Viruses' possible role in Alzheimer's; kids and marijuana candies; crossword strategies: Upstate Medical University's HealthLink on Air for Sunday, Aug. 21, 2022

Host Amber Smith: Coming up next on Upstate's "HealthLink on Air," a microbiologist tells about his research into the suspected connection between herpesviruses and Alzheimer's disease.

Eain Murphy, PhD: ... The herpesvirus family predates the vertebrate-invertebrate split. The evolution of these herpesviruses have been hand in hand with human evolution, and, as such, they've become masters at undermining a lot of our antiviral immune responses. ...

Host Amber Smith: And the medical director of the Upstate New York Poison Center shares important precautions about marijuana edibles.

Vincent Calleo, MD: ... They'll take oneedible, and they won't feel an effect, they'll take a second or a third, and it may be 60, 90, 120 minutes in some cases before they start to feel an effect. As a result, they can have a significant effect because they took in more than they normally would have. ...

Host Amber Smith: All that, and a visit from The Healing Muse. But first, the news.

This is Upstate Medical University's "HealthLink on Air," your chance to explore health, science and medicine with the experts from Central New York's only academic medical center. I'm your host, Amber Smith.

On this week's show, we'll hear about a troubling spike in the number of calls to the Upstate New York Poison Center about children and teens ingesting marijuana edibles.

But first, a microbiologist tells about his research into herpes and Alzheimer's disease.

From Upstate Medical University in Syracuse, New York, I'm Amber Smith. This is "HealthLink on Air."

In the ongoing search to understand why someone develops Alzheimer's, scientists have explored many potential causes, including particular genes and a history of head injuries. There's also thought to be a connection to the herpesvirus. Here to help us understand this research is Dr. Eain Murphy. He's an associate professor of microbiology and immunology, and he's got expertise in herpesviruses. Welcome to "HealthLink on Air," Dr. Murphy.

Eain Murphy, PhD: Thank you, Amber. Good morning.

Host Amber Smith: I know there are a variety of different herpesviruses. Which one do you think might play a role in the development of Alzheimer's disease?

Eain Murphy, PhD: Actually, there's nine herpesviruses, and most people have a majority of them to begin with. EBV (Epstein-Barr virus) is an example. Chickenpox is another example. The ones that I am particularly interested in the case of Alzheimer's are herpes simplex virus 1 (HSV-1) and HHV-6 (human herpesvirus 6). Herpes simplex virus 1 causes the common cold sores you see in individuals, and HHV-6 is a virus that most kids get; it's roseola. They also call it cheek slap (or slapped cheek) syndrome, and most kids get it. You just fight it off, and it's not a big deal.

However, all herpesviruses, when you have them once, you have them for life, because they remain with the host forever, and it's spontaneous reactivations. So, on a regular basis, anybody walking around is probably harboring, I believe the current estimates are, 3.2 different herpesviruses.

Host Amber Smith: So we're not born with herpesviruses, are we?

Eain Murphy, PhD: No, we're not. We get herpesviruses in infections. The most common methodology for catching the herpesvirus is a lot of kids in day cares. Kids in day cares are great incubators for passing around viruses amongst each other.

And for the most part, if you have a healthy, competent immune system, the viruses are fairly benign. They don't cause a lot of issues. It's only after times of stress or immune suppression that the viruses come back and cause problems.

Host Amber Smith: So, you said herpes simplex 1 and 6 are the ones that you're concerned with?

Eain Murphy, PhD: Those are the ones I predominantly work on, and those are the ones that have recently been affiliated with neurological diseases, particularly Alzheimer's.

Host Amber Smith: Tell me again, how do they spread?

Eain Murphy, PhD: Herpesviruses are predominantly spread through saliva. You'll see that they're in body fluids, and so a lot of times there's other herpesviruses that are blood-borne, but for the ones that I'm particularly considering, they're neurotropic viruses, they replicate very well in neurons (nerve cells), but they're originally transmitted in saliva, and they get into cells that are called mucosal epithelial cells. And these are cells that are basically around all of the wet parts on the inside of your body. They code our different organs. And so we have them in our mouth, and it's easy for the virus to get into those cells. It'll replicate there, a small level of replication, and then the virus will eventually find its way to neurons and replicate to high levels there and remain latent in the neurons for the rest of your life.

Host Amber Smith: You mentioned one of the herpesviruses, simplex 1, causes the cold sores.

Eain Murphy, PhD: Correct.

Host Amber Smith: Are there other symptoms? Would we know if we were infected with a herpesvirus?

Eain Murphy, PhD: Well, for the most part, there's a lot of people walking around that are asymptomatic that are carrying this virus. So it's a bigger concern for those individuals that have the virus and they don't know they have the virus. There's blood tests you can take to screen to see if you're seropositive, meaning your body's making antibodies against that virus. And that's kind of our indication that you've encountered the virus in the past, but for the most part, it isn't screened because it's not as strong a medical concern for us to be worried about.

There's other viruses, if you go in and they do a blood test to see if you're carrying antibodies against those pathogens, but for the most part, herpes simplex viruses traditionally were considered not that problematic for individuals. It's unfortunate you get a cold sore, but it wasn't really a life-or-death issue. And so it never moved up the rank to be something that was predominantly screened by blood on a regular basis.

Host Amber Smith: You said these herpesviruses, once we have them, they're with us for life.

Eain Murphy, PhD: Correct.

Host Amber Smith: They're just dormant, not necessarily doing anything?

Eain Murphy, PhD: That's correct. For the most part, these viruses remain latent. They hide in our host cells by shutting down a lot of the activities of the virus.

So when our immune system's surveilling our cells for foreign pathogens, these viruses have adapted very, very well to remain hidden in cells and don't give any overt signs, so our immune system doesn't detect them.

It's kind of interesting, though. My laboratory works on other herpesviruses also, and the herpesvirus family predates the vertebrate/invertebrate split. So these have co-evolved with humans. In fact, one of the viruses we work on in laboratory, cytomegalovirus, you could find in mollusks, so the evolution of these herpesviruses have been hand in hand with human evolution, and as such, they've become masters at undermining a lot of our antiviral immune responses.

Host Amber Smith: All of what you just said is really scary.

Eain Murphy, PhD: Well, we harbor a lot of viruses that don't cause any problem. if you look at a predominant amount of the human genome, it's occupied by remnants of viruses we've encountered in the past, and we've passed them down genetically. And so, at any one point, if you were to surveil your skin, you'd probably be able to detect a whole bunch of different viruses.

Luckily, we have potent antiviral responses, and we have immune systems that keep those in check. And for a virus to establish a productive infection, it needs to overcome a lot of hurdles, and so we've successfully made it here this far in the evolution of life because we can fight off these viruses.

And so amongst those are herpesviruses. We get them, for the most part, they really don't cause many problems in us, but we are carriers of a lot of herpesviruses, and they remain dormant and latent in us. However, in the case of herpes simplex 1, which is what I'm predominantly working on in the case of Alzheimer's, individuals will get herpes simplex 1, and then there's sporadic reactivations of the virus, mostly during times of stress. So you'll see, like, a lot of college students when they're prepping for their exams, always get cold sores because they're under a lot of stress. It's correlated with, exposure to UV (ultraviolet) light, which is stress inducing, hormonal changes in women during their menstrual cycle -- these can all induce reactivations of the virus, and that's why we have sporadic reactivations of herpes simplex. The most overt outward signs we could see of it are lesions on the lips.

Host Amber Smith: So is it your theory that Alzheimer's is sort of a flare-up of a herpesvirus?

Eain Murphy, PhD: No. So, the way I got into this is I traditionally worked on another virus, human cytomegalovirus, but in 2018, four seminal papers came out linking herpesviruses to Alzheimer's.

The first one was a large study that was done in Taiwan in which they took 33,000 different individuals. And they were able to do a large study, prospective study, saying, what do these individuals have outwards in terms of disease? And they could correlate with anything. And what they found is there was a large incident rate of dementia in individuals who had herpesvirus infections. However, those that were undergoing antiviral therapies for herpesviruses didn't show that dementia. So it suggested that maybe the herpesviruses may be leading towards this dementia.

Another paper that came out in 2018 was mouse model systems for Alzheimer's in which they have a mouse that they transgenically, or introduce genes into the mouse, that make the mouse very prone to having Alzheimer's-like symptoms.

In that scenario, they were able to take these mice, infect them with herpesviruses, herpes simplex 1, and the mice that received the virus got dementialike symptoms a lot quicker, and Alzheimer's-like symptoms a lot quicker, to a higher degree, and many of the mice succumb to Alzheimer's-like phenotypes (observable traits). So that was indicative that maybe this might be a causative agent.

The other two papers came out, and those were in Cell Neuron, two very large journals. One showed that if you were to isolate parts of the human brain from an Alzheimer's patient, you can go ahead and notice that in the regions of the brain that had the disease versus regions of the same individual where the tissue was normal, you could find herpes simplex virus DNA, RNA and proteins, but not in the same individual in parts of the brain that were termed normal under examination.

And then another study showed that ... so, going back into the disease of Alzheimer's, you really need three conditions for Alzheimer's. One is inflammation, and we know that inflammation could be caused by viral infections. The other one is accumulation of a protein on the outside of a neuron. And that's beta-amyloid. This other paper suggests that herpesvirus infections increase the depositing of beta-amyloid outside of a neuron. So that suggests that when you infect a neuron, what we see in Alzheimer's may be an aspect of a viral infection.

That's where my work comes in. So I mentioned there's three things. The one was inflammation. The other one is accumulation of beta-amyloid on the outside of the cell. But another ingredient that you need to have a diagnosis of Alzheimer's is accumulation of a protein on the inside of the cell, and that's tau protein.

So neurons, if you could imagine it, are these cells that have these long projections that reach out to a neighboring cell, a neighboring neuron, and that's how we do our neuronal transmissions. To provide rigidity to that long arm that stretches out, the axon, we have these proteins in there called microtubules, and they're kind of like the girders in a building that provide rigidity to this long, stretching arm.

There's this protein called tau, that coats that, that provides additional structural support to those microtubules that we can establish a long axon that reaches across much larger than we see normal cells. Some of these axons are very, very long.

During Alzheimer's disease, patients have the protein tau that normally coats these long microtubule girders that provide rigidity, what they do is they get hyperphosphorylated, which is a modification of the protein. And then they accumulate, and they form an aggregate inside the cell. And this does two things. It makes a cell unhealthy, and it also destabilizes the long axon supports, which we need for neuronal transmission. So what we didn't know in the case of Alzheimer's is, if herpesviruses can cause inflammation and they can cause the accumulation of beta-amyloid outside the cell, what is it doing to tau inside the cell?

And so that's where I started research projects saying, will infection of these neurons cause accumulation of tau inside the cells, the third ingredient we need for Alzheimer's? And, in fact, that is the case.

So, going into the biology of tau, there's two major alternate isoforms (similar forms) of tau. There's one with three repeats of a region. And there's another one with four repeats of a region. And in healthy individuals, we have equal molar amounts of that. So you have the same amount of 3R's, 4R. In individuals where we see that tau is accumulating inside the neuron, similar to what we see in Alzheimer's, there's a shift of that ratio, so that there's either more 3R than 4R or more 4R than 3R.

And when you have a shift in the ratios, then you have the protein start to aggregate. And that's an initiating event we see during Alzheimer's. My research was to determine whether herpesvirus infections can shift the accumulation of 3R and 4R tau. And in fact, the reason I got involved in this is, I'm, as any scientist; we find that we're standing on the shoulders of giants that went before us. And there was a lot of research that went on saying that herpesvirus infections of neuronal cells can cause alternate splicing of transcripts, and transcripts that mRNA, the blueprints making proteins, are ultimately spliced so that you can have one mRNA that encodes a protein, be adjusted in its mRNA level, and that would give rise to a different type of protein, a different isoform of the protein.

And what others have found is that herpesvirus infections can alter the splicing of transcripts, mRNA transcripts, and the result would be that you have different isoforms of proteins.

That's what occurs in tau formation. Tau is ultimately spliced so that the mRNA either includes or excludes that extra repeat region, so you have either 3R and 4R, and we know we need an equal amount of it. However, when we infect cells with herpes simplex virus, it shifts the splicing, so we get more 4R.

And so we think that this might be the last ingredient that we would need in a case where you would say herpesvirus infections may be drivers of Alzheimer's. We get the inflammation. We knew already that it causes accumulation of beta-amyloid outside the cell. And now, finally, we think we may have the link as to what's occurring inside the cell.

With this, I think it makes more sense that we should be more focused on looking at herpesviruses as being drivers of this disease than we have in the past.

Host Amber Smith: Upstate's "HealthLink on Air" has to take a short break, but we'll be back with more about the science of herpesviruses and Alzheimer's disease.

Welcome back to Upstate's "HealthLink on Air," with your host, Amber Smith. I'm talking with associate professor Dr. Eain Murphy. He's a microbiologist at Upstate who studies the connection between herpesviruses and Alzheimer's disease.

So if someone had this herpesvirus in the past, and many of us have, is there anything we can do to guard against it doing this and setting us up for Alzheimer's?

Eain Murphy, PhD: I want to put this in proper context. I don't believe that herpesvirus infections alone may be the driver of Alzheimer's. It should be mentioned that less than 5% of Alzheimer's cases are familial linked -- only 5% are genetically linked -- 95% are of unknown etiology (cause). We don't know what the driver is for those.

Something interesting I would want to point out, too, is we do have biomarkers though, that suggest that if you have a specific gene, you're more likely to get Alzheimer's, even though it's not genetically linked. And one of those is the ApoE4 gene. If you have ApoE4 isoform of this protein, as opposed to ApoE3, which is what most people have, your incidence of getting Alzheimer's has increased eight- to tenfold.

Now what's also interesting, and it's also leading me down the pathway to think that herpesviruses are involved in the progression of Alzheimer's, is that ApoE4 has been found to increase the infectivity of cells by herpesviruses. If you take a neuronal cell and express ApoE4, it's more likely to get infected with a herpesvirus than it is if you expressed a normalized form, ApoE3.

So the biomarker we've been using for years to look to see if somebody has an increased probability of getting Alzheimer's in fact aids an infection for herpes simplex virus 1.

But going to back to your point that you raised, is there something that we should be doing, or should we be concerned if we're herpes simplex virus infected?

And my point would be, I don't know if herpes simplex virus infection alone is sufficient for promoting the whole disease. I would strongly lay the claim that I think it's definitely involved, but there could easily also be environmental factors or genetic factors we haven't identified yet.

So the sheer fact that you're herpes simplex virus positive, you have the virus, it doesn't dictate that you're going to get Alzheimer's. So I don't want to cause a panic on that. In fact, many people have herpes simplex virus infections and progressed a hundred years, and they don't have any symptoms of Alzheimer's. So, not to start a huge panic.

But I do think that because these viruses sporadically reactivate on a regular basis, we talked about that before, with stress and different conditions, that continued insult of the virus replicating in neurons may be something that just pushes a cell to an environment where Alzheimer's disease and Alzheimer's progression may be favored, as opposed to somebody who was not harboring the virus, if that makes sense.

Host Amber Smith: Do scientists generally agree with you? Do they think that herpesvirus plays a role in Alzheimer's?

Eain Murphy, PhD: Well, this is a brand-new field, and the funny thing is, you'll probably get (more) scientists using each other's dirty laundry than they would grasping onto each other's ideas if they differ with their own. But in all fairness, I think we're going to find the case that herpesvirus infections are going to be underlying a lot of diseases. And a specific example is, just recently, Epstein-Barr virus, which is mononucleosis, and people joke around EBV stands for "everybody's virus." I mean, the seropositivity, meaning the individuals encountered, are massive, over 90%. They just found a link between that and multiple sclerosis. That was just a strong study that came out just about a year ago.

And so I think that it's not surprising. I think if you make a strong enough claim and provide enough evidence, I think you would convince people that this is easily a plausible cause of what might be driving somebody to be prone to getting Alzheimer's disease.

Host Amber Smith: At this point, do we have theories about what triggers it from going from probable or maybe to having Alzheimer's?

Eain Murphy, PhD: No. This is a problem with Alzheimer's, and I think anybody who's going to be looking at an Alzheimer's situation, is the disease is very, very slow, and it's a progressive disease, and it takes over a decade before we start seeing outward symptoms of it. So making those links are problematic.

And the other thing that we do then to get around that is we use model systems. And so right now, a lot of people use murine model systems, mouse models, in which they can replicate the phenotypes of Alzheimer's and see if you can manipulate that situation. The problem is, mice aren't humans, right? They're very much different. And so it's very hard to model on that.

So what I've done is, I've set up a collaboration with a very, very good group that's run by my friend who's at Albany in the Neural Stem Cell Institute. What they do is, they develop these organoids, and these organoids, what they can do is, they can take a skin cell from an adult, de-differentiate them to make them look like a stem cell, and then they can re-differentiate them down specific pathways.

So you could take a stem cell, make it into a neuron. They do this for making livers and all these other things. My friend, David Butler, who's at the Neural Stem Cell Institute right up here at Albany, very close to us, has a team there that are making these small organoids, which are like little mini brains.

They're smaller than a pea, and if you dissect them, you could see that these organoids have all of the differentiated cells you would find in a small brain. And so what we're doing now is we're using this as a model system. It's human tissue, and we're now infecting these and finding in these tissues, we're seeing that our hypothesis is correct, that there's alternate splicing of tau, this protein that accumulates inside a cell. And we could see aggregation of the protein based on its modification states afterwards, phosphorylation.

The other thing that's really interesting now is because this group is so good at it, they're able to take skin cells from people who have the ApoE4 isoform, and people who have the ApoE3 isoform make them stem cells.

And then you can go in and use a technology called CRISPR technology, and they could switch in one person's cell, stem cell, the ApoE4 isoform to the ApoE3 isoform and then make organoids of both. So now, genetically, these organoids are identical except for one gene, and now this will allow us to dissect the impact of ApoE4 expression on herpesviruses, promoting a pro-Alzheimer's disease state.

David Butler's been instrumental in this work, and he works in a group with another skilled scientist, Sally Temple, and the two of them have developed this model system that we're able to use here. And it's the case that I'll run over to Albany, or he'll drive the two hours this way, and we swap cells and viruses and do our experiments on both ends. So it's been a great, beneficial situation for both of us.

Host Amber Smith: You're focused on herpesviruses, but are there other viruses that you're looking at as playing a role in Alzheimer's development, as well?

Eain Murphy, PhD: I recently wrote a grant, which was funded by the NIH (National Institutes of Health) to pursue this research, and we originally wanted to look at both HHV-6 and the other virus I mentioned and herpes simplex 1, but the scope of that grant got very large, and we decided for our first pass, we're going to look at predominantly the herpes simplex virus, and so we're doing that first, but we hope to expand this also to HHV-6A, the other virus I talked about as being a possible causative agent.

The reason we focused on herpes simplex 1 is that there was a lot more resources and reagents available to us to start that research sooner. HHV-6A is an understudied virus, and there's not a lot of resources for us to do the work. And so we wanted to prioritize our efforts on the one virus that the resources were there for.

Host Amber Smith: As you learn more about what these viruses do and how they work, are you thinking at all of a way to stop them in their tracks?

Eain Murphy, PhD: Well, that study I originally mentioned, in 2018, they did a prospective study on these more than 33,000 individuals in Taiwan. And they found that individuals that had herpesvirus infections and were taking antiviral medications had reduced levels of dementia. And so it could very well be that we have had drugs that are sitting around for the last 30 years -- acyclovir, valganciclovir -- things we use to block herpesvirus infections may slow the progressive state of Alzheimer's.

I would like to say that. I don't have the evidence to say it yet, but part of the problem with making an Alzheimer's drug pharmaceutically would be that, and this may be a bit political, but patents last 20 years. And so if a company's going to go and make a drug, and it takes them 15 years to get through a clinical trial, they only have a five-year patent window on the drug.

So it might not be financially viable for a company to make a drug along the scenario to block Alzheimer's. However, we may already have, on the shelf, drugs that may slow the progressive state of Alzheimer's, if it comes to pass that I'm correct that herpes simplex virus infections are involved in the progression of Alzheimer's.

The other solution people have mentioned, the solution to that problem, would be for things that are slow, progressive diseases, we extend the patent window to 35 years or 40 years for that one type of family of drugs. I don't want to get into that or not, but right now it's problematic. And a lot of companies don't want to invest in slow progressive disease therapeutics because the window for determining whether there's efficacy is really, really long, and it chews up the patent window.

Host Amber Smith: So, potentially, if someone is diagnosed with Alzheimer's and they are found through a blood test to have herpes simplex 1, are clinicians using herpes medications or could they at this point, and would it have any effect?

Eain Murphy, PhD: They're not, at this point. This is still new research. We're just making these links. And so it has to go through a lot of validation, and they'll have to go through clinical trials and all that. So I don't see any clinicians at this point providing antiviral drugs as a therapeutic remedy for Alzheimer's progression. We're hoping to get to that point. And so we need to publish our work and get it more generally accepted after peer review.

But at this point, where we're at right now is, still doing the bench science (laboratory research). So my laboratory is a bench science, and we'd love to do the bench side to bedside, but that involves a lot larger study than we have the resources and capacity to do just in my laboratory.

Host Amber Smith: So we're a long ways off from knowing this for sure, but could you envision that these herpesviruses are more meaningful than we're treating them now, and do we need to come up with some vaccines or something to protect people from being infected with a herpesvirus to begin with?

Eain Murphy, PhD: That's a great point. An example would be Epstein-Barr virus, and it's linked now to MS (multiple sclerosis).

And so I think that there is now going to be a reprioritization of generation of vaccines that are targeting. So they've made a lot of vaccines against herpes simplex virus in the past, both simplex 1 and simplex 2, with limited results. But now, I think, with new vaccine methodologies on the horizon here with mRNA vaccines and things like that, we may be at a point now that we can expand our ability to make, quickly, effective vaccines. And now that herpes simplex viruses where I said before they're uncomfortable, but they're fairly benign, and it wasn't really a priority. If they find that it is linked to something as a progressive disease, like Alzheimer's, then maybe it'll move up the food chain on which ones get a vaccine priority versus others.

Host Amber Smith: Well, Dr. Murphy, you've got some fascinating research underway, and I really appreciate you making time to tell us about it.

Eain Murphy, PhD: Oh, thank you very much. I hope to come back and tell you more of our exciting results soon.

Host Amber Smith: My guest has been Dr. Eain Murphy, an associate professor of microbiology and immunology at Upstate. I'm Amber Smith for Upstate's "HealthLink on Air."

Marijuana edibles can be particularly dangerous for kids -- next, on Upstate's "HealthLink on Air."

From Upstate Medical University in Syracuse, New York, I'm Amber Smith. This is "HealthLink on Air." The Upstate New York Poison Center is seeing an increase in calls about children and teens who've ingested marijuana edibles. Here to provide advice about edibles is Dr. Vince Calleo. He's the medical director of the poison center. Welcome back to "HealthLink on Air," Dr. Calleo.

Vincent Calleo, MD: Thanks so much, Amber. It's great to be back.

Host Amber Smith: Now is this increase in calls about kids who intended or who accidentally ate cannabis-containing food products?

Vincent Calleo, MD: What we've seen overall in the course of the last few years is an increase in the overall number of cases of pediatric exposures to edible forms of marijuana products. Now, generally once we start to get into the teenage years, it's a lot more challenging to know if something was truly unintentional or accidental, or whether it was something a teenager was trying to do. But, what we have found is there's been a very large increase in the number of cases between the ages of zero to 5, where those almost exclusively end up being accidental or unintentional exposures.

Host Amber Smith: Are these edibles the candy-looking edibles, the gummies or the chocolates?

Vincent Calleo, MD: So it's kind of a mix of a lot of different things. I always tell people that from the poison center, sometimes it's a little bit more challenging to have the really granular details for what the product may have been, simply because we're getting calls coming into the center. But the majority of the time, what we've found is that these products tend to be some form of substance that resembles a candy or a baked good. And that tends to be the most frequent thing that we see for these accidental pediatric exposures.

Host Amber Smith: Now, how big of an increase in the numbers are you seeing?

Vincent Calleo, MD: So, if we're looking at the numbers for, again, just looking in particular at that age range of zero to 5, what we found is that in 2019, we had just under 10 calls for pediatric exposures in this age range. And from January of 2022 up through the end of July/very early beginning of August, we found that we had over 60 calls for that same age range. So, what we found is that based on what we have right now, we're already over six times where we were four years ago for that particular age range. And to be honest with you, we anticipate that number is still going to continue to go up because there's still many months left in this year. So we're on pace to see record numbers of unintentional pediatric exposures to edible products at our center. And so we're on the lookout for that going forward.

Host Amber Smith: Are you seeing similar increases in children over the age of 5 and teenagers?

Vincent Calleo, MD: We definitely did see an overall increase in the number of cases that were called into the center for all children, between the ages of zero to 19. I don't have the exact numbers in front of me right now for what the numbers were, but the number increase was very substantial from 2019 up through 2022.

Host Amber Smith: Now, is the theory behind the sharp increase that because these products are now legal in New York, they're more available?

Vincent Calleo, MD: I always hesitate to say exactly what the cause of these things may be, but I think you hit the nail on the head in speaking to the availability of these products. Whether legalization directly impacted this or not, I don't know. But with that being said, we have found that many more people are reporting using edible forms of THC (delta-9-tetrahydrocannabinol, the main psychoactive ingredient in marijuana) now that it's legalized. And if we're looking at the numbers before the legalization, they were much lower. Now they are higher. Kind of like you said, Amber, I think that one of the main reasons why we saw such a large increase is because these products are more available. And because they look like forms of candy or baked goods, things that are very enticing for small children, they're a lot more likely to go ahead and try to eat these products if they see them sitting out, just because they look like normal sweets.

Host Amber Smith: Have you seen this trend? Have you talked to other poison centers in the country about a trend like this once marijuana was legalized in their states?

Vincent Calleo, MD: It's very interesting that you mention that because there is some published literature out there that looks at a couple of different states, and we have found that our trend is not dissimilar from them in that once legalization occurred, the number of unintentional exposures did go up. And I think, again, it's just because as these products become more available, there's an increased chance that they may be accidentally left out or in a place where a child could get into them. And as a result, you see more children being exposed.

Host Amber Smith: This is Upstate's "HealthLink on Air" with your host, Amber Smith. I'm talking with Dr. Vince Calleo. He's the medical director of the Upstate New York Poison Center -- at 1-800-222-1222 -- and we're talking about how marijuana edibles can be dangerous and how the poison center is seeing a huge increase in calls about them.

Now I'd like to ask you about the difference or the meaningful differences between the effects of marijuana that is smoked versus marijuana that is ingested. Is one more dangerous than the other?

Vincent Calleo, MD: Well, I always tell people that the amount of a substance that you use can really impact how much it affects your body. So if you use enough of anything, it could be dangerous and life threatening. But one of the reasons why we think that edible forms of THC can potentially pose a little bit more of a danger is because when people are using them recreationally, they may think that the amount of time it takes to have an effect from it is similar to if the product was smoked. And in reality, these edible forms of THC can take a lot longer to kick in. So it's not uncommon for us, particularly to see in the teenage or adult population, for patients to call the poison center or be seen in a hospital, saying, "I wasn't feeling an effect, so I took another one," and then all of a sudden they start to feel the effects very, very quickly. So, because they'll take oneedible and they won't feel an effect, they'll take a second or a third, and it may be 60, 90, 120 minutes in some cases before they start to feel an effect. And as a result, they can have a very significant effect because they took in a lot more of the product than they normally would have, thinking that it takes the same amount of time as smoked marijuana to give you that same type of effect. So from that standpoint, it can pose more of a danger if it's not taken properly.

Host Amber Smith: So this can be an issue for adults. Is it a special concern when it's a young child?

Vincent Calleo, MD: It is. So there are a lot of differences that exist between young children, teenagers and adults, and the way that the child's body may respond to something may be different than it will respond from an adult standpoint. And as a result, these children can have much more significant effects, especially because they're much less likely to take an appropriate -- I say "appropriate" dose, but when we're thinking about things from an adult standpoint, if they know to take one gummy, they may just take one gummy. As opposed to a child, if they see a package, they may take multiple gummies because they think it's like a normal pack of fruit snacks or a normal pack of gummies. So as a result, they can get a much larger dose, and children are much smaller, meaning the dose they take in terms of the amount per weight is relatively higher than it is for an adult. And because children are different from the way that their bodies kind of deal with these different medications or substances, they can have more serious and pronounced effects, in many cases, than we typically see with an adult.

Host Amber Smith: If a parent realizes that their child has ingested an edible, but the child seems fine, is there anything the parents need to do, just to be safe?

Vincent Calleo, MD: The first thing I would tell them is to stay calm, because it's not uncommon when this occurs to see families get very, very nervous, much like they would if a child got into any substance. But I always remind families that the time it takes for the body to start to see an effect from these edible forms of marijuana can be very delayed. So even if your child appears to be acting normally, it doesn't mean that they may not get sick. And so if you think your child had gotten into a product, please feel free to call us at the poison center so we can help provide guidance as to how to best take care of your child or loved one. Because like we talked about before, these products can be very, very dangerous. And our job here at the poison center is to help decrease the bad outcomes that could potentially result from these exposures.

Host Amber Smith: These products being legal, you know, a lot of people, a lot more people have them in their homes, and it sounds like you're advising them to treat them like other medications. Keep them up and away from kids?

Vincent Calleo, MD: That's exactly it, Amber. I always remind families to treat edible forms of THC exactly like you treat any dangerous medication. Keep these medications out of sight and out of reach of children. Remember, out of sight, out of mind goes a long way with a small child. And also, if you have available a medication lockbox, keep your edibles in there with it. Lockboxes aren't perfect, but it certainly provides another barrier to help decrease the likelihood, particularly of a young child accidentally getting into these forms of THC. So using a medication lockbox, keeping them out of sight and out of reach, and not taking the product in front of a child can really help decrease the chances that the child may be accidentally or unintentionally exposed.

Host Amber Smith: When a call comes into the poison center, I'm curious how the nurses and doctors and pharmacists at the poison center actually determine if a child needs to be brought to the hospital or see their physician after they've ingested an edible. What sorts of questions are you going to ask the parent?

Vincent Calleo, MD: It really depends on each scenario, but in general, what we like to do here is try to get an overall picture for how old the child is, how much the child weighs, how much of the product they may have been exposed to, when the exposure occurred, if the child's having any symptoms, and some additional information from there. Fortunately here at the poison center, we're very, very lucky to have a very highly trained staff of, like you mentioned, Amber, of doctors and nurses and pharmacists who can answer your questions and help to provide the best guidance on how to safely care for your child. Now, in all reality, there is a good chance that if a child was unintentionally exposed to an edible form of marijuana, they may need to be seen by a health care professional, either a pediatrician or in the emergency department, just to make sure they're safe. Because these products can take a while to start to see an effect, one thing we worry about is that we may not be able to accurately guess who's going to develop significant symptoms and who may have mild ones. So that's why it's always very important to try and seek health care evaluation, or at least the guidance from the poison center to help make that best decision in terms of how to safely, effectively care for your loved one.

Host Amber Smith: Once you've ingested the marijuana product, is there something else that can be done to negate the effects of the marijuana, or to neutralize what has been ingested?

Vincent Calleo, MD: A lot of that depends on how long after the child ingested it that they can get to a health care facility. There is a medication that we use from the toxicology standpoint called activated charcoal. And what this is, is a solution that someone can drink, and it helps to bind to different types of medications or substances. And as a result, it may decrease how much can get into the bloodstream or the body by being absorbed. Now the longer it is from the exposure, the less likely it is that that charcoal is likely to be effective. But with that being said, if you can get it in the child very early and get them to drink it, it may help to decrease the chances that they'll get very, very sick from the THC product.

Now, once you've started to see an effect from the substance on the child, a lot of times it's challenging to think, OK, is there a quote/unquote "antidote" I can give someone? And the answer to that really is there's not. But more importantly than that, from our standpoint, is helping to provide what we call very good supportive care. And essentially that's ensuring that the body's heart rate, blood pressure, oxygen, all those things, we help to keep those at a normal range so that the body can do what it does best. And that's break down the substances in a safe way until the child can get back to normal. So while there may not be a specific antidote, early and timely intervention may be a good way to help get some activated charcoal in their system to decrease how much their body may absorb. But if it's already in their system, we can help to provide that good supportive measure that they need to really have a good outcome.

Host Amber Smith: Do you ever advise parents to induce vomiting?

Vincent Calleo, MD: So, that's not something that we advise doing on a routine basis. In many years past, people used to use something like syrup of ipecac or different things to help make people vomit afterwards. And what we found is that that actually could potentially be dangerous because, in particular if they notice that a child has gotten into one of their products and their mental status or how they respond to the outside world, essentially, if that's changed, and they vomit, there is a good chance that some of that vomit actually may go down the wrong pipe into the lungs and cause a lot of damage. So we don't routinely recommend inducing vomiting or anything like that.

Host Amber Smith: Well, I want to remind listeners your website at upstate.edu/poison has a lot of information on there, including where to obtain free lockboxes. But I know you've also made a video recently aimed at families to help educate about this marijuana-edible issue. So, I want to make sure people are aware that the Upstate New York Poison Center is also on Facebook, so they can find you there, and they can find the video there and lots of other information as well.

Vincent Calleo, MD: Yes. That's all correct. And we're really hoping that this can help to spread the message about some of the ways to help keep children safe.

Host Amber Smith: Well, I appreciate you making time for this interview, Dr. Calleo.

Vincent Calleo, MD: The pleasure was mine, so, thank you.

Host Amber Smith: My guest has been Dr. Vincent Calleo, the medical director of the Upstate New York Poison Center. And once again, that number is 1-800-222-1222. I'm Amber Smith for Upstate's "HealthLink on Air".

Dr. Rachel Fabi is an assistant professor of bioethics at Upstate Medical University. She enjoys constructing crossword puzzles, and she has a side gig writing for The New York Times' "Wordplay" column. So what advice does she have for solving crossword puzzles?

Rachel Fabi, PhD: I would recommend checking out The New York Times' "Wordplay" column, especially with the early week puzzles. The Monday, Tuesday, Wednesday puzzles of The New York Times are the easiest ones of the week. Those are also the columns that I write. I write the Monday, Tuesday and Wednesday columns.

The goal of my column is to help new solvers get better and to learn to recognize patterns and the sorts of things that you'll see in clues, like what does it mean when there's a question mark, or what does it mean when a clue is in quotation marks? Or what does it mean if it ends with "comma, say, question mark"? If you don't do a lot of puzzles, and you're just getting into it, you'll have no idea what that means. And so we write the column for new solvers, with the idea of being here's some tips, to get into it.

Aside from plugging my own column, other things that I recommend to new solvers is to just keep solving, because the more exposure you get to these things that are just in crossword puzzles, these clues to what's going on with the clues, the more you see that, the more you'll understand it quickly.

And the third thing I recommend is to solve the USA Today puzzle. It is written at the easiest level of all of the daily puzzles that are published in newspapers. It is consistently really high quality. It is consistently really inclusive. The constructor slate is really diverse. I think 75% of their puzzles are written by women, compared with other puzzles out there where it's closer to 25%. They've been really intentional about shifting that gender ratio, and so the USA Today is just my favorite beginner puzzle for new solvers to check out.

When you see a clue in quotations, it means that it is looking for an entry that is colloquial that means the same thing. And so it just means what is something that you might say that means the same thing as the thing in quotes?

If your clue is, a noun and it's plural, then your entry is going to be plural. So the part of speech has to match, the tense has to match, that sort of thing.

Brackets usually mean that, the clue is not necessarily a word or that the entry isn't necessarily a word, that you would say; it's more of an action. So for instance, in brackets, you might see, this is a clue that I wrote [more tuna, please]. And the answer was "meow," right? You're not speaking the word "meow," it's just something that means the same thing.

When you have ellipses in the middle of a clue, it means that the first part of the clue before the ellipses is the clue to the entry. And so is the second part. But they're not necessarily related to each other. So it's basically giving you two clues to the same entry. And the "dot-dot-dot" is sort of a way of saying, "Isn't it funny that these two things are related, or that they can both mean the same thing, even though they seem different?"

Another common thing that you'll see in crossword clues is an indication that the answer is going to be in a non-English language. And so sometimes that will be in the form of, like, at the end of the clue, you'll see (Fr), which just means "in French," right? But more commonly, in the clue itself, you'll have a word in that language. So you'll see a French word in this clue or a Spanish word or a German word in the clue, and that tells you that what you're looking for is going to be in French or Spanish or German, or whatever language.

If getting deeper into crosswords more than just solving occasionally is something that you're interested in, again, starting with the USA Today is a good on-ramp, and I think people who, really, this is meant for, people who really love this, will find from that entry point, a lot of different directions that you can go. You can, get involved with sort of crossword Twitter, and that's a whole space where you can connect with other constructors and other solvers. There are tournaments that you can do. Many of them have been online over the last two years, for obvious reasons. But I think, you have opportunities to compete and connect with other people, either online or in real life, and yeah, it's a really welcoming, kind, generous community. People are always looking to mentor new constructors and people who want to learn how to make puzzles. People are generous with their time and happy to help new constructors.

And so, it's a fun space to sort of explore.

Host Amber Smith: You've been listening to Dr. Rachel Fabi from Upstate Medical University.

And now, Deirdre Neilen, editor of Upstate's literary and visual arts journal, The Healing Muse, with this week's selection.

Deirdre Neilen, PhD: Physicians often feel they inhabit two worlds simultaneously. They live with their patients, and they live with their families. A single day may contain a world of joy and a world of sorrow, and they must navigate these very different spaces. Thomas Mampalam is a neurosurgeon in northern California. His poetry has also appeared in JAMA (Journal of the American Medical Association). His poem "Pride and Shame" illustrates the highs and lows of his work.

A good case is a new baby displayed with pride.

In the waiting room, the surgeon stands tall in stride.

Surgery went perfectly just as planned.

Home tomorrow. The family shakes his hand.

Ready for the next task, he declares God's will.

Those years of toil were not such a bitter pill.

Does he deserve a special treat?

A chai latte at a café down the street.

A bad case is a deformed and shameful beast.

He will flee to a foreign city in solitary retreat.

Time crystallizes, matter changes state

like a supersaturated precipitate.

Atoms freely flowing in a prior stage

now are trapped in a lattice cage.

He is humbled and forlorn.

God in heaven do not scorn.

All eyes on him, he counsels the family.

Step by step, day by day is the homily.

This is a known complication.

He warns of a long rehabilitation.

Her husband slouches in the chair.

In a chamber, their voices echo despair.

Their lives are changed forevermore.

The surgeon slips out the sliding door.

Selin Tuysuzoglu Sagalowsky is a pediatric emergency medicine physician. Her poem "Breakfast Elegy" shows a seemingly happy moment between mother and son at breakfast. Yet it brings another moment to the mother's mind when she had to tell a parent that she could not, they could not, save the child. Here is "Breakfast Elegy":

After the egg cracks, and is halved,

I run my finger along its moist inner

membrane. It is the cool of loam

after rain in Stavanger, of forest and fjord,

and of her forehead after death set in,

eyes half open, my finger sweeping her brow

with the same motion, one born

of maternal habit, sweeping a child's brow,

because we had ceased the resuscitation

and my hands were idle.

I sift yolks from the glare, tenderly

picking shards. Chalazae, thick and braided,

tether their sun, until fall: fume of my pan

hissing, all butter and burn. Beyond

last night's Trauma Room doors, a mother watched

me stroke her daughter's hair, and wailed, intuiting final rites.

It's good, mama, he says, the albumin bright

on my son's lips, a flash of river light in winter woods.

what hope might look like. The eggshells, split on the counter,

curl like peels of birch bark, vacant and bare.

They are made of crystals, you know,

that outermost layer, it is called the bloom.

Host Amber Smith: This has been Upstate's "HealthLink on Air," brought to you each week by Upstate Medical University in Syracuse, New York.

Next week on "HealthLink on Air" -- a look at the role of institutional review boards at research universities.

If you missed any of today's show or for more information on a variety of health, science and medical topics, visit our website at healthlinkonair.org. Upstate's "HealthLink on Air" is produced by Jim Howe, with sound engineering by Stephen Shaw.

This is your host, Amber Smith, thanking you for listening.