Posted on Patient Talk

Placenta may hold clues for early autism diagnosis and intervention

Loss of placental hormone linked to brain and social behavior changes


New UC Davis MIND Institute research has identified a novel human gene linked to fetal brain development and autism . The discovery also links the gene to the mother’s early prenatal vitamin use and placental oxygen levels.

In a study published Feb. 16 in Genome Biology, the researchers used genomic sequencing to find a DNA methylation signature in the placenta of newborns eventually diagnosed with autism. This signature mark was linked to early fetal neurodevelopment.

“By taking an unbiased approach to investigating placental DNA methylation differences, we discovered a novel gene in a poorly mapped region of the genome associated with autism, ” said Janine LaSalle, lead author on the study and professor of microbiology and immunology at UC Davis Health.

Autism is a complex neurological condition linked to genetic and environmental factors. The U.S. Centers for Disease Control and Prevention (CDC) estimates that one in 44 children are diagnosed with autism. It is much more prevalent in males than females.

Why studying the placenta is important

The placenta supports fetal development in the uterus. It regulates oxygen supply and metabolism and provides hormones and neurotransmitters critical for the fetus’ developing brain.

“The placenta is an often misunderstood and overlooked tissue, despite its importance in regulating and thereby reflecting events critical to brain development in utero. It is like a time capsule for finding things that happened in utero. For decades, hospital births have thrown away placentae despite this tissue being a gold mine for finding molecular clues to child outcomes,” LaSalle said.

During pregnancy, the fetus might experience oxidative stress, an imbalance of free radicals and antioxidants in the body. This is common in normal brain development. However, in some cases, exposure to environmental factors such as air pollution and pesticides can lead to excessive oxidative stress. This state can lead to cell and tissue damage or delayed neurodevelopment.

“Oxidative stress is normal.  But excessive oxidative stress may come from environmental exposures linked to autismsuch as air pollution, pesticides, maternal obesity and inflammation,” LaSalle said.

The epigenome is a set of chemical compounds and proteins that tell the DNA what to do. These compounds attach to DNA and modify its function. One such compound is CH3 (known as the methyl group) which leads to DNA methylation. The neonatal epigenome can reflect past interactions between genetic and environmental factors during early development. It may also influence future health outcomes.

The placenta is a promising tissue for identifying DNA methylation changes at genes that also function in the fetal brain. This study examined the association of autism with placental DNA methylation.

Finding factors in mother’s placenta that might predict autism

The researchers studied the development of 204 children born to mothers enrolled in the MARBLES and EARLI studies. These mothers had at least one older child with autism and were considered with higher probability of having another child with autism m. When these children were born, the mothers’ placentae were preserved for future analysis.

At 36 months, the children got diagnostic and developmental assessments. Based on these tests, the researchers grouped the children under “typically developing” (TD), “with autism ” and “non-typical development” (Non-TD).

The researchers also extracted and quantified the DNA from the placenta tissues. They divided the placenta samples into discovery, replication and specificity replication groups.

For the discovery group, they split and sequenced 92 samples (46 ASD, 46 TD) from the MARBLES study using whole-genome bisulfite sequencing (WGBS) and whole-genome sequencing (WGS). To determine if differential methylation was reproducible in a different population, the replication group included WGBS data from 16 ASD and 31 TD samples from the EARLI study.

The specificity replication group had 21 autism , 13 Non-TD and 31 TD placenta samples from the MARBLES study. The researchers used these samples to determine if methylation changes were specific to autism .

Finally, they performed whole genome sequencing on 41 ASD and 37 TD MARBLES children.

Placenta to reveal insights into genes related to autism

The researchers identified a block of differential methylation in autism at 22q13.33, a region in chromosome 22 not previously linked to autisk . They located and characterized a novel gene known as LOC105373085 within that region and renamed it NHIP (neuronal hypoxia inducible, placenta associated).

To understand the function of this gene, they detected the levels of NHIP expression in human cell lines and brain tissue. They tested the responsiveness of NHIP to hypoxia, a state of low oxygen levels in the tissues. The researchers found that NHIP is a gene that gets turned on in neurons following hypoxia and regulates other gene pathways with functions in neuronal development and response to oxidative stress.  Higher NHIP levels increased the cell division in an embryonic cell line.

This is important because in the placenta, hypoxia triggers placental cell division to make further contact with maternal blood vessels to supply enough oxygen for the developing brain.

“We found that the NHIP gene is active in the brain, responsive to oxidative stress, and influences expression of other known genes associated with autism,” LaSalle said. “In most pregnancies, the placenta experiences some inevitable levels of stress. We think that NHIP is there to buffer the effects of excessive oxidative stress.”

Prenatal vitamins and autism

Another remarkable finding from the study was the role prenatal vitamins play in regulating the work of NHIP. Prenatal vitamins are high in folic acid and can reduce oxidative stress.

Prenatal vitamins use during the first month of pregnancy showed a significant protective effect among individuals with genetic differences at 22q13.33 NHIP region. Taking prenatal vitamins in the first month of pregnancy seems to provide essential metabolic elements to counteract the genetic inheritance of reduced NHIP responsiveness to oxidative stress.

“In line with previous studies, we found that taking a prenatal vitamin is essential when planning a pregnancy,” said LaSalle. “Findings from our study provide key insights that may help in identifying newborns more likely to develop autism and getting them into an earlier intervention or just knowing to watch them sooner.”

 The researchers pointed out that these results will require further replication before being used diagnostically.

Posted on Autism

Study performs cost analysis of popular autism interventions

Female protective effect: Yale researchers find clues to sex differences in autism


Working in schools as an occupational therapist and board-certified behavior analyst, Gretchen Scheibel would often see students, parents and educators at crisis points. Though youths receiving special education services would take part in interventions intended to help them reach their ideal educational outcomes, some students showed little to no progress, or they may have engaged in severe or dangerous behaviors. That sometimes led to students being removed from their neighborhood schools and parents taking legal action against school districts. Over a 15-year period, Scheibel worked in schools and with parents in seven states across the country, often seeing firsthand how special education interventions were tried with little thought to how much they cost in terms of money, time and student outcomes.

“I had an opportunity to see what was happening on the ground in a lot of different school districts. When kids are at a crisis point, it wasn’t one incident that led to them being sent out of a school or a classroom,” said Scheibel, now a doctoral candidate in special education at the University of Kansas. “It was a long history where they weren’t receiving interventions that could help them. I came to KU to get my Ph.D. to think about that more.”

The questions of how much special education interventions cost and whether they work led to a study co-written by Scheibel and published in the journal Exceptional Children that conducted an economic evaluation of two commonly used interventions for students with autism spectrum disorder. The results showed implementing interventions with emerging evidence or those shown to be ineffective or harmful can consume curriculum and professional development funds, as well as valuable teacher and student time, without a strong promise of positive outcomes.

Scheibel and co-authors Thomas Zane, director of KU’s online behavior analysis program, and Kathleen Zimmerman, assistant professor of special education, selected two interventions called DIRFloortime and Rapid Prompting Method, classified in research literature as emerging and limited in evidence, respectively. Scheibel said the goal of the study was not to advocate for or against any specific intervention but to conduct an economic evaluation on two that are popular, even if controversial, to provide a different way to think about interventions.

The researchers conducted a cost analysis of the two interventions, using an approach known as “the ingredients method.” They analyzed all the ingredients it would take to implement the interventions in a school, including the cost of teachers’ time, training and material costs, and the potential cost of compensatory services if a parent pursues legal action due to lack of appropriate intervention. They calculated the cost for DIRFloortime to be $9,976 for the first year and Rapid Prompting Methods’ first-year cost to be $32,159.

However, Scheibel cautioned against taking those estimates literally.

“When you’re talking about value and dollar costs in this sense, a school district doesn’t necessarily need to have $32,000 cash on hand to implement the intervention. It’s more of a way to view all the resources that will be used when the intervention is implemented on the same scale.”

The authors argue the more important factor is to give districts an idea of what an intervention will cost and what its potential benefits and harms to the student, school and family are before a decision is made on whether to adopt it. This information is also beneficial with interventions that are already commonly used in schools such as the two analyzed in the study. Furthermore, they said that such economic evaluations of special education interventions should be included in research studies. This information can be helpful in the initial research stages when researchers are determining whether an intervention works, what population it could benefit and also in the synthesis stage, when individual intervention studies are looked at collectively to determine if they are likely to be effective in schools.

“We are arguing that we should be including cost analysis in research, especially in the synthesis phase. That will allow the teachers and educators receiving the information to make a more contextualized, informed decision,” Scheibel said.

Posted on Diabetes, Weight Loss

Gastric bypass is best weight loss option for diabetes patients, study finds

Easy-To-Follow Weight-Loss Guidelines for Men


Bariatric surgery—either gastric bypass or sleeve gastrectomy—is recommended for people with type 2 diabetes and a body mass index of 40 or above. But the optimal treatment remains unclear and may depend on the severity of the patient’s diabetes.

Using data from previous studies and databases, researchers at Columbia University’s Vagelos College of Physicians and Surgeons, led by Chin Hur, MD, MPH, created a model to investigate the effectiveness, quality of life gains, costs, and complications of gastric bypass, sleeve gastrectomy, and medical therapy among patients over a five-year period.

The study is the first to consider diabetes severity in a comparison of gastric bypass and sleeve gastrectomy, which are the two most popular forms of bariatric surgery in the United States.

Gastric bypass is a more complex procedure than sleeve gastrectomy, and previous studies show it is associated with more complications. Gastric bypass creates a small pouch in the stomach that is attached to the small intestine, so that food bypasses much of the stomach and some of the small intestine. After the surgery, less food can be ingested and absorbed. In sleeve gastrectomy, the stomach is permanently reduced to about one quarter of its original size, but no bypass is created.

The new analysis projected that gastric bypass leads to greater weight loss and a greater rate of remission of diabetes than sleeve gastrectomy or medical therapy, which involves lifestyle counseling and medication.

Gastric bypass surgery also was projected to produce the best results regardless of diabetes severity.

“Determining which groups may benefit from a specific strategy is an important step toward personalized medicine,” says Hur.

“Our study suggests that in most cases, gastric bypass is the preferred strategy when looking at a five-year time frame, despite higher upfront surgical costs and complicati

Posted on Diabetes

Study identifies potential new approach for treating diabetes complications

A potential new treatment approach for complications relating to diabetes has been described today in the open-access eLife journal.

Diabetes is a serious condition that causes the blood sugar level to become too high. In patients with diabetes, the overproduction of cellular reactive oxygen species (ROS) – highly reactive chemicals formed from oxygen – can lead to severe tissue damage. The new study suggests that the repression of a protein complex called hypoxia-inducible factor-1 (HIF-1) contributes to this overproduction of ROS, and is therefore an attractive therapeutic target.

“Hypoxia, a condition where oxygen levels drop in our tissues, has also recently been identified as a harmful player in diabetes,” explains Xiao-Wei Zheng, Senior Lab Manager at Karolinska Institutet, Stockholm, Sweden, and a co-first author of the study alongside Sampath Narayanan and Cheng Xu, also from Karolinska Institutet. “In our study, we wanted to find out if the overproduction of cellular ROS in diabetes is caused by impaired responses to hypoxia due to the inhibition of HIF-1 by high blood sugar levels.”

To answer this question, Zheng, Narayanan, Xu and colleagues recruited 13 non-smoking volunteers with type 1 diabetes and 11 healthy volunteers. They exposed the participants to mild and intermittent hypoxia five times in total for one hour. They took blood samples from the participants before and immediately after exposure to hypoxia, and analysed the changes in their ROS levels. The results showed that hypoxia led to increased ROS levels in the volunteers with diabetes, while those without the condition were unaffected.

As hypoxia increases cellular ROS levels in diabetes, and HIF-1 helps cells to respond to hypoxia, the team hypothesised that repressing HIF-1 would contribute to the overproduction of ROS. To test this, they analysed the relation between HIF-1, glucose levels, and ROS production and its functional consequences, in cells taken from mouse kidneys and directly in the kidneys of mouse models of diabetes. They found that high glucose levels repressed HIF-1 both in hypoxic cells and in the mouse kidneys through a mechanism that relied on enzymes called HIF prolyl-hydroxylases (PHDs). This repression of HIF-1 contributed in turn to the excess production of ROS.

Finally, the team demonstrated that restoring HIF-1 function in the mice reduced the overproduction of ROS in their tissue cells and protected the animals’ kidneys against cell death and injury.

“We’ve shown that the repression of HIF-1 plays a central role in ROS overproduction and tissue damage in diabetes, and is therefore a potential treatment target for these complications,” concludes Sergiu Catrina, Lecturer/Senior Physician at Karolinska Institutet, and a co-senior author of the study alongside Fredrik Palm, from Uppsala University, Sweden. “These results are timely, since the first PHD inhibitor that can activate HIF-1 has recently been approved for clinical use in patients with chronic kidney diseases. If our findings are verified by future studies, then similar inhibitors could be tested as potential new therapies for diabetes.”

Posted on Multiple Sclerosis

New study enhances potential of cognitive test for improving outcomes for individuals with multiple sclerosis

Turmeric and Multiple Sclerosis
Multiple Sclerosis



 A team of researchers published results of a study of the Symbol Digit Modalities Test (SDMT), a measure widely used for cognitive assessment in research and clinical settings. Their article,” A much needed metric: Defining reliable and statistically meaningful change of the oral version Symbol Digit Modalities Test,” (10.1016/j.msard.2021.103405) was published online in Multiple Sclerosis and Related Disorders on November 16. 2021. The authors represent four study sites: Kessler Foundation, Pennsylvania State University, University of Missouri-Kansas City, and University of Washington.

Despite agreement on what constitutes group-level change for the SDMT (4 points), studies of what constitutes meaningful change on the individual level are lacking. To help address this gap, 219 healthy adults were enrolled in the multi-site trial and followed up at 6 months and one year. Results showed reliable change scores of 7 to 9 points at 6 months, and 8 to 12 points at one year. These findings indicate the need for higher cut points for the SDMT on the individual level, suggesting that a change score of 8 would be the recommended cut off at 6 months and one year,

Defining statistically significant change in the SDMT is critical, according to lead author Lauren Strober, PhD, senior research scientist in the Center for Neuropsychology and Neuroscience at Kessler Foundation. “In the population with multiple sclerosis, the SDMT is used to measure deficits in processing speed,” noted Dr. Strober, “which we know adversely affect functional independence, activities of daily living, and overall quality of life. Standardizing normative data for this tool will help us more accurately assess changes over time for each person” she added, “This will enable is to better predict disease progression and improve outcomes for individuals in terms of employment, driving, and activities of daily living.”