah; Nardi, Olivier; Orlikowski, David; Annane, Djillali

    2013-10-01

    Duchenne muscular dystrophy (DMD) is an inherited myogenic disorder due to mutations in the dystrophin gene on chromosome Xp21.1. Heart failure is a classical complication in this disease. Little data are available about systolic dyssynchrony in DMD. We sought to assess the prevalence of left ventricular dysfunction and systolic asynchrony in DMD patients using echocardiographic parameters. We performed electrocardiography and echocardiography for adult's patients with DMD. For systolic dyssynchrony assessment, echocardiography-Doppler was performed and completed by tissular Doppler imaging. 48 DMD were included in our study. Age ranged from 20 to 37 years. QRS duration >120 ms was present in 10 patients/48 and 1 patient disclosed a QRS duration >150 ms. Left ventricular (LV) ejection fraction (EF) ranged from 10 to 62 % with a median of 43 %. Inter-ventricular asynchrony was found in 11.9 % of patients with EF < 35 % and in 2.6 % of patients with EF > 35 %. Intra-ventricular asynchrony was present in 6 % of patients with EF < 35 %. We found a high prevalence of LV dysfunction in DMD. Systolic ventricular asynchrony seems frequent particularly in patients with EF < 35 %.

  7. Genetic therapeutic approaches for Duchenne muscular dystrophy.

    PubMed

    Foster, Helen; Popplewell, Linda; Dickson, George

    2012-07-01

    Despite an expansive wealth of research following the discovery of the DMD gene 25 years ago, there is still no curative treatment for Duchenne muscular dystrophy. However, there are currently many promising lines of research, including cell-based therapies and pharmacological reagents to upregulate dystrophin via readthrough of nonsense mutations or by upregulation of the dystrophin homolog utrophin. Here we review genetic-based therapeutic strategies aimed at the amelioration of the DMD phenotype. These include the reintroduction of a copy of the DMD gene into an affected tissue by means of a viral vector; correction of the mutated DMD transcript by antisense oligonucleotide-induced exon skipping to restore the open reading frame; and direct modification of the DMD gene at a chromosomal level through genome editing. All these approaches are discussed in terms of the more recent advances, and the hurdles to be overcome if a comprehensive and effective treatment for DMD is to be found. These hurdles include the need to target all musculature of the body. Therefore any potential treatment would need to be administered systemically. In addition, any treatment needs to have a long-term effect, with the possibility of readministration, while avoiding any potentially detrimental immune response to the vector or transgene.

  8. Therapeutic developments in spinal muscular atrophy

    PubMed Central

    Sproule, Douglas M.; Kaufmann, Petra

    2010-01-01

    Spinal muscular atrophy (SMA), a potentially devastating disease marked by progressive weakness and muscle atrophy resulting from the dysfunction and loss of motor neurons of the spinal cord, has emerged in recent years as an attractive target for therapeutic intervention. Caused by a homozygous mutation to the Survival of Motor Neurons 1 (SMN1) gene on chromosome 5q, the severity of the clinical phenotype in SMA is modulated by the function of a related protein, Survival of Motor Neurons 2 (SMN2). SMN2 predominantly produces an unstable SMN transcript lacking exon 7; only about 10% of the transcription product produces a full-length, functional SMN protein. Several therapeutic strategies have targeted this gene with the goal of producing increased full-length SMN transcript, thereby modifying the underlying mechanism. Drugs that have increased SMN2 function, in vitro, are now explored for potential therapeutic benefit in this disease. Alternative approaches, including neuroprotective, muscle anabolic, gene and cell replacement strategies, also hold promise. The recent advances in preclinical research and the development of a wider range of animal models for SMA continue to provide cautious optimism that effective treatments for SMA will eventually emerge. PMID:21179609

  9. The genetics of spinal muscular atrophies.

    PubMed

    Wee, Claribel D; Kong, Lingling; Sumner, Charlotte J

    2010-10-01

    This article reviews clinical, genetic, and therapeutic advances in spinal muscular atrophies (SMAs), inherited disorders characterized by motor neuron loss and muscle weakness. There has been progress in defining the clinical and genetic features of at least 16 distinct forms of SMA. The genes associated with 14 of these disorders have been identified in the last decade, including four within the last year: TRPV4, ATP7A, VRK1, and HSPB3. Genetic testing is now available for many SMAs, providing important diagnostic and prognostic information. Cell and animal models of SMAs have been used to further understand how mutations in SMA-associated genes, which code for proteins involved in diverse functions such as transcriptional regulation, RNA processing, and cytoskeletal dynamics, lead to motor neuron dysfunction and loss. In the last year, there has also been remarkable progress in preclinical therapeutics development for proximal SMA using gene therapy, antisense oligonucleotides, and small molecules. The advances in the clinical and genetic characterization of different forms of SMAs have important implications for clinical evaluation and management of patients. The identification of multiple, novel SMA-causing genes will lead to an improved understanding of motor neuron disease biology and may provide novel targets for therapeutics development.

  10. Emerging treatment options for spinal muscular atrophy.

    PubMed

    Burnett, Barrington G; Crawford, Thomas O; Sumner, Charlotte J

    2009-03-01

    The motor neuron disease spinal muscular atrophy (SMA) is one of the leading genetic killers of infants worldwide. SMA is caused by mutation of the survival motor neuron 1 (SMN1) gene and deficiency of the survival motor neuron (SMN) protein. All patients retain one or more copies of the SMN2 gene, which (by producing a small amount of the SMN protein) rescues embryonic lethality and modifies disease severity. Rapid progress continues in dissecting the cellular functions of the SMN protein, but the mechanisms linking SMN deficiency with dysfunction and loss of functioning motor units remain poorly defined. Clinically, SMA should to be distinguished from other neuromuscular disorders, and the diagnosis can be readily confirmed with genetic testing. Quality of life and survival of SMA patients are improved with aggressive supportive care including optimized respiratory and nutritional care and management of scoliosis and contractures. Because SMA is caused by inadequate amounts of SMN protein, one aim of current SMA therapeutics development is to increase SMN protein levels in SMA patients by activating SMN2 gene expression and/or increasing levels of full-length SMN2 transcripts. Several potential therapeutic compounds are currently being studied in clinical trials in SMA patients.

  11. Glutamate NMDA receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure

    PubMed Central

    Li, Nanxin; Liu, Rong-Jian; Dwyer, Jason M.; Banasr, Mounira; Lee, Boyoung; Son, Hyeon; Li, Xiao-Yuan; Aghajanian, George; Duman, Ronald S.

    2011-01-01

    Background Despite widely reported clinical and preclinical studies of rapid antidepressant actions of glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonists, there has been very little work examining the effects of these drugs in stress models of depression that require chronic administration of antidepressants, or the molecular mechanisms that could account for the rapid responses. Methods We used a rat 21-day chronic unpredictable stress (CUS) model to test the rapid actions of NMDA receptor antagonists on depressant-like behavior, neurochemistry, and spine density and synaptic function of prefrontal cortex (PFC) neurons. Results The results demonstrate that acute treatment with the non-competitive NMDA channel blocker ketamine or the selective NR2B antagonist Ro 25-6981 rapidly ameliorates CUS-induced anhedonia and anxiogenic behaviors. We also find that CUS exposure decreases the expression levels of synaptic proteins and spine number and the frequency/amplitude of synaptic currents (EPSCs) in layer V pyramidal neurons in the PFC, and that these deficits are rapidly reversed by ketamine. Blockade of the mammalian target of rapamycin (mTOR) protein synthesis cascade abolishes both the behavioral and biochemical effects of ketamine. Conclusions The results indicate that the structural and functional deficits resulting from long-term stress exposure, which could contribute to the pathophysiology of depression, are rapidly reversed by NMDA receptor antagonists in an mTOR-dependent manner. PMID:21292242

  12. Selective opioid agonist and antagonist competition for [3H]-naloxone binding in amphibian spinal cord.

    PubMed

    Newman, L C; Wallace, D R; Stevens, C W

    2000-11-24

    Opioids elicit antinociception in mammals through three distinct types of receptors designated as mu, kappa and delta. However, it is not clear what type of opioid receptor mediates antinociception in non-mammalian vertebrates. Radioligand binding techniques were employed to characterize the site(s) of opioid action in the amphibian, Rana pipiens. Naloxone is a general opioid antagonist that has not been characterized in Rana pipiens. Using the non-selective opioid antagonist, [3H]-naloxone, opioid binding sites were characterized in amphibian spinal cord. Competitive binding assays were done using selective opioid agonists and highly-selective opioid antagonists. Naloxone bound to a single-site with an affinity of 11.3 nM and 18.7 nM for kinetic and saturation studies, respectively. A B(max) value of 2725 fmol/mg protein in spinal cord was observed. The competition constants (K(i)) of unlabeled mu, kappa and delta ranged from 2.58 nM to 84 microM. The highly-selective opioid antagonists yielded similar K(i) values ranging from 5.37 to 31.1 nM. These studies are the first to examine opioid binding in amphibian spinal cord. In conjunction with previous behavioral data, these results suggest that non-mammalian vertebrates express a unique opioid receptor which mediates the action of selective mu, kappa and delta opioid agonists.

  13. 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. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Effects of low-intensity resistance exercise with slow movement and tonic force generation on muscular function in young men.

    PubMed

    Tanimoto, Michiya; Ishii, Naokata

    2006-04-01

    We investigated the acute and long-term effects of low-intensity resistance exercise (knee extension) with slow movement and tonic force generation on muscular size and strength. This type of exercise was expected to enhance the intramuscular hypoxic environment that might be a factor for muscular hypertrophy. Twenty-four healthy young men without experience of regular exercise training were assigned into three groups (n = 8 for each) and performed the following resistance exercise regimens: low-intensity [ approximately 50% of one-repetition maximum (1RM)] with slow movement and tonic force generation (3 s for eccentric and concentric actions, 1-s pause, and no relaxing phase; LST); high-intensity ( approximately 80% 1RM) with normal speed (1 s for concentric and eccentric actions, 1 s for relaxing; HN); low-intensity with normal speed (same intensity as for LST and same speed as for HN; LN). In LST and HN, the mean repetition maximum was 8RM. In LN, both intensity and amount of work were matched with those for LST. Each exercise session consisting of three sets was performed three times a week for 12 wk. In LST and HN, exercise training caused significant (P < 0.05) increases in cross-sectional area determined with MRI and isometric strength (maximal voluntary contraction) of the knee extensors, whereas no significant changes were seen in LN. Electromyographic and near-infrared spectroscopic analyses showed that one bout of LST causes sustained muscular activity and the largest muscle deoxygenation among the three types of exercise. The results suggest that intramuscular oxygen environment is important for exercise-induced muscular hypertrophy.

  15. Behavioral and 5-HT antagonist effects of ritanserin: a pure and selective antagonist of LSD discrimination in rat.

    PubMed

    Colpaert, F C; Meert, T F; Niemegeers, C J; Janssen, P A

    1985-01-01

    The newly synthesized compound and putative 5-HT2 antagonist ritanserin, but not the structurally related compound R 56413, resembles pirenperone in that it acts as a pure antagonist in an LSD-saline drug discrimination assay in the rat. Ritanserin exceeded pirenperone in terms of behavioral specificity; the lowest effective dose of ritanserin in antagonizing LSD was one order of magnitude higher than that of pirenperone, but the compound depressed rate of operant responding only at doses that were about 1000-fold higher than those at which pirenperone was effective. Ritanserin exerted effects in an open field test which were reminiscent of anxiolytic drug activity in the rat; its effects were greater than those of pirenperone, R 56413 and the benzodiazepines chlordiazepoxide and diazepam. The results of experiments on antagonism of 5-HT-induced hypothermia and of the 5-HTP-induced head-twitch response fail to support the possibility that the putative anxiolytic effects of ritanserin in the rat can be ascribed simply to a pharmacologically defined action at 5-HT receptors.

  16. Antagonist mechanical contribution to resultant maximal torque at the ankle joint in young and older men.

    PubMed

    Simoneau, Emilie M; Billot, Maxime; Martin, Alain; Van Hoecke, Jacques

    2009-04-01

    A recorded muscular torque at one joint is a resultant torque corresponding to the participation of both agonist and antagonist muscles. This study aimed to examine the effect of aging on the mechanical contributions of both plantar- and dorsi-flexors to the resultant maximal voluntary contraction (MVC) torques exerted at the ankle joint, in dorsi-flexion (DF) and plantar-flexion (PF). The estimation of isometric agonist and antagonist torques by means of an EMG biofeedback technique was made with nine young (mean age 24 years) and nine older (mean age 80 years) men. While there was a non-significant age-related decline in the measured resultant DF MVC torque (-15%; p=0.06), there was a clear decrease in the estimated agonist MVC torque exerted by the dorsi-flexors (-39%; p=0.001). The DF-to-PF resultant MVC torque ratio was significantly lower in young than in older men (0.25 vs. 0.31; p=0.006), whereas the DF-to-PF agonist MVC torque ratio was no longer different between the two populations (0.38 vs. 0.35; p>0.05). Thus, agonist MVC torques in PF and DF would be similarly affected by aging, which could not be deduced when only resultant torques were examined.

  17. Serum creatinine level: a supplemental index to distinguish Duchenne muscular dystrophy from Becker muscular dystrophy.

    PubMed

    Zhang, Huili; Zhu, Yuling; Sun, Yiming; Liang, Yingyin; Li, Yaqin; Zhang, Yu; Deng, Langhui; Wen, Xingxuan; Zhang, Cheng

    2015-01-01

    To improve assessment of dystrophinopathy, the aim of this study was to identify whether serum creatinine (Crn) level reflects disease severity. Biochemical, Vignos score, and genetic data were collected on 212 boys with dystrophinopathy. Serum Crn level had a strong inverse correlation with Vignos score by simple correlation (r = -0.793) and partial correlation analysis after adjustment for age, height, and weight (r = -0.791; both P < 0.01). Serum Crn level was significantly higher in patients with in-frame than out-of-frame mutations (Z = -4.716,  P < 0.01) and in Becker muscular dystrophy (BMD) patients than Duchenne muscular dystrophy (DMD) patients at ages 4, 5, 7, and 9 yr (all P < 0.0125). After adjusting for age, height, and weight, BMD patients still had a significantly higher serum Crn level than DMD patients (β = 7.140,  t = 6.277,  P < 0.01). Serum Crn level reflected disease severity and may serve as a supplemental index to distinguish DMD from BMD in clinical practice.

  18. Muscular factors are of importance in tension-type headache.

    PubMed

    Jensen, R; Bendtsen, L; Olesen, J

    1998-01-01

    Recent studies have indicated that muscular disorders may be of importance for the development of increased pain sensitivity in patients with chronic tension-type headache. The objective of the present study was to investigate this hypothesis by examining the pain perception in tension-type headache with and without muscular disorders defined as increased tenderness. We examined 28 patients with episodic tension-type headache, 28 patients with chronic tension-type headache, and 30 healthy controls. Pericranial myofascial tenderness was recorded with manual palpation, and pressure pain detection and tolerances in cephalic and extracephalic locations with an electronic pressure algometer. In addition, thermal pain sensitivity and electromyographic activity were recorded. The main result was significantly lower pressure pain detection thresholds and tolerances in all the examined locations in patients with chronic tension-type headache with a muscular disorder compared to those without a muscular disorder. There were no such differences in any of the examined locations when the two subgroups of patients with episodic tension-type headache were compared. Thermal pain sensitivity did not differ between patients with and without a muscular disorder, while electromyographic activity levels were significantly higher in patients with chronic tension-type headache with than in those without a muscular disorder. Our results strongly indicate that prolonged nociceptive stimuli from the pericranial myofascial tissue sensitize the central nervous system and, thereby, lead to an increased general pain sensitivity. Muscular factors may, therefore, be of major importance for the conversion of episodic into chronic tension-type headache. The present study complements the understanding of the important interactions between peripheral and central factors in tension-type headache and may lead to a better prevention and treatment of the most prevalent type of headache.

  19. 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…

  20. Modeling Spinal Muscular Atrophy in Drosophila

    PubMed Central

    Mukherjee, Ashim; Kankel, Mark W.; Sen, Anindya; Sridhar, Vasanthi; Fulga, Tudor A.; Hart, Anne C.; Van Vactor, David; Artavanis-Tsakonas, Spyros

    2008-01-01

    Spinal Muscular Atrophy (SMA), a recessive hereditary neurodegenerative disease in humans, has been linked to mutations in the survival motor neuron (SMN) gene. SMA patients display early onset lethality coupled with motor neuron loss and skeletal muscle atrophy. We used Drosophila, which encodes a single SMN ortholog, survival motor neuron (Smn), to model SMA, since reduction of Smn function leads to defects that mimic the SMA pathology in humans. Here we show that a normal neuromuscular junction (NMJ) structure depends on SMN expression and that SMN concentrates in the post-synaptic NMJ regions. We conducted a screen for genetic modifiers of an Smn phenotype using the Exelixis collection of transposon-induced mutations, which affects approximately 50% of the Drosophila genome. This screen resulted in the recovery of 27 modifiers, thereby expanding the genetic circuitry of Smn to include several genes not previously known to be associated with this locus. Among the identified modifiers was wishful thinking (wit), a type II BMP receptor, which was shown to alter the Smn NMJ phenotype. Further characterization of two additional members of the BMP signaling pathway, Mothers against dpp (Mad) and Daughters against dpp (Dad), also modify the Smn NMJ phenotype. The NMJ defects caused by loss of Smn function can be ameliorated by increasing BMP signals, suggesting that increased BMP activity in SMA patients may help to alleviate symptoms of the disease. These results confirm that our genetic approach is likely to identify bona fide modulators of SMN activity, especially regarding its role at the neuromuscular junction, and as a consequence, may identify putative SMA therapeutic targets. PMID:18791638

  1. Spinal muscular atrophy: a time for screening.

    PubMed

    Prior, Thomas W

    2010-12-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations in the survival motor neuron (SMN1) gene, affecting approximately 1 in 10,000 live births. Even though a specific therapy for SMA is not currently available, a newborn screening test may allow the child to be enrolled in a clinical trial before irreversible neuronal loss occurs and enable patients to obtain more proactive treatments. Until an effective treatment is found to cure or arrest the progression of the disease, prevention of new cases through carrier detection and prenatal diagnosis becomes extremely important. The correlation between the SMA phenotype and the SMN2 copy number and the demonstration that sufficient SMN protein from SMN2 in transgenic mice can ameliorate the disease has made the SMN2 gene an obvious target that is being modulated in current therapeutic trials. Most recent work, utilizing gene therapy, has also shown a rescue of the phenotype in the mouse model. Since SMA children are often asymptomatic at birth, newborn screening is a means which will allow the implementation of the most early intervention to take place, before the irreversible loss of motor neurons. Since there is no effective cure for SMA presently, prevention through the identification of carriers becomes an important alternative and has recently been initiated. Treatment and prevention of SMA are complementary responses to the scourge presented by SMA. This review first describes the molecular genetics of SMA and then focuses on newborn screening, as a means of ensuring the earliest intervention, and the prevention through population carrier screening.

  2. 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.

  3. Forced oscillation technique in spinal muscular atrophy.

    PubMed

    Gauld, Leanne M; Keeling, Lucy A; Shackleton, Claire E; Sly, Peter D

    2014-09-01

    Spinal muscular atrophy (SMA) causes respiratory compromise that is difficult to assess in young children. The forced oscillation technique (FOT) is commercially available for children as young as 2 years of age and is nonvolitional. The aim of this study was to assess the usefulness of FOT in young children with SMA. Children with SMA aged < 10 years were recruited. FOT was performed every 3 months for 12 months (five visits). Spirometry and assisted and unassisted peak cough flow (PCF) were performed where possible. Polysomnography was performed on children with type 2 SMA. Clinical information included SMA type, chest infections, Cobb angle, medications, and mobility. Regression analysis assessed relationships between FOT and FVC, PCF, and apnea/hypopnea index (AHI). Analysis of variance sought relationships to clinical characteristics. Twelve children (seven male) were recruited; mean age was 6.26 (± 2.59) years. Respiratory reactance at 8 Hz (Xrs8) (mean z score, +1.41; SD, 1.90; P < .03) and respiratory resistance at 8 Hz (Rrs8) (mean z score, +0.66; SD, 1.34; P = .12) were abnormal. Four children performed spirometry. Linear relationships to Xrs8 exist: FVC (R2, 0.54), unassisted PCF (R2, 0.33), assisted PCF (R2, 0.43), and AHI (R2, 0.32). Over 12 months, Xrs8z score worsened (rate of change of +1.08, P < .001) and Rrs8z score worsened (rate of change +0.51, P < .001). No relationship (P > .05) was found between clinical characteristics and FOT values. FOT is feasible in young children with SMA, with abnormal values of reactance and resistance on grouped data, worsening over 12 months. Xrs8 is related to respiratory tests used to monitor progress in SMA (FVC, PCF, AHI). Further research on the value of FOT in managing individuals is warranted.

  4. 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

  5. Duchenne Muscular Dystrophy: From Diagnosis to Therapy.

    PubMed

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

    2015-10-07

    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.

  6. Antagonistic Interactions among Marine Pelagic Bacteria

    PubMed Central

    Long, Richard A.; Azam, Farooq

    2001-01-01

    Recent studies suggest that bacterial abundance and species diversity in the ocean's water column are variable at the millimeter scale, apparently in response to the small-scale heterogeneity in the distribution of organic matter. We hypothesized that bacterium-bacterium antagonistic interactions may contribute to variations in community structure at the microscale. We examined each of the 86 isolates for their inhibition of growth of the remaining 85 isolates by the Burkholder agar diffusion assay. More than one-half of the isolates expressed antagonistic activity, and this trait was more common with particle-associated bacteria than with free-living bacteria. This was exemplified by members of the α subclass of the class Proteobacteria (α-proteobacteria), in which production of antagonistic molecules was dominated by attached bacteria. We found that γ-proteobacteria (members of the orders Alteromonadales and Vibrionales) are the most prolific producers of inhibitory materials and also the most resilient to them, while members of the Bacteriodetes were the organisms that were least productive and most sensitive to antagonistic interactions. Widespread interspecies growth inhibition is consistent with the role of this phenomenon in structuring bacterial communities at the microscale. Furthermore, our results suggest that bacteria from pelagic marine particles may be an underutilized source of novel antibiotics. PMID:11679315

  7. Antagonistic and synergistic interactions among predators.

    PubMed

    Huxel, Gary R

    2007-08-01

    The structure and dynamics of food webs are largely dependent upon interactions among consumers and their resources. However, interspecific interactions such as intraguild predation and interference competition can also play a significant role in the stability of communities. The role of antagonistic/synergistic interactions among predators has been largely ignored in food web theory. These mechanisms influence predation rates, which is one of the key factors regulating food web structure and dynamics, thus ignoring them can potentially limit understanding of food webs. Using nonlinear models, it is shown that critical aspects of multiple predator food web dynamics are antagonistic/synergistic interactions among predators. The influence of antagonistic/synergistic interactions on coexistence of predators depended largely upon the parameter set used and the degree of feeding niche differentiation. In all cases when there was no effect of antagonism or synergism (a ( ij )=1.00), the predators coexisted. Using the stable parameter set, coexistence occurred across the range of antagonism/synergism used. However, using the chaotic parameter strong antagonism resulted in the extinction of one or both species, while strong synergism tended to coexistence. Whereas using the limit cycle parameter set, coexistence was strongly dependent on the degree of feeding niche overlap. Additionally increasing the degree of feeding specialization of the predators on the two prey species increased the amount of parameter space in which coexistence of the two predators occurred. Bifurcation analyses supported the general pattern of increased stability when the predator interaction was synergistic and decreased stability when it was antagonistic. Thus, synergistic interactions should be more common than antagonistic interactions in ecological systems.

  8. Antagonist-Elicited Cannabis Withdrawal in Humans

    PubMed Central

    Gorelick, David A.; Goodwin, Robert S.; Schwilke, Eugene; Schwope, David M.; Darwin, William D.; Kelly, Deanna L.; McMahon, Robert P.; Liu, Fang; Ortemann-Renon, Catherine; Bonnet, Denis; Huestis, Marilyn A.

    2013-01-01

    Cannabinoid CB1 receptor antagonists have potential therapeutic benefits, but antagonist-elicited cannabis withdrawal has not been reported in humans. Ten male daily cannabis smokers received 8 days of increasingly frequent 20-mg oral Δ9-tetrahydrocannabinol (THC) dosages (40–120 mg/d) around-the-clock to standardize cannabis dependence while residing on a closed research unit. On the ninth day, double-blind placebo or 20- (suggested therapeutic dose) or 40-mg oral rimonabant, a CB1-cannabinoid receptor antagonist, was administered. Cannabis withdrawal signs and symptoms were assessed before and for 23.5 hours after rimonabant. Rimonabant, THC, and 11-hydroxy-THC plasma concentrations were quantified by mass spectrometry. The first 6 subjects received 20-mg rimonabant (1 placebo); the remaining 4 subjects received 40-mg rimonabant (1 placebo). Fourteen subjects enrolled; 10 completed before premature termination because of withdrawal of rimonabant from clinical development. Three of 5 subjects in the 20-mg group, 1 of 3 in the 40-mg group, and none of 2 in the placebo group met the prespecified withdrawal criterion of 150% increase or higher in at least 3 visual analog scales for cannabis withdrawal symptoms within 3 hours of rimonabant dosing. There were no significant associations between visual analog scale, heart rate, or blood pressure changes and peak rimonabant plasma concentration, area-under-the-rimonabant-concentration-by-time curve (0–8 hours), or peak rimonabant/THC or rimonabant/(THC + 11-hydroxy-THC) plasma concentration ratios. In summary, prespecified criteria for antagonist-elicited cannabis withdrawal were not observed at the 20- or 40-mg rimonabant doses. These data do not preclude antagonist-elicited withdrawal at higher rimonabant doses. PMID:21869692

  9. Antagonist-elicited cannabis withdrawal in humans.

    PubMed

    Gorelick, David A; Goodwin, Robert S; Schwilke, Eugene; Schwope, David M; Darwin, William D; Kelly, Deanna L; McMahon, Robert P; Liu, Fang; Ortemann-Renon, Catherine; Bonnet, Denis; Huestis, Marilyn A

    2011-10-01

    Cannabinoid CB1 receptor antagonists have potential therapeutic benefits, but antagonist-elicited cannabis withdrawal has not been reported in humans. Ten male daily cannabis smokers received 8 days of increasingly frequent 20-mg oral Δ⁹-tetrahydrocannabinol (THC) dosages (40-120 mg/d) around-the-clock to standardize cannabis dependence while residing on a closed research unit. On the ninth day, double-blind placebo or 20- (suggested therapeutic dose) or 40-mg oral rimonabant, a CB1-cannabinoid receptor antagonist, was administered. Cannabis withdrawal signs and symptoms were assessed before and for 23.5 hours after rimonabant. Rimonabant, THC, and 11-hydroxy-THC plasma concentrations were quantified by mass spectrometry. The first 6 subjects received 20-mg rimonabant (1 placebo); the remaining 4 subjects received 40-mg rimonabant (1 placebo). Fourteen subjects enrolled; 10 completed before premature termination because of withdrawal of rimonabant from clinical development. Three of 5 subjects in the 20-mg group, 1 of 3 in the 40-mg group, and none of 2 in the placebo group met the prespecified withdrawal criterion of 150% increase or higher in at least 3 visual analog scales for cannabis withdrawal symptoms within 3 hours of rimonabant dosing. There were no significant associations between visual analog scale, heart rate, or blood pressure changes and peak rimonabant plasma concentration, area-under-the-rimonabant-concentration-by-time curve (0-8 hours), or peak rimonabant/THC or rimonabant/(THC + 11-hydroxy-THC) plasma concentration ratios. In summary, prespecified criteria for antagonist-elicited cannabis withdrawal were not observed at the 20- or 40-mg rimonabant doses. These data do not preclude antagonist-elicited withdrawal at higher rimonabant doses.

  10. 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

  11. Inhibition of Prostaglandin D Synthase Suppresses Muscular Necrosis

    PubMed Central

    Mohri, Ikuko; Aritake, Kosuke; Taniguchi, Hidetoshi; Sato, Yo; Kamauchi, Shinya; Nagata, Nanae; Maruyama, Toshihiko; Taniike, Masako; Urade, Yoshihiro

    2009-01-01

    Duchenne muscular dystrophy is a fatal muscle wasting disease that is characterized by a deficiency in the protein dystrophin. Previously, we reported that the expression of hematopoietic prostaglandin D synthase (HPGDS) appeared in necrotic muscle fibers from patients with either Duchenne muscular dystrophy or polymyositis. HPGDS is responsible for the production of the inflammatory mediator, prostaglandin D2. In this paper, we validated the hypothesis that HPGDS has a role in the etiology of muscular necrosis. We investigated the expression of HPGDS/ prostaglandin D2 signaling using two different mouse models of muscle necrosis, that is, bupivacaine-induced muscle necrosis and the mdx mouse, which has a genetic muscular dystrophy. We treated each mouse model with the HPGDS-specific inhibitor, HQL-79, and measured both necrotic muscle volume and selected cytokine mRNA levels. We confirmed that HPGDS expression was induced in necrotic muscle fibers in both bupivacaine-injected muscle and mdx mice. After administration of HQL-79, necrotic muscle volume was significantly decreased in both mouse models. Additionally, mRNA levels of both CD11b and transforming growth factor β1 were significantly lower in HQL-79-treated mdx mice than in vehicle-treated animals. We also demonstrated that HQL-79 suppressed prostaglandin D2 production and improved muscle strength in the mdx mouse. Our results show that HPGDS augments inflammation, which is followed by muscle injury. Furthermore, the inhibition of HPGDS ameliorates muscle necrosis even in cases of genetic muscular dystrophy. PMID:19359520

  12. Muscular hydrostat mechanism for lip protrusion in speech

    NASA Astrophysics Data System (ADS)

    Murano, Emi Z.; Stone, Maureen; Honda, Kiyoshi

    2005-09-01

    The lip is an organ consisting mostly of muscle similar to the tongue. While the tongue is known as a muscular hydrostat, it is unclear whether the lip is also. In this paper the muscular hydrostat issue was explored from the anatomical and functional point of view using high-resolution static MRI (hr-MRI 0.125 mm/pixel) and tagged-cineMRI (t-MRI). A 3-D reconstruction of the lips and its muscles was obtained from hr-MRI during sustained vowels /i/ and /u/. The muscular geometry of the orbicularis oris, mentalis, and depressor labii inferior muscles were superimposed onto the principal strains that depicts compression and expansion of the internal tissue obtained from t-MRI. It is shown that (1) orbicularis oris muscle shape can predict both the borderline of glabrous and hairy skin and the manner in which the lips are protruded; (2) the lips volume is almost identical for both speech tasks; and (3) direction and intensity of compression of orbicularis oris and mentalis muscle bundles imply the role of these muscles in the protrusion appearance. These results indicate that the muscular architecture and volume preserving characteristics of the lips are consistent with a muscular hydrostat. [This work was supported by NIH (USA) and NiCT (Japan).

  13. TRIM proteins in therapeutic membrane repair of muscular dystrophy.

    PubMed

    Alloush, Jenna; Weisleder, Noah

    2013-07-01

    Muscular dystrophy represents a major unmet medical need; only palliative treatments exist for this group of debilitating diseases. Because multiple forms of muscular dystrophy arise from compromised sarcolemmal membrane integrity, a therapeutic approach that can target this loss of membrane function could be applicable to a number of these distinct diseases.One promising therapeutic approach involves the process the cell uses to repair injuries to the plasma membrane. Recent discoveries of genes associated with the membrane repair process provide an opportunity to promote this process as a way to treat muscular dystrophy. One such gene is mitsugumin 53 (MG53), a member of the tripartite motif (TRIM) family of proteins (TRIM72), which is an essential component of the membrane repair pathway in muscle. Recent results indicate that MG53/TRIM72 protein can be directly applied as a therapeutic agent to increase membrane repair capacity of many cell types and treat some aspects of the disease in mouse models of muscular dystrophy. There is great potential for the use of recombinant human MG53 in treating muscular dystrophy and other diseases in which compromised membrane integrity contributes to the disease. Other TRIM family proteins may provide additional targets for therapeutic intervention in similar disease states.

  14. Assessment of disease activity in muscular dystrophies by noninvasive imaging.

    PubMed

    Maguire, Katie K; Lim, Leland; Speedy, Sedona; Rando, Thomas A

    2013-05-01

    Muscular dystrophies are a class of disorders that cause progressive muscle wasting. A major hurdle for discovering treatments for the muscular dystrophies is a lack of reliable assays to monitor disease progression in animal models. We have developed a novel mouse model to assess disease activity noninvasively in mice with muscular dystrophies. These mice express an inducible luciferase reporter gene in muscle stem cells. In dystrophic mice, muscle stem cells activate and proliferate in response to muscle degeneration, resulting in an increase in the level of luciferase expression, which can be monitored by noninvasive, bioluminescence imaging. We applied this noninvasive imaging to assess disease activity in a mouse model of the human disease limb girdle muscular dystrophy 2B (LGMD2B), caused by a mutation in the dysferlin gene. We monitored the natural history and disease progression in these dysferlin-deficient mice up to 18 months of age and were able to detect disease activity prior to the appearance of any overt disease manifestation by histopathological analyses. Disease activity was reflected by changes in luciferase activity over time, and disease burden was reflected by cumulative luciferase activity, which paralleled disease progression as determined by histopathological analysis. The ability to monitor disease activity noninvasively in mouse models of muscular dystrophy will be invaluable for the assessment of disease progression and the effectiveness of therapeutic interventions.

  15. Muscular, skeletal, and neural adaptations following spinal cord injury.

    PubMed

    Shields, Richard K

    2002-02-01

    Spinal cord injury is associated with adaptations to the muscular, skeletal, and spinal systems. Experimental data are lacking regarding the extent to which rehabilitative methods may influence these adaptations. An understanding of the plasticity of the muscular, skeletal, and spinal systems after paralysis may be important as new rehabilitative technologies emerge in the 21st century. Moreover, individuals injured today may become poor candidates for future scientific advancements (cure) if their neuromusculoskeletal systems are irreversibly impaired. The primary purpose of this paper is to explore the physiological properties of skeletal muscle as a result of spinal cord injury; secondarily, to consider associated changes at the skeletal and spinal levels. Muscular adaptations include a transformation to faster myosin, increased contractile speeds, shift to the right on the torque-frequency curve, increased fatigue, and enhanced doublet potentiation. These muscular adaptations may be prevented in individuals with acute paralysis and partially reversed in individuals with chronic paralysis. Moreover, the muscular changes may be coordinated with motor unit and spinal circuitry adaptations. Concurrently, skeletal adaptations, as measured by bone mineral density, show extensive loss within the first six months after paralysis. The underlying science governing neuromusculoskeletal adaptations after paralysis will help guide professionals as new rehabilitation strategies evolve in the future.

  16. Congenital segmental spinal muscular atrophy: a case report.

    PubMed

    Savaş, Tülin; Erol, Ilknur; Özkale, Yasemin; Saygi, Semra

    2015-03-01

    Spinal muscular atrophies are genetic disorders in which anterior horn cells in the spinal cord and motor nuclei of the brainstem are progressively lost. We present a patient with arthrogryposis due to congenital spinal muscular atrophy predominantly affecting the upper limbs. Spinal muscular atrophies with onset at birth may be a cause of arthrogryposis. Localized forms of neurogenic arthrogryposis have been divided into cervical and caudal forms. Our case is similar to the cases described by Hageman et al (J Neurol Neurosurg Psychiatry 1993;56:365-368): severe symmetric lower motor neuron deficit in the upper extremities at the time of birth, no history of injury to the cervical spinal cord or the brachial plexus during delivery, and severe muscle wasting suggesting chronic denervation in utero. Because there was improvement of our patient's situation, her disease was also possibly nonprogressive and sporadic. To our knowledge, this is the first reported case of a Turkish patient with congenital cervical spinal muscular atrophy. Congenital cervical spinal muscular atrophy affecting predominantly the upper limbs is a relatively rare form of motor neuron disease and should be considered in the differential diagnosis of infants with congenital contractures and severe muscle weakness by wasting mainly confined to the upper limbs. © The Author(s) 2014.

  17. 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

  18. Recognition and reciprocity in encounters with women with chronic muscular pain.

    PubMed

    Steihaug, Sissel; Malterud, Kirsti

    2002-09-01

    Experiences from 11 treatment groups for women with chronic muscular pain showed that recognition had a major impact on the way the participants benefited from treatment. In this article, based on Anne-Lise Løvlie Schibbye's psychological theories, we explore and analyse how recognising interaction can be enacted in practice. Qualitative action research design. Ongoing treatment groups in Stovner/Oslo for women with chronic muscular pain. A total of 31 women took part in 3 treatment groups with movement training and group discussions. Video recordings from six group discussions were analysed using Part Process Analysis (PPA), a qualitative research method addressing interaction on a micro-level. PPA demonstrates how recognition is expressed by specific types of behaviour, and how recognition can lead to change and development of the participants in the treatment groups. Schibbye's recognition model, with emphasis on a fundamental respect for the experience perspective of the opposite party, may also help the doctor to understand the patient better, particularly in difficult relationships where there seem to be insurmountable differences between the doctor's and patient's perspectives.

  19. Adaptable setups for magnetic drug targeting in human muscular arteries: Design and implementation

    NASA Astrophysics Data System (ADS)

    Hajiaghajani, Amirhossein; Hashemi, Soheil; Abdolali, Ali

    2017-09-01

    Magnetic drug targeting has been used to steer magnetic therapeutic agents and has received much attention for capillaries and human brain arteries. In this paper, we focus on noninvasive targeting of nanoparticles in muscular arteries, in where the vessel diameter and blood flow are much challengingly higher than brain capillaries. We aim to design a low intensity magnetic field which avoids potential side effects on blood cells while steers particles with high targeting rate. The setup design procedure is considerably flexible to be used in a wide variety of large vessels. Using particle tracing, a new method is proposed to connect the geometry of the vessel under the action of targeting to the required magnetic force. Specifications of the coil which is placed outside the body are derived based on this required force. Mutual effects of coil dimensions on the produced magnetic force are elaborated and summarized in a design flowchart to be used for arbitrary muscular vessel sizes. The performance of the optimized coil is validated by in vitro experiments and it is shown that particles are steered with the average efficiency of 80.2% for various conditions.

  20. Building the French Muscular Dystrophy Association: the role of doctor/patient interactions.

    PubMed

    Bach, M A

    1998-08-01

    The process of creating the French Muscular Dystrophy Association (AFM) is analysed through the interactions between the medico-scientific community on the one hand, and patients and their families on the other, from the 1950s to 1986. Each stage of its development was characterized by a particular mode of co-operation between lay people and doctors. Starting in 1958, the Association built a close relationship with a single partner, Jean Demos, a paediatrician and biochemist who developed a new vasodilation therapy based on his controversial vascular theory of muscular dystrophy. Around 1966, some AFM members, disappointed by Demos' treatment, decided to collaborate with other specialists, primarily neurologists, but channelled most of their resources in social action. Two other organizations were then created around Dr. Demos: the first (Union de Myopathes de France (UMF) acted as a "grass-roots organization" for maintaining "therapeutic orthodoxy" among patients and supporting his research through political lobbying; the other, composed of a handful of wealthy individuals, raised private funds for his laboratory. In the late 1970s, some UMF members questioned Demos' approach. They united with AFM to form a single association and created a Scientific Council representing all French groups interested in neuromuscular diseases. The co-operation established between these two collective partners proved to be most fruitful for both parties.

  1. Combining Elements from Two Antagonists of Formyl Peptide Receptor 2 Generates More Potent Peptidomimetic Antagonists.

    PubMed

    Skovbakke, Sarah Line; Holdfeldt, André; Nielsen, Christina; Hansen, Anna Mette; Perez-Gassol, Iris; Dahlgren, Claes; Forsman, Huamei; Franzyk, Henrik

    2017-08-24

    Structural optimization of a peptidomimetic antagonist of formyl peptide receptor 2 (FPR2) was explored by an approach involving combination of elements from the two most potent FPR2 antagonists described: a Rhodamine B-conjugated 10-residue gelsonin-derived peptide (i.e., PBP10, RhB-QRLFQVKGRR-OH) and the palmitoylated α-peptide/β-peptoid hybrid Pam-(Lys-βNspe)6-NH2. This generated an array of hybrid compounds from which a new subclass of receptor-selective antagonists was identified. The most potent representatives displayed activity in the low nanomolar range. The resulting stable and potent FPR2-selective antagonists (i.e., RhB-(Lys-βNphe)n-NH2; n = 4-6) are expected to become valuable tools in further elucidation of the physiological role of FPR2 in health and disease.

  2. Implementation of a fluorescence-based screening assay identifies histamine H3 receptor antagonists clobenpropit and iodophenpropit as subunit-selective N-methyl-D-aspartate receptor antagonists.

    PubMed

    Hansen, Kasper B; Mullasseril, Praseeda; Dawit, Sara; Kurtkaya, Natalie L; Yuan, Hongjie; Vance, Katie M; Orr, Anna G; Kvist, Trine; Ogden, Kevin K; Le, Phuong; Vellano, Kimberly M; Lewis, Iestyn; Kurtkaya, Serdar; Du, Yuhong; Qui, Min; Murphy, T J; Snyder, James P; Bräuner-Osborne, Hans; Traynelis, Stephen F

    2010-06-01

    N-Methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels that mediate a slow, Ca(2+)-permeable component of excitatory synaptic transmission in the central nervous system and play a pivotal role in synaptic plasticity, neuronal development, and several neurological diseases. We describe a fluorescence-based assay that measures NMDA receptor-mediated changes in intracellular calcium in a BHK-21 cell line stably expressing NMDA receptor NR2D with NR1 under the control of a tetracycline-inducible promoter (Tet-On). The assay selectively identifies allosteric modulators by using supramaximal concentrations of glutamate and glycine to minimize detection of competitive antagonists. The assay is validated by successfully identifying known noncompetitive, but not competitive NMDA receptor antagonists among 1800 screened compounds from two small focused libraries, including the commercially available library of pharmacologically active compounds. Hits from the primary screen are validated through a secondary screen that used two-electrode voltage-clamp recordings on recombinant NMDA receptors expressed in Xenopus laevis oocytes. This strategy identified several novel modulators of NMDA receptor function, including the histamine H3 receptor antagonists clobenpropit and iodophenpropit, as well as the vanilloid receptor transient receptor potential cation channel, subfamily V, member 1 (TRPV1) antagonist capsazepine. These compounds are noncompetitive antagonists and the histamine H3 receptor ligand showed submicromolar potency at NR1/NR2B NMDA receptors, which raises the possibility that compounds can be developed that act with high potency on both glutamate and histamine receptor systems simultaneously. Furthermore, it is possible that some actions attributed to histamine H3 receptor inhibition in vivo may also involve NMDA receptor antagonism.

  3. Antagonist pharmacology of desensitizing and non-desensitizing nicotinic acetylcholine receptors in cockroach neurons.

    PubMed

    Salgado, Vincent L

    2016-09-01

    Two α-bungarotoxin-sensitive nicotinic acetylcholine (ACh) receptor subtypes in neurons of the American cockroach have been identified as desensitizing (nAChD) and selectively inhibitable with 100nM imidacloprid, and non-desensitizing (nAChN) and selectively inhibitable with 100pM methyllycaconitine. In this paper, the single-electrode voltage-clamp technique was used to measure concentration-response relations for the action of ACh and five antagonists on pharmacologically separated nAChD and nAChN receptors of acutely dissociated neurons from thoracic ganglia of the American cockroach. A dual bath and U-tube perfusion system was used to achieve rapid application of ACh in the continued presence of antagonists, which was essential to accurately measure inhibition by rapidly-reversible antagonists. ACh activated both receptors with an EC50 of 7μM and the antagonist potencies were (nAChD/nAChN in nM): dihydro-β-erythroidine: 1.0/5.6, d-tubocurarine: 1000/34, condelphine: 0.39/0.65, phencyclidine: 74/980 and mecamylamine 47/1150. While each of these antagonists displayed some subtype selectivity, none are selective enough to be used as subtype-selective tools. These results bring to a total of 16 the number of nicotinic compounds that have been measured on nAChD and nAChN currents. Characterization of these receptors is important for understanding the role of nAChRs in the insect nervous system and the mechanism of action of insecticides.

  4. NOP Receptor Mediates Anti-analgesia Induced by Agonist-Antagonist Opioids

    PubMed Central

    Gear, Robert W.; Bogen, Oliver; Ferrari, Luiz F.; Green, Paul G.; Levine, Jon D.

    2014-01-01

    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 ~90 minutes 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 U69,593 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 J113397, 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

  5. Evidence for allosteric interactions of antagonist binding to the smoothened receptor.

    PubMed

    Rominger, Cynthia M; Bee, Wei-Lin Tiger; Copeland, Robert A; Davenport, Elizabeth A; Gilmartin, Aidan; Gontarek, Richard; Hornberger, Keith R; Kallal, Lorena A; Lai, Zhihong; Lawrie, Kenneth; Lu, Quinn; McMillan, Lynette; Truong, Maggie; Tummino, Peter J; Turunen, Brandon; Will, Matthew; Zuercher, William J; Rominger, David H

    2009-06-01

    The Smoothened receptor (Smo) mediates hedgehog (Hh) signaling critical for development, cell growth, and migration, as well as stem cell maintenance. Aberrant Hh signaling pathway activation has been implicated in a variety of cancers, and small-molecule antagonists of Smo have entered human clinical trials for the treatment of cancer. Here, we report the biochemical characterization of allosteric interactions of agonists and antagonists for Smo. Binding of two radioligands, [(3)H]3-chloro-N-[trans-4-(methylamino)cyclohexyl]-N-{[3-(4-pyridinyl)-phenyl]methyl}-1-benzothiophene-2-carboxamide (SAG-1.3) (agonist) and [(3)H]cyclopamine (antagonist), was characterized using human Smo expressed in human embryonic kidney 293F membranes. We observed full displacement of [(3)H]cyclopamine by all Smo agonist and antagonist ligands examined. N-[(1E)-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)methylidene]-4-(phenylmethyl)-1-piperazinamine (SANT-1), an antagonist, did not fully inhibit the binding of [(3)H]SAG-1.3. In a functional cell-based beta-lactamase reporter gene assay, SANT-1 and N-[3-(1H-benzimidazol-2-yl)-4-chlorophenyl]-3,4,5-tris(ethyloxy)-benzamide (SANT-2) fully inhibited 3-chloro-4,7-difluoro-N-[trans-4-(methylamino)cyclohexyl]-N-{[3-(4-pyridinyl)phenyl]methyl}-1-benzothiophene-2-carboxamide (SAG-1.5)-induced Hh pathway activation. Detailed "Schild-type" radioligand binding analysis with [(3)H]SAG-1.3 revealed that two structurally distinct Smoothened receptor antagonists, SANT-1 and SANT-2, bound in a manner consistent with that of allosteric modulation. Our mechanism of action characterization of radioligand binding to Smo combined with functional data provides a better understanding of small-molecule interactions with Smo and their influence on the Hh pathway.

  6. 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

  7. Progress in corticotropin-releasing factor-1 antagonist development

    PubMed Central

    Zorrilla, Eric P.; Koob, George F.

    2010-01-01

    Corticotropin-releasing factor (CRF) receptor antagonists have been sought since the stress-secreted peptide was isolated in 1981. Although evidence suggests the limited efficacy of CRF1 antagonists as antidepressants, CRF1 antagonists might be novel pharmacotherapies for anxiety and addiction. Progress in understanding the two-domain model of ligand–receptor interactions for CRF family receptors might yield chemically novel CRF1 receptor antagonists, including peptide CRF1 antagonists, antagonists with signal transduction selectivity and nonpeptide CRF1 antagonists that act via the extracellular (rather than transmembrane) domains. Novel ligands that conform to prevalent pharmacophore and exhibit drug-like pharmacokinetic properties have been identified. The therapeutic utility of CRF1 antagonists should soon be clearer: several small molecules are currently in Phase II/III clinical trials for depression, anxiety and irritable bowel syndrome. PMID:20206287

  8. Spinal muscular atrophy functional composite score: A functional measure in spinal muscular atrophy.

    PubMed

    Montes, Jacqueline; Glanzman, Allan M; Mazzone, Elena S; Martens, William B; Dunaway, Sally; Pasternak, Amy; Riley, Susan O; Quigley, Janet; Pandya, Shree; De Vivo, Darryl C; Kaufmann, Petra; Chiriboga, Claudia A; Finkel, Richard S; Tennekoon, Gihan I; Darras, Basil T; Pane, Marika; Mercuri, Eugenio; Mcdermott, Michael P

    2015-12-01

    With clinical trials underway, our objective was to construct a composite score of global function that could discriminate among people with spinal muscular atrophy (SMA). Data were collected from 126 participants with SMA types 2 and 3. Scores from the Hammersmith Functional Motor Scale-Expanded and Upper Limb Module were expressed as a percentage of the maximum score and 6-minute walk test as percent of predicted normal distance. A principal component analysis was performed on the correlation matrix for the 3 percentage scores. The first principal component yielded a composite score with approximately equal weighting of the 3 components and accounted for 82% of the total variability. The SMA functional composite score, an unweighted average of the 3 individual percentage scores, correlated almost perfectly with the first principal component. This combination of measures broadens the spectrum of ability that can be quantified in type 2 and 3 SMA patients. © 2015 Wiley Periodicals, Inc.

  9. ACTION Act

    THOMAS, 111th Congress

    Sen. Dodd, Christopher J. [D-CT

    2009-02-24

    Senate - 02/24/2009 Read twice and referred to the Committee on Health, Education, Labor, and Pensions. (All Actions) Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:

  10. 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

  11. Idiopathic intracranial hypertension in a child with Duchenne muscular dystrophy.

    PubMed

    Weig, Spencer G; Zinn, Matthias M; Howard, James F

    2011-12-01

    Duchenne muscular dystrophy is an X-linked, recessively inherited disorder characterized by progressive weakness attributable to the absence of dystrophin expression in muscle. In multiple studies, the chronic administration of corticosteroids slowed the loss of ambulation that develops in mid to late childhood. Corticosteroids, however, frequently produce unacceptable side effects, including Cushingoid appearance and weight gain. Deflazacort, an oxazoline analogue of prednisolone, produces equivalent benefits on muscle with fewer reported Cushingoid side effects. We present a 9-year-old boy with Duchenne muscular dystrophy who developed morbid obesity and subsequent idiopathic intracranial hypertension after 2 years of receiving deflazacort. Although deflazacort is typically thought to produce less obesity than prednisone, severe Cushingoid side effects may occur in some individuals. To our knowledge, this description is the first of idiopathic intracranial hypertension complicating chronic corticosteroid treatment of Duchenne muscular dystrophy.

  12. Pharmacologic and genetic therapy for childhood muscular dystrophies.

    PubMed

    Escolar, D M; Scacheri, C G

    2001-03-01

    The outstanding advances in the molecular characterization of muscle diseases, including muscular dystrophies, inflammatory myopathies, and ion channel disorders, have resulted in the identification of potential targets for pharmacologic and genetic therapy in the best characterized of these diseases. The most common myopathy in children, Duchenne muscular dystrophy (DMD), is the focus of active pharmacologic clinical trials. Genetic transfer therapy research for this and other dystrophies is rapidly moving forward. However, as new approaches for treatment are being actively investigated, the current modality of treatment for all myopathies is still in the realm of physical medicine and rehabilitation. The focus of this review is on the advances in pharmacologic and genetic therapy research in DMD and limb girdle muscular dystrophies.

  13. Psychometric properties of Yelland and Tiggemann's Drive for Muscularity Scale.

    PubMed

    Tod, David; Morrison, Todd G; Edwards, Christian

    2012-06-01

    The purpose of the current study was to examine the dimensionality and validity of Yelland and Tiggemann's Drive for Muscularity Scale (YT-DMS). Participants were college students (305 women, M(AGE)=20.15 years, SD=4.00; 356 men, M(AGE)=20.24 years, SD=3.85) who completed the YT-DMS, the Drive for Muscularity Attitudes Questionnaire, the Drive for Leanness Scale, the Drive for Thinness Scale, and a socio-demographic questionnaire. Results indicated the YT-DMS had a stable unidimensional factor structure in both genders, and the pattern of relationships generally supported the measure's criterion and construct validity. These results reveal the YT-DMS has promise, but helps identify possible areas for improvement, such as a greater focus on sampling the content domain associated with the drive for muscularity.

  14. Psychosocial predictors of drive for muscularity in male collegiate athletes.

    PubMed

    Galli, Nick; Petrie, Trent; Reel, Justine J; Greenleaf, Christy; Carter, Jennifer E

    2015-06-01

    The purpose of this study was to examine the simultaneous relation of general and sport-specific pressures about body weight and shape, negative affect, and body satisfaction to drive for muscularity (DM) in male collegiate athletes. Participants were 183 male athletes who were drawn from three NCAA Division I institutions and represented 17 different sports. As hypothesized, after controlling for BMI and sport type, sport-specific pressures, negative affect, and body satisfaction were significant predictors, and accounted for 15-34% of the variance in muscularity-oriented body image and muscularity behaviors; general pressures however were not significantly related. These findings offer insight into the personal and social antecedents of DM in male athletes, and serve as a starting point for future research on DM in this population.

  15. 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.

  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.

  17. Evaluation of muscular stabilization ability during a static workout.

    PubMed

    Staniszewski, Michał; Urbanik, Czesław; Staniszewski, Tadeusz

    2010-01-01

    The aim of this research was to determine the moving and stabilizing functions of selected groups of muscles during the process of static workout. 15 students of the Academy of Physical Education were tested in non-competitive training. Muscular torques achieved during flexing and extending big limb joints were used as the determinant of force. Comparative analysis of torque values achieved in passive stabilization (with support) and muscular stabilization (without support) in elbow and knee joints was carried out. The value of the force applied to the passively stabilizing element in a given measurement during the flexion of elbow and the extension of knee joint was tested. The results of these tests allowed us to learn the value of muscular torques and - after statistical analysis - the relationship between them in particular functions.

  18. Respiratory surveillance of patients with Duchenne and Becker muscular dystrophy.

    PubMed

    Spehrs-Ciaffi, Virginia; Fitting, Jean William; Cotting, Jacques; Jeannet, Pierre-Yves

    2009-01-01

    Duchenne muscular dystrophy is is the most common form of the childhood muscular dystrophies. It follows a predictable clinical course marked by progressive skeletal muscle weakness, lost of ambulation before teen-age and death in early adulthood secondary to respiratory or cardiac failure. Becker muscular dystrophy is less common and has a milder clinical course but also results in respiratory and cardiac failure.Altough recent advances in respiratory care and new technologies have improved the outlook many patients already received only a traditional non-interventional approach. The aims of this work are: to analyse the pathophysiology and natural history of respiratory function in these diseases, to descript their clinical manifestations, to present the diagnostics tools and to provide recommendations for an adequated respiratory care in this particular population based on the updated literature referenced.

  19. Gene therapy for muscular dystrophy: moving the field forward.

    PubMed

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

    2014-11-01

    Gene therapy for the muscular dystrophies has evolved as a promising treatment for this progressive group of disorders. Although corticosteroids and/or supportive treatments remain the standard of care for Duchenne muscular dystrophy, 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 the therapeutic progress with emphasis on evolving preclinical 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.

  20. Preclinical studies for gene therapy of Duchenne muscular dystrophy.

    PubMed

    Odom, Guy L; Banks, Glen B; Schultz, Brian R; Gregorevic, Paul; Chamberlain, Jeffrey S

    2010-09-01

    The muscular dystrophies are a diverse group of genetic disorders without an effective treatment. Because they are caused by mutations in various genes, the most direct way to treat them involves correcting the underlying gene defect (ie, gene therapy). Such a gene therapy approach involves delivering a therapeutic gene cassette to essentially all the muscles of the body in a safe and efficacious manner. The authors describe gene delivery methods using vectors derived from adeno-associated virus that are showing great promise in preclinical studies for treatment of Duchenne muscular dystrophy. It is hoped that variations on these methods might be applicable for most, if not all, of the different types of muscular dystrophy.