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36-397: Living with muscular dystrophy , a genetic disease that is causing him to lose the use of his body, Kaïs is awoken every morning by a different member of his family. While his body is paralyzed, at night he dreams that he is the hero of his favorite manga, along with his brothers, Fehd the bodybuilder and Zaid the ninja. The film won the first ever Prix Iris for Best Short Documentary at

72-556: A genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. The disorders differ as to which muscles are primarily affected, the degree of weakness, how fast they worsen, and when symptoms begin. Some types are also associated with problems in other organs . Over 30 different disorders are classified as muscular dystrophies. Of those, Duchenne muscular dystrophy (DMD) accounts for approximately 50% of cases and affects males beginning around

108-448: A long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics , such as valproic acid . Since at least 2003 they have been investigated as possible treatments for cancers, parasitic and inflammatory diseases. To carry out gene expression, a cell must control the coiling and uncoiling of DNA around histones . This is accomplished with the assistance of histone acetyl transferases (HAT), which acetylate

144-599: A range of symptoms. Muscle degeneration may be mild or severe. Problems may be restricted to skeletal muscle , or muscle degeneration may be paired with effects on the brain and other organ systems. Several forms of the congenital muscular dystrophies are caused by defects in proteins thought to have some relationship to the dystrophin-glycoprotein complex and to the connections between muscle cells and their surrounding cellular structure. Some forms of congenital muscular dystrophy show severe brain malformations, such as lissencephaly and hydrocephalus . Miyoshi myopathy, one of

180-481: A small subset of genes, leading to transcriptional activation of some genes, but repression of an equal or larger number of other genes. Non-histone proteins such as transcription factors are also targets for acetylation with varying functional effects. Acetylation enhances the activity of some transcription factors such as the tumor suppressor p53 and the erythroid differentiation factor GATA1 but may repress transcriptional activity of others including T cell factor and

216-433: A symptom of depression. Multiple studies have shown that treatment with an HDI helps to upregulate expression of BDNF: valproic acid commonly used to treat epilepsy and bipolar disorder as well as sodium butyrate both increased expression of BDNF in animal models of depression. One study which traced GDNF levels in the ventral striatum found increased gene expression upon treatment with SAHA . Pre-clinical research on

252-480: Is valproic acid , marketed as a drug under the trade names Depakene , Depakote , and Divalproex . As of 2008, HDIs were being studied as a mitigator for neurodegenerative diseases such as Alzheimer's disease and Huntington's disease . Enhancement of memory formation was increased in mice given vorinostat , or by genetic knockout of the HDAC2 gene in mice. While that may have relevance to Alzheimer's disease, it

288-573: Is commonly used as a candidate for mood disorder treatment: studies using it both alone and in co-treatment with fluoxetine report subjects with increased performance on both TST and FST in addition to increased expression of BDNF. Pan-HDAC inhibitors have shown anticancer potential in several in in vitro and in vivo studies, focused on Pancreatic, Esophageal squamous cell carcinoma (ESCC), Multiple myeloma, Prostate carcinoma, Gastric cancer, Leukemia, breast, Liver cancer, ovarian cancer ( belinostat ), non-Hodgkin lymphoma and Neuroblastoma. Because of

324-752: Is in most muscle cells and works to strengthen the muscle fibers and protect them from injury as muscles contract and relax. It links the muscle membrane to the thin muscular filaments within the cell. Dystrophin is an integral part of the muscular structure. An absence of dystrophin can cause impairments: healthy muscle tissue can be replaced by fibrous tissue and fat, causing an inability to generate force. Respiratory and cardiac complications can occur as well. These mutations are either inherited from parents or may occur spontaneously during early development . Muscular dystrophies may be X-linked recessive , autosomal recessive , or autosomal dominant . Diagnosis often involves blood tests and genetic testing . There

360-559: Is involved in research, advocacy, and services for individuals affected by muscular dystrophy. The organization provides resources that contribute to understanding and addressing this condition. Histone deacetylase inhibitor Histone deacetylase inhibitors ( HDAC inhibitors , HDACi , HDIs ) are chemical compounds that inhibit histone deacetylases . Since deacetylation of histones produces transcriptionally silenced heterochromatin , HDIs can render chromatin more transcriptionally active and induce epigenomic changes. HDIs have

396-761: Is no cure for any disorder from the muscular dystrophy group. Several drugs designed to address the root cause are currently available including gene therapy ( Elevidys ), and antisense drugs ( Ataluren , Eteplirsen etc.). Other medications used include glucocorticoids ( Deflazacort , Vamorolone ); calcium channel blockers ( Diltiazem ); to slow skeletal and cardiac muscle degeneration, anticonvulsants to control seizures and some muscle activity, and Histone deacetylase inhibitors ( Givinostat ) to delay damage to dying muscle cells . Physical therapy , braces , and corrective surgery may help with some symptoms while assisted ventilation may be required in those with weakness of breathing muscles . Outcomes depend on

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432-478: Is not addressed by pharmacological treatments. Environmental stressors, namely traumatic stress in childhood such as maternal deprivation and early childhood abuse have been studied for their connection to a high risk of depression in adulthood. In animal models, these types of trauma have been shown to have significant effects on histone acetylation , particularly at gene loci which have known connection to behavior and mood regulation. 2011 research focused on

468-459: The 23rd Quebec Cinema Awards in 2021, and was a Canadian Screen Award nominee for Best Short Documentary at the 10th Canadian Screen Awards in 2022. This article related to a Canadian documentary film of the 2020s is a stub . You can help Misplaced Pages by expanding it . This article about an animated film of the 2020s is a stub . You can help Misplaced Pages by expanding it . Muscular dystrophy Muscular dystrophies ( MD ) are

504-460: The 18 known human histone deacetylases as of 2015 were classified into four groups (I-IV): The "classical" HDIs act exclusively on Class I, II and Class IV HDACs by binding to the zinc -containing catalytic domain of the HDACs. These classical HDIs can be classified into several groupings named according to the chemical moiety that binds to the zinc ion (except cyclic tetrapeptides which bind to

540-760: The ability to walk, and died at an early age became more prominent in medical journals. In the following decade, French neurologist Guillaume Duchenne gave a comprehensive account of the most common and severe form of the disease, which now carries his name – Duchenne MD. In 1966 in the US and Canada, Jerry Lewis and the Muscular Dystrophy Association (MDA) began the annual Labor Day telecast The Jerry Lewis Telethon , significant in raising awareness of muscular dystrophy in North America. Disability rights advocates, however, have criticized

576-406: The acetylation/deacetylation of histones and/or non-histone proteins such as transcription factors. Histone acetylation and deacetylation play important roles in the modulation of chromatin topology and the regulation of gene transcription. Histone deacetylase inhibition induces the accumulation of hyperacetylated nucleosome core histones in most regions of chromatin but affects the expression of only

612-468: The age of four. Other relatively common muscular dystrophies include Becker muscular dystrophy , facioscapulohumeral muscular dystrophy , and myotonic dystrophy , whereas limb–girdle muscular dystrophy and congenital muscular dystrophy are themselves groups of several – usually extremely rare – genetic disorders. Muscular dystrophies are caused by mutations in genes , usually those involved in making muscle proteins. The muscle protein, dystrophin,

648-488: The arms and legs during a 24-week trial significantly delayed the functional loss of muscular dystrophy. It can be done in a safe and feasible manner, even with boys late in their ambulation stage. However, eccentric exercises, or intense exercises causing soreness should not be used as they can cause further damage. Occupational therapy assists the individual with MD to engage in activities of daily living (such as self-feeding and self-care activities) and leisure activities at

684-907: The co-activator ACTR . Recent studies [...] have shown that the estrogen receptor alpha (ERalpha) can be hyperacetylated in response to histone deacetylase inhibition, suppressing ligand sensitivity and regulating transcriptional activation by histone deacetylase inhibitors. Conservation of the acetylated ER-alpha motif in other nuclear receptors suggests that acetylation may play an important regulatory role in diverse nuclear receptor signaling functions. A number of structurally diverse histone deacetylase inhibitors have shown potent antitumor efficacy with little toxicity in vivo in animal models. Several compounds are currently in early phase clinical development as potential treatments for solid and hematological cancers both as monotherapy and in combination with cytotoxics and differentiation agents." Based on their homology of accessory domains to yeast histone deacetylases,

720-446: The degree of acetylation nonhistone effector molecules and, therefore, increase or repress the transcription of genes by this mechanism. Examples include: ACTR , cMyb, E2F1 , EKLF , FEN 1, GATA , HNF-4, HSP90 , Ku70 , MKP-1 , NF-κB , PCNA , p53, RB , Runx, SF1 Sp3, STAT , TFIIE , TCF , YY1 , etc. HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics. The prime example of this

756-438: The different muscular dystrophies follow various inheritance patterns ( X-linked , autosomal recessive or autosomal dominant ). In a small percentage of patients, the disorder may have been caused by a de novo (spontaneous) mutation . The diagnosis of muscular dystrophy is based on the results of muscle biopsy , increased creatine phosphokinase (CpK3), electromyography , and genetic testing . A physical examination and

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792-463: The disease to the family and individual. Prognosis depends on the individual form of muscular dystrophy. Some dystrophies cause progressive weakness and loss of muscle function, which may result in severe physical disability and a life-threatening deterioration of respiratory muscles or heart. Other dystrophies do not affect life expectancy and only cause relatively mild impairment. In the 1860s, descriptions of boys who grew progressively weaker, lost

828-634: The distal muscular dystrophies, causes initial weakness in the calf muscles, and is caused by defects in the same gene responsible for one form of limb–girdle muscular dystrophy . Currently, there is no cure for muscular dystrophy. In terms of management, physical therapy , occupational therapy , orthotic intervention (e.g., ankle-foot orthosis ), speech therapy, and respiratory therapy may be helpful. Low intensity corticosteroids such as prednisone , and deflazacort may help to maintain muscle tone. Orthoses (orthopedic appliances used for support) and corrective orthopedic surgery may be needed to improve

864-726: The lysine residues in core histones leading to a less compact and more transcriptionally active euchromatin , and, on the converse, the actions of histone deacetylases (HDAC), which remove the acetyl groups from the lysine residues leading to the formation of a condensed and transcriptionally silenced chromatin. Reversible modification of the terminal tails of core histones constitutes the major epigenetic mechanism for remodeling higher-order chromatin structure and controlling gene expression . HDAC inhibitors (HDI) block this action and can result in hyperacetylation of histones, thereby affecting gene expression. The open chromatin resulting from inhibition of histone deacetylases can result in either

900-631: The massive effect of pan-HDAC inhibition, witnessed by the very low dosage concentration used and by the countless biological functions affected, many scientists have focused their attention on combining the less specific HDACi treatment with other more specific anti-cancer drugs, such as the efficacy of the combination treatment with the pan-HDAC inhibitor LBH589 ( panobinostat ) and the BET bromodomain JQ1 compound. Trichostatin A (TSA) and others are being investigated as anti-inflammatory agents. One study noted

936-417: The most independent level possible. This may be achieved with use of adaptive equipment or the use of energy-conservation techniques. Occupational therapy may implement changes to a person's environment, both at home or work, to increase the individual's function and accessibility; furthermore, it addresses psychosocial changes and cognitive decline which may accompany MD, and provides support and education about

972-460: The patient's medical history will help the doctor determine the type of muscular dystrophy. Specific muscle groups are affected by different types of muscular dystrophy. An MRI can be used to assess the white matter of the nervous system and measure the merosin levels in young boys. An absence of merosin in young boys will result with neurological deficits and changes in the white matter. Congenital muscular dystrophy includes several disorders with

1008-435: The quality of life in some cases. The cardiac problems that occur with Emery–Dreifuss muscular dystrophy (EDMD) and myotonic muscular dystrophy may require a pacemaker . The myotonia (delayed relaxation of a muscle after a strong contraction) occurring in myotonic muscular dystrophy may be treated with medications such as quinine. Low-intensity, assisted exercises, dynamic exercise training, or assisted bicycle training of

1044-532: The specific type of disorder. Many affected people will eventually become unable to walk and Duchenne muscular dystrophy in particular is associated with shortened life expectancy. Muscular dystrophy was first described in the 1830s by Charles Bell . The word "dystrophy" comes from the Greek dys , meaning "no, un-" and troph- meaning "nourish". The signs and symptoms consistent with muscular dystrophy are: The majority of muscular dystrophies are inherited ;

1080-760: The telethon for portraying those living with the disease as deserving pity rather than respect. On December 18, 2001, the MD CARE Act was signed into law in the US; it amends the Public Health Service Act to provide research for the various muscular dystrophies. This law also established the Muscular Dystrophy Coordinating Committee to help focus research efforts through a coherent research strategy. The [Muscular Dystrophy Association]( https://en.wikipedia.org/wiki/Muscular_Dystrophy_Association ) (MDA)

1116-426: The up-regulation or the repression of genes. As of 2015, the histone deacetylase inhibitors were a "new" class of cytostatic agents that inhibit the proliferation of tumor cells in culture and in vivo by inducing cell cycle arrest, differentiation and/or apoptosis. Histone deacetylase inhibitors exert their anti-tumour effects via the induction of expression changes of oncogenes or tumour suppressors through modulating

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1152-509: The use of panobinostat , entinostat , romidepsin , and vorinostat specifically for the purpose of reactivating latent HIV in order to diminish the reservoirs. Vorinostat was noted as the least potent of the HDAC inhibitors in this trial. Another study found that romidepsin led to a higher and more sustained level of cell-associated HIV RNA reactivation than vorinostat in latently infected T-cells in vitro and ex vivo . Givinostat (ITF2357)

1188-619: The use of HDI therapy for depression after studies on depressed patients in the middle of a depressive episode found increased expression of HDAC2 and HDAC5 mRNA compared to controls and patients in remission. As of 2011 various HDIs have been studied for their connection to the regulation of mood and behavior, each having different, specific effects on the regulation of various genes. The most commonly studied genes include Brain-derived neurotrophic factor (BDNF) and Glial cell line-derived neurotrophic factor (GDNF) both of which help regulate neuron growth and health, whose down regulation can be

1224-718: The use of HDIs to treat depression use rodents to model human depression. The tail suspension test (TST) and the forced swimming test (FST) measure the level of defeat in rodents— usually after treatment with chronic stress— which mirrors symptoms of human depression. Alongside tests for levels of HDAC mRNA, acetylation and gene expression these behavioral tests are compared to controls to determine whether or not treatment has been successful in ameliorating symptoms of depression. Studies which used SAHA or Entinostat ( MS-275 ) found treated animals displayed gene expression profiles similar to those treated with fluoxetine , and displayed similar anti-depressant like behavior. Sodium butyrate

1260-985: The zinc ion with a thiol group). As of 2005, some examples in decreasing order of the typical zinc binding affinity were: As of 2007, "second-generation" HDIs included the hydroxamic acids  : trichostatin A , vorinostat (SAHA), belinostat (PXD101), resminostat , abexinostat , givinostat , LAQ824 , ivaltinostat , nanatinostat and panobinostat (LBH589); and the benzamides  : entinostat (MS-275), tacedinaline (CI994), zabadinostat , and mocetinostat (MGCD0103). The sirtuin Class III HDACs are dependent on NAD+ and are, therefore, inhibited by nicotinamide , as well as derivatives of NAD, dihydrocoumarin, naphthopyranone, and 2-hydroxynaphthaldehydes. HDIs should not be considered to act solely as enzyme inhibitors of HDACs. A large variety of nonhistone transcription factors and transcriptional co-regulators are known to be modified by acetylation. HDIs can alter

1296-653: Was shown that some cognitive deficits were restored in actual transgenic mice with a model of Alzheimer's disease (3xTg-AD) by orally administered nicotinamide, a competitive HDI of Class III sirtuins. 2012 research into the causes of depression highlighted some possible gene-environment interactions that could explain why after much research, no specific genes or loci have emerged which would indicate risk for depression 2016 studies estimate that even after successive treatments with multiple antidepressants, almost 35% of patients did not achieve remission, suggesting that there could be an epigenetic component to depression which

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