Lauren Quetsch, University of Arkansas. CREDIT University of Arkansas
At least half of all autistic children experience some form of aggression, such as hitting, kicking or name-calling, while their parents are tasked with helping them cope and integrate socially. Yet the prevalence and characterization of aggressive behaviors across autistic development are poorly understood.
To address this knowledge gap, researchers in the Family and Community Intervention Lab at the University of Arkansas compared autistic children to non-autistic children on different types of aggressive behaviors over three critical developmental periods and found that parents of autistic children reported more frequent aggression at greater intensities than non-autistic children.
“Aggression represents a pervasive and serious problem faced by autistic youths and their families,” said Lauren Quetsch, assistant professor of psychology and lead author of “Understanding aggression in autism across childhood: Comparisons with a non-autistic sample.”
“While our knowledge about the unique needs of autistic children has grown exponentially over the last several decades, we still have a long way to go,” she said. “And understanding the role aggression plays in autistic youths’ lives can help us to better address our gaps in care.”
Between December 2020 and March 2021, Quetsch and her colleagues gathered quantitative and qualitative data on 450 autistic and 432 non-autistic children. The data were broken down into three age-matched groups — younger than six, six to 12 and 13 to 17. The children were compared on multiple caregiver-report measures of aggressive and disruptive behavior across these key developmental periods.
The researchers’ analysis of the data revealed higher levels of verbal aggression and disruptive behavioral intensity for autistic children across all three stages of development. Autistic children younger than six had more significant levels of physical aggression than their non-autistic peers. However, these levels became equal to non-autistic peers as the children aged.
In the qualitative study, non-autistic children more frequently expressed anger in a controlled manner, according to parents, whereas autistic children were more apt to quickly lose their temper.
“We surmise that this can be attributed to several factors,” Quetsch said. “Frustration from regularly being misunderstood, challenges with recognizing emotions in others or expressing their own emotions to others, sensory overstimulation, and even co-occurring health challenges, such as physical discomfort from gastrointestinal issues and exhaustion due to irregular sleeping patterns, all likely contribute to aggression.”
A cell therapy using myeloid cells bound to drug delivery microparticles reduces disease burden in a preclinical multiple sclerosis model.
Shown on the left, is an immunofluorescence image of a monocyte with its outer cell membrane stained in green and nucleus stained in blue, and to which the team has attached backpacks loaded with anti-inflammatory drugs stained in red. The illustration on the right shows how drug-loaded backpacks can be easily attached to primary monocytes isolated from peripheral blood, using an antibody fragment binding a specific surface protein. Wyss Institute at Harvard University
Multiple sclerosis (MS) is a devastating autoimmune disease that destroys the protective myelin covering around nerves, disrupting communication between the brain and body, and causing patients’ ability to move and function to progressively decline. The MS atlas reported in 2020 that someone is diagnosed with MS every five minutes around the world, adding to about 2.8 million individuals that currently have to live with the disease. Alarmingly, since 2013, the world-wide prevalence of MS has risen by 30%.
A key driver of MS is the sudden inflammation of nerves caused by so-called myeloid cells of the “innate” immune system in vulnerable regions of the brain and spinal cord, which together form the central nervous system (CNS). These “acute inflammatory lesions” then attract other myeloid cells, as well as self-reactive T and B cells that belong to the immune system’s second arm, known as the “adaptive immune system” and directly attack the myelin covering. While no cure is available for MS, existing disease-modifying therapies in the form of small molecule and protein drugs either directly target the self-reactive immune cells or broadly dampen inflammation. However, many of those therapies cause severe side effects in different parts of the body, including the immune system itself, and thus carry significant health risks.
To transform potentially inflammatory myeloid cells into therapeutic cells, they isolated and cultured monocytes (a type of myeloid cell) from the bone marrow of donor mice and stably attached tiny microparticles, termed “backpacks,” to the cells’ surfaces. These backpacks are loaded with anti-inflammatory molecules that direct the carrier cells’ differentiation into anti-inflammatory cells in vivo. When infused back into a mouse model of MS, the backpack-laden monocytes were able to affect MS-specific immune responses, and partially reverse hind limb paralysis and improve motor functions. The results are published in the Proceedings of the National Academy of Sciences (PNAS).
“Current MS therapies do not specifically target myeloid cells. These are very plastic cells that can toggle between different states and are thus hard to control. Our biomaterial-based backpack approach is a highly effective way to keep them locked into their anti-inflammatory state,” said senior author Samir Mitragotri, Ph.D., who is a Core Faculty member at the Wyss Institute. “In many ways simpler than other cell therapies, myeloid cells can be easily obtained from patients’ peripheral blood, modified with backpacks in a short culture step, and reinfused back into the original donor, where they find their way to inflammatory lesions and affect the MS-specific immune response not only locally, but more broadly.” Mitragotri is also the Hiller Professor of Bioengineering and Hansjörg Wyss Professor of Biologically Inspired Engineering at SEAS.
Many cell therapies, such as the famed CAR-T cell therapies, require the mobilization of immune cells from specific tissue compartments in the body with drugs, genetic modification, and then amplification over weeks outside of the body. Myeloid cells can be directly retrieved using established methods and modified with backpacks within hours, making the therapy more easily translatable. In addition, some myeloid cell types possess the ability to traverse the blood-brain barrier, which makes them particularly suitable for treating CNS diseases.
New spin for cellular backpacks
Mitragotri’s group had previously found that when they attached small disc-shaped backpacks to cells of the myeloid lineage, they remained stably exposed on the cells’ surface, whereas many other cells would readily internalize and inactivate them. Adding certain molecules to the backpacks allowed the team sustained control over the cells’ behavior. They made use of this finding in a tumor-fighting cell therapy consisting of backpack-laden macrophages, which is a specific type of myeloid cell. In their new study, they focused on monocytes, which also belong to the myeloid differentiation lineage and are a precursor to macrophages. Monocytes can effectively infiltrate the brain and then differentiate into macrophages, which are one of the predominant inflammatory cell types in active MS lesions.
“Because of their ability to invade the CNS, infiltrate inflammatory lesions, and differentiate into macrophages, a backpack strategy allowing control over monocyte differentiation made extreme sense,” said first author Neha Kapate, a graduate student working with Mitragotri. “We decided on backpacks that contained interleukin-4 [IL-4] and dexamethasone, two molecules that we later found to provide a synergistic anti-inflammatory effect.”
The team fabricated their micrometer-size backpacks via a process known as serial “spin coating,” in which thin films made up of a PLGA polymer and other biocompatible substances, and containing the anti-inflammatory molecules are layered on top of each other like layers of an onion. As a final step, the outer surface of the backpack was furnished with an antibody fragment to allow it to stick to monocytes.
Cellular backpacks get legs
To test the backpack-laden monocytes for their therapeutic efficacy, the researchers isolated monocytes from healthy donor mice and, in a short cell culture step, attached the backpacks to them. They then infused the modified cells into a mouse model of MS, known among researchers as experimental autoimmune encephalomyelitis (EAE) model. “When we infused backpack-carrying monocytes and, in parallel, unaltered control monocytes into EAE mice with ongoing nerve inflammation, backpack-carrying monocytes more effectively infiltrated into inflamed CNS lesions. They also reduced inflammation inside the lesions and shifted the local and systemic MS-associated immune response towards a therapeutic outcome,” said Kapate. “The resulting anti-inflammatory monocytes also elicited cross-talk effects with other immune cell populations, such as specific T helper cells that are linked to the self-directed adaptive auto-immune response.”
The disease symptoms in EAE mice treated with backpack-laden monocytes were significantly improved and, by the end of the study, the animals merely exhibited a limp tail, compared to complete a paralysis in the control animals’ hind limbs. The treatment also extended the animals’ survival – all mice receiving backpack-carrying monocytes survived to the end of the study, whereas a significant number of the control mice had died. Importantly, the magnitude of therapeutic benefit the team observed is on par with reported therapeutic treatments that had been tested in other studies using the same model. Since the EAE model mainly mimics the progressive form of MS and not the more prevalent “relapsing-remitting” form, with which the disease begins in about 85% of MS patients, and which at later stages can also become progressive, the team plans to also investigate their approach in models of relapsing-remitting MS. Being able to suppress inflammation early on could have enormous benefits for patients.
“The ability of this team to convert a potentially pathogenic type of immune cell into a therapeutic one for MS, which is extremely hard or impossible to treat, could open an entirely new path to treat patients with a variety of neurological diseases,” said Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, and the Hansjörg Wyss Professor of Bioinspired Engineering at SEAS.
Young children with common ear, nose, and throat (ENT) issues may be at subsequent risk of autism or high levels of demonstrable autism traits, suggests research published online in the open access journal BMJ Open.
Early identification and treatment of ENT conditions may improve these children’s quality of life and potentially help shed light on some of the origins of autism, say the researchers.
The causes of autism are likely to involve an interplay of genetic, environmental, and biological factors, and the origins of each autistic trait may also differ, note the researchers.
Previous research suggests that ENT conditions, such as ear infections, ‘glue ear’, and sleep disordered breathing, may have a role in the development of autism. But most of this evidence is based on health records, which may have biased these findings, because parents of children with suspected autism may be more likely than other parents to seek medical help for their offspring, explain the researchers.
To avoid this, the researchers drew on participants in the long term Children of the 90s study, also known as the Avon Longitudinal Study of Parents and Children (ALSPAC). This has tracked the health of more than 14,000 children since birth and that of their parents from the early 1990s onwards.
The current study is based on comprehensive data for more than 10,000 young children who were closely monitored throughout their first 4 years.
Their mothers completed 3 questionnaires when their children were aged 18, 30, and 42 months, which were designed to record the frequency of 9 different signs and symptoms relating to the ear, nose, and throat as well as any hearing problems.
They also completed 3 questionnaires when their children were just over 3, nearly 6, and 9 years old. These were designed to pinpoint speech coherence, social and communication issues, repetitive and abnormal behaviours, and sociability, traits which are characteristic of autism. A diagnosis of autism was confirmed from educational records and parental feedback, among other sources.
Adjustments were made for 10 potentially influential ‘environmental’ factors: early or late birth; sex; number of mother’s previous pregnancies resulting in a live or stillbirth; breast feeding; postnatal depression; mother’s educational achievements; mother’s smoking at 18 weeks of pregnancy; mother’s belief in her own agency; child’s exposure to environmental tobacco smoke at 15 months; child’s attendance at a crèche/other daycare by the age of 30 months.
In all, 177 children had a probable diagnosis of autism:139 boys and 38 girls. Those with autism traits were defined as the 10% of the sample with the highest trait scores.
Early evidence of breathing through the mouth, snoring, ear pulling or poking, reddened and sore ears, worse hearing during a cold, and rarely listening were all more commonly associated with high scores on each of the 4 autism traits, and with a diagnosis of autism.
Pus or sticky discharge from the ears was also associated with autism and with poor coherent speech.
Among the different ages tested, strong associations were particularly observed when the child was aged 30 and 42 months. Children with high scores on autistic traits at 30 months had more ENT signs. Autism itself was significantly associated with all signs except for symptoms of sleep apnoea (interrupted breathing during sleep).
Factoring in the 10 environmental features made little difference to the results. For example, children with discharge from their ears were more than 3 times as likely to have autism, while those with impaired hearing during a cold were more than twice as likely to do so. And children who failed to react to nearby noise were more than 6 times as likely to have autism at this age.
However, the researchers point out: ** “These ENT signs and symptoms are very common in childhood and most children who experience them do not go on to be diagnosed with autism. For example, of the group of around 1700 children who snored at age 30 months, most (1660) weren’t diagnosed with autism later on.”
The researchers acknowledge various limitations, including the loss of some children to subsequent monitoring, as is the case with any long term study, and the lack of ethnic diversity among the Children of the 90s participants, limiting the wider applicability of the findings.
What’s more, the children weren’t examined consistently to determine a diagnosis of autism; rather, a strategy to assess the probability of a diagnosis using a variety of different sources was used instead.
But they nevertheless conclude that the associations they found “may be important because (1) these ear and respiratory signs may be early markers of increased risk of autism, (2) they may inform the origins of autism, or (3) they may highlight co-occurring conditions that if treated may lead to a better quality of life for children with autism.”
They add: “This study adds to the evidence that, compared with a typical population of the same age, early ear and upper respiratory symptoms are more common in those subsequently diagnosed with autism or with extreme levels of autistic traits.”
But they caution: “It is not possible to determine whether these ENT conditions have a causal role in the development of autistic traits or are related to an unmeasured factor.
“One possibility, for example, could be the consequence of the increased prevalence of minor physical anomalies in individuals with autism, including anatomical differences in the structure and/or positioning of the ear, with such differences in ear morphology increasing the risk of ENT conditions.”
A new study published in Diabetologia (the journal of the European Association for the Study of Diabetes [EASD])finds that individuals who experienced childhood adversity are at increased risk of developing type 2 diabetes (T2D) in early adulthood.
The research was conducted by Assistant Professor Leonie K. Elsenburg and colleagues at the Section of Epidemiology, Department of Public Health, University of Copenhagen, Copenhagen, Denmark and aimed to determine whether there was a link between childhood adversity and the development of T2D in early adulthood (16-38 years) among men and women.
The worldwide prevalence of T2D among adolescents and young adults has increased substantially over the past century, primarily driven by changes in lifestyles and obesity rates. This is of particular concern because early onset of the disease (before 40 years of age) appears to have a more aggressive pathology, and the individuals affected are of working age, may require lifelong treatment and face an increased risk of complications. These factors combined make identifying the risk factors for T2D in early adulthood a matter of crucial important to public health.
Childhood adversity can involve experiences such as maltreatment, physical or mental illness in the family, and poverty and has been associated with the development of diabetes even in young adults. Adverse events and circumstances can trigger physiological stress responses and affect the behaviour of the nervous system, hormones and the body’s immune response. They can also impact mental wellbeing and lead to behavioural changes that negatively impact health such as poor sleep, smoking, reduced physical activity and sedentary behaviour, increased alcohol use, and unhealthy eating which can lead to obesity and an elevated risk of developing T2D.
Previous research has revealed an association between maltreatment in childhood and the development of T2D in young adulthood, but evidence for a link with other types of adversity is scarce and sex-specific estimates are lacking. The authors also note: “There is a need for methodological improvements in this research area, including a need for prospective studies using objective and more comprehensive measures of childhood adversity.”
The researchers used data from the Danish life course cohort study (DANLIFE) which includes on the backgrounds and childhood adversities of children born in Denmark since 1 January 1980. To enable follow-up from age 16 onwards, the study sample was limited to those individuals born up to 31 December 2001 and excluded individuals diagnosed with diabetes in childhood, those with insufficient data on covariate factors, and anyone who emigrated or died before age 16.
This study population was divided into five childhood adversity groups based on annual counts of exposure (from 0 to 15 years of age) to adversities in each of three dimensions: material deprivation (family poverty and parental long-term unemployment), loss or threat of loss (parental somatic illness, sibling somatic illness, parental death, sibling death) and family dynamics (foster care placement, parental psychiatric illness, sibling psychiatric illness, parental alcohol abuse, parental drug abuse and maternal separation).
In these five groups, children experienced: 1. relatively low levels of adversity across childhood (54%); 2. material deprivation specifically in early childhood (20%); 3. material deprivation throughout childhood and adolescence (13%); 4. relatively high levels of somatic illness or death in the family (9%); and 5. relatively high levels of adversity across all three dimensions (3%)
Out of the study population of 1,277,429, a total of 2,560 women and 2,300 men developed T2D during the follow-up which lasted a mean 10.8 years. The authors found that compared with the “Low adversity” group, the risk of developing T2D in early adulthood was higher in all other adversity groups for both men and women. In the “High Adversity” group, which was characterised by high rates of adversity across all three dimensions, the risk of developing diabetes was 141% higher in men and 58% higher in women, translating into 36.2 and 18.6 additional cases per 100,0000 person-years among men and women, respectively.
After adjusting for parental education level, size for gestational age and preterm birth, the effect estimates were reduced, particularly for women in the “High Adversity” group. Compared to their counterparts who experienced low adversity during childhood, their additional risk of developing T2D was reduced from 58% to 23%, translating into 6.4 additional cases per 100,000 person-years instead of 18.6 per 100,000 person-years. Most of the reduction in the estimated risk was the result of adjusting for parental education level.
The authors found that the relative risks of developing T2D following childhood adversity were lower among women than men across all groups. In addition, the absolute effects (in terms of the number of additional cases of diabetes per 100,000 person-years) were also lower among women than men, except in the case of experiencing material deprivation in childhood, where the absolute effect was comparable between men and women.
The study reveals that individuals exposed to childhood adversity, such as poverty, illness or death in the family, and dysfunctional households are at higher risk of developing type 2 diabetes in young adulthood compared with those who experience low levels of adversity in childhood. These findings are strengthened by the large size of this population-based study, as well as its freedom from selection or recall bias. In addition, the authors point out that there is a close relationship between parental education levels children’s experience of adversity which explains some of the observed association.
The researchers conclude that a share of the T2D cases arising in young adulthood could likely be prevented through early interventions targeting the fundamental causes of childhood adversity, to reduce or even eliminate their negative effect on children’s lives.
new study by researchers at Uppsala University and Uppsala University Hospital shows that men who have a neurodevelopmental disorder, such as autism and ADHD, also have a slightly increased risk of testicular cancer, or seminoma. This is the first study to show such a link, with the results to be published in the British Journal of Cancer.
Testicular cancer is the most common form of cancer in young men, and its underlying causes are still largely unknown.
“As testicular cancer can be surgically removed, thus curing the disease, it is important to seek care in time if you feel a lump in your testicle,” notes Ingrid Glimelius, Senior Consultant at the Department of Oncology at Uppsala University Hospital and Professor at Uppsala University.
The new study focused on patients with testicular cancer in Sweden. A total of 6,166 patients were included and then compared with 61,660 age-matched men without testicular cancer. Medical register data was used to investigate whether psychiatric diagnoses prior to cancer diagnosis were more common in patients with testicular cancer than in the control group.
In general, the researchers did not find an increased risk of testicular cancer in patients with a psychiatric diagnosis, but the group with a neurodevelopmental disorder in particular saw a significant increase in the risk of the seminoma type of testicular cancer.
Although the researchers found that there was an increased risk of seminoma among people with neurodevelopmental disorders the absolute risk increase was less than one percent. The risk of testicular cancer is therefore still very low even among boys and men with conditions such as autism and ADHD, and there is no need to worry if you have these diagnoses. However, the results are intriguing in terms of attempts to get closer to explaining the mechanisms of testicular cancer occurrence.
“The study also found that people with a neurodevelopmental disorder were a median of four years younger when they developed cancer and were more likely to have more advanced disease at diagnosis,” adds Glimelius.
“We also saw that people with a previous psychiatric diagnosis had a slightly increased risk of dying from their testicular cancer compared to people without a previous psychiatric diagnosis, although testicular cancer survival rates were generally very good in both groups,” says Anna Jansson, doctoral student at Uppsala University and Physician at Uppsala University Hospital.
This is the first research study to provide a link between neurodevelopmental disorders and the risk of testicular cancer. Previously known risk factors include having an undescended testicle as a baby or having a father or brother with testicular cancer.
“We do not know why we are seeing a link between neurodevelopmental disorders and the risk of testicular cancer, but we believe that early life events have an impact; perhaps even as early as the foetal stage,” continues Jansson.
“Since we can see a reduced survival rate among people with a mental health issue, it is important for the health care system, the individuals in question and their families to be aware that they may also be affected by another illness, and to ensure they seek treatment if they feel a lump in their testicle. This disease can be cured in most people today,” adds Glimelius.
FACTS: Testicular cancer * In Sweden, approximately 360 men are diagnosed with testicular cancer each year, and testicular cancer is the most common cancer among young men aged 15–35. * The most common symptom of testicular cancer is feeling a lump in the testicle. * The specific cause of testicular cancer is unknown, but some risk factors have been identified, such as the fact that around 10% of those affected have had surgery for an undescended testicle in childhood and that a hereditary predisposition is noted in around 1–3% of those affected. The risk is deemed most severe if you have a brother who has also had testicular cancer. * Treatment involves surgery to remove the diseased testicle. The disease can also be cured if it has spread beyond the testicle by way of chemotherapy, which makes testicular cancer one of the most survivable cancers today.
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