Tuesday, February 28, 2023

Lewis Capaldi and Tourette syndrome

Lewis Capaldi's fans showed their support for the singer after he suffered a Tourette syndrome episode while performing onstage during his Feb. 21 concert in Frankfurt, Germany. 

In a viral video a fan shared to TikTok, the Scotland native, 26, was performing his 2019 hit "Someone You Loved" when he began experiencing tics and eventually turned away from the microphone as he stopped mid-song. 

At that point, the audience pitched in and sang the chorus: 

Now the day bleeds/ Into nightfall/ And you’re not here/ To get me through it all/ I let my guard down/ And then you pulled the rug/ I was getting kind of used to being someone you loved. 

"We support you!! @LewisCapaldi" the fan captioned the video. 

"Fans finishing off the song for Lewis as he was (struggling) with his Tourette's >>" the fan wrote on the video. 

Tourette syndrome is a nervous system disorder that causes people to experience uncontrollable "tics," according to the Centers for Disease Control and Prevention. Tics are sudden and repetitive twitches, movements or sounds. 

People with the disease usually develop symptoms in early childhood between the ages of 5 and 10. Though symptoms often decrease through adolescence and early adulthood and may disappear entirely, many people continue to suffer from Tourette into adulthood and sometimes their conditions worsen with age. 

Capaldi first revealed his diagnosis during an Instagram live in September, according to People magazine. He shared that he has always had Tourette, though he was unaware before being diagnosed, and he often suffers from shoulder twitches due to his condition. 

"The worst thing about it is when I’m excited I get it, when I'm stressed I get it, when I’m happy I get it. It happens all the time," Capaldi said. 

"Some days, it’s more painful than others, and some days it’s less painful. It looks a lot worse than it is. Sometimes it’s quite uncomfortable … but it comes and goes." 

The musician said he initially feared that he had "some horrible degenerative disease." However, Capaldi said he had previously noticed he was twitching in interviews from 2018, adding that his diagnosis "makes so much sense"  

"I do the shoulder twitch quite a lot," he told his Instagram followers. "And you see underneath every TikTok and stuff, people are like, 'Why is he twitching?', which is fine. Curiosity is fine. I get it." 

Capaldi said that he came forward with his diagnosis because he didn't want people to think he was "taking cocaine." 

"It's a new thing. I haven't really learned much about it — I'm learning," he added. "I've got Botox on my shoulder to stop it moving. It worked for a bit." 

In January, the "Before You Go" singer shared a TikTok video in which he was seen experiencing tics during a performance. In the clip, he was seen in bed as he addressed his fans while the video played in a separate window next to him.  

"I've seen this video doing the rounds a little bit on TikTok, and I see people in the comments concerned because I've twitching quite a lot, " he said. "Sort of looking uncomfortable. 

"I've got Tourette's, so I'm just twitching quite a bit here. I have no issue in the slightest. I'm absolutely fine. It's just this happens when I get, like, tired, nervous, excited, whatever. It just gets more intense. 

"I'm not doing it now at all because I'm lying in my bed in my pants," he added. "But this is at the end of an hour and a half gig, and I'm singing in front of 15,000 people. So, I'm tired, and I'm also very excited because this whole arena is singing my songs back to me." 

Capaldi thanked fans who attended his concert, noting it was "incredible." 

"Love you so much," he said. " See you later. Get a ticket if you haven't." 


Video: https://twitter.com/yourpositivenws/status/1628777120217329667/video/1

also: https://www.youtube.com/watch?v=WoyE8vEAD9U



Monday, February 27, 2023

Progress in treatment of essential tremor

Currently available medications do not offer safe and effective relief for the often debilitating symptoms experienced by many of the estimated 10 million Americans with essential tremor (ET). Researchers at Brigham and Women’s Hospital are working to develop novel therapies for these patients by applying innovative drug design concepts to validated disease targets. 

The sole FDA-approved drug for ET is the β-adrenergic antagonist propranolol, an unselective beta-blocker that only reduces tremor amplitude by up to 50% and does not reduce frequency. Furthermore, propranolol produces clinical benefits in just 40% of patients. Worse yet, many patients discontinue treatment due to fatigue, bradycardia, and other side effects. 

Meanwhile, although 74% of ET patients respond well to ethanol, daily use of this therapeutic option is not a viable solution. 

Kevin Hodgetts, PhD, director of the Brigham’s Laboratory for Drug Discovery in Neuroscience (LDDN), is leading efforts to develop a therapeutic compound to safely treat ET patients who are treatment-resistant to propranolol and who respond to ethanol. He and his team calculate that the compound will provide symptom relief in over 3 million new ET patients.


Collaborating With a World-leading ET Expert 

Dr. Hodgetts is a medicinal chemist who previously worked in the pharmaceutical industry, focusing on drug discovery. He joined the LDDN, which seeks to transform discoveries in the basic biology of disease into opportunities for drug discovery, in 2012. 

Earlier this year, Harvard Medical School named Dr. Hodgetts a recipient of a Blavatnik Therapeutics Challenge Award, which included the two-year, $1 million grant that is funding his current research aimed at finding a therapeutic compound for ET. Elan Louis, MD, chair of the Department of Neurology at UT Southwestern Medical Center and one of the world’s leading ET authorities, is an expert advisor for this research. 

Using GABAA PAMs as a Starting Point in Drug Discovery 

The LDDN is taking an innovative approach to drug discovery for ET. The team began by identifying compounds—gamma-aminobutyric acid type A (GABAA) positive allosteric modulators (PAMs)—that achieved clinical efficacy in ET but had intolerable on-target adverse effects. (GABA acting via GABAA receptors is the brain’s major inhibitory neurotransmitter system and regulates excessive brain excitability, which is associated with ET.) Importantly, the team also determined these compounds’ toxicity source: excessive potentiation. 

“Current drugs stimulate the target too much,” Dr. Hodgetts explains. “For ET, compounds don’t need as much activity to be efficacious. We’re using assays to predict which compounds have the activity we want without the excessive side effects. In other words, we’re trying to dial down compound activity to what we think will be therapeutic, yet safe.” 

Using GABAA PAMs as a starting point, Dr. Hodgetts and his colleagues are applying medicinal chemistry to make new molecules that are slightly different and then test them for changes in activity and off-target safety effects. 

“It’s an iterative process, and we try to improve the molecule stage by stage,” Dr. Hodgetts says. “If we think we have an exciting molecule, we send it to one company to do the pharmacokinetics and see how much of it gets into the blood and the brain. And when we find a compound that has the activity and safety we require, we send it to another company for a mouse model of essential tremor.” 

One point of focus for the LDDN is harmane, a GABAA negative allosteric modulator (NAM) that Dr. Louis has shown is increased in ET patients. “We’ve modeled some of our compounds around harmane to mimic its structure,” Dr. Hodgetts says. “And we’ve found that by doing medicinal chemistry on that structure, we can reverse the activity of harmane, which can cause tremors. So that’s part of the target of our compounds—to block the actions of harmane.” 

Drug Shows Encouraging Efficacy and Safety Results 

Preliminary studies of one prospective drug using in vivo models demonstrated that it delivered on-target efficacy with reduced adverse effects. 

The LDDN continues to make and test compounds to pinpoint the optimal one for development. The planned development path includes an initial assessment of the clinical efficacy of the drug as monotherapy, followed by a combination trial. Through the Harvard Business School’s Nucleate program, an MBA student has been paired with a research scientist in the lab to explore the possibility of starting a company or finding investors to fund clinical trials. 

“ET is not as well-known as Parkinson’s disease, and it’s not as debilitating—though it can be as it progresses,” Dr. Hodgetts says. “Since many ET patients are embarrassed to have ‘the shakes,’ they tend to stay inside and withdraw from society. So we believe our drug could have quite an impact.”