The document summarizes Long QT Syndrome Type 3 (LQT3), a genetic condition caused by mutations in the SCN5A gene which codes for cardiac sodium channels. LQT3 causes abnormal prolongation of the QT interval on electrocardiograms. It is characterized by cardiac arrhythmias, fainting spells, and risk of sudden death. Treatment options for LQT3 include sodium channel blockers like mexiletine and flecainide, which can help shorten the QT interval. However, LQT3 tends to be less responsive to typical beta blocker therapy than other forms of Long QT Syndrome. The SCN5A gene contains over 150 known mutations that have been linked to
The long QT syndrome (LQTS) is a rare inherited heart condition in which delayed repolarization of the heart following a heartbeat increases the risk of episodes of torsades de pointes (TDP, a form of irregular heartbeat that originates from the ventricles). These episodes may lead to palpitations, fainting and sudden death due to ventricular fibrillation. Episodes may be provoked by various stimuli, depending on the subtype of the condition.The condition is so named because of the appearances of the electrocardiogram (ECG/EKG), on which there is prolongation of the QT interval. In some individuals the QT prolongation occurs only after the administration of certain medications.
A fellow of the American Board of Anti-Aging and Regenerative Medicine, Dr. John J. Fosbinder is an adjunct assistant professor of emergency medicine at A.T. Still University School of Osteopathic Medicine. Among other topics, Dr. John "Joe" Fosbinder has held lectures on pulmonary embolism, fatal pediatric overdoses, and prolonged QT syndrome.
A patient may be diagnosed with long QT syndrome (LQTS) if their EKG displays abnormal heart rhythms that show that they are susceptible to rapid and chaotic heartbeats. Until an irregular heartbeat occurs, many patients are unaware of the condition. An episode of such irregular heartbeat (arrhythmia) can cause seizures or fainting.
Fainting, medically referred to as syncope, is the temporary loss of muscle control and consciousness due to low blood flow to the brain. Startling events, such as when a nearby phone or alarm rings unexpectedly, can cause an LQTS patient to lose consciousness. Also, mood changes such as excitement, fear, or anger can trigger fainting in LQTS patients. In some patients, the loss of consciousness may be preceded by a short period of blurred vision, lightheadedness, or weakness.
The long QT syndrome (LQTS) is a rare inherited heart condition in which delayed repolarization of the heart following a heartbeat increases the risk of episodes of torsades de pointes (TDP, a form of irregular heartbeat that originates from the ventricles). These episodes may lead to palpitations, fainting and sudden death due to ventricular fibrillation. Episodes may be provoked by various stimuli, depending on the subtype of the condition.The condition is so named because of the appearances of the electrocardiogram (ECG/EKG), on which there is prolongation of the QT interval. In some individuals the QT prolongation occurs only after the administration of certain medications.
A fellow of the American Board of Anti-Aging and Regenerative Medicine, Dr. John J. Fosbinder is an adjunct assistant professor of emergency medicine at A.T. Still University School of Osteopathic Medicine. Among other topics, Dr. John "Joe" Fosbinder has held lectures on pulmonary embolism, fatal pediatric overdoses, and prolonged QT syndrome.
A patient may be diagnosed with long QT syndrome (LQTS) if their EKG displays abnormal heart rhythms that show that they are susceptible to rapid and chaotic heartbeats. Until an irregular heartbeat occurs, many patients are unaware of the condition. An episode of such irregular heartbeat (arrhythmia) can cause seizures or fainting.
Fainting, medically referred to as syncope, is the temporary loss of muscle control and consciousness due to low blood flow to the brain. Startling events, such as when a nearby phone or alarm rings unexpectedly, can cause an LQTS patient to lose consciousness. Also, mood changes such as excitement, fear, or anger can trigger fainting in LQTS patients. In some patients, the loss of consciousness may be preceded by a short period of blurred vision, lightheadedness, or weakness.
Early repolarization (ER), consisting of a J-point elevation, notching or slurring of the terminal portion of the R wave (J wave), and tall/symmetric T wave, is a common finding on the 12-lead electrocardiogram. For decades, it has been considered as benign, barring sporadic case reports and basic electrophysiology research that suggested a critical role of the J wave in the pathogenesis of idiopathic ventricular fibrillation (VF). In 2007-2008, a high prevalence of ER in patients with idiopathic VF was reported and subsequent studies reinforced the results. This PPT describes the current state of knowledge concerning ER syndrome associated with sudden cardiac death.
Brugada syndrome is the most common cause of sudden death in men < 40 years of age in south asia with no pre existing cardiac abnormalities, this presentation will help you understand brugada syndrome ...
The so Called Brugada Syndrome The True HistoryBortolo Martini
The syndrome of sudden Death, right bundle branch block and ST elevation was firstly described by A.Nava and B. Martini in 1988-1989, and only five years later by the Brugada Brothers. The ECG pattern is due to a conduction disturbance of the RVOT, caused by fibrofatty substitution of that structure.
Brugada Syndrome is a inherited sodium channel disorder leading to life threatening ventricular fibrillation in young population. diagnosis and ICD therapy could be life saving.
Early repolarization (ER), consisting of a J-point elevation, notching or slurring of the terminal portion of the R wave (J wave), and tall/symmetric T wave, is a common finding on the 12-lead electrocardiogram. For decades, it has been considered as benign, barring sporadic case reports and basic electrophysiology research that suggested a critical role of the J wave in the pathogenesis of idiopathic ventricular fibrillation (VF). In 2007-2008, a high prevalence of ER in patients with idiopathic VF was reported and subsequent studies reinforced the results. This PPT describes the current state of knowledge concerning ER syndrome associated with sudden cardiac death.
Brugada syndrome is the most common cause of sudden death in men < 40 years of age in south asia with no pre existing cardiac abnormalities, this presentation will help you understand brugada syndrome ...
The so Called Brugada Syndrome The True HistoryBortolo Martini
The syndrome of sudden Death, right bundle branch block and ST elevation was firstly described by A.Nava and B. Martini in 1988-1989, and only five years later by the Brugada Brothers. The ECG pattern is due to a conduction disturbance of the RVOT, caused by fibrofatty substitution of that structure.
Brugada Syndrome is a inherited sodium channel disorder leading to life threatening ventricular fibrillation in young population. diagnosis and ICD therapy could be life saving.
ARVD is one of important coardiomyopathy in our clinical practice,early diagnosis, risk stratification and early diagnosis of CHF, management of VT will make big difference in patient life
Using WES in Distant Relationships to Identify Cardiomyopathy GenesGolden Helix
Using WES in distant relationships to identify cardiomyopathy genes Cardiomyopathy (DCM; MIM 115200) are myocardial diseases that are frequently hereditary, yet remain gene-elusive for 60% of affected families. Traditional gene discovery techniques dependent on multigenerational samples are difficult to apply. This is because 1. Disease is often impenetrant in the youngest generation, 2. Samples are often not available in the oldest generation and 3. Incomplete penetrance and variable expressivity are common across all generations. However, a detailed family history will often identify definitively affected but distantly related individuals. Such families are highly powered for gene discovery using whole exome sequencing (WES) and analysis in SNP and Variation Suite (SVS) software.
As one of many examples, we report a 4-generation pedigree with a hereditary DCM phenotype. Three affected males in the family underwent cardiac transplant, and agreed to provide samples and participate in WES. The affected individuals had tested negative on a 46-gene clinical pan-cardiomyopathy panel. Explanted hearts demonstrated cardiomegaly with marked biventricular dilatation, fibrosis and pronounced histopathological findings.
WES identified rare, possibly deleterious, heterozygous variants in 13 genes, including a novel 1-bp heterozygous deletion (c.913delC) in exon 4 of BAG3. The identified variant was PCR amplified and established by Sanger sequencing. BAG3 protein is significantly expressed in striated and cardiac muscle and colocalizes with Z-discs. Knockdown studies on BAG3 in mice and zebrafish models have demonstrated a DCM phenotypes and heart failure. Here we conclude that c.913delC in BAG3 is a contributing mutation in our family, and endorse WES and SVS as powerful tools for disease-gene identification, where classical linkage studies are not applicable in terms of sample size or disease-penetrance in autosomal dominant pedigrees.
Causes for syncope are multifaceted. Hormonal etiology, specifically hypothyroidism, is associated with cardiac arrhythmias [1]. Sinus bradycardia, low voltage, nonspecific T-wave changes and dissociative atrioventricular (AV) abnormalities are some of descriptive electrocardiographic features [2]. In the majority of well know clinical presentations complete AV block requires the insertion of a permanent pacemaker. However hypothyroidism related bradycardia and consequential symptomatic AV blocks could be reversible with timely and proper management.
We report a case of severe hypothyroidism resulting in insertion of transient pacemaker with favorable clinical course and fully reversible complete AV block after accordant pharmacological hormonal substitution.
Dr. Feroze Momin presents Chronic Lymphocytic Leukemia - Review and new Insights.
To read about Dr. Feroze Momin: http://conquercancers.com/ourdoctorso1.html
To read about Cancer Treatment Center in Michigan:
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Introduction: Aging-associated vascular stiffening augments cardiovascular disease risk in the elderly. Research to identify targetable cellular and molecular mechanisms is of key interest as no current therapies are available to specifically target vascular stiffening. In this context, enzymes that mediate remodeling of the vascular matrix and those that promote cellular dysfunction are attractive targets. In pre-clinical models, pulse wave velocity (PWV), the gold standard measure of in vivo vascular stiffness, can be measured longitudinally and non-invasively, to make inroads towards the discovery and validation of potential targets.
A novel target and model: We have identified a central role for tissue transglutaminase (TG2) in vascular stiffening during aging. TG2 is a multifunctional protein of the transglutaminase family, whose primary function is to assist in the formation of a strong and stable matrix by catalyzing crosslinking of matrix proteins. Recent studies have shown that TG2 has putative crosslinking-independent functions in aging-associated vascular stiffening and dysfunction. The crosslinking independent mechanisms of TG2 remain incompletely understood due to the lack of pre-clinical models and specific inhibitors that can selectively inhibit a single function of TG2. Thus, we developed a novel knock-in mouse, the TGM2-C277S mouse, by mutating the active site cysteine of TG2 using the CRISPR-Cas9 gene editing technology to selectively target its crosslinking function.
Results and conclusion: We first validated the TGM2-C277S mouse and confirmed that this mutation removes TG2’s crosslinking function but retains its crosslinking independent functions. We next compared PWV wild type (WT), global TG2 knockout (TG2-/-), and the TGM2-C277S mice, to identify the contributions of the crosslinking-dependent and crosslinking-independent functions of TG2 to vascular aging in vivo. PWV increased significantly with age in WT mice, and to a much lower magnitude in the TGM2-C277S mice. TG2-/- mice were further protected against aging associated increase in PWV. Together, these studies show that TG2 contributes significantly to overall vascular stiffening in aging through both crosslinking dependent and crosslinking independent functions.
The learning objectives are:
To understand changes in pulse wave velocity (PWV) with age in mouse models
To determine the specific role of tissue transglutaminase (TG2) in vascular aging
To evaluate the role of vascular matrix vs. VSMCs to overall in vivo stiffness described by PWV
My Prostate Cancer Story by Paul SchellhammerTony Crispino
With permission of Dr. Schellhammer this slide deck should be interesting to any PCa patient. Dr. Schellhammer is a former president of the American Urological Association and a leading authority on prostate cancer. He has fought i long battle. He and his colleague, Paul Lange operated on each other and had vastly different results.
Acetabularia Information For Class 9 .docxvaibhavrinwa19
Acetabularia acetabulum is a single-celled green alga that in its vegetative state is morphologically differentiated into a basal rhizoid and an axially elongated stalk, which bears whorls of branching hairs. The single diploid nucleus resides in the rhizoid.
2024.06.01 Introducing a competency framework for languag learning materials ...Sandy Millin
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Published classroom materials form the basis of syllabuses, drive teacher professional development, and have a potentially huge influence on learners, teachers and education systems. All teachers also create their own materials, whether a few sentences on a blackboard, a highly-structured fully-realised online course, or anything in between. Despite this, the knowledge and skills needed to create effective language learning materials are rarely part of teacher training, and are mostly learnt by trial and error.
Knowledge and skills frameworks, generally called competency frameworks, for ELT teachers, trainers and managers have existed for a few years now. However, until I created one for my MA dissertation, there wasn’t one drawing together what we need to know and do to be able to effectively produce language learning materials.
This webinar will introduce you to my framework, highlighting the key competencies I identified from my research. It will also show how anybody involved in language teaching (any language, not just English!), teacher training, managing schools or developing language learning materials can benefit from using the framework.
Exploiting Artificial Intelligence for Empowering Researchers and Faculty, In...Dr. Vinod Kumar Kanvaria
Exploiting Artificial Intelligence for Empowering Researchers and Faculty,
International FDP on Fundamentals of Research in Social Sciences
at Integral University, Lucknow, 06.06.2024
By Dr. Vinod Kumar Kanvaria
Model Attribute Check Company Auto PropertyCeline George
In Odoo, the multi-company feature allows you to manage multiple companies within a single Odoo database instance. Each company can have its own configurations while still sharing common resources such as products, customers, and suppliers.
Safalta Digital marketing institute in Noida, provide complete applications that encompass a huge range of virtual advertising and marketing additives, which includes search engine optimization, virtual communication advertising, pay-per-click on marketing, content material advertising, internet analytics, and greater. These university courses are designed for students who possess a comprehensive understanding of virtual marketing strategies and attributes.Safalta Digital Marketing Institute in Noida is a first choice for young individuals or students who are looking to start their careers in the field of digital advertising. The institute gives specialized courses designed and certification.
for beginners, providing thorough training in areas such as SEO, digital communication marketing, and PPC training in Noida. After finishing the program, students receive the certifications recognised by top different universitie, setting a strong foundation for a successful career in digital marketing.
Operation “Blue Star” is the only event in the history of Independent India where the state went into war with its own people. Even after about 40 years it is not clear if it was culmination of states anger over people of the region, a political game of power or start of dictatorial chapter in the democratic setup.
The people of Punjab felt alienated from main stream due to denial of their just demands during a long democratic struggle since independence. As it happen all over the word, it led to militant struggle with great loss of lives of military, police and civilian personnel. Killing of Indira Gandhi and massacre of innocent Sikhs in Delhi and other India cities was also associated with this movement.
Biological screening of herbal drugs: Introduction and Need for
Phyto-Pharmacological Screening, New Strategies for evaluating
Natural Products, In vitro evaluation techniques for Antioxidants, Antimicrobial and Anticancer drugs. In vivo evaluation techniques
for Anti-inflammatory, Antiulcer, Anticancer, Wound healing, Antidiabetic, Hepatoprotective, Cardio protective, Diuretics and
Antifertility, Toxicity studies as per OECD guidelines
2. Introduction
LQTS:
Romano-Ward Syndrome (RWS): autosomal
dominant
Affects 1 in 7000 people in the US
Displays cardiac abnormalities
Causes 4000 deaths
Mortality rate: up to 6% by when patients turn 40
3. LQT3 overview
Autosomal dominant disease characterized by
prolonged ventricular repolarization
Mutation in chromosome 3p21-24
3p21-24 is loci for the gene SCN5A or NaV1.5
that codes for the alpha helix of the voltage
gated sodium channel
Affects inactivation gate of sodium channel
Cause to gain of function of sodium current
4. Jiang, Changan, Donald Atkinson, Jeffrey A. Towbin, Igor Splawski, Michael H.
Lehmann, Hua Li, Katherine Timothy, R. Thomas Taggart, Peter J. Schwartz, G.
Michael Vincent, Arthur J. Moss, and Mark T. Keating. "Two Long QT Syndrome
Loci Map to Chromosomes 3 and 7 with Evidence for Further
Heterogeneity." Nature Genetics8.2 (1994): 141-47. Print.
6. Amin, A. Roodsari, A, and Tan, H. (2010) Cardiac sodium
channelopathies. Eur J Physiol.
7. Occurrence of LQT3 in childhood
The QT length
prolongers as the age
increases
Graph:
solid bars :-carriers of mutant
Open bars :-non carriers
Source:- Developmental aspects of long QT syndrome type 3
8. Sign and Symptoms
Arrhythmia Clinical features:
Partial or total loss of Long ST segments with
consciousness a late appearing T
wave
Abdominal pain and
Has QTc >490+/- 40 ms
GI complications
10. The SCN5A Gene
Member of the human voltage-gated sodium
channel gene family
Consists of 28 exons and is 80kb long
Sodium channel are responsible for rapid
influx of sodium ions
Highly expressed in cardiac muscle
Encodes a protein of 2016 amino acids
11. Protein Encoded by SCN5A
SCN5A codes for a very large channel protein
Contain 4 homologous domains (DI-DIV)
Each domain contains 6 membrane
spanning segments (S1-S6)
LQT3 is associated with a deletion, missense
and insertion mutation
12. Wang, QING, ZHIZHONG Li, JIAXIANG Shen, and MARK T. Keating. "Genomic Organization of the Human SCN5A Gene Encoding the Cardiac Sodium Channel."
13. Mutations in SCN5A Gene
More than 150 mutations have been reported in
the SCN5A gene
77 mutations are known to have caused
LQT3
Other mutations are associated with Brugada
syndrome.
14. Treatments
Common treatments for Long QT syndrome is
beta blocker therapy. However, LQT3 is less
responsive toward the typical beta blocker.
Clinical treatments have been done to block the
Ina in LQT3 . Sodium channel blockers such as
Mexiletine
Flecainide
15. Treatments
Mexiletine shortens QT interval by 535±32 to 445±31 ms
Both Mexiletine and Flecainide shortens the action
potential duration and decreases the maximum voltage.
At an average Flecainide blood level of .11ug/ml, the QT
shortens by 27.1 milliseconds when compared to placebo
therapy
16. REFERENCES
• Baars, H. F., Smagt, J. J., & Doevendans, P. (2010). Clinical cardiogenetics. (1st ed., p. 149). Springer.
• Bankston, J., & Kass, R. (2010). Molecular determinants of local anesthetic action of beta-blocking drugs: Implications
for therapeutic management of long qt syndrome variant 3. NIH Public Access
• Beinart, R., Michailidis, A., Gurevitz, O., & Gilkson, M. (2009). Is flecainide dangerous in long QT-3 patients? Journal
compilation, 32, 143-145.
• Brisbane, J. (2006 (Updated 2009)). Acce review summary: The long qt-syndrome (lqts). Office of Population Health
Genomics, Government of Western Australia, Department of Health.
• Moss, A., Windle , J., Hall, W., Zareba, W., Robinson, J., McNitt , S., Severski, P, Rosero, S, et al. (2005). Safety and
efficacy of flecainide in subjects with long QT-3 syndrome (ΔKPQ mutation): A randomized, double-blind, placebo-
controlled clinical trial. Annals of Noninvasive Electrocardiology, 10(4), 59-66.
• Ruan, Y., Liu, N., Napolitano, C., & Priori, S. (2008). Therapeutic strategies for Long-QT syndrome: Does the molecular
substrate matter?. Circ Arrhythm Electrophysiol, 1, 290-297.
• Schwartz, P., Priori, S., Locati, E., Napolitano, C., Cantù, F., Towbin, J., Keating, M., & Hammoude, H, et al. (1995).
Long QT syndrome patients with mutations of the
• SCN5A and HERG genes have differential responses to Na channel blockade and to increases in heart rate.
Circulation, (92), 3381-3386.
• Sovari, A. (2012, January 10). Long QT syndrome. Retrieved from http://emedicine.medscape.com/article/157826-
overview
• Wang , H., Zheng, Y., Yang, Z., Li , C., & Liu, Y. (2003). Effect of mexiletine on long QT syndrome model. Chinese
Pharmacological Society, 4, 316-320.
• http://www.wikigenes.org/e/gene/e/6331.html
Editor's Notes
Romano-Ward Syndrome is a form of LQTS. RWS is an autosomal dominant defect that affects 1 in 7000 people in the US, as stated in a 2000 study. RWS patients shows cardiac abnormalities but normal hearing, whereas other forms of LQTS displays hearing loss as a symptom. LQT3 is under the category of Romano-Ward Syndromes. It is not specified how many people die from LQT3 every year, but LQTS is assumed to have caused 4000 deaths in the US alone. The mortality rate of LQTS reaches up to 6% by when patients turn 40.
As we said before, LQT3 is an autosomal dominant disease. It is caused by a mutation in the chromosome 3p21-24.This mutation results in the inactivation gate of the sodium channel to not work properly. It slows down the inactivation gate, so it cannot close, therefore ventricular repolarization is prolonged. This causes the sodium inward current to increase.
This figure shows chromosome 3 and the specific location of LQT3. LQT3 is genetically mapped between D3S1211 and D3S1767.This is the chromosome 3, and LQT3 is located on the p-arm.
LQT1, LQT2, and LQT3 all account for 90% for the patients who suffer from LQTS.This chart (the red box) shows that the percentage of LQT3 among those who have LQTS is between 10-15%. Although, I have read many other studies that have stated that the percentage is around 9, or a range between 7-10%. Either way, the general idea is that LQT3 is not as common as LQT1 and LQT2. In the yellow box, it shows that by the age of 40, 18% of the patients with LQT3 will have a cardiac event (which includes syncope—loss of consciousness, cardiac arrest, or even sudden death). This number is small compared to those of LQT1 and LQT2. BUT the percentage of dying during an event is 20% in LQT3 patients, which is HIGHER than those of LQT1 and LQT2, which is pointed out in the green box.Sleep and rest are triggers for LQT3, therefore the percentage of attacks happening during sleeping or resting is 39%, and 64% of those attacks can be considered as being lethal, which are shown in the blue boxes.
. (A) QT interval for carriers (solid bars) and non-carriers (open bars) in different age groups. (B) ST-segment elevation. Open bars for 0 to 1 year and solid bars for 1 to 3 years are not visible, because the values are 0.0 ± 0.0 mm. Mean ± SD. *p < 0.05.
Long QT due to gain in the inward sodium current QTc calculated using Bazette formula = QT/RR RR=interval between each QRS complex
T-wave morphology (monophasic or multiphasic) Ergometry :- the study of physical work activity, including that performed by specific muscles or muscle groups. The studies may involve testing with equipment such as stationary bicycles, treadmills, or rowing machines
The SCN5A gene stands for sodium channel, voltage-gated, type 5, alpha subunit and it is a member of the human voltage-gates sodium channel family. It consists of 28 exons and it is 80 kilobases long. Since sodium channels are responsible for the rapid influx of sodium ions that initiate and propagate action potentials in most excitable cells, the SCN5A gene is highly expressed in myocardiac muscle but shows little or no expression in skeletal muscle, liver and uterus. It encodes for a large protein of 2016 amino acids with a molecular weight of 227kDa.
The Schematic representation of LQT3 mutation in the sodium channel. As you can see the voltage-gated Na+ channel α-subunit is composed of four homologous domains (DI–DIV), each of which contains 6 putative membrane =spanning segments (S1-S6). The KPQ mutation is localized in the linker between domains III and IV of the channel protein.
Currently, there have been more than 150 mutations reported with the SCN5A gene, mostly in individuals who suffer from LQT3 and Brugada syndrome.LQT3 was localized to chromosome 3 at loci 3p21-24The LTQ type 3 syndrome is associated with a deletion mutation of 3 amino acids, lysine, proline, and glutamine and is refered to as the KPQ mutation and is located at the 1505-1507 positions. There are more mutations associated with LQT 3 in which
Common treatment toward Long QT Syndrome is usually beta blocker therapy. However LQT3 is less responsive toward it. Beta blockers inhibit normal epinephrine mediated sympathetic actions. It prevents the heart from beating fast during exercise or stressful events. Beta-blockers would seem to be a potentially harmful course of treatment because of the slowing of heart rate that accompanies reduced adrenergic input. Sodium channel blockers such as mexiletine and flecainide have been used as treatment instead.
Mexiletine has the ability to shorten the QT interval by being helping block the excess inward sodium current. It can also shorten the action potential duration in a cellular model and decrease the maximum voltage. Mexiletine shortens the QT interval by 535±32 to 445±31 ms.Flecainide is a Ic sodium channel blocker that is mostly used on patients with Brugada Syndrome. It is also used as a long term treatment for LQT3 because it shortens QT interval. Low doses of this drug can perform significant progress. At an average flecainide blood level of .11ug/ml, the QT shortens b 27.1 millisecond when compared to placebo therapy