Day: March 19, 2024

Categories : NeurologyTags :

ADHD Medication Associated with Reduced Mortality

On By ModernMedia
Photo by Annie Spratt on Unsplash

A Swedish study of more than 140 000 individuals with attention-deficit/hyperactivity disorder (ADHD) found that initiation of ADHD medication was significantly associated with a 21% lower mortality two years after diagnosis, according to results published in JAMA. This reduction was especially pronounced for unnatural-cause mortality. Females and males also saw different reductions in types of mortality.

ADHD is the most prevalent neurodevelopmental condition, affecting 5.9% of youths and 2.5% of adults worldwide, according to the 2021 World Federation of ADHD International Consensus Statement. The disorder is associated with a broad range of psychiatric and physical comorbidities, as well as adverse functional outcomes. Furthermore, individuals with ADHD are at twice the risk of premature death, mainly due to unnatural causes.

Randomised controlled trials have demonstrated that ADHD medications, including stimulant and nonstimulant medications, are effective in reducing core ADHD symptoms for children and adults with ADHS. Pharmacoepidemiological studies have also shown reduced risks of negative outcomes, including injuries, traffic collisions, and criminality, which would be expected to decrease the mortality rate. However, there are concerns regarding the cardiovascular safety of ADHD medications, especially following long-term use, which could increase the mortality rate.

To date, three studies have examined the association between ADHD medication and mortality with mixed results. These studies had significant limitations, such as the absence of a control group. To date, there has been no study on the association in adults with ADHD. There are increasing diagnoses of ADHD among adults, who have a higher prevalence of somatic comorbidities, including cardiovascular diseases and other conditions, compared with children and adolescents.

Using the Swedish national registers, the researchers investigated whether initiation of ADHD medication was associated with mortality, using the target trial emulation approach to avoid key biases in pharmacoepidemiological studies.

They assessed for all 6 medications licensed for ADHD treatment in Sweden (methylphenidate, amphetamine, dexamphetamine, lisdexamfetamine, atomoxetine, and guanfacine) during the 2007-2020 period. Analysis of the data showed that, for a two-year follow-up, lower all-cause (hazard ratio [HR], 0.79) and unnatural-cause (HR, 0.75) mortality for the ADHD medication group, but there was no significant association with natural-cause mortality (HR, 0.86). Under unnatural causes, accidental poisoning mortality was halved (HR, 0.47).

Subgroup analysis revealed that for females, the only significant reduction in mortality was for natural causes. The authors noted that this may be due to higher rates of comorbid depression, sleep disorder, atrial fibrillation, and asthma.

When follow-up was extended to five years, associations attenuated save for unnatural-cause mortality (HR, 0.89).

The authors concluded, “ADHD medication may reduce the risk of unnatural-cause mortality by alleviating the core symptoms of ADHD and its psychiatric comorbidities, leading to improved impulse control and decision-making, ultimately reducing the occurrence of fatal events, in particular among those due to accidental poisoning.”

For limitations, the observational nature of the study cannot establish causation, and the authors noted confounding effects such as nonpharmaceutical treatment of ADHD. Potential type I error resulting from multiple comparisons regarding cause-specific mortality and subgroup analyses meant the results are only exploratory. Two more limitations were uncertain adherence to medication and potential misclassification of deaths such as potential cases of suicide being marked as accidental poisoning.

Categories : Cardiovascular DiseaseTags :

Timed Therapy with Intense Light can Benefit Cardiovascular Health

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Managing circadian rhythms through intense light and chronologically timed therapy can help prevent or treat a variety of circulatory system conditions including heart disease, according to a new study published in Circulation Research.

“The impact of circadian rhythms on cardiovascular function and disease development is well established,” said the study’s lead author Tobias Eckle, MD, PhD, professor of anaesthesiology at the University of Colorado School of Medicine.

“However, translational preclinical studies targeting the heart’s circadian biology are just now emerging and are leading to the development of a novel field of medicine termed circadian medicine.”

The senior author is Professor Tami A. Martino, PhD, distinguished chair in molecular and cardiovascular research at the University of Guelph in Ontario, Canada.

The study reviews current circadian medicine research, focusing on the use of intense light therapy following surgery, utilizsng light to treat cardiac injury, exploring how cardiovascular disease can differ between men and women and administering drugs at specific times of day to coincide with the body’s internal clock to speed healing.

It also urges more aggressive use of this therapy in humans, rather than relying on mostly animal models.

“There are literally millions of patients who could benefit from this,” Eckle said.

“The treatments are almost all low-risk. Some involve using light boxes and others use drugs that are already on the market.”

Circadian rhythms significantly influence how the cardiovascular system operates. Timing is everything. Blood pressure and heart rates follow distinct patterns, peaking during the day and ebbing at night. When this is disrupted, it leads to worse cardiovascular disease outcomes including myocardial infarction and heart failure. Light is critical in maintaining the proper balance and functioning of the body. Shift employees who may work night hours then day hours often have worse cardiac outcomes.

Eckle, who has studied circadian rhythm and health for years, said intense light can help heal the body after heart surgery while protecting it from injury during surgery, including reducing the chances of cardiac ischemia.

According to the researchers, when light hits the human eye it is transmitted to the suprachiasmatic nucleus, a structure in the brain’s hypothalamus that regulates most circadian rhythms in the body.

Intense light stabilizes the PER2 gene and increases levels of adenosine, which blocks electrical signals in the heart that cause irregular rhythms, making it cardiac protective.

Eckle has used light therapy with patients after surgery and seen positive results including lower levels of troponin, a key protein whose elevation can signal a heart attack or stroke.

Given the mounting evidence that intense light and timed drug treatments are effective, he said, it is time to move forward with more clinical trials.

“Circadian rhythms play a crucial role in cardiovascular health, influencing the timing of onset and severity of cardiovascular events and contributing to the healing process from disease,” Eckle said. “Studies in humans are clearly required. Regarding intense light therapy, chronotherapy and restricted feeding are low-risk strategies that should be tested sooner than later.”

Source: University of Colorado Anschutz Medical Campus

Categories : Neurology PaediatricsTags :

Could a Simple Eye Reflex Test Pick up Autism in Children?

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Photo by Helena Lopes on Unsplash

Scientists at UC San Francisco that they may have discovered a new way to test for autism by measuring how children’s eyes move when they turn their heads. They found that children with a variant of a gene that is associated with severe autism are hypersensitive to this motion.

The gene, SCN2A, makes an ion channel that is found throughout the brain, including the region that coordinates movement – the cerebellum. Several variants of this gene are also associated with severe epilepsy and intellectual disability.

The researchers found that children with these variants have an unusual form of the reflex that stabilizes the gaze while the head is moving, called the vestibulo-ocular reflex (VOR). In children with autism, it seems to go overboard, and this can be measured with a simple eye-tracking device.

The discovery, published in the journal Neuron, could help to advance research on autism, which affects 1 out of every 36 children in the United States. And it could help to diagnose kids earlier and faster with a method that only requires them to don a helmet and sit in a chair.

“We can measure it in kids with autism who are non-verbal or can’t or don’t want to follow instructions,” said Kevin Bender, PhD, a professor in the UCSF Weill Institute for Neurosciences and co-senior author of the study. “This could be a game-changer in both the clinic and the lab.”

A telltale sign of autism in an eye reflex

Of the hundreds of gene mutations associated with autism, variants of the SCN2A gene are among the most common.

Since autism affects social communication, ion channel experts like Bender had focused on the frontal lobe of the brain, which governs language and social skills in people. But mice with an autism-associated variant of the SCN2A gene did not display marked behavioral differences associated with this brain region.

Chenyu Wang, a UCSF graduate student in Bender’s lab and first author of the study, decided to look at what the SCN2A variant was doing in the mouse cerebellum. Guy Bouvier, PhD, a cerebellum expert at UCSF and co-senior author of the paper, already had the equipment needed to test behaviors influenced by the cerebellum, like the VOR.

The VOR is easy to provoke. Shake your head and your eyes will stay roughly centered. In mice with the SCN2A variant, however, the researchers discovered that this reflex was unusually sensitive. When these mice were rotated in one direction, their eyes compensated perfectly, rotating in the opposite direction.

But this increased sensitivity came at a cost. Normally, neural circuits in the cerebellum can refine the reflex when needed, for example to enable the eyes to focus on a moving object while the head is also moving. In SCN2A mice, however, these circuits got stuck, making the reflex rigid.

A mouse result translates nearly perfectly to kids with autism

Wang and Bender had uncovered something rare: a behaviour that arose from a variant to the SCN2A gene that was easy to measure in mice. But would it work in people?

They decided to test it with an eye-tracking camera mounted on a helmet. It was a “shot in the dark,” Wang said, given that the two scientists had never conducted a study in humans.

Bender asked several families from the FamilieSCN2A Foundation, the major family advocacy group for children with SCN2A variants in the US, to participate. Five children with SCN2A autism and eleven of their neurotypical siblings volunteered.

Wang and Bender took turns rotating the children to the left and right in an office chair to the beat of a metronome. The VOR was hypersensitive in the children with autism, but not in their neurotypical siblings.

The scientists could tell which children had autism just by measuring how much their eyes moved in response to their head rotation.

A CRISPR cure in mice

The scientists also wanted to see if they could restore the normal eye reflex in the mice with a CRISPR-based technology that restored SCN2A gene expression in the cerebellum.

When they treated 30-day-old SCN2A mice – equivalent to late adolescence in humans – their VOR became less rigid but was still unusually sensitive to body motion. But when they treated 3-day-old SCN2A mice – early childhood in humans – their eye reflexes were completely normal.

“These first results, using this reflex as our proxy for autism, point to an early window for future therapies that get the developing brain back on track,” Wang said.

It’s too early to say whether such an approach might someday be used to directly treat autism. But the eye reflex test, on its own, could clear the way to more expedient autism diagnosis for kids today, saving families from long diagnostic odysseys.

“If this sort of assessment works in our hands, with kids with profound, nonverbal autism, there really is hope it could be more widely adopted,” Bender said.

Source: University of California – San Francisco

Categories : Genetics Metabolic DisordersTags :

Smart Moo-ve for Diabetes Treatment: Insulin Produced in Cow’s Milk

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Photo by Pixabay on Pexels

An unassuming brown bovine from the south of Brazil has made history as the first transgenic cow capable of producing human insulin in her milk. The advancement, led by researchers from the University of Illinois Urbana-Champaign and the Universidade de São Paulo, could herald a new era in insulin production, one day eliminating drug scarcity and high costs for people living with diabetes.

“Mother Nature designed the mammary gland as a factory to make protein really, really efficiently. We can take advantage of that system to produce a protein that can help hundreds of millions of people worldwide,” said Matt Wheeler, professor in the Department of Animal Sciences, part of the College of Agricultural, Consumer and Environmental Sciences (ACES) at U. of I.

Wheeler is lead author on a new Biotechnology Journal study describing the development of the insulin-producing cow, a proof-of-concept achievement that could be scaled up after additional testing and FDA approval.

Precise insertion of DNA

Wheeler’s colleagues in Brazil inserted a segment of human DNA coding for proinsulin – the protein precursor of the active form of insulin – into cell nuclei of 10 cow embryos. These were implanted in the uteruses of normal cows in Brazil, and one transgenic calf was born. Thanks to updated genetic engineering technology, the human DNA was targeted for expression – the process whereby gene sequences are read and translated into protein products – in mammary tissue only.

“In the old days, we used to just slam DNA in and hope it got expressed where you wanted it to,” Wheeler said. “We can be much more strategic and targeted these days. Using a DNA construct specific to mammary tissue means there’s no human insulin circulating in the cow’s blood or other tissues. It also takes advantage of the mammary gland’s capabilities for producing large quantities of protein.”

When the cow reached maturity, the team unsuccessfully attempted to impregnate her using standard artificial insemination techniques. Instead, they stimulated her first lactation using hormones. The lactation yielded milk, but a smaller quantity than would occur after a successful pregnancy. Still, human proinsulin and, surprisingly, insulin were detectable in the milk.

“Our goal was to make proinsulin, purify it out to insulin, and go from there. But the cow basically processed it herself. She makes about three to one biologically active insulin to proinsulin,” Wheeler said. “The mammary gland is a magical thing.”

The insulin and proinsulin, which would need to be extracted and purified for use, were expressed at a few grams per liter in the milk. But because the lactation was induced hormonally and the milk volume was smaller than expected, the team can’t say exactly how much insulin would be made in a typical lactation.

Conservatively, Wheeler says if a cow could make 1 gram of insulin per liter and a typical Holstein makes 40 to 50 litres per day, that’s a lot of insulin. Especially since the typical unit of insulin equals 0.0347 milligrams.

“That means each gram is equivalent to 28,818 units of insulin,” Wheeler said. “And that’s just one liter; Holsteins can produce 50 liters per day. You can do the math.”

The team plans to re-clone the cow, and is optimistic they’ll achieve greater success with pregnancy and full lactation cycles in the next generation. Eventually, they hope to create transgenic bulls to mate with the females, creating transgenic offspring that can be used to establish a purpose-built herd. Wheeler says even a small herd could quickly outcompete existing methods – transgenic yeast and bacteria – for producing insulin, and could do so without having to create highly technical facilities or infrastructure.

“With regard to mass-producing insulin in milk, you’d need specialized, high-health-status facilities for the cattle, but it’s nothing too out of the ordinary for our well-established dairy industry,” Wheeler said. “We know what we’re doing with cows.”

An efficient system to collect and purify insulin products would be needed, as well as FDA approval, before transgenic cows could supply insulin for the world’s diabetics. But Wheeler is confident that day is coming.

“I could see a future where a 100-head herd, equivalent to a small Illinois or Wisconsin dairy, could produce all the insulin needed for the country,” he said. “And a larger herd? You could make the whole world’s supply in a year.

Source: University of Illinois College of Agricultural, Consumer and Environmental Sciences