Before I launch into this topic, I want to point out that I am a big fan of Patrick Bet-David. I love how he called out Neil DeGrasse Tyson for trying to push vaccines on people when they have NOT been proven to be effective. He gave RFK a great platform to have a vaccine debate with Adam Dershowitz. He did an interview with Del Bigtree. And he spoke up about how it was wrong for YouTube to delete a Judy Mikovitz interview when it first surfaced during the early days of the pandemic. I highly recommend watching all those videos, especially the one about Dr. Mikovits. His insights and opinions on YouTube's censorship make it pretty clear why he has such a large audience!
Well, I was listening to this PBD Podcast/video last night, and it was enlightening to hear Adam Sosnick from Valuetainment come right out and say he sees RFK Jr's voice as the biggest thing that's holding him back. You can hear what he says in the video below. It will play right at the 11:28 mark, where Adam says this:
"The biggest thing he has to overcome, quite frankly, and as someone who has dealt with this myself: his voice issue. God, if he just had a normal voice, or if he used the... synthesizer... I think that's the biggest problem he has because he makes a lot of sense. The voice is just tough to listen to, sometimes."
It was an eye-opening moment. I knew Kennedy's voice was an obstacle, and maybe not a small one. My boyfriend (a biiiiiig Trump supporter 😝) has made comments about how hard it is to listen to Kennedy's voice. But Adam suddenly made it clear that there could be a LOT of people who might actually VOTE FOR KENNEDY, INSTEAD OF TRUMP, if he was just easier to listen to.
Human beings are simple creatures who want simple things. And we Americans live in a world where we want everything to be easy and pleasant. We can be really spoiled, compared to the rest of the world. We want our cars to be air conditioned. We want toilet paper to be soft. We want our drinks to be icy cold. We want our food to be fast and tasty, no matter how much fat, sugar and salt is in it.
The majority of Americans are all about IMMEDIATE GRATIFICATION, and sadly, too many people don't think about the consequences. Look at what happened with Operation Warp Speed! Trump rushed out a bunch of vaccines nice and quick, but few people seemed to want to take the time to do their own research, to see if the government and news media was REALLY telling us the truth about the safety and efficacy of the vaccines.
People want information handed to them in a nice, easy-to-listen-to 30 minute segment at 6:00 pm, in the same way they can cruise through McDonalds and have someone hand them their fast food Big Mac combo in a paper bag at the drive-thru window.
It just hit me that Kennedy's voice actually takes some WORK to listen to. Those of us who don't mind listening to Kennedy, tend to be those kinds of people who don't mind doing the extra work. We'll pick truth over pleasant sounding promises, any day. I think a lot of people in America feel like they work hard enough, and they don't want to have to do any EXTRA work. A lot of us are probably the types who are more likely to eat brown rice over white rice, not because it tastes better, but because we know it's good for us. Not that I'm saying I always choose brown over white, but I won't refuse it like some people would.
People want the internet to give them the answers they're looking for in 5 seconds (which I swear is the biggest reason people are clueless about the dangers of vaccines). People want TV newscasters to look pleasant and have smooth voices, and if they don't have that, they'll change the channel. My boyfriend is a Trump supporter who finds it very hard to listen to Kennedy's voice. So many people have NO PATIENCE!
It was interesting to watch Patrick Bet David's interrupt Adam when he started talking about this. Maybe it was just my imagination, or maybe the timing was just a coincidence, but I had to wonder if PBD interrupted Adam because he did NOT like Adam talking about this issue on his show, because PBD really wants Trump to win, and doesn't want RFK to know that if he could find a way to make his voice smoother, he really could end up taking away a lot of votes from Trump!
It's very obvious PBD is a huge Trump supporter. He makes no qualms about saying he's a dyed-in-the wool capitalist. Trump would likely be a much better financial choice for Republicans like him, who make a lot of money in business, have a lot of real estate (like PBD's $25 Million mansion in Florida) and stock investments. Not dissin' on PBD, I really like a lot of things about him and his show, but it's clear Trump would be a better FINANCIAL choice for him. I just wish PBD could see that KENNEDY would be a better choice for his KIDS and GRANDKIDS, in the long term. OK that is my opinion, but my VERY strong opinion, based on things like THIS and THIS and THIS.
Looking at PBD's body language, he seems to grow visibly uncomfortable when Adam talks about this topic. Adam also brings up a synthesizer, like that could be an option for Kennedy to use. Suddenly, PBD interrupts Adam in the middle of his sentence, to point out that some battery needs to be changed. Patrick crosses his arms, and almost seems to shoot Adam a dirty look.
I realize, all this could be my imagination... maybe it was just a coincidence that PBD interrupted Adam at that exact moment, because some battery really did need to be changed right then. But couldn't he have waited just a few more seconds, to let Adam finish speaking? It just seemed odd how PBD's body language went from relaxed, to uncomfortable, right after Adam brought the topic up. It was clear that Adam was saying he LIKES Kennedy, and he gave the impression that there's a good chance he'd vote for him if his voice wasn't such an issue.
Knowledge is power. Information is ammunition. And in my opinion, Adam could have just handed RFK some really valuable information, because if one of their listeners is able to give Kennedy the information he needs, to improve his voice, he really could win the presidency.
And PBD might have to pay a whole lot more in taxes : D.
This is the video where Adam Sosnick mentions RFK's voice...
I've heard Kennedy say that he's had a lot of different people try to recommend various different things to him, for his vocal condition, and he's hesitant to try things until he can clearly see that it worked for someone who has his exact condition. I do get that. But in my opinion, there are lot of things he could try (like antioxidants) that are not just for spasmodic dysphonia, but also for better overall health.
I have some theories about what might help him, but wanted to do some additional research. I've copied some of the research on this page.
Moving Research Forward for More Effective Treatments Panel
Could antioxidants be beneficial for Spasmodic Dysphonia?
https://www.dysphonia.org/sdbb-archive/107.html
| anyone have any thoughts about antioxidants and SD? |  | ||
| Archive | |||
| Posted by: LarBec ® 11/14/2003, 12:32:11 | From reading postings in the past, I gather that most people who have commented about increased vitamin intake have not perceived vitamin supplements (and the like)to have any appreciable benefits for SD. I myself tried Vitamin B supplements (as suggested by a few friends) and noticed no difference in my voice. About 5 months ago, I started a daily regimen of drinking 1 tablespoon of wild blueberry concentrate diluted in a half glass of water (equivalent to 1 cup of wild blueberries). I did that because a friend said that a similar regimen had helped to lower her cholesterol significantly. Blueberries are among the best antioxidant sources, of course, and antioxidants have been shown to be good for the brain (and for improving night vision). Curiously, my ADSD voice is now stronger than it's been in a few years (though it's hardly my old "normal" voice). In fact, I haven't had a Botox injection in 6 months and my otolaryngologist told me yesterday that I should continue to postpone the next injection. I'm certainly not saying blueberries are any type of cure, but I'm wondering if other SD'ers have had any experience in upping their consumption of antioxidants. Sorry this was so long. Thanks, Larry |
2023 Symposium | Everything You Wanted to Know about Voice
Cannabis 101 and Spasmodic Dysphonia
Treatment Paths for Spasmodic Dysphonia and Related Voice Conditions Panel | NSDA Virtual Symposium
- A 2006 meta-analysis of four randomized clinical trials found that a daily 600 mg intravenous infusion of ALA for three weeks reduced pain, numbness, and paresthesia in diabetic patients with DSP. The study also found that ALA improved neuropathic deficits.
- A 2023 subgroup analysis of 10 randomized controlled trials (RCTs) found that ALA treatment reduced sensory symptoms of DSPN in a dose-dependent manner. The study also found that ALA treatment had favorable effects on TSS and global satisfaction score.
Daily Vocal Routine for a Strong Voice 🙌 (MP3 Downloads)
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Alpha-Lipoic Acid and Diabetic Neuropathy
Abstract
Diabetic neuropathy presents a major public health problem. It is defined by the symptoms and signs of peripheral nerve dysfunction in diabetic patients, in whom other causes of neuropathy have been excluded. Pathogenetic mechanisms that have been implicated in diabetic neuropathy are: a) increased flux through the polyol pathway, leading to accumulation of sorbitol, a reduction in myo-inositol, and an associated reduced Na+-K+-ATPase activity, and b) endoneurial microvascular damage and hypoxia due to nitric oxide inactivation by increased oxygen free radical activity. Alpha-lipoic acid seems to delay or reverse peripheral diabetic neuropathy through its multiple antioxidant properties. Treatment with alpha-lipoic acid increases reduced glutathione, an important endogenous antioxidant. In clinical trials, 600 mg alpha-lipoic acid has been shown to improve neuropathic deficits. This review focuses on the relationship of alpha-lipoic acid and auto-oxidative glycosylation. It discusses the impact of alpha-lipoic acid on hyperglycemia-induced oxidative stress, and examines the role of alpha-lipoic acid in preventing glycation process and nerve hypoxia.
Introduction
Diabetic neuropathy is defined by the signs and symptoms of peripheral nerve dysfunction in diabetic patients, in whom other causes of neuropathy have been excluded [1]. Diabetic neuropathy includes a number of different syndromes, depending on the classes of nerve fibers involved [2]. According to the San Antonio Convention, the major groups of neurologic disorders in patients with diabetes mellitus are: 1. subclinical neuropathy defined by abnormalities in electrodiagnostic and quantitative sensory testing, 2. diffuse clinical neuropathy with distal sensorimotor and autonomic syndromes, and 3. focal syndromes [3].
At least 25% of diabetic patients are affected by distal symmetric polyneuropathy, which is a major public health problem, as it is responsible for considerable morbidity and mortality [4-7]. Distal symmetric polyneuropathy is a major contributing factor for diabetic foot ulcer, osteoarthopathy, osteomyelitis, and lower limb amputation. The latter is fifteen times higher in diabetic patients than in the general population [5, 8]. Neuropathic pain affects approximately 16% of diabetic patients [9]. This subjective symptom impairs quality of life and sleeping as it usually gets worse at night [1, 8]. It is often the major complaint that motivates patients to seek health care [10]. However, treatment of painful diabetic symmetric polyneuropathy is still a challenge for the physician [11].
Treatment of diabetic neuropathy is based on: 1. aiming at near-normoglycemia, 2. pathogenetically oriented therapy, 3. symptomatic therapy, and 4. avoidance of risk factors [8]. Near-normoglycemia is generally accepted as the first approach towards preventing diabetic neuropathy [12, 13]. As normoglycemia is difficult to achieve, additional treatment of painful symptoms is frequently required [14]. Pathogenetically oriented therapy may delay, stop, or reverse the progression of neuropathy and may alleviate pain. Whilst symptomatic therapy does not influence the course leading to neuropathy, it may alleviate painful symptoms [15].
Antidepressants (SSRIs and tricyclic), opioids (e.g. controlled-release oxycodone), and older anticonvulsants (e.g. carbamazepine) all seem to alleviate pain, but have several adverse side effects [16]. Newer anticonvulsants such as gabapentin and pregabalin have a high affinity binding to α2-δ subunit of voltage-activated calcium channels. They combat painful diabetic neuropathy, partly via calcium channel modulation in the pathogenesis of diabetic neuropathy [16, 17].
Pathogenesis of diabetic neuropathy
The pathogenesis of diabetic neuropathy is complicated. The following mechanisms seem to be involved: 1. increased flux through the polyol pathway, mediated by aldose reductase and sorbitol dehydrogenase, leading to accumulation of sorbitol and depletion of myo-inositol. The latter reduction is associated with reduced Na+-K+-ATPase activity [8]. 2. Endoneurial microvascular damage and hypoxia due to nitric oxide inactivation [18]. 3. Accumulation of advanced glycation end products (AGEs) that exert their damaging effects by binding to specific receptors on the surface of neurons. Binding of AGEs to their receptors causes oxidative stress and activates nuclear factor-κB (NF-κB). There is increasing evidence that the diverse agents able to activate NF-κB elevate levels of reactive oxygen species (ROS). Also, chemically distinct antioxidants and overexpression of antioxidant enzymes can inhibit NF-κB activation [8, 18-20]. 4. Increased nerve lipid peroxidation in vivo. The most reliable index of increased oxidative stress is reduction in GSH [18]. 5. Activation of protein kinase C (PKC) by increased release of intracellular diacylglycerol (DAG) due to glycolysis. Hyperglycemia activates PKC, especially its βII isoform through increased de novo synthesis of DAG. The increased activity of PKCβ may impair endoneurial blood flow. Recently, hyperglycemia has been associated with activation of PKC and increase in Nav1.7 tetrodotoxin-sensitive voltage-gated sodium channel isoform; both of which play a critical role in the perception of pain [21-24]. 6. Alterations in mitogen-activated protein kinases (MAPKs) result in a signaling cascade involved in the pathogenesis of peripheral diabetic neuropathy [25]. 7. Abnormal Ca2+ homeostasis and signaling [26].
As mentioned above, hyperglycemia-induced ischemic and auto-oxidative lipid peroxidation is suggested to cause diabetic neuropathy (Figure (Figure1).1). Streptozotocin-induced experimental diabetic neuropathy in rats is associated with a nerve blood flow deficit of 50% [18]. Endoneurial hypoxia is secondary to a reduction in nerve blood flow and increased endoneurial vascular resistance. Hyperglycemia acts via a reduction in nitric oxide resulting in impaired microvascular tone, reduced nerve blood flow, and endoneurial hypoxia [27, 28]. Hypoxic nerve can continue to function on glucose alone under anoxic circumstances via anaerobic glycolysis. A detrimental effect is hyperactivity of the polyol pathway resulting in an increase in sorbitol and a reduction in myo-inositol [27-30]. Nevertheless, sorbitol per se is non-toxic and it seems likely that mechanisms other than nerve sorbitol accumulation cause neuropathy. The reduction in myo-inositol has been linked to neuropathy via reduction in Na+-K+-ATPase activity [31-37]. The mechanism of myo-inositol reduction by hyperactivity of the polyol pathway is not completely known, but hyperglycemia could reduce nerve myo-inositol by competitive inhibition of peripheral nerve myo-inositol uptake. Osmolyte and non-osmolyte mechanisms could be involved [38, 39].
Increased oxidative stress in diabetes appears to be mainly due to hyperglycemia, which leads to AGE formation and polyol pathway activation, resulting in subsequent formation of reactive oxygen species. AGE: advanced glycation end product.
The effectiveness and tolerability of aldose reductase inhibitors and protein kinase C inhibitors are currently being investigated [40]. Besides, acetyl-L-carnitine is deficient in diabetes. Substitution with acetyl-L-carnitine corrects perturbations of neural Na+-K+-ATPase, myo-inositol, and nitric oxide. It also improves nerve fiber regeneration and alleviates symptoms, particularly pain in patients with established diabetic neuropathy [41-43]. Alpha-lipoic acid seems to normalize endoneurial Na+-K+-ATPase activity in experimental diabetic nerves [44]. As observed in retinal cells, the improved Na+-K+-ATPase activity could improve myo-inositol uptake by the Na+-myo-inositol co-transporter [34-37]. Alpha-lipoic acid has an effect on glucose uptake, thereby increasing polyol pathway activity [44]. It is known to increase Krebs cycle activity, too [45]. The effects of alpha-lipoic acid on glucose uptake and polyol metabolites, as well as the ability of alpha-lipoic acid to increase pyruvate dehydrogenase and α-ketoglutarate activity in a number of non-neural tissues, suggest that the effects of alpha-lipoic acid on the polyol pathway and the Krebs cycle are worth further exploration [44, 45].
Oxidative stress and alpha-lipoic acid
Hyperglycemia-induced oxidative stress induces programmed cell death of nerves, which contributes to the pathology of diabetic neuropathy [46, 47]. A study found reduced frequency of apoptosis in diabetic animals that were treated with the antioxidant taurine [48]. Another study reported increased frequency of programmed cell death in cultured dorsal root ganglia when glucose was added [49]. The role of oxidative stress in nerve damage has been extensively studied in experimental diabetes and in diabetic subjects [50-55]. Motor nerve and sensory nerve conduction velocities are the principal endpoints in studying the therapeutic effectiveness of alpha-lipoic acid on nerve function. Alpha-lipoic acid has been shown to improve motor nerve conduction velocity in experimental diabetic neuropathy and protect peripheral nerves from ischemia in rats [54, 55].
Treatment with alpha-lipoic acid increases reduced glutathione (GSH) in vivo and in vitro [56-59]. GSH is an important endogenous antioxidant. Together with lipoic acid it seem to play a major role in redox-dependent mechanisms of various cellular targets [18, 59-61]. Alpha-lipoic acid is a powerful lipophilic free radical scavenger of peripheral nerve both in vitro and in vivo [62, 63]. As diabetes has been associated with increased production and/or decreased clearance of ROS, oxidative stress has been suggested to contribute to defective nerve blood supply and endoneurial oxidative damage [64, 65]. The increased availability of glucose in diabetes induces enhanced production of AGEs. This process is defined as auto-oxidative glycosylation and is considered the major cause of increased ROS production among diabetic subjects [66]. The increased availability of glucose leads to glycation of antioxidant enzymes [67-70]. Therefore, the process of glucose auto-oxidation might be responsible for enhanced ROS production and for decreased availability or activity of antioxidant enzymes [71, 72]. Furthermore, fructose, which is increased due to the activation of the polyol pathway, leads to the formation of AGE precursors [73] (Figure (Figure2).2). Alpha-lipoic acid has additional actions such as stimulating nerve growth factor and promoting fiber regeneration [74, 75].
The polyol pathway converts glucose to fructose via production of sorbitol. AR: aldose reductase. SDH: sorbitol dehydrogenase. AR inhibitors: aldose reductase inhibitors. SDH: sorbitol dehydrogenase.
History of alpha-lipoic acid
R-alpha-lipoic acid (1, 2-dithiolane-3-pentanoic acid) was discovered in 1937 by Snell et al., who found that certain bacteria needed a compound from potato extract for growth [76]. In 1951, the so-called potato-growth factor was isolated by Reed and colleagues, and lipoic acid was discovered as a molecule that assists in acyl-group transfer and as a co-enzyme in the Krebs cycle [77, 78]. In the 1980s, alpha-lipoic acid was recognized as a powerful antioxidant. It is the only fat- and water-soluble antioxidant. It is produced by animals and humans [79], and can be found in liver, skeletal muscle, potatoes, and broccoli [80, 81]. Nutritional supplements of alpha-lipoic acid are typically comprised either of R-alpha-lipoic acid alone or a racemic mixture of R-alpha-lipoic acid and S-alpha-lipoic acid [79].
Alpha-lipoic acid in clinical practice
Diabetic patients with neuropathy treated with alpha-lipoic acid 600 mg i.v. daily for three weeks, have reduced pain, paresthesias, and numbness [14, 80, 81]. According to a recent meta-analysis comprising 1,258 patients, the same treatment ameliorated neuropathic symptoms and deficits after three weeks [81]. Acute infusion of alpha-lipoic acid improved nitric oxide-mediated endothelium-dependent vasodilation in diabetic patients, and improved microcirculation in patients with diabetic polyneuropathy [60-65, 81-89].
Oral treatment with alpha-lipoic acid for five weeks improved neuropathic symptoms and deficits in 187 patients with diabetic symmetrical polyneuropathy. This is an encouraging finding as deficits are major risk factors in the development of neuropathic foot ulcer [10, 90-92]. An oral dose of 600 mg once daily seems to provide the optimum risk-to-benefit ratio in the SYDNEY 2 trial [10]. The adverse effects (mainly nausea) with the 1,200 mg dose daily occurred in 21% of patients, somewhat higher than that observed in the ALADIN I (15%) and ALADIN II study (7%), with the same dose of alpha-lipoic acid [10, 93, 94]. In the seven-month ALADIN III trial, 509 subjects received either 600 mg of alpha-lipoic acid or placebo. While no significant difference was noted in subjective symptom evaluation among the groups, treatment with alpha-lipoic acid was associated with improved nerve function [95].
In the ISLAND Study, 300 mg of alpha-lipoic acid was applied as monotherapy and in combination with 150 mg imbesartan daily. There was a significant increase in endothelium-dependent flow-mediated vasodilation of the brachial artery, by 44% and 75% respectively, compared with placebo treatment after four weeks. This effect was accompanied by reductions in plasma levels of interleukin-6 and plasminogen activator-1, suggesting that alpha-lipoic acid may improve endothelial dysfunction via anti-inflammatory and antithrombotic mechanisms [96]. These anti-inflammatory and antithrombotic properties have previously been observed in streptozotocin-diabetic rats by significant decreases in fibrinogen factor VII and von Willebrand factor (vWF) after treatment with alpha-lipoic acid [97].
Alpha-lipoic acid has been shown to downregulate the expression of cell-adhesion molecules ICAM-1 and VCAM-1 in a dose-dependent manner [98]. These observations might be of preventive and/or therapeutic benefit in arteriosclerosis and other inflammatory disorders [18]. Clinical and postmarketing surveillance studies have revealed a highly favorable safety profile of the drug [99]. Nevertheless, further studies are necessary to assess the neurophysiological and clinical properties of alpha-lipoic acid.
Conclusions
Distal symmetric polyneuropathy is a major public health problem causing substantial morbidity and mortality among diabetic patients. Its pathogenesis remains complicated. Increased flux through the polyol pathway, which leads to accumulation of sorbitol, depletion of myo-inositol, endoneurial microvascular damage, and hypoxia seem to be the underlying pathogenetic mechanisms. The latter is due to nitric oxide inactivation and accumulation of AGEs that exert their damaging effects by binding to specific receptors on the surface of neurons, leading to activation of NF-κB.
The role of oxidative stress in nerve damage has been extensively studied in experimental and clinical diabetes. Alpha-lipoic acid has been shown to improve motor-nerve conduction velocity in experimental diabetic neuropathy, and to protect peripheral nerves from ischemia in rats.
Treatment with alpha-lipoic acid increases GSH in vivo and in vitro. GSH is an important endogenous antioxidant, and together with lipoic acid, it seems to play a predominant role in the redox-dependent mechanisms of various cellular targets. As diabetes has been associated with increased production and/or decreased clearance of ROS, oxidative stress has been suggested to contribute to defective nerve blood supply and endoneurial oxidative damage.
Recently, trials have been conducted with neuropathic diabetes patients who received 600 mg alpha-lipoic acid. The treatment reduced pain, paresthesias, and numbness. Further studies are needed to determine the effectiveness of alpha-lipoic acid in reducing pain and/or preventing the progression of diabetic neuropathy.
Disclosures: The authors report no conflict of interests.
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