Day: July 17, 2024

Categories : PaediatricsTags :

Siblings of Autistic Children have Higher Risk of Autism

On By ModernMedia
Photo by Ben Wicks on Unsplash

Siblings of autistic children have a 20% chance of being autistic themselves – about seven times higher than the rate in infants with no autistic siblings, according to new research published in Pediatrics.

The study, by UC Davis MIND Institute distinguished professor Sally Ozonoff and the Baby Siblings Research Consortium, is based on a large, diverse group of families at research sites across the United States, Canada, and the United Kingdom. It confirms the same research group’s 2011 findings about the likelihood of autism in siblings, and adds news information suggesting it is more common, not less, in historically underrepresented groups.

Increasing autism rates prompt new study

“The rate of autism diagnosis in the general community has been steadily increasing since our previous paper was published,” Ozonoff explained. Ozonoff has studied the recurrence of autism in families for decades.

The latest estimates from the Centers for Disease Control and Prevention show that about 1 in 36 children has autism.  In 2011, the estimate was 1 in 68.

Ozonoff noted that there have also been changes in autism diagnostic criteria over the past decade. In addition, there is a growing awareness of autism in girls.

“So, it was important to understand if these had any impact on the likelihood of autism recurrence within a family,” she said.

The 2011 paper found a recurrence rate of 18.7%, while the new paper found a rate of 20.2% – a small but not significant increase.

“This should reassure providers who are counseling families and monitoring development. It should also help families plan for and support future children,” Ozonoff said.

A larger, more diverse study

The new study included data from 1605 infants at 18 research sites. All infants had an older autistic sibling.

“This study was much larger than the first and included more racially diverse participants,” Ozonoff said. The original study included 664 children.

Researchers followed the children from as early as six months of age for up to seven visits. Trained clinicians assessed the children for autism at age three using the Autism Diagnostic Observation Schedule (ADOS-2), a well-validated tool. The data were gathered from 2010 to 2019.

Sex of first autistic child, multiple autistic siblings key factors

Researchers found that the sex of the first autistic child influenced the likelihood that autism would recur within a family.

“If a family’s first autistic child was a girl, they were 50% more likely to have another child with autism than if their first autistic child was a boy,” Ozonoff said. “This points to genetic differences that increase recurrence likelihood in families who have an autistic daughter.”  

The researchers also found that a child with multiple autistic siblings has a higher chance of autism (37%) than a child with only one sibling on the spectrum (21%).

The sex of the infant was also associated with the likelihood of familial recurrence. If the later-born infant was a boy, they were almost twice as likely as a girl to be diagnosed themselves.

“The familial recurrence rate if the new baby was a boy was 25%, whereas it was 13% if the new baby was a girl,” Ozonoff explained. “This is in line with the fact that boys are diagnosed with autism about four times as often as girls in general.”

Race, maternal education level influence recurrence

The researchers found that race and the mother’s education level were likely factors as well. In non-white families, the recurrence rate was 25%. In white families, the recurrence rate was about 18%. In families where the mother had a high school education or less, recurrence was 32%. With some college, the rate was 25.5%, and with a college degree the rate was 19.7%. When the mother had a graduate degree, it dropped to 16.9%.

“These findings are new – and critical to replicate,” Ozonoff explained. “They do mirror the recent CDC findings that autism is more prevalent in children of historically underrepresented groups.” She noted that this reversed a longtime trend of lower prevalence in those groups. 

Most importantly, said Ozonoff, if these findings are replicated, they may indicate that there are social determinants of health that may lead to higher rates of autism in families. She emphasized that this study was not designed to answer those critical questions, and more research is needed.

Tracking outcomes

Unlike the first study, the researchers also tracked families who dropped out of the three-year study to see if their outcomes differed from those who did. “We wondered whether families who stayed in the study may have had children who were more affected — making them more worried about their development,” she explained.

That could have biased the estimates of recurrence to be higher than they really were. The current study showed that was not the case.

“So, now we have two large, independent studies that report familial recurrence in the same range,” Ozonoff said. “This reinforces how important it is that providers closely monitor the siblings of autistic children for delays in social development or communication. This is especially true in families who have reduced access to care, because early diagnosis and intervention are critical.”

Categories : CancerTags :

Why are Some Cancers Resistant Even Before the First Treatment?

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Squamous cancer cell being attacked by cytotoxic T cells. Image by National Cancer Institute on Unsplash

In cancer, it is well known that small numbers of drug-resistant cells likely exist in tumours even before they’re treated. In something of a paradox, before treatment, these mutants have been repeatedly shown to have lower fitness than the surrounding ancestor cells from which they arose. It leads to a scenario that seems to break Darwin’s rules. Why is it that these least-fit cells survive?

In a new study published in PRX Life, researchers at Case Western Reserve University and Cleveland Clinic reveal a fascinating discovery: interactions between these mutants and their ancestors, like two species in an ecosystem, may hold the key to understanding this paradox.

Their findings suggest these ecological interactions play a pivotal role in reducing the costs of resistance, providing a path to survival for preexisting resistance. And not just in lung cancer, but across various biomedical contexts where drug resistance is a challenge, including other cancers, pathogens and even parasites.

The study

Combining computer simulations and analytical results, the study establishes a mathematical framework to examine the impact of these ecological interactions on the evolutionary dynamics of resistance.

“This is a really exciting finding because it settles some fundamental disagreements between classical population genetics and theoretical ecology,” said the study’s principal investigator Jacob Scott, staff physician-scientist at Cleveland Clinic and an associate professor of physics and medicine at Case Western Reserve.

The study also highlights the clinical relevance of these findings by genetically engineering common resistance mechanisms observed in non-small-cell lung cancer, a disease notorious for preexisting resistance to targeted therapies.

Each genetically engineered cancer cell line experienced a benefit from being with its ancestor, in the group’s evolutionary game assay when cultured with their treatment sensitive ancestor, just as the new theory predicted, bringing closure to the paradox.

“Our findings offer an attractive new hypothesis for why treatment resistance is so common: The resistant cells are saved from extinction by the other cells surrounding them through an ecological mechanism,” said Jeff Maltas, the study’s lead author and a post-doctoral fellow at Case Western Reserve. “These results provide a novel treatment strategy: designing treatments that disrupt the ecological interaction that allows resistance to gain a foothold in the first place, rather than developing new drugs for increasingly resistant populations.”

The hope is that this multidisciplinary research may lead to innovative approaches to fighting cancer and infectious diseases, the researchers said.

Source: Case Western Reserve University

Categories : Metabolic DisordersTags :

New Method Could Boost GLP-1 Agonists While Reducing Side Effects

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Photo by I Yunmai on Unsplash

By modulating a network of proteins found in the central nervous system, the effectiveness and reduce the side effects of glucagon-like peptide (GLP)-1 agonists.

The study, published in the Journal of Clinical Investigation, focused on two proteins called melanocortin 3 and melanocortin 4 found primarily on the surface of neurons in the brain that play a central role in regulating feeding behaviour and maintaining the body’s energy balance.

Melanocortin 3 and melanocortin 4 impact everything from sensing long-term energy stores to processing signals from the gut regarding short-term fullness, or satiety, said U-M physiologist Roger Cone, who led the study.

The GLP-1 agonist class, which includes semaglutides and tirzepatides, has received substantial attention recently for their effectiveness in treating not only type 2 diabetes, but also obesity, heart disease and potentially addiction. They work by mimicking a natural satiation hormone, triggering the brain to reduce feeding behaviour.

“So the obvious question for us was: How do these GLP-1 drugs, which work by manipulating satiety signals, function when we prime the melanocortin system?” said Cone, professor of molecular and integrative physiology at the U-M Medical School and director of the U-M Life Sciences Institute where his lab is located.

Working in mouse models, Cone and his colleagues tested the effects of several hormones that reduce food intake. They compared the results in normal mice with mice that genetically lacked the MC3R protein, in mice that were given chemicals to block the activity of MC3R, and in mice that were given a drug to increase the activity of MC4R. (Because MC3R is a natural negative regulator of MC4R, meaning it decreases the activity of MC4R, blocking MC3R and increasing MC4R activity has similar effects.)

In all cases, Naima Dahir, first author of the study and a postdoctoral research fellow in Cone’s lab, and colleagues found that adjusting the melanocortin system – either by inhibiting MC3R or increasing MC4R activity – made the mice more sensitive to GLP-1 drugs and other hormones that affect feeding behaviour. The mice that were given a GLP-1 drug in combination with an MC4R agonist or MC3R antagonist showed up to five times more weight loss and reduced feeding than mice receiving only the GLP-1 drugs.

“We found that activating the central melanocortin system hypersensitises animals to the effects of not just GLP-1s, but to every anti-feeding hormone we tested,” Cone said.

The researchers also measured activity in parts of the brain thought to trigger nausea in response to GLP-1 drugs and observed no increased activation when GLP-1 drugs were combined with alterations to the melanocortin system. In contrast, priming of the melanocortin neurons significantly increased GLP-1 drug activation of neurons in hypothalamic feeding centres in the brain.

The findings indicate that pairing the existing GLP-1 drugs with an MC4R agonist could increase sensitivity to the desired effects of the drugs by up to fivefold, without increasing unwanted side effects. Ultimately, this approach could enable patients who are sensitive to the side effects to take a lower dose, or could improve the results in patients who have not responded to the existing drug dosages. Further drug development and clinical testing are needed before this can occur.

While this research has been conducted only in mouse models, Cone is optimistic that the results will translate well to humans.

“The melanocortin system is highly conserved in humans,” he said. “Everything we’ve observed in the mouse over the past decades studying these proteins has also been found in humans, so I suspect that these results would also be translatable to patients.”

Source: University of Michigan

Categories : Respiratory DiseasesTags :

Respiratory Bacteria ‘Turns off’ Immune System to Survive

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Scanning electron microscope image of bacteria responsible for Haemophilus influenzae type B infections. Photographer Alain Grillet. Copyright Sanofi Pasteur

Researchers from The University of Queensland have identified how a common bacterium is able to manipulate the human immune system during respiratory infections and cause persistent illness.

The research, led by Professor Ulrike Kappler from UQ’s School of Chemical and Molecular Biosciences, studied the virulence mechanisms of Haemophilus influenzae, a bacterium that plays a significant role in worsening respiratory tract infections.

“These bacteria are especially damaging to vulnerable groups, such as those with cystic fibrosis, asthma, the elderly, and Indigenous communities,” Professor Kappler said.

“In some conditions, such as asthma and chronic obstructive pulmonary disease, they can drastically worsen symptoms.

“Our research shows the bacterium persists by essentially turning off the body’s immune responses, inducing a state of tolerance in human respiratory tissues.”

Professor Kappler said the bacterium had a unique ability to ‘talk’ to and deactivate the immune system, convincing it there was no threat.

The researchers prepared human nasal tissue in the lab, growing it to resemble the surfaces of the human respiratory tract, then monitored gene expression changes over a 14-day ‘infection’.

They found limited production of inflammation molecules over time, which normally would be produced within hours of bacteria infecting human cells.

“We then applied both live and dead Haemophilus influenzae, showing the dead bacteria caused a fast production of the inflammation makers, while live bacteria prevented this,” Professor Kappler said.

“This proved that the bacteria can actively reduce the human immune response.”

Co-author and paediatric respiratory physician Emeritus Professor Peter Sly from UQ’s Faculty of Medicine, said the results show how Haemophilus influenzae can cause chronic infections, essentially living in the cells that form the surface of the respiratory tract.

“This is a rare behaviour that many other bacteria don’t possess,” Emeritus Professor Sly said.

“If local immunity drops, for example during a viral infection, the bacteria may be able to ‘take over’ and cause a more severe infection.”

The findings will lead to future work towards new treatments to prevent these infections by helping the immune system to recognise and kill these bacteria.

“We’ll look at ways of developing treatments that enhance the immune system’s ability to detect and eliminate the pathogen before it can cause further damage,” Professor Kappler said.

The research was published in PLOS Pathogens.

Source: University of Queensland