Category Archives: Physiology

Physiology

Should You Avoid All Alcohol? Here’s What the Experts Think – Healthline

Is alcohol good for you or bad? Does it depend on the quantity?

According to a recent study by a group of scientists at Oxford University in England, theres no safe dose for alcohol consumption.

The observational study looked at data from more than 25,000 middle-aged adults. The study found that moderate consumption is more closely associated with adverse effects on the brain than was previously known. They found that alcohol was negatively associated with global brain gray matter volume. Also, individuals with comorbidities like high blood pressure and a high BMI, or those who binge drink, may be more susceptible to these adverse effects.

For decades, doctors have described moderate drinking a maximum of one drink per day for women and two a day for men as low risk and perhaps even good for health.

But that view appears to be shifting. Last year, an expert advisory committee for the 2020 Dietary Guidelines for Americans recommended that the daily limit be lowered to one drink for men. One drink is said to be equivalent to 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of liquor.

Experts are mixed on the benefits of alcohol, but they are clear on the harm of too much drinking. Binge drinking can increase the risk for high blood pressure, stroke, and congestive heart failure. Experts also agree that alcohol is a proven cause of several kinds of cancer, including breast and liver cancer.

Alcohol is associated with dementia. Even moderate intake can affect brain dementia, said Kenechukwu Mazue, a nuclear cardiology fellow at Massachusetts General Hospital in Boston. Theres really no safe level.

While Mazue has seen studies that suggest that wine may have health benefits, he counsels patients to stay within limits set by the U.S. Department of Health and Human Services.

For those who dont drink, I dont ask them to start because of the potential for alcohol dependency.

Shivendra Shukla, PhD, the Margaret Proctor Mulligan Professor of medical pharmacology and physiology at the University of Missouri in Columbia, warns even a small amount of alcohol can be damaging.

Shukla has researched binge drinking and chronic drinking over the last 25 years.

Alcoholic consumption in any amount is bad, Shukla said. Alcohol has a domino effect. Alcohol is a very mysterious chemical. Once in the body, it has multiple pathways by which it can exert damaging effects. Its just like a cluster bomb. The consequences can be very injurious.

Dr. Jeanette Tetrault, a professor of medicine and addiction specialist at the Yale School of Medicine, takes a more measured view of alcohol consumption.

We know that there are negative health effects related to alcohol consumption, she said. We know there are situations where any drinking can have negative health effects, including for populations such as pregnant women, adolescents. Our messaging as providers needs to be to look at individual circumstances and assess the risk and health effects of individuals. Abstinence-only does not work. Weve seen public health campaigns like that fail in the past.

A message that alcohol is bad and should be avoided at all costs could lead to the loss of a clinical relationship between providers and patients, she said.

Dr. Patricia Molina, professor and head of the Department of Physiology at the Louisiana State University School of Medicine in New Orleans, shares a similar view. Yes, alcohol use in certain populations such as those with chronic diseases should be discouraged, said Molina, a physician and past president of the American Physiological Society.

The message should be alcohol consumption in moderation, said Molina. The pattern of consumption can have a significant impact on health. Talk with a physician if you have a chronic disease.

Follow this link:
Should You Avoid All Alcohol? Here's What the Experts Think - Healthline

Physiology

Naval aviation bridges medicine, engineering to advance aerospace tech – The Southern Maryland Chronicle

NAVAL AIR WARFARE CENTER AIRCRAFT DIVISION, (Patuxent River, Md.) The Naval Air Warfare Center Aircraft Division (NAWCAD) is advancing its human systems technology by combining best practices from the medical and engineering communities.

The warfare center recently stood up the Aeromedical Monitoring and Analysis branch comprised of licensed medical military officers bridging their perspective with engineering disciplines to improve operational capabilities like night vision technology, hearing protection, mission planning software, and more.

Medicine and engineering seldom wholly come together, said NAWCAD Aeromedical Monitoring and Analysis branch head Cmdr. Matthew Doubrava, a Navy Flight Surgeon board certified in Aerospace Medicine and Occupational Medicine. Our team of biomedical scientists looks forward to bringing human oriented science and a medical perspective to enhance our Navys advanced technology.

The uniformed medical specialists have a broad range of academic expertise including aerospace and occupation medicine, optometry and vision science, audiology, research and aviation physiology, and experimental psychology. With these skillsets, they will work directly alongside NAWCAD engineers, testers, and aviators to enhance their research, development, tests, and evaluation to advance aerospace technology. Adding this expertise will help create technology more relevant to human capability, and fill knowledge gaps where technical professionals typically hold little experience.

The Navys challenge with physiological episodes showed us how critically important a medical perspective can be, said Doubrava. Were working to stay ahead of the curve what is the next physiological episode on the horizon and how can we prevent it?

NAWCADs lineup of clinical scientists completed health care professional and graduate school, and entered the Navy to receive specialized training as aeromedical and research professionals. Most attended the six-month Aeromedical Officer Course that consists of a specialized flight school syllabus and clinical training in Pensacola, Florida. As an aeromedical officer, they hold a Navy aeronautical rating that requires a monthly minimum of aircrew flight time making them uniquely qualified as aeromedical professionals. While their primary mission is medical research, they are required to accrue flight time with fleet aviators for continued understanding of naval aviations evolving systems.

NAWCAD advances capability and operational readiness for naval aviation and our warfighters. The warfare center is where naval aviation takes flight through research, development, test, evaluation, and sustainment of both fielded and not-yet fielded naval platforms and technologies that ensure Americas Sailors and Marines always go into conflict with significant advantage. With sites in Patuxent River, Maryland, Lakehurst, New Jersey, and Orlando, Florida, the command is the Navys largest warfare center with a diverse force of military, civilians, and contractors building the Navy of today, the Navy of tomorrow, and the Navy after next.

Like Loading...

Related

See the original post here:
Naval aviation bridges medicine, engineering to advance aerospace tech - The Southern Maryland Chronicle

Physiology

Gene therapy for overactive bladder | TCRM – Dove Medical Press

Introduction

Overactive bladder (OAB) is a disorder characterized by urgency and frequency with and without urinary incontinence. It affects 15% to 25% of the general population older than 40 years of age.15 Current guidelines recommend non-subtypeselective oral antimuscarinics or 3-adrenergic receptor agonists as primary pharmacotherapy.68 Although these agents modulate the neurotransmitter-mediated signals that cause OAB-related symptoms,9 some, such as anticholinergics, are associated with challenging adverse effects that limit compliance, and they may not be effective in all patients.611 Chemodenervation agents may improve symptoms with similar or even greater efficacy compared with oral agents; however, treatment with botulinum toxin may result in unwanted post-procedural outcomes such as urinary retention and urinary tract infections. Other treatments for OAB are limited by cost and invasiveness, require general anesthesia (eg, sacral neuromodulation), or have limited efficacy and require inconvenient weekly treatment sessions (eg, percutaneous tibial nerve stimulation).12 Thus, while bladder-targeted treatments are available, there remains an unmet need for locally administered interventions to treat OAB.

The large-conductance, voltage- and calcium-activated K+ channel, known as the big potassium (BK) or Maxi-K channel, is highly expressed on urinary bladder smooth muscle cells and regulates bladder detrusor muscle function.13 BK channel activation reduces smooth muscle cell excitability, and therefore modulation of this channels activity by the introduction of a locally instilled plasmid expressing the BK channel is a potential novel approach to OAB treatment. This article reviews the physiological importance and regulation of the BK channel in the bladder, as well as the potential of BK channel modulation with gene therapy in the management of OAB.

When functioning normally, the bladder has a change in internal volume from nearly zero to >400 mL during its filling cycle.14 During voluntary or involuntary voiding, the detrusor smooth muscle cells go from a state of low tension to a rapid contraction in order to empty the bladder. Detrusor smooth muscle is organized in contractile units in a syncytium connected by gap junctions that facilitate the spread of contractile function throughout the detrusor muscle tissue.15 These contractile units show spontaneous depolarizations leading to uncoordinated contractile activity that has little effect on intravesical pressure but is essential for maintaining tone of the bladder wall.16 The spontaneous activity in turn generates afferent nerve activity and the sensation of bladder filling.17,18 Increases in the spontaneous activity leading to increased afferent nerve activity have been considered important in the generation of OAB symptoms.

In order to produce an emptying contraction, coordination of the activity of the muscle units is necessary, and this is provided by excitatory input from the parasympathetic system.17 Bladder emptying contraction is initiated by a massive release of acetylcholine from the pelvic nerve, which stimulates muscarinic (M3) receptors on the detrusor smooth muscle cell, and triggers an intracellular signaling cascade that leads to simultaneous membrane depolarization of all detrusor muscle cells. This results in the opening of voltage-dependent Ca2+ channels at the cell surface and a massive influx of extracellular calcium. High intracellular Ca2+ is sensed by calmodulin, an intracellular messenger protein, which leads to the activation of myosin light chain kinase and muscle contraction.17

Relaxation of detrusor smooth muscle cells is mediated, at least in part, when K+ channels open to allow the efflux of K+ ions, and hyperpolarization of the cell membrane is produced, leading to diminished intracellular calcium levels and reduction of the spontaneous activity and thus reduced detrusor muscle tone.13 This mechanism operates during the filling phase, when OAB symptoms are experienced, and has no effect on the emptying contraction. Thus, restoration/maintenance of the endogenous ionic mechanisms that govern smooth muscle cell tone, through targeted gene therapy, is an attractive approach to the treatment of any disease or disorder characterized by altered smooth muscle cell physiologyincluding OAB. The BK or Maxi-K channel is the K channel subtype most responsible for creating and maintaining the cells resting membrane potential.

Gene therapy can be used to treat diseases and conditions such as OAB. Specifically, we suggest that tissue or organ-specific overexpression of key modulators of smooth muscle function can mitigate pathophysiological features of diseases as diverse as hypertension, asthma, irritable bowel, erectile dysfunction, and OAB. The explicit scientific rationale, in the case of the bladder, is driven by the supposition that targeted, locally delivered, gene therapy can address the pathophysiological changes in molecular and biochemical pathways that result in dysfunctional control of detrusor smooth muscle tone, which in turn, manifests as OAB.

In this scenario, gene therapy can be used to restore, reduce, or enhance the expression of the normal gene products that control key cellular actions.19 Aging and disease can modify normal gene expression, for example, by elaboration of splice variants whose downstream products alter normal cellular physiology to result in dysfunctional bladder control. The introduction of carefully selected genes into a significant fraction of affected cells can return the cells and organs to more normal physiology and function.

The bladder is notably amenable to such an approach for 3 main reasons. First, the bladder is readily accessible via the urethra for delivery of therapeutic genes to the urothelium, neural network, and/or underlying detrusor myocytes.20,21 Second, therapeutic administration is local, and thus the main part of the corresponding activity should be confined to the bladder. In fact, these 2 points have recently been demonstrated in pilot clinical studies of naked DNA gene therapies for OAB, which have produced no evidence of systemic effects.22 Third, relatively modest transfection efficiency can be therapeutically tolerated, as the bladders myocytes communicate with each other through intercellular channels, referred to as gap junctions. This latter mechanism leverages the important role that gap junctions play in the coordinated contractile responses mediated by the extant syncytial smooth muscle cell network to ensure complete bladder emptying upon appropriate parasympathetic activation.15,20 More specifically, although only a small proportion of myocytes might incorporate and express the therapeutic naked DNA gene, the presence of an intercellular network of gap junctions allows corrective changes in gene expression to facilitate passage of current-carrying ions and secondary messenger molecules from cell to cell throughout the bladder wall.23

Again, it appears that the large-conductance, voltage- and calcium-activated BK (Maxi-K) channel is the K channel subtype most responsible for creating and maintaining the cells resting membrane potential.13 The BK channel consists of a tetramer of pore-forming -subunits that are typically surrounded by modulatory -subunits.24,25 The -subunit is encoded by a single gene called Slo or KCNMA1 that is located on the long arm of chromosome 10.26 Activation by either membrane depolarization or increased intracellular Ca2+ increases the permeability of the BK channel permitting outward K+ efflux across the cell membrane down the electrochemical gradient, resulting in hyperpolarization and reduced cellular excitability (Figure 1). Since increased myogenic activity may contribute to bladder overactivity, increasing the number of BK channels (via gene transfer) has a rational scientific basis.

Figure 1 Schematic depiction of the central role of the BK channel in regulation of myogenic tone in bladder smooth muscle. As shown, detrusor smooth muscle exhibits spontaneous myogenic contractile activity (spikes) associated with depolarizations. The depolarizations are associated with Ca2+ influx via voltage-dependent calcium channels (VDCCs). Ca2+-induced Ca2+ release from the sarcoplasmic reticulum activates BK channels via sparks, but BK channels are also activated via more global increases in intracellular calcium, and eventually the cell is repolarized. The repolarization closes (temporarily) the VDCC, and spike activity is reduced.

Overall, the BK channels in bladder smooth muscle act to promote detrusor relaxation and limit the amplitude and duration of spontaneous or nerve-induced detrusor contraction.13 Several lines of evidence suggest the importance of BK channels for modulating and sustaining the bladders resting state. In normal detrusor smooth muscle, the BK channel is expressed at high levels.27,28 In fact, the conductance of the BK channelthat is, the rate of K+ ions passing through the channelis an order of magnitude greater than the conductance of other K+ channels.29 The BK channel is therefore unique among K+ channels in its responsiveness either to membrane depolarization or a rise in intracellular calcium, enabling it to integrate these contraction-governing signals.13 Consistent with these electrophysiological properties, in mice, for example, knockout of BK channel -subunits is associated with increased detrusor contractility and urination frequency.30 In mouse bladder myocytes, deletion of the BK -subunit or pharmacologic blockade of transient BK currents is sufficient to depolarize the cell membrane.31,32

Ion channel dysfunction, often referred to as channelopathy, is often associated with disorders of smooth muscle.33 In the case of the BK channel, mutations, splice variants, or low levels of channel expression in bladder myocytes would be expected to lead to increased intracellular Ca2+ levels and abnormal responsiveness to cholinergic signaling.13,34 Using detrusor smooth muscle tissue samples obtained from 33 patients during open bladder surgeries, neurogenic detrusor overactivity was associated with decreased BK channel expression and function, leading to increased detrusor smooth muscle excitability and contractility.35 BK channel dysfunction may also heighten the responsiveness of the central nervous system to sensory signals from the bladder, a phenomenon called central sensitization, which appears to occur in illnesses such as irritable bowel syndrome and fibromyalgia.36 High levels of gap junction expression would likewise be expected to make the bladder smooth muscle cells hypersensitive to cholinergic stimulation, presumably due to excessive diffusion of Ca2+ ions among detrusor coupled myocytes.15,3739 Indeed, upregulation of connexin 43, a predominant connexin protein expressed in human bladder gap junctions, has been identified in patients with urgency incontinence.32

The use of gene therapy to treat bladder dysfunction may have intrinsic advantages over conventional pharmacotherapies when the therapeutic target is subject to epigenetic modification. It was recently demonstrated that diabetes results in epigenetic changes in the methylation pattern of the detrusor genome which are mostly, but not entirely, normalized with glycemic control.40 This phenomenon is known as hyperglycemic memory and would likely contribute to the persistence of bladder dysfunction even in diabetic patients that achieve glycemic control. The KCNMA1 gene (encoding the BK channel, -subunit) was identified in the subset of genes encoded by genomic loci that had modulated methylation patterns with diabetes that were not reversed with glycemic control. The changes in methylation pattern correlated with expression of the BK channel -subunit protein; its expression was downregulated with diabetes that was not reversed with insulin treatment. Although decreased expression and activity of KCNMA1 in the diabetic bladder has been reported (and used to support targeting BK channel activity to treat diabetic bladder dysfunction), expression was previously not known to be subject to hyperglycemic memory. Gene therapy overcomes hyperglycemic memory by introducing exogenous DNA into the bladder that has not been subject to epigenetic modification, restoring BK channel activity. In contrast, pharmacologic approaches to increase BK channel activity in the bladder of diabetic patients, even patients who have achieved glycemic control, would have no target to act on, or have such low levels of expression that activation is insufficient for physiological effect. Therefore, the strategy of increasing BK channel activity to treat patients with bladder dysfunction involving epigenetic modification will be more effective using gene therapy (which overexpress the KCNMA1 gene) than the use of pharmacologic agents (which may have no or little target to activate).

Gene therapies are often designed for the purpose of gene augmentation or the introduction of a functional gene into a cell with deficient expression of the desired gene product.19 To ensure sufficient expression, the gene delivery system must permit uptake by the targeted cells, protect the exogenous nucleic acid from degradation by host-cell nuclease enzymes, and ensure intracellular transport of the gene to the cell nucleus. To these ends, viral vectors have often been used. However, viral-based gene therapy has been associated with severe adverse events and risk of mortality, leading to increased investigations of non-viral vectors.19,41,42

Naked plasmid DNA (pDNA) is one such non-viral vector option. Naked pDNA is significantly less immunogenic relative to viral and retroviral vectors.43 Further, naked pDNA has less potential for integration into the host cells genome, thereby reducing the risk of adverse events associated with insertional mutagenesis, position-effect variegation, or inflammatory immune responses.41,44 However, gene transfer via naked pDNA is also limited by low transfection efficiency and transient expression of the transgene, necessitating the administration of large quantities of the vector.41 Organs and systems successfully targeted by naked pDNA in preclinical and clinical studies have included the heart, central nervous system, pancreas, penis, and skeletal muscle.41,4547

URO-902 is a 6880-base-pair naked pDNA incorporating a DNA sequence synthesized from the messenger RNA (mRNA) that encodes the human BK channel -subunit (Figure 2).21,48 To ensure robust expression of the encoded protein in eukaryotic cells, the -subunit code is flanked at its upstream end by a CMV promoter (from cytomegalovirus) to initiate DNA transcription and at its downstream end by a polyadenylation signal (from the bovine growth hormone gene) to terminate transcription and protect the transcript from enzymatic degradation. In addition, the plasmid incorporates sequences that are frequently used in plasmid construction to facilitate its selection and replication in Escherichia coli cultures. None of the modules enable the plasmid to replicate in eukaryotic cells, thereby confining the treatment to targeted cells transfected with the plasmid.

Figure 2 The URO-902 plasmid construct. For further construct details, see Melman et al.48 BGH, bovine growth hormone; CMV, cytomegalovirus.

Within targeted cells, URO-902 enters the cell presumably via endocytosis and then transits the cell nucleus through a nuclear pore. The type of plasmid promoter driving BK expression determines which cells will express the protein. URO-902 uses a CMV promoter, which is a nonspecific promoter that is active in all cells. Smooth muscle cellspecific promoters, such as the smooth muscle -actin (SMAA) promoter, also have been incorporated into the plasmid backbone and were shown to be physiologically active.49,50 In the nucleus, pDNA for the BK -subunit is transcribed by the host cell into an mRNA, which is translated into protein in the cytoplasm. The expressed BK -subunit channels are then inserted into the cell membrane via the cells endogenous machinery. Reverse transcription polymerase chain reaction (RT-PCR) measures show that the gene is expressed in erectile smooth muscle for up to 6 months.51 The hypothesis underlying the development of URO-902 as a gene therapy for OAB is that increased expression of BK channels in bladder myocytes may enhance the cellular capacity to expel K+ ions, promoting membrane hyperpolarization and reducing excitability (Figure 1). The resulting smooth muscle relaxation would be expected to reduce the symptoms associated with OAB.

Transfer of DNA encoding the BK channel -subunit was first tested as a potential treatment for erectile dysfunction.21 In 2 rat models, intracavernosal injection of a plasmid incorporating the -subunit gene yielded improvement in the ratio of intracavernous pressure to systemic arterial blood pressure.5153 A dose-dependent effect on erectile response to cavernous nerve stimulation was seen for up to 6 months. Improvement in erectile function also was identified in atherosclerotic male cynomolgus monkeys, where intracorporal BK channel gene transfer also enhanced sexual behaviorimplying that erectile function per se may lead to increased sexual function.49

In a phase 1 safety study, 11 men with severe erectile dysfunction who were unresponsive to pharmacotherapy but otherwise in good health were treated with open-label URO-902 administered as a single dose by intracavernosal injection.47,48 The tested dose levels were 0.5, 1, 5, and 7.5 mg. Patients were monitored for 6 months with annual follow-up for 2 years. The therapy was well tolerated, with no adverse events considered to be gene-transfer-related and no clinically significant changes in physical, laboratory, or electrocardiographic parameters. Semen samples obtained up to 4 weeks after URO-902 dosing showed no evidence of the plasmid. At the 2 highest doses, a clinical response persisted throughout the 6-month study period. A phase 2 study in 26 men confirmed the tolerability of URO-902, with all events being mild and considered not related to study drug.54

To evaluate potential use in OAB, preclinical research established the ability of bladder instillation of pDNA encoding the BK -subunit to ameliorate the bladder overactivity observed in rats following partial urethral obstruction.55 These studies were followed by phase 1 safety studies of female patients with OAB.22 In each of 2 such trials, the participants were otherwise healthy, non-fertile women with non-neurogenic (idiopathic) OAB and associated detrusor overactivity of at least 6-month duration (Table 1). Moreover, study participants were required to document at least 8 micturitions per day and at least 5 urgency urinary incontinence episodes per week at baseline, without clinically significant stress incontinence. Each woman received a single double-blind dose of URO-902 or placebo administered by intravesical instillation in one trial (ION-02 [NCT00495053]) and by direct detrusor injection in another trial (ION-03 [NCT01870037]). For instilled URO-902, the tested dose levels were 5 and 10 mg. For injected URO-902, dose levels were 16 and 24 mg divided among 20 to 30 injection sites. Patients were assessed and monitored for 6 months with periodic follow-up for an additional 18 months.

Table 1 Baseline Characteristics by Study Drug Treatment in Women Participating in Phase 1 URO-902 Trials

In ION-02 (intravesical installation), the 90-mL dose of URO-902 was instilled through a small-diameter catheter into the lumen of the bladder, and patients were requested to retain the solution in the bladder for at least 2 hours.22 In ION-03 (direct injection), URO-902 was injected approximately 2 mm into the detrusor muscle with a BoNee needle through a rigid cystoscope, without general or regional anesthesia, and 20 injections of either 0.2 mL (16-mg dose) or 30 injections of 0.2 mL (24-mg dose) each were spaced approximately 1 cm apart.22 Prior to direct injection, 40 mL of 2% lidocaine was instilled into the bladder, and 10 mL of 2% xylocaine gel was instilled into the urethra.

In both studies, few treatment-related adverse events were noted. Of 34 participants in both studies, only 3 had treatment-related adverse events, and 1 of those patients received placebo. Furthermore, there were no adverse events leading to an early withdrawal from the study (Tables 2 and 3).22 One serious adverse event was reported in ION-03: exacerbation of pre-existing asthma in a patient treated with 16 mg URO-902. This event was not considered related to the investigational agent. Across both trials, no patients experienced urinary retention as a reported adverse event.22

Table 2 Reported Adverse Events by Study Drug Treatment Among Women Participating in the Phase 1 ION-02 URO-902 Trial

Table 3 Reported Adverse Events by Study Drug Treatment Among Women Participating in the Phase 1 ION-03 URO-902 Trial

Among the 16 women receiving URO-902 by instillation, post-dose urine samples showed no evidence of the plasmid.22 Among the 9 women receiving URO-902 by injection, post-dose samples obtained after dosing detected the plasmid in the urine of 4 patients and in the blood of 1 patient 15 minutes after dosing. There was no evidence of the plasmid in later samples.22

In both ION-02 and ION-03, the efficacy of URO-902 for the treatment of OAB was assessed by several endpoints.22 In ION-02, patients receiving URO-902 by intravesical instillation exhibited no significant changes in the mean number of voids or urgency incontinence episodes at either dose. Nevertheless, several efficacy signals were detected. Across URO-902 recipients, the mean reduction in detrusor contractions from baseline to week 24 was trending toward significance (P<0.0508). At week 8, the 5-mg subgroup showed a >40% mean reduction in urgency incontinence episodes.22

In ION-03, URO-902 administered by direct detrusor injection showed greater efficacy compared with results of ION-02.22 Improvement of OAB manifestations included a dose-dependent reduction in the mean number of micturitions and urgency episodes per day, with statistical significance versus placebo for the 24-mg dose at post-dose time points including weeks 12 and 24 (Figure 3A and B). These improvements were accompanied by a decrease in urgency incontinence episodes per day, with dose dependence observed at week 24 (Figure 3C). For micturitions per day and urgency episodes per day, the mean improvement at both URO-902 doses was statistically significant versus placebo at week 1, whereas placebo recipients showed no improvement throughout the trial. In future trials, these higher doses of URO-902 may lead to further improved response. URO-902 recipients also reported improvements versus baseline in quality of life (QoL) as measured by the Kings Health Questionnaire, a healthrelated QoL instrument specific for urinary incontinence. At multiple post-dose visits, statistically significant improvements were reported in domain scores measuring impact on life, physical limitations, role limitations, social limitations, and sleep/energy.22

Figure 3 Mean changes from baseline in (A) micturitions, (B) urgency episodes, and (C) UUI episodes by treatment group during the ION-03 study of URO-902.22 Data on file from Dr. Melman. *P<0.05 versus placebo. P values are derived from a linear mixed model with the number of urgency episodes or number of voids as dependent variables, treatments, time point, and interaction of time and treatment.

Abbreviations: BL, baseline; SE, standard error; UUI, urge urinary incontinence.

It has been demonstrated that large molecular weight proteins, such as nerve growth factor, botulinum toxin,56 and wheat germ agglutinin conjugated to horseradish peroxidase,57 are capable of retrograde transport to dorsal root ganglia from intradetrusor injection sites. A similar transport of the injected plasmid in ION-03 is possible, and, provided that this is the case, a contribution to the lack of dose dependence in toxicity and in efficacy cannot be excluded. However, in a recently published study,58 it was the absence of the BK channel and not increased expression that resulted in decreased neuromuscular transmission. Additionally, because URO-902 uses a nonspecific promoter, it is possible that there may be an effect on neurons in the bladder.

As different injection techniques and doses were used for delivery of URO-902 in ION-02 and ION-03, results from these studies cannot be compared. At present, it is not known whether direct detrusor injection or intravesical instillation will yield the best gene expression in patients with OAB, nor is it established which technique may ultimately be more effective at reducing the symptoms of OAB. As long-term animal studies may pose challenges with multiple survival surgeries, further in-human studies are required to optimize and refine the use of URO-902.

Among transmembrane ion channels in bladder smooth muscle cells, the BK channel has a particularly crucial role in modulating smooth muscle excitability and thus detrusor tone and contraction. The rationale for URO-902 as a gene therapy for OAB is that enhanced expression of BK channel -subunits in bladder myocytes may decrease detrusor smooth muscle cell excitability leading to decreased afferent activity. In turn, this leads to decreased urgency, urinary frequency, and urge urinary incontinence. In preclinical research, gene transfer via naked pDNA encoding the BK channel -subunit led to improvement in animal models of detrusor overactivity. In adult female patients with OAB, secondary analyses of efficacy endpoints suggested sustained benefits through 24 weeks of post-dose monitoring, especially with direct detrusor injection of the gene therapy, which were accompanied by improvements in QoL. These findings warrant continued investigation of URO-902 in larger-scale clinical studies.

Medical writing and editorial support was provided to the authors by The Curry Rockefeller Group, LLC, Tarrytown, NY, and was funded by Urovant Sciences.

ION-03 was supported in part by National Institute on Aging grant R44DK093279. Urovant Sciences provided funding for medical writing and editorial support, which was provided by The Curry Rockefeller Group, LLC.

K-EA has nothing to disclose. GJC is co-founder, director, and shareholder of Ion Channel Innovations, LLC, and has a US Patent Application Appl. No. 16/612286; 371(c) Date: November 8, 2019 (US National Phase of Intl Appl. No. PCT/US2018/032574; Intl Filing Date: May 14, 2018) For: Compositions And Methods For Treating Idiopathic Overactive Bladder Syndrome And Detrusor Overactivity, pending to Urovant. KD is a shareholder of Ion Channel Innovations, LLC, and received research funds from Urovant. ER reports relationships with Ion Channel Innovations, LLC, during the conduct of the study and with Urovant in the form of consulting honoraria. AM reports an NIH grant for Ion Channel Innovations, LLC, and consultant relationship with Urovant; he was co-founder of Ion Channel Innovations, LLC.

1. Abrams P, Artibani W, Cardozo L, et al. Reviewing the ICS 2002 terminology report: the ongoing debate. Neurourol Urodyn. 2009;28(4):287. doi:10.1002/nau.20737

2. Van Kerrebroeck P, Abrams P, Chaikin D, et al. The standardization of terminology in nocturia: report from the standardization subcommittee of the International Continence Society. BJU Int. 2002;90(suppl 3):1115. doi:10.1046/j.1464-410X.90.s3.3.x

3. Reynolds WS, Fowke J, Dmochowski R. The burden of overactive bladder on US public health. Curr Bladder Dysfunct Rep. 2016;11(1):813. doi:10.1007/s11884-016-0344-9

4. Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003;20(6):327336. doi:10.1007/s00345-002-0301-4

5. Irwin DE, Kopp ZS, Agatep B, Milsom I, Abrams P. Worldwide prevalence estimates of lower urinary tract symptoms, overactive bladder, urinary incontinence and bladder outlet obstruction. BJU Int. 2011;108(7):11321138. doi:10.1111/j.1464-410X.2010.09993.x

6. Gormley EA, Lightner DJ, Burgio KL, et al. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline. J Urol. 2012;188(6 Suppl):24552463.doi:10.1016/j.juro.2012.09.079

7. Lightner DJ, Gomelsky A, Souter L, Vasavada SP. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline amendment 2019. J Urol. 2019;202(3):558563. doi:10.1097/ju.0000000000000309

8. Maman K, Aballea S, Nazir J, et al. Comparative efficacy and safety of medical treatments for the management of overactive bladder: a systematic literature review and mixed treatment comparison. Eur Urol. 2014;65(4):755765.doi:10.1016/j.eururo.2013.11.010

9. Yamada S, Ito Y, Nishijima S, Kadekawa K, Sugaya K. Basic and clinical aspects of antimuscarinic agents used to treat overactive bladder. Pharmacol Ther. 2018;189:130148.doi:10.1016/j.pharmthera.2018.04.010

10. Yeowell G, Smith P, Nazir J, Hakimi Z, Siddiqui E, Fatoye F. Real-world persistence and adherence to oral antimuscarinics and mirabegron in patients with overactive bladder (OAB): a systematic literature review. BMJ Open. 2018;8(11):e021889. doi:10.1136/bmjopen-2018-021889

11. Coupland CAC, Hill T, Dening T, Morriss R, Moore M, Hippisley-Cox J. Anticholinergic drug exposure and the risk of dementia: a nested case-control study. JAMA Intern Med. 2019;179(8):10841093. doi:10.1001/jamainternmed.2019.0677

12. Lo C-W, Wu M-Y, Yang SS-D, Jaw F-S, Chang S-J. Comparing the efficacy of onabotulinumtoxinA, sacral neuromodulation, and peripheral tibial nerve stimulation as third line treatment for the management of overactive bladder symptoms in adults: systematic review and network meta-analysis. Toxins. 2020;12(2):128. doi:10.3390/toxins12020128

13. Petkov GV. Central role of the BK channel in urinary bladder smooth muscle physiology and pathophysiology. Am J Physiol Regul Integr Comp Physiol. 2014;307(6):R571584. doi:10.1152/ajpregu.00142.2014

14. Lukacz ES, Sampselle C, Gray M, et al. A healthy bladder: a consensus statement. Int J Clin Pract. 2011;65(10):10261036. doi:10.1111/j.1742-1241.2011.02763.x

15. Wang H-Z, Brink PR, Christ GJ. Gap junction channel activity in short-term cultured human detrusor myocyte cell pairs: gating and unitary conductances. Am J Physiol Cell Physiol. 2006;291(6):C13661376. doi:10.1152/ajpcell.00027.2006

16. Andersson K-E. Detrusor myocyte activity and afferent signaling. Neurourol Urodyn. 2010;29(1):97106. doi:10.1002/nau.20784

17. Andersson K-E, Arner A. Urinary bladder contraction and relaxation: physiology and pathophysiology. Physiol Rev. 2004;84(3):935986. doi:10.1152/physrev.00038.2003

18. Chakrabarty B, Bijos DA, Vahabi B, et al. Modulation of bladder wall micromotions alters intravesical pressure activity in the isolated bladder. Front Physiol. 2019;9:1937. doi:10.3389/fphys.2018.01937

19. Anguela XM, High KA. Entering the modern era of gene therapy. Annu Rev Med. 2019;70(1):273288. doi:10.1146/annurev-med-012017-043332

20. Christ GJ, Hodges S. Molecular mechanisms of detrusor and corporal myocyte contraction: identifying targets for pharmacotherapy of bladder and erectile dysfunction. Br J Pharmacol. 2006;147(Suppl S2):S4155. doi:10.1038/sj.bjp.0706627

21. Melman A, Davies K. Gene therapy for erectile dysfunction: what is the future? Curr Urol Rep. 2010;11(6):421426. doi:10.1007/s11934-010-0145-1

22. Rovner E, Chai TC, Jacobs S, et al. Evaluating the safety and potential activity of URO-902 (hMaxi-K) gene transfer by intravesical instillation or direct injection into the bladder wall in female participants with idiopathic (non-neurogenic) overactive bladder syndrome and detrusor overactivity from two double-blind, imbalanced, placebo-controlled randomized phase 1 trials. Neurourol Urodyn. 2020;39(2):744753. doi:10.1002/nau.24272

23. Campos de Carvalho AC, Roy C, Moreno AP, et al. Gap junctions formed of connexin43 are found between smooth muscle cells of human corpus cavernosum. J Urol. 1993;149(6):15681575. doi:10.1016/S0022-5347(17)36455-8

24. Knaus HG, Garcia-Calvo M, Kaczorowski GJ, Garcia ML. Subunit composition of the high conductance calcium-activated potassium channel from smooth muscle, a representative of the mSlo and slowpoke family of potassium channels. J Biol Chem. 1994;269(6):39213924. doi:10.1016/S0021-9258(17)41720-0

25. Latorre R, Castillo K, Carrasquel-Ursulaez W, et al. Molecular determinants of BK channel functional diversity and functioning. Physiol Rev. 2017;97(1):3987. doi:10.1152/physrev.00001.2016

26. Tseng-Crank J, Foster CD, Krause JD, et al. Cloning, expression, and distribution of functionally distinct Ca2+-activated K+ channel isoforms from human brain. Neuron. 1994;13(6):13151330. doi:10.1016/0896-6273(94)90418-9

27. Petkov GV, Bonev AD, Heppner TJ, Brenner R, Aldrich RW, Nelson MT. 1-Subunit of the Ca2+-activated K+ channel regulates contractile activity of mouse urinary bladder smooth muscle. J Physiol. 2001;537:443452. doi:10.1111/j.1469-7793.2001.00443.x

28. Ohi Y, Yamamura H, Nagano N, et al. Local Ca2+ transients and distribution of BK channels and ryanodine receptors in smooth muscle cells of guinea-pig vas deferens and urinary bladder. J Physiol. 2001;534:313326. doi:10.1111/j.1469-7793.2001.t01-3-00313.x

29. Latorre R, Miller C. Conduction and selectivity in potassium channels. J Membr Biol. 1983;71(12):1130. doi:10.1007/BF01870671

30. Meredith AL, Thorneloe KS, Werner ME, Nelson MT, Aldrich RW. Overactive bladder and incontinence in the absence of the BK large conductance Ca2+-activated K+ channel. J Biol Chem. 2004;279(35):3674636752. doi:10.1074/jbc.M405621200

31. Mimata H, Nomura Y, Emoto A, Latifpour J, Wheeler M, Weiss RM. Muscarinic receptor subtypes and receptor-coupled phosphatidylinositol hydrolysis in rat bladder smooth muscle. Int J Urol. 1997;4(6):591596. doi:10.1111/j.1442-2042.1997.tb00315.x

32. Neuhaus J, Pfeiffer F, Wolburg H, Horn L-C, Dorschner W. Alterations in connexin expression in the bladder of patients with urge symptoms. BJU International. 2005;96(4):670676. doi:10.1111/j.1464-410X.2005.05703.x

33. Bailey CS, Moldenhauer HJ, Park SM, Keros S, Meredith AL. KCNMA1-linked channelopathy. J Gen Physiol. 2019;151(10):11731189. doi:10.1085/jgp.201912457

34. Davies KP, Zhao W, Tar M, et al. Diabetes-induced changes in the alternative splicing of the slo gene in corporal tissue. Eur Urol. 2007;52(4):12291237. doi:10.1016/j.eururo.2006.11.028

35. Hristov KL, Afeli SAY, Parajuli SP, Cheng Q, Rovner ES, Petkov GV. Neurogenic detrusor overactivity is associated with decreased expression and function of the large conductance voltage- and Ca2+-activated K+ channels. PLoS One. 2013;8(7):e68052. doi:10.1371/journal.pone.0068052

36. Reynolds WS, Dmochowski R, Wein A, Bruehl S. Does central sensitization help explain idiopathic overactive bladder? Nat Rev Urol. 2016;13(8):481491.doi:10.1038/nrurol.2016.95

37. Zhou F, Li H, Zhou C, et al. Structural and functional changes in gap junctional intercellular communication in a rat model of overactive bladder syndrome induced by partial bladder outlet obstruction. Exp Ther Med. 2016;11(6):21392146.doi:10.3892/etm.2016.3246

38. Okinami T, Imamura M, Nishikawa N, et al. Altered detrusor gap junction communications induce storage symptoms in bladder inflammation: a mouse cyclophosphamide-induced model of cystitis. PLoS One. 2014;9(8):e104216.doi:10.1371/journal.pone.0104216

39. Imamura M, Negoro H, Kanematsu A, et al. Basic fibroblast growth factor causes urinary bladder overactivity through gap junction generation in the smooth muscle. Am J Physiol Renal Physiol. 2009;297(1):F4654.doi:10.1152/ajprenal.90207.2008

40. Wang Y, Tar MT, Davies KP. Hyperglycemic memory in the rat bladder detrusor is associated with a persistent hypomethylated state. Physiol Rep. 2020;8:e14614.doi:10.14814/phy2.14614

41. Jayant RD, Sosa D, Kaushik A, et al. Current status of non-viral gene therapy for CNS disorders. Expert Opin Drug Deliv. 2016;13(10):14331445.doi:10.1080/17425247.2016.1188802

42. Chira S, Jackson CS, Oprea I, et al. Progresses towards safe and efficient gene therapy vectors. Oncotarget. 2015;6(31):3067530703.doi:10.18632/oncotarget.5169

43. Hardee CL, Arvalo-Soliz LM, Hornstein BD, Zechiedrich L. Advances in non-viral DNA vectors for gene therapy. Genes. 2017;8(2):65. doi:10.3390/genes8020065

44. Athanasopoulos T, Munye MM, Yanez-Munoz RJ. Nonintegrating gene therapy vectors. Hematol Oncol Clin North Am. 2017;31(5):753770.doi:10.1016/j.hoc.2017.06.007

45. Hagstrom JE, Hegge J, Zhang G, et al. A facile nonviral method for delivering genes and siRNAs to skeletal muscle of mammalian limbs. Mol Ther. 2004;10(2):386398. doi:10.1016/j.ymthe.2004.05.004

46. Yamada Y, Tabata M, Abe J, Nomura M, Harashima H. In vivo transgene expression in the pancreas by the intraductal injection of naked plasmid DNA. J Pharm Sci. 2018;107(2):647653.doi:10.1016/j.xphs.2017.09.021

47. Melman A, Bar-Chama N, McCullough A, Davies K, Christ G. hMaxi-K gene transfer in males with erectile dysfunction: results of the first human trial. Hum Gene Ther. 2006;17(12):11651176.doi:10.1089/hum.2006.17.1165

48. Melman A, Bar-Chama N, McCullough A, Davies K, Christ G. The first human trial for gene transfer therapy for the treatment of erectile dysfunction: preliminary results. Eur Urol. 2005;48(2):314318.doi:10.1016/j.eururo.2005.05.005

49. Christ GJ, Andersson KE, Williams K, et al. Smooth-muscle-specific gene transfer with the human maxi-K channel improves erectile function and enhances sexual behavior in atherosclerotic cynomolgus monkeys. Eur Urol. 2009;56(6):10551066.doi:10.1016/j.eururo.2008.12.016

50. Melman A, Biggs G, Davies K, Zhao W, Tar MT, Christ GJ. Gene transfer with a vector expressing Maxi-K from a smooth muscle-specific promoter restores erectile function in the aging rat. Gene Ther. 2008;15(5):364370.doi:10.1038/sj.gt.3303093

51. Melman A, Zhao W, Davies KP, Bakal R, Christ GJ. The successful long-term treatment of age related erectile dysfunction with hSlo cDNA in rats in vivo. J Urol. 2003;170(1):285290.doi:10.1097/01.ju.0000063375.12512.6e

52. Christ GJ, Day N, Santizo C, et al. Intracorporal injection of hSlo cDNA restores erectile capacity in STZ-diabetic F-344 rats in vivo. Am J Physiol Heart Circ Physiol. 2004;287(4):H15441553.doi:10.1152/ajpheart.00792.2003

53. Christ GJ, Rehman J, Day N, et al. Intracorporal injection of hSlo cDNA in rats produces physiologically relevant alterations in penile function. Am J Physiol. 1998;275(2):H600608.doi:10.1152/ajpheart.1998.275.2.H600

54. Arun N. Treatment of erectile dysfunction with hMaxi-K gene transfer: safety report from phase IIA study. Eur Urol. 2018;12(2):e1706.

55. Christ GJ, Day NS, Day M, et al. Bladder injection of naked hSlo/pcDNA3 ameliorates detrusor hyperactivity in obstructed rats in vivo. Am J Physiol Regul Integr Comp Physiol. 2001;281(5):R16991709.doi:10.1152/ajpregu.2001.281.5.R1699

56. Papagiannopoulou D, Vardouli L, Dimitriadis F, Apostolidis A. Retrograde transport of radiolabelled botulinum neurotoxin type A to the CNS after intradetrusor injection in rats. BJU Int. 2016;117(4):697704.doi:10.1111/bju.13163

57. Kruse MN, Erdman SL, Puri G, de Groat WC. Differences in Fluorogold and wheat germ agglutinin-horseradish peroxidase labelling of bladder afferent neurons. Brain Res. 1993;613(2):352356.doi:10.1016/0006-8993(93)90926-e

58. Wang X, Burke SRA, Talmadge RJ, Voss AA, Rich MM. Depressed neuromuscular transmission causes weakness in mice lacking BK potassium channels. J Gen Physiol. 2020;152(5):e201912526. doi:10.1085/jgp.201912526

See original here:
Gene therapy for overactive bladder | TCRM - Dove Medical Press

Physiology

Electrocardiogram 1: purpose, physiology and practicalities – Nursing Times

An electrocardiogram monitors the hearts electrical activity and is used in many clinical settings. This article explores how the technique works and is undertaken

An electrocardiogram assesses the hearts electrical activity; it is commonly used as a non-invasive monitoring device in many different healthcare settings. This article, the first in a three-part series, discusses cardiac electrophysiology, indications for an electrocardiogram, monitoring and troubleshooting.

Citation: Jarvis S (2021) Electrocardiogram 1: purpose, physiology and practicalities. Nursing Times [online]; 117: 6, 22-26.

Author: Selina Jarvis is research nurse, Guys and St Thomas NHS Foundation Trust.

An electrocardiogram (ECG) is a quick bedside investigation that assesses the electrical activity of the heart. It is a non-invasive, cheap technique that provides critical information about heart rate and rhythm, and helps assess for cardiac disease. ECG monitoring is used often in many different healthcare settings, including acute care, cardiac care and preoperative assessment.

This article, the first in a three-part series, discusses cardiac electrophysiology, indications for an ECG, monitoring and troubleshooting. Part2 of the series will take a methodical approach to interpretation, with a focus on cardiac ischaemia; part3 will explore cardiac rhythm and conduction abnormalities.

The heart is an organ that acts as a mechanical pump; it consists of four chambers (right and left atria, and right and left ventricles) that contract sequentially during the cardiac cycle and are regulated by an electrical conducting system. To understand the basics of an ECG, it is important to consider the normal electrophysiology of the heart, in which a cardiac electrical impulse is generated and transmitted to the heart muscle, leading to contractions (the heartbeat).

There are two main cell types in the heart:

Cardiomyocytes contract and relax in response to an electrical stimulus. During their resting state, inside the cells there are high internal levels of potassium ions (K+), compared with outside the cells; along with negatively charged proteins, which creates a chemical gradient. Outside the cardiomyocytes there are more sodium ions (Na+) and calcium ions (Ca2+) compared with inside the cell. Overall, this means there is a voltage difference across the cell membrane, called transmembrane potential (TMP). When there is net movement of Na+ and Ca2+ into the cell, TMP becomes more positive; when there is net movement of positive ions out of it, TMP becomes more negative.

In response to an electrical stimulus, cardiomyocytes become depolarised and fast Na+ channels open on the cell membrane, allowing Na+ into the cell; because this is positively charged, the TMP becomes more positive, increasing to -70millivolts (mV) (resting potential is -90mV). This is the point at which enough Na+ fast channels have opened to generate an inward Na+ current, and is known as the threshold potential. When the charge becomes greater than -40mV, L-type calcium channels open and allow an inward flux of Ca2+. This results in excitation-contraction coupling, which leads to the contraction of muscles in the heart. Following this, repolarisation occurs; the cardiac membrane potential returns to the resting state and no muscle contraction occurs.

The hearts electrical conducting system (Fig1) regulates its overall electrical activity and includes the following components:

Each heartbeat is initiated by an electrical impulse generated by the SAN; this impulse passes through the atria to the AVN, then through the right and left ventricles, the bundle of His, subsequent bundle branches and the Purkinje fibres. As a result, the atria and ventricles contract sequentially as the impulse is conducted through the different regions of the heart. In normal circumstances, the SAN is the hearts pacemaker; however, if there is a problem with the SAN, another conducting region centre such as the AVN, bundle of His or bundle branches can assume the role of the pacemaker in an occurrence known as an escape rhythm (Jarvis and Saman, 2018; Newby and Grubb, 2018).

In healthy individuals, the chambers of the heart contract and relax in a coordinated manner, referred to as systole and diastole respectively. The right and left atria synchronise during atrial systole and diastole, while the right and left ventricles synchronise during ventricular systole and diastole. One complete cycle of these events is called the cardiac cycle, during which the pressure in the cardiac chambers rises and falls, causing the opening and closure of heart valves that regulates blood flow between the chambers.

Pressures on the left side of the heart are around five times higher than those on the right side, but the same volume of blood is pumped per cardiac beat. In the cardiac cycle, blood moves from high- to low-pressure areas (Marieb and Keller, 2018).

The ECGs origin dates back to the discovery of the heart muscles electric activity. In 1901, Willem Einthoven made a breakthrough that facilitated the first steps towards electrocardiography, for which he subsequently won a Nobel Prize in 1924 (Yang et al, 2015).

ECGs are used as a technique to diagnose cardiac disease and to detect abnormal heart rhythm. They may also be used as a general health assessment in certain occupations, including aviation, diving and the military (Chamley et al, 2019). According to professional societies, adequate education for medical staff is critical for ECG monitoring and developing skills in interpreting waveforms and ECG data (Sandau et al, 2017).

In routine clinical practice, there are four main approaches to monitoring cardiac rhythm:

The 12-lead ECG is a non-invasive method of monitoring the hearts electrical activity. This bedside test can provide important diagnostic information or be used as part of a baseline assessment; Box1 outlines some indications for using it.

If there is a concern that a patients acute symptoms may have a cardiac cause, continuous cardiac monitoring might be used in a hospital setting. This may help with:

Continuous cardiac monitoring is also an important component of non-invasive monitoring of vital signs, with clinical benefits in medical ward settings (Sun et al, 2020).

The ECG is a graphical representation of the hearts electrical activity, plotting its voltage on a vertical axis against time on a horizontal axis. It is recorded onto ECG paper, which runs at a speed of 25mm per second. Standard pink ECG paper is made up of 5x5mm squares, each containing 25 smaller 1x1mm squares. The 1mm width of each small square represents 40milliseconds. On the vertical axis, the height of an ECG wave or deflection represents its amplitude (Prutkin, 2020). Fig2 shows what a normal ECG looks like and its relationship with the stages of the cardiac cycle.

During the normal cardiac cycle, the atrial contraction that takes place is associated with a P-wave (atrial depolarisation) and is of low amplitude because the muscle is relatively thin in the atria. This contrasts with the QRS complex, which represents the electrical impulse as it spreads through the ventricles (ventricular depolarisation). The first deflection of the QRS complex is the Q-wave, which is a negative wave that begins septal depolarisation. The R-wave represents depolarisation of the left ventricular myocardium and the next negative deflection is the S-wave, which represents terminal depolarisation. The T-wave occurs after that and represents the repolarisation of the ventricles.

The ECG also records a number of other parameters:

It is important to know the normal ranges for the various ECG parameters (Table1): if any measurements are outside the normal range, thought and investigation are needed to ascertain why and decide on a course of action. Parts 2 and 3 of this series will discuss this in more detail.

It is important to remember that the electrical lead actually represents the differences in electrical potentials measured in two points in space. The conduction of electrical impulses between these two points in space can be detected via electrodes that are positioned at various points on the body; this is then displayed as a waveform on the ECG machine/monitor.

There are several configurations of electrode positioning; continuous ECG monitoring uses a 3-lead configuration but the standard 12-lead ECG comprises:

To position the chest electrodes accurately, it is important to first identify the sternal angle (angle of Louis); this is done by feeling the bony prominence at the top of the sternum, which articulates with the second rib above the second intercostal space. By moving the fingers downwards, the fourth intercostal space can be felt: here, the electrodes for V1 and V2 should be placed to the right and left of the sternum respectively. By feeling the fifth intercostal space and moving the fingers to the middle of the clavicle, V4 can be placed on the midclavicular line. V3 should then be placed midway between V2 and V4. V5 is placed in the fifth intercostal space, more lateral to the anterior axillary line, and V6 is placed in the fifth intercostal space in the midaxillary line.

To record the limb leads (Fig3b), four electrodes are placed on the body. In the upper limbs, an electrode pad is placed below the right clavicle (arm), the next electrode pad is placed below the left clavicle (arm); in the lower limbs, a cable is connected to an electrode pad placed on the left hip/ankle (LL) and on the right hip/ankle (RL).

It is important to follow local policy. All of the limb electrodes are placed on bony areas, rather than muscle, to avoid motion artifact caused by muscle oscillation. Positioning electrodes in this formation allows the heart to be electrically mapped in three dimensions.

When undertaking any cardiac monitoring, the first step is to give the patient a simple explanation of the purpose of the test and what they should expect, as well as gaining their informed consent. It is important to ensure they are not allergic to the gel used on the ECG electrodes by asking if they have had any previous reactions.

It is critical that the health professional can accurately place the electrodes this will help avoid inaccurate diagnosis and treatment and it is important to have good contact between the electrode and the skin, which should be clean and dry. Excessive hair may need to be shaved and oily skin cleaned with alcohol or gauze. The electrodes are then attached to the patient in line with the machines instructions. The ECG is displayed on the machines monitor and should be checked for clarity, wave size and any interference.

Inadequate ECG monitoring can be dangerous; for example, misreading artifacts (electrocardiographic impulses unrelated to cardiac electrical activity) during ECG monitoring can be costly and cause delays to care. Other potential problems and how to resolve them are listed in Table 2.

An excellent ECG trace must be acquired to aid appropriate interpretation and provide the best care. The Society of Cardiological Science and Technologys (2020) ECG guidance has more information about the reporting standards used by professional societies.

ECG monitoring is standard for patients in a variety of settings. Understanding the basic physiology underpinning the electrical and mechanical events of the heart is crucial for ECG interpretation. Part 2 of this series will focus on this and present important ischaemic pathologies, while part 3 will cover cardiac rhythm disorders and conduction defects.

Selina Jarvis was a recipient of the Mary Seacole Development Award and is focused on improving care for patients with cardiac disease.

References

Chamley RR et al (2019) ECG interpretation. European Heart Journal; 40: 32, 2663-2666.

Jarvis S, Saman S (2018) Cardiac system 1: anatomy and physiology. Nursing Times [online]; 114: 2, 34-37.

Marieb EN, Keller S (2018) Essentials of Human Anatomy and Physiology. Pearson.

Newby DE, Grubb NR (2018) Cardiovascular disease. In: Ralston SH et al (eds) Davidsons Principles and Practice of Medicine. Elsevier.

Prutkin JM (2020) ECG Tutorial: Electrical Components of the ECG. uptodate.com

Sandau KE et al (2017) Update to practice standards for electrocardiographic monitoring in hospital settings: a scientific statement from the American Heart Association. Circulation; 136: 19, e273-e344.

Society of Cardiological Science and Technology (2020) Clinical Guidelines by Consensus: ECG Reporting Standards and Guidance. SCST.

Sun L et al (2020) Clinical impact of multi-parameter continuous non-invasive monitoring in hospital wards: a systematic review and meta-analysis. Journal of the Royal Society of Medicine; 113: 6, 217-224.

Yang XL et al (2015) The history, hotspots, and trends of electrocardiogram. Journal of Geriatric Cardiology; 12: 4, 448-456.

Here is the original post:
Electrocardiogram 1: purpose, physiology and practicalities - Nursing Times

Physiology

Women and endurance running part one: how to train with your cycle – Canadian Running Magazine

Dr. Stacy Simsis a researcher, entrepreneur, recreational athlete and scientist whose area of expertise is exercise physiology and sports nutrition. Early in her career, she became frustrated by the fact that the vast majority of sports science treated women like small men most studies were conducted on men, and all the training, recovery and nutrition principles we learned from those studies were applied to women, despite the fact that female physiology is different from that of a man. We sat down with her to talk about these differences to determine how women runners can work with their bodies to become stronger, faster and healthier athletes.

RELATED: Why sports medicine research needs more women

Today, in Part One of this series, we will be diving into the female menstrual cycle and how it affects training. Part Two will cover nutrition strategies to boost performance throughout your cycle and how contraceptives affect training, and Part Three will look at puberty, perimenopause and menopause.

One of the most obvious differences between women and men, of course, is the female menstrual cycle. For years, a womans period was seen as being detrimental to her performance, but Sims says this is entirely false.

If you dont have a period, its detrimental [to your performance], she explains. Having a period means youre healthy, youre adapting and youre resilient to stress.

Sims explains that the reason having a period developed such a negative connotation in sports is because of the way sport developed. In the beginning, she says it acted as a male demonstration of aggression, with an emphasis on traditionally male qualities, like speed, strength, aggression and power. There has always been a taboo around the female menstrual cycle, so when you bring that into the sporting context, it came across as a weakness. Because of this, the idea that not having a period meant you were just as strong or trained just as hard as the men became endemic in sport.

This couldnt be farther from the truth. Having a period means youre getting enough nutrients to support your health and your training, your body is responding well to training adaptations and stress, your sleep patterns are good, your endocrine system is healthy and youre in an energy balance. No longer getting a regular period is the first red flag that something is amiss, and sets you up for health complications down the road, like loss of bone density, irregular sleep patterns and hormone dysfunction, among others.

Sims says that for so long, women have been told that when theyre on their periods, they should feel flat, tired, awful and that they should be hiding. Instead, she argues, we should be telling women the opposite that their periods are an opportunity to increase the intensity of their training sessions.

The more we get women to move during their periods, the better it is and the less symptomatology they have, she explains.

From a physiology standpoint, this also makes a lot of sense. The week that youre on your period (days one through seven of your cycle) is when your hormones are at their lowest point, and this makes your body more resilient to stress. This, then, is the time to do more high-intensity sessions, because you recover much better. The only caveat to this, says Sims, is women who experience heavy bleeding during the first couple of days of their period. In this case, you want to keep moving but shift the focus from high intensity to technical work like drills, or simply moving for movings sake. You can hit your training hard again once the heavy bleeding subsides.

The myths and perceptions around bleeding need to be extracted from the training conversation, says Sims.

Around ovulation, which is usually around day 14 of the cycle for most women, is another good time to schedule a hard training session. After that, as your levels of estrogen and progesterone begin to rise again, Sims suggests focusing more on steady-state runs. Finally, the five days before your period starts, which is when your body is most affected by hormones, should be treated more like a de-load or off-week. This is the time to back off the intensity and focus on other aspects of training like running drills, de-loading in the gym and working on technique. Every woman will be slightly different, so its important to track your cycle and take note of the days you feel better and the days you feel worse, and adjust your training plan accordingly. While there are many ways to do this, Sims is a big fan of the app, Wild AI.

If youre coaching a team of female athletes, Sims recommends coming up with a system that allows you to keep track of where each of your athletes are at, so that you can adjust their training accordingly (or, at the very least, adjust your expectations of individual athletes depending on the day).

This is where training is different than performance, says Sims. Train according to your menstrual cycle, but we know that the psychological aspect of performance supersedes the physiological.

If, for example, your race ends up falling on a day during your cycle that you typically dont feel your best, its easy to let that get to your head. Putting certain nutrition interventions in place and boosting yourself up mentally will help you overcome whatever physiological downfall you might be experiencing.

We have to separate out performance versus training, which hasnt been done well yet, explains Sims. When we talk about performance, theres never a negative point in the menstrual cycle. When we talk about training, there are ups and downs. We can get better training adaptations when our bodies are more resilient to stress, and then start to taper down to support that hard training. But for performance, just go, just hit it hard.

The key takeaway from this is that a womans period should not be seen as a detriment to performance, but rather as a tool to make her a better athlete. If women can learn to work with their physiology rather than against it, they will be healthier, happier and faster runners.

RELATED: Exercising and your period: changing the conversation

Read more here:
Women and endurance running part one: how to train with your cycle - Canadian Running Magazine

Physiology

Quantifying stress & anxiety: Why corporate wellness programs will play a pivotal role in this paradigm shift – MedCity News

The past decade has seen us come on leaps and bounds as a society in our awareness and understanding of the scale and impact of mental health problems. In recent years, the focus has switched somewhat from reaction to prevention in parallel with the healthcare industry as a whole, in a bid to secure the sustainability of care services.

The economic impact of the mental health epidemic is a key driver behind governments and businesses move towards more preventive wellbeing initiatives. For instance, the World Health Organization (WHO) estimates that mental health problems in the workplace cost the global economy $1 trillion annually in lost productivity.

Stress and anxiety contribute heavily to this statistic. Stress is defined as the bodys reaction to feeling threatened or under pressure. Anxiety, which is often linked to stress, is defined as a feeling of unease, such as worry or fear, which can be mild or severe and is the main symptom of several mental disorders.

In the UK, for example, 57% of all working days lost to ill health were due to stress and anxiety in 2018. Its a similar story in the US, where its estimated that over half of all working days lost annually from absenteeism are stress-related, with the annual cost in 2013 alone equating to over $84 billion.

Stress and anxiety can also have a significant impact on an individuals physical health, affecting their work performance and productivity and causing further absenteeism. This form of poor mental health can impact physical health either directly through autonomic nervous system activity or indirectly as a result of unhealthy behaviors (e.g. poor diet, physical inactivity, alcohol abuse and smoking), increasing an individuals risk of developing cardiovascular problems.

It is therefore in an effort to break this chain, and in doing so save costs long-term, that employers are increasing their focus on establishing effective wellness programs, meaning any promotional activity or organizational policy that supports healthy behavior in the workplace and improves health outcomes. Corporate wellness programs nowadays include anything from healthy eating education, financial advice and access to weight loss and fitness programs, to more direct healthcare such as on-site medical screening, stress management, smoking cessation programs, and counseling services (in the form of employee assistance programs).

And this certainly can save costs long-term! Most famously, Johnson & Johnson leaders estimate that wellness programs have cumulatively saved the company $250 million on healthcare costs over the past decade; with a return of $2.71 for every dollar spent between 2002 and 2008. Its no surprise, then, that in 2020 the workplace wellness industry was estimated to be worth $48 billion globally.

Recent innovations in the space include the integration of wearable or smartphone technologies, used by employees to monitor and collect physical health data. These technologies provide employees with real-world physiological health insights to further incentivize participation in programs and increase and maintain their engagement. They simultaneously provide employers with an insight into the overall physical health of their workforce.

A golden opportunity to transform our relationship with mental health

However, with this most recent integration of digital health technologies comes a hitherto unrecognized opportunity to transform our understanding and treatment of mental health and wellbeing.

One of the primary barriers to delivering quality mental health care throughout history has been the difficulty in establishing accurate and objective methods to diagnose, assess and monitor treatment outcomes for psychological conditions. As was explained so eloquently by Washington University in November last year, if patients display symptoms of a heart attack, there are biological tests that can be run to look for diagnostic biomarkers that determine whether they are indeed suffering a heart attack or not. However, in the case of mental health disorders, the window by which we access the mind is still through psychological questioning, not biological parameters.

Mental health professionals screen, diagnose and monitor the symptoms and outcomes of patients through self-reported methods prone to excess subjectivity and therefore unreliability, such as diagnostic interviews and questionnaires. A patients self-reported symptoms are correlated with the ICD or DSM diagnostic manuals, yet challenges arise in the high heterogeneity of mental illnesses, low inter-rate reliability (i.e. poor agreement between clinicians diagnoses) and high comorbidity.

There is therefore a need to expand further than solely symptom-based to biology-based characterization of mental health conditions if we are to combat this unreliability and establish more evidence-based methods for diagnosis and monitoring, similar to our approach to physical illness.

So, how do we do this?

The National Institute for Mental Health for instance has already taken the first steps towards this with the RDoC (Research Domain Criteria). Advancements in MRI technology have also enabled research into understanding brain activity in certain depressive conditions.

But the most exciting development lies in the proliferation of wearable and smartphone health monitoring technologies. As the ability to collect vast amounts of physiological health data becomes more and more ubiquitous, the opportunity to utilize machine learning (ML) to extract new insights into the physiology of each individual grows larger.

With this comes the chance to uncover and establish personalized digital biomarkers for mental health conditions; described as indicators of mental state that can be derived through a patients use of a digital technology. These digital biomarkers can cover physiology (e.g. heart rate), cognition (e.g. eye movement on screens), behavioral (e.g. via GPS) and social (e.g. call frequency) factors. However, it is physiology that concerns us here.

Corporate wellness programs provide the perfect environment to explore the use of wearables and smartphone sensors in uncovering digital biomarkers which link physical health to mental wellbeing due to the huge potential benefits for all parties involved; employers and employees.

For example, by validating elements of cardiopulmonary functions as a digital biomarker for excess stress or anxiety disorders (a relationship for which some empirical evidence already exists), employers can not only identify stress and anxiety risks in the workplace and intervene earlier to protect employee mental wellbeing, but also establish an evidence-based approach for evaluating the effectiveness of workplace wellness initiatives. This is due to the fact that quantitative cardiopulmonary data would serve as a reliable measure of employee stress and/or mental wellbeing.

Employees, on the other hand, are empowered with insight into direct correlations between how they feel and their physical health. Therefore their increased engagement in wellness programs will improve their efficacy in preventing the deterioration of their mental health. For this reason, accessibility and ease-of-use must remain top of mind when choosing health monitoring technologies.

Finally, establishing digital biomarkers which correlate physiological parameters with mental health and wellbeing not only has the potential to provide more reliable tools for guiding diagnosis and evaluating patient outcomes but will also improve our understanding of the pathophysiology of mental disorders, in turn allowing for more effective preventive measures.

Photo: Creativeye99, Getty Images

Read more:
Quantifying stress & anxiety: Why corporate wellness programs will play a pivotal role in this paradigm shift - MedCity News

Physiology

Is riding an electric bike good exercise, or just convenient transportation? – The Irish Times

Does riding an electric bike to work count as exercise, and not just a mode of transportation?

It can, if you ride right, according to a pragmatic new study comparing the physiological effects of e-bikes and standard road bicycles during a simulated commute. The study, which involved riders new to e-cycling, found that most could complete their commutes faster and with less effort on e-bikes than standard bicycles, while elevating their breathing and heart rates enough to get a meaningful workout.

But the benefits varied and depended, to some extent, on how peoples bikes were adjusted and how they adjusted to the bikes. The findings have particular relevance at the moment, as pandemic restrictions loosen and offices reopen, and many of us consider options other than packed trains to move ourselves from our homes to elsewhere.

Few people bike to work. Asked why, many tell researchers that bike commuting requires too much time, perspiration and accident risk. Simultaneously, though, people report a growing interest in improving their health and reducing their ecological impact by driving less.

In theory, both these hopes and concerns could be met or minimised with e-bikes. An alluring technological compromise between a standard, self-powered bicycle and a scooter, e-bikes look almost like regular bikes but are fitted with battery-powered electric motors that assist pedalling, slightly juicing each stroke.

With most e-bikes, this assistance is small, similar to riding with a placid tailwind, and ceases once you reach a maximum speed of about 30km/h or stop pedalling. The motor will not turn the pedals for you.

Essentially, e-bikes are designed to make riding less taxing, which means commuters should arrive at their destinations more swiftly and with less sweat. They can also provide a psychological boost, helping riders feel capable of tackling hills they might otherwise avoid. But whether they also complete a workout while e-riding has been less clear.

So, for the new study, which was published in March in the Translational Journal of the American College of Sports Medicine, researchers at Miami University in Oxford, Ohio decided to ask inexperienced cyclists to faux-commute. To do so, they recruited 30 local men and women, aged 19 to 61, and invited them to the physiology lab to check their fitness levels, along with their current attitudes about e-bikes and commuting.

Then, they equipped each volunteer with a standard road bike and an e-bike and asked them to commute on each bike at their preferred pace for approximately 5km. The cyclists pedalled around a flat loop course, once on the road bikes and twice with the e-bike. On one of these rides, their bike was set to a low level of pedal assistance, and on the other, the oomph was upped until the motor sent more than 200 watts of power to the pedals. Throughout, the commuters wore timers, heart rate monitors and facial masks to measure their oxygen consumption.

Afterward, to no ones surprise, the scientists found that the motorised bikes were zippy. On e-bikes, at either assistance level, riders covered the 5km several minutes faster than on the standard bike about 11 or 12 minutes on an e-bike, on average, compared to about 14 minutes on a regular bike. They also reported that riding the e-bike felt easier. Even so, their heart rates and respiration generally rose enough for those commutes to qualify as moderate exercise, based on standard physiological benchmarks, the scientists decided, and should, over time, contribute to health and fitness.

But the cyclists results were not all uniform or constructive. A few riders efforts, especially when they used the higher assistance setting on the e-bikes, were too physiologically mild to count as moderate exercise. Almost everyone also burned about 30 per cent fewer calories while e-biking than while road riding 344 to 422 calories on average on an e-bike versus 505 calories on a regular bike which may be a consideration if someone is hoping to use bike commuting to help lose weight.

And several riders told the researchers they worried about safety and control on the e-bikes, although most, after the two rides, reported greater confidence in their bike-handling skills, and found the e-commutes, compared to the road biking, more fun.

This study, though, was obviously small-scale and short-term, involving only three brief pseudo-commutes. Still, the findings suggest that riding an e-bike, like other forms of active transport, can be as good for the person doing it as for the environment, says Helaine Alessio, the chair of the department of kinesiology at Miami University, who led the new study with her colleague Kyle Timmerman and others.

But to increase your potential health benefits the most, she says, keep the pedal assistance level set as low as is comfortable for you. Also, for the sake of safety, practice riding a new e-bike or any standard bike on a lightly trafficked route until you feel poised and secure with bike handling.

Wear bright, visible clothing, too, and choose your commuting route wisely, Dr Alessio says. Look for bike paths and bike lanes whenever possible, even if you need to go a little bit out of your way. New York Times

View original post here:
Is riding an electric bike good exercise, or just convenient transportation? - The Irish Times

Physiology

Why we find the sound of our voice cringeworthy – Scroll.in

As a surgeon who specialises in treating patients with voice problems, I routinely record my patients speaking. For me, these recordings are incredibly valuable. They allow me to track slight changes in their voices from visit to visit, and it helps confirm whether surgery or voice therapy led to improvements.

Yet I am surprised by how difficult these sessions can be for my patients. Many become visibly uncomfortable upon hearing their voice played back to them.

Do I really sound like that? they wonder, wincing.

(Yes, you do.)

Some become so unsettled they refuse outright to listen to the recording much less go over the subtle changes I want to highlight.

The discomfort we have over hearing our voices in audio recordings is probably due to a mix of physiology and psychology.

For one, the sound from an audio recording is transmitted differently to your brain than the sound generated when you speak.

When listening to a recording of your voice, the sound travels through the air and into your ears what is referred to as air conduction. The sound energy vibrates the ear drum and small ear bones. These bones then transmit the sound vibrations to the cochlea, which stimulates nerve axons that send the auditory signal to the brain.

However, when you speak, the sound from your voice reaches the inner ear in a different way. While some of the sound is transmitted through air conduction, much of the sound is internally conducted directly through your skull bones. When you hear your own voice when you speak, it is due to a blend of both external and internal conduction and internal bone conduction appears to boost the lower frequencies.

For this reason, people generally perceive their voice as deeper and richer when they speak. The recorded voice, in comparison, can sound thinner and higher-pitched, which many find cringeworthy.

There is a second reason hearing a recording of your voice can be so disconcerting. It really is a new voice one that exposes a difference between your self-perception and reality. Because your voice is unique and an important component of self-identity, this mismatch can be jarring. Suddenly you realise other people have been hearing something else all along.

Even though we may actually sound more like our recorded voice to others, I think the reason so many of us squirm upon hearing it is not that the recorded voice is necessarily worse than our perceived voice. Instead, we are simply more used to hearing ourselves sound a certain way.

A study published in 2005 had patients with voice problems rate their own voices when presented with recordings of them. They also had clinicians rate the voices. The researchers found that patients, across the board, tended to more negatively rate the quality of their recorded voice compared with the objective assessments of clinicians.

So if the voice in your head castigates the voice coming out of a recording device, it is probably your inner critic overreacting and you are judging yourself a bit too harshly.

Neel Bhatt is an Assistant Professor of Otolaryngology, UW Medicine at the University of Washington.

This article first appeared on The Conversation.

Continue reading here:
Why we find the sound of our voice cringeworthy - Scroll.in

Physiology

Compound may prevent risk of form of arrhythmia from common medications – Washington University in St. Louis Newsroom

Dozens of commonly used drugs, including antibiotics, anti-nausea and anticancer medications, have a potential side effect of lengthening the electrical event that triggers contraction, creating an irregular heartbeat, or cardiac arrhythmia called acquired Long QT syndrome. While safe in their current dosages, some of these drugs may have a more therapeutic benefit at higher doses, but are limited by the risk of arrhythmia.

Through both computational and experimental validation, a multi-institutional team of researchers has identified a compound that prevents the lengthening of the hearts electrical event, or action potential, resulting in a major step toward safer use and expanded therapeutic efficacy of these medications when taken in combination.

The team found that the compound, named C28, not only prevents or reverses the negative physiological effects on the action potential, but also does not cause any change on the normal action potential when used alone at the same concentrations. The results, found through rational drug design, were published online in Proceedings of the National Academy of Sciences (PNAS) on May 14.

The research team was led by Jianmin Cui, professor of biomedical engineering in the McKelvey School of Engineering at Washington University in St. Louis; Ira Cohen, MD, PhD, Distinguished Professor of Physiology and Biophysics, professor of medicine and director of the Institute for Molecular Cardiology at the Renaissance School of Medicine at Stony Brook University; and Xiaoqin Zou, professor of physics, biochemistry and a member of the Dalton Cardiovascular Research Center and Institute for Data Science and Informatics at the University of Missouri.

The drugs in question, as well as several that have been pulled from the market, cause a prolongation of the QT interval of the heartbeat, known as acquired Long QT Syndrome, that predisposes patients to cardiac arrhythmia and sudden death. In rare cases, Long QT also can be caused by specific mutations in genes that code for ion channel proteins, which conduct the ionic currents to generate the action potential.

Although there are several types of ion channels in the heart, a change in one or more of them may lead to this arrhythmia, which contributes to about 200,000 to 300,000 sudden deaths a year, more deaths than from stroke, lung cancer or breast cancer.

The team selected a specific target, IKs, for this work because it is one of the two potassium channels that are activated during the action potential: IKr (rapid) and IKs (slow).

The rapid one plays a major role in the action potential, said Cohen, one of the worlds top electrophysiologists. If you block it, Long QT results, and you get a long action potential. IKs is very slow and contributes much less to the normal action potential duration.

It was this difference in roles that suggested that increasing IKs might not significantly affect normal electrical activity but could shorten a prolonged action potential.

Cui, an internationally renowned expert on ion channels, and the team wanted to determine if the prolongation of the QT interval could be prevented by compensating for the change in current and inducing the Long QT Syndrome by enhancing IKs. They identified a site on the voltage-sensing domain of the IKs potassium ion channel that could be accessed by small molecules.

Zou, an internationally recognized expert who specializes in developing new and efficient algorithms for predicting protein interactions, and the team used the atomic structure of the KCNQ1 unit of the IKs channel protein to computationally screen a library of a quarter of a million small compounds that targeted this voltage-sensing domain of the KCNQ1 protein unit. To do this, they developed software called MDock to test the interaction of small compounds with a specific protein in silico, or computationally.

By identifying the geometric and chemical traits of the small compounds, they can find the one that fits into the protein sort of a high-tech, 3D jigsaw puzzle. While it sounds simple, the process is quite complicated as it involves charge interactions, hydrogen bonding and other physicochemical interactions of both the protein and the small compound.

We know the problems, and the way to make great progress is to identify the weaknesses and challenges and fix them, Zou said. We know the functional and structural details of the protein, so we can use an algorithm to dock each molecule onto the protein at the atomic level.

One by one, Zou and her lab docked the potential compounds with the protein KCNQ1 and compared the binding energy of each one. They selected about 50 candidates with very negative, or tight, binding energies.

Cui and his lab then identified C28 using experiments out of the 50 candidates identified in silico by Zous lab. They validated the docking results by measuring the shift of voltage-dependent activation of the IKs channel at various concentrations of C28 to confirm that C28 indeed enhances the IKs channel function. They also studied a series of genetically modified IKs channels to reveal the binding of C28 to the site for the in silico screening.

Cohen and his lab tested the C28 compound in ventricular myocytes from a small mammal model that expresses the same IKs channel as humans. They found that C28 could prevent or reverse the drug-induced prolongation of the electrical signals across the cardiac cell membrane and minimally affected the normal action potentials at the same dosage. They also determined that there were no significant effects on atrial muscle cells, an important control for the drugs potential use.

We are very excited about this, Cohen said. In many of these medications, there is a concentration of the drug that is acceptable, and at higher doses, it becomes dangerous. If C28 can eliminate the danger of inducing Q-T prolongation, then these drugs can be used at higher concentrations, and in many cases, they can become more therapeutic.

While the compound needs additional verification and testing, the researchers say there is tremendous potential for this compound or others like it and could help to convert second-line drugs into first-line drugs and return others to the market. With assistance from the Washington University Office of Technology Management, they have patented the compound, and Cui has founded a startup company, VivoCor, to continue to work on the compound and others like it as potential drug candidates.

The work was accelerated by a Leadership and Entrepreneurial Acceleration Program (LEAP) Inventor Challenge grant Washington University in St. Louis in 2018 funded by the Office of Technology Management, the Institute of Clinical and Translational Sciences, the Center for Drug Discovery, the Center for Research Innovation in Biotechnology, and the Skandalaris Center for Interdisciplinary Innovation and Entrepreneurship.

This work was done by an effective drug design approach: identifying a critical site in the ion channel based on understanding of structure-function relation, using insilico dockingto identify compounds that interact with the critical site in the ion channel, validating functional modulation of the ion channel by the compound, and demonstrating therapeutic potential in cardiac myocytes, Zou said. Our three labs form a great team, and without any of them, this would not be possible.

The McKelvey School of Engineering at Washington University in St. Louis promotes independent inquiry and education with an emphasis on scientific excellence, innovation and collaboration without boundaries. McKelvey Engineering has top-ranked research and graduate programs across departments, particularly in biomedical engineering, environmental engineering and computing, and has one of the most selective undergraduate programs in the country. With 140 full-time faculty, 1,387 undergraduate students, 1,448 graduate students and 21,000 living alumni, we are working to solve some of societys greatest challenges; to prepare students to become leaders and innovate throughout their careers; and to be a catalyst of economic development for the St. Louis region and beyond.

Lin Y, Grinter S, Lu Z, Xu X, Wang H Z, Liang H, Hou P, Gao J, Clausen C, Shi J, Zhao W, Ma Z, Liu Y, White, K M, Zhao L, Kang P W, Zhang G, Cohen I, Zou X, Cui J. Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects. Proceedings of the National Academy of Sciences (PNAS), date, DOI.

This research was supported by grants from the National Institutes of Health (R01 HL126774, R01 DK108989, R01 GM109980, R35GM136409; the American Heart Association (13GRNT16990076). The computations were performed on the high-performance computing infrastructure supported by NSF CNS-1429294 and the HPC resources supported by the University of Missouri Bioinformatics Consortium (UMBC).

Authors Jianmin Cui and Jingyi Shi are cofounders of a startup company, VivoCor LLC, which is targeting IKs for the treatment of cardiac arrhythmia.

See more here:
Compound may prevent risk of form of arrhythmia from common medications - Washington University in St. Louis Newsroom